international journal ofc ardiology · volume 201, supplement 1, december 2015 issn 0167-5273 a...
TRANSCRIPT
Volume 201, Supplement 1, December 2015 ISSN 0167-5273
www.ijc.elsevier.com
A polypill strategy for global secondary cardiovascular prevention: a worldwide reality
Guest EditorValentín Fuster
Editor-in-ChiefAndrew J.S. Coats
International Journal of
CARDIOLOGY
Affiliated with the International Society for Adult Congenital Heart Disease
Available online at www.sciencedirect.com
for online access via your library
Affiliated with the International Societyfor Adult Congenital Heart Disease
A polypill strategy for global secondary cardiovascular prevention: a worldwide reality
Guest Editor: Valentín Fuster
This supplement has been sponsored by Ferrer
For a full and complete Guide for Authors, please go to: http://www.elsevier.com/locate/ijcard
© 2015 Elsevier Ireland Ltd.
This journal and the individual contributions contained in it are protected under copyright, and the following terms and conditions apply to their use in addition to the terms of any Creative Commons or other user license that has been applied by the publisher to an individual article:
Photocopying
Single photocopies of single articles may be made for personal use as allowed by national copyright laws. Permission is not requiredfor photocopying of articles published under the CC BY license nor for photocopying for non-commercial purposes in accordance withany other user license applied by the publisher. Permission of the publisher and payment of a fee is required for all other photocopying,including multiple or systematic copying, copying for advertising or promotional purposes, resale, and all forms of document delivery.Special rates are available for educational institutions that wish to make photocopies for non-profit educational classroom use.
Derivative Works
Users may reproduce tables of contents or prepare lists of articles including abstracts for internal circulation within their institutions or companies. Other than for articles published under the CC BY license, permission of the publisher is required for resale or distribution outside the subscribing institution or company.
For any subscribed articles or articles published under a CC BY-NC-ND license, permission of the publisher is required for all other derivative works, including compilations and translations.
Storage or Usage
Except as outlined above or as set out in the relevant user license, no part of this publication may be reproduced, stored in a retrievalsystem or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without priorwritten permission of the publisher.
Permissions
For information on how to seek permission visit www.elsevier.com/permissions or call: (+44) 1865 843830 (UK) / (+1) 215 239 3804 (USA).
Author rights
Author(s) may have additional rights in their articles as set out in their agreement with the publisher (more information at http://www.elsevier.com/authorsrights).
Notice
No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability,negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the materialherein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosagesshould be made.
Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does notconstitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer.
Funding Body Agreements and Policies
Elsevier has established agreements and developed policies to allow authors whose articles appear in journals published by Elsevier, to comply with potential manuscript archiving requirements as specified as conditions of their grant awards. To learn more about existing agreements and policies please visit http://www.elsevier.com/fundingbodies
Vol. 201, Supplement 1
December 2015CONTENTS
Affi liated with the International Societyfor Adult Congenital Heart Disease
Cited in: Elsevier BIOBASE/Current Awareness in Biological Sciences; Current Contents (Life Sciences; Clinical Medicine); EMBASE / Excerpta Medica;Index Internacional de Cardiología; Index Medicus (MEDLINE); Sociedad Iberoamericana de Información Científi ca (SIIC); Research Information Systems.
A polypill strategy for global secondary cardiovascular prevention: a worldwide reality
Global burden of CVD: focus on secondary prevention of cardiovascular diseaseSameer Bansilal, José M. Castellano, Valentín Fuster S1
The cardiovascular polypill: clinical data and ongoing studiesJosé M. Castellano, Héctor Bueno, Valentín Fuster S8
The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular preventionJuan Tamargo, José M. Castellano, Valentín Fuster S15
International Journal of Cardiology 201 S1 (2015) S1–S7
The global cardiovascular disease pandemic, current status and future projections
Despite encouraging advances in our knowledge of the
prevention, diagnosis and treatment of atherothrombosis,
cardiovascular disease (CVD) remains a major cause of disability
and premature death throughout the world [1]. Globally an
estimated 16.7 million deaths in the year 2010 were attributed
to CVD; with projections showing a staggering 23.3 million
by 2030. CVD mortality rates are considered equivalent to the
combined number of deaths due to nutritional deficiencies,
infectious diseases, and maternal and perinatal conditions [2].
This massive growth of CVD during the last decade is mainly due
to the increasing incidence in low-and middle-income countries
(LMICs) [2]. In 2012, the Developed and Caucasus and Central
Asia regions had the highest CVD death rates in the world (>400
deaths per 100,000 population, in both genders). Lowest CVD
death rates were estimated for the Oceania region (85 deaths per
100,000 population, in both genders) [3] (Fig. 1).
CVDs (including coronary heart disease (CHD), stroke and
other CVD) cause more than 4 million deaths each year in the
53 countries of the World Health Organization (WHO) European
Region and over 1.9 million deaths in the European Union
(EU) countries [4]. Data from the Organisation for Economic
Co-operation and Development (OECD) show that in 2010,
coronary heart disease (CHD) alone was responsible for 13% of
all deaths in EU member states. However, mortality from CHD
varies considerably being generally higher in the countries of the
former communist bloc. Rates are also relatively high in Finland
and Malta, being several times higher than in France, Portugal,
the Netherlands and Spain. Rates are generally lower in the
southern countries, frequently considered to be a consequence
of the Mediterranean diet. In all countries, death rates for CHD
are higher for men than women in 2012 [4] (Fig. 2).
Since the mid-1990s, CHD mortality rates have declined
in most European countries. Declining tobacco consumption
contributed significantly to reducing mortality rates but
improvements in medical care have also played a part. A recent
study compared short-term outcomes in patients with acute
myocardial infarction (MI) in the United Kingdom (UK) and
Sweden. Unadjusted 30-day mortality was more than a third
higher in the UK (10.5% [95% CI: 10.4–10.6]) than in Sweden
(7.6% [95% CI: 7.4–7.7]) in 2004–2010. The authors suggest that
the difference is mostly due to the more rapid adoption of new
technologies and recommendations for practice in Sweden than
in the UK despite similar spending on acute MI in both countries
[5]. In the United States of America (USA), CHD alone caused
375,295 deaths. Each year an estimated 635,000 Americans have
a new coronary attack (defined as first hospitalized MI or CHD
death) [6].
K E Y W O R D S
Global cardiovascular disease
Secondary prevention
Therapeutic adherence
Accessibility to drugs
A B S T R A C T
Despite encouraging advances in prevention and treatment of atherothrombosis, cardiovascular
disease (CVD) remains a major cause of deaths and disability worldwide and will continue to grow
mainly due to the increase in incidence in low and middle income countries (LMIC). In Europe and the
United States of America (USA), coronary heart disease (CHD) mortality rates have decreased since the
mid-1990s due to improvements in acute care, however the prevalence of CHD is increasing largely in
part due to the overall aging of the population, increased prevalence of cardiovascular (CV) risk factors,
and improved survival of patients after a CV event. Data from clinical trials has consistently proven
the efficacy of pharmacologic interventions with aspirin, statins, and blood pressure (BP)-lowering
agents in reducing the risk of CV events and total mortality in the ever growing pool of patients in
secondary prevention. However, large gaps between indicated therapy and prescribed medication can
be observed worldwide, with very low rates of use of effective therapies in LMIC countries. Adherence
to medication is very poor in chronic patients, especially those treated with multiple pharmacologic
agents, and has been directly correlated to a greater incidence of recurrent CV events and increase in
direct and indirect healthcare costs. In this article, we review the global burden of CV disease, status of
secondary prevention therapy and major barriers for treatment adherence.
© 2015 Elsevier Ireland Ltd. All rights reserved.
