innovations in cardiovascular disease management
TRANSCRIPT
H E A L T H C A R E
Innovations in Cardiovascular DiseaseManagementLatest surgical procedures, drugs and medical devices
By Melissa Zebrowski
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Paul Taylor
Paul Taylor is an independent market analyst for the medical industry with a BSc and
PhD in Biochemistry from the University of Liverpool and an MBA from Oxford
Brookes University. Dr Taylor has worked in the medical industry as a senior
marketing executive for 20 years creating and implementing strategic business and
marketing plans for major multinational medical device companies before establishing
himself as an independent research analyst.
For the last 10 years Dr Taylor has focused on the structure, organisation and
functioning of the European health care systems with particular interest on
reimbursement systems, analysing specific European product market segments and
advising/preparing strategic business and marketing plans for international
pharmaceutical, medical devices and healthcare technology companies.
Copyright © 2007 Business Insights Ltd This Management Report is published by Business Insights Ltd. All rights reserved. Reproduction or redistribution of this Management Report in any form for any purpose is expressly prohibited without the prior consent of Business Insights Ltd. The views expressed in this Management Report are those of the publisher, not of Business Insights. Business Insights Ltd accepts no liability for the accuracy or completeness of the information, advice or comment contained in this Management Report nor for any actions taken in reliance thereon. While information, advice or comment is believed to be correct at the time of publication, no responsibility can be accepted by Business Insights Ltd for its completeness or accuracy.
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Table of Contents
Innovations in Cardiovascular Disease Management
Executive Summary 10
The Management of Cardiovascular Disease 10 Cardiovascular and Interventional Procedures 11 Emerging Coronary Stents and Stent Systems 12 Innovations in Minimally Invasive Cardiac Surgery 13 Cardiovascular Drugs in Early Stage Development 14 New and Emerging Cardiovascular Drugs 14
Chapter 1 The Management of Cardiovascular Disease 18
Summary 18 Introduction 19 The Global Burden of Cardiovascular Disease 19 CVD remains the leading cause of death in the United States 19 CVD Rates in Central and Eastern Europe 21 Noncommunicable Diseases in the Developing World 21 Background to the Major Cardiovascular Conditions 23 Coronary Artery Disease (CAD) 23 Atherosclerosis 23 Angina Pectoris 25 Acute Myocardial Infarction (MI) 27 Heart Valve Disorders 29 Aortic heart valve 29 Mitral Valve Disease 30 Pulmonary Valve Disease 32 Tricuspid Valve Disease 32 High Blood Pressure: Hypertension 32 Heart Rhythm Disorders (Heart Arrhythmia) 33
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Peripheral Vascular Disease 35 Peripheral Artery Disease (PAD) 35 Peripheral Venous Disorders (PVD) 37 Stroke or Cerebrovascular Accidents (CVA) 38 Ischaemic Stroke 38 Haemorrhagic stroke 38
Chapter 2 Latest Developments in Cardiovascular and PCI Procedures 42
Summary 42 Introduction to Percutaneous Coronary Interventions 43 Indications for PCI 44 PCI Procedural Volumes 44 PCI Used Primarily to Treat Unstable Angina and acute ST-elevation MI 45 Inter-country Variance in PCI Procedural Rates 46 China and India: Huge growth potential and market development 47 Latest Developments in PCI Procedures 49 Embolic Protection Devices 49 Current Products 50 Development Stage Products and Current Status 55 Future Technologies and Trends 58 Coronary Atherectomy 59 Rotational Coronary Atherectomy (Rotoblation) 59 Directional Coronary Atherectomy (DCA) 59 Orbital Atherectomy 60 Ablative laser-assisted angioplasty 60
Chapter 3 Emerging Coronary Stents and Stent Systems 64
Summary 64 Emerging Coronary Stents and Stent Systems 65 Key Events 65 Introduction of Drug-Eluting Stents (DES) 67 Development of Drug-Eluting Stents 70 Sirolimus (Rapamycin) 70 Paclitaxel 71 Tacrolimus 72 Everolimus (RAD-001) 73 Zotarolimus (also called ABT-578) 73 DES – Recent News, Product Developments and Clinical Trial Updates 74
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Market Developments and Forecasts for Drug-Eluting Stents 77 Emergence of Bioabsorbable Stents 82 Biomaterials and Bioabsorbable Polymers 83 Further Coronary Stent Developments and Technological Trends 85 Novel Coating Technologies 85 Gene Therapy technologies and its Potential Use to Prevent Restenosis 86 Coronary Stents and Endothelial Progenitor Cells (EPCs) 87 Nanotechnologies and Drug-Eluting Coronary Stents 88 Development of Novel Estradiol Containing Drug-Eluting Stents 88 Stem-Cell Derived Endovascular Cells 89
Chapter 4 Innovations in Minimally Invasive Cardiac Surgery (MICS) 92
Summary 92 Introduction 93 Minimally Invasive Direct Coronary Artery Bypass (MID-CAB) 93 Indications for MIDCAB 94 Off-Pump Coronary Artery Bypass (OP-CAB) 94 Indications for OP-CAB 94 Minimally Invasive Port Access 95 Indications for Minimally Invasive Port Access 96 Robotic Assisted Coronary Artery Bypass (RA-CAB) 96 Current and Emerging Technologies 98 Robotics in Minimally Invasive Cardiac Surgery 98 Robotic Systems 98 Computer Aided Cardiac Surgery 100 Virtual Reality in Cardiac Surgery 100 Laser Heart Surgery or transmyocardial Laser revascularization (TMLR) 101 The CO2 Heart Laser System 101 The holmium:YAG (yttrium aluminium garnet) laser 102 The excimer laser 102
Chapter 5 Cardiovascular Drugs in Early Stage Development 106
Summary 106 Introduction 107 Early Developments in Key Cardiovascular Disease Classes 107 Angina 107 Arrhythmiasis 110 Atherosclerosis 112 Atrial Fibrillation 115 Congestive Heart Failure 116
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Hypercholesterolemia 118 Hypertension 120 Myocardial Infarction 122 Thrombosis 124
Chapter 6 New and Emerging Cardiovascular Drugs 128
Summary 128 Introduction 129 Anti-Hypertensives 129 Tekturna (Aliskiren) 130 Development of a New Class of Renin Inhibitors 132 Exforge (valsartan plus amlodipine) 133 CHF-1521 134 Cleviprex(TM) (Clevidipine) 135 Antihypertensives: Current Pipeline and Late Stage Development 136 Cardoxal (MC-4232) (MC-1 cardioprotectant plus lisinopril) 138 Darusentan 139 Ambrisentan 139 Nebivolol 140 Zanipress® / Zanitek® 140 Thelin™ (Sitaxsentan) 141 TBC3711 142 Anti-Dyslipidemics 143 Pfizer discontinues torcetrapib development 144 R1658 145 Simcor (Niaspan® (extended-release niacin) and simvastatin (generic Zocor®)) 145 CRESTOR® (rosuvastatin) and CRESTOR/ABT-335 combination 147 Synordia 149 Lapaquistat (TAK-475) 150 SLx-4090 151 AEGR-733 152 Compound Number 256073 and 501516 153 LBM642 153 Dyslipidaemia: Current Pipeline and Late Stage Development 154 Anti-Thrombotics 156 Rivaroxaban (BAY59-7939) 156 Rendix (dabigatran etexilate, BIBR-1048) 157 Idraparinux 157 Apixaban 158 SSR-126517 158 Exanta/ximelagatran 159 Anti-Thrombotics: Current Pipeline and Late Stage Development 160 Anti-Arrhythmics 161 Stedicor (Azimilide) 163
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Multaq (Dronedarone) 164 Vernakalalant (RSD 1235) 165 Tecadenoson CVT510 167 Pulzium IV (Tedisamil) 167 Anti-Arrhythmics: Current Pipeline and Late Stage Development 168
Chapter 7 Appendix 170
Methodology Statement 170 Primary Data and Information Gathering 170 Secondary Data and Information Gathering 170 Market Share Analysis and Market Forecast Predictions 171 Glossary 173 Index 182
List of Figures Figure 1.1: Breakdown of Deaths from Cardiovascular Diseases, USA 2002 20 Figure 1.2: Leading causes of death in developing countries, 2002 23 Figure 2.3: Use of Percutaneous Coronary Intervention in Europe, 2005 46 Figure 3.4: Estimated number of Stent Procedures (BMS & DES) % Total Number of PTCA
Procedures 69 Figure 3.5: Actual and projected revenues from Coronary Stents, Worldwide sales- 2006 81 Figure 3.6: Market Share Analysis, DES v BMS World, 2006 82
List of Tables Table 1.1: Age- and gender-specific incidence of recognised MI 28 Table 1.2: Age- and gender-specific incidence of unrecognised MI 28 Table 2.3: Estimated volume of cardiovascular procedures by region (US 2002) 45 Table 2.4: PCI procedure rates in Selected Countries, 2005 49 Table 5.5: Selected Early Stage Anti Anginal Drug Developments 108 Table 5.6: Selected Early Stage Anti Arrhythmiasis Drug Developments 110 Table 5.7: Selected Early Stage Atherosclerosis Drug Developments 112 Table 5.8: Selected Early Stage Atrial Fibrillation Drug Developments 115 Table 5.9: Selected Early Stage Congestive Heart Failure Drug Developments 116 Table 5.10: Selected Early Stage Hypercholesterolemia Drug Developments 118 Table 5.11: Selected Early Stage Hypertension Drug Developments 120 Table 5.12: Selected Early Stage Myocardial Infarction Drug Developments 122 Table 5.13: Selected Early Stage Thrombosis Drug Developments 125 Table 6.14: Characteristics of Major Classes of Lipoproteins 144
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Table 6.15: AstraZeneca’s Current Anti-Dyslipidaemia Pipeline 149 Table 6.16: Classification of Anti-Arrhythmics 162
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Executive Summary
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Executive Summary
The Management of Cardiovascular Disease
Cardiovascular disease is the term used for a variety of ailments including chronic heart
failure, atrial fibrillation, angina and peripheral arterial disease, amongst others. The
US has by far the highest prevalence of cardiovascular disease, with Japan and
Germany in second and third place respectively.
Despite a decline in CVD (cardiovascular disease) in the US it still remains the
leading cause of death and accounts for 53% of all deaths in the US.
Increased concern over the rising mortality rates in central and Eastern Europe
caused by CVD, where it is almost double that of the worst affected countries in the
European Union. Despite issues about the quality and accuracy of data, the country
causing most concern is the Russian Federation.
CVD are recognized to have a considerable economic impact on rapidly growing
markets in the developing world. Improved economic conditions are expected to
increase the high risk factors associated with CVD, like high blood pressure,
tobacco use, alcohol consumption, cholesterol, obesity and a sedentary lifestyle.
Syndromes that are associated with acute coronary syndromes are correlated with
age and the prevalence of cardiovascular risk factors. Unstable angina, which has
the highest incidence rate across the seven major pharmaceutical markets, is
estimated to be particularly prevalent in the UK and the US and low in Japan and
Italy.
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Cardiovascular and Interventional Procedures
Since the introduction of Percutaneous Coronary Interventions (PCI) or
Percutaneous Transluminal Coronary (PTCA) the number of procedures carried out
has increased dramatically, becoming one of the most common medical
interventions performed and has transformed the practice of revascularization for
coronary disease.
42.6% of all percutaneous coronary interventions carried out in Europe in 2005
were used primarily to treat unstable angina. 20.2% of all percutaneous coronary
interventions were used to treat acute ST-elevation Myocardial Infarction (STEMI).
PCI procedural rates differ greatly in different regions across the world. Germany
has the highest procedural rate in the world with an estimated 225,500 carried out
in 2005/2006 (2,765 pmp), compared to China with an estimated total of 95,912
PCI procedures (73 pmp) and India with an estimated total of 42,123 PCI
procedures (41 pmp).
Emerging technologies and recent product developments include embolic
protection devices incorporating distal filters such as the FilterWire EZ™ Embolic
Protection System developed by Boston Scientific, distal balloon occlusive devices
like TriActiv FX(R) Embolic Protection System from Kensey Nash and proximal
balloon occlusive devices such as the Parodi Anti-Emboli System (PAES)
developed by ArteriA Medical Science.
Other developments include the emergence of Rotational Coronary Atherectomy
(Rotoblation), Directional Coronary Atherectomy (DCA). Orbital Atherectomy and
Ablative laser-assisted angioplasty and innovative minimally invasive technologies
and techniques.
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Emerging Coronary Stents and Stent Systems
Drug-eluting stents have been regarded as a breakthrough technology and an
effective method of reducing restenosis. Since their introduction, they have had a
dramatic impact on the growth and development of coronary stents worldwide.
Current estimates show that 95.9% of all PCI procedures in 2006 included a
coronary stent of one sort or another (BMS or DES). The proportion of drug-eluting
stents had increased from 2.6% in 2002 to 68.9% in 2006.
Given current market conditions, it is anticipated that drug-eluting stents will be
used in nearly 80% of PCI procedures in Europe by 2012.
Currently, drug eluting stents incorporate Sirolimus (rapamycin), Paclitaxel,
Tacrolimus, Everolimus (RAD-001) and Zotarolimus (also called ABT-578).
The worldwide market for coronary stents was valued at $6.18 billion in 2006, with
a projected value of $13.34 billion by the year 2013 (CAGR 11.6%).
The worldwide market for drug-eluting stents has been valued at $5.14 billion in
2006, and is expected to increase to $12.40 billion by the year 2013 (CAGR
13.4%).
The world market for bare metal stents is currently valued at $1.04 billion but is
expected to decline in value to $0.94 billion by the end of the forecast period
(CAGR –1.4%).
There are now four major manufacturers of coronary stents. These are Cordis
(Johnson & Johnson), Boston Scientific Corporation, Medtronic and Abbott
Laboratories (Abbott Vascular). Cordis (Johnson & Johnson) and Boston Scientific
Corporation dominate the drug-eluting stent market.
There are concerns amongst clinicians about a number of problems or
complications associated with drug-eluting stents. These complications are
primarily concerned with late developing stent thrombosis, allergic inflammatory
reactions, long term antiplatelet therapy and non-compliance.
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One of the attractive materials recognized as having the potential for use in
bioabsorbable stents is the polymer called poly L-lactic acid (PLLA). Several stent
designs have been built using PLLA mono filaments and appear to be a viable
alternative to metal in some preliminary studies.
Other novel technological developments include Absorbable Metal Stent (AMS)
Technologies, the development of novel coating technologies, gene therapy
technologies and its potential use to prevent restenosis, coronary stents and
Endothelial Progenitor Cells (EPCs), nanotechnologies and drug-eluting coronary
stents, development of novel Estradiol containing drug-eluting stents, development
of regenerative stents using stem-cell derived endovascular cells.
Innovations in Minimally Invasive Cardiac Surgery
New and innovative, minimally invasive surgical technologies are poised to replace
the traditional, highly invasive protocols used in open-heart surgery.
Currently, there are three types of procedural approaches. These are Minimally
Invasive Direct Coronary Artery Bypass (MID-CAB) surgery, Off-Pump Coronary
Artery Bypass (OP-CAB), and Port Access Surgery.
Minimally Invasive Port Access Surgery is indicated for Multi-Vessel Coronary
Artery Bypass Grafting (CABG), Mitral Valve Repair or Replacement (MVR),
MVR/Tricuspid Repair, MVR Redo, MVR/CABG, Aortic Valve Replacement
(AVR) and Congenital Heart Defect Surgery, including Atrial Septal Defect (ASD)
& Ventricular Septal Defect (VSD).
Beating heart OP-CAB is currently recognized as a technique significantly reducing
the mortality and morbidity associated with the use of traditional cardiopulmonary
bypass procedures. This procedure is indicated for multivessel disease requiring
revascularization and where normal cardiopulmonary bypass is contraindicated.
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Robotic Assisted Coronary Artery Bypass (RA-CAB) systems such as The
Automated Endoscopic System for Optimal Positioning (AESOP), The Da Vinci
System and The Zeus Robotic System are becoming increasingly popular.
Computer aided cardiac surgery including virtual reality in cardiac surgery,
TransMyocardial Laser Revascularization (TMLR) including CO2 heart laser
systems, holmium:YAG (yttrium aluminium garnet) lasers and the excimer lasers
are changing the face of cardiac surgery.
Cardiovascular Drugs in Early Stage Development
There are a total of 126 new chemical entities currently in preclinical stage for nine
principle disease areas described in this chapter; Angina, Atherosclerosis,
Arrhythmiasis, Atrial Fibrillation, Congestive Heart Failure, Hypercholesterolemia,
Hypertension, Myocardial Infarction, Thrombosis.
There are a total of 51 new chemical entities currently in Phase I trials for the same
nine principle disease areas and a total of 122 new chemical entities currently in
Phase II trials
Atherosclerosis represents the clinical area where there are the largest number of
preclinical and Phase I developments currently being studied. There are a total of
32 chemical entities currently in preclinicals and a total of 11 new chemical entities
have been identified in Phase I of development.
New and Emerging Cardiovascular Drugs
Two key anti-hypertensives are forecast to launch in 2007: Novartis’ Rasilez
(aliskiren) and Exforge (valsartan plus amlodipine).
On the 6th March 2007, the US FDA approved Tekturna® (aliskiren) for use in the
US for Novartis. On the 28th September 2006, Novartis submitted Tekturna to the
European Medicines Evaluation Agency (EMEA) as a treatment for high blood
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pressure. Although approval has not been provided by the EMEA at the time of
writing, it is expected by the end of 2007.
It is anticipated that Exforge will be available to patients in the US in September
2007, pending the patent expiry of amlodipine besylate. In January 2007 Novartis
announced that the European Commission has granted approval for Exforge® with
its initial launch into Germany followed by launches in most other European Union
countries throughout the year, pending expiration of the patent protection for
Norvasc. The EU decision applies in all 27 EU member states plus Iceland and
Norway
In December 2006, Pfizer announced that it would discontinue the development of its
cholesterol drug torcetrapib. Torcetrapib was one of Pfizer's most promising pipeline
drugs and was anticipated to replace revenue lost when Lipitor’s patent protection
expires in 2010.
In April 2007, Abbott Laboratories announced that they had submitted a NDA to the
FDA for a fixed-dose combination of Niaspan® (extended-release niacin) and
simvastatin. Abbott Laboratories anticipate that they will obtain marketing approval
for Simcor by the third quarter 2007 and hope to launch at the beginning 2008.
A major blow to the anti-thrombotics pipeline is the discontinuation of AstraZeneca’s
Exanta in January 2006, due to concerns of liver toxicity. Exanta (ximelagatran) was
expected to achieve high sales when launched and to challenge sales of warfarin.
Solvay Pharmaceuticals announced on 25th April 2007 that they had submitted and
filed a dossier for intravenous anti-thrombotic tedisamil for approval by the US
FDA as well as by the authorities of European Union countries.
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CHAPTER 1
The Management of Cardiovascular Disease
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Chapter 1 The Management of Cardiovascular Disease
Summary
Cardiovascular disease is the term used for a variety of ailments including chronic heart failure, atrial fibrillation, angina and peripheral arterial disease, amongst others. The US has by far the highest prevalence of cardiovascular disease, with Japan and Germany in second and third place respectively.
Despite a decline in CVD (cardiovascular disease) in the US it still remains the leading cause of death and accounts for 53% of all deaths in the US.
Increased concern over the rising mortality rates in central and Eastern Europe caused by CVD, where it is almost double that of the worst affected countries in the European Union. Despite issues about the quality and accuracy of data, the country causing most concern is the Russian Federation.
CVD are recognised to have a considerable economic impact on rapidly growing markets in the developing world. Improved economic conditions are expected to increase the high risk factors associated with CVD, like high blood pressure, tobacco use, alcohol consumption, cholesterol, obesity and a sedentary lifestyle.
Syndromes that are associated with acute coronary syndromes are correlated with age and the prevalence of cardiovascular risk factors. Unstable angina, which has the highest incidence rate across the seven major pharmaceutical markets, is estimated to be particularly prevalent in the UK and the US and low in Japan and Italy.
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Introduction
The term cardiovascular disease (CVD) is a generic term used to describe the variety of
diseases and conditions affecting the circulatory system (heart, heart valves, blood, and
vasculature of the body). It includes a wide variety of different conditions such as
arteriosclerosis, coronary artery disease (CAD), arrhythmia disorders, heart valve
disorders, diseases of the aorta and its branches, disorders of the peripheral vascular
system (PVD) and other congenital and acquired abnormalities of the circulatory
system. These diseases may be primary conditions—such as hypertension and
hypercholesterolemia that may lead to atherosclerosis, CAD, or PVD—or secondary
manifestations of the primary disease, including coronary heart disease (CHD)
(myocardial infarction (MI) and angina pectoris) and stroke.
The Global Burden of Cardiovascular Disease
According to many sources including the World Health Organisation (WHO)
cardiovascular disease is indisputably the world’s number one killer accounting for
over 14.7 million deaths in 1990. In a series of recent publications the WHO reported
that currently the number of deaths attributed to cardiovascular disease had increased to
over 16.5 million. By the year 2020 it is predicted that cardiovascular disease will
account for over 25 million deaths globally, including 19 million in developing
countries such as China and India.
CVD remains the leading cause of death in the United States
Despite the decline of 25% between 1994 and the year 2004, CVDs remain the leading
cause of death in the United States. According to the latest data from the American
Heart Association, CVD claims over 927,000 lives each year accounting for 38.0% of
all deaths (or 1 of every 2.6) in the United States in 2002. Figure 1.1 provides an
analysis of the breakdown of deaths from different cardiovascular disease in the United
States in 2002.
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The American Heart Association stated in their Heart Disease and Stroke Statistics –
2005 that Coronary Heart Disease (CHD) accounted for a total of 494,382 deaths
whilst Myocardial Infarction accounted for a further 179,514 deaths in the United
States in 2002. The American Stroke Association reported that strokes account for over
162,000 deaths each year or the equivalent of 6.2% of all deaths in the United States.
The remaining deaths being attributed to heart failure, and hypertension and
hypertensive heart disease. In 2003, congenital cardiovascular defects contributed only
0.5 percent of CVD deaths; however, they remain a leading cause of death in infants
and children. For example, congenital heart defects accounted for 1,445 infant deaths in
2003, or nearly 26% of infant deaths from all congenital defects.
Figure 1.1: Breakdown of Deaths from Cardiovascular Diseases, USA 2002
Congestive Heart Failure6.0%
Other13.0%
Stroke18.0%
Coronary Heart Disease53.0%
Rheumatic Heart Disease0.5%
High Blood Pressure5.0% Diseases of the
Arteries4.0%
Congenital Cardiovascular
Defects0.5%
Source: Center for Disease Control; National Centre for Health Statistics Business Insights Ltd
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CVD Rates in Central and Eastern Europe
Despite concerted efforts by national governments throughout the European Union to
reduce some of the risk factors associated with CVD it still remains the leading cause
of death accounting for over 1.5 million deaths each year. Nearly half (42 percent) of
all deaths in the EU are from CVD (46 percent of deaths in women and 38 percent of
deaths in men) and between one-third and one-half of deaths from CVD are from CHD
and over one-fourth are from stroke. The picture is just as bleak in Europe as a whole.
According to the European Heart Network, CVD currently accounts for an estimated 4
million deaths throughout Europe. Worryingly, mortality from the CVD is rising in
central and Eastern Europe, where it is almost double that of the worst affected
countries in the European Union. Despite issues about the quality and accuracy of data,
the country causing most concern is the Russian Federation. The Russian Federation
has the highest death rate due to CVD in the world with a reported 1,167 deaths per
100,000 men and 540 deaths per 100,000 women.
Noncommunicable Diseases in the Developing World
Cardiovascular diseases and other noncommunicable diseases were traditionally
considered to be diseases of industrialised countries – the so-called "Western diseases"
- brought about by ways of life utterly different from those in most of Africa, Asia and
many other parts of the developing world.
The reality is quite different. CVDs have not only emerged in all but the very poorest
countries, but are already well advanced. This growing burden has real potential to
hinder social and economic development. Figure 1.2 provides an analysis of the deaths
attributable to the 16 leading causes in the developing countries of Africa, Southeast
Asia, Western Pacific, Eastern Mediterranean and Africa, illustrating the consequences
of CVDs in the developing world.
Risk factors are indicators of future health status, and five of the top 10 risks
worldwide are specific to noncommunicable diseases. These include raised blood
pressure, tobacco use, alcohol consumption, cholesterol and obesity. This is part of the
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well-documented epidemiological transition called the "double burden" that sees the
arrival of the whole group of noncommunicable diseases with their shared risk factors
on top of the persisting threat of communicable diseases.
In the economically stable countries such as the United States, France, Germany, the
United Kingdom and Italy, death from cardiovascular disease may occur after a
relatively long and productive life. Conversely in the developing countries such as
India and China almost half of deaths attributed to CVD are amongst the relatively
young and who are in the prime of their working lives. Their deaths are not only
personal tragedies, but they could also have a devastating impact on economic growth
and development in these countries.
One reason for the epidemic of cardiovascular disease is the surge in life expectancy
due to a decline in deaths related to infectious diseases and nutritional deficiencies. In
India, for example, life expectancy rose from 41.2 years in 1951 to 61.7 years by 2003
(General Register of India 2003). In China, the current average life expectancy is 72
years but this is projected to rise dramatically to 85 years by the year 2050. Ironically,
these extra years provide a longer time period for such risk factors as smoking, high-fat
diet, and sedentary lifestyle to set the stage for heart attack and stroke.
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Figure 1.2: Leading causes of death in developing countries, 2002
0 2,000,000 4,000,000 6,000,000 8,000,000 10,000,000
12,000,000
Maternal conditions
Diabetes mellitus
Diseases of the genitourinary system
Neuropsychiatric disorders
Malaria
Digestive diseases
Childhood diseases
Tuberculosis
Diarrhoeal diseases
Perinatal conditions
HIV/AIDS
Respiratory diseases
Respiratory infections
Injuries
Malignant neoplasms
Cardiovascular diseases
Low Mortality Developing Countries High Mortality Developing Countries
Source: World Health Report (WHO) 2003 Business Insights Ltd
Background to the Major Cardiovascular Conditions
Coronary Artery Disease (CAD)
Atherosclerosis
Atherosclerosis (more commonly called "hardening of the arteries") is a degenerative
disease which covers a variety of conditions caused by fatty or calcium deposits in the
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artery walls, causing them to thicken. This fatty material, known as plaque, thickens,
hardens, and may eventually block the arteries.
Plaque is a complex structure made up of a combination of cholesterol, other fatty
materials, calcium, and blood components that stick to the artery wall lining. Plaques
may be presented in different shapes and sizes but they always form a type of hard
shell or scar like covering. Sometimes plaques become unstable and can eventually
rupture or burst. If a plaque ruptures it causes blood clotting inside the artery, which
can stop blood flow completely.
There are no specific defining symptoms of atherosclerosis, rather the symptoms are
highly variable and differ from patient to patient. Patients with mild atherosclerosis
typically have symptoms of cardiovascular diseases and signs and myocardial
infarction. However, many patients with anatomically advanced disease may have no
symptoms and may not even experience functional impairment. Initially thought to be a
chronic, slowly progressive, degenerative disease, it is now apparent that
atherosclerosis is a disease with periods of activity and quiescence. Although a
systemic disease, it affects different organ systems in different patients for reasons that
remain unclear.
Atherosclerosis results in progressive luminal narrowing of an artery due to
accumulation of fibrous plaque. This results in impairment of flow once more than 50-
70% of the lumen diameter is obstructed. The impairment in the flow rate results in
inadequate blood supply to the target organ, should there be an increased demand for
oxygen as a result of increased metabolic activity. This can manifest itself in the form
of stable angina pectoris, intermittent claudication, or mesenteric angina.
Atherosclerosis is typically caused by the separation of a plaque or denudation of the
endothelium overlying a fibrous plaque. This will cause the exposure of the highly
thrombogenic subendothelium and underlying lipid core. This could result in the
formation of a thrombus, which may partially or completely occlude flow in the
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involved artery. The clinical symptoms of the partial or complete acute occlusion of an
artery are unstable angina pectoris, myocardial infarction, transient ischemic attack,
and stroke. Atheroembolism is a distinct clinical entity that may occur spontaneously
or as a complication of aortic surgery, angiography, or thrombolytic therapy in patients
with advanced and diffuse atherosclerosis.
Angina Pectoris
Angina, otherwise known as angina pectoris, is a clinical syndrome characterised by
severe pain and/or discomfort which usually originates in the chest and may radiate to
the shoulder, arm, jaw, neck, back or other areas. The pain is often described as
tightness, squeezing, crushing, burning, choking or aching. It is caused by inadequate
blood flow through the blood vessels (coronary vessels) of the heart muscle
(myocardium). In the U.S. and Europe, the most common cause of angina is
artherosclerosis.
There are three forms of angina-
Stable angina: Stable angina is a repeating pattern of chest pain which has not
changed in character, frequency, intensity or duration for several weeks. The level
of activity or stress that provokes angina is predictable and the pattern changes
slowly. Stable angina is the most common form and it appears gradually;
Unstable angina: Unstable angina describes a syndrome that is intermediate
between stable angina and myocardial infarction (heart attack). Unstable angina is
characterized by an accelerating or "crescendo" pattern of chest pain that lasts
longer than in stable angina, occurs at rest or with less exertion than stable angina,
or is less responsive to medication. Eugene Braunwald recently suggested that
unstable angina was sub-divided into 5 separate categories. He described these as:
(i) Nonocclusive thrombus on a pre-existing atheromatous plaque, which
has usually undergone disruption.
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(ii) Dynamic obstruction, i.e. various forms of coronary spasm.
(iii) Progressive mechanical obstruction, due to progression of
atherosclerotic lesions or the development of restenotic lesions after
angioplasty.
(iv) Inflammation and/or infection of an atheromatous plaque, as yet
unproven.
(v) Secondary to systemic diseases that impair oxygen delivery (e.g.
anaemia) or increase heart work (e.g. thyrotoxicosis);
Variant angina (Prinzmetal’s angina): Variant angina pectoris or coronary artery
spasm (Prinzmetal’s angina) is caused by a vasospasm, a spasm that narrows the
coronary artery and lessens the blood flow to the heart. Prinzmetal's Angina usually
occurs in arteries already narrowed by atherosclerosis, in fact most people with it
have severe coronary atherosclerosis in at least one major vessel. The spasm
usually occurs very close to the blockage. Unlike stable and unstable angina,
Prinzmetal's Angina usually occurs when a person is at rest or sleep and not after
physical exertion or emotional stress. It is associated with acute myocardial
infarction, severe cardiac arrhythmias including ventricular tachycardia and
fibrillation, and sudden cardiac death;
Population based studies in countries with high or relatively high coronary artery
disease rates indicate that the prevalence is related to both age and gender. In men aged
45-54 years the rate is 2-5%, increasing to 11-20% in the 65 to 74 year age group. Pre-
menopausal women enjoy a relatively low prevalence of coronary artery disease,
estimated at 0.5-1% between the ages of 45-54 years. In post-menopausal women the
prevalence increases rapidly to equal that of men by the age of 75.
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Acute Myocardial Infarction (MI)
Acute myocardial infarction (AMI), or more commonly known as “heart attack”, is the
rapid development of myocardial necrosis caused by a critical imbalance between the
oxygen supply and demand of the myocardium. It occurs when oxygen delivery to and
waste removal from the myocardium falls below normal levels with oxygen demand
exceeding supply. As a consequence, the metabolic machinery of myocardial cells is
impaired, leading to various degrees of systolic (contractile) and diastolic (relaxation)
dysfunction. Acute myocardial infarction is usually diagnosed indirectly through
techniques that demonstrate reduced myocardial blood flow.
The most common cause of AMI is narrowing of the epicardial blood vessels due to
atheromatous plaques. This plaque sometimes ruptures and separates from the blood
vessel wall with the subsequent exposure of the basement membrane. This results in
platelet aggregation, thrombus formation, fibrin accumulation, hemorrhage into the
plaque, and varying degrees of vasospasm. This can result in partial or complete
occlusion of the vessel and subsequent myocardial ischemia. Provided that reperfusion
can be performed within 4-6 hours of total occlusion of the vessel it is possible to
salvage the myocardium, reducing morbidity and mortality. If total occlusion occurs for
more than 4-6 hours then myocardial necrosis takes place.
The symptoms of MI include chest discomfort such as pressure, squeezing, fullness, or
pain in the centre of the chest that lasts more than a few minutes or that goes away and
then returns. Symptoms also may include pain or discomfort in one or both arms, the
back, neck, jaw, or stomach; shortness of breath (either accompanying chest discomfort
or occurring earlier); breaking out in a cold sweat; and feelings of nausea or light-
headedness. If blood flow is not restored to the ischemic region within a short time
period, cardiac tissue death occurs.
Myocardial infarction (MI) is the most prominent of ischaemic heart diseases.
Throughout the 1990s, deaths from ischaemic heart diseases have declined
considerably in most Western countries. Changing coronary event rates is the major
28
determinant of this decline, whereas improved coronary care and secondary prevention
were responsible for decreased event rates. Despite these promising developments,
ischaemic heart diseases will remain a major health issue during the decades ahead for
several reasons. First, ischaemic heart diseases will persist at early ages in individuals
with a genetic predisposition and in those with an unfavourable clinical risk profile.
Furthermore, survivors of an acute coronary syndrome constitute a population with
chronic cardiac conditions and remain at increased risk of future fatal and non-fatal
cardiac events. In addition, evidence exists that patients and doctors fail to adequately
put effective preventive measures into practice. Last, but not the least, populations in
the Western world are ageing and as such heart disease is expected to increase in
proportion to the ageing population.