Global burden of CVD: focus on secondary prevention of cardiovascular disease
Sameer Bansilala,b, José M. Castellanoa,b,c, Valentín Fustera,b,*
a Mount Sinai Cardiovascular Institute, New York, USAb Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainc HM Hospitales, Hospital Universitario Montepríncipe, Madrid, Spain
* Corresponding author at: Mount Sinai Heart. One Gustave L. Levy Place,
Box 1030 New York City, NY 10029. Tel.: +1212.241.3852; fax: +1212.423.9488.
E-mail address: [email protected] (V. Fuster).
0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
International Journal of Cardiology
j our na l homepage: www.e lsev ie r.com/ loca te / i j card
S2 S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7
Several studies in Europe have demonstrated that due to
stabilisation of the incidence of MI and the case-fatality decrease,
the prevalence of CHD is increasing. Recurrent CVD events are
common in people who have already had a MI. Various studies
have found a recurrence rate of close to 50% for any CVD event
[7,8] or for subsequent revascularisation [9] in the year after an
MI, and up to 75% of patients have a recurrent event within 3 years
[8,10] (Fig. 3). A recent report from Denmark showed increasing
prevalence of CHD associated with a decline in mortality and
ageing of the population. The number of prevalent cases of
CHD in Denmark increased from 125,000 in 2000 to 150,000
in 2009 and the number of people having survived an acute MI
increased from 67,000 to 72,000. This study showed that about
3% of the Danish population has CHD [11]. A recent study sought
to characterise the incidence for first and recurrent acute MI in
England in 2010 by means of a population based national-linked
database study. Overall, the annual age-standardised event rate
of all acute MI (first and recurrent) per 100,000 was 174 (95%
CI: 173–176) in men and 73.7 (95% CI: 72.9–74.5) in women. Of
all the events that occurred: 83% were first acute MIs and 13%
were re-infarctions. One-third (32%) of all acute MIs were fatal,
with about two-thirds of deaths being sudden acute MI deaths.
Similar proportions of all events were first and recurrent acute MI
deaths (23% and 21%, respectively) [12]. In the USA, an estimated
300,000 have a recurrent attack [6]. In addition, 17.1% of acute MI
were followed by a readmission within 30 days in 2009. For 1.6%
of the index admissions the reason for readmission was a new
MI, while for 2.0% the reason was a scheduled revascularization,
for 2.3% it was heart failure or shock and the remaining 11.2%
of index admissions were readmitted for other conditions and
procedures [10].
As short-term survival in acute MI hospitalised patients
improves, it becomes more important to understand the
implications for longer-term prognosis, both with respect to
survival and the risk of recurrence [13]. Factors associated with
higher risk of recurrence include: older age, socioeconomic
status, no revascularization procedures, presence of co-
Less or equal to 200 CV deaths per 100,000population
201 to 400 CV deaths per 100,000 population More than 400 CV deaths per 100,000population
Fig. 1. CV death rates per 100,000 population (age-standardized rates), the World Health Organization 2012 [3].
35
49
51
51
52
55
55
68
68
73
75
81
84
84
86
91
103
108
111
116
124
143
157
163
177
240
267
282
291
300
336
372
383
484
86
104
131
91
111
124
219
145
132
167
140
158
153
173
156
182
182
209
197
220
242
221
259
320
287
387
387
528
418
446
500
508
657
773
0 200 400 600 800 1000
France
Netherlands
Luxembourg
Portugal
Spain
Belgium
Liechtenstein
Greece
Denmark
Cyprus
Turkey
Switzerland
Italy
Slovenia
Norway
United Kingdom
European Union (28 countries)
Sweden
Germany
Poland
Ireland
Serbia
Austria
Finland
Bulgaria
Malta
Croa
Estonia
Romania
Czech Republic
Hungary
Slovakia
Latvia
Lithuania
Age-standardised rates per 100,00 popul
MALES
FEMALES
Fig. 2. Ischaemic heart disease mortality rates 2012 (or nearest year) from the
Eurostat Statistics Database [60].
S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7 S3
morbidities, and lack of adherence to secondary prevention
medication [12]. Both clinical care and secondary prevention are
important in improving the long-term outcome of hospitalized
patients with acute MI.
Current status of secondary prevention, accessibility and adherence to cardiovascular drugs
According to a WHO report, effective reduction of CV mortality
should be based on three key points: surveillance (mapping
and monitoring the epidemic of CVDs), prevention (reducing
exposure to risk factors) and management (equitable health care
for people with CVD) [14] (Fig. 4).
Overwhelming data from clinical trials show that pharma-
cologic interventions with aspirin, statins, and BP (BP)-lowering
agents considerably reduce the risk of vascular events and total
mortality [15–17]. Current European Cardiovascular Prevention
Guidelines in patients with established coronary artery disease
recommend the use of antiplatelet therapy, lipid-lowering agents
when low-density lipoprotein (LDL) cholesterol ≥2.5 mmol/L,
a beta-blocker, and additional BP-lowering agents in the case
of a systolic BP ≥140 mm Hg, unless contraindicated [18,19].
The American Heart Association and the American College of
Cardiology Foundation (AHA/ACCF) Guidelines promote the
standard use of cholesterol-and BP-lowering agents, regardless
of the initial levels of LDL cholesterol or BP in patients with
established vascular disease [20,21].
In clinical practice, a substantial proportion of CHD patients
should be treated with aspirin, a statin, and BP-lowering agents
as a result of tailored and/or step-up therapy. However, large
gaps between indicated therapy and prescribed medication can
be observed worldwide, with very low rates of use of effective
therapies in LMICs countries [22,23]. In the secondary prevention
setting in high-income countries, around 60% of patients
are prescribed anti-platelet therapy, 50% beta-blockers, 40%
angiotensin converting enzyme inhibitor (ACEI) or angiotensin-
receptor blocker (ARB) and almost 70% statins [23]. An analysis
of data from the Antiplatelet Treatment Observational Registry
(APTOR) in 14 European countries showed that only 43% of
patients who had an acute coronary syndrome (ACS) event
between 2007-2009 were receiving optimal secondary prevention
(defined as use of aspirin and clopidogrel as well as three or
more of the following post-discharge medications: statins,
beta-blockers, ARB/ACEI, exercise or diet) at baseline and 1-year
post-discharge. There was considerable variation by country in
prescription of optimal therapy with highest rates reported for
Austria/Hungary and lowest rates for the Czech Republic [24]
(Fig. 5). The results of a prospective epidemiological registry
conducted in Europe showed that the overall use of combination
therapy with aspirin, statin, and ≥1 BP-lowering agent increased
substantially from 9% in 1996 to 66% in 2009. Except for CHD,
the trend to use combination therapy addressed to different risk
factors increases very slowly and that means that there are still
a high proportion of high risk patients not achieving a complete
protection [25]. In the USA, Muntner et al. estimated that among
patients with a history of CV disease, only 44.5% received aspirin,
87.8% received antihypertensive medication, and 64.6% received
statins [26]. The WHO study on Prevention of Recurrences of
Myocardial Infarction and StrokE (WHO-PREMISE) study found
that in some LMICs fewer than 40% of acute MI patients received
ACEIs, and only 20% received statins [27]. The Prospective Urban
Rural Epidemiological (PURE) study of individuals from rural and
urban communities in countries at various stages of economic
development aged 35–70 years confirmed that adherence
with drugs for secondary prevention in patients with CVD was
generally low and worst in the low income countries; with over
80% receiving none of the effective drug treatments in South Asia
[23].
Another fact that might affect the therapy of patients with
CVD is the accessibility to medication, which is highly different
among the different regions and countries of the world. In
the EU, although there are differences between countries in
relationship to healthcare systems the availability of drugs
is very high compared to the LMICs. Cameron et al. assessed
the availability of a basket of 15 medicines in the public and
private sectors of 36 LMICs. Overall, generic medicines were
not adequately available in both the public and private sectors
(median availability of 38% and 64%, respectively) [29]. An
analysis performed by Commonwealth Fund survey revealed
that in the USA, particularly the relatively young and healthy,
are more likely to use prescription drugs than are the residents
of Australia, Canada, Germany, the Netherlands, New Zealand,
and the UK, but they also experience more financial barriers
in accessing medications and spend more out-of-pocket for
prescriptions. In the USA, there are also larger income-related
inequities in pharmaceutical use [28].