Table 1.1: Age- and gender-specific incidence of recognised MI Person years No. of cases Incidence rate per 1000 person years 95% CI) Men Women Men Women Men Women All individuals 10 262 17 859 86 55 8.4 (6.6, 10.2) 3.1 (2.3, 3.9) 55–59 905 1 387 3 2 3.3 (–0.4, 7.1) 1.4 (–0.6, 3.4) 60–64 2 477 3 623 11 8 4.4 (1.8, 7.1) 2.2 (0.7, 3.7) 65–69 2 572 3 700 22 5 8.6 (5.0, 12.1) 1.4 (0.2, 2.5) 70–74 1 968 3 378 25 16 12.7 (7.7, 17.7) 4.7 (2.4, 7.1) 74–79 1 300 2 693 12 10 9.2 (4.0, 14.5) 3.7 (1.4, 6.0) ≥80 1 040 3 078 13 14 12.5 (5.7, 19.3) 4.6 (2.2, 6.9)
Source: The Rotterdam Study Business Insights Ltd
Table 1.2: Age- and gender-specific incidence of unrecognised MI Person years No. of cases Incidence rate per 1000 person years 95% CI) Men Women Men Women Men Women All individuals 8 866 14 638 37 52 4.2 (2.8, 5.5) 3.6 (2.6, 4.5) 55–59 8.39 1 258 1 3 1.2 (–1.1, 3.5) 2.4 (–0.3, 5.1) 60–64 2 317 3 278 6 6 2.6 (0.5, 4.7) 1.8 (0.4, 3.3) 65–69 2 321 3 320 7 11 3.0 (0.8, 5.3) 3.3 (1.4, 5.3) 70–74 1 735 2 922 15 5 8.6 (4.3, 13.0) 1.7 (0.2, 3.2) 74–79 1 015 2 118 6 15 5.9 (1.2, 10.6) 7.1 (3.5, 10.7) ≥80 640 1 743 2 12 3.1 (–1.2, 7.5) 6.9 (3.0, 10.8)
Source: The Rotterdam Study Business Insights Ltd
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Heart Valve Disorders
There are four valves in the heart: the aortic valve, the mitral valve, the tricuspid valve,
and the pulmonary valve. The valves keep the blood flowing in one direction. They
open when the pressure of the blood pushes them in the forward direction and they
close when the pressure on the other side of the valve pushes them back. Diseased
valves may be too stiff to open easily or they may fail to close completely. There are a
number of different heart valve disorders. In brief these are:
Aortic heart valve
There are 2 principle diseases of the aortic valve: aortic regurgitation or insufficiency
and aortic stenosis.
Aortic Regurgitation or Aortic insufficiency: This is a heart valve disease in which
the aortic valve weakens or balloons, preventing the valve from closing tightly.
This leads to backward flow of blood from the aorta (the largest blood vessel) into
the left ventricle (the left lower chamber of the heart). Aortic insufficiency affects
approximately 5 out of every 10,000 people. It is most common in men between the
ages of 30 and 60. In its most serious form, aortic regurgitation is caused by an
infection that leaves holes in the valve leaflets. Other causes, though rare, may
include:
Marfan syndrome, a connective tissue condition where patients have long
bones and very flexible joints;
Endocarditis;
ankylosing spondylitis (arthritis of the spine);
dissecting aortic aneurysm;
aortic stenosis, a narrowing of the aortic valve that is often causes some
degree of aortic regurgitation.
30
Aortic Stenosis: Aortic stenosis is a narrowing or blockage of the aortic valve. This
valve regulates the blood flow from the heart's lower-left chamber (the left
ventricle) into the aorta. The aorta is the main blood supplier to the rest of the body.
Aortic stenosis happens when the valve leaflets become coated with deposits. The
deposits change the shape of the leaflets and reduce blood flow through the valve.
The left ventricle has to work harder to make up for the reduced blood flow. Over
time, the extra work can weaken the heart muscle.
Aortic stenosis is more common among men. Congenital defects and rheumatic
fever are the main causes of aortic stenosis in people under 50. In some cases,
people are born with a bicuspid aortic valve, meaning the valve has 2 leaflets
instead of 3. This may also cause aortic stenosis. In elderly patients, calcium
deposits and the growth of fibrous tissue on the aortic valve can distort the leaflets
or cause them to fuse together. This is called calcification, and it can make the
different leaflets almost look like a single one. Other causes include a history of
other valve disease, coronary artery disease, or a heart murmur. People with aortic
stenosis may not have symptoms for years.
Mitral Valve Disease
There are 3 types of mitral valve disease:
Mitral Valve Prolapse (MVP): In a normal valve the flow of blood goes from the
left atrium to the left ventricle. Upon closing it prevents blood from going back into
the left atrium. With MVP the flaps don't close evenly. One or both flaps collapse
backwards, sometimes allowing a small amount of blood to leak through the valve.
MVP is a genetic disorder and seems to affect women three times more than men.
MVP is frequently diagnosed in healthy people and is, for the most part, harmless.
Most people suffer no symptoms at all. MVP affects about 15 to 25 percent of the
population. Forty percent of these people have dysautonomia (MVP Syndrome).
Seventy percent of patients have depression. Only 2 percent of MVP patients have
actual structural problems. At least 40 to 60 percent of MVPS patients suffer from
panic attacks. MVPS patients often have low energy levels. Forty to 50 percent of
echocardiograms do not detect MVP. MVP is also called floppy valve syndrome,
31
Barlow's or Reid-Barlow's syndrome, ballooning mitral valve, midsystolic-click-
late systolic murmur syndrome, or click murmur syndrome. MVP can be present
from birth or develop at any age and occurs equally in both men and women. The
list of symptoms mentioned in various sources for mitral-valve prolapse includes:
heart murmuring, heart click, mitral regurgitation, dizziness, skipping heart, racing
heart, chest pain and shortness of breath.
Mitral regurgitation: Acute mitral regurgitation is a disorder in which the heart's
mitral valve suddenly does not close properly, causing blood to leak (back-flow)
into the left atrium (upper heart chamber) when the left ventricle (lower heart
chamber) contracts. Chronic mitral regurgitation is a long-term disorder in which
the valve (mitral valve) that separates the left upper chamber of the heart (atrium)
from the left lower chamber (ventricle) does not close properly. Some of the
possible causes of mitral regurgitation include congenital heart defects, rheumatic
fever, prior heart attack, heart inflammation and heart infection. Mitral
regurgitation is common in older age groups and is twice as common in women.
The incidence of mitral valvular stenosis varies considerably in different parts of
the world. It is more common (and presents earlier) in the Middle East, India and
the Far East than elsewhere. It is more common in women and presents in
developed countries in the fourth or fifth decades of life. Its incidence in older
people approximates that of acute rheumatic fever.
Mitral Stenosis: This is the narrowing of the mitral heart valve. The principle
underlying condition causing mitral stenosis is rheumatic fever usually from
childhood times. The symptoms of mitral stenosis are similar for mitral
incompetence and diastolic murmur.
32
Pulmonary Valve Disease
There are essentially 2 different forms of pulmonary valve disease i.e. regurgitation or
pulmonary incompetence i.e. poorly closing leaking pulmonary heart valve and
pulmonary valve stenosis. Pulmonary valve stenosis is a condition, usually present at
birth (congenital), in which outflow of blood from the right ventricle (lower chamber)
of the heart is obstructed at the level of the pulmonic valve (the valve which separates
the heart from the pulmonary artery).
Tricuspid Valve Disease
Tricuspid valve disease refers to damage to the tricuspid heart valve. This valve is
located between the atrium (upper chamber) and the ventricle (lower pumping
chamber) of the right side of the heart. The tricuspid valve has three cusps, or flaps,
that control the direction and flow of blood. The two main types of tricuspid valve
disease are tricuspid stenosis - narrowing of the tricuspid valve and tricuspid
regurgitation - backflow of blood into the atrium from the ventricle due to improper
closing of the tricuspid valve flaps. Other tricuspid valve disease includes rheumatic
tricuspid valve disease and tricuspid insufficiency. Rheumatic fever is the most
common cause of tricuspid valve disease. Less common causes include congenital
heart problems, heart attack or coronary heart disease, congestive heart failure,
endocarditis, and trauma to the heart and occasionally tumours.
High Blood Pressure: Hypertension
Blood pressure is measured by two numbers; systolic pressure and diastolic pressure.
Systolic pressure measures cardiac output and refers to the pressure in the arterial
system at its highest. Diastolic pressure measures peripheral resistance and refers to
arterial pressure at its lowest. Blood pressure is normally measured at the brachial
artery with a sphygmomanometer (pressure cuff) in millimeters of mercury (mm Hg)
and given as systolic over diastolic pressure.
A blood pressure reading thus appears as two numbers. The upper number is the
systolic pressure, which is the peak force of blood as the heart pumps it. The lower
33
number is the diastolic pressure, which is the pressure when the heart is filling or
relaxing before the next beat. Normal blood pressure for an adult is 120/70 (on
average), but normal for an individual varies with the height, weight, fitness level, age,
and health of a person. Hypertension, or high blood pressure, is defined as a reading of
140/90 on three consecutive measurements at least six hours apart. Consistently high
blood pressure causes the heart to work harder than it should and can damage the
coronary arteries, the brain, the kidneys, and the eyes and is a major cause of stroke.
Hypertension is classified as either primary (or essential) hypertension or secondary
hypertension. Primary hypertension has no specific origin but is strongly associated
with lifestyle. It is responsible for 90 to 95 percent of diagnosed hypertension and is
treated with stress management, changes in diet, increased physical activity, and
medication (if needed). Secondary hypertension is responsible for 5 to 10 percent of
diagnosed hypertension. It is caused by a preexisting medical condition such as
congestive heart failure, kidney failure, liver failure, or damage to the endocrine
system.
Heart Rhythm Disorders (Heart Arrhythmia)
Heart rhythm disorders or arrhythmias are defined as abnormal rhythms of the heart
and is a disruption of the normal electrical impulses controlling the speed of the
heartbeat. The electrical system regulating heartbeat consists of 2 main areas of control
and a series of conducting pathways.
The sinoatrial node (or SA) is located in the right atrium. It provides the main
control and is the source of each beat. The SA node also keeps up with the body's
overall need for blood and increases the heart rate when necessary, such as during
exercise, emotional excitement, or illness such as fever. The SA node is sometimes
called the "natural pacemaker" of the heart;
Electrical impulses leave the SA node and travel through special conducting
pathways in the heart to the other controller, the atrioventricular, or AV, node. The
purpose of the AV node is to provide a pathway for impulses from the atria to the
34
ventricles. It also creates a delay in conduction from the atria to the ventricle. This
causes the atria to contract first and allow the ventricles to fill with blood before
they contract themselves.
Abnormal heart rhythms or arrhythmias fall into three general classes: excessively slow
heart rates, known as bradyarrhythmias or bradycardias, and overly rapid heart rates,
known as tachyarrhythmias or tachycardias; the location (ventricles-lower chambers of
heart or atria-upper chambers) or premature heartbeats; and the beat (steady or chaotic
and irregular) described as fibrillations.
Bradycardias: This is the term used to describe excessively slow heartbeats. A
normal heart contracts about 100,000 times each day, at a rate of 60 to 100 times a
minute. The weak pace may mean the heart doesn't beat often enough to ensure
blood flow. Slow heart rates can be the result of certain medications, congenital
heart disease, or the degenerative processes of aging. Heart block (or AV Block)
and Sick Sinus Syndrome are forms of bradycardia;
Tachycardias: The term tachycardia refers to a rapid heartbeat of over 100 beats per
minute. There are two predominant types of tachycardia: supraventricular
tachycardia (SVT) and ventricular tachycardia (VT). SVT or paroxysmal SVT
occurs when any structure above the ventricle (usually the atria or the AV node)
produces a regular, rapid discharge. The most common type of SVT is atrial
fibrillation (AT), an irregular and rapid heartbeat in the upper chambers of the heart
(or atria). Ventricular tachycardia arises from the ventricles and cause a very rapid
heart rate. This is usually a life-threatening tachycardia and needs immediate
medical attention, possibly electrical shock or defibrillation;
Premature heartbeats: Premature heartbeats occur when the heart's regular rhythm
is interrupted by early or premature beats. It may feel as if the heart has skipped a
beat. If the beat arises from locations in the atria (upper chambers) it is called
premature atrial contractions (PACs). Premature ventricular beats (also called
premature ventricular contractions or PVCs) arise from the ventricles (lower
chambers);
35
Fibrillation: Fibrillation describes a heartbeat that is chaotic, or irregular, and may
seem to skip beats or beat out of rhythm. This occurs when a chamber of the heart
goes into spasm and fails to pump. There are two types of fibrillation: atrial
fibrillation and ventricular fibrillation.
Peripheral Vascular Disease
There are essentially two different forms of peripheral vascular disease. These are
Peripheral Artery Disease (PAD) and Peripheral Venous Disorders (PVD)
Peripheral Artery Disease (PAD)
Peripheral Artery disease (PAD) is a group of diseases that affects the body’s blood
vessels (the arteries and capillaries) and describes all of the conditions that can affect
the arteries of the body outside of the heart as opposed to coronary artery disease
(CAD) which refers to conditions within the heart. Peripheral arterial disease is a type
of artherosclerosis, in which the arteries become hardened and narrowed. It is often
named after the artery that is affected. There are four major areas where peripheral
arterial disease (PAD) produces symptoms and have clinical significance and relevance
to this report. These are:
Carotid artery disease (CAD): carotid artery disease is a form of peripheral artery
disease in which there is a hardening of the artery otherwise known as
atherosclerosis in the carotid arteries (a more detailed description of atherosclerosis
is provided below). These arteries, which lie in the neck, carry oxygen-rich blood to
the brain and face. During atherosclerosis, the inside of the artery is gradually
narrowed with a build-up of fatty plaque. The stenosis or occlusion of the artery can
occur as a direct result of the narrowing of the artery as a result of plaque buildup
or as plaque hardens (calcifies), there is a chance pieces may break off and travel
further downstream in the artery. If the pieces of plaque become stuck in an artery
and obstruct the flow of oxygen-rich blood, the person can suffer a stroke or an
ischemic stroke. This is caused by a severe lack of oxygen-rich blood reaching the
brain or a cerebral ischemia;
36
Renal artery disease: renal artery stenosis (RAS) is a condition in which the blood
vessels (the suprarenal and renal arteries) that feed oxygen-rich blood to the
kidneys become obstructed. The renal arteries usually arise at 90 degrees from the
aorta at the level of the intervertebral disc between L1 and L2. Renal artery stenosis
is usually caused by atherosclerosis (narrowing of the artery due to the build-up of
plaque), fibromuscular disease in which fibrous tissue grows in the arterial wall, or
scar tissue caused by injury to the kidney. Renal artery stenosis is a common cause
of high blood pressure (hypertension) because it can restrict blood flow to the
kidneys, which can result in elevated blood pressure. The kidneys serve as filters,
and they remove waste products and excess fluids from the body. In this role, they
receive almost one-third of the body’s blood flow, and any obstruction in their
function has an effect throughout the body;
Peripheral artery disease (PAD/LEPAD): peripheral artery disease of the lower
extremities is usually presented as atherosclerosis of the major arteries of the legs.
The three arteries that are usually affected include Iliac arteries (located inside the
lower abdomen), Femoral arteries (located in the thigh), Tibial arteries (located
below the knee).
Normally oxygen-rich blood flows down these three arteries to supply the muscles
of the buttocks, legs and feet. As a result of atherosclerosis the blood flow down
these arteries is impeded as a result of the narrowing and hardening the arteries, in
the same way it can impede blood flow to the heart;
Mesenteric artery disease (MAD): mesenteric artery disease or mesenteric artery
ischemia (MAI) is the narrowing or blockage of one or more of the three
mesenteric arteries including the inferior and superior mesenteric arteries, which
are the major arteries supplying the small and large intestines. The narrowing or
blockage of the arteries is caused by either atherosclerosis, or hardening of the
arteries or alternatively, it can be caused by a blood clot (embolus), which travels
through the bloodstream and suddenly blocks one of the mesenteric arteries. The
source of these clots is usually the heart or the aorta. Such an embolus is seen more
commonly in patients with heart arrhythmias such as atrial fibrillation, which
37
predisposes patients to formation of clots within the chambers of the heart. With the
beating of the heart, these clots break loose and can travel to the arteries of the
intestine.
Peripheral Venous Disorders (PVD)
The second type of peripheral vascular disease is peripheral venous disorders.
Peripheral venous disorders or venous disease indicate problems in the flow of oxygen-
poor blood from the extremities back toward the heart. Venous circulation is comprised
of superficial veins and deep veins. Unlike arteries, veins contain one-way valves that
permit the flow of blood toward the heart at a very low pressure. There are a number of
different peripheral venous disorders including thrombophlebitis.
Thrombophlebitis is a condition in which a blood clot (a thrombus) has formed inside a
vein, causing the surrounding veins to become inflamed (phlebitis). There are two
types of thrombophlebitis: superficial vein thrombus (SVT) and deep vein thrombosis
(DVT). SVT causes little medical risk. However, DVT can be life-threatening if the
blood clot or pieces of the blood clot break loose and travel to another part of the body,
lodging in another blood vessel and causing an embolism. If pieces of the clot lodge in
an artery of the lungs, it could cause a potentially fatal pulmonary embolism.
A second form of peripheral venous disorder is known as Chronic Venous
Insufficiency (CVI). Chronic venous insufficiency is a form of vein disease in which
the veins of the leg no longer allow normal blood flow (incompetent). Vein
incompetence is characterized by problems involving valves within the vein. Valves
are distributed throughout all of the veins and allow blood to flow passively but in only
one direction, towards the heart. Incompetent vein valves allow blood to flow in both
directions, thus allowing blood to pool or “stagnate,” particularly in more areas of the
body such as the legs. If untreated, some patients with CVI will experience pain,
swelling, discoloration or ulcers that do not heal.
38
Stroke or Cerebrovascular Accidents (CVA)
A stroke is normally defined as a sudden, nonconvulsive loss of neurologic function
due to an ischemic or hemorrhagic intracranial vascular event. In general,
cerebrovascular accidents (CVAs) are classified according to their anatomic location in
the brain, vascular distribution, etiology, age of the affected individual, and
hemorrhagic vs. nonhemorrhagic nature. There are two major causes of stroke:
Ischaemic Stroke
This is caused as a result of:
Cerebral thrombosis: A cerebral thrombosis occurs when a blood clot forms inside
the brain, stopping the flow of blood to or from the brain. The most common cause
for the formation of a blood clot is the hardening of the arteries, or atherosclerosis.
The fatty deposits (plaques) that have built up in the arteries carrying blood to the
brain can cause clots to form on the plaques that narrow or block the flow of
oxygen and nutrients to the brain.
Cerebral embolism: Cerebral embolism is also caused by a blood clot, air bubble or
fat globule (embolism). An embolic stroke is caused by a blood clot formed in
another part of the body that breaks loose, travels through the bloodstream, and
blocks an artery carrying oxygen and nutrients to the brain. When traveling through
the body the blood clot is called an embolus;
Lacunar stroke: a blockage in the tiny blood vessels deep within the brain.
Haemorrhagic stroke
This is caused by bleeding within or around the brain, resulting in compression and
injury to the tissue. The broken blood vessel prevents needed oxygen and nutrients
from reaching brain cells. There are essential two forms of hemorrhagic stroke. These
are:
Subarachnoid hemorrhage: This occurs when a blood vessel on the surface of the
brain bleeds into the area between the brain and skull (the subarachnoid space).
39
Subarachnoid hemorrhage, which accounts for 5 to 10 percent of strokes, is one of
the deadliest type of strokes. While ischemic strokes have a 30-day mortality rate of
20 percent, subarachnoid bleeds kill 40% of their victims in the same time,
disabling half the survivors;
Intracerebral hemorrhagic (ICH): This occurs when a blood vessel bursts within the
brain. Intracerebral hemorrhage, or ICH, accounts for 10 to 15 percent of all
strokes. It most frequently results from high blood pressure as found in people with
hypertension, eclampsia, and abuse of some drugs. A third of intracerebral bleeds
result in intraventricular hemorrhage, or bleeding within the brain's ventricles. ICH
has a mortality rate of 44 percent after 30 days.
A considerable amount of information about the incidence, mortality rates for stroke
has been gathered from the Framingham Heart Study. This study was originally
commissioned to determine long-term trends in the incidence, lifetime risk, severity,
and 30-day risk of death from clinical stroke. The original 9,152 participants were
recruited in 1948 in Massachusetts USA. A recently published update of the original
Framingham Study has revealed that since then, the risk of stroke by age 90 has
decreased from 19.5 percent to 14.5 percent in men 65 and older, and from 18.0 percent
to 16.1 percent for women. However the authors concluded that although the incidence
has declined the severity of stroke has not decreased, and 30-day mortality has
decreased significantly only in men, perhaps due to older age at onset of stroke and
more severe strokes in women.
40
41
CHAPTER 2
Latest Developments in Cardiovascular and PCI
Procedures
42
Chapter 2 Latest Developments in Cardiovascular and PCI Procedures
Summary
Since the introduction of Percutaneous Coronary Interventions (PCI) or Percutaneous Transluminal Coronary (PTCA) the number of procedures carried out has increased dramatically, becoming one of the most common medical interventions performed and has transformed the practice of revascularization for coronary disease.
42.6% of all percutaneous coronary interventions carried out in Europe in 2005 were used primarily to treat unstable angina. 20.2% of all percutaneous coronary interventions were used to treat acute ST-elevation Myocardial Infarction (STEMI).
There are significant differences in PCI procedural rates in different regions across the world. Germany has the highest procedural rate in the world with an estimated 225,500 carried out in 2005/2006 (2,765 pmp) compared with China with an estimated total number of 95,912 PCI procedures (73 pmp) and India with an estimated total number of 42,123 PCI procedures (41 pmp).
Emerging technologies and recent product developments include the market entry of embolic protection devices incorporating distal filter devices such as the FilterWire EZ™ Embolic Protection System developed by Boston Scientific, distal balloon occlusive devices such as TriActiv FX(R) Embolic Protection System from Kensey Nash and proximal balloon occlusive devices such as the Parodi Anti-Emboli System (PAES) developed by ArteriA Medical Science.
Other developments include the emergence of Rotational Coronary Atherectomy (Rotoblation), Directional Coronary Atherectomy (DCA). Orbital Atherectomy and Ablative laser-assisted angioplasty and innovative minimally invasive technologies and techniques.
43
Introduction to Percutaneous Coronary Interventions
Percutaneous Coronary Interventions (previously called Angioplasty, Percutaneous
Transluminal Coronary, or Balloon Angioplasty) is a technique used to widen the
narrowing in the artery without surgery. The basic idea of angioplasty is to position a
catheter with a small inflatable balloon on the end within the narrowed section of the
artery. The balloon is then inflated, which pushes outward against the narrowing and
surrounding wall of the artery. The inflated balloon opens the narrowed artery by
splitting and compressing the plaque and slightly stretching the wall of the artery. The
balloon may be inflated several times during angioplasty. Each balloon is made of
special materials that allow it to inflate to a specific size. The interventionalist selects a
balloon that will be approximately the same size as the artery.
Andreas Gruentzig in Zurich, Switzerland carried out the first PCI procedure in 1977.
It wasn’t until the mid 1980s that the procedure became popular and more widely used
throughout Europe when at that time PCI was commonly performed through a catheter
inserted into the patient’s femoral artery, which is located in the groin area. In the mid-
1990s an alternative approach using either brachial or radial artery access was
developed. Since the original procedure was carried out a variety of new innovative
technologies have been introduced. This includes the introduction of a variety of
products including balloon catheters, coronary guiding catheters and guidewires,
introducers/sheaths, inflation devices, and arterial access closure devices as well as
other ancillary items. The introduction of these products coupled with improved
angiographic imaging modalities, are making it possible to use PCI to treat an
increasingly wide range of coronary artery blockages.
Since the introduction of PCI the procedure has increased dramatically, becoming one
of the most common medical interventions performed and has transformed the practice
of revascularization for coronary disease. Initially used in the treatment of patients with
stable angina and discrete lesions in a single coronary artery, coronary angioplasty has
multiple indications today, including unstable angina, acute myocardial infarction (MI),
and multivessel coronary artery disease. With the combination of sophisticated
44
equipment, experienced operators, and modern drug therapy, coronary angioplasty has
evolved into an effective nonsurgical modality for treating patients with CAD.
Indications for PCI
According to the British Cardiovascular Intervention Society (BCIS) and the European
Society of Cardiology (ESC) the principle indications for PCI are stable and unstable
angina, angina equivalent (e.g. dyspnea, arrhythmia, dizziness/syncope) so as to relieve
anginal symptoms, to retard disease progression, and to prevent death or myocardial
infarction. In patients presenting with evolving myocardial infarction, immediate
revascularization by means of primary percutaneous intervention is today considered to
be the best treatment option. In clinical practice however indications for
revascularization are determined as much by availability as by risk assessment.
According to the European Heart Survey being conducted by the European Society of
Cardiology (ESC) and presented at the European Heart Survey Symposium in
Barcelona September 2006 treatment of stable angina accounted for 42.6% of a sample
of 13,544 patients taken from 143 hospitals from 30 ESC member countries. Acute
coronary syndrome accounted for the remaining 57.4%. An analysis of the all
indications by type is provided in Figure 2.1.
PCI Procedural Volumes
Between 1979 and 1985 the number of PCIs performed in the United States
skyrocketed from 2000 to 82 000. This stunning growth reflected the fact that by 1985
many of the nation’s thousands of invasive cardiologists had transformed themselves
into interventionalists by attending brief demonstration courses or by being mentored
by a colleague who had already done so. This growth continued throughout the 1990s
and by the year 2002 had reached to 657,000 or the equivalent of 2,334 per million
population. Table 2.3 provides an analysis of the number of inpatient cardiovascular
procedures by region in the United States in the year 2002.
45
Table 2.3: Estimated volume of cardiovascular procedures by region (US 2002)
Region Procedures NorthEast MidWest South West Total Angioplasty 211 323 416 254 1,204 PTCA 110 182 229 136 657 Stenting 105 138 186 118 547 Cardiac Revascularization 104 117 204 90 515 Diagnostic Cardiac Catheterizations 281 342 585 255 1,463 Endarterectomy 33 29 55 17 134 Implantable Defibrillators 20 14 20 9 63 Open-Heart Surgery 160 156 258 135 709 Pacemakers 50 36 78 35 199 Valves 30 15 30 18 93 Total Vascular and Cardiac Surgery 1094 1352 2061 1067 5,574 Figures in thousands Estimates are based on a sample of inpatient records from short-stay hospitals in the United States (National Hospital Discharge Survey).
Source: Health Resources Utilization Branch, CDC/NCHS. Business Insights Ltd
PCI Used Primarily to Treat Unstable Angina and acute ST-elevation MI
According to data and information gathered from the European Heart Survey:
European Society of Cardiology and the European Association of Percutaneous
Cardiovascular Interventions (EAPCI) 42.6% of all percutaneous coronary
interventions carried out in Europe in 2005 were used primarily to treat unstable
angina. 20.2% of all percutaneous coronary interventions were used to treat acute ST-
elevation Myocardial Infarction (STEMI). A total of 59% of all percutaneous coronary
interventions procedures carried out were for the treatment of various forms of angina.
46
Figure 2.3: Use of Percutaneous Coronary Intervention in Europe, 2005
Stable Angina42.6%
Post Unstable Angina 9.3%Unstable Angina
7.1%
Post NSTEMI8.1%
NSTEMI5.8%
Post STEMI6.9%
STEMI20.2%
Source: European Society of Cardiology and the European Association of PercutaneousCardiovascular Interventions (EAPCI) Business Insights Ltd
Inter-country Variance in PCI Procedural Rates
Table 2.4 illustrates the differences between PCI procedural rates from some selected
countries from the developed world compared with selected countries from the
developing world. Germany has the highest procedural rate in the world with an
estimated 225,500 carried out in 2005/2006 (2,765 pmp). This compares with 131,665
procedures carried out in France (2,194 pmp) and a total of 70,142 (1,165 pmp) in the
United Kingdom. In contrast India and China have dramatically lower procedural rates
compared with the norm in Europe and North America.
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China and India: Huge growth potential and market development
The latest official information from China is that a total of 95,912 PCI procedures are
carried out in a country with a population of 1,313 million (73 pmp). Similarly the
latest official figures from India suggests that only 42,123 PCI procedures are carried
out in India (41 pmp) in 2005. There is however clear and incontrovertible evidence to
suggest that there is considerable underreporting in these countries. In China for
example it is estimated that in 2006 over 170,000 PCI procedures took place increasing
to an estimated 201,000 PCI procedures in 2007 (+18.4%). Given that on average an
estimated 1.3 stents are used per procedure this represents a total of 219,000 stent
placements in 2006 and 263,000 stent placements in 2007.
Similarly in India industry sources estimate that 74,000 PCI procedures took place in
2006 increasing to over 84,000 in 2007 (+13.5%). It has been estimated that on average
1.5 stents are used in India per procedure. As a result over 111,000 stents were
implanted in India in 2006 and an estimated 126,600 stents will have been implanted
by the end of 2007.
Given the economic development taking place in these countries these markets
represent a massive investment opportunity with predicted compounded annual growth
rates expected to be between 20-35% over the next decade. Key features of the Chinese
PCI market structure are:
PCI is currently available in 754 hospitals among the 30 provinces and there are
more than 50 hospitals performing PCI in 4 provinces: Shandong (70), Beijing (60),
Guangdong (60) and Shanghai (50);
a total of 95 912 PCIs were performed in 2005 among the 30 provinces and about
50% of these procedures were finished in five provinces (Beijing: 20%, Shanghai:
8.9%, Shandong: 7.6%, Liaoning: 6.1% and Shanxi 6.0%;
PCI procedure numbers of more than 1000 were conducted in 7 hospitals, between
500 - 999 in 13 hospitals, between 300 - 499 in 41 hospitals, between 100 - 299 in
149 hospitals and less than 100 in more than 50% of all hospitals;
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in several regions with high Gross Domestic Product (GDP) figures such as Jiangsu
Province, Zhejiang Province, Guangdong Province, Shandong Province and Hainan
Province, the rate of PCI/total population is significantly lower than other regions
with comparable GDP and as such there is greater potential for higher PCI numbers
in the future from these regions;
an estimated 60% of all stents implanted were drug eluting stents;
in Singapore, the number of patients who underwent PCI procedures increased
from 2450 in 1999 to 3225 in 2003.
In 2004 India had a total of 86 hospitals in the country where a total of 32,665 PCI
procedures were carried out. By 2006 the number of participating centers carrying out
PCI procedures had increased to 109 with a corresponding increase in PCI procedures
to 42,123 (+28.9%). There are significant regional zone differences within India. Of the
total of 109 participating centers the Northern region of India has 23 centers (11,212
PCI procedures), the Eastern region has 5 centers (1,166 PCI procedures), the Central
region has 22 centers (6,895 PCI procedures), the Sothern region has 35 centers
(10,961 PCI procedures) and the Western region has 25 centers (11,899 PCI
procedures).
Clearly both India and China are markets which currently have significantly lower
procedural rates compared with the mature markets of North America and Europe.
However given the growth rates of their economies and subsequent structural and
financing improvements in the healthcare systems these markets represent huge
opportunities for companies who have the ability to commit resources and create
suitable sales and marketing structures in both countries.
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Table 2.4: PCI procedure rates in Selected Countries, 2005 Population Total Estimated Procedures per million (million) Procedures population (pmp) Australia 20.7 28,300 1,364 China 1,313.9 95,912 73 Czech 10.2 11,508 1,125 Estonia 1.3 421 312 Finland 5.2 7,850 1,500 France 60.0 131,665 2,194 Germany 82.6 225,500 2,765 Greece 11.2 5,828 520 Hungary 10.1 2,850 282 India 1,027.0 42,123 41 Italy 57.9 115,000 1,983 Norway 4.5 10,847 2,380 Spain 41.8 32,019 759 United States 281.4 657,000* 2,334 United Kingdom 60.2 70,142 1,165 * Data obtained from (Health Care in America: Trends in Utilization. CDC/NCHS 2003). This states that an estimated 657,000 PTCA procedures were performed on 640,000 patients in 2002 in the United States. From 1987 to 2002 the number of procedures increased 324 percent.
Source: European Heart Survey: European Society of Cardiology and the European Association of PercutaneousCardiovascular Interventions (EAPCI) Business Insights Ltd
Latest Developments in PCI Procedures
Embolic Protection Devices
It is now known that atheromatous plaques are formed over time by deposition of low
density lipoprotein, calcium mineral and a variable amount of fibrous connective tissue
within the walls of arteries. This progressively reduces the diameter of the artery
lumen. As a result of the narrowing of the artery, lumen blood flow becomes
progressively restricted and situations arise where the plaque eventually may occlude
the entire lumen and cause total blood flow obstruction, leading to tissue infarction.
Plaques which have a large lipid pool, a thin fibrous cap and a high density of
macrophages (which release many things including matrix metalloproteinases) are
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known to become morphologically unstable (vulnerable plaques) and thus have a
higher tendency to rupture.
As the atheroma becomes unstable, parts of the plaque break off and embolise
downstream, leading to infarcts. One of the most significant events known to trigger
plaque embolisation is surgical or interventional removal of the atheroma. This
mechanical disruption of the plaque quite often releases a shower of emboli
downstream, with frequent intra- or post- operative complications. Recent data from
The European Society of Cardiology (ESC) confirms that distal embolisation is a
relatively common event, particularly during high-risk interventions such as in cases
treating saphenous vein grafts (SVG) and acute myocardial infarctions (AMIs), and can
produce serious complications including heart attacks and strokes. This has lead to the
development of devices to help prevent periprocedural distal embolisation, known as
Embolic Protection Devices (EPDs).
Current Products
Currently there are 3 different types of cerebral embolic protection devices: filters,
distal occlusion balloons, and proximal occlusion balloons.
Distal Filter Devices
These are positioned distally to the area of treatment in order to trap the debris during
the procedure. They are the easiest to use, do not interrupt antegrade flow, and allow
for contrast injection during the procedure for lesion and arterial visualization.
Arguably the best known distal filter system is the FilterWire EZ™ Embolic Protection
System developed by Boston Scientific. This device uses a suspended loop design and
placement in curved vessels with good vessel wall apposition. The conforming filter
frame is designed to ensure reliable wall apposition in varying vessels sizes and
changes of vessel structures. The advantage with this form of system is that it maintains
flow while capturing liberated debris. Originally the safety and performance of the
FilterWire EZ System was evaluated in the CABERNET Trial in conjunction with the
recently approved NexStent® Carotid Stent and Monorail® Delivery System. Later the
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FIRE trial and BLAZE register demonstrated the safety and efficacy of the FilterWire
EX™ Embolic Protection System during angioplasty/stenting of saphenous vein grafts
comparing it to the PercuSurge GuardWire Plus® System.
The FilterWire EZ™ Embolic Protection System was cleared by the FDA in August
2004 for use in coronary saphenous vein graft (SVG) interventions. Boston Scientific
announced in the press release that the FilterWire EZ™ Embolic Protection System had
undergone a number of product modifications including a new suspended loop design,
a new pre-loaded, peel-away delivery sheath and improved delivery and lesion crossing
using a silicone coating on the spring tip. A further announcement was made by Boston
Scientific on the 14th December 2006 that they had received FDA approval to market
the FilterWire EZ™ Embolic Protection System for use in carotid artery stenting
(CAS) procedures. The FilterWire EZ™ Embolic Protection System is currently the
market-leading embolic protection device for carotid artery stenting procedures outside
the U.S.
Another well-known and renowned distal filter device known as the RX ACCUNET™
Embolic Protection System had originally been developed and marketed by Guidant for
use with the FDA-approved RX ACCULINK® Carotid Stent System. As a result of the
head lined and protracted competitive acquisition of Guidant by Boston Scientific in
April 2006 Guidant was required by the Federal Trade Commission (FTC) and the
European Commission to comply with their antitrust laws by completing the
acquisition of Guidant’s vascular intervention and endovascular business by Abbott.
This product is currently only available in the United States. Guidant originally
designed a post-approval study of carotid artery stenting in high surgical risk patients,
called CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover
Rare Events) in March 2006. The latest data from this and the Emboshield and Xact
Post Approval Carotid Stent Trial (EXACT) was presented at the 3rd April i2 Summit
2007. This was a program run in tandem with the American College of Cardiology
(ACC) 2007 Scientific Sessions and cosponsored by the ACC and the Society for
Cardiovascular Angiography and Interventions (SCAI). The results demonstrated a
“pleasing trend" with respect to reductions in death and stroke rates across the studies,
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in both symptomatic and asymptomatic patients. Abbott Vascular continues to market
and promote both the RX ACCULINK® Carotid Stent System and the RX
ACCUNET™ Embolic Protection System in the United States.
The Rubicon Filter System (Rubicon Filter, made by Boston Scientific Corp. and
Rubicon Medical Corp.) is a third filter DPD system that includes the Constraint And
Remote Actuating Technology (CARAT(TM)) platform. Other ancillary components
supplied with the system for convenience of use include an introducer, a syringe for
flushing the capture catheter, and two torque devices. On the 14th April 2005, the
European Commission approved for use in the European Union (EU) an embolic
protection system (Rubicon Filter, made by Boston Scientific Corp. and Rubicon
Medical Corp.) for the prevention of distal embolization in saphenous vein graft
(SVG), native coronary artery, and carotid artery interventional procedures. Two
separate trials were conducted to determine the safety and efficiency of the product in
Europe. The RULE-SVG study involved 54 patients with either SVG or native
coronary artery disease and included a number of high-risk stenting procedures. The
second trial was the RULE-Carotid study, where the device was employed in 60
patients with significantly blocked carotid arteries.
The device has not been approved by the FDA; its application in SVG procedures is
currently being investigated in U.S. clinical studies.
A fourth system has been developed by EV3 Inc and is known as the SpiderFX™
Embolic Protection Device. The SpiderFX™ Embolic Protection Device is indicated
for use in removing embolic material (thrombus/debris) while performing angioplasty
and stenting procedures in carotid arteries and in coronary saphenous vein bypass
grafts. It is available in both the US and Internationally. EV3 Inc announced on the 27th
January 2007 that the new carotid stent the Protégé® RX had been approved by the
U.S. Food and Drug Administration for marketing in the U.S. The Protégé is a self-
expanding Nitinol stent which is part of a carotid stent system when paired with eV3's
SpideRX® Embolic Protection Device.
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On the 8th January 2007 EV3 announced that they and FoxHollow Technologies, Inc.
had entered into an agreement to conduct a joint clinical study of FoxHollow's calcium
cutting device (The RockHawk) and ev3's SpideRX endovascular devices to seek
approval for the treatment of calcified lesions in peripheral artery disease. As part of
the agreement, FoxHollow will have the exclusive right to market the two devices
together in the United States. The RockHawk device, currently under development, is a
specialized version of FoxHollow's SilverHawk(R) Plaque Excision System that is
optimized for the treatment of calcified lesions in the peripheral arteries.
On the 3rd April 2007 EV3 announced that they have entered into a joint marketing and
distribution agreement with Volcano Corporation. Under the terms of the agreement,
Volcano will have the opportunity to sell ev3's SpiderFX Embolic Protection Device in
conjunction with their Intravascular Ultrasound (IVUS) and Functional Measurement
(FM) devices for use in saphenous vein grafts (SVG's) in the U.S.
Distal Balloon Occlusive Devices
Distal balloon occlusive devices temporarily occlude the vessel distally to the lesion
during the intervention, thereby capturing and aspirating the atheromatous and
thrombotic debris liberated by the lesion before it reaches the capillary bed. Distal
balloon occlusion embolic protection devices typically consist of a hollow wire with an
inflatable occlusion balloon at the distal tip. The balloon is inflated to occlude the
artery distal to the treated lesion, where embolic particles are captured and removed
either via an aspiration catheter, or flushing toward the external carotid artery. The
main advantage with such devices is complete protection by capturing particles of all
sizes. In addition, distal balloon systems usually have a smaller crossing profile and are
more flexible than distal filter systems; however, the interruption of blood flow during
protection, while tolerated by most, may lead to complications in some patients.
The largest experience with distal protection devices comes from the PercuSurge-
GuideWire, an occlusive balloon device. The PercuSurge-GuideWire was
commercially released in the United States in June 2001 and had been commercially
54
available in Europe since 1999. Percusurge Inc was acquired by Medtronic in October
2000 for $225 million and has since been discontinued and replaced by the Guardwire
Temporary Occlusion and Aspiration System from Medtronic.
Another system emerging as a market leader is the TriActiv FX® Embolic Protection
System manufactured and marketed by Kensey Nash. In December 2001, Kensey Nash
announced commencement of the 50-site, 800-patient ‘Protection During Saphenous
Vein Graft Intervention to Prevent Distal Embolization (PRIDE)’ randomized trial for
its TriActiv Balloon Protected Flush Extraction System. In January 2002, the company
received CE-Mark approval for the device, allowing its sale within the EU. In March
2005 Kensey Nash began enrolling patients into the ASPIRE (Angioplasty in SVGs
with Post Intervention Removal of Embolic Debris). The enrollment was completed in
November 2005. In March 2006 Kensey Nash announced the results of this trial at the
American College of Cardiology (ACC) conference in Atlanta, Georgia. In January of
the same year Kensey Nash Corporation submitted a 510(k) application to the U.S.
Food and Drug Administration (FDA) for the new TriActiv FX(R) System. In July
2006 Kensey Nash announced that it has received 510(k) clearance for the next
generation TriActiv FX(R) Embolic Protection System from FDA.
Proximal Balloon Occlusive Devices
These temporarily occlude the vessel proximally to the lesion during the intervention.
Proximal occlusion balloons with flow reversal are placed before the lesion is accessed
and are therefore the only type of device that allows crossing of the stenosis under
protection.
ArteriA Medical Science developed the Parodi Anti-Emboli System (PAES), which
had been marketed throughout Europe under CE-Mark approval for the prevention of
cerebral embolization during peripheral angioplasty and stenting procedures. Contrary
to distal balloon occlusion systems, the unique PAES proximal balloon occlusion
device never had to cross the lesion without protection already in place. On November
18th 2004 Gore Medical announced that they had acquired all of the assets of ArteriA
55
Medical Systems. The Parodi Anti-Emboli System (PAES) was replaced by the GORE
Neuro Protection System, also developed by Dr Juan Parodi, and in July 2006 Gore
announced that they had started to enroll patients into the EMPiRE (Embolic Protection
with flow Reversal) Clinical Study.
A second proximal balloon protection device known as The Mo.Ma Proximal Flow
Blockage Cerebral Protection Device from the Italian company Invatec is another
example of a proximal balloon occlusive device. The Mo.Ma protects the brain from
embolization by two highly compliant atraumatic balloons, blocking antegrade blood
flow from the CCA (Common Carotid Artery) and retrograde blood flow from the ECA
(External Carotid Artery).
A third example of a proximal balloon protection device is the Proxis (TM) embolic
protection device from St Jude Medical. The Proxis Embolic Protection System was
originally developed by Velocimed, LLC ("Velocimed"), a privately-owned company
located in Maple Grove, Minnesota. Velocimed, LLC was acquired by St Jude Medical
in early 2005 and on the 23rd May 2005 they announced the launch of the Premere(TM)
PFO closure device, the Proxis(TM) embolic protection device, and the Venture(TM)
wire control catheter at the EuroPCR 2005 meeting in Paris, France.
The Proxis(TM) embolic protection device is currently under review by the U.S. Food
and Drug Administration (FDA) and was included in a study known as the
PROXIMAL Embolic Protection Trial. The PROMIXAL trial assessed whether Proxis
was substantially equivalent to previously-cleared devices as determined by the rate of
major adverse cardiac events (MACE) at 30 days, the primary endpoint of the trial.
Proxis proved equivalent to previously-cleared devices.
Development Stage Products and Current Status
Liquid Embolism Protection Technologies or Occlusive Gels (Gore Medical)
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W. L. Gore & Associates, Inc. (Gore) announced on the 7th July that they had acquired
Neural Intervention Technologies, Inc. a medical device company developing a novel
liquid embolic material for the treatment of blood vessel defects.
NIT was founded in 2003 based on the ALGEL™ technology developed by Drs.
Timothy Becker and Daryl Kipke and licensed from the University of Michigan and
AzTE, a technology transfer company for Arizona State University. The ALGEL
product now known as the GORE Embolic Liquid (GEL) is an alginate based embolic
material designed to fill blood vessel defects thereby displacing blood pressure effects
and preventing vessel rupture. The material is delivered by microcatheters using a
controlled delivery system for the treatment of vascular diseases such as cerebral
Arteriovenous Malformations (AVMs) and aneurysms
Gore Medical announced on the 20th December 2006 that they had successfully treated
the first patient using the GORE Embolic Liquid (GEL) in the MAGELAN trial
(prospective Multicentre feAsibility trial to evaluate the safety and performance of
Gore Embolic Liquid used in presurgical embolisation of cerebral arteriovenous
malformatioN). The first phase of the study is expected to include ten to twenty five
patients and is designed to demonstrate the safety and performance of the liquid.
AEPD (MIV Therapeutics Inc)
On the 18th March 2005 MIV Therapeutics, Inc. a developer of next-generation
biocompatible coatings and drug delivery technologies, announced that they executed
an agreement to acquire SagaX Medical Technologies Inc. SagaX Medical
Technologies Inc., a research and development centre in Herzliya, Israel had been
developing a proprietary Aortic Embolic Protection Device (AEPD). The AEPD filters
the blood in the aorta - one of the main arteries directing blood to the brain -- capturing
embolic particles originating in the heart released during heart surgery and other
invasive cardiology procedures. This filtration prevents the embolic particles from
traveling upstream in the direction of the patient's brain.
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On March 10th 2006 MIV Therapeutics Inc announced that based on the favorable
preclinical studies conducted after the acquisition of SagaX Medical Technologies Inc
it had accelerated development of AEPD device for surgical patients. At that time MIV
Therapeutics Inc through its SagaX subsidiary were seeking to have the device ready
for clinical use within 14 months, subject to regulatory approval.
In August 2006 MIV Therapeutics, Inc were invited to present their Aortic Embolic
Protection Device (AEPD) technology to the 18th Annual Scientific Symposium of
Transcatheter Cardiovascular Therapeutics (TCT) October 2006.
FiberNet® Embolic Protection System (Lumen Biomedical)
In July 2003 Lumen Biomedical, Inc. was founded with the goal of developing and
commercializing a unique and improved embolic protection device known as the
FiberNet® Embolic Protection System. The FiberNet® Embolic Protection system
consists of an expandable filter mounted on a 0.014” wire, along with a rapid exchange
focal-suction retrieval catheter. The filter is composed of numerous strands of polymer
fibers, bundled to form a cartridge. When the device is deployed, the filter strands flare
out radially, seeks the vessel wall and completely fills the vessel. The filter fibers are of
sufficient density to efficiently trap very small particulate matter (≥40 microns), while
simultaneously allowing blood flow. Upon completion of the intervention, the filter is
brought down and retracted into the focal-suction retrieval catheter.
This product is currently only available for investigational use, and a number of clinical
trials are underway to determine the safety and efficacy of the product. These trials
include The EPIC European Study, The EPIC US Feasibility Study, The RETRIEVE
European Study, the New Zealand Multi-Center Clinical Embolic Protection Device
Trial (NET) and the Novel Embolic protection Trial - Peripheral Vasculature (NET-
PV). Enrollment for these studies is presently underway, and once completed larger
pivotal studies will be instigated.
Watchman (Atritech)
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Atritech is an emerging medical device company focused on preventing atrial
fibrillation (AF) related stroke through technology. Atritech is currently conducting a
pivotal study of the WATCHMAN® system in the United States known as the
PROTECT AF Study (Protect AF - WATCHMAN Left Atrial Appendage System for
Embolic PROTECTion in Patients with Atrial Fibrillation). The PROTECT AF study
has been designed to demonstrate the safety and efficacy of the WATCHMAN® device
in patients with non-valvular atrial fibrillation who require treatment for potential
thrombus formation. In addition participants must be eligible for warfarin therapy and
who have at least one of the following risk factors: Congestive heart failure,
Hypertension, Age 75+ years, Diabetes mellitus and/or prior Stroke or TIA. Currently
this study is in Phase III and is due for completion in 2008.
The WATCHMAN® left atrial appendage system is made of nitinol (a self expanding
metal) with the atrial facing surface covered with a thin permeable polyester material.
The device is constrained within a catheter until delivery in the LAA and is available in
multiple sizes to accommodate the unique anatomy of each patient.
Future Technologies and Trends
While embolic protection devices are quickly becoming standard of care for carotid
artery stenting and interventions for degenerated saphenous vein grafts, their full
potential is likely to be realized if they can be used successfully for acute coronary
syndrome (ACS). Several issues may need to be addressed in greater detail before these
devices can be used routinely for ACS interventions. For example, how effective will
these devices be to capture microemboli smaller than 100 um? What are the risks of
inducing vessel injury when introducing the devices through small caliber coronaries?
Regardless of these and other questions, DPDs represent an exciting, useful new
technology, and refinements to existing DPDs will continue to expand their use in
interventional cardiology.
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Coronary Atherectomy
These procedures are sometimes used in during angioplasty to help clear plaque as an
adjunct to balloon angioplasty and stenting. There are a number of technologies
currently available as follows:
Rotational Coronary Atherectomy (Rotoblation)
These devices consist of a special catheter, with an acorn-shaped, diamond-coated tip
(the burr) which is guided to the point of narrowing in your coronary artery over a thin
guide wire and is driven by an air turbine. The tip spins at a high speed and grinds
away the plaque on your artery walls. The microscopic particles are washed safely
away into blood stream and filtered out by your liver and spleen. This process is
repeated as needed to allow for better blood flow. The RotaLink® Plus System from
Boston Scientific Corporation is the dominant product in the market.
Another device known as the SilverHawk® Plaque Excision System (Foxhollow) is a
device used to remove plaque that commonly blocks arteries and interrupts blood flow.
Unlike stenting and other methods of opening the artery, the SilverHawk removes the
source of the problem – plaque build-up – instead of simply compressing it against the
vessel wall. The SilverHawk® Plaque Excision System is available in both Europe and
the United States.
Directional Coronary Atherectomy (DCA)
These devices allow the cutting of plaque from a blocked artery to restore blood flow.
Often this method is used when plaque is too hard to use a balloon angioplasty. In a
directional coronary artherectomy, the catheter tip is equipped with a bladed device
that cuts away the plaque and stores the little pieces in a tiny container. The plaque is
removed when the catheter is withdrawn from the artery. This technique also is useful
in larger arteries with "softer" plaque. The FLEXI-CUT Directional Debulking System
is the newest DCA from Abbott Vascular.
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Orbital Atherectomy
Orbital atherectomy technology is the proprietary technologies of Cardiovascular
Systems Inc. The device consists of an eccentrically shaped wire coil that rotates a
diamond-coated ablating crown at high speed in an orbital path around the periphery of
the lumen. Use of an orbital rather than rotational motion creates lateral pressure
between the atherosclerotic plaque and the ablating crown, thereby minimizing the risk
of deep vascular injury that is associated with other transluminal interventions.
The design also allows blood and saline to flow through the treatment area, thereby
minimizing the risk of thermal trauma and ischemia.
In January 2005 CSI received clearance from the FDA to market the orbital
atherectomy system (OAS) for the purpose of treating stenosis in synthetic
arteriovenous shunts, used to provide vascular access for dialysis patients. On May 19
2005, the European Commission approved a peripheral atherectomy device (Orbital,
made by Cardiovascular Systems, Inc.) for the treatment of peripheral artery disease in
countries within the EU.
Ablative laser-assisted angioplasty
During the 1980s, a variety of different laser types were examined to determine their
efficacy and safety for use in coronary angioplasty. The first two lasers examined were
Argon (514 nm) and Nd:YAG (neodymium:yttrium-aluminum-garnet) (1060 nm)
continuous wave lasers. These lasers were used to destroy atherosclerotic lesions
primarily via non-specific thermal action; in essence they burn the lesion.
Unfortunately, both argon and Nd:YAG continuous wave induced considerable thermal
damage to surrounding vessel tissue.
Since then an alternative laser technology, the excimer laser has been used for the
ablation of obstructive coronary lesions. Its active medium is composed of rare gas
halides (binary halogens) that emit light in the ultra-violet spectrum. The laser-light
energy forces electrons from atoms, splitting chemical bonds. Thus the atherosclerotic
61
lesion is destroyed in a photoablative rather than a thermal fashion. Fortunately, ultra-
violet excimer lasers have proved more effective at clearing coronary lesions than other
lasers evaluated, and are associated with little corollary thermal damage. Results from
the use of excimer lasers have been encouraging but not altogether satisfactory. There
have been reported improvements to the outcomes of complex lesions but others have
reported serious complications, predominantly related to the damage of neighboring,
healthy vessel tissue.
The Spectranetics CVX-300® excimer laser system is an example of a photoablative
technology system. It is used to treat complex cardiovascular disease by ablating
plaque, thrombus and calcium into tiny particles that are easily absorbed into the blood
stream. The disposable catheters use high-energy “cool” ultraviolet light to remove
arterial blockages in the legs and heart, as well as the scar tissue holding problematic
cardiac leads in place, reducing complications and improving clinical outcomes. The
Spectranetics excimer laser system is the only excimer laser system approved in the
United States and Europe for use in multiple, minimally invasive cardiovascular
applications.
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63
CHAPTER 3
EMERGING CORONARY STENTS AND STENT SYSTEMS
64
Chapter 3 Emerging Coronary Stents and Stent Systems
Summary
Current estimates show that 95.9% of all PCI procedures in 2006 included a coronary stent of one sort or another (BMS or DES).
The world-wide market for coronary stents was valued at $6.18 billion in 2006, with a projected value of $13.34 billion by the year 2013 (CAGR 11.6%).
The worldwide market for DES’s has been valued at $5.14 billion in 2006, and is expected to increase to $12.40 billion by the year 2013 (CAGR 13.4%). The world market for BMS’s is currently valued at $1.04 billion but is expected to decline in value to $0.94 billion by the end of the forecast period (CAGR –1.4%).
There are now four major manufacturers of coronary stents. These are Cordis (Johnson & Johnson), Boston Scientific Corporation, Medtronic and Abbott Laboratories (Abbott Vascular).
There are concerns amongst clinicians about a number of problems or complications associated with drug-eluting stents. These complications are primarily concerned with late developing stent thrombosis (LDST), allergic inflammatory reactions, long term antiplatelet therapy and non-compliance.
Recent Developments include the use of bioabsorbable stents from poly L-lactic acid (PLLA). Several stent designs have been built using PLLA mono filaments and appear to be a viable alternative to metal in some preliminary studies.
Other novel technological developments include Absorbable Metal Stent (AMS) Technologies, the development of novel coating technologies, gene therapy technologies and its potential use to prevent restenosis, coronary stents and Endothelial Progenitor Cells (EPCs), nanotechnologies and drug-eluting coronary stents, development of novel Estradiol containing drug-eluting stents, development of regenerative stents using stem-cell derived endovascular cells.
65
Emerging Coronary Stents and Stent Systems
Key Events
The term “stent” originated from the English dentist Charles Stent in the 19th Century
after he developed a mold with which he formed an impression of the teeth and oral
cavity. The term "stent" later became associated with a device that held a skin graft in
position, a support for tubular structures that were being anastomosed, and more
recently, an endovascular scaffolding to relieve and prevent vascular obstructions. In
1964 Charles Dotter developed the concept of using a prosthetic device which would
maintain the integrity of the lumen of diseased vessels.
Despite the poor results of the original non surgical developments Charles Dotter
developed some new devices in the 1980s made from "memory metal" nitinol. The
potential for the use of such a device in the nonsurgical treatment of vascular disease
had become self-evident, and experimentation with a variety of innovative devices
started. The concept of a stent mounted on a balloon was introduced by Palmaz in 1985
when he implanted woven stainless steel grafts mounted on angioplasty balloon
catheters into dogs. Jacques Puel in Toulouse, France, and shortly afterward Ulrich
Sigwart in Lausanne, Switzerland, implanted the first stents in human coronary arteries
in 1986; between 1987 through 1989 Schatz maintained a multicenter registry of
elective Palmaz-Schatz stent implantations in native coronary arteries.
The first coronary stent to be approved for clinical use was Cook’s Gianturco-Roubin
Stent (GRS). Its approved indication for use was not for the prevention of restenosis,
but for the prevention of abrupt closure of an artery following balloon angioplasty.
Abrupt closure is the sudden collapse and constriction of an artery shortly after
removal of the angioplasty balloon, resulting in complete blockage of blood flow in the
vessel. This condition occurs in 2-10% of all angioplasty procedures.
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Prior to the introduction of stents, abrupt closure generally necessitated emergency
bypass surgery. The Cook GRS stent, which employed a coil design, was effective in
preventing abrupt closure, but at least based on the results of early experience with the
device did not reduce restenosis to a clinically significant degree. The Palmaz-Schatz
slotted-tube stent, developed by Johnson & Johnson Interventional Systems, was
shown to produce a clinically significant reduction in restenosis. Results from the
ongoing STRESS trial demonstrated that patients receiving the Palmaz-Schatz stent
experienced a restenosis rate of only 15% versus a rate of 30% for patients treated with
balloon angioplasty alone. Based on the results of that study, the Palmaz-Schatz stent
was rapidly adopted throughout Europe and the U.S. for reducing the rate of restenosis
following balloon angioplasty. Since the early to mid 1990s a diverse variety of stents
have become clinically available, varying in composition, configuration, and size.
These included the Wallstent, Palmaz-Schatz stent, Wiktor stent, Gianturco-Roubin
stent, Cordis stent, AVE stent, and multilink stent.
Stents are made from metal, and in every design, a compromise is made between
scaffolding properties and flexibility. Metals induce a varying degree of
thrombogenesis, necessitating anticoagulation or antiplatelet therapy, and induce
significant intimal hyperplasia; both factors that discourage the use of stents in small
vessels or in situations of diminished flow. Furthermore, the long-term effects of a
metallic prosthesis within the vascular system, although seemingly benign, are
unknown.
Some of the developments that occurred during the late 1990s included the
investigation of surface charge and texture of stents by galvanization and ion
bombardment. Palmaz-Schatz stents coated with platinum, gold, and copper alter both
the surface charge and texture, consequently affecting the surface charge and texture.
Similarly developments took place examining the development of stents made of
materials that can be degraded or absorbed. Bioabsorbable polymers may for example
help avoid the potential for late complications and thus have the potential to prevent
elastic recoil, thrombosis, neointimal proliferation, and systemic side effects.
67
However, in spite of these developments the major problem encountered with modern
coronary stents is that of in-stent restenosis due to the proliferation of intimal tissues
within the stent which can lead to the necessity of reintervention. Current rates of in-
stent restenosis are between 15-25 percent. Management of in-stent restenosis has been
difficult, and as more complex lesions are now being treated, the magnitude of the
problem has become a source of concern among cardiologists. Recent technological
advancements such as intravascular brachytherapy and drug-eluting stents—developed
specifically for the prevention of in-stent restenosis—indicate that this problem also
will eventually be resolved, removing any remaining barriers to widespread adoption of
stents for CAD treatment.
Introduction of Drug-Eluting Stents (DES)
Considerable advances have been made since the late 1990s into resolving the problem
of restenosis and research focused on the use of pharmaceuticals rather than purely
mechanical devices as a means of reducing the incidence of restoisis. The concept is to
combine the principle of mechanical scaffolding (stent) with that of local
pharmacological action (drug). The ultimate goal is to provide a controlled, local
release of an efficient drug that inhibits the development of neointimal hyperplasia
from the stent surface. This research led to the creation of stents known as Drug-
Eluting Stents (DES) which deliver prolonged and sufficient drug concentrations to
overcome the problems associated with restenosis. There are three distinct components
of a DES system which need to be compatible with each other in order to work
properly i.e. the stent that carried the drug coating, the carrier vehicle (polymer) and
the drug. The various drugs have been incorporated into stents, or "active" stents.
Categories can be divided into: (i) anti-inflammatories, (ii)metalloproteinase inhibitors,
(iii) NO donors, (iv) anti-sclerosing agents, (v) antiproliferatives, (vi) anti-neoplastics
and (vii) “molecular” approaches (genes, cells, antisense).
The emergence of drug-eluting stents as a breakthrough technology has been heralded
as the dawning of a new era of cardiovascular treatments, and since their introduction
have had a dramatic impact on the growth and development of coronary stents
worldwide. Figure 2.2 illustrates the market development of Bare Metal Stents (BMSs)
68
throughout the 1990s and the impact on the market following the launch of Drug-
Eluting Stents (DESs) at the beginning of the new millenium as a percentage of the
total number of PCI procedures in Europe.
Current estimates show that in 2006 95.9% of all PCI procedures included a coronary
stent of one sort or another (BMS or DES). The proportion of drug-eluting stents had
increased from 2.6% in 2002 to 68.9% in 2006. It is anticipated that by 2012, given the
current market knowledge and the development in the structure of the coronary stent
marketplace, drug-eluting stents will be used in approximately 79.8% of PCI
procedures in Europe. These predictions are based on the following assumptions; drug-
eluting stents continue to provide proven efficacy in clinical trials and reduce the level
of restenosis compared to those highlighted in earlier trials, suitable funding is made
available through the national healthcare reimbursement structures, drug-eluting stents
become more readily accepted amongst interventional cardiologists as the method of
choice, and there is increased product choice from companies obtaining marketing
approval in Europe.
69
Figure 3.4: Estimated number of Stent Procedures (BMS & DES) % Total Number of PTCA Procedures
0
20
40
60
80
100
120
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
*
2008
*
2009
*
2010
*
2011
*
2012
*
% o
f Pro
cedu
res
% + Stent BMS DES
Source: British Cardiovascular Intervention Society (BCIS), European Society of Cardiology (ESC) and National Cardiovascular Societies Business Insights Ltd
* Estimate
70
Development of Drug-Eluting Stents
A large number of clinical trails/studies have been, and continue to be, conducted to
determine both the safety and efficacy of drug-eluting stents. Specifically, initial
studies have been conducted to determine the safety and efficacy of sirolimus and
paclitaxel-eluting stents.
Sirolimus (Rapamycin)
Sirolimus (rapamycin) occurs naturally and is a macrocyclic lactone with a potent
immunosuppressive action. It inhibits cellular proliferation by blocking cell cycle
progression in the G1-S interphase. The first published pilot trial of a sirolimus-coated
stent in humans was the First in Man (FIM) study. This was conducted in São Paulo,
Brazil on thirty consecutive patients. Each patient received a single 18-mm sirolimus-
coated BX Velocity stent (Cordis Corp.). Each stent contained sirolimus 140 µg/cm[2]
blended with a mixture of nonerodable polymers. Fifteen patients received a fast-
release formulation (< 15-day drug release), and 15 patients received a slow-release
formulation (>/= 28-day release). An additional 15 patients in Rotterdam, The
Netherlands, received the slow-release formulation.
The first-in-man study was quickly followed by the RAVEL trial (RAndomized study
with the sirolimus-eluting Bx VELocityTM balloon expandable stent), a multicenter,
larger-scale trial designed to determine the safety and efficacy of the use of sirolimus-
eluting versus uncoated stainless steel stents in patients with de novo coronary lesions.
The FIM and RAVEL trials were then followed by the SIRIUS trial (SIRolImUS-
Coated BX Velocity Balloon-Expandable Stent in the Treatment of Patients with De
Novo Coronary Artery Lesions) and the European equivalent known as the E-SIRIUS
Study.
The DIRECT trial, supported by Cordis (J&J) compared the results of “direct stenting”
(stent placement without balloon pre-dilation) with those obtained using conventional
balloon pre-dilatation in the Sirius trial. In March 2004, results of the DIRECT trial
71
showed that the Cypher sirolimus-eluting coronary stent yields the same strong patient
outcomes with or without balloon pre-dilatation. In April 2002, Cordis received CE
mark approval to market its Cypher Select sirolimus-eluting coronary stent in the EU,
and gained FDA approval for the treatment of in-stent restenosis in the United States
on April 24th 2003.
Paclitaxel
A naturally occuring antitumour drug, Paclitaxel is a microtubule-stabilizing agent. It
induces abnormal polymerization of tubulin, forming stable but dysfunctional
microtubules - thereby blocking the mitotic cycle at the metaphase/anaphase transition.
A number of trials have been conducted to determine the efficacy of Paclitaxel. The
TAXUS I study was the first experience with a paclitaxel-eluting stent in humans. The
objective of this trial was to compare the safety of the TAXUS® NIR® Paclitaxel-
Eluting Stent to uncoated control NIR® Stent. The original TAXUS I study included a
total of sixty-one patients who were randomized to either a single 15-mm TAXUS
NIRx paclitaxel-eluting stent (Boston Scientific Corporation) or a similar stent (NIR
stent; Medinol Ltd., Jerusalem, Israel) without drug. This was followed by a series of
other TAXUS studies. Based on the results of this study the TAXUS™ paclitaxel-
eluting coronary stent system was launched by Boston Scientific in Europe during
February 2003. This was followed by an announcement that Boston Scientific
Corporation had received approval from the U.S. Food and Drug Administration (FDA)
to market the TAXUS™ Express2™ paclitaxel-eluting coronary stent system in the
United States on the 4th March 2004. Boston Scientific Corporation announced on the
3rd April 2007 that they had received approval from the Japanese Ministry of Health,
Labor and Welfare (MHLW) to market the TAXUS® Express2™ paclitaxel-eluting
coronary stent system in Japan. The Company plans to launch the product after
reimbursement approval is granted.
Other key clinical trials used to determine the safety and efficacy of Paclitaxel include
the ASPECT (ASian Paclitaxel-Eluting stent Clinical Trial) trial. This was used to
evaluate a different type of paclitaxel-eluting stent than that used in the TAXUS trials
72
where no polymer was used to adhere paclitaxel to the stent. The ELUTES (The
European Evaluation of Paclitaxel-Eluting Stent) study was used to evaluate the
efficacy and safety of a nonpolymer paclitaxel-eluting stent using either the V Flex
Plus bare metal stent (Cook Inc.) as a control or one of four doses of paclitaxel: 0.2
µg/mm, 0.7 µg/mm, 1.4 µg/mm, or 2.7 µg/mm. Subsequent to this trial the paclitaxel V
Flex Plus PTX stent (Cook Inc.) has been approved for use in Europe. Due to patent
issues there are currently no plans to market the V Flex Plus PTX stent in the United
States.
The DELIVER clinical trial, a randomized U.S-based study comparing the paclitaxel-
coated ACHIEVE™ Drug Eluting Coronary Stent System manufactured by Cook
Incorporated to the PENTA™ Coronary Stent manufactured by Guidant. Cook
Incorporated's ACHIEVE™ paclitaxel-Eluting Coronary Stent System, which is used
to reduce the rate at which arteries reclog following angioplasty, received its CE Mark
approval for sale in Europe on the 3rd September 2002. On the 5th September 2002, just
a few days after receiving clearance to sell its ACHIEVE™ Drug Eluting Stent System
in Europe, Cook® received CE Mark approval to market its paclitaxel-coated V-Flex™
Plus PTX Coronary Stent System in the European Union.