Low adherence: prevalence, causes and burden of disease of
non-adherence
On the other hand, adherence to prescribed medication – the
extent to which patients take their medications as prescribed –
Women
Men
Years since first AMI0 1 2 3 4 5 6 7
Cum
ulat
ive
inci
denc
e
0
0.
05
0.
1
0.
15
Fig. 3. Risk of a second acute myocardial infarction (AMI) over 7 years among
30-day survivors of first acute MI by gender, 2004 to 2010, England [13].
Fig. 4. Vision on how to address cardiovascular disease (CVD): World Health
Organization 2011 [1].
S4 S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7
is generally poor for all diseases but especially poor for chronic
conditions requiring long-term drug treatment such as CVD
[29,30]. A systematic review of studies in adherence among
patients with CVD showed that overall adherence was 57% over
a median of 24 months [31]. In a systematic review and meta-
analysis of 44 unique prospective studies (cohort, nested case–
control, or clinical trial) comprising 1,978,919 non-overlapping
participants at high CV risk, showed that 60% of included
participants had good adherence (adherence ≥80%) to CV
medications [32].
WHO has categorized potential barriers for medication
non-adherence into five groups, including patient, condition,
treatment, socioeconomic, and health system related factors
[33,34]. The most common barriers for medication non-
adherence have been the focus of numerous investigations of
adherence [35,36]. The cross-sectional Phase 1 of the FOCUS
(Fixed-Dose Combination Drug for Secondary Cardiovascular
Prevention) study showed that the risk of being non-adherent
was associated with younger age, depression, being on a complex
medication regimen, poorer health insurance coverage, and a
lower level of social support [37]. The concern about medication
side effects and patient’s lack of confidence in the benefit of
treatment all play a role in the lack of adherence. Poor provider-
patient relationship and difficulties accessing physicians or
pharmacies are, among other, relevant socioeconomic factors
[38]. Choudhry et al. conducted a retrospective study in a
cohort of lower income post-MI retired patients in the USA.
Results showed that only 38.6% of patients receiving a statin
after discharge were fully adherent [39]. Finally, Akincigil et al.
examined the duration of CV treatment within 24 months after
a MI. 7% of patients receiving ACEI prescription discontinued
treatment within 1 month, 22% at 6 months, 32% at 1 year and
50% at 2 years [40]. Finally, suboptimal medication adherence
is associated with racial/ethnic minority groups. Ens et al.
literature review examining factors contributing non-adherence
to CV medications in South Asian´s (India and Pakistan) showed
that medication side-effects, cost, forgetfulness and higher
frequency of dosing contributed to non-adherence. South Asian
immigrants also faced language barriers, which contributed to
non-adherence [41].
Many studies have evaluated the effect of adherence with
prescribed medications on outcomes in patients with existing
CVD who need secondary prevention therapy [42–44]. These
studies show that good adherence (generally defined as >80%
adherence) to the combined therapy with aspirin, ACEI, beta-
blockers and statins is associated with improved outcomes
(reduction in CV events, all-cause mortality or CVD mortality,
and reduced medical or pharmacy costs) [42–44]. So, in the
previously cited systematic review and meta-analysis conducted
by Chowduhry et al. of participants at high CV risk (≥18 years
old), risk estimates of CVD (defined as any fatal or non-fatal
CHD, stroke or sudden cardiac death) and/or all-cause mortality
(defined as mortality from any cause) outcomes were reported.
Overall, 60% (95% CI: 52–68%) of included participants had good
adherence (adherence ≥80%) to CV medications. The relative
risk reduction (RRR) of any CV disease in the adherent patients
was of a 20% when compared to patients with poor adherence
(RR 0.80 [95% CI: 0.77–0.84]) Corresponding RRR in all-cause
mortality was of a 38% in good vs. poor adherers (RR 0.62
[95% CI: 0.57–0.67]. These associations remained consistent
across subgroups representing different study characteristics.
According to these results, a considerable proportion of all CVD
events (approximately a 9% in Europe) could be attributed to
poor adherence to vascular medications alone [32]. In the USA,
Newby et al analyzed the use of evidence based therapies during
the period from 1995 to 2002 for patients with documented CHD
in the Duke Databank for Cardiovascular Disease. They showed
that consistent use of CV medication in patients with CHD was
asso ciated with statistically significant lower adjusted mortality
[45].
The burden of acute coronary syndromes (ACS) to healthcare
services in five European countries (UK, France, Germany, Italy
and Spain) was determined including medications prescribed,
intervention rates and hospital utilisation as well as health
outcomes during the first year following a diagnosis of ACS. All
costs were reported in 2004 Euros. Overall, the major contributors
to total costs were hospital stay and revascularisation procedures.
The total cost of ACS was estimated to be €1.9 billion in the UK,
€1.3 billion in France, €3.3 billion in Germany, €3.1 billion in
Italy and €1.0 billion in Spain. The cost per ACS patient ranged
from €7,009 in the UK to €12,086 in Italy [46]. The results of a
systematic review studying the impact of medication adherence
on CHD costs and outcomes found that the annual cost of
treating an adherent compared to a non-adherent patient was
significantly different ($4,040 versus $4,940 respectively, p<0.01)
[47]. A systematic review concluded that the overall costs of care
are lower in patients who are adherent to secondary prevention,
although medication costs are higher in adherent patients than
those who do not take their prescribed medications [47]. Finally,
out-of-pocket payments for the treatment of CV diseases lead to
significant costs for households in LMICs. Up to 71% of patients
who had an acute stroke were found to face catastrophic health
expenditure in China, and 37% of them fell below the poverty
line (1 USD per day) after paying for healthcare bills [48].
This evidence shows the potential of strategies that increase
adherence to cut direct healthcare costs.
Strategies to improve adherence to medications: an integrated approach
Different disease specific, patient, provider and health
system barriers have already been identified as key players to
be addressed in order to increase adherence across populations
[38,49]. Measures to enhance adherence to help maximize the
potentials of effective cardiac therapies in the clinical setting
are urgently required. This is reflected in the ESC Cardiovascular
prevention Guidelines, where adherence assessment in
secondary prevention is a Class 1A recommendation stating
that physicians must assess adherence to medication, and
identify reasons for non-adherence in order to tailor further
interventions to fulfill the individual needs of the patient or
person at risk [19].
38%41%
34%
25%
63%
28%
71%
46%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Spai
n
UK
Fran
ce
Czec
h R
epub
lic
Ger
man
y
Gre
ece
Nor
dic
Aus
tria
-Hun
gary
Belg
ium
-Net
herl
ands
Paen
ts (%
)
Fig. 5. Use of optimal therapy by country cluster after hospital discharge [24].
S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7 S5
Patient-targeted strategies
Strategies to address therapy-related barriers to medication
adherence in patients with CV disease have primarily focused
on reducing the complexity of the prescribed medical regimen.
Polypharmacy is a potentially modifiable and important
component of adherence to medical therapy for patients with
chronic conditions. Different ad-hoc tools such as electronic
medication aid caps have been developed to be delivered
directly to the patient to enhance use of CV medications as
prescribed. In addition, technology based strategies such as
cutting edge-technology in pill bottles which communicate with
a health-coach [50] are being studied at this time. As a matter
of fact, the Randomized Evaluation to Measure Improvements
in Non-adherence from Low-Cost Devices (REMIND) trial is
currently evaluating the impact on medication adherence of
three different pill-box devices [51]. Data showing the efficiency
of these approaches is still lacking. Another novel strategy that
attempts to address the adherence issue is the use of a CV polypill
as evidence suggests that reducing dosage demands is the most
effective single approach to enhancing medication adherence
[19]. Including the key medications necessary to reduce CV
risk into a single, once daily dose pill improves treatment
adherence, and could reduce CV events, hospitalizations and
therefore lower costs [52,53]. The Heart Outcomes Prevention
Evaluation (HOPE-4) trial [34] and the Secondary prevention of
CardiovascUlaR disease in the Elderly (SECURE) trial are large
CV outcomes-based randomized controlled trials testing the
polypill concept.
Provider-targeted strategies
Strategies aimed at improving patient´s knowledge towards
CV disease and use of medication as prescribed have increasingly
focused on the role of highly labor intensive multidisciplinary
care teams. These programs involve, between others, strategies
such as individual counseling, medication education, pharmacy
post-discharge programs and visiting nurse or nurse-practitioner
based services. Berben et al. evaluated which strategies CV nurses
and allied health professional utilize to enhance medication
adherence. Results showed that educational interventions were
the most frequently used tools. As a matter of fact, participants
reported using a higher proportion of educational/cognitive
interventions (36%) than counseling/behavioral (32%) or psycho-
logical/effective interventions (23%). Reading materials about
CV care was the most used adherence-enhancing specific
intervention, with 66% of respondents using it frequently. Only
the half of the participants (48%) reported that they frequently
trained patients on how to properly take their medications as
prescribed during their inpatient recovery [54]. Nieuwkerk et al.
examined the effect of nurse-led counseling program regarding
CV risk on adherence to statins. Patients taking statins for either
primary or secondary prevention of CV disease were randomized
to routine care or to the intervention arm. The intervention
consisted of nurse-led individualized counseling regarding CV
risk and subsequent regular visits to assess the degree of control
of dyslipidemia and other CV risk factors. At the completion of
the trial, self-reported adherence to statins was significantly
higher in the intervention arm as compared to those who
received routine care (100% vs. 95%; p<0.05) [55]. The addition
of a clinical pharmacist to monitor patients with CVD can lead
to an improvement in CVD patients in many areas, including
patient improvement of adherence medications and preventing
potential drug-related problems. Hohmann et al evaluated the
adherence to hospital discharge medication in patients with
ischemic stroke before and after implementing a program
provided by a clinical pharmacist. In the intervention group, the
clinical pharmacist listed the medication at discharge and gave
detailed information for all medication changes during hospital
stay. Significant differences between the control group and
intervention group were established with regard to adherence to
both antithrombotic medications (83.8% control group vs. 91.9%
intervention group, p=0.033) and to statin therapy (69.8% control
group vs. 87.7% intervention group; p<0.001) [56]. None of these
studies mentioned before reported economic outcomes.
Health system-targeted strategies
Medication non-adherence is increasingly recognized to
be associated with socioeconomic adversity. Factors such as
poverty and in particular food insufficiency and hunger [57],
and unstable housing [58] have been associated with medication
non-adherence in other chronic conditions such as human
immunodeficiency virus and acquired immune deficiency
syndrome (HIV/AIDS). In relation to CVD, low socioeconomic
status has been found to be associated with low adherence in a
number of different environments. Pharmacy benefit programs
have a direct influence on adherence to medicines. Higher copays
and restricted benefits lead to a reduction in use of medicines
as prescribed. The Rand study performed in the USA found
that doubling copays for commonly used drug classes reduced
adherence by 25% to 45% [57].
Strategies may be more effective if they: 1) are designed
for specific groups; 2) take into account behavioral patterns;
and 3) are based on evidence-based specific tools or programs.
Multifaced strategies simultaneously directed at patients,
physicians/practices, and healthcare or social systems targeting
physician prescribing behavior as well as interventions to
reduce social, financial and treatment-related barriers to enable
patients to adhere to prescribed therapy have been found to be
most effective in low income groups. Moreover, complex multi-
factorial strategies, addressing different barriers have been
mostly assessed without previous evaluation of their individual
components [59]. Individual interventions such as simplifying
dosage regimens and fixed combination pills appear to be the
most effective tool. The European Guidelines on CVD prevention
recommend all the physicians to reduce dosage demands of their
patients to the lowest feasible level and additionally, to provide
clear advice regarding the benefits and possible adverse effects
of the medication as well as of the duration and timing of dosing.
It is recommended to consider patients’ habits and preferences
and to ask patients in a non-judgmental way how the medication
works for them, discussing possible reasons for non-adherence
(e.g. side effects, worries). After the assessment of adherence it
is important to implement repetitive monitoring and feedback,
offering multisession or combined behavioral interventions
in the case of persistent non-adherence through physicians
assistants and/or trained nurses [19].
Conclusion
It is clear that the current CVD pandemic calls for a revision
of the way we implement healthcare worldwide, as well as new
simple, efficacious and efficient strategies to contain the growth
of the disease worldwide.
The scenario in LMIC is especially worrisome, as many regions
suffer what has been called the double burden of disease (that
is, developing regions where communicable diseases are highly
prevalent are also suffering the health toll from chronic, non-
communicable diseases). In high income countries the higher
survival rate after a CV event, the aging of the population and
the increase in prevalence of CV risk factors has increased the
S6 S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7
cost of treating CVD to a degree that will not be sustainable even
in the wealthiest economies. Even in high income European
countries where medication accessibility is guaranteed the
efficacy of proven treatments is severely hampered due to
poor adherence rates to pharmacologic therapy (consistently
shown to be about 45–60% in secondary prevention). Hence,
interventions toward improving adherence rates could have a far
greater impact on public health than any individual treatment.
Barriers to medication adherence might be surpassed through
programs delivered through the healthcare system, through
multidisciplinary care teams or directly by the patient by
reducing the dosage demands which could include the intake
of CV polypills. Hence, from a public health perspective, it is of
highest importance implement existing and innovative strategies
to achieve adequate adherence to secondary CV prevention
medication in order to ensure efficacy of treatment.
Conflict of Interest Statement
Nothing to declare.
References
[1] Writing C, Smith SC, Jr., Collins A, Ferrari R, Holmes DR, Jr., Logstrup S, McGhie
DV, Ralston J, Sacco RL, Stam H, Taubert K, Wood DA and Zoghbi WA. Our time:
a call to save preventable death from cardiovascular disease (heart disease
and stroke). Glob Heart. 2012;7:297-305.
[2] Organization WH and UNAIDS. Prevention of cardiovascular disease: World
Health Organization; 2007.
[3] WHO. WHO. Data and statistics.
[4] Nichols M, Townsend N, Scarborough P and Rayner M. Cardiovascular disease
in Europe: epidemiological update. Eur Heart J. 2013;34:3028-34.
[5] Chung SC, Gedeborg R, Nicholas O, James S, Jeppsson A, Wolfe C, Heuschmann
P, Wallentin L, Deanfield J, Timmis A, Jernberg T and Hemingway H. Acute
myocardial infarction: a comparison of short-term survival in national out-
come registries in Sweden and the UK. Lancet. 2014;383:1305-12.
[6] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de
Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela
BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB,
McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K,
Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ,
Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW,
Turner MB, American Heart Association Statistics C and Stroke Statistics S.
Heart disease and stroke statistics--2015 update: a report from the American
Heart Association. Circulation. 2015;131:e29-322.
[7] Tuppin P, Neumann A, Danchin N, Weill A, Ricordeau P, de Peretti C and
Allemand H. Combined secondary prevention after hospitalization for myo-
cardial infarction in France: analysis from a large administrative database.
Arch Cardiovasc Dis. 2009;102:279-92.
[8] Andres E, Cordero A, Magan P, Alegria E, Leon M, Luengo E, Botaya RM, Garcia
Ortiz L and Casasnovas JA. Long-term mortality and hospital readmission after
acute myocardial infarction: an eight-year follow-up study. Rev Esp Cardiol
(Engl Ed). 2012;65:414-20.
[9] Bischoff B, Silber S, Richartz BM, Pieper L, Klotsche J, Wittchen HU and Study-
Group D. Inadequate medical treatment of patients with coronary artery dis-
ease by primary care physicians in Germany. Clin Res Cardiol. 2006;95:405-12.