Tacrolimus
Tacrolimus, a macrolide hydrophobic immunosupressant, anti-inflammatory and
topical immunodilator has been found to inhibit Neo intimal proliferation. Tacrolimus
inhibits the proliferation of smooth muscle cells with higher potency than endothelial
cells, thus allowing the rapid integration of the stent into the vessel wall. Tacrolimus is
being used in two studies being conducted by JOMED N.V. These trials are PRESENT
(The Preliminary Safety Evaluation of Nanoporous Tacrolimus eluting stents) which
was started in January 2002 and EVIDENT (The Endovascular Investigation
Determining the Safety of New Tacroliomus-eluting stent studying sephanous vein
graft stenosis) started in September 2002. Abbott acquired the assets of JOMED N.V’s
coronary and peripheral interventional business for approximately $68 million in cash
in 2003 and subsequently in early 2006 Abbott agreed to acquire Guidant’s
interventional vascular and endovascular solutions businesses for $4.1 billion in
73
connection with Boston Scientific’s acquisition of Guidant. Abbott would also pay
$250 million each upon government approvals to market Guidant’s drug-eluting stent
in the U.S. and in Japan.
Everolimus (RAD-001)
Everolimus is a relatively new mTOR (mammalian Target of Rapamycin) inhibitor
drug used as an immunosuppressant to prevent rejection of organ transplants. It, along
with other mTOR inhibitors, is used as a cancer suppressing drug. It is related to
sirolimus (Rapamycin), and works in the same way. The first trial carried out to
determine the efficacy of everolimus was known as FUTURE 1 (The First Use to
Underscore Reduction in Restenosis with Everolimus trial). This trial showed
impressive reductions in late in-stent lumen loss and restenosis in 42 patients who all
received the everolimus-coated Challenge stent (Biosensors International USA,
Newport Beach CA). A further trial known as FUTURE II was also conducted to
compare the everolimus-eluting stent against bare metal stents. A trial known as
SPIRIT FIRST was conducted to evaluate the safety and efficacy of an everolimus-
eluting cobalt chromium coronary stent among patients with a single de novo coronary
lesion. The results were presented at the 2005 Cardiovascular Research Therapeutics
Sessions, Washington D.C. Further large-scale pivotal clinical trials known as SPIRIT
II and SPIRIT III were conducted to compare XIENCE V to the TAXUS paclitaxel
eluting coronary stent system. 6 month results of these trials were presented at the
European Society of Cardiology Scientific Congress in September 2006. Twelve-
month results from SPIRIT II and nine-month results from SPIRIT III will be presented
in the first half of 2007.
Zotarolimus (also called ABT-578)
Zotarolimus is a patent-protected compound licensed to Medtronic by Abbott
Laboratories. Zotarolimus inhibits smooth muscle cell proliferation – believed to be a
key contributor to restenosis, or the reclogging of arteries – by blocking the function of
the cell cycle regulatory protein mTOR. By inhibiting the mTOR function, zotarolimus
blocks progression of the cell cycle, potentially inhibiting the growth of new tissue.
74
Medtronic have conducted a number of trials under the name of ENDEAVOR. The first
trial, ENDEAVOR I began in 2003 and was conducted at sites in Australia and New
Zealand. Preliminary ENDEAVOR I 12-month results were released in May at
EuroPCR in Paris and final 12-month results were released in August 2004 at the
European Society of Cardiologists (ESC) in Munich.
The ENDEAVOR II Pivotal Clinical Trial completed enrollment of 1,200 patients in
January 2004. ENDEAVOR II is a randomized, double-blind trial that evaluated the
safety and efficacy of the Endeavor Drug-Eluting Coronary Stent compared to the
Driver™ cobalt alloy stent and will support product approvals in various countries.
Thirty-day results from the trial were released at EuroPCR in May 2004 and the 8/9-
month data was presented at the American College of Cardiology (ACC) meeting in
March 2005 and at PCR in May 2005.
The ENDEAVOR III Clinical Trial completed enrollment in September 2004 and is a
confirmatory, randomized trial evaluating the safety and efficacy of the Endeavor Drug
Eluting Coronary Stent as compared to the Cypher™ Sirolimus-eluting stent marketed
by Cordis Corporation.
DES – Recent News, Product Developments and Clinical Trial Updates
The market for drug-eluting stents continues to evolve through research and
development into new and innovative technologies by both the market leaders and new
start-up companies using clinical trials to provide proof of safety and efficacy. This
includes the extension of existing trials to substantiate the results of previous studies,
determine the long-term safety of drug-eluting stents as well as initiating new trials to
evaluate new products. Some of the recent product developments and clinical trial
updates are provided below.
The results of the large-scale pivotal clinical trials known as SPIRIT II (European
AND Asia-Pacific) and SPIRIT III (United States and Japan) comparing XIENCE V to
the TAXUS paclitaxel eluting coronary stent system were presented at the American
75
College of Cardiology’s 56th Annual Scientific Session in New Orleans in March
2007. The results showed a statistically significant reduction in major adverse cardiac
events (MACE) favoring XIENCE V to the TAXUS. SPIRIT IV is currently enrolling
patients and will evaluate the safety and efficacy of XIENCE V for the treatment of
coronary artery disease in a more complex patient population in the United States.
SPIRIT V is an international clinical trial that will provide additional clinical
experience with XIENCE V in approximately 3,000 patients at 100 clinical sites
throughout Europe, Asia, Canada and Latin America. SPIRIT WOMEN is the world’s
first drug-eluting stent trial to study only women and will evaluate the characteristics of
women undergoing stent implantation as well as the performance of XIENCE V in
those patients in Europe, Asia-Pacific, Canada and Latin America.
On the 1st September 2006 Boston Scientific Corporation announced that they were
planning to launch the Abbott's XIENCE™ V Everolimus-Eluting Coronary Stent
System (distributed by Boston Scientific as the PROMUS Stent) internationally
through a distribution agreement established between Abbott Vascular and Boston
Scientific Corporation. The PROMUS Stent received CE Mark approval in October
2006 allowing Boston Scientific to distribute the stent in select countries of the
European Economic Area. It will also be available in selected countries in Asia, Latin
America and Eastern Europe. Pending U.S. Food and Drug Administration (FDA)
approval, the PROMUS Stent is expected to become available in the United States in
the first half of 2008.
Medtronic recently announced that it has received reimbursement approval in France
for the Endeavor® drug-eluting coronary stent (DES) system. The announcement was
made following publication in the official French government journal, “Journal Officiel
de la République Française,” on June 8, 2006. The company said the stent will be
available June 21 to public and private hospitals throughout France, providing
physicians and patients with a clinically-proven option for the treatment of coronary
artery disease in one of the largest DES markets in Europe. The Endeavor stent is not
yet available in the United States. However, Medtronic filed its first Pre-Market
Approval module with the U.S. Food and Drug Administration last October and the
76
company expects FDA approval in mid-2007 based on the results of the ENDEAVOR
IV study. The Endeavor stent has been commercially available in most of Europe and
in many other international markets since August 2005. Medtronic subsequently
announced in October 2006 that it would begin a new, large-scale clinical trial focusing
on the safety of drug-eluting stents. This trial known as PROTECT (Patient Related
OuTcomes with Endeavor versus Cypher stenting Trial) will be the largest randomized
stent trial ever conducted to assess and compare key safety measures of two drug-
eluting stents. The trial will compare the Medtronic Endeavor® zotarolimus-eluting
coronary stent system and the Johnson & Johnson Cypher® sirolimus-eluting stent.
Medtronic has reaffirmed its commitment to the drug-eluting market through the
development of its second generation drug-eluting stent the Endeavor RESOLUTE.
The Endeavor RESOLUTE is a zotarolimus-eluting stent system incorporating a
proprietary, new biocompatible polymer called BioLinx. Medtronic announced on the
25th October 2006 that the results of the first-in-man study of the RESOLUTE stent
system had proven positive
On the 22nd July 2004 Boston Scientific Corporation announced they had received an
Investigational Device Exemption from the U.S. Food and Drug Administration (FDA)
to begin its ATLAS clinical trial. ATLAS was the first clinical trial using Boston
Scientific's new Liberté coronary stent as a platform for its paclitaxel-eluting coronary
stent system.
Conor Medsystems (now part of Johnson and Johnson) announced on the 11th May
2006 that they had initiated the RAPID (Reduced Anti-platelet therapy with
Pimecrolimus Drug-eluting stent) clinical trial to evaluate the safety and efficacy of the
company's pimecrolimus-eluting cobalt chromium coronary stent system, known as
Corio™. Pimecrolimus, which was in-licensed by Conor from Novartis Pharma AG in
March 2006, is a cell-selective inhibitor of the production and release of pro-
inflammatory cytokines. Inflammation is believed to be one of the key mechanisms
causing restenosis, or the excess proliferation of vascular smooth muscle cells, as well
as other vascular diseases such as unstable plaques and diabetic lesions. Because
77
pimecrolimus is not an anti-mitotic compound, it is believed not to inhibit re-
endothelialization, or the growth of the endothelial cells that line the interior surface
and maintain the healthy functioning of blood vessels.
Market Developments and Forecasts for Drug-Eluting Stents
Figure 2.3 provides an analysis of the actual and predicted revenue growth for coronary
stents in the world. The world market for coronary stents in 2006 has been valued at
$6.18 bn, with a projected value of $13.34 billion by the year 2013 (CAGR 11.6%).
The world market for drug-eluting stents has been estimated to be valued at $5.14 bn in
2006 and is expected to increase in value to $12.40 bn by the year 2013 (CAGR
13.4%). The world market for bare metal stents is currently valued at $1.04 bn but is
expected to decline in value to $0.94 bn by the end of the forecast period (CAGR
1.4%).
The structure of the market in the different geographic regions comes as a result of the
disparity between the different reimbursement structures. For example, in the United
States Medicare Center for Medicare Services (CMS) established the reimbursement
policy for drug-eluting stents to be conditional to the FDA approval and pay
differentially for alternative stents so the hospitals are not penalized for using the more
expensive drug-eluting products. Growth in the market for drug-eluting stents has been
much slower as a result of disparate healthcare structures each having different
reimbursement systems which influences the choice of stent and the reimbursement
value.
Although these forecast figures represent the foreseeable market value for coronary
stents the latest evidence suggests that drug-eluting stents have a tendency to cause late
stent thrombosis or dangerous blood clots. The introduction of this market variable may
result in an increased use of bare metal stents and as a direct result of these concerns
the market has experienced slight decline in the usage rate of drug-eluting stents
particularly in the United States.
78
Figure 2.3 provides an analysis of the market shares in 2006 comparing the leading
suppliers of drug-eluting stents and bare metal stents. There are now four major
manufacturers of coronary stents. These are Cordis (Johnson & Johnson), Boston
Scientific Corporation, Medtronic and Abbott Laboratories (Abbott Vascular). Cordis
(Johnson & Johnson) and Boston Scientific Corporation have dominated the drug-
eluting stent market
Cordis Corporation (a subsidiary of Johnson & Johnson) has occupied the leading
position in the cardiology market for a number of years with a comprehensive portfolio
of interventional and minimally invasive products. Cordis also have a large and
sophisticated sales force operating throughout the world as well as strength in their
proprietary technologies and intellectual property. Currently Business Insights Ltd have
determined that despite the competitive activity primarily from Boston Scientific
Corporation and a variety of manufacturing issues with the Cypher Stent, they are
currently still the worlds largest supplier of drug-eluting stents with an estimated
market share of 43.5%.
Boston Scientific Corporation is currently the second largest market supplier for drug-
eluting stents with an overall market share of 37.7%. It has gained market share
through aggressive marketing utilizing their strong cardiology sales force, and through
the acquisition of proprietary technologies and intellectual property through product
research and development and through acquisition (e.g. Interventional Technologies in
April 2001). Boston Scientific Corporation has a particularly strong market position in
the United States and is the market leader for drug-eluting stents.
A number of significant developments have occurred recently altering the structure and
dynamics of the market place. The most important development has been the
completion of the combination between Guidant by Boston Scientific Corporation in
April 2006. This followed a protracted series of bids and counter bids between Cordis
Corporation (Johnson & Johnson) and Boston Scientific Corporation over a 2 year
period to gain control of Guidant, its business, and its proprietary technologies. In order
to comply with both the European Commission and U.S. antitrust laws Boston
79
Scientific Corporation were required to ensure that Guidant’s vascular intervention and
endovascular businesses were acquired by Abbott Laboratories (to be incorporated
within their subsidiary Abbott Vascular). The completion of this acquisition by Abbott
Laboratories (from Guidant) was concluded on the 21st April 2006 just before the
closing of the Boston Scientific-Guidant transaction.
The consequence of this “combination” has had a number of ramifications to the
structure of the market. Boston Scientific has as a direct result of the “combination”
protected its market position in the drug-eluting stent market by preventing Cordis
Corporation acquiring the proprietary technologies of Guidant. In subsequent
developments Boston Scientific have managed to circumvent the antitrust laws by
establishing distribution agreements in September 2006 with Abbott Vascular for
Abbott's XIENCE™ V Everolimus-Eluting Coronary Stent System. Boston Scientific
will distribute the XIENCE™ V Everolimus-Eluting Coronary Stent System under the
name of the PROMUS Stent. Guidant, prior to its acquisition by Boston Scientific, was
the market leader in the bare metal stent market.
This is expected to strengthen the market position of Boston Scientific over the next
few years as they were, up until February 2007, the only company currently offering
two distinct drug-eluting stent platforms. In a move which was a direct competitive
response Johnson and Johnson announced on the 1st February 2007 they had acquired
Conor MedSystems Inc. Conor manufactures the CoStar® drug-eluting stent, a second
generation drug-eluting stent that has gained the CE mark on the 17th February 2006
and is currently sold throughout Europe, Latin America and certain countries in Asia
by BIOTRONIK. The stent utilizes a unique design of mini-reservoirs, or dimples, in
the stent surface which hold a bioabsorbable polymer.
The CoStar has not yet gained FDA approval for sale in the United States and is for
investigational use only. Conor MedSystems Inc instigated the CObalt chromium
STent with Antiproliferative for Restenosis (COSTAR) I pilot study and COSTAR II
Pivotal clinical trial study and the EUROSTAR (EUROpean cobalt chromium STent
with Antiproliferative for Restenosis) Trials to determine the safety and efficacy of the
80
CoStar® drug-eluting stent. There are ongoing patent battles waging between Conor
(now J&J) and Boston Scientific, regarding use of the drug paclitaxel. These battles
will no doubt fuel a new front for the "Stent Wars". They may also fuel Johnson &
Johnson into exploring different drugs for use with the Conor stent design.
Biotronik AG - based in Buelach, Switzerland - announced on the 16th December 2006
they had enrolled the first patient into their pimecrolimus drug eluting coronary stent
FIM study, ProLimus I. This development became feasible after Biotronik AG signed
an agreement with Novartis Pharma AG to evaluate certain Novartis pharmaceutical
compounds for its drug eluting stent platforms, of which one is Pimecrolimus. The
ProLimus I trial is a prospective, non-randomized, multi-center study assessing the
safety and clinical performance of the ProGenic pimecrolimus eluting stent in patients
with single de-novo coronary artery lesions. In total 60 patients will be enrolled in 5
centers in Belgium and Germany, with the patients will undergoing clinical follow-up
at 30 days, 6 months, 12 months and annually up to 3 years.
The Singapore quoted company Biosensors International is another example of a
company specializing in devices for interventional cardiology. Biosensors International
has two drug-eluting stent platforms – the Axxion™ and the BioMatrix® stent systems.
The Axxion™ stent system incorporates an innovative non-polymeric Paclitaxel drug-
eluting stent system. The non-polymeric coating is a permanent biocompatible and
non-thrombogenic stent coating known as Glycocalix. The BioMatrix® stent system is
based on their proprietary BMS known as the S-stent. This DES uses their proprietary
drug, Biolimus A9® and the bioabsorbable polylactic acid (PLA) polymer coating. An
announcement was made on the 12th July 2005 that Biosensors International
Netherlands-based subsidiary, Occam International B.V, had received CE Mark
approval for the Axxion™ stent system.
Others recent developments include the license agreement between Surmodics and
CardioMind made in July 2005 to create a new drug-eluting stent platform which uses
81
the SurModics' ENCORE(TM) Drug Delivery Polymer Matrix with CardioMind's
novel ultra low-profile stent system. Medivas and Picarus also created an agreement in
July 2005 for the use of the MediVas biomaterial drug delivery technology in
conjunction with Picarus' core technology to develop drug-eluting stents (DES). Both
of these deals involve the use of drug delivery technologies to improve the success rate
of stents.
Figure 3.5: Actual and projected revenues from Coronary Stents, Worldwide sales- 2006
.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Rev
enue
($b)
BMS DES Total
Source: Business Insights Ltd Business Insights Ltd
82
Figure 3.6: Market Share Analysis, DES v BMS World, 2006
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
CordisCorporation
(J&J)
BostonScientific
Corporation
Medtronic AbbottLaboratories
SorinBiomedica
Cardio
BIOTRONIKGmbH & Co
Others
Mar
ket S
hare
DES BMS Total Stent
Source: Business Insights Ltd Business Insights Ltd
Emergence of Bioabsorbable Stents
There have been several recent studies conducted to examine some concerns amongst
clinicians about a number of problems or complications associated with drug-eluting
stents. These are primarily concerned with late developing stent thrombosis, allergic
inflammatory reactions, long term antiplatelet therapy and non-compliance. Although
cardiologists are recommending and prescribing anti-clotting (antiplatelet) medications
such as clopidogrel (Plavix) or ticlopidine (Ticlid) for twelve months and aspirin for
life there are growing concerns that late developing stent thrombosis could be a major
complication for DESs. In order to overcome these problems and in recognition of the
advantages of non-metallic implants, which would otherwise interfere with magnetic
83
resonance imaging and multi-slice computerized CT scanning, researchers are
developing new types of "bioabsorbable" stents that may reduce or eliminate these
risks.
Biomaterials and Bioabsorbable Polymers
One of the attractive materials recognized as having the potential for use in a
bioabsorbable stents is the polymer called poly L-lactic acid (PLLA). Several stent
designs have been built using PLLA monofilaments and appear to be a viable
alternative to metal in some preliminary studies. Furthermore, the results of studies
incorporating an antiproliferative agent onto the PLLA stents have been encouraging.
One such stent the BVS stent from Abbott Vascular has a bioabsorbable structure
made of polylactic acid and a coating that controls the release of the drug everolimus.
In order to determine the safety and efficacy of this stent Abbott Vascular initiated a
study referred to as ABSORB. The ABSORB trial is a prospective, non-randomized
(open label) study and has been designed to enroll up to 60 patients in Belgium,
Denmark, France, New Zealand, Poland and The Netherlands. In this study researchers
from the Erasmus Medical Center in the Netherlands have been assessing the safety
(Major Adverse Cardiac Events (MACE) and stent thrombosis rate) at 30, 180, and 270
days, with an annual follow-up for up to five years and successful deployment of the
bioabsorbable drug-eluting stent. The six-month results from the first 30 patients in the
trial were presented at the 56th Annual American College of Cardiology Scientific
Session in New Orleans on the 24th March 2007. These demonstrated no stent
thrombosis and a low (3.3 %) hierarchical rate of ischemia-driven MACE such as heart
attack or repeat intervention.
The proprietary polymers developed by Bioabsorbable Therapeutics, Inc. (BTI) is
another example of a bioabsorbable stent The IDEAL Stent is deployed like current
stents; utilizes an anti-inflammatory, therapeutic drug-delivery polymer; and permits
delivery of multiple drugs with tunable release kinetics. The stent acts like a scaffold
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for tissue growth during the initial six months, but once the artery has healed, the
IDEAL Stent is absorbed by the body, leaving no permanent implant.
Another example of a reabsorbable stent is the development of the REVA Medical
reabsorbable stent that has a patented “Slide and Lock” geometry. Slide and Lock
geometry allows stent elements to slide and lock into position upon balloon expansion
during stent placement and possesses steel-like strength. On the 6th August 2002 REVA
entered into an exclusive worldwide rights agreement for a tyrosine-derived
polycarbonate co-polymer developed at Rutgers University agreement with Integra
LifeSciences Holdings Corporation. On the 16th November 2004 Boston Scientific
Corporation announced that they had made an equity investment in and secured an
exclusive option to purchase REVA Medical Inc. Although the terms of the agreement
were not disclosed it is clear that Boston Scientific Corporation are already seeking to
establish its presence in the emerging absorbable stent market.
Another biabsorbable stents is also being developed as a result of a joint venture
agreement between Endovasc and TissueGen resulting in Endovasc-TissueGen
Research Sponsors LLC. The purpose of this partnership is to develop a totally
bioresorbable drug-eluting cardiovascular stent for the advanced treatment of coronary
artery disease. Endovas has co-licensed its patented time-release prostaglandin E-1
drug and Tissuegen is contributing its technology related to drug-releasing polymer
fiber scaffolds. Many cardiovascular experts believe this type of stent will be the stent
of the future. As the drug elutes into the vessel, the stent dissolves, leaving nothing to
set up restenosis or thrombus occlusions.
Another company involved in the development of absorbable stents is Amaranth
Medical Inc. They announced on the 26th September 2006 that they established an
agreement between Bio*One Capital of Singapore and Charter Life Sciences of Palo
Alto, California for financing of $7.5 million. This financing is to be used to fund the
development of the company's absorbable stents and to initiate clinical trials.
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Absorbable Metal Stent (AMS) Technologies
Biotronik GmbH & Co. KG, a European manufacturer of biotechnologies based in
Switzerland, has developed an absorbable metal stent (AMS) technology. The alloy
stent is made of 93% magnesium and 7% rare-earth metals. It induces rapid
endothelialization, has low thrombogenicity, and a degradation time of 2-3 months.
Magnesium was chosen because it is an essential mineral in the body (the body
requires approximately 350 mg/day) and the stent is made of < 4.5 mg of magnesium.
The alloy also has calcium antagonist and antiarrhythmic properties and, of importance,
is not associated with any adverse allergic reactions. A clinical trial known as AMS
FIM BTK (First-in-Man Below the Knee) has been conducted and a second trial
PROGRESS AMS (Clinical Performance and Angiographic Results of Coronary
Stenting with Absorbable Metal Stents) is currently in progress. The last notification of
developments in this trial were published on the 13th March 2006 and presented at the
Innovation in Intervention i2 Summit 2006, March 11-14, 2006, Atlanta, Georgia.
Further Coronary Stent Developments and Technological Trends
Novel Coating Technologies
Lombard Medical plc based in Abingdon in the United Kingdom has been developing
a new next generation of drug carrier known as the PEP™ (programmable elution
profile). The PEP™ polymer allows drug release kinetics to be accurately programmed,
allowing both the timing and amount of drug release to be controlled. PEP™ coated
stents have demonstrated post 28 days implant showing normal neointimal
development with no evidence of polymer detachment, cell necrosis, inflammation or
fibrin deposition. The ability to “program” the release kinetics of a given drug can be
used to optimize the stent performance. Lombard Medical states for example that
PEP™ can be programmed to release Rapamycin from a few hours up to 50 days.
PEP™ is compatible with many hydrophobic and hydrophilic drugs and can attach to
Heparin or other biomolecules to improve the anti-thrombogenic properties of the stent
surface. They can also be programmed to elute more than one drug from the same stent,
both with individually programmed release kinetics. Lombard Medical state that the
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ability to program the elution rates of more than one drug is a breakthrough in the
concept of drug eluting stents making it possible to treat each separate stage in the
prevention of restenosis. As different drugs may be more effective at a different point
in the cycle since disease onset a timed approach is important.
In a related field AllVivo Vascular (AVI) has developed a Biomimetric coating
designed to prevent the inflammatory process that leads to restenosis while still
providing a favorable surface for healing and regeneration of the endothelium. The
Biomimetric coating has been designed by polymer scientists at the University of Utah
and clinical immunologists at Uppsala University. AVI’s coronary stent coating has
two parts. One part is a proprietary End Group Activated Polymer (EGAP). The EGAP
surface technology transforms traditional device materials into biocompatible and
thromboresistant surfaces and further enables the attachment of biologically active or
therapeutic compounds. The second part of the coating is a protein called factor H
which interrupts the inflammatory processes that lead to restenosis. AVI has developed
this coating through the preclinical stage and is preparing to initiate a FIM study.
Gene Therapy technologies and its Potential Use to Prevent Restenosis
There is considerable interest and research being conducted to determine how genes
can be delivered to artery walls by stents to reduce the risk of restenosis. The technique
currently being examined involves to imbedding the selected gene in the biodegradable
polymer, which coats the stent. The purpose is then to allow a controlled release of the
gene into cells in the arterial wall using an appropriate molecular carrier (the vector).
The purpose of the gene therapy vector is to deliver the gene and incorporate it in the
target cell population. Once this has occurred the vector is then designed to either
inactivate or degrade naturally within the cell. These properties are not easily achieved,
and the design of gene therapy vectors continues to be an active area of research.
Robert J. Levy, M.D, at The Children's Hospital of Philadelphia has developed a
technique where a water-soluble compound, polyallylamine biphosphonate, binds to
the stent's metal alloy surface in a layer with the thickness of only a single molecule.
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The biphosphonate holds and gradually releases adenovirus particles of the type used to
deliver therapeutic genes.
Similar studies have demonstrated that acceleration of reendothelialization can
attenuate restenosis and inhibit stent thrombosis. These effects have been mainly
attributed to the potency of vascular endothelial growth factor (VEGF) in serving as an
endothelial mitogen. Work supporting this hypothesis was conducted using
aBiodivYsio stent which was electropolished, cleaned, and coated with a
phosphorylcholine polymer (PC) with or without phVEGF-2 plasmid. Further work is
required to valid the safety and efficacy of this procedure.
Coronary Stents and Endothelial Progenitor Cells (EPCs)
Endothelial Progenitor Cells (EPCs), here circulating at concentrations of 3-10
cells/mm3 , have the ability to differentiate into functional endothelial cells and have
been shown to be involved in the process of angiogenesis. Since interventional
procedures such as stenting causes damage to the endothelial lining of coronary
arteries, the capacity of the system to quickly and completely reconstitute the lining of
the damaged surface is overwhelmed. EPC capture technology enhances this process
and facilitates the natural healing process of damaged arterial segments. This
accelerated healing will lessen the chance of subacute thrombosis and reduce the
restenotic response. Researchers have examined the prospect of vascular endothelium
healing using EPCs as a more natural and consequently safer approach to the
prevention of restenosis.
OrbusNeich (formerly known as Orbus Medical Technologies) is at the forefront with
their product the Genous Bioengineered R Stent using their proprietary Endothelial
Progenitor Cells Capture Technology. The principle of this technology is to promote
the establishment of a functional endothelial monolayer and thereby provide the
endogenous modulators necessary for efficient healing (using the endothelial
progenitor cell EPC) leading to inhibition of neointimal hyperplasia and platelet
aggregation, as well as improved vasomotor tone. OrbusNeich conducted a HEALING-
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FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) study to
determine the safety of their stent in 16 patients with stable angina. This was followed
by the HEALING-II study which was a multi-centered, prospective non-randomized
trial using 63 patients in 10 centers. Enrollment was initiated in May 2004 and
completed in October 2004. The interim 18 month follow-up results of this study were
published in May 2006. A further trial known as the HEALING-IIb study was then
initiated in July 2006 with the enrollment of the first patients initiated in August 2006.
OrbusNeich announced on the 22nd August 2005 that they had received CE Mark
approval for its Genous Bio-engineered R stent.
Nanotechnologies and Drug-Eluting Coronary Stents
Researchers have been exploring the use of nanotechnologies to develop a new type of
nano-structured ceramic coating which is used to incorporate the drug. DebioTech S.A,
based in Switzerland, have developed the DebioStent. This has a nano-structured
ceramic coating with different porosities which incorporates the drug. This product has
evolved as a result of a collaborative agreement reached between the Laboratory of
Powder Technology and DebioTech in February 2006.
Development of Novel Estradiol Containing Drug-Eluting Stents
Estradiol is known as a vasculoprotective in premenopausal women. These effects are
probably related to the capacity of estradiol to inhibit smooth muscle proliferation and
migration, hasten re-endothelialization, and restore normal endothelial function
following balloon artery injury, as shown in recent animal studies. Furthermore, 17-
beta-estradiol is a low-molecular-weight, hydrophobic, and lipophilic hormone, which
makes it suitable for loading and delivery from a stent for the prevention of in-stent
restenosis. The first study to determine the feasibility of using 17-beta-estradiol-eluting
stents to inhibit restenosis in humans was the Estrogen and Stents To Eliminate
Restenosis (EASTER) study. Having demonstrated efficacy, a variety of new and
innovative drug-eluting stents have been developed. These include the
Duravest/Estracure 17-ß-estradiol stent which with its estrogen-based drug utilizes a
safe, targeted and biologically-mediated suppression of the repair process and holds
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substantial promise for not only improved safety and efficacy but even a pro-healing
effect.
SurModics Inc. and X-Cell Medical Inc. announced on the 9th July 2006 that they
have entered into a license agreement for the use of SurModics' Bravo(TM) Drug
Delivery Polymer Matrix with X-Cell's ETHOS Drug Eluting Coronary Stent System.
The ETHOS drug eluting stent incorporates the Bravo polymer matrix to deliver a
second generation formulation of 17 beta-estradiol.
A further twist to the development of 17-beta-estradiol eluting drugs has been the
incorporation of 17-beta-estradiol to a Rapamycin-Eluting Stent. The Rapamycin Plus
Estradiol-Eluting Stents Versus Rapamycin-Eluting Stents For The Reduction of
Coronary Restenosis (ISAR-PEACE) trial was designed to assess the efficacy of the
Rapamycin plus 17-beta-estradiol-eluting stent vs a rapamycin-eluting stent. The
results from ISAR-PEACE are similar to those seen previously with estradiol-alone
eluting stents. There seems to be no apparent immediate benefit in reducing restenosis
rates. Whether it may have some delayed beneficial (or detrimental) effect on the long-
term follow-up has yet to be determined.
Stem-Cell Derived Endovascular Cells
On the 1st October 2006 Axordia Ltd, Lombard Medical Technologies PLC and the
Centre for Stem Cell Biology (CSCB) and the Cardiovascular Research Unit (CVRU)
both at Sheffield University announced that they had created a consortium to develop a
regenerative stent. The consortium has received significant funding through the
Technology Program from both the Department of Trade and Industry (DTI) and the
Medical Research Council (MRC) in the United Kingdom. The technology involves
attaching Axordia’s proprietary, stem cell-derived endovascular cells to Lombard Medical’s
PEP™ programmable polymer coating on the stent surface. The principle is to allow the body
to promote controlled vascular repair and heal the damaged coronary artery vessel wall.
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Other research projects include the use of CD34+ stem cells to promote either
angiogenesis, the growth of new capillaries; arteriogenesis, the maturation and
enlargement of existing arteries and arterioles; or vasculogenesis, the sprouting of new
arteries and arterioles in-patients with chronic myocardial ischemia (CMI). The
University of Wisconsin is one of 15 research sites in the United States who are
involved in a clinical trial known as the Autologous Cellular Therapy CD34-Chronic
Myocardial Ischemia (ACT34-CMI) Trial. The first patients were enrolled into the trial
at the beginning of 2007 and the first procedure was conducted on the 7th March 2007.
The trial is sponsored by the Cellular Therapies business unit of Baxter Healthcare
Corporation.
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CHAPTER 4
INNOVATIONS IN MINIMALLY INVASIVE CARDIAC SURGERY
(MICS)
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Chapter 4 Innovations in Minimally Invasive Cardiac Surgery (MICS)
Summary
New and innovative, minimally invasive surgical technologies are poised to replace the traditional, highly invasive protocols used in open-heart surgery.
Currently, there are three types of procedural approaches. These are Minimally Invasive Direct Coronary Artery Bypass (MID-CAB) surgery, Off-Pump Coronary Artery Bypass (OP-CAB), and Port Access Surgery.
Minimally Invasive Port Access Surgery is indicated for Multi-Vessel Coronary Artery Bypass Grafting (CABG), Mitral Valve Repair or Replacement (MVR), MVR/Tricuspid Repair, MVR Redo, MVR/CABG, Aortic Valve Replacement (AVR) and Congenital Heart Defect Surgery, including Atrial Septal Defect (ASD) & Ventricular Septal Defect (VSD).
Beating heart OP-CAB is currently recognized as a technique significantly reducing the mortality and morbidity associated with the use of traditional cardiopulmonary bypass procedures. This procedure is indicated for multivessel disease requiring revascularization and where normal cardiopulmonary bypass is contraindicated.
Robotic Assisted Coronary Artery Bypass (RA-CAB) systems such as The Automated Endoscopic System for Optimal Positioning (AESOP), The Da Vinci System and The Zeus Robotic System are becoming increasingly popular.
Computer aided cardiac surgery including virtual reality in cardiac surgery, TransMyocardial Laser Revascularization (TMLR) including CO2 heart laser systems, holmium: YAG (yttrium aluminium garnet) lasers and the excimer lasers are changing the face of cardiac surgery.
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Introduction
Minimally invasive surgical technologies have revolutionized the practice of medicine
over the past decade, with important and impressive breakthroughs in many areas. The
one area which had lagged behind the introduction of these innovative technologies had
been the earlier development of minimally invasive techniques and technologies as a
replacement to the traditional, highly invasive protocol used in open-heart surgery.