[10] Stranges E, Barrett M, Wier LM and Andrews RM. Readmissions for heart
attack, 2009. 2012.
[11] Koch MB, Davidsen M, Andersen LV, Juel K and Jensen GB. Increasing preva-
lence despite decreasing incidence of ischaemic heart disease and myocardial
infarction. A national register based perspective in Denmark, 1980-2009. Eur
J Prev Cardiol. 2015;22:189-95.
[12] Smolina K, Wright FL, Rayner M and Goldacre MJ. Incidence and 30-day case
fatality for acute myocardial infarction in England in 2010: national-linked
database study. Eur J Public Health. 2012;22:848-53.
[13] Smolina K, Wright FL, Rayner M and Goldacre MJ. Long-term survival and
recurrence after acute myocardial infarction in England, 2004 to 2010. Circ
Cardiovasc Qual Outcomes. 2012;5:532-40.
[14] Alwan A. Global status report on noncommunicable diseases 2010: World
Health Organization; 2011.
[15] Law M, Morris J and Wald N. Use of blood pressure lowering drugs in the pre-
vention of cardiovascular disease: meta-analysis of 147 randomised trials in
the context of expectations from prospective epidemiological studies. Bmj.
2009;338.
[16] Antithrombotic Trialists C, Baigent C, Blackwell L, Collins R, Emberson
J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C,
Roncaglioni MC and Zanchetti A. Aspirin in the primary and secondary pre-
vention of vascular disease: collaborative meta analysis of individual partici-
pant data from randomised trials. Lancet. 2009;373:1849-60.
[17] Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland
LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J and Collins R.
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-
analysis of data from 170,000 participants in 26 randomised trials. Lancet.
2010;376:1670-81.
[18] Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville
J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries
S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez
S, Op Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E,
Fitzgerald T, Cooney MT, Dudina A, Vahanian A, Camm J, De Caterina R, Dean
V, Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD,
McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Altiner
A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H, Hakansson
J, Kjeldsen SE, Larsen m L, Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T,
Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF, Tokgozoglu
L, Wiklund O, Zampelas A, European Society of C, European Association for
Cardiovascular P, Rehabilitation, Council on Cardiovascular N, European
Association for Study of D, International Diabetes Federation E, European
Stroke I, Society of Behavioural M, European Society of H, Europe W, European
Heart N and European Atherosclerosis S. European guidelines on cardiovas-
cular disease prevention in clinical practice: full text. Fourth Joint Task Force
of the European Society of Cardiology and other societies on cardiovascular
disease prevention in clinical practice (constituted by representatives of nine
societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14 Suppl
2:S1-113.
[19] Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren M, Albus C,
Benlian P, Boysen G and Cifkova R. European Guidelines on cardiovascular dis-
ease prevention in clinical practice (version 2012). European heart journal.
2012;33:1635-1701.
[20] Stone N, Robinson J, Lichtenstein A, Goff Jr D, Lloyd-Jones D, Smith Jr S,
Blum C and Schwartz J. ACC/AHA Cholesterol Guideline Panel. Treatment
of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in
adults: synopsis of the 2013 American College of Cardiology/American Heart
Association cholesterol guideline. Ann Intern Med. 2014;160:339-43.
[21] Smith SC, Jr., Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA,
Gibbons RJ, Grundy SM, Hiratzka LF, Jones DW, Lloyd-Jones DM, Minissian
M, Mosca L, Peterson ED, Sacco RL, Spertus J, Stein JH, Taubert KA, World
Heart F and the Preventive Cardiovascular Nurses A. AHA/ACCF Secondary
Prevention and Risk Reduction Therapy for Patients with Coronary and
other Atherosclerotic Vascular Disease: 2011 update: a guideline from the
American Heart Association and American College of Cardiology Foundation.
Circulation. 2011;124:2458-73.
[22] Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U and Group
ES. Cardiovascular prevention guidelines in daily practice: a comparison
of EUROASPIRE I, II, and III surveys in eight European countries. Lancet.
2009;373:929-40.
[23] Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi
R, Iqbal R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-
Jaramillo P, Oguz A, Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren
A, Teo KK and Prospective Urban Rural Epidemiology Study I. Use of second-
ary prevention drugs for cardiovascular disease in the community in high-
income, middle-income, and low-income countries (the PURE Study): a
prospective epidemiological survey. Lancet. 2011;378:1231-43.
[24] Zeymer U, Berkenboom G, Coufal Z, Belger M, Sartral M, Norrbacka K, Bakhai A
and investigators A. Predictors, cost, and outcomes of patients with acute cor-
onary syndrome who receive optimal secondary prevention therapy: results
from the antiplatelet treatment observational registries (APTOR). Int J Cardiol.
2013;170:239-45.
[25] Lafeber M, Grobbee DE, Spiering W, van der Graaf Y, Bots ML, Visseren FL and
Group SS. The combined use of aspirin, a statin, and blood pressure-lowering
agents (polypill components) in clinical practice in patients with vascular dis-
eases or type 2 diabetes mellitus. Eur J Prev Cardiol. 2013;20:771-8.
[26] Muntner P, Mann D, Wildman RP, Shimbo D, Fuster V and Woodward M.
Projected impact of polypill use among US adults: medication use, cardiovascu-
lar risk reduction, and side effects. American heart journal. 2011;161:719-725.
[27] Mendis S, Abegunde D, Yusuf S, Ebrahim S, Shaper G, Ghannem H and Shengelia
B. WHO study on Prevention of REcurrences of Myocardial Infarction and
StrokE (WHO PREMISE). Bull World Health Organ. 2005;83:820-9.
[28] Accessibility PD. Issues in International Health Policy. 2010.
[29] Haynes RB, McKibbon KA and Kanani R. Systematic review of randomised tri-
als of interventions to assist patients to follow prescriptions for medications.
Lancet. 1996;348:383-6.
[30] O’Flaherty M, Buchan I and Capewell S. Contributions of treatment and life-
style to declining CVD mortality: why have CVD mortality rates declined so
much since the 1960s? Heart. 2013;99:159-62.
[31] Naderi SH, Bestwick JP and Wald DS. Adherence to drugs that prevent
cardiovascular disease: meta-analysis on 376,162 patients. Am J Med.
2012;125:882-7 e1.
S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7 S7
[32] Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B,
Mendis S, Hofman A, Mant J and Franco OH. Adherence to cardiovascular
therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J.
2013;34:2940-8.
[33] Sabaté E. Adherence to long-term therapies: evidence for action: World
Health Organization; 2003.
[34] Castellano JM, Sanz G, Fernandez Ortiz A, Garrido E, Bansilal S and Fuster V. A
polypill strategy to improve global secondary cardiovascular prevention: from
concept to reality. J Am Coll Cardiol. 2014;64:613-21.
[35] Perreault S, Blais L, Lamarre D, Dragomir A, Berbiche D, Lalonde L, Laurier
C, St-Maurice F and Collin J. Persistence and determinants of statin therapy
among middle-aged patients for primary and secondary prevention. Br J Clin
Pharmacol. 2005;59:564-73.
[36] Kassab Y, Hassan Y, Abd Aziz N, Ismail O and AbdulRazzaq H. Patients’ adher-
ence to secondary prevention pharmacotherapy after acute coronary syn-
dromes. Int J Clin Pharm. 2013;35:275-80.
[37] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L,
Guzman L, Linares JC, Garcia F, D’Aniello F, Arnaiz JA, Varea S, Martinez F,
Lorenzatti A, Imaz I, Sanchez-Gomez LM, Roncaglioni MC, Baviera M, Smith
SC, Jr., Taubert K, Pocock S, Brotons C, Farkouh ME and Fuster V. A polypill
strategy to improve adherence: results from the FOCUS project. J Am Coll
Cardiol. 2014;64:2071-82.
[38] Osterberg L and Blaschke T. Adherence to medication. N Engl J Med.
2005;353:487-97.