However, dramatic new developments in new minimally invasive technologies,
techniques and protocols for cardiovascular surgery since the mid-1990s has
transformed the way heart surgery is being conducted and with it a market which is
evolving and growing rapidly through progressive development into less invasive
forms of heart surgery. Minimally invasive heart surgery refers to several approaches
for bypassing critically blocked arteries that are less difficult and risky than
conventional open-heart surgery (coronary artery bypass grafting - CABG).
Currently, there are three types of procedural approaches. These are Minimally
Invasive Direct Coronary Artery Bypass (MID-CAB) surgery, Off-Pump Coronary
Artery Bypass (OPCAB), and Port Access Surgery. In addition, Robotic Assisted
Coronary Artery Bypass (RACAB) has emerged as an important technological advance
allowing for the considerable improvement in accuracy of operations to beyond the
scale of human ability. Patients who have one these procedures instead of open heart
surgery have a lower risk of complications associated with the heart-lung machine such
as stroke, lung problems, kidney problems, and problems with mental clarity and
memory. In addition to reduced complications, other benefits of minimally invasive
heart surgery are faster recovery and reduced hospital costs.
Minimally Invasive Direct Coronary Artery Bypass (MID-CAB)
MID-CAB (minimally invasive direct coronary artery bypass) is a coronary artery
bypass procedure done on a beating heart through a minimal access incision. MID-
CAB is suitable for patients with blockage(s) in the arteries on the front of the heart -
i.e. the left anterior descending (LAD) artery and its diagonal branches. This procedure
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allows the surgeon to perform bypass surgery without splitting the entire breastbone.
Unlike conventional open-heart bypass surgery, which requires a large incision, MID-
CAB employs a tiny, 6-10 cm "keyhole" incision on the patient's left chest to gain
access to the heart. Surgeons may use MID-CAB incisions with or without the heart-
lung machine.
Indications for MIDCAB
Due to the limited size of the MIDCAB incision, only certain patients are eligible
candidates for the procedure. Patients where there is a clear indication for MIDCAB
include:
isolated disease to the anterior descending or first diagonal artery;
multivessel disease in patients with significant concurrent medical illnesses for
whom cardiopulmonary bypass poses a significant risk, such as patients with
chronic renal failure, diffuse atherosclerosis of the ascending aorta, advanced age,
or respiratory insufficiency;
patients with religious convictions that preclude the use of blood products.
Off-Pump Coronary Artery Bypass (OP-CAB)
With OPCAB the surgeon makes a vertical incision in the chest; the size of an incision
used in conventional bypass surgery, and splits the breastbone. The difference is that
the heart-lung machine is not used. A stabilizing device is used to restrict movement of
small segments of the heart so that the surgeon can operate on it while it is still beating.
This procedure enables the surgeon to perform multiple (4-5) vessel bypass surgery on
a beating heart.
Indications for OP-CAB
Beating heart OP-CAB is currently recognized as a technique which significantly
reduces the mortality and morbidity associated with the use of traditional
cardiopulmonary bypass procedures. Recent progress in mechanical stabilizers has
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made a significant contribution to improving the efficacy of beating-heart surgery.
Although OP-CAB avoids cardiopulmonary bypass (CAB) it is only applicable to a
relatively small segment of the population with coronary heart disease (5%-10%).
These indications are:
Multivessel disease requiring revascularization;
Contraindications or increased risk for cardiopulmonary bypass, such as severe
myocardial dysfunction; immunosuppression; history of transient ischemic attacks
or cerebrovascular accidents; heavily calcified aortas; aortic disease with increased
risk of dissection, rupture or embolization; impaired renal function or need for
dialysis; history of previous surgery
Patients who refuse blood transfusions and blood products;
Other high-risk patients such as those with advanced age, respiratory problems or
other systemic disease;
Minimally Invasive Port Access
The port access technique allows surgeons to forgo the traditional sternotomy (a cut
through the breastbone) and operate on the heart through a number of smaller incisions.
The patient is hooked up to a heart lung machine without opening the chest. The
anastomosis or other procedure can thus be performed on an arrested heart allowing for
greater surgical precision. The comparatively small incisions required here greatly
reduce the amount of post-operative pain experienced by the patient, speed recovery
and scar less noticeably.
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Indications for Minimally Invasive Port Access
Minimally Invasive Port Access is progressively moving from an investigative
technique into a proven surgical procedure. It is used today for a variety of procedures
including Mult-Vessel Coronary Artery Bypass Grafting (CABG), Mitral Valve Repair
or Replacement (MVR), Aortic Valve Replacement (AVR) and congenital heart defect
surgery, including Atrial Septal Defect (ASD) AND Ventricular Septal Defects (VSD).
Robotic Assisted Coronary Artery Bypass (RA-CAB)
RA-CAB is the latest advance in coronary surgery. Surgeons use a robotic device to
enable coronary bypass without separating the breastbone at all. Surgeons do not have
direct contact with the patient, but perform the operation while watching a videoscreen.
As the technology becomes more advanced, the surgeon may perform coronary bypass
from a distant site (i.e., from another room or another geographical location).
Robotically assisted cardiac surgery uses the principles of endoscopic surgery to
minimise the trauma associated with open heart surgery and essentially eliminates the
tremor effect, and the non-intuitive feel of manoeuvring such instruments. It enables
the use of minimally invasive techniques in coronary artery bypass grafting by scaling
hand motions, decreasing tremor, and enhancing manipulation. In these procedures,
endoscopes and other instruments are inserted through small incisions or “ports” to
access the surgical site.
In this procedure three small pencil-sized ports are used. Through one port a tiny high-
powered, voice-operated camera or endoscope is inserted and held by a robotic arm.
Two further robotic arms that control the surgical equipment are inserted in the other
ports. With this technology the surgeon manipulates the instruments with the help of a
computer. An endoscope is passed through a tiny incision in the chest wall, and two
surgical instruments are passed through additional tiny incisions. The surgeon views
the image provided by the endoscope on a computer screen. Instead of manipulating
the surgical instruments directly, the surgeon manipulates them via a computer console.
The computer interprets the surgeon's hand movements and causes the surgical
instruments to respond accordingly.
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Robotic cardiac surgery has evolved from the various forms of endoscopic surgery
such as laparoscopic and thoracoscopic surgery which was introduced during the late
1980s and early 1990s. Endoscopic heart surgery however only achieved limited
success as the procedures are more complicated where the heart is beating and the
necessary surgical manoeuvres tend to significantly more complex.
There are a number of issues relating to the use of standard endoscopic instruments for
use in cardiac surgery. Standard endoscopic equipment operates with only four degrees
of freedom and as a result there is a considerable reduction in dexterity. In addition
when working through a fixed entry point, such as a trocar, the operator must reverse
hand motions (the fulcrum effect). At the same time, instrument shaft shear, or drag,
induces the need for higher manipulation forces, leading to hand muscle fatigue. Also,
human motor skills deteriorate with visual motor incompatibility, which itself is
commonly associated with endoscopic surgery. In order to overcome these issues
computer-enhanced instrumentation systems were developed during the early 1990s.
These systems provide both telemanipulation and micromanipulation of tissues in
confined spaces. The surgeon operates from a console, immersed in a three-
dimensional view of the operative field. Through a computer interface, the surgeon’s
motions are reproduced in scaled proportion through “microwrist” instruments that are
mounted on robotic arms inserted through the chest wall. These instruments emulate
human X-Y-Z axis wrist activity throughout seven full degrees of freedom.
The current indications for robotic assisted cardiac surgery systems are:
coronary artery bypass surgeries;
mitral valve repair;
epicardial pacemaker leads for biventricular resynchronisation.
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Current and Emerging Technologies
Robotics in Minimally Invasive Cardiac Surgery
Robotic-assisted surgery uses surgical robotic equipment imitating surgical
movements. There are a number of major advantages associated with the associated
minimally invasive surgery procedures including the ability to operate through small
ports rather than large incisions, resulting in shorter recovery times, fewer
complications and reduced hospital stays.
Robotic Systems
The Da Vinci System
The first truly robotic surgical systems were developed in 1995 when researchers at
SRI International (formerly known as Stanford Research Institute) in collaboration with
Intuitive Surgical. They developed the first robotic system known as the da Vinci
System. In use, a surgeon sits at a console several feet away from the operating table
and manipulates the robot's surgical instruments. The robot has three hands attached to
a free-standing cart. One arm holds a camera (endoscope) that has been passed into the
patient through small openings. The surgeon operates the other two hands by inserting
fingers into rings. The arms use a technology called EndoWrist--flexible wrists that
surgeons can bend and twist like human wrists. The surgeon uses hand movements and
foot pedals to control the camera, adjust focus, and reposition the robotic arms. The da
Vinci has a three-dimensional lens system, which magnifies the surgical field up to15
times. Another surgeon stays beside the patient, adjusting the camera and instruments if
needed.
The da Vinci robotic surgical system and Endowrist instruments were initially
approved for use throughout Europe in January 1999. Intuitive Surgical have received
permission from DGM, their Notified Body and agent of the Danish Government, to
affix the CE mark to their da Vinci Surgical System and EndoWrist instruments. To
maintain authorisation to apply the CE mark, they are subject to annual surveillance
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audits and periodic re-certification audits. To date they have met these requirements
and their certificate is valid until December 2010.
In July 2000 the da Vinci System was approved by the FDA for use in laparoscopic
surgical procedures such as removal of the gallbladder and surgery for severe
heartburn. In March 2001, the FDA cleared da Vinci for use in general non-cardiac
thoracoscopic (inside the chest) surgical procedures--surgeries involving the lungs,
oesophagus, and the internal thoracic artery. In May 2001, the FDA cleared da Vinci
for use during laparascopic removal of the prostate (radical prostatectomy). On
November 13th 2002 Intuitive Surgical, Inc. announced that the FDA has cleared the da
Vinci Surgical System for use in mitral valve repair surgery. In July 2004 the FDA
gave approval for the da Vinci to be used in cardiac revascularisation procedures and in
June 2005 it was approved by the FDA for use in paediatric surgical procedures. At the
time of writing more than 571 da Vinci Systems are in use in major hospitals and
surgical facilities throughout North America, South America, Europe, the Middle East
and Asia. On January 11th 2006 Intuitive Surgical, Inc. announced the market
introduction of the da Vinci(R) S(TM) Surgical System. The list price for the da Vinci
S System is currently $1.53 million, which is approximately $200,000 more than the
standard da Vinci System.
The Automated Endoscopic System for Optimal Positioning (AESOP)
The AESOP was originally developed by Computer Motion Inc as an endoscopic robot
system for holding cameras for minimally invasive surgery. Aesop's function is quite
simple merely to maneuver a tiny video camera inside the patient according to voice
controls provided by the surgeon. By doing so, Aesop has eliminated the need for a
member of the surgical team to hold the endoscope in order for a surgeon to view his
operative field in a closed chest procedure. This advance marked a major development
in closed chest or port-access bypass techniques, as surgeons could now directly and
precisely control their operative field of view.
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On March 17th 2003 Intuitive Surgical Inc and Computer Motion Inc signed a
definitive merger agreement. As a result of this, merger Intuitive Surgical Inc acquired
the proprietary technologies developed by Computer Motion Inc for both the AESOP
and the Zeus Robotic System.
The Zeus Robotic System
The ZEUS System also developed by Computer Motion is another surgical robot in the
process of being cleared by the FDA. The system is being used in Europe primarily in
Germany. Intuitive Surgical Inc no longer promotes either the AESOP or ZEUS
products but does provide service and technical support to their installed customer
sites. Intuitive Surgical Inc. has discontinued pursuing any further regulatory approvals
for these two products.
Computer Aided Cardiac Surgery
Virtual Reality in Cardiac Surgery
Virtual reality is best described as a collection of technologies that allow people to
interact efficiently with 3D computerised databases in real time using their natural
senses and skills. Virtual reality is being applied to a wide range of medical areas,
including remote and local surgery, surgery planning, medical education and training,
treatment of phobias and other causes of psychological distress, skill training, and pain
reduction. It is also used for the visualization of large-scale medical records, and in the
architectural planning of medical facilities. Virtual reality in cardiac surgery involves
applications of interactive computer technologies to help perform, plan and simulate
surgical procedures. Virtual reality is used to guide the surgeon, sometimes with a
robot to execute the procedure under the surgeon's control (to remove hand tremor and
scale down manipulations for key-hole surgery, for example). In other words, virtual
reality is used to give the surgeon 3D interactive views of areas within the patient.
Planning is carried out preoperatively, to find the best approach to surgery, involving
minimum damage. Simulation is mostly used in training, using patient data often
registered with anatomical information from an atlas.
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Laser Heart Surgery or transmyocardial Laser revascularization (TMLR)
The concept of the "laser" was attributed to Albert Einstein in 1905. The terms
"excimer" and "laser" are acronyms. Excimer is an acronym for excited dimer, while
laser stands for light amplification by stimulated emission of radiation. Lasers were
introduced for interventional cardiology in the late 1980s. Initially interventionists
were enthusiastic about them but there were issues concerning laser related
complications, mainly dissections and perforations. Since then the current generation of
xenon chloride excimer lasers, produced by Spectranetics Corporation, (the CVX-300®
Laser System) are being used for coronary and peripheral angioplasty, pacemaker and
implantable cardioverter/defibrillator lead extractions, and transmyocardial
revascularization. Laser energy from the xenon chloride laser is produced when HCI
gas is excited by electrical energy and emits monochromatic, coherent light at a
wavelength of 308 nm. This laser energy ablates inorganic material by photochemical
mechanisms that involve the breaking of molecular bonds without the generation of
heat.
Transmyocardial laser revascularization (TMLR) is based on the use of a high-powered
carbon dioxide or other lasers that interject a strong energy pulse into the left ventricle,
vaporising the ventricular muscle and creating a transmural channel with a 1-mm
diameter. The procedure can be used to create channels along the free left ventricular
wall but not the septum. These channels are placed 1 cm apart in the ischemic
myocardium. TMLR is performed to improve myocardial oxygenation, eliminate or
reduce angina, and to improve the patient's cardiovascular function. Currently there are
3 types of laser systems used in TMLR. These are:
The CO2 Heart Laser System
The CO2 Heart Laser System is a laser that vaporises the heart tissue in a fraction of a
second creating a channel through the wall of the heart that is about 1 mm wide. The
number of channels will be determined by the size of the oxygen-deprived areas of the
heart. The latest development has been the launch of a special high-energy,
computerised ECG-synchronized CO2 laser called the CO2 Heart Laser 2 (PLC Medical
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Systems). On the 8th March 2001 PLC Medical Systems announced that they had
received CE Mark approval for its next-generation CO2 Heart Laser 2. The CE Mark
allows PLC to begin marketing the smaller, more mobile TMR laser throughout the
European Union and other countries that base regulatory clearance on the European CE
Mark. In January of this year, PLC announced that the Company received U.S FDA
approval to market the next-generation CO2 Heart Laser 2 system. On May17th 2006
PLC Systems Inc. announced that Ktec Corporation, PLC's exclusive distributor in
Japan, received approval from the Japanese Ministry of Health, Labor and Welfare
(MHLW) to market PLC Systems' first generation CO2 TMR Heart Laser System
(HL1) in Japan.
The holmium:YAG (yttrium aluminium garnet) laser
The holmium:YAG (yttrium aluminium garnet) laser is also an infrared laser. The
primary action of both of these lasers is the vaporization of water that causes tissue
ablation. The holmium:YAG laser requires multiple bursts to establish a single channel,
therefore creating a channel that is not uniformly straight. Studies have documented
that the amount of adjacent thermal injury to the surrounding tissue may be greater
with the holmium:YAG laser than with the CO2 laser, but over time the distinctive
qualities of the channels become indiscernible. On the 10th October 2006 Cardiogenesis
Corporation announced that they had received CE Mark approval for marketing its
advanced combination delivery system called the PHOENIX Combination Delivery
System.
The excimer laser
The excimer laser is another type of laser used to perform TMLR. It is an ultraviolet
laser that causes ablation by breaking the protein bonds that hold the myocardial tissue
together. This laser also requires multiple bursts to create a single channel. The benefit
of the holmium: YAG and excimer lasers over the CO2 laser is in the ability to perform
percutaneous transmyocardial revascularization (PTMR). This investigational
procedure utilises a laser beam that is delivered fiberoptically, and allows it to be
103
placed through a catheter. PTMR is a less invasive approach that can be accomplished
in the cardiac catheterization laboratory.
104
105
Chapter 5
CARDIOVASCULAR DRUGS IN EARLY STAGE DEVELOPMENT
106
Chapter 5 Cardiovascular Drugs in Early Stage Development
Summary
There are a total of 126 new chemical entities currently in Preclinicals in 9 principle disease areas described in this chapter i.e. Angina, Atherosclerosis, Arrhythmiasis, Atrial Fibrillation, Congestive Heart Failure, Hypercholesterolemia, Hypertension, Myocardial Infarction, Thrombosis.
There are a total of 51 new chemical entities currently in Phase I in 9 principle disease areas described in this chapter i.e. Angina, Atherosclerosis, Arrhythmiasis, Atrial Fibrillation, Congestive Heart Failure, Hypercholesterolemia, Hypertension, Myocardial Infarction, Thrombosis.
There are a total of 122 new chemical entities currently in Phase II in 9 principle disease areas described in this chapter i.e. Angina, Atherosclerosis, Arrhythmiasis, Atrial Fibrillation, Congestive Heart Failure, Hypercholesterolemia, Hypertension, Myocardial Infarction, Thrombosis.
Atherosclerosis represents the clinical area where there are the largest number of preclinical and Phase I developments currently being studied. There are a total of 32 chemical entities currently in preclinicals and a total of 11 new chemical entities have been identified in Phase I of development
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Introduction
This chapter examines some of the more exciting research and development projects
exploring the potential for new early phase cardiovascular drugs by drug class and
examines the potential for new and innovative approaches to the treatment of
cardiovascular diseases.
Early Developments in Key Cardiovascular Disease Classes
Angina
Despite great strides having been made in the treatment of various cardiovascular
conditions many pharmaceutical preparations, such as the wide range of anti-anginal
drugs currently available (long-acting nitrates, beta blockers and calcium channel
blockers), are overlooked in favor of revascularization using PCI or Coronary Bypass.
Although these revascularization procedures alleviate or prevent anginal symptoms
they have not been able to improve survival or reduce the incidence of myocardial
infarction in patients with stable angina pectoris. As a result the search continues to
develop anti-anginal drugs that reduce the adverse affects, improve patient outcomes,
and extend the range of indications. Table 5.5 provides a review of the early stage
development for pharmaceutical preparations. Arguably the compounds which exhibit
the most potential include YM758, a Phase II anti-anginal drug being developed by
Astellas Pharma Inc. Compound YM758 is a cardiac If channel inhibitor indicated for
the treatment of stable angina and atrial Fibrillation (ventricular rate control therapy)
where it enhances excessive pulse conduction. It is predicted by Astellas Pharma Inc
that worldwide sales of cardiovascular compounds including compound YM758 will
exceed ¥270 billion ($2.2 billion) by the end of year 2010.
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Table 5.5: Selected Early Stage Anti Anginal Drug Developments Company Name Product Name Phase of Development Pierre Fabre Medicament F15845 PC SCOLR Pharma Inc Nifedipine PC SCOLR Pharma Inc Verapamil PC Torrent Pharmaceuticals, Ltd. TRC-282 PC Allos Therapeutics Inc Efaproxyn (efaproxiral) I Daiichi Sankyo Company Ltd CS-780 I Dov Pharmaceutical Inc DOV Diltiazem I Sanofi-Aventis AVE9488 I Angiogenix, Inc. Acclaim II Asahi Kasei Corporation AT-877 (oral) II Asahi Kasei Corporation Fasudil hydrochloride II Astellas Pharma Inc YM758 II Circ Pharma Limited IS5MN PM (isosorbide-5-mononitrate) II Futura Medical plc Eroxon (glyceryl trinitrate) II Sanofi-Aventis Ataciguat (HMR1766) II Cardium Therapeutics Inc Generx (Ad5FGF4) III Dimera Incorporated Transdermal Progesterone Cream III Solvay S.A. Tedangin / KC-8857 (tedisamil) III Biovail Corporation Tiazac XC (diltiazem hydrochloride) PA Novadel Pharma Inc NitroMist (nitroglycerin) Lingual Aerosol A Par Pharmaceutical Companies Inc NitroMist (nitroglycerin) Lingual Aerosol A
Source: Medtrack Business Insights Ltd
Similarly Solvay Pharmaceuticals is currently developing tedisamil (KC-8857), a novel
antiarrhythmic with additional anti-ischaemic properties, which acts via potassium
channel blockade. This drug can be categorized as a class III antiarrhythmic agent due
to its effects of action potential and QT interval prolongation in these patients. This
agent was initially developed for its anti-ischaemic properties and Phase I trials have
shown tedisamil to be an effective bradycardic agent, as well as causing a reverse rate-
dependent QT interval prolongation. Subsequent Phase II results have confirmed that in
patients with ischaemic heart disease, tedisamil had beneficial haemodynamic and anti-
ischaemic effects.
Phase III studies in patients with ischaemic heart disease indicated that tedisamil is an
effective agent for the treatment of angina, resulting in a dose-dependent increase in
anginal threshold (with a decrease in anginal attacks, increased exercise capacity
during treadmill exercise and decreased electrocardiographic signs of exercise induced
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ischaemia) in comparison to placebo. Although tedisamil has been shown to be an
effective anti-ischaemic agent, and with Phase III trials for angina pectoris now
completed, the company are now pursuing the use of tedisamil for the treatment of
atrial fibrillation, for which tedisamil is still in Phase II/III clinical trials. Launch data
are not yet known.
Another compound being developed by Angiogenix Inc called Acclaim began Phase II
clinical trials in January 2004. Acclaim (organic nitrate combined with L-arginine), an
oral proprietary nitrate therapeutic shown to induce coronary vasodilation while
overcoming the significant problem of drug tolerance, is Angiogenix Inc’s lead product
candidate for the treatment of chronic angina.
Sanofi Aventis also have a strong pipeline portfolio for new and innovative drugs under
development for the treatment of stable and chronic angina. This includes the
compounds AVE9488 (an e-NOS transcription enhancer) and HMR 1069 (a Guanylate
Cyclase activator) in Phase I and ataciguat (HMR1766) guanylate cyclase activator
currently in Phase IIa.
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Arrhythmiasis
Table 5.6 provides an assessment of the current anti-arrhythmiasis drugs in early stage
of development. In comparison to some of the other cardiovascular disease areas there
are relatively few drugs in early development for the treatment of arrhythmiasis.
Table 5.6: Selected Early Stage Anti Arrhythmiasis Drug Developments Company Name Product Name Phase of Development CV Therapeutics Inc CVT3619 PC CV Therapeutics Inc Ranexa (ranolazine) PC Sanofi-Aventis SAR114646 PC Torrent Pharmaceuticals, Ltd. TRC-303 PC Wyeth GAP-134 PC AstraZeneca Plc AZD1305 Estimated filing MAA and NDA 2009 I CyDex, Inc. Captisol-Enabled Amiodarone I Wyeth ZP123 / GAP486 (rotigaptide) II Zealand Pharma A ZP123 / GAP486 (rotigaptide) II CV Therapeutics Inc Tecadenoson III
Source: Medtrack Business Insights Ltd
Wyeth Pharmaceuticals are currently developing 2 drugs for use in treating ventricular
arrhythmias. These are GAP-134 currently in preclinicals and rotigaptide (GAP-486)
currently in Phase II. Rotigaptide (GAP-486) had been originally developed by Zealand
Pharma who then in 2003 outlicensed rotigaptide to Wyeth Pharmaceuticals. During
2003 and 2004, Zealand Pharma was responsible for supplementary pharmacology
while Wyeth was responsible for clinical development.
Three Phase I trials have been completed investigating the safety and tolerability of
rotigaptide. Rotigaptide was administered as constant intravenous infusion in healthy
volunteers in (i) an ascending single dose study (24 hours infusion) (79 individuals),
(ii) an ascending dose study (six-day continuous intravenous infusion) (36 individuals),
and (iii) infusion with rotigaptide in combination with oral digoxin therapy, a
commonly-prescribed medication for congestive heart failure, with a narrow
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therapeutic window. Rotigaptide was safe and well tolerated in each trial and no drug-
drug interaction with digoxin was observed. The most frequently reported adverse
effect was tissue response at the injection site.
In June 2005, Wyeth commenced an interventional Phase II prevention, randomized,
double-blind, placebo controlled, parallel assignment, efficacy study in patients with
chronic heart disease and acute myocardial infarction. The primary objective of the
trial is to determine whether the administration of rotigaptide will decrease the
occurrence of ventricular arrhythmias in these patients. The study is being conducted as
an international, multi-center, dose finding efficacy trial with about 500 patients at
approximately 80 sites. Zealand Pharma is targeting to receive data based on this study
in 2007.
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Atherosclerosis
Table 5.7 provides an assessment of the current drugs in early stage of development for
the treatment of atherosclerosis. There are a total of 32 chemical entities currently in
preclinicals and a total of 11 new chemical entities have been identified in Phase I of
development.
Table 5.7: Selected Early Stage Atherosclerosis Drug Developments Company Name Product Name Phase of Development Abbott Laboratories KH01500 PC Abbott Laboratories KH01503 PC Abbott Laboratories Reverse D-4F PC Ardana plc EP80317 PC Arena Pharmaceuticals Inc Niacin receptor agonist PC Arisaph Pharmaceuticals, Inc. ARI-1778 PC BioInvent International AB BI-204 PC Biomedica foscama IRFI 042 PC Bristol-Myers Squibb Company EXEL2255 / Liver X Receptor antagonist PC Chronogen CHGN005 PC CliniGenetics SA Docosixine PC CV Therapeutics Inc Reverse cholesterol transport PC Cytos Biotechnology AG Adiponectin PC Cytos Biotechnology AG IL1aQb PC CytRx Corporation Iroxanadine PC Dr Reddys Laboratories Ltd DRL 16805 PC Eli Lilly & Co LY465608 PC Eli Lilly & Co LYYYY PC Exelixis Inc EXEL2255 / Liver X Receptor antagonist PC Exelixis Inc XL335 / Farnesoid X Receptor antagonist PC Genentech Inc BI-204 PC Imclone Systems Inc VEGFR-1 inhibitors / Anti-FLT-1 inhibitors PC Kyoto Pharmaceutical Industries KY-455 PC Liponex Inc. CRD510 PC Miravant Medical Technologies MV-0611 PC Miravant Medical Technologies MV0633 PC Phosphagenics Limited APA-01 and Statin PC Portola Pharmaceuticals, Inc. Platelet Adhesion Inhibitor PC Roche Holdings Ltd Trimeric ApoA-I PC Surface Logix SLx-3XXX PC Vascular Biogenics Ltd. CI-201 PC Wyeth XL335 / Farnesoid X Receptor antagonist PC Dr Reddys Laboratories Ltd RUS 3108 I Genfit GFT 505 I GlaxoSmithKline plc 568859 I GlaxoSmithKline plc 856553 I GlaxoSmithKline plc GSK677116 / 677116 I Continued… Company Name Product Name Phase of Development
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GlaxoSmithKline plc Rilapladib / SB 659032 I Karo Bio AB Liver X receptor (LXR) I Merck & Co Inc MK-6213 I Novartis AG APP018 / D-4F I Trigen Holdings AG PR-15 I Wyeth LXR-623 I
Source: Medtrack Business Insights Ltd
On the 1st May, 2007 Trigen Holdings AG announced the successful completion of its
first-in-man Phase I study of PR-15, the company's innovative platelet adhesion
inhibitor. The action of PR-15 has been likened to that of a `vascular sticking plaster'
due to its ability to prevent firm platelet adhesion to sites of arterial wall damage
including ruptured atherosclerotic plaques. Such adhesion is the first step in platelet
activation and aggregation leading to myocardial infarction (heart attack) and stroke,
and potentially stimulating further progression of atherosclerosis. PR-15 is being
developed as a novel agent to treat acute arterial thrombosis and prevent or retard
progression of atherosclerosis. On December 13th 2006 Trigen announced the initiation
of a Phase I clinical study with its novel lesion-specific platelet adhesion inhibitor PR
15 following strong efficacy displayed in pre-clinical models. PR-15 is being evaluated
in a Phase I single dose clinical study in 36 volunteers at a site in Germany which aims
to define the safety, tolerability and PK/PD profile of the drug candidate. PR-15 is
being developed as a novel agent to treat acute arterial thrombosis and prevent
progression of atherosclerosis following an acute event. On April 11th 2005 Trigen
Holdings plc and ProCorde GmbH announced that they have merged their interests into
Trigen Holdings AG. The combination of Trigen and ProCorde creates a leader in
cardiovascular drug discovery and development, focusing on thrombosis and vascular
dysfunction.
In addition to the early stage developments described in Table 5.7 there are a further 15
Phase II clinical trials that have been identified. On the 2nd July 2007 Anthera
Pharmaceuticals Inc. announced that enrollment of 200 patients in the Phase II
PLASMA (Phospholipase Levels and Serological Markers of Atherosclerosis) trial has
been completed significantly ahead of schedule. The company plans to announce the
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preliminary results later this year and is evaluating the further expansion of the trial.
On 13th April 2007 Anthera Pharmaceuticals, Inc. announced that enrollment has begun
in the company's multi-center Phase II clinical trial (PLASMA -- Phospholipase Levels
and Serological Markers of Atherosclerosis). PLASMA is a double-blind, randomized,
parallel group, placebo controlled study among subjects with stable coronary artery
disease (CAD). Subjects will be randomized to receive either placebo tablets or one of
four orally active doses of A-002. A-002 is a potent inhibitor of secretory
phospholipase A2 (sPLA2) - a family of enzymes which lead to the release of
damaging free fatty acids and lysophospholipids, both of which play a role in the
inflammatory process. The duration of study drug therapy will be eight weeks and
approximately 200 patients in 60 sites in the US and Europe will be enrolled.
On the 4th January 2007 Anthera Pharmaceuticals Inc. announced the US Food and
Drug Administration had approved its Investigational New Drug (IND) application for
its lead cardiovascular compound A-002. As a result of this approval, Anthera will
initiate a multi-center Phase 2 clinical trial (PLASMA - Phospholipase Levels And
Serological Markers of Atherosclerosis) to examine the effect of A-002 on secretory
phospholipase A2 (sPLA2) levels and other well established markers of inflammation
and cardiovascular risk in patients with stable coronary artery disease due to underlying
atherosclerosis. PLASMA is expected to complete enrollment by the fourth quarter of
2007. On the 6th September 2006 Anthera Pharmaceuticals Inc announced it had
entered into a license agreement with Eli Lilly and Company and Shionogi & Co. Ltd.
under which Anthera has obtained worldwide (except for Japan) development and
commercialization rights to an entire platform of clinical and preclinical inhibitors of
phospholipase A2 (PLA2) developed by Lilly and Shionogi as part of their
collaboration.
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Atrial Fibrillation
Table 5.8 provides an assessment of the current drugs in early stage of development for
the treatment of atrial fibrillation. There are a total of 6 chemical entities currently in
preclinicals and a total of 4 new chemical entities have been identified in Phase I of
development.
Table 5.8: Selected Early Stage Atrial Fibrillation Drug Developments Company Name Product Name Phase of Development Devgen nv Dev0304 PC Nissan Chemical Industries, Ltd. NTC-801 PC Symphony Medical, Inc. AV-1 PC SyntheMed Inc Repel-AFIB Drug Delivery PC Teijin Pharma Limited NTC-801 PC Xenon Pharmaceuticals Inc. XEN501 PC Bristol-Myers Squibb Company Ion Channel Inhibitor I ICAgen Inc Ion Channel Inhibitor I Inotek Pharmaceuticals, Inc INO-8875 / PJ-875 I Xention Limited XEN-D0101 I (formerly Xention Discovery Ltd)
Source: Medtrack Business Insights Ltd
Presently in Phase I clinical trials, on 22nd December 2005 Icagen Inc. provided an
update on the Company's atrial fibrillation program undertaken in collaboration with
Bristol-Myers Squibb Company. Bristol-Myers Squibb has been conducting the clinical
development of this program, including a Phase I proof-of-concept study which was
initiated in 2004. As a result of slow enrollment into this proof-of-concept study,
Bristol-Myers Squibb has decided to discontinue this specific clinical trial and is now
considering alternative trial designs.
On the 20th December 2002 Icagen Inc announced the renewal of its research and
development agreement with Bristol-Myers Squibb Company for the discovery and
development of small molecule drugs targeting a specific ion channel involved in atrial
fibrillation, a common cardiovascular disorder in which the heart beats irregularly.
Bristol-Myers Squibb and Icagen elected to renew the collaboration in order to further
116
build upon the significant progress made to date in this area. The renewal provides for
continued research and development funding by Bristol-Myers Squibb.
Congestive Heart Failure
Table 5.9 provides an assessment of the current drugs in early stage of development for
the treatment of congestive heart failure. There are a total of 17 chemical entities
currently in preclinicals and a total of 7 new chemical entities have been identified in
Phase I of development.
Table 5.9: Selected Early Stage Congestive Heart Failure Drug Developments
Company Name Product Name Phase of Development Asklepios BioPharmaceutical Inc. BNP-CHF PC Azevan Pharmaceuticals, Inc. SRX246 PC Biocon Ltd Oral hBNP PC BTG plc Aldosterone antagonists PC Cardiome Pharma Corp BRPM program PC CV Therapeutics Inc CVT-4325 PC Cytopia JAK2 inhibitor PC NanoCor Therapeutics, Inc. Carfostin PC Novavax Inc E-Selectin tolerogen PC NOXXON Pharma AG NOX-F37 PC Opexa Therapeutics Inc Cardiac Stem Cell Therapy PC Palatin Technologies Inc PT-19 PC Sangamo BioSciences Inc ZFP TF PC Sanofi-Aventis AVE4890 PC Unigene Laboratories Inc Calcitonin Gene-Related Peptide (CGRP) PC VasoGenix Pharmaceuticals, Inc. Calcitonin Gene Related Peptide (CGRP) PC Warren Pharmaceuticals, Inc. Tissue Protective Cytokines PC Adenosine Therapeutics, LLC Apadenoson I Cardiome Pharma Corp LY458202 (GED-aPC) I Celladon Corporation Mydicar / SERCA2a gene I Eli Lilly & Co LY458202 (GED-aPC) I NovaCardia, Inc. KW-3902 (Oral) I PDL BioPharma Inc Ularitide I Teijin Pharma Limited TPC-806 I
Source: Medtrack Business Insights Ltd
117
On 17th May 2007 Celladon Corporation and Targeted Genetics Corporation
announced the initiation of a Phase I clinical trial of MYDICAR (AAV1/SERCA2a) in
patients with cardiomyopathy and symptoms of heart failure. Mydicar utilizes an
adeno-associated virus (AAV) vector to deliver the SERCA2a gene to heart muscle
tissue.
The trial, titled "Calcium Up-Regulation by Percutaneous Administration of Gene
Therapy In Cardiac Disease (CUPID Trial)" is a Phase I/II, two-stage, dose-escalation
trial designed to evaluate the safety and feasibility of a single coronary artery infusion
using four dose-levels of an AAV1 vector expressing the transgene for SERCA2a to
subjects with ischemic or non-ischemic cardiomyopathy and NYHA Class III/IV
symptoms of heart failure.
On the 2nd June 2005 Celladon Corporation announced that its collaborators presented
successful results of heart failure trials conducted in large animal models. Such data
presented on the treatment of advanced heart failure in preclinical models using
Celladon's therapeutic agents targets the Sarcoplasmic Reticulum ATPase2a
(SERCA2a) pump. The SERCA2a pump is a central control point for progression of
heart failure, and treatments targeting this pathway essentially reversed the
deterioration in cardiac function in experimental models.
On the 30th April 2007 Cardiome Pharma Corp. announced that it has signed an
exclusive in-licensing agreement with Eli Lilly and Company for LY458202 ("GED-
aPC"), a clinical-stage drug candidate, whereby Cardiome has been granted exclusive
worldwide rights to GED-aPC for all indications. Lilly has successfully completed a
46-person Phase I single-dose placebo-controlled safety study in healthy volunteers for
GED-aPC.
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Hypercholesterolemia
Table 5.10 provides an assessment of the current drugs in early stage of development
for the treatment of Hypercholesterolemia. There are a total of 10 chemical entities
currently in preclinicals and a total of 1 new chemical entity has been identified in
Phase I of development.
Table 5.10: Selected Early Stage Hypercholesterolemia Drug Developments Company Name Product Name Phase of Development Alnylam Pharmaceuticals Inc ALN-PCS01 PC Ardana plc EP80317 PC AVI BioPharma Inc NeuGene HMG-CoA reductase Inhibitor PC Forbes Medi-Tech Inc FM-VP4 with Zocor PC Nisshin Seifun Group Lactobacillus paracasei NLB163 PC REPLICor Inc. REP 9C PC Samaritan Pharmaceuticals Inc SP-1000 PC SCOLR Pharma Inc Niacin PC Shire plc TX-1501 PC World Health Energy, Inc. MAHDL01 PC Microbia MD-0727 I
Source: Medtrack Business Insights Ltd
On the 1st February 2007, Alnylam Pharmaceuticals, Inc. announced that it presented
new pre-clinical data at the "RNAi for Target Validation and as a Therapeutic"
Keystone Symposium held January 28 - February 2, 2007 in Keystone, Colorado. On
the 5th December 2006 Alnylam Pharmaceuticals Inc announced that it will advance a
systemically delivered RNAi therapeutic for the treatment of hypercholesterolemia as
its next clinical development program. This program, in collaboration with University
of Texas (UT) Southwestern Medical Center at Dallas, is focused on evaluating new
approaches for reducing LDL cholesterol levels using RNAi therapeutics directed to
the disease target called proprotein convertase subtilisn/kexin type 9, or PCSK9.
Alnylam expects to submit an investigational new drug (IND) application for this
program in 2007.
119
On the 10th April 2007 Samaritan Pharmaceuticals Inc. announced it received a notice
that a European Patent has been granted to Samaritan's SP-1000 (Cholesterol
Recognition Sequence) drug for the treatment of cardiovascular disease. The European
patent is an examined document, and is enforceable as a patent after registration
requirements have been fulfilled in designated countries. Samaritan is taking the
appropriate steps to register the patent in the following European countries: Austria,
Belgium, Switzerland/Liechtenstein, Spain, France, Great Britain, Italy, the
Netherlands, and Sweden.
On the 28th March 2006 Samaritan Pharmaceuticals Inc. announced that it has new
preclinical data gathered in a series of animal studies that shows its cardiovascular drug
SP-1000 reduces blood cholesterol. Advancing to animal preclinical studies, SP-1000
data indicated that it removes cholesterol from the LDL bad cholesterol-apolipoprotein
complex and it reduces blood cholesterol levels in two different types of
hypercholesterolemic animal models. These models included genetically engineered
and diet-induced hypercholesterolemic animals. This new preclinical data is being
prepared to submit to a peer-reviewed journal.
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Hypertension
Table 5.11 provides an assessment of the current drugs in early stage of development
for the treatment of Hypercholesterolemia. There are a total of 12 chemical entities
currently in preclinicals and a total of 8 new chemical entities have been identified in
Phase I of development. Currently the leading anti-hypertensive is Norvasc with global
sales in 2005 of $5bn, an increase of 3.9% from 2004. In the US, sales of Norvasc was
$2.6 billion in 2006 a slight increase from sales of $2.5 billion in 2005. Higher growth
rates were seen for other leading anti-hypertensive drugs such as Novartis’ Co-Diovan. In
the US, sales of Co-Diovan was $1.003 billion in 2006 a significant increase from sales of
$0.840 billion in 2005. Co-Diovan/Diovan have benefited from positive clinical trial
results, in particular a controlled trial of Co-Diovan resulted in additional lowering of
systolic and diastolic blood pressure compared to Diovan alone.
Table 5.11: Selected Early Stage Hypertension Drug Developments
Company Name Product Name Phase of Development
BioLineRx, Ltd. BL-2040 PC BTG plc Aldosterone antagonists PC Cary Pharmaceuticals Inc. Tempol PC Exelixis Inc XL550 PC Merck & Co Inc NCX 899 PC NicOx S.A. NCX 899 PC Novavax Inc NX-302 (clonidine) PC Rottapharm (Rotta Research Laboratorium SpA) CR 2991 PC Rottapharm (Rotta Research Laboratorium SpA) CR 3834 PC Speedel SPP1100 series PC Torrent Pharmaceuticals, Ltd. TRC-9XXX PC Vitae Pharmaceuticals, Inc. Renin Inhibitor PC (formerly Concurrent Pharmaceuticals) Daewoong Pharmaceutical Co. Ltd. Doxazosin SR I Dov Pharmaceutical Inc DOV Diltiazem I Eurand Zanidip MR (lercanidipine I hydrochloride) / LCP-Lerc IntelGenx Corp. INT001 I LifeCycle Pharma Zanidip MR (lercanidipine I hydrochloride) / LCP-Lerc Medicure Inc MC-4262 I Novartis AG LCI699 I Novartis AG VNP489 I
Source: Medtrack Business Insights Ltd
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On the 14th November 2006 NicOx S.A. announced very good preclinical results on a
prototype compound from its ongoing research collaboration with Merck & Co. Inc as
were reported by the two companies in an oral presentation at the American Heart
Association (AHA) Scientific Sessions. These results suggest that NicOx' proprietary
nitric oxide-donating technology may have the potential to improve the blood pressure
lowering activity of antihypertensive agents. Enalapril, a common anti-hypertensive
drug and equimolar doses of NCX 899, a nitric oxide-donating derivative of enalapril,
were studied in aged spontaneously hypertensive rats, a validated model of
hypertension. NicOx and Merck consider NCX 899 as a prototype compound for
demonstrating the increased activity of nitric oxide- donating antihypertensive agents.
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Myocardial Infarction
Table 5.12 provides an assessment of the current drugs in early stage of development
for the treatment of myocardial infarction. There are a total of 16 chemical entities
currently in preclinicals and a total of 4 new chemical entities have been identified in
Phase I of development.
Table 5.12: Selected Early Stage Myocardial Infarction Drug Developments Company Name Product Name Phase of Development BioDiem Ltd BDM-K PC BioLineRx, Ltd BL-1040 PC Cardax Pharmaceuticals, Inc. Cardax (astaxanthin) PC CliniGenetics SA Nimoxine PC Diffusion Pharmaceuticals LLC TBC (trans bipolar carotenoid) molecules PC MI BioSciences, Inc. DMI-4983 PC EpiCept Corp MX1013 / CV1013 PC Evolutec Group plc rEV576 PC Lev Pharmaceuticals Inc C1-INH PC Lpath Inc Sphingomab PC Molecular Targeting Technologies, Inc. Myoseal PC RegeneRx Biopharmaceuticals Inc Thymosin Beta 4 PC StemPath, Inc. SP200aFL PC iaCell Inc Unrestricted Somatic Stem Cells / USSCs PC Warren Pharmaceuticals, Inc. Tissue Protective Cytokines PC Xigen S.A. XG-102 / D-JNKI PC Amorcyte Inc. AMR-001 I DeCODE genetics Inc DG051 I Hunter-Fleming Ltd HF0220 I Osiris Therapeutics Inc Provacel I
Source: Medtrack Business Insights Ltd
On June 6th 2007, BioLineRx Ltd announced it has submitted a request to a European
regulatory agency to begin pilot (Phase I/II) clinical trials of BL-1040, an absorbable
implant to treat cardiac tissue damaged as the result of an acute myocardial infarction
(heart attack or MI). The submission comes following BioLineRx's successful
completion of pre-clinical studies of BL-1040. The multi-center, open label study will
be conducted at several sites in selected European countries and Israel. The results of
the study will provide feasibility data that the Company will use to support the pivotal
123
clinical trial that is intended to form the basis of the pre-market approval application
for BL-1040 with the U.S. Food and Drug administration.
On the 27th June 2006 Amorcyte Inc announced it has signed an exclusive agreement
for the development and manufacturing of Amorcyte's lead product, AMR-001, with
Progenitor Cell Therapy LLC. The Phase I trial is open at Emory University School of
Medicine. Amorcyte is in final negotiations to open the trial in another leading
cardiology center within 90 days. Amorcyte is actively recruiting patients for the trial.
On the 8th May 2007 Amorcyte, Inc. announced the completion of the second of four
dose cohorts in its Phase I clinical trial. The trial will now await review of the data by
the data safety monitoring board (DSMB) in accordance with the protocol. The Phase I
trial initially opened in June at the Emory University School of Medicine in Atlanta,
Georgia under Principal Investigator, Arshed A. Quyyumi, MD, FRCP, FACC. The
second and third sites to were the Vanderbilt University School of Medicine and the
Texas Heart Institute at St. Luke's Episcopal.
On the 25th March 2007 Osiris Therapeutics, Inc. announced the positive six-month
results in a groundbreaking clinical trial evaluating Provacel, an adult mesenchymal
stem cell (MSC) therapy for the treatment of heart disease. In a 53-patient, double-
blind, placebo-controlled study evaluating the safety and preliminary efficacy of the
intravenous administration of Provacel, heart attack patients receiving the therapy had
significantly lower rates of adverse events, such as cardiac arrhythmias, as well as
significant improvements in heart, lung and overall condition. Administration of
Provacel was found to be well tolerated at all dose levels.
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Thrombosis
Table 5.13 provides an assessment of the current drugs in early stage of development
for the treatment of thrombosis. There are a total of 23 chemical entities currently in
preclinicals and a total of 12 new chemical entities have been identified in Phase I of
development. BMS/Sanofi-Aventis’ Plavix (clopidogel) an anti-platlet and used for the
treatment of patients that have had a stroke or MI, or are diagnosed as having concomitant
hypertension and vascular disease leads the market with sales of $5.8bn in 2005, an
increase of 16.4% from the previous year.
According to IMS data sales of Plavix in the United States alone amounted $2.831 billion
in 2006, a significant decrease since 2005 when they stood at $3.377 billion. Plavix’s sales
in the United States have come under significant pressure from generic competition,
particularly from the generic competitor made by Apotex in 2006. Bristol Myers Squibb
and Sanofi-Aventis are locked in a patent battle with Apotex of Canada, which
launched a generic version of the blood thinner on August 8 2006 in spite of unresolved
litigation. Under terms negotiated between Apotex, Bristol and Sanofi, Apotex was
allowed a window to launch its version of Plavix before Bristol and Sanofi challenged
the launch in court. This provision allowed Apotex to "flood the market", according to
Bristol's lawyers, with cheaper generic Plavix. Apotex's generic Plavix had already
captured up to 78 per cent market share for new prescriptions and could continue to
hold that depending on how much stock it sold.
Another threat to Plavix is from its main competitor, aspirin, which is highly effective,
well tolerated and widely genericized. In January 2005, data from a small-scale trial
published in The New England Journal of Medicine indicated that Plavix had a much
higher risk of recurrent ulcers, compared to aspirin plus Nexium (esomeprazole).
Plavix administration demonstrated an 8.6% renewed ulcer bleeding, compared to 0.7%
induced when patient took aspirin and Nexium combined. If this data is demonstrated
in a widescale trial, and built upon by showing data for Plavix plus Nexium, this may
impact future sales growth.
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Table 5.13: Selected Early Stage Thrombosis Drug Developments Company Name Product Name Phase of Development Ablynx nv ALX-0081 PC Advanced Gene Technology Corp. AGT168 PC AERES Biomedical Ltd. ABC-48 PC Affimed Therapeutics AG AFM14 PC Arena Pharmaceuticals Inc APD791 PC AstraZeneca Plc AZD1283 PC BioInvent International AB TB-402 PC Biotie Therapies Oyj Alpha2Beta1 Integrin Inhibitors PC Cerylid Pty Ltd CBL1309 PC Chromos Molecular Systems, Inc CHR-1201 / NHAT PC CliniGenetics SA Nimoxine PC EluSys Therapeutics, Inc. tPA HP PC HealthLinx Limited CR001 PC formerly Cryptome Pharmaceuticals) MediciNova Inc MN-447 PC MediciNova Inc MN-462 PC Medicure Inc MC-45308 PC Pfizer Inc ADP receptor antagonist PC ThromboGenics NV Anti-Factor VIII antibody PC Thrombotargets Corporation TT-C01 PC Toray Industries, Inc. TRA-418 PC Torii Pharmaceutical Co., Ltd. FUT-187 (sepimostat mesilate) PC TransTech Pharma, Inc. TTP896 PC Yuhan Anti-Thrombotic Agent PC Ajinomoto Co., Inc. AJW200 I Akzo Nobel NV Org 27306 I Emisphere Technologies Inc Oral Low Molecular Weight Heparin I Kissei Pharmaceutical Co., Ltd. KFA-1982 I Merck KGaA EMD 503982 I Merrion Pharmaceuticals MER-102 I Myriad Genetics Inc MPC-0920 I NV Organon Org 27306 I Teijin Pharma Limited TC-10 I Trigen Holdings AG Flovagatran / TGN 255 I Trigen Holdings AG TGN 167 / TRI 50b-oral I Wyeth Diaplasinin / PAI-749 I
Source: Medtrack Business Insights Ltd
On the 1st November 2006 MediciNova Inc. announced the acquisition of two novel
small molecule cardiovascular agents from Meiji Seika Kaisha Ltd. MN-447 and MN-
462 are antithrombic (anti-clotting) agents that represent novel approaches to blood
clot formation and lysis respectively, and are expected to treat a variety of thrombotic
disorders.
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On the 12th February 2007 ThromboGenics NV and BioInvent International AB
announced they have received approval from the Danish Medicines Agency to initiate a
Phase I clinical trial of the novel anticoagulant TB-402. TB-402 is a human antibody
binding to Factor VIII which plays a crucial role in the coagulation of the blood. The
project is being developed within the framework of the alliance between
ThromboGenics and BioInvent. The study is a randomized, placebo-controlled, dose
escalation trial in healthy volunteers, and the objective is to investigate safety,
tolerability and pharmacokinetic properties of the candidate drug. It is expected that the
first subjects will be recruited in the study soon, and that the results will be presented in
late 2007. Given a positive outcome of the initial Phase I study, the parties plan to
follow this up with a Phase IIa programme in patients undergoing orthopedic surgery
who are at risk of thrombosis. TB-402 is also expected to be developed as a potential
treatment to prevent blood clot formation in connection with certain types of heart
arrhythmia, such as atrial fibrillation.
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Chapter 6
NEW AND EMERGING CARDIOVASCULAR DRUGS
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Chapter 6 New and Emerging Cardiovascular Drugs
Summary
Two key anti-hypertensives are forecast to launch in 2007: Novartis’ Rasilez (aliskiren) and Exforge (valsartan plus amlodipine).
On the 6th March 2007, the US FDA approved Tekturna® (aliskiren) for use in the US for Novartis. On the 28th September 2006, Novartis submitted Tekturna to the European Medicines Evaluation Agency (EMEA) as a treatment for high blood pressure. Approval by the EMEA is expected by the end of 2007.
It is anticipated that Exforge will be available to patients in the US in September 2007, pending the patent expiry of amlodipine besylate. In January 2007 Novartis announced that the European Commission has granted approval for Exforge®. The EU decision applies in all 27 EU member states plus Iceland and Norway
In December 2006, Pfizer announced that it would discontinue the development of its cholesterol drug torcetrapib. Torcetrapib was one of Pfizer's most promising pipeline drugs and was anticipated to replace revenue lost when Lipitor’s patent protection expires in 2010.
In April 2007, Abbott Laboratories announced that they had submitted a NDA to the FDA for a fixed-dose combination of Niaspan® (extended-release niacin) and simvastatin. Abbott Laboratories anticipate that they will obtain marketing approval for Simcor by the third quarter 2007 and hope to launch at the beginning 2008.
A major blow to the anti-thrombotics pipeline is the discontinuation of AstraZeneca’s Exanta in January 2006, due to concerns of liver toxicity. Exanta (ximelagatran) was expected to achieve high sales when launched and to challenge sales of warfarin.
Solvay Pharmaceuticals announced on 25th April 2007 that they had submitted and filed a dossier for intravenous anti-thrombotic tedisamil for approval by the US FDA as well as by the authorities of European Union countries.
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Introduction
This chapter reviews the status and progress of cardiovascular drugs in their late stage
development proving analysis of completed and ongoing clinical trials, with information
on launch dates and forecast sales by cardiovascular therapeutic class.
Anti-Hypertensives
Antihypertensives are a class of drugs that are used in medicine and pharmacology to
treat hypertension (high blood pressure). There are many classes of antihypertensives,
which - by varying means - act by lowering blood pressure. The major classes are
Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin II Receptor
Antagonists, Alpha/Beta Blockers, Beta Blockers, Centrally Acting, Peripherally
Acting, Calcium Channel Blockers (CCB), Diuretics, Drugs Acting on Vascular
Smooth Muscle and other miscellaneous preparations.
Growth in the anti-hypertensives market is principally driven by sales of the ARBs,
which continue to benefit from patent protection. Sales of the Angiotensin II Receptor
Blockers (ARBs) have increased following the expansion of the ACE-intolerant
population (due to an increase in prescribing of ACE inhibitors) and positive trial
results for major brands in additional indications
Evidence suggests that reduction of the blood pressure by 5-6 mmHg can decrease the
risk of stroke by 40%, of coronary heart disease by 15-20%, and reduces the likelihood
of dementia, heart failure, and mortality from cardiovascular disease. Preliminary
research suggests that antihypertensives may lower the risk of Alzheimer’s disease.
The level of innovation within the antihypertensives market is relatively active, with
many drugs in development offering minimal increased safety, efficacy and tolerability
compared to currently marketed products. However, the launch of Novartis’ Tekturna
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(aliskiren) in the United States early in 2007 and the anticipated launch in Europe later in
2007 early 2008 will provide the first-in-class of a new class of antihypertensive drugs, the
direct renin inhibitors. Previous attempts at treating hypertension by novel mechanisms
have failed, with the most notable attempt being Bristol-Myers Squibb’s Vanlev
(omapatrilat), which was set to be the first in class of antihypertensive agents, the
vasopeptidase inhibitors.
Tekturna (Aliskiren)
Novartis’ Tekturna (aliskiren), formerly known as Rasilez™ is the first in FDA approved
drug in a class of orally active transition-state renin inhibitors. Renin inhibitors represent
the newest generation of drugs capable of blocking the clinically relevant renin-
angiotensin cascade. They block - in contrast to ACE-inhibitors and Angiotensin II
receptor antagonists - this cascade at its top, i.e. at the level of its first enzyme (renin).
This mode of action promises high specificity, excellent tolerability and the potential
for treating hypertension and associated diseases. Tekturna is a potent and specific in
vitro inhibitor of human renin and has good water solubility and low lipophilicity.
Novartis’ Tekturna (aliskiren, SPP100) is been developed as a result of a collaborative
agreement between Novartis and the Swiss based company Speedel. Speedels lead product
candidate SPP100 (aliskiren, Tekturna®), was in-licensed from Novartis in 1999 and
licensed-back to Novartis Pharma in 2002 for further development and
commercialization.
In March 2004 Novartis started trials with Tekturna in Phase III as monotherapy for
hypertension and in Phase IIb as combination therapy. However, clinical trail data did not
present significant improvements in blood pressure control compared to currently marketed
antihypertensive drugs, but Tekturna has shown additional benefits of reducing early
morning elevations to blood pressure. Moreover, at the end of the trial when study
medication was withdrawn, the blood pressure lowering effect of Tekturna persisted as
diastolic blood pressure did not return to pre-study medication levels for two weeks.
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Clinical data presented for Tekturna as a monotherapy and in combination with a diuretic,
an ACE inhibitor and a CCB, show strong efficacy but with no significant advantage over
established therapies. However, Novartis’ key aim is to prove that the renin-inhibition
provides improved end-organ protection. Ongoing biomarker studies are anticipated to
provide further support for Tekturna, which is dependent on positive impacts on kidney
and cardiovascular function.
Oral renin inhibitors have the potential to become the next blockbuster antihypertensive
drug class. The introduction of the renin inhibitors will mark the first novel treatment for
hypertension in over a decade and, because of this, many physicians will want to try
Tekturna on their difficult-to-control patients, particularly in combination with other
classes of antihypertensive drugs such as the ACE inhibitors and CCBs. Tekturna’s ability
to control blood pressure over a 24-hour period, leading to true 24-hour efficacy, has the
potential to reduce many of the cardiovascular outcomes associated with hypertension,
such as stroke.
Phase 3 trials with Tekturna are ongoing in the United States, Europe, and Japan.
Novartis made the first regulatory submission for Tekturna to the US FDA on the 20th
April 2006 based on data from more than 6,000 patients in 34 trials. On the 28th
September 2006 Novartis submitted Tekturna to the European Medicines Evaluation
Agency (EMEA) for approval as a treatment for people with high blood pressure using
data from more than 7,800 patients with high blood pressure from 44 clinical trials. On
the 6th March 2007 Novartis announced that the US FDA had approved Tekturna®
(aliskiren) for use in the United States. On the 21st May 2007 a single-tablet
combination of two high blood pressure medicines - the recently approved direct renin
inhibitor Tekturna® (aliskiren) and the widely-used diuretic hydrochlorothiazide - was
submitted for US regulatory approval. Although approval had not been provided by the
EMEA at the time of writing it is expected that approval to be attained by the end of
2007.
Novartis will be ideally placed to market Tekturna® (aliskiren) as they currently market
the leading antihypertensive. Although Tekturna® (aliskiren) has the potential to lead to
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cannibalization of Diovan’s sales, it is predicted they will use separate sales forces to
promote Diovan and Tekturna® (aliskiren) using differentiated target populations to
ensure that market share is not taken from Diovan. Sales of Tekturna® (aliskiren) are
predicted to reach $700m by 2011.
Development of a New Class of Renin Inhibitors
SPP600 Series, SPP635, SPP800 Series, SPP1000 Series and SPP1148 are renin
inhibitors included in the research and development pipeline of the Swiss based
biotechnology company Speedel.
In December 2001, Speedel acquired exclusive worldwide rights to Roche's renin
inhibitor programme. The agreement covers a new class of renin inhibitors that has
been discovered by Roche. Through this agreement Speedel obtains exclusive access to
late-stage research compounds as well as related structure-activity knowledge.
The SPP600 series is a novel group of renin inhibitors being developed in a targeted
lead optimization programme by Speedel Experimenta. Under this programme Speedel
is generating its own molecules and intellectual property
In February 2005 Speedel Experimenta successfully completed the first human micro-
dosing studies of new renin inhibitors SPP630 and SPP635 for the treatment of
hypertension and for protecting end-organs such as the heart, kidneys and blood
vessels. On the 31st October 2006 Speedel announced that they had reached another
significant milestone in the development of its family of renin inhibitors with the start
of a Phase IIa clinical trial with SPP635 for the treatment of hypertension. The trial is
expected to finish in about Q3 2007.
Speedel has reached late-stage preclinical profiling of a new series of renin inhibitors
designated as the SPP1100 series. Currently SPP1148 is the most promising compound
candidate from the SPP1000 series of renin inhibitors. The SPP1148, indicated for the
treatment of hypertension and related end-organ disease, entered Phase I in January
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2007. The Phase I trial will test the safety and tolerability of single and multiple oral
doses in healthy volunteers and first results are expected in Q4 2007. SPP1148 is part
of the SPP1100 series of renin inhibitors invented by Speedel Experimenta, the
company’s late-stage research unit, established in 2002.
SPP1148 was selected on the basis of better animal bioavailability, positive effects on
renal failure models in animals, and its suitability for manufacturing. The SPP1100
series is based on a new chemical entity compared to other renin inhibitors and this
diversity adds further strength to the pipeline.
Exforge (valsartan plus amlodipine)
In addition to Tekturna®, Novartis has been developing another highly anticipated anti-
hypertensive known as Exforge. Exforge combines in one tablet the two most commonly
prescribed hypertension medicines in their categories -- Diovan(R) (valsartan) and
Norvasc(R) (amlodipine besylate). Exforge is indicated for patients whose blood
pressure is not adequately controlled on any dihydropyridine calcium channel blocker
(CCB) or angiotensin receptor blocker (ARB). Also, it is appropriate for patients who
experience dose-limiting side effects on either component, such as amlodipine-induced
edema, dizziness and flushing.
In clinical trials Exforge demonstrated clinically significant blood pressure reductions.
Adverse reactions were generally mild and transient in nature. The most common side
effects in clinical trials were peripheral edema, nasopharyngitis, upper respiratory tract
infections and dizziness. The incidence of peripheral edema was statistically lower in
people treated with Exforge than in people treated with amlodipine monotherapy.
Novartis has developed Exforge as part of a lifecyle management technique to protect sales
of Diovan, once it loses patent protection. Exforge shares common molecules with both
FDC therapies Co-Diovan (common component being the ARB valsartan) and Lotrel (the
common component being the CCB amlodipine). Novartis is hoping that physicians will be
persuaded to switch patients currently using Co-Diovan or Lotrel to Exforge, as Exforge
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has a better tolerability. Exforge is forecast to take market share from existing patient
groups rather than expand the market.
Novartis had not released much information relating to late stage clinical trials for Exforge,
but at the company’s annual analyst meeting in January 2006 they provided some
indication as to the safety and efficacy of Exforge in severe hypertensive patients. Phase III
clinical trial data for Exforge was presented American Society of Hypertension in May
2006. Over 80% of Exforge patients studied reached their recommended blood pressure
goals, with reductions in blood pressure of up to 43 mmHg in some groups. In addition,
Exforge also showed a lower incidence of peripheral edema (swelling of the ankles)
compared to those taking amlodipine alone.
On the 22nd December 2006 Novartis announced that the US FDA had issued
“tentative” approval of Exforge as a new treatment option for patients with high blood
pressure. The US FDA issued this approval notice because Exforge has met all the
required standards for safety, efficacy and manufacturing quality. Exforge is expected
to be available to patients in the US in late September 2007, pending the expiration of
market exclusivity and patent protection for amlodipine besylate.
On the 18th January 2007 Novartis announced that the European Commission has
granted approval for Exforge® with its initial launch into Germany followed by
launches in most other European Union countries throughout the year, pending
expiration of the patent protection for Norvasc. The EU decision applies in all 27 EU
member states plus Iceland and Norway.
CHF-1521
CHF-1521 is a fixed-dose combination of the CCB manidipine and the ACE delapril, being
developed by Chiesi. CHF-1521 is currently in registration in the US and has already been
approved in Italy. Chiesi is ready to launch CHF-1521 in Italy, but is waiting for an official
pricing and reimbursement status from the Italian Medicines Agency (AIFA).
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Clinical trial data for CHF-1521 is limited, but does indicate that a combination of the CCB
manidipine with the ACE delapril is a safe and effective treatment for hypertension
compared to other combination treatments, such as ACE/diuretic combinations. CHF-1521
will face competition from the market leading combination ACE/CCB: Novartis’s Lotrel
(benazepril plus amlodipine). Additionally, there are two other ACE/CCB combinations,
AstraZeneca’s Lexxel (enalapril plus felodipine) and Abbott’s Tarka (trandalopril plus
verapamil).
There are relatively few other ACE/CCB combinations on the market, and because of this
CHF-1521 has ideal market conditions for a successful launch. However, the efficacy of
combined manidipine and delapril is lower compared to other combinations that could be
developed. Novartis’s pipeline combination product Exforge (valsartan plus amlodipine) is
considered to be better received by prescribing physicians and be a huge commercial
success. Sales of CHF-1521 are forecast to reach $5m in 2011, with a launch date of 2008.
Cleviprex(TM) (Clevidipine)
Cleviprex(TM) (Clevidipine) is a novel, investigational drug belonging to a well-
known class of drugs called dihydropyridine calcium channel antagonists. It is the first
third-generation dihydropyridine calcium channel blocker that acts rapidly and reliably,
is vascular- and arterial- selective, and has an ultrashort half-life.
In May 2003 The Medicines Company exercised an option negotiated in March 2002 to
acquire exclusive worldwide development and commercial rights of Clevelox from
AstraZeneca.
In total, Cleviprex(TM) (Clevidipine) has been evaluated in 3 Phase I studies, 8 Phase
II studies and 5 Phase III clinical studies which have been conducted in healthy
volunteers cardiac surgery patients, in patients with essential hypertension, and include
comparative studies versus nitroglycerin nicardipine and sodium nitroprusside. The
Medicines Company announced on the 27th March 2007 the results of 3 Phase III
clinical trials known as ECLIPSE. The ECLIPSE program included a total of 1,964
cardiac surgery patients each enrolled in one of three randomized, open-label trials
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comparing Cleviprex to current intravenous antihypertensive agents: nitroglycerin,
sodium nitroprusside or nicardipine (ECLIPSE-NTG, ECLIPSE-SNP and ECLIPSE-
NIC trials, respectively).
Another safety study known as the VELOCITY study is now completed. The primary
objective of this study was to evaluate if patients presenting through the emergency
department with severe hypertension can have their blood pressure lowered in a safe
and controlled fashion using clevidipine. Secondary objectives in this study include
time to reach target blood pressure and hemodynamic measurements. This study
employs an open label, single arm design.
Additional clinical trials of clevidipine are underway to investigate
electrocardiographic safety in healthy volunteers; pharmacokinetics,
pharmacodynamics and safety in patients with mild to moderate essential hypertension
during prolonged hours (>72 hours) continuous infusion, and safety and efficacy in
patients with severe hypertension.
Based on the results of the Phase III trials that have been conducted the Medicines
Company expects to submit a new drug application to the FDA for Cleviprex(TM)
(clevidipine) in June 2007 with an anticipated launch date of late 2007 and early 2008.
Antihypertensives: Current Pipeline and Late Stage Development
Tekturna (formerly known as Rasilez™) or Aliskiren by Novartis. Aliskiren is an
oral direct renin inhibitor (SPP100) and is indicated as adjunctive treatment for
hypertensive patients with stable heart failure. A new drug application for aliskiren was
submitted to the US FDA in early 2006. Novartis has also submitted aliskiren to the
European Medicines Agency and is not yet licensed in Canada.
Exforge (Valsartan plus amlodipine) by Novartis. Exforge is indicated for patients
whose blood pressure is not adequately controlled on any dihydropyridine calcium
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channel blocker (CCB) or angiotensin receptor blocker (ARB). Approved both in the
US and Europe. Anticipated launch throughout 2007.
CHF-1521 (Manidipine+delapril) by Chiesi Farmaceutici SpA. CHF-1521 is a
fixed-dose combination of the CCB manidipine and the ACE delapril. Phase III clinical
trials completed and currently in registration process in the US
Clevelox (Clevidipine, i.v.) by The Medicines Company/ AstraZeneca. Clevidipine
belongs to a well-known class of drugs called dihydropyridine calcium channel
antagonists. Completion of Phase III ECLIPSE clinical trials anticipated submission of
results to the US FDA in June 2007.