[39] Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC and Shrank WH. Trends
in adherence to secondary prevention medications in elderly post-myocardial
infarction patients. Pharmacoepidem Dr S. 2008;17:1189-1196.
[40] Akincigil A, Bowblis JR, Levin C, Jan S, Patel M and Crystal S. Long-term adher-
ence to evidence based secondary prevention therapies after acute myocar-
dial infarction. J Gen Intern Med. 2008;23:115-121.
[41] Ens TA, Seneviratne CC, Jones C, Green TL and King-Shier KM. South Asians’
cardiac medication adherence. Eur J Cardiovasc Nurs. 2014;13:357-68.
[42] Ho PM, Magid DJ, Shetterly SM, Olson KL, Maddox TM, Peterson PN, Masoudi
FA and Rumsfeld JS. Medication nonadherence is associated with a broad
range of adverse outcomes in patients with coronary artery disease. American
heart journal. 2008;155:772-779.
[43] Dagenais GR, Pogue J, Fox K, Simoons ML and Yusuf S. Angiotensin-converting-
enzyme inhibitors in stable vascular disease without left ventricular systolic
dysfunction or heart failure: a combined analysis of three trials. The Lancet.
2006;368:581-588.
[44] Mukherjee D, Fang J, Chetcuti S, Moscucci M, Kline-Rogers E and Eagle KA.
Impact of combination evidence-based medical therapy on mortality in
patients with acute coronary syndromes. Circulation. 2004;109:745-749.
[45] Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER,
Muhlbaier LH and Califf RM. Long-term adherence to evidence-based secondary
prevention therapies in coronary artery disease. Circulation. 2006;113:203-12.
[46] Taylor MJ, Scuffham PA, McCollam PL and Newby DE. Acute coronary syn-
dromes in Europe: 1-year costs and outcomes. Current Medical Research and
Opinion®. 2007;23:495-503.
[47] Bitton A, Choudhry NK, Matlin OS, Swanton K and Shrank WH. The impact
of medication adherence on coronary artery disease costs and outcomes: a
systematic review. Am J Med. 2013;126:357 e7-357 e27.
[48] Heeley E, Anderson CS, Huang Y, Jan S, Li Y, Liu M, Sun J, Xu E, Wu Y, Yang
Q, Zhang J, Zhang S, Wang J and China QI. Role of health insurance in avert-
ing economic hardship in families after acute stroke in China. Stroke.
2009;40:2149-56.
[49] Marcum ZA, Sevick MA and Handler SM. Medication nonadherence: a diag-
nosable and treatable medical condition. JAMA. 2013;309:2105-6.
[50] Mwaka AD, Wabinga HR and Mayanja-Kizza H. Mind the gaps: a qualitative
study of perceptions of healthcare professionals on challenges and proposed
remedies for cervical cancer help-seeking in post conflict northern Uganda.
BMC family practice. 2013;14:193.
[51] Choudhry NK, Krumme AA, Ercole PM, Girdish C, Isaman DL, Matlin OS,
Brennan TA, Shrank WH and Franklin JM. Rationale and design of the
Randomized Evaluation to Measure Improvements in Non-adherence from
Low-Cost Devices (REMIND) trial. Contemporary clinical trials. 2015;43:53-59.
[52] Castellano JM, Sanz G and Fuster V. Evolution of the polypill concept and
ongoing clinical trials. Canadian Journal of Cardiology. 2014;30:520-526.
[53] Castellano JM, Sanz G, Peñalvo JL, Bansilal S, Fernández-Ortiz A, Alvarez L,
Guzmán L, Linares JC, García F and D’Aniello F. A polypill strategy to improve
adherence: results from the FOCUS project. Journal of the American College of
Cardiology. 2014;64:2071-2082.
[54] Berben L, Bogert L, Leventhal ME, Fridlund B, Jaarsma T, Norekvål TM, Smith
K, Strömberg A, Thompson DR and De Geest S. Which interventions are used
by health care professionals to enhance medication adherence in cardio-
vascular patients? A survey of current clinical practice. European Journal of
Cardiovascular Nursing. 2011;10:14-21.
[55] Nieuwkerk PT, Nierman MC, Vissers MN, Locadia M, Greggers-Peusch P, Knape
LP, Kastelein JJ, Sprangers MA, de Haes HC and Stroes ES. Intervention to
improve adherence to lipid-lowering medication and lipid-levels in patients
with an increased cardiovascular risk. The American journal of cardiology.
2012;110:666-672.
[56] Hohmann C, Neumann-Haefelin T, Klotz JM, Freidank A and Radziwill R.
Adherence to hospital discharge medication in patients with ischemic stroke
A prospective, interventional 2 phase study. Stroke. 2013;44:522-524.
[57] Kalichman SC and Grebler T. Stress and poverty predictors of treatment adher-
ence among people with low-literacy living with HIV/AIDS. Psychosomatic
medicine. 2010;72:810.
[58] Parashar S, Palmer AK, O’Brien N, Chan K, Shen A, Coulter S, Montaner JS and
Hogg RS. Sticking to it: the effect of maximally assisted therapy on antiretrovi-
ral treatment adherence among individuals living with HIV who are unstably
housed. AIDS and Behavior. 2011;15:1612-1622.
[59] Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A,
Agoritsas T, Mistry N, Iorio A and Jack S. Interventions for enhancing medica-
tion adherence. Cochrane Database Syst Rev. 2014;11.
[60] Eurostat. Database -Eurostat.
last page reference
International Journal of Cardiology 201 S1 (2015) S8–S14
Global burden of cardiovascular disease: a call for action
Cardiovascular disease (CVD) is the leading cause of morbidity
and mortality worldwide. The last decade has attested to the rapid
globalization of the consumer society, which has profoundly
impacted lifestyles and cardiovascular (CV) risk factors at a global
scale. The growth of poor eating habits, obesity, and hypertension
are relentlessly contributing to the development of an epidemic
of CVD, the consequences of which have had the highest toll
on low and middle-income economies (LMIC). The immediate
consequence of this socio-demographic shift had a landmark in
2010 when the World Health Organization (WHO) reported more
than 17 million deaths globally were attributed to CVD, over 80%
of which occurred in LMIC [1]. Moreover, global CVD mortality
estimates project more than 23.6 million CVD related deaths by
2030 [2]. Ischaemic heart disease and cerebrovascular diseases,
the most frequent CVDs, are major causes of disability resulting
in 130 million disability-adjusted life years (DALYs) lost in 2010
[1].
In parallel, high income countries, where accessibility to
resources is high, are encountering what has been termed as
the ‘CVD mortality paradox’ [3], which describes the inverse
relationship between CVD mortality and cost. In the US, the
death rate from CVD has fallen about 39 percent between 2001
and 2012 [2] as well as in most European countries [4], yet the
burden and risk factors remain alarmingly high and the costs of
treating CVD in high income countries are staggering. Data from
the Heart Disease and Stroke Statistics from 2015 showed that
the annual direct and indirect cost of CVD and stroke in the US
United States is an estimated $320.1 billion. This figure includes
$195.6 billion in expenditures (direct costs, which include the
cost of physicians and other professionals, hospital services,
prescribed medications, and home health care, but not the cost of
nursing home care) and $124.5 billion in lost future productivity
attributed to premature CVD and stroke mortality in 2011
(indirect costs) [2]. In other words, CVD and stroke accounted
for 15% of total health expenditures in 2011, more than any major
diagnostic group [5]. In Europe, the total cost of CVD is estimated
at €196 billion a year, of which 54% is due to health care costs,
K E Y W O R D S
Cardiovascular polypill
Secondary prevention
Primary prevention
Treatment adherence
A B S T R A C T
Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy,
lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular
exercise, weight loss, smoking cessation) is the cornerstone of secondary prevention. It is now clear
that even in those undergoing PCI or bypass surgery, appropriate lifestyle modification and aggressive
medical therapy are paramount for optimizing long-term outcomes. However, what has emerged from
studies that examined the role of medical therapy in the context of coronary heart disease is that
only ~50% of the patients in these studies are achieving target treatment goals for blood pressure,
lipid and glycemic control. Non-adherence is thought to be a very large contributor to this problem;
across all health-care categories, non-adherence is estimated to account for $290 billion of annual
health-care expenditure in the United States and €1.25 billion in European Union, with poor adherence
to CVD medication accounting for 9% of all European CVD events. Socioeconomic factors may have a
role in patients’ discontinuing their medications, and a major initiative to combat this problem is the
increasing focus on the polypill. The idea of combining numerous medications into a single tablet
to reduce CV risk was first proposed more than a decade ago. This combined formulation not only
significantly enhances patient convenience and adherence but also drives savings for the healthcare
systems. Several randomized clinical trials have consistently demonstrated the effects of polypills
on CV risk factors and adherence, and major trials are underway to study the effect on hard clinical
outcomes.
© 2015 Elsevier Ireland Ltd. All rights reserved.
The cardiovascular polypill: clinical data and ongoing studies
José M. Castellanoa,b,c, Héctor Buenoa,d,e, Valentín Fustera,c,*
a Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainb Hospital Universitario Montepríncipe, HM Hospitales, Madrid, Spaind Hospital Universitario 12 de Octubre and Instituto de investigación i+12, Madrid, Spaine Universidad Complutense de Madrid, Madrid, Spainc Mount Sinai Cardiovascular Institute, New York, USA
* Corresponding author at: Mount Sinai Heart, One Gustave L. Levy Place,
Box 1030 New York City, NY 10029. Tel.: +1 212 241 3852; fax: +1 212 423 9488.
E-mail address: [email protected] (V. Fuster).
0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
International Journal of Cardiology
j our na l homepage: www.e lsev ie r.com/ loca te / i j card
J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14 S9
24% due to productivity losses and 22% due to informal care
of people with CVD [4]. Health care costs represent €212 per
capita per annum, which is around 9% of the total health care
expenditure across the EU. The economic impact of CVD in LMICs
has been estimated to reduce gross domestic product by up to
6.77% [6], which has already been impairing economic growth
in certain regions.
Optimizing secondary prevention in patients with CVD
remains as a big unmet need worldwide. The causes of inade-
quate secondary prevention are multiple. First, lack of treatment
adherence in patients is a serious problem that has been
overlooked in recent decades. The problem is most apparent
in patients with chronic diseases and has been reported in
all countries studied, irrespective of the health care system,
economic situation, and education level [7]. Levels of adherence
in secondary prevention, irrespective of the assessment tool,
have consistently been shown to be about 50% [8,9]. Together
with the type of drug, one of the main reasons for treatment
discontinuation is its complexity and, particularly, the number
of doses (ie, pills, capsules) that the patient must take every
day [10]. The problem is bigger in LMIC, where access to the
healthcare system may be limited and medical attention deficient.
Medication is frequently unavailable or too expensive, given that
health care coverage in LMIC is practically nonexistent and drugs
in the private sector are expensive. The WHO-PREMISE study
found that in some LMICs fewer than 40% of acute myocardial
infarction patients received ACEIs, and only 20% received statins
[11]. The Prospective Urban Rural Epidemiological (PURE) study
included individuals from rural and urban communities in
countries at various stages of economic development in order
to establish accessibility to CV pharmacotherapy. The study
confirmed that adherence with drugs for secondary prevention
in patients with established CVD was generally low and worst in
the low-income countries; with over 80% receiving none of the
effective drug treatments in South Asia [12]. Thus, any attempt
to apply individualized medicine in those countries according to
our standards is a pipe dream. Despite the efforts of healthcare
authorities, professionals, and scientific bodies, the situation
in developed countries is still far from ideal. In countries with
adequate accessibility to treatment, there is a need to increase
effectiveness, which demands improving treatment adherence.
Evolution of the polypill concept
Limitations on real world applicability of various public
health strategies to influence dietary and physical habits
make it unfeasible to have a significant impact in a reasonable
timeframe (such as educational efforts, legislation, dietary
recommendations, public health system infrastructure to meet
preventive needs, etc.). Hence, the concept of the polypill was
proposed as a simple, innovative and cost-effective public health
strategy to influence accessibility to medications and adherence
to treatment at a global scale. For some health professionals,
the idea of a polypill for CV prevention is merely an interesting
concept that is of limited usefulness and applicability. For
others, however, the polypill could save thousands of lives if
used in the proper context and with the correct indication. What
is clear to most is that the global burden of CVD requires new,
simple approaches to impede the growth of CVD by effectively
improving quality of care.
The concept of the CV polypill is now more than a decade old.
It was originally proposed in 2001 by a WHO and Wellcome Trust
expert group [13] and subsequently specified as a combination of
four drugs (beta-blocker, angiotensin converting enzyme [ACE]
inhibitor, aspirin and a statin), which was estimated to reduce
CVD events by 75% in people with clinical evidence of CVD
[14]. Reservations about this CV prevention strategy certainly
are multifactorial, but a decisive part has clearly been played
by the original interpretations of the role of the polypill and
its possible indications. In 2003, Wald and Law claimed that a
polypill containing six components and administered to each
individual older than 55 years, irrespectively of their risk factors
status, would reduce the incidence of cardiovascular disease by
more than 80% [15]. This “vaccination approach” found strong
opposition among the scientific community because of the
unknown consequences of medicalizing an entire population,
the costs of potential adverse reactions, psychological effects
in a healthy population, as well as the possibility of promoting
unhealthy lifestyle habits. Without suitable clinical studies
demonstrating its efficacy, this strategy is unlikely to gain
the acceptance of health care professionals and regulating
authorities.
Based on Wald and Law’s initial idea, various authors
proposed a more selective use of polypills for primary prevention
in individuals without CVD but high CV risk [16]. There is no
definitive proof of the efficacy, safety, or cost-effectiveness of
this approach, although its feasibility has been shown in several
pilot studies [17,18]. Overall, the studies show that the use of a
CV polypill significantly increases treatment adherence [19–21].
None of these studies had the power to detect differences in
the rate of new coronary events. Therefore, the results of new
studies, some currently underway, are required to confirm that
the polypill can play a role in the primary prevention of coronary
disease.
The use of a polypill strategy has been advocated for secon-
dary prevention in patients with CVD, particularly those who
have already had a myocardial infarction [22]. This strategy may
improve treatment accessibility and affordability in developing
countries and increase treatment adherence, still poor in all
socioeconomic levels, which increases subsequent event rates
and health care costs. The main strengths of a polypill strategy
are the significant beneficial impact on adherence, as shown
in numerous randomized clinical trials [9,19–21], and cost-
effectiveness, where polypills have been shown to be cost
saving for health care systems [23–27]. Therefore, polypill
based strategies for optimizing CV prevention are attractive
options both for LMIC and developed countries. In this context,
the Fuster-CNIC-Ferrer polypill was developed as a response
to the current challenging global scenario of CVD. It is a three-
component polypill, comprising aspirin, a statin and an ACE
inhibitor, designed for secondary prevention in patients who
have already suffered a CV event. This polypill was designed as
a key element for a comprehensive public health program of CV
prevention, which necessarily must include education of patients
and physicians on health promotion and changes in lifestyle.
From conceptual debate to worldwide reality: clinical evidence supporting the use of a cardiovascular polypill as a public health strategy
Evidence is available on the efficacy, safety, tolerability,
affordability and effect on adherence of polypills for the primary
and secondary prevention of CVD. All CV polypills that have
been developed before the Fuster-CNIC-Ferrer CV polypill have
not achieved the regulatory requirements to be approved in any
European country or in USA.
Primary prevention
Several pilot studies have demonstrated the feasibility of the
polypill-based primary prevention strategy [28–31]. In summary,
these randomized trials have shown that the combination
S10 J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14
of several antihypertensive agents, a statin, and aspirin can
substantially reduce blood pressure and lipid levels (Table 1). The
pills were well tolerated and showed low rates of adverse effects
and discontinuation. The trials have also shown high adherence
rates, although most have studied for short duration.
Secondary prevention
The potential value of applying the polypill concept for
secondary prevention has been recognized by different expert
panels, including the WHO and the Combination Pharmacotherapy
and Public Health Research Working Group who advocate
carrying out research that provides further evidence on the use
of a polypill in this area [32–34]. For secondary prevention, TIPS-
2 reported significant reductions in BP and LDL-C in patients with
stable CVD or diabetes with the use of the combination drugs
used in TIPS-1, that is a polypill containing 3 BP-lowering drugs
(atenolol 50 mg, hydrochlorothiazide 12.5 mg, and ramipril 5
mg), 20 mg of simvastatin, and 100 mg of aspirin. In total, 518
individuals eligible for secondary prevention were randomly
allocated to receive either a single polypill, or 2 capsules of the
polypill plus K+ supplementation for 8 weeks. Compared with
Table 1Principal Clinical Trials using a CV Polypill
Trial/Sample Size/Principal Investigator(s)
Population Polypill Composition Outcomes Status
Primary prevention
Indian Polycap Study (TIPS)
n=2053
Yusuf S, Pais P
Men and women aged 40–80 years
without CVD and with at least 1 CV
risk factor in India
Aspirin 100 mg, simvastatin
20 mg, ramipril 5 mg,
hydrochlorothiazide 12.5 mg,
atenolol 50 mg
Feasibility; effect
on risk factor levels;
safety and tolerability
Completed
Poly-Iran: Phase II Study of Heart
Polypill Safety and Efficacy in Primary
Prevention of CV Disease
n=475
Marshall T, Malekzadeh R,
Malekzadeh F
Men and women aged
50–80 years without indications or
contraindications for aspirin,
BP-lowering drugs, and statins in
Iran
Aspirin 81 mg,
hydrochlorothiazide 12.5 mg,
enalapril 2.5 mg,
atorvastatin 20
Effect on risk factor
levels; safety and
tolerability
Completed
Combination Therapy Trial
n=200
Furberg C, Mendis S, Soliman EZ.
Age >40 years without CVD and with
estimated 10-year total CVD risk
score >20% in Sri Lanka
Aspirin 75 mg, simvastatin
10 mg, lisinopril 10 mg,
hydrochlorothiazide 10 mg
(Red Heart Pill 2b)
Effect on estimated
10-year total CVD risk
score
Completed
IMProving Adherence using
Combination Therapy (IMPACT)
n=497
Rodgers A, Selak A.
Established CVD or 5-year risk ≥15% Aspirin 75 mg, simvastatin
40 mg, and lisinopril 10 mg
with either atenolol 50 mg or
hydrochlorothiazide 12.5 mg
Effect on adherence to
recommended drugs
and mean change in
blood pressure and
LDL-chol at 12 months
Completed
Indian Polycap Trial (TIPS)-3
n=5000
Yusuf S, Pais P, Xavier D, Liu L.
Primary prevention with estimated
yearly CVD event rate of >1% using
the INTERHEART risk score in China
and India
Polycap; dose to be chosen
after completion of the
TIPS-K trials
Major CVD events;
neurocognitive
function
Estimated study
completion date:
January 2019
Heart Outcomes Prevention Evaluation
(HOPE)-3
n=12,500
Yusuf S, Lonn E
Primary prevention in men aged >55
years and women aged >65 years
with at least 1 CV risk factor and
women aged >60 years with at least
2 risk factors and with average BP
and cholesterol levels in 22 countries
Rosuvastatin 10 mg,
candesartan 16 mg/
hydrochlorothiazide 12.5 mg
(2×2 factorial design)
Major CVD events;
neurocognitive
function; renal
function
Estimated study
completion date:
March 2016
Secondary prevention
FOCUS Trial in Secondary Prevention
Phase 1: n=2000, Phase 2: n=800
Fuster V
Survivors of myocardial infarction in
Spain and Latin American countries
Aspirin 100 mg, simvastatin
40 mg, ramipril 2.5, 5, 10 mg
(Trinomia)
Adherence; feasibility;
effect on risk factor
levels; safety and
tolerability
Completed
Use of a Multidrug Pill In Reducing CV
Events UMPIRE
n=2000
Thom SA, Rodgers A
Established CVD or high-risk primary
prevention (5-year CVD risk of >15%)
in India, Netherlands, UK
Aspirin 75 mg, atenolol
50 mg, simvastatin 40 mg,
lisinopril 10 mg (Red Heart
Pill 1) or aspirin 75 mg,
hydrochlorothiazide 12.5 mg,
simvastatin 40 mg, lisinopril
10 mg (Red Heart Pill 2)
Adherence; effect
on risk factor levels;
safety and tolerability;
CVD events
(secondary outcome)
Completed
Patel
n=623
Established CVD or high risk primary
prevention (5-year CVD risk of >15%)
Australia
Aspirin 75 mg, simvastatin
40 mg, lisinopril 10 mg and
either atenolol 50 mg or
hydrochlorothiazide 12.5 mg.
Adherence to
medications, systolic
blood pressure and
total cholesterol.
Completed
SECURE Trial
n=3200
Fuster V, Castellano JM
Elderly population (>65 years) with a
diagnosis of AMI
Trinomia (Aspirin 100,
Ramipril 2.5, 5 or 10mg,
Atorvastatin 40mg)
Composite primary
endpoint of
cardiovascular
death, nonfatal MI,
nonfatal ischaemic
stroke and urgent
revascularization
Ongoing.
Estimated study
completion date:
April 2020.
J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14 S11
the single dose, the double-dose, or full-dose, reduced systolic
and diastolic BPs and LDL-C levels by an additional 2.8 mmHg,
1.7 mmHg, and 6.6 mg/dl, respectively. Both doses were similarly
well tolerated. The investigators anticipate that the full-dose
regimen would reduce the risk of CHD by 75%, and of stroke by
65% [35].
The Use of a Multidrug Pill In Reducing cardiovascular Events
(UMPIRE) study was the first randomized trial designed to
assess the long-term effect of a polypill strategy in improving
patients’ adherence to medication in CV prevention [20]. This
trial included 2,004 patients (88% with CVD) from 3 European
countries and India. Two different polypill strategies were used
at the physicians’ discretion: 75 mg aspirin, 10 mg lisinopril,
40 mg simvastatin, and either 50 mg atenolol or 12.5 mg
hydrochlorothiazide. At the end of the study (median follow-up
15 months), adherence to medication in the polypill group was
85%, compared with 60% in the standard-care group (p<0.001).
BP and LDL-cholesterol levels were reduced with the polypill
strategy to a greater extent than with standard care, but the
differences were modest (2.6 mmHg and 4.2 mg/dl, respectively;
p<0.001 for each). No significant differences were reported in the
incidence of serious adverse effects between the groups.
The IMPACT trial evaluated 513 adults at high risk of CVD (with
established CVD or 5-year risk of ≥15%), who were recommended
for treatment with antiplatelet, statin, and 2 or more BP-
lowering drugs, and were randomized to continued usual care
or to polypill treatment (with 2 possible approaches: aspirin 75
mg, simvastatin 40 mg, and lisinopril 10 mg with either atenolol
50 mg or hydrochlorothiazide 12.5 mg) and included 12 months’
follow-up. The investigators found that, in line with other
studies, adherence to all 4 recommended drugs was greater
among polypill than usual care participants at 12 months (81% vs
46%; relative risk 1.75, 95% CI 1.52-2.03, p<0.001) [21].
Patel et al. recently published the results of an open-label,
randomized trial involving 623 participants recruited in
Australian general practices [36]. Participants had established
CVD or an estimated five-year CVD risk of ≥15%, with indications
for antiplatelet, statin and ≥2 blood pressure lowering drugs
(‘combination treatment’) and