Cardoxal (MC-4232) by Medicure Inc. This is a combination drug containing MC-1,
a cardioprotective drug with the ACE inhibitor, lisinopril. Cardoxal (MC-4232) is used
for the treatment of diabetic patient suffering with high blood pressure. Completed
Phase II MATCHED study (MC-1 and ACE Therapeutic Combination for
Hypertensive Diabetics). Plans to commence pivotal Phase III clinical development
program 2007. Planned launch date 2010-2011.
Darusentan by Gilead Sciences (Gilead acquired Myogen November 2006).
Darusentan is a type-A selective (ERA) and potent inhibitor of endothelin-induced
vasoconstriction. Darusentan is indicated for the treatment of patients with resistant
hypertension. Phase II completed and enrollment taking place in 2 Phase III clinical
trials.
Nebivolol by Mylan Laboratories/, Forest Laboratories, Inc. Nebivolol is a
selective beta 1-adrenergic (cardioselective) receptor antagonist indicated for the
treatment of hypertension. Marketed in 50 countries outside the North America.
Currently under U.S. regulatory review for the treatment of hypertension.
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SPP600 Series, SPP635, SPP800 Series, SPP1000 Series and SPP1148 (renin
inhibitors) by Speedel. These NCEs are indicated as adjunctive treatment for
hypertensive patients with stable heart failure. Preclinical, Phase I and Phase IIa
(SPP635).
Thelin™ (Sitaxentan) by Encysive Pharmaceuticals. Indicated for patients with
primary pulmonary hypertension and pulmonary hypertension associated with
connective tissue disease (CTD). Marketing authorization granted for in the European
Union August 2006. Currently marketed in 4 European countries i.e. Ireland, Germany,
The Netherlands and the UK. The FDA has designated the review as a Class 2
resubmission and issued a new Prescription Drug User Fee Act (PDUFA) target action
date of June 15, 2007.
Zanitek® by RECORDATI SpA. This is a combination drug containing CCB Zanidip
(lercanidipine), and the ACE inhibitor enalapril. Zanitek® is used to treat hypertension.
Completed clinical trials and due to be launched in Germany in May 2007 and rest of
Europe throughout 20072008.
Cardoxal (MC-4232) (MC-1 cardioprotectant plus lisinopril)
Cardoxal (MC-4232) is a novel combination drug for the treatment of diabetic patients with
hypertension being developed by Medicure. Cardoxal (MC-4232) is a fixed dose combination
product containing MC-1 (pyridoxal 5’-phosphate), and the ACE inhibitor lisinopril. MC-1
is a naturally occurring, cardioprotective small molecule, which has been shown to act by
protecting cardiomyocytes. Medicure is developing Cardoxal (MC-4232) for patients with
coexisting conditions of diabetes and hypertension.
A Phase II trial was initiated in April 2004 to assess the safety and efficacy of Cardoxal
(MC-4232) in 15 hypertensive patients. Following positive data generated from this trial,
Medicure initiated the MATCHED (MC-1 and ACE therapeutic combination for
hypertensive diabetics) trial, a randomized, parallel group, cross-over, double-blind,
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placebocontrolled comparison of MC-1 alone and in combination with lisinopril. In
September 2005, Medicure announced positive results from the study, with all primary
blood pressure and metabolic endpoints being met. Phase III trials are in the process of
being initiated and as a result of the current positive clinical trial data Cardoxal is likely to
receive a high level of partnering interest. Partnering for this product is essential for
Medicure to gain access to additional clinical expertise and to gain the funding required to
advance the drug through later-stage clinical development. Cardoxal is forecast to launch in
2010, reaching sales of $15-20m in 2011.
Darusentan
Myogen Inc. had been developing Darusentan a type-A selective endothelin receptor
antagonist (ERA) and potent inhibitor of endothelin-induced vasoconstriction.
Darusentan has progressed through to Phase IIb clinical trials. In June 2006 Myogen
initiated Phase III clinical trials to evaluate darusentan for patients with resistant
hypertension. Because the study had enrolled patients very slowly, they made
modifications to the study’s protocol which, following discussion with regulatory
authorities was allowed as a method of increasing the enrollment rate in the study. On
the 17th November 2006 Gilead Sciences Inc acquired Myogen Inc.
Ambrisentan
With the purchase of Myogen Inc Gilead Sciences Inc acquired Myogen’s lead product
candidate, ambrisentan. Ambrisentan is a non-sulfonamide, propanoic acid-class,
endothelin receptor antagonist that is selective for the endothelin type-A (ET(A))
receptor. Activation of the ET(A) receptor by endothelin, a small peptide hormone,
leads to vasoconstriction and cell proliferation. PAH is associated with elevated
endothelin blood levels. Ambrisentan has been granted orphan drug designation for the
treatment of PAH in both the United States and European Union.
In December 2006, Gilead Sciences Inc completed the submission of a New Drug
Application (NDA) to the FDA for marketing approval of ambrisentan (5 mg and 10
mg) for the once-daily treatment of pulmonary arterial hypertension (PAH). In
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February 2007, the FDA granted Gilead Sciences Inc a priority review status for the
NDA for marketing approval of ambrisentan, and established a target review date of
June 2007. On the 23rd March 2007 Gilead Sciences, Inc. announced that
GlaxoSmithKline's Marketing Authorization Application (MAA) for ambrisentan for
the treatment of pulmonary arterial hypertension (PAH) was validated by the European
Medicines Agency (EMEA) following a review by the Committee for Medicinal
Products for Human Use (CHMP). Following the validation of an MAA, the dossier is
distributed to members of the CHMP for formal review. As a result of this validation
Gilead will receive a milestone payment from GlaxoSmithKline.
Nebivolol
Nebivolol is a selective beta 1-adrenergic (cardioselective) receptor antagonist with
vasodilating properties and is already approved and successfully marketed for the
treatment of hypertension in more than 50 countries outside of North America. On 1st
May 2007 Mylan Laboratories announced that they had a submitted a response to the
approvable letter issued by the US FDA for nebivolol currently under U.S. regulatory
review for the treatment of hypertension. Upon acceptance of this response, Forest
Laboratories Inc anticipates the FDA will complete its review of nebivolol's NDA
within six months. Forest licensed nebivolol from Mylan Laboratories in January 2006
and has responsibility for all sales and marketing as well as the current and future
development programs.
Zanipress® / Zanitek®
The Italian company Recordati has been developing Zanipress® / Zanitek®
(lercanidipine+enalapril), a fixed dose combination of its lead cardiovascular product, the
CCB Zanidip (lercanidipine), and the ACE inhibitor enalapril. Both lercanidipine and
enalapril have been shown to be effective antihypertensive drugs as monotherapies, with
lercanidipine possessing a better side-effect profile compared to other dihydropyridine
CCBs, such as amlodipine. There are some concerns as to whether Zanipress will be a
commercial success, which center around poor physician awareness of the product and
unwillingness to prescribe it during its first years on the market and opinions regarding the
relative merits of an ACE/CCB combination.
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On the 27th July 2006 Recordati announced that they had received the approval for
Zanitek®, from the BfArM, the German medicines agency. Germany will act as
Reference Member State in the mutual recognition approval process for the rest of
Europe which is expected to be completed during 2007. A further announcement was
made on the 21st December 2006 when Recordati announced that they had signed a
non-exclusive agreement with sigma-tau, a leading Italian pharmaceutical company, for
the marketing and sale of Zanitek® in Italy (known as Zaneril® in Italy). The launch is
expected to take place at the beginning of 2008 following approval in 2007. Other
agreements have already been completed with other companies for the sale of
Zanitek®, in France, Spain, Benelux, the Nordic countries including Finland, Korea,
Australia, Taiwan, the Middle East including Israel, and South Africa.
Thelin™ (Sitaxsentan)
Encysive Pharmaceuticals (formerly Texas Biotechnology Corporation), is developing
a sulfonamide class endothelin receptor antagonists under the generic name of
Sitaxsentan and plans to market it under the brand name of Thelin™. Thelin™ is
proving to be effective in the treatment of a variety of diseases such as hypertension
where the regulation of vascular constriction is important. Encysive Pharmaceuticals
received European Union marketing authorization for THELIN from the European
Commission in August 2006 and is currently being marketed in Germany, the UK,
Ireland, and on the 16th April 2007 became available in The Netherlands for the
treatment of pulmonary arterial hypertension (PAH).
Encysive Pharmaceuticals announced in December 2006 that the US FDA has accepted
for review the Company's complete response to the July 24, 2006 approvable letter
regarding its NDA for THELIN. The FDA has designated the review as a Class 2
resubmission and issued a new Prescription Drug User Fee Act (PDUFA) target action
date of June 15, 2007.
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TBC3711
Encysive Pharmaceuticals is also developing the next-generation endothelin antagonist
for both oral and intravenous formulations. TBC3711 is more potent than THELIN,
with selectivity for the endothelin A receptor of 100,000:1 versus the endothelin B
receptor. This higher selectivity may make TBC3711 effective in treating high blood
pressure, particularly in patients with resistant hypertension where current anti-
hypertension drugs are ineffective in lowering blood pressure. Encysive
Pharmaceuticals expect that Phase II dose-ranging studies of oral TBC3711 in the
treatment of resistant hypertension will recommence in 2007. Encysive
Pharmaceuticals have also filed an Investigational New Drug (IND) application with
the FDA seeking approval to evaluate intravenous TBC3711 in a currently undisclosed
indication.
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Anti-Dyslipidemics
Dyslipidemia is abnormal lipid metabolism. It is very common among people with
Type 2 diabetes, and most frequently involves increased levels of triglycerides, very
low density lipoprotein (VLDL) cholesterol, and low-density lipoprotein (LDL)
cholesterol, as well as decreased levels of high-density lipoprotein (HDL). The major
classes of lipoproteins are provided in Table Table 6.14. These abnormalities appear to
be caused by increased secretion of VLDL particles from the liver due to increased
concentrations of free fatty acids and glucose.
The anti-dyslipidemic market is saturated with third-generation statins, and thus superior
therapies are difficult to develop. Advancement in the anti-dyslipidemic market lies in the
fibrate class, with drug classes such as Peroxisome Proliferator-Activated Receptor
(PPAR) alpha agonists potentially expanding the adjunctive market. In addition, patients
with mixed dyslipidemia and diabetes are increasing, expanding the patient population.
Pfizer’s Lipitor is currently the most widely used treatment for lowering cholesterol and
the best-selling pharmaceutical product of any kind in the world. Pfizer’s Lipitor
(atorvastatin) / Torcetrapib - combination therapy had the potential to be a major “block
buster”, but was discontinued in late 2006 due to safety concerns. The discontinuation of
torcetrapib will have an impact on the other member of the CETP inhibitor pipeline drugs,
in particular Roche’s JTT-705. Roche acquired the exclusive worldwide rights (excluding
Japan and Korea) to develop and commercialize Japan Tobacco’s CETP inhibitor, JTT-
705, in 2004. The agent is being developed for the prevention of heart disease in low HDL
patients and for the treatment of hyperdyslipidemia. The drug is currently in Phase II in the
Netherlands and Phase I in Japan.
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Table 6.14: Characteristics of Major Classes of Lipoproteins Category Composition Origin Chylomicrons Exogenous/dietary Trigylcerides Gut Very-Low-Density-Lipoproteins Trigylcerides Liver (VLDP) Intermediate-Density Lipoproteins Cholesterol Esters and VLDL/HDL Trigylcerides Catabolism Low Density Lipoproteins Cholesterol VLDL Catabolism High-Density-Lipoproteins (HDL) Cholesterol Liver, Gut
Source: Pathophysiology, Diagnosis, Treatment Options of Dyslipidemia Business Insights Ltd
Pfizer discontinues torcetrapib development
Pfizer announced on the 2nd December 2006 that it discontinued the development of its
cholesterol drug torcetrapib. Torcetrapib was one of Pfizer's most promising pipeline drugs
and anticipated to replace revenue lost when Lipitor’s patent protection expires in 2010.
The decision to discontinue torcetrapib came after an independent Data Safety Monitoring
Board recommended ending the study due to an unexpected high incidence of mortality
and cardiovascular events. An analysis of the data from the ILLUMINATE trial showed
that a greater number of deaths and adverse side effects had occurred in the group receiving
torcetrapib compared with those patients receiving Lipitor; 81 deaths versus 51. However,
Pfizer noted that while torcetrapib, like Lipitor, affects the body's levels of cholesterol, the
new findings do not provide efficacy concerns related to Lipitor, as the two drugs act via
different mechanisms.
The failure of Pfizer Inc's experimental cholesterol drug torcetrapib has clearly:
Created a major market opportunity for recently approved drugs such as Vytorin
(marketed as Inegy outside the U.S.) and Zetia (marketed as Ezetrol outside the
U.S.) from Schering-Plough Corp and Merck and AstraZeneca Plc's Crestor.
Cast a shadow over the future of similar drugs from other members of the CETP
inhibitor pipeline drugs being developed by rival companies such as Roche Holding
AG and Merck & Co Inc. However Roche Holding AG are continuing with the
development of RI658 despite the setback with Pfizers Torcetrapib.
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R1658
R1658, licensed from Japan Tobacco, is a cholesteryl ester transfer protein (CETP)
inhibitor with a unique mechanism of action that is designed to raise levels of HDL-C,
or “good” cholesterol (a lack of HDL-C is associated with an increased risk of
cardiovascular disease). Phase II studies are nearing completion; the data indicate that
the compound has a good safety profile and the desired effects on HDL-C and other
blood lipids (fats). The results of these studies will form the basis for a decision in
2007 on entry into phase III testing. Roche Holding AG remains confident that despite
the recent discontinuation of Torcetrapib by Pfizer, product development of R1658 will
continue. R1658 has not been associated with any adverse cardiovascular changes or
any increase in blood pressure when given to patients as monotherapy or in
combination with statins. Nor did R1658 affect cardiovascular parameters in animal
models.
Simcor (Niaspan® (extended-release niacin) and simvastatin (generic Zocor®))
Simcor®, a fixed-dose combination of Niaspan and simvastatin (generic Zocor®) to
treat lipid disorders was originally being developed by Kos Pharmaceuticals for the
treatment of mixed dyslipidemia.
The statins are widely used to lower cholesterol levels via inhibition of 3-hydroxy-3-
methylglutaryl coenzyme A reductase. Several large randomized controlled trials have
shown that statins reduce the risks for vascular death, nonfatal myocardial infarction,
stroke, and the need for arterial revascularization procedures, all in relation to the
lowering of low-density lipoprotein (LDL) cholesterol levels. Six statins are available
worldwide: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and
rosuvastatin; pitavastatin is available only in Japan and India.
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Simvastatin is the second leading statin in the global market and is supported by a strong
clinical trial program and a proven safety profile. Generic simvastatin became available in
the US in mid-2006. More patients are expected to receive simvastatin due to the lower
cost of the drug in comparison to Lipitor once the patent has expired globally. Therefore,
more patients could potentially receive the simvastatin+niacin drug combination.
Niaspan (extended release niacin) was launched in 1997 by Kos Pharmaceuticals and is the
most potent HDL increasing agent currently on the market. As long as the cost of the
combination drug is cheaper than the sum of the separate entities this combination is a
promising addition to the market.
At the beginning of July 2005, Kos Pharmaceutical announced the start of a landmark
study to evaluate whether combination therapy with niacin and simvastatin is superior to
simvastatin alone in preventing cardiovascular events such as heart attack, stroke and acute
coronary syndromes. The AIM-HIGH Study (Atherothrombosis Intervention in Metabolic
syndrome with low HDL-C/high Triglyceride and Impact on Global Health outcomes) is
the first large-scale study using combination therapy with niacin and simvastatin to
evaluate whether there is a benefit of treating low HDL-C levels and high triglyceride
levels in vascular disease patients, who have attained NCEP LDL-C.
Kos Pharmaceuticals was acquired by Abbott Laboratories on the 6th November 2006 for a
total transaction value of $3.7 billion. Kos Pharmaceuticals was originally founded in
1988 and had pioneered the development of HDL therapies. With this acquisition Abbott
Laboratories acquired Kos Pharmaceuticals’ two lead products i.e. Niaspan® (niacin
extended-release tablets), an extended-release niacin product that raises HDL, or good
cholesterol levels; and Advicor® (niacin extended-release/ lovastatin tablets), a
Niaspan/lovastatin combination product that treats patients with multiple lipid
disorders. In addition Abbott Laboratories acquired late-stage pipeline products
including Simcor®, a fixed-dose combination of Niaspan and simvastatin (generic
Zocor®). This acqisition by Abbott Laboratories compliments Abbott's lipid
management portfolio, which includes on-market TriCor® (fenofibrate tablets); a next-
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generation fenofibrate, ABT-335; and a TriCor/Crestor® development program with
AstraZeneca announced in July 2006.
On the 20th April 2007 Abbott Laboratories announced that they had submitted a NDA to
the FDA for a fixed-dose combination (Simcor) of Niaspan® (extended-release niacin)
and simvastatin. Abbott Laboratories anticipate that they will obtain marketing approval
for Simcor by the third quarter 2007 and hope to launch at the beginning 2008.
CRESTOR® (rosuvastatin) and CRESTOR/ABT-335 combination
In July 2006 Abbott Laboratories and AstraZeneca announced that they had created a
collaboration to co-develop and market a combination treatment that will target all
three important blood lipids – LDL-C "bad" cholesterol, HDL-C "good" cholesterol,
and triglycerides – in one single pill as part of a comprehensive treatment regimen.
Under the agreement, the companies will initiate two parallel programs: a CRESTOR®
(rosuvastatin calcium)/TriCor® (fenofibrate tablets) fixed-dose combination and a
CRESTOR/ABT-335 combination.
ABT-335 is Abbott's proprietary next-generation fibrate fenofibrate currently in Phase
III clinical trials under the official title A Multicenter, Randomized, Double-Blind,
Prospective Study Comparing the Safety and Efficacy of ABT-335 and Atorvastatin
Calcium Combination Therapy to ABT-335 and Atorvastatin Calcium Monotherapy in
Subjects with Mixed Dyslipidemia. TriCor is from the same class of medications called
fibrates. Fibrates help lower triglyceride levels by reducing the amount of VLDL (the
triglyceride-carrying particle that circulates in the blood), which speeds up the removal
of triglycerides
CRESTOR is part of a class of medications called statins, and has been shown to
reduce LDL and raise HDL cholesterol. This combination could potentially address
LDL and HDL cholesterol and triglycerides simultaneously in one single pill.
CRESTOR is currently included in several trials as detailed below to form the basis of
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AstraZeneca's application to the FDA for an update to the CRESTOR Prescribing
Information.
The results from the METEOR study, supported by data from the ASTEROID study
and including the ORION trial, formed the basis of the atherosclerosis regulatory
submissions filed in the European Union and the United States in January 2007. These
submissions seek to expand the use of CRESTOR to include the treatment of
atherosclerosis with the purpose of impacting the progression of the disease in patients
in whom lipid-lowering therapy is indicated.
METEOR (Measuring Effects on intima media Thickness: an Evaluation Of
Rosuvastatin) was a 24-month, randomized, double-blind, placebo-controlled,
international study to evaluate the effect of CRESTOR 40mg in 984 asymptomatic,
hypercholesterolaemic patients with a low risk of coronary heart disease (Framingham
ten year risk <10 percent) and evidence of sub-clinical atherosclerotic disease as
determined by a thickened carotid artery wall (maximum intima media thickness (IMT)
>1.2 and <3.5 mm). METEOR used B-mode ultrasound imaging to assess and measure
change in mean maximum IMT of 12 vessel sites in the carotid artery.
ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular
Ultrasound-Derived Coronary Atheroma Burden) was a 104-week, open label, single-
arm, blinded endpoint study designed to study the effect of CRESTOR 40mg in 507
patients who had undergone coronary angiography and who had evidence of coronary
artery disease (CAD).
ORION (Outcome of Rosuvastatin Treatment on Carotid Artery Atheroma: a
Magnetic Resonance Imaging ObservatioN) was the first study to use advanced, high
resolution MRI to investigate the effect of a statin – CRESTOR - on the change in the
composition of plaques in the carotid artery wall. Forty-three (43) patients with
moderate hypercholesterolemia and established carotid atherosclerosis were treated
with either CRESTOR low dose (5 mg) or high dose (40/80 mg) for two years.
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Currently the CRESTOR/ABT-335 combination is in Phase II and a NDA is expected
to be placed on filed by AstraZeneca in 2009. AstraZeneca is also conducting a
comprehensive research and development program into NCEs for the treatment of
dyslipidaemia under the compound names AGI-1067, AZD2479, AZD6610, AZD8450
and AZD4121. It is planned to incorporate these compounds into the on-going
CRESTOR trials to target the different types of dyslipidaemia/ metabolic disturbance.
Table 6.15: AstraZeneca’s Current Anti-Dyslipidaemia Pipeline Segment Compound Target Indication Phase Dyslipidaemia AGI-1067 Atherosclerosis Phase III AZD2479 Dyslipidaemia Phase I AZD6610 Dyslipidaemia Phase I AZD8450 Dyslipidaemia Preclinical AZD4121 Dyslipidaemia Preclinical
Source: AstraZeneca Business Insights Ltd
Synordia
Solway pharmaceuticals have developed Synordia. Synordia contains the active
substances fenofibrate and metformin hydrochloride. The film-coated tablets contain
80 mg fenofibrate and 500 mg metformin, 80 mg fenofibrate and 850 mg metformin, or
54 mg fenofibrate and 850 mg metformin. This single-pill combination was in the
process of being developed by Fournier and is currently in Phase III development in
Europe for the treatment of hyperlipidemia and dyslipidemia due to type 2 diabetes and
metabolic syndrome. Fournier also expects to evaluate the prevention of type 2 diabetes
and cardiovascular events caused by hyperlipidemia and dyslipidemia in metabolic
syndrome. Fournier signed an agreement with Merck-Lipha for worldwide development of
the fixed combination.
However, this combination is for a very niche population and due to dosing complexities it
is most likely that it will be prescribed by specialists. Physicians are likely to prescribe
fenofibrate + metformin to diabetes patients whom they would normally prescribe these
medications individually.
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The application for marketing approval of Synordia was submitted in July 2006 to the
EMEA. In December 2006, Fournier withdrew its application to the notified the
Committee for Medicinal Products for Human Use (CHMP), stating that they were not
able to respond to requests for additional information within the allowed timeframe. The
withdrawal of the application from the EMEA suggests that the product’s launch will be
severely delayed and as yet the launch date is unknown.
Cost will be the major factor to affect the success of the combination as Tricor loses patent
expiry at the same time as the combination is launched and metformin is already cheaply
available. It will therefore be essential that it is competitively priced. The advantages of
this combination are ease of administration which in turn could help to increase
compliance. Synordia is predicted to gain sales of $120m in 2011, however this is an
optimistic forecast due to the launch date being postponed.
Lapaquistat (TAK-475)
Takeda Pharmaceuticals have been developing at their Global Research and
Development Centre (Europe) in London (UK) a squalene synthase inhibitor or
cholesterol absorption inhibitors known as Lapaquistat (TAK-475). Reserachers from
Takeda reported the results of a phase 2 study evaluating different doses of lapaquistat
compared with atorvastatin in patients with primary hypercholesterolemia at the
American heart Association (AHA) meeting in Chicago November 2006. Lapaquistat
produced significant reductions in LDL-C, total cholesterol, and apolipoprotein B
(apoB), although these reductions were not as great as seen with atorvastatin. Unlike
atorvastatin, however, significant increases were seen in high-density lipoprotein
cholesterol (HDL-C) at higher doses of lapaquistat.
Squalene synthase inhibitors are believed to have potential advantages over statins,
which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. HMG-
CoA catalyzes the conversion of HMG-CoA to mevalonate and thus serves as the
primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Squalene
synthase acts downstream of mevalonate, catalyzing the dimerization of farnesyl-
pyrophosphate to squalene. This is the first step in the cholesterol biosynthetic pathway
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that is solely committed to the production of cholesterol and researchers believe that
blockade at this site may avoid the effects associated with decreased formation of
isoprenolated intermediates and metabolites in the pathway beyond HMG-CoA
reductase.
Currently Takeda Pharmaceuticals are conducting a series of Phase 3 clinical trials.
The most recently commissioned trials includes one with more than 7000 dyslipidemic
patients in Australia, Canada, Europe, South Africa, South America, and the United
States. The purpose of the study is to evaluate the differences in efficacy and safety of
Lapaquistat (TAK-475) and simvastatim compared to a placebo when administered
together or alone in subjects with primary hypercholesterolemia. In addition, a further
Phase 3 clinical trial which started in September 2006 is being conducted to compare
the effect of Lapaquistat (TAK-475) and ezetimibe on low density lipoprotein (LDL-C)
level in subjects with primary dyslipidemia.
SLx-4090
Surface Logix is developing a novel, orally administered Microsomal Triglyceride
Transfer Protein (MTP) inhibitor known as SLx-4090 for the treatment of dyslipidemia
and familial hypercholesterolemia. SLx-4090 is a potent, small-molecule inhibitor of
MTP that has been designed to act selectively in the enterocytes lining the GI tract. It
prevents the formation of chylomicrons which are used to transport triglyceride and
cholesterol into the systemic circulation. The novelty of SLx-4090 is that it is selective
for enterocytes and is not absorbed into the systemic circulation, and thus allows
activity against fat uptake while avoiding toxicity at other sites of MTP expression
including the liver, heart, testis, ovary, and eye.
SLx-4090 has completed a phase 1 study confirming that it is active in the gut,
significantly blocking fat absorption, but not present in systemic circulation. A repeat
dose study (RDS) and a Phase IIa study in patients with familial dyslipidemia began in
January 2007.
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AEGR-733
Bristol-Myers Squibb originally created a study group to search for inhibitors of the
Microsomal Triglyceride Transfer Protein (MTP) after it was discovered that genetic
defects in MTP lead to profoundly low levels of LDL. As a result of the work carried
out they discovered the study drug, originally known as BMS-201038. Bristol-Myers
Squibb then donated it to University of Pennsylvania School of Medicine for use in
clinical trials in patients with severe cholesterol problems. Daniel J. Rader MD,
Director of Preventive Cardiology and the Clinical and Translational Research Center
at the University of Pennsylvania School of Medicine and principal investigator,
designed and carried out a study in homozygous familial hypercholesterolemia (FH).
FH is a high-risk condition refractory to conventional therapy, and this trial recorded a
remarkable 51% reduction in low-density lipoprotein (LDL) or “bad cholesterol”
levels. Due to the success in the study, University of Pennsylvania School of Medicine
licensed the drug to Aegerion Pharmaceuticals Inc. for further development as AEGR-
733.
Currently Aegerion is conducting an on-going phase II clinical trial involving AEGR-
733, alone and in combination with Zetia(R) (ezetimibe). In the study, patients treated
with a combination of 10 mg dose of Zetia(R) and 5 mg AEGR-733 achieved a LDL
reduction of 35% after 4 weeks. Patients treated with Zetia(R) alone achieved a 20%
reduction in LDL cholesterol. There was no difference in discontinuation rates between
the patients treated with the combination of AEGR 733 plus 10 mg of Zetia(R) vs.
those treated with 10 mg of Zetia(R) alone.
Final study results for the current trial are expected in the first quarter of 2007.
Aegerion plans to initiate several additional Phase II trials in early 2007, including one
that will examine the LDL-lowering efficacy of various doses of AEGR 733 used in
combination with Lipitor® vs. the agents used as monotherapy
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Compound Number 256073 and 501516
GlaxoSmithKline is developing two novel compounds for the treatment of
dyslipidaemia. These are compound number 256073, high affinity nicotinic acid
receptor (HM74A) agonist and 501516 a peroxisome proliferator-activator receptor
(PPAR) delta agonist. Currently compound number 256073 is in Phase I and compound
number 501516 is in Phase II.
The compound number 501516 is being developed in collaboration with Ligand
Pharmaceuticals. Ligand Pharmaceuticals has earned a $1mn milestone payment from
GlaxoSmithKline as a result of GSK’s decision to continue Phase I development of
501516. The collaboration was originally established in 1992 and the research phase
successfully completed in 1997 with the identification of a novel lead structure that
activates selected PPAR subfamily members, and the additional identification of a
different lead compound that shows activity in preclinical models for lowering LDL
cholesterol by up-regulating LDL receptor gene expression in liver cells. Ligand
Pharmaceuticals retains the right to develop and commercialise products arising from
collaborations in markets not exploited by GlaxoSmithKline, or where
GlaxoSmithKline is not developing a product for the same indication.
In 1999, several PPAR leads were advanced to exploratory development. GW501516
was selected for clinical development and Phase II trials were initiated for
cardiovascular disease and dyslipidemia. GW501516 is currently on hold pending the
review of preclinical studies.
LBM642
Novartis have been developing an early stage novel compound under the name of
LBM642. This is a dual agonist of PPAR alpha and gamma, which in a recent
dyslipidemia study suggests that the molecule has the potential for efficacy in
metabolic syndrome, a disease cluster including diabetes, high cholesterol, and obesity.
The results show this compound may overcome many of the disadvantages of other
PPAR alpha/gamma dual agonists, in particular weight gain and edema.
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Dyslipidaemia: Current Pipeline and Late Stage Development
Simcor Niaspan® (extended-release niacin) and simvastatin (generic Zocor®) by
Abbott Laboratories. Niaspan is used to raise HDL "good" cholesterol levels, and
simvastatin is effective in reducing LDL "bad" cholesterol levels. Submitted a NDA to
the FDA 20th April 2007.
CRESTOR® (rosuvastatin) and CRESTOR/ABT-335 combination by Abbott
Laboratories and AstraZeneca. Combination treatment that will target all three
important blood lipids – LDL-C "bad" cholesterol, HDL-C "good" cholesterol, and
triglycerides. CRESTOR/ABT-335 combination is in Phase II and a NDA is expected
to be filed by AstraZeneca in 2009. ABT-335 is Abbott's currently in Phase III clinical
trials.
Synordia (Fenofibrate and metformin hydrochloride) by Solway Pharmaceuticals
through acquisition of Fournier in July 2005. Indicated for the treatment of
hyperlipidemia and dyslipidemia due to type 2 diabetes and metabolic syndrome.
Application for marketing approval of Synordia was submitted in July 2006 to the
EMEA. In December 2006, Fournier withdrew its application to the CHMP. Waiting to
resubmit with new data.
Lapaquistat (TAK-475) by Takeda Pharmaceuticals. Indicated for the treatment of
primary hypercholesterolemia. In Phase 3 clinical trials.
SLx-4090 by Surface Logix. SLx-4090 is a novel Microsomal Triglyceride Transfer
Protein (MTP) inhibitor that is in development for the treatment of dyslipidemia and
familial hypercholesterolemia (FH). SLx-4090 has completed a phase 1 study which
has confirmed that it is active in the gut significantly blocking fat absorption but the
drug is not present in the systemic circulation. A repeat dose study (RDS) and a Phase
IIa study in patients with familial dyslipidemia started in January 2007.
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AEGR-733 by Aegerion Pharmaceuticals, Inc. Indicated for the treatment of familial
hypercholesterolemia (FH). Inhibitors of the Microsomal Triglyceride Transfer Protein
(MTP). Phase II trials
Compound 256073 and 501516 by GlaxoSmithKline in collaboration with Ligand
Pharmaceuticals. Indicated for the treatment of dyslipidemia. Currently compound
256073 is in Phase I and compound 501516 is in Phase II trials.
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Anti-Thrombotics
Thrombosis is normally defined as the formation of a solid blood clot in an arterial or
venous vessel. The mechanism of blood coagulation or haemostasis is triggered when
the blood comes in contact with an acutely (wound) or chronically (atherosclerosis)
damaged vessel wall. Deep Vein Thrombosis, or DVT, is a condition in which blood
clots form in a vein deep in the body. A DVT usually forms in the veins in the legs, but
this can also occur in other veins of the body. If a blood clot dislodges and travels in
the blood stream, it may become stuck in the lungs, causing a pulmonary embolism; in
the heart, causing a heart attack; or in an artery in the brain, causing a stroke.
Rivaroxaban (BAY59-7939)
Rivaroxaban (BAY-59-7939) is a new orally available direct FXa inhibitor under
development by Bayer and Ortho-McNeil Pharmaceutical for the treatment of deep vein
thrombosis (DVT) and its secondary prevention. The development product is currently in
late-stage development with the presentation of Phase II clinical studies having been made
at the World Congress of Cardiology at Barcelona, Spain in September 2006.
Rivaroxaban (BAY-597939) is currently in Phase III clinical development for the
primary prevention of VTE after major elective orthopedic surgery. The RECORD
(REgulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and
PE) study programme began in December 2005 and recruitment is on track and
progressing well. First filing for market authorization in this indication is planned in
late 2007. In addition to these trials further Phase III trials are being conducted to study
stroke prevention in atrial fibrillation, and for the treatment of venous
thromboembolism (VTE). These further Phase III trials started recruiting in early 2007
and based on the finalization of study design, the companies are targeting a regulatory
filing of rivaroxaban for these indications in 2010.
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Rivaroxaban (BAY-597939) is forecast to gain high sales, reaching $3bn in 2011, making
it the highest selling anti-coagulant. BAY-597939 satisfies the large unmet need for orally
available anticoagulants which are sufficiently potent and safe enough to replace warfarin.
Rendix (dabigatran etexilate, BIBR-1048)
Rendix (dabigatran etexilate, BIBR-1048), in development by Boehringer Ingelheim, is an
oral drug that is converted to dabigatran (BIBR-953), a potent direct thrombin inhibitor.
BIBR-1048 is currently undergoing Phase III clinical trials for the prevention of DVT
following Major Orthopedic Surgery (MOS) and the prevention of stroke in atrial
fibrillation. The half-life of BIBR-1048 is approximately eight hours after single-dose
administration and up to 17 hours with repeated dosing, which could lead to once daily
dosing.
In January 2006, Boehringer Ingelheim officially announced the launch of the RE-
VOLUTION trial program, planned to involve a total of 27,000 patients worldwide. The
RE-VOLUTION program includes the recruitment of 15,000-patient within the RE-LY
Phase III study in SPAF, the 2,000-patient studies RE-MODEL and RE-MOBILIZE in
VTE prevention after knee surgery and the 3,300-patient study RE-NOVATE in VTE
prevention after hip surgery.
For the prevention of DVT, post-orthopedic surgery pivotal studies have been
completed and the first submission for Europe has been completed. A further
submission to gain marketing authorization by the FDA is planned later in 2007 once
additional study results have become available. It is anticipated that filings with the
FDA and the EMEA are expected to take place simultaneously sometime in 2009.
Furthermore, predicted that sales of Rendix could reach $1.5 billion by the year 2011.
Idraparinux
Idraparinux sodium is being developed by Sanofi-Aventis and is a long-acting
anticoagulant that catalyses the inhibition of activated factor X (Xa) by antithrombin,
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thus interrupting the coagulation cascade. Idraparinux, like fondaparinux, is a synthetic
analogue of the pentasaccharide sequence in heparins, but because idraparinux is
methylated, its binding affinity is far higher. Idraparinux is administered by a once
weekly subcutaneous injection, resulting in stable therapeutic anticoagulant levels
without the need for monitoring (although the monitoring requirements need
confirmation). Idraparinux sodium is currently in Phase III clinical trials to evaluate its
efficacy and safety versus Low Molecular Weight Heparin (LMWH) followed by
adjust-dose Vitamin K Antagonist (VKA) for three to six months (Van Gogh DVT and
PE studies). It is anticipated that the Phase III clinical trials will be completed by early
2008 and marketing authorization obtained in third quarter 2008.
Apixaban
Apixaban (BMS-562247) being developed by Bristol-Myers Squibb (BMS) is the follow-
on compound to BMS’ oral FXa inhibitor razaxaban for the treatment of thrombosis and is
defined as an orally active inhibitor of coagulation factor Xa with anticoagulant
activity. Apixaban directly inhibits factor Xa, thereby interfering with the conversion
of prothrombin to thrombin and preventing formation of cross-linked fibrin clots. By
March 2005, apixaban had superseded razaxaban and was in Phase II clinical trials.
In October 2006, BMS reported that it had initiated a Phase III trial in the MOS setting.
The company is also investigating the potential of apixaban in the prevention of
thromboembolic events in patients undergoing treatment for advanced cancer. If
successful, this indication could result in marketing synergies between the company’s
cardiovascular and oncology divisions.
SSR-126517
Sanofi-Aventis is developing the long-acting Factor Xa inhibitor SSR-126517 (biotinylated
idraparinux), as a back-up compound for idraparinux. The biotinylation allows idraparinux
to be rapidly removed from the blood using avidin if bleeding becomes uncontrolled. Lack
of reversibility has been a major concern in a long-acting antithrombotic agent and affected
the perception of idraparinux as a contender in the setting of long-term VTE prophylaxis
and SPAF. Currently 2 Phase III clinical trials are on-going:
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In March 2006, the Phase III bioequipotency study EQUINOX was initiated,
comparing idraparinux and SSR-126517 in 700 DVT patients in North America,
Europe, South America, Australia, New Zealand, Russia and South Africa. The
primary endpoints were bioequivalence to idraparinux and efficacy of avidin (SSR-
29261) in neutralizing SSR-126517. The secondary endpoint was time to steady-
state anti-Factor Xa activity.
In June 2006, the Phase III trial CASSIOPEA (Official title International,
Randomized, Double-Blind, Double-Dummy, Parallel Group Study of Treatment
With SSR126517E (3.0 mg s.c. Once-Weekly) Versus Oral INR-Adjusted Warfarin
in the Treatment of Patients With Symptomatic Pulmonary Embolism) was
initiated, comparing recurrence of VTE events after three months treatment with
once-weekly SSR-126517 or oral warfarin. It is intended that this trial will enroll
3,200 patients with PE in the Americas, Europe, Asia, Africa and Australasia.
Exanta/ximelagatran
Exanta® or Ximelagatran is a new oral anticoagulant. It is a small compound that is
absorbed and converted to the active substance Melagatran. Melagatran can also be
given by injection (as can a number of other anticoagulants). Exanta® interferes with
thrombin which is the final step in the activation of the clotting pathway. This group of
drugs is known as direct thrombin inhibitors.
In February 2006, AstraZeneca withdrew Exanta from the market and halted its
development on patient safety grounds. The decision to discontinue Exanta was based
on new clinical trial data indicating a potential risk of severe liver injury. The data
came from a clinical trial to examine the use of Exanta after orthopaedic surgery to
prevent venous thromboembolism over 35 days, longer than was currently approved for
marketing.
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Anti-Thrombotics: Current Pipeline and Late Stage Development
BAY-59-7939 (Rivaroxaban) by Bayer Healthcare/Ortho-McNeil. Indicated for
VTE prophylaxis in patients undergoing MOS; long-term secondary prevention of VTE
in patients who have had an initial episode of VTE; and SPAF. Phase II completed. On-
going Phase III, marketing authorisation planned for 2010.
BIBR-1048 (Rendix/dabigatran etexilate) by Boehringer Ingelheim. Indicated for
the prevention of DVT following Major Orthopaedic Surgery (MOS) and stroke in
atrial fibrillation. Phase III.
Idraparinux by Sanofi-Aventis. Indicated for the initial treatment for deep-vein
thrombosis (DVT), or pulmonary embolism (PE). Currently in Phase III trials.
BMS-562247 (Apixaban) by Bristol-Myers Squibb. Indicated for the prevention of
DVT following Major Orthopaedic Surgery (MOS) and the prevention of stroke in
atrial fibrillation. Currently in Phase III trials.
SSR-126517 (Biotinylated Iraparinux) by Sanofi-Aventis. Indicated for the initial
treatment for deep-vein thrombosis (DVT) and secondary prevention, or pulmonary
embolism (PE). Phase III.
Exanta® or Ximelagatran by AstraZeneca. Indicated for the initial treatment for
deep-vein thrombosis (DVT) and secondary prevention, or pulmonary embolism (PE).
Discontinued from February 2006.
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Anti-Arrhythmics
Arrhythmias are defined as irregular heart rhythms, or an abnormality in the timing or
pattern of the heartbeat, causing the heart to beat too rapidly, too slowly, or irregularly.
Tachycardia is the term for a heartbeat that's too fast. Bradycardia is the term for a
heartbeat that's too slow. Atrial fibrillation (AF) is the most common form of
arrhythmia, or irregular heartbeat whilst Ventricular fibrillation is a severe cardiac
arrhythmia that can result in sudden cardiac death. It's a rapid, uncontrolled contraction
of the left ventricle (pumping chamber of the heart). Drugs used to treat cardiac
arrhythmias are provided in Table 6.16.
Comprehensive epidemiology data on the prevalence of arrhythmias is difficult to
come by as a result of the complex nature of the condition. However, accurate data for
AF does exist and suggests a prevalence of chronic AF in the seven major markets of
8.5 million individuals in 2005, which will rise to over 10 million individuals by 2015.
The antiarrhythmics market across the seven major markets has experienced a sharp
decline in sales over recent years, primarily due to the loss of patent protection for
Sanofi-Aventis' Cordarone (amiodarone) in the US in 2002 and with it the emergence
of generic equivalents causing an erosion in pricing. However, moving forward it
appears that the antiarrhythmics market is on the brink of rapid expansion due to the
expected launch of five novel products between 2007 and 2010, and a billion dollar
market looks set to triple in size by 2015.
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Table 6.16: Classification of Anti-Arrhythmics Class I — Sodium Class II — Beta Class III — Potassium Class IV — Calcium channel blockers blockers channel blockers channel blockers Disopyramide (Norpace) Acebutolol (Sectral) Amiodarone (Cordarone, Pacerone) Diltiazem (Cardizem, Tiazac) Flecainide (Tambocor) Atenolol (Tenormin) Azimilide (Stedicor) Verapamil (Calan, Covera, Isoptin) Lidocaine (Xylocaine) Betaxolol (Kerlone) Bepridil Mexiletine (Mexitel) Bisoprolol (Zebeta) Dofetilide (Tikosyn) Moricizine (Ethmozine) Carvedilol (Coreg) Ibutalide (Corvert) Procainamide (Procan, Esmolol Sotalol (Betapace) Procanabid, Pronestyl) Propafenone (Rythmol) Metoprolol (Toprol, Lopressor) Tedisamil Quinidine (Various) Nadolol (Corgard) Tocainide (Tonocard) Propranolol (Inderal) Sotolol (Betapace) Timolol (Blocadren)
Source: Business Insights Ltd Business Insights Ltd
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Stedicor (Azimilide)
Stedicor (Azimilide) is a class III antiarrhythmic agent that - unlike other agents of its
class - prolongs cardiac repolarization by blocking both the rapidly (IKr) and slowly
(IKs) activating components of the delayed rectifier potassium channel (IK). The most
important consequence of this is apparent rate-independent activity, so that, unlike
other class III antiarrhythmics, azimilide does not lose efficacy at high heart rates.
Both preclinical and Phase II clinical studies demonstrated the efficacy of azimilide and its
safety in the management of supraventricular and ventricular tachycardia. In 1999, the
FDA stated that P&G did not have sufficient data to file for approval, after a second set of
pivotal trials (the ASAP trials) in AF patients failed to show a benefit. However, a meta-
analysis of the four ASAP trials presented at the 2000 AHA Scientific Sessions showed a
significant overall effect of Stedicor compared to placebo. In addition, the results of the
innovative ALIVE trial presented in November 2001 showed the drug had a promising
safety profile. Azimilide has better tolerability and safety data than amiodarone, as well as
a shorter half-life. However, it has the potential to induce torsade de pointes and severe
neutropenia, although the incidences of both are very low.
P&G Pharmaceuticals had forecast to submit Stedicor (azimilide) for approval with the
FDA during 2007, with an expected launch date during the first quarter of 2008. However
the latest information is that it is currently unavailable in Europe either as an approved
product or on a named patient basis. According to P&G Pharmaceuticals there are no
further plans to submit Stedicor (azimilide) for regulatory approval either in Europe or
the US and no further plans to conduct any other large scale clinical trials. This is despite
the on-going larger study called Shock Inhibition Evaluation with AzimiLiDe
(SHIELD) being conducted to confirm the original findings of the pilot study.
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Multaq (Dronedarone)
Sanofi-Aventis’ Multaq (dronedarone) is a non-iodinated benzofuran derivative that has
been developed to overcome the limiting iodine-associated adverse effects of the
commonly used antiarrhythmic drug, amiodarone. Dronedarone resembles amiodarone in
its antiadrenergic effects and its ability to lower the heart rate, prolong action potential
duration without a high risk of inducing torsade de pointes, and coronary vasodilator
actions. Preliminary preclinical evidence suggests that, as an “improved” version of
amiodarone, dronedarone confers efficacy benefits on cardiac electrical activity similar to
those of amiodarone but lacks the amiodarone-like chronic electrophysiological
characteristics associated with proarrhythmic effects.
In January 2003, the Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe
Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was
discontinued following the Data Safety Monitoring Board’s (DSMB’s) recommendation.
The Phase II trial was evaluating dronedarone in high-risk patients with congestive heart
failure (CHF) and ventricular dysfunction. The results indicated a potential excess risk of
death with 24 deaths out of the active treatment group versus 10 deaths on placebo. It is
believed that the excess mortality associated with dronedarone resulted from inappropriate
withdrawal of ACE inhibitor or angiotensin receptor blocker therapy, and that it did not
result directly from treatment with dronedarone. The DSMB however confirmed that it was
safe to continue the investigation of dronedarone in the further two phase 3 trials of
dronedarone. These were the EURopean Trial In Atrial Fibrillation or Flutter Patients
Receiving Dronedarone for the MaIntenance of Sinus Rhythm (EURIDIS) and the
American-Australian Trial With Dronedarone in Atrial Fibrillation or Flutter Patients
for the Maintenance of Sinus Rhythm (ADONIS). The ERATO (Efficacy and safety of
dronedarone for The control of ventricular rate) trial, amultinational, multi-center,
double-blind, randomized study comparing two parallel groups of patients with
permanent AF was also conducted at the same time. This study was undertaken in 35
centers across nine European countries and enrolled 174 patients with symptomatic
permanent AF of at least 6 months. Both these trials provided positive results in
January 2004 and as a result Dronedarone was filed with the US FDA and the
European Regulatory Authority, EMEA, in June 2005.
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However on the 31st August 2006 Sanofi-aventis announced that it had received a non
approvable letter from the U.S. FDA for Multaq (Dronedarone) in the treatment of
Atrial Fibrillation / Atrial Flutter. As part of a related move Sanofi-aventis announced
on the 7th September 2006 that it had taken the decision to withdraw the European
application for Marketing Authorization of Multaq (Dronedarone). In order to make a
more adequate assessment of the benefit-risk balance of the product, the Committee for
Medicinal Products for Human Use (CHMP) has requested additional clinical data
which cannot be provided within the timeframe of the current procedure.
Sanofi-aventis plans to resubmit a European application for Marketing Authorization in
atrial fibrillation/atrial flutter during the first semester of 2008. A new filing in the
United States is expected during the first semester of 2008 on the basis of the clinical
data of the ongoing Phase III ATHENA study. ATHENA is a Placebo-Controlled,
Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400mg Bid for
the Prevention of Cardiovascular Hospitalization or Death from Any Cause in patients
With Atrial Fibrillation/Atrial Flutter (AF/AFL). The primary objective of this study
was to assess the efficacy of dronedarone in preventing cardiovascular hospitalizations
or death from any cause, and the secondary objective was to evaluate on a large scale
the tolerability of dronedarone in the targeted population of patients suffering from
atrial fibrillation.
Vernakalalant (RSD 1235)
Vernakalalant (RSD 1235) is a new chemical entity (NCE) investigational drug
currently being developed by Cardiome Pharma and their co-development partner,
Astellas Pharma US, Inc and is designed to treat atrial fibrillation with the potential to
overcome the limitations of current drugs used to treat the disease. Its mechanism of
action involves the selective blockade of multiple ion channels in the heart that are
known to be active during episodes of atrial fibrillation. Cardiome Pharma recently
announced that RSD1235 has been assigned the name vernakalant hydrochloride by the
United States Adopted Names (USAN) Council. All future references to RSD1235 (iv)
will now be vernakalant (iv), and references to RSD1235 (oral) will be vernakalant
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(oral). The commercial brand name for vernakalant (iv) will be finalized in the near
future.
The drug is currently being developed for two potential applications: (1) vernakalant
(iv) is being evaluated as an intravenous pharmacological converting agent designed to
terminate an atrial fibrillation episode and return the heart to normal rhythm; and (2)
vernakalant (oral) is being evaluated as an oral maintenance therapy for the long-term
prevention of atrial fibrillation recurrence.
Cardiome Pharma has, and is presently, currently conducting a series of pivotal Phase III
trials under the acronym ACT (Arrhythmic Conversion Trial). These trials have
demonstrated that Vernakalant (iv) (RSD 1235) has substantial effects on cardioverting
persistent AF of approximately seven days or less to sinus rhythm. For example, in the first
Arrhythmic Conversion Trial (ACT 1) RSD1235 converted AF to sinus rhythm in
approximately 50% of patients compared with minimal conversion in the placebo group.
As anticipated with a drug whose major electrophysiological alterations occur in atrial
tissue, there was a non-significant increase in the QT interval in these patients. Two Phase
III called ACT 1 and ACT 3 have been completed and the results were released in
December 2004 and September 2005 respectively. An additional Phase 3 study
evaluating patients with post-operative atrial arrhythmia, called ACT 2, and an open-
label safety study evaluating recent-onset AF patients, ACT 4, are ongoing.
Cardiome Pharma announced in August 2005 that they had successfully completed
Phase 1 studies required to advance clinical testing of vernakalant (oral) into a Phase 2
study. In December 2005, they announced the initiation of a Phase 2a pilot study of
vernakalant (oral) for the prevention of recurrence of atrial fibrillation. The double-
blind, placebo-controlled, randomized, dose-ranging study was designed to measure the
safety and tolerability, pharmacokinetics and preliminary efficacy of vernakalant (oral)
in up to 28 days of oral dosing in patients at risk of recurrent atrial fibrillation. After
announcing the positive results of the Phase 2a pilot study in September 2006 Cardiome
Pharma announced in December 2006 that they had initiated a Phase 2b clinical study of
vernakalant (oral) to further evaluate the safety and tolerability, pharmacokinetics and
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preliminary efficacy of vernakalant (oral) in up to 90 days of oral dosing in patients at
risk of recurrent atrial fibrillation.
Cardiome Pharma learnt on the 31st May 2006 that the U.S. FDA for the New Drug
Application (NDA) had issued a "refusal to file" for RSD1235 (iv). In accordance with
application regulations, the FDA is required to accept or refuse an application within
60 days of the completion of the filing, which occurred on March 31 2006. Subsequent
to this Cardiome Pharma announced on the 18th December 2006 that Astellas Pharma US
had re-submitted the NDA to seek the approval of the U.S FDA to market Vernakalant
(iv). On the 19th February 2007 notification was made by the FDA that they had
accepted the NDA for review. Cardiome Pharma are currently under a standard 10-
month review, with their Prescription Drug User Fee Act (PDUFA) date in October
2007. Cardiome Pharma are confident that market Vernakalant (iv) will receive
approval, and that marketing of this product will begin in the first quarter of 2008.
Tecadenoson CVT510
Tecadenoson is a selective A1-adenosine receptor agonist being developed by C.V.
Therapeutics for the reduction of rapid heart rate for patients with paroxysmal
supraventricular tachycardia (PSVT). C.V Therapeutics Inc announced on the 27th
November 2002 that they had initiated a Phase III Clinical Trial to Evaluate the
Management of PSVT during Electrophysiologic Study with Tecadenoson
(TEMPEST). This is a Phase III, multi-center, double-blind, placebo-controlled trial;
181 patients with inducible PSVT in the electrophysiology laboratory were randomized
to receive placebo or one of five dosing regimens of tecadenoson via rapid intravenous
bolus. CV Therapeutics has not yet submitted a new drug application to the FDA or
equivalent application to any other foreign regulatory authorities for tecadenoson.
Pulzium IV (Tedisamil)
Solvay Pharmaceuticals is currently developing tedisamil (KC-8857), a novel
antiarrhythmic with additional anti-ischaemic properties which acts via potassium
channel blockade. This drug can be categorized as a class III antiarrhythmic agent due
168
to its effects of action potential and QT interval prolongation in these patients. This
agent was initially developed for its anti-ischaemic properties and Phase I trials have
shown tedisamil to be an effective bradycardic agent, as well as causing reverse rate-
dependent QT interval prolongation. Subsequent Phase II results have confirmed that in
patients with ischaemic heart disease, tedisamil had beneficial haemodynamic and anti-
ischaemic effects. Phase III studies in patients with ischaemic heart disease indicated
that tedisamil is an effective agent for the treatment of angina, resulting in a dose-
dependent increase in anginal threshold (with a decrease in anginal attacks, increased
exercise capacity during treadmill exercise and decreased electrocardiographic signs of
exercise induced ischaemia) in comparison to placebo. Solvay Pharmaceuticals
announced on the 25th April 2007 that they had submitted and filed a dossier for
intravenous tedisamil for approval by the US FDA as well as by the authorities of
European Union countries.
Anti-Arrhythmics: Current Pipeline and Late Stage Development
Stedicor (Azimilide) by Proctor and Gamble. A Class III Antiarrhymic agent for the
chronic treatment of atrial fibrillation, atrial flutter and paroxysmal supraventricular
tachycardia (PSVT). Class III Antiarrhymic agent as adjunct therapy for patients with
implantable cardioverter defibrillator Company has no further plans to seek regulatory
approval despite continuing with the Phase III SHIELD clinical trial.
Multaq (Dronedarone) by Sanofi-Aventis. Class III Antiarrhymic agent for
maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter.
Currently in Phase III ATHENA Trial. Company plans to resubmit a European
application for Marketing Authorization first quarter 2008. A new filing in the US is
expected during the first quarter of 2008.
Tecadenoson (CVT510) by CV Therapeutics. An Intravenous selective A1
Adenosine Receptor Agonist/treatment of paroxysmal supraventricular tachycardia.
Phase III TEMPEST Trial on-going. No submission of regulatory approval to-date.
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Pulzium IV (TedIsamII) by Solway. Intravenous mixed potassium channel
blocker/rapid conversion of recent onset atrial fibrillation or flutter to normal sinus
rhythm . Phase III on-going. Company submitted and filed NDA dossier 25th April
2007 for approval by the US FDA as well as by the authorities of European Union
countries.
RSD 1235 (Vernakalalant) by Cardiome Pharma and Astellas Pharma.
Intravenous antiarrhymic agent/acute conversion atrial fibrillation to normal sinus
rhythm. Phase III clinical trial 18th December 2006 re-submitted the NDA dossier to
seek the approval of the USFD.
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Chapter 7 Appendix
Methodology Statement
The methods used to gather data, information on proprietary technologies,
technological trends, market forecasts and projections used in the preparation of this
report are broadly divided into three different methods.
Primary Data and Information Gathering
Data on individual product and company sales was gathered through extensive
interviews with manufacturers, end users, suppliers, distributors, and other relevant
sources. These interviews typically include marketing managers, sales managers,
distributor managers and owners, sales representatives and managers responsible for
research and development (R&D). In addition, interviews were conducted with senior
managers amongst competing companies to determine the strategic direction and focus
of the technological advances being made and the sales and marketing policies being
adopted. Representatives from the leading suppliers i.e. AstraZeneca, Bristol-Myers
Squibb, Boston Scientific Corporation, Cordis Corporation (J&J), GlaxoSmithKline,
Gore Medical, Sanofi-Aventis, Novartis, Takeda Pharmaceuticals, and Mylan
Laboratories were interviewed as well as individuals from other participating
companies; Atritech, Chiesi Farmaceutici SpA, Medicure Inc, Bioabsorbable
Therapeutics, Inc and Occam International B.V. This was done to ensure that the data
derived from competitive interviews was accurate the information was verified and
corroborated by other interviews and by secondary sources such as articles in the trade
press, press releases, annual reports, online databases and government reports.
Secondary Data and Information Gathering
Information was obtained from numerous secondary data sources including statistics
provided by various cardiovascular associations including British Cardiovascular
Intervention Society (BCIS), The European Society of Cardiology (ESC), European
171
Association of Percutaneous Cardiovascular Interventions (EAPCI), the Health
Economics Research Centre, Department of Public Health, University of Oxford, The
Center for Disease Control (CDC), The American Stroke Association, The National
Center for Health Statistics (NCHS), The National Institute for Clinical Excellence
(NICE), The European Medicines Evaluation Agency (EMEA) and the American Heart
Association (AHA). In addition further information was obtained about the incidence
and prevalence of cardiovascular disease from the World Health Organization (WHO),
the Organization for Economic Co-operation and Development (OECD) and the British
Heart Foundation. Furthermore, the European Cardiovascular Societies were contacted
to determine the potential for the continued treatment of some cardiovascular diseases
using minimally invasive techniques and the level of expectation concerning the
anticipated market introduction of new and novel cardiovascular drugs. A considerable
amount of further information was obtained from numerous publications in the
scientific and trade literature.
While these are believed to be the best secondary sources of data for various disorders
associated with medical devices and pharmaceuticals used in the diagnosis and
treatment of cardiovascular diseases, the estimation of trends from this data is
complicated by periodic changes in reporting and classification methods. In addition to
the use of corporate annual and quarterly reports, data was obtained from security
offering prospectuses, Forms 10-K and 10-Q, and product catalogs and price lists. This
data was used along with other sources of data on company revenues (investment
analysts’ reports, Reuters, Dun & Bradstreet, the CorpTech Directory, and personal
communications from executives of various companies) to develop historic and current
estimates of market revenues. Prices used in projections of market revenues are average
prices paid by the end-user for the products and are derived via supplier and user
quotations or estimates based on typical industry discounts from list prices.
Market Share Analysis and Market Forecast Predictions
Information and data including estimates on market values, growth rates and market
share data were gathered from the methods described and were incorporated into
172
proprietary computer forecasting and market share analysis models. The forecast model
was used to derive market estimates for future years. It incorporates a rate factor, which
helps determine the speed with which the market develops, which is similar to that
observed for markets for other medical products and is adjusted to match historic data
for the market under analysis.
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Glossary
AAV Adeno-Associated Virus
ACC American College of Cardiology
ACE Angiotensin-Converting Enzyme
ACS Acute Coronary Syndrome
AEPD Aortic Embolic Protection Device
AESOP The Automated Endoscopic System for Optimal Positioning
AF Atrial Fibrillation
AHA American Heart Association
AIFA Italian Medicines Agency
ALIVE Trial AzimiLide post-Infarct surVival Evaluation Trial
AMI Acute Myocardial Infarction
AMS Absorbable Metal Stent
ARB Angiotensin Receptor Blocker
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ASAP Azimilide Supraventricular Arrhythmia Program
ASD Atrial Septal Defect
ATP AntiTachycardia Pacing
ARB Angiotensin Receptor Blocker
AVR Aortic Valve Replacement
BB Beta Blockers
BCIS British Cardiovascular Intervention Society
BfArM Bundesinstituts für Arzneimittel und Medizinprodukte (Federal Institute
for Drugs and Medical Devices Germany)
BMS Bare Metal Stent
CABG Coronary Artery Bypass Grafting
CAGR Compounded Annual Growth Rate
CCA Common Carotid Artery
CCB Calcium Channel Blocker
CDC Center for Disease Control
CE Conformité Européenne
175
CETP Cholesteryl Ester Transfer Protein
CHF Congestive Heart Failure
CHD Coronary Heart Disease
CHMP Committee for Medicinal Products for Human Use
CMS Center for Medicare Services
CSCB Centre for Stem Cell Biology
CVA CerebroVascular Accidents
CVRU Cardiovascular Research Unit
DCA Directional Coronary Atherectomy
CVI Chronic Venous Insufficiency
CVD CardioVascular Disease
DES Drug-Eluting Stent
DSMB Data Safety Monitoring Board
DTI Department of Trade and Industry
DVT Deep Vein Thrombosis
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EAPCI European Association of PercutaneousCardiovascular Interventions
ECA External Carotid Artery
EGAP End Group Activated Polymer
EMEA European Medicines Evaluation Agency
EPC Endothelial Progenitor Cells
ERAs Endothelin receptor antagonists
ESC European Society of Cardiology
ETA Endothelin Type-A receptor
EPD Embolic Protection Devices
ERS The European Respiratory Society
EU European Union
FDA Fedreal Drug Administration
FH Familial Hypercholesterolemia
FIM First in Man
GDP Gross Domestic Product
177
GINA The Global Initiative for Asthma
HDL High-Density-Lipoproteins
ICH intraCerebral Haemorrhagic
IDF-Europe The International Diabetes Federation—European Region
IND Investigational New Drug
LAD Left Anterior Descending (LAD) artery
LASER Light Amplification by Stimulated Emission of Radiation
LDL Low-Density Lipoprotein
LMWH Low Molecular Weight Heparin
LVEF Low Left Ventricular Ejection Fraction
MAA Marketing Authorization Application
MAD Mesenteric Artery Disease
MAI Mesenteric Artery Ischemia
MHLW Japanese Ministry of Health, Labor and Welfare
MI Myocardial Infarction
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MICS Minimally Invasive Cardiac Surgery
MID-CAB Minimally Invasive Direct Coronary Artery Bypass
MOS Major Orthopaedic Surgery
MRC Medical Research Council
MTP Microsomal Triglyceride Transfer Protein
MVP Mitral Valve Prolapse
MVR Mitral Valve Repair or Replacement
NCE New Chemical Entity
NCHS National Center for Health Statistics
NDA New Drug Application
Nd:YAG Neodymium:Yttrium-Aluminum-Garnet
NICE Institure for Clinical Excellence
NYHA New York Heart Association
OAS Orbital Atherectomy System
OECD Organisation for Economic Co-operation and Development
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OP-CAB Off-Pump Coronary Artery Bypass
PACS Premature Atrial Contractions
PAD Peripheral Artery Disease
PAH Pulmonary Arterial Hypertension
PC PhosphorylCholine polymer
PCD-Europe Primary Care Diabetes Europe
PCI Percutaneous Coronary Intervention
PDUFA Prescription Drug User Fee Act
PE Pulmonary Embolism
PLA PolyLactic Acid
PLLA Poly L-lactic Acid
PPAR Peroxisome Proliferator-Activated Receptor
PTCA Percutaneous Transluminal Coronary or Balloon Angioplasty
PSVT Paroxysmal SupraVentricular Tachycardia
PTMR Percutaneous TransMyocardial Revascularization
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PVC Premature Ventricular Contractions
PVD Peripheral Vascular Disease
RA-CAB Robotic Assisted Coronary Artery Bypass
RAS Renin Angiotensin System
RDS Repeat Dose Study
SA SinoAtrial
SHIELD Trial SHock Inhibition Evaluation with AzimiLiDe Trial
SPAF Stroke in Patients with Atrial Fibrillation
STEMI ST-elevation Myocardial Infarction
SVG Saphenous Vein Grafts
SVT SupraVentricular Tachycardia
TCT Transcatheter Cardiovascular Therapeutics
TMLR Transmyocardial laser revascularization
USAN United States Adopted Names
VEGF Vascular Endothelial Growth Factor
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VF Ventricular Fibrillation
VKA Vitamin K Antagonist
VLDP Very-Low-Density-Lipoproteins
VSD Ventricular Septal Defect
VT Ventricular Tachycardia
VTE Venous ThromboEmbolism
YAG Yttrium Aluminium Garnet
WHO World Health Organisation
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Index
Abbott, 12, 15, 51, 59, 64, 72, 73, 75, 78, 79, 83, 112, 128, 135, 146, 147, 154
Acute myocardial infarction, 27
Africa, 21, 141, 151, 159
Angina Pectoris, 25
Anti Anginal, 108
Anti-Arrhythmics, 161, 162, 168
Anti-Dyslipidemics, 143
Anti-Hypertensives, 129
Anti-Thrombotics, 156, 160
Arrhythmiasis, 14, 106, 110
Asia, 21, 74, 75, 79, 99, 159
Atherosclerosis, 14, 23, 24, 106, 112, 113, 114, 149
Atrial Fibrillation, 14, 58, 106, 115, 164, 165, 173, 180
Bare Metal Stents, 67
Bioabsorbable, 66, 82, 83, 170
Boston Scientific, 11, 12, 42, 50, 51, 52, 59, 64, 71, 73, 75, 76, 78, 79, 80, 84, 170
Cardiovascular Disease, iii, 10, 17, 18, 19, 20, 107
China, 11, 19, 22, 42, 46, 47, 48, 49
Cholesterol, 119, 144
Computer, 14, 92, 99, 100
Congestive Heart Failure, 14, 106, 116, 164, 175
Conor MedSystems Inc, 79
Cordis (Johnson & Johnson),, 12, 64, 78
Coronary Stents, 12, 64, 65, 81, 87, 88
Drug Developments, 108, 110, 112, 115, 116, 118, 120, 122, 125
Dyslipidaemia, 149, 154
Everolimus, 12, 73, 75, 79
France, 22, 46, 49, 55, 65, 75, 83, 119, 141
Gene Therapy, 86, 117
Germany, 10, 11, 15, 18, 22, 42, 46, 49, 80, 100, 113, 134, 138, 141, 174
Hypercholesterolemia, 14, 106, 118, 120, 176
Hypertension, 14, 32, 33, 58, 106, 120, 134, 179
India, 11, 19, 22, 31, 42, 46, 47, 48, 49, 145
Investigational New Drug, 114, 142, 177
Italy, 10, 18, 22, 49, 119, 134, 141
Lasers, 101
Medtronic, 12, 54, 64, 73, 75, 76, 78
Minimally, 13, 92, 93, 95, 96, 98, 178
Paclitaxel, 12, 71, 80
Phase I, 14, 58, 106, 107, 108, 109, 110, 111, 112, 113, 115, 116, 117, 118, 120, 122, 123, 124, 126, 130, 132, 134, 135, 136, 137, 138, 139, 142, 143, 145, 147, 149, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 163, 164, 165, 166, 167, 168, 169
Phase II, 14, 58, 106, 107, 108, 109, 110, 111, 113, 126, 130, 132, 134, 135, 136, 137, 138, 139, 142, 143, 145, 147, 149, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 163, 164, 165, 166, 167, 168, 169
183
Phase III, 58, 108, 130, 134, 135, 136, 137, 139, 147, 149, 154, 156, 157, 158, 159, 160, 165, 166, 167, 168, 169
Pipeline, 136, 149, 154, 160, 168
Preclinical, 138, 149
Renin Inhibitors, 132
Robotic, 14, 92, 93, 96, 97, 98, 100, 180
Sirolimus (Rapamycin), 70
Stroke, 20, 38, 58, 171, 180
Study, 28, 39, 55, 57, 58, 70, 146, 147, 148, 159, 167, 180
Tacrolimus, 12, 72
Thrombosis, 14, 106, 124, 125, 156, 175
Trial, 50, 51, 55, 57, 71, 74, 76, 90, 117, 164, 165, 166, 167, 168, 173, 180
United Kingdom, 22, 46, 49, 85, 89
United States, 19, 20, 22, 44, 45, 49, 51, 53, 58, 59, 61, 71, 72, 74, 75, 77, 78, 79, 90, 124, 130, 131, 139, 148, 151, 165, 180
Zotarolimus, 12, 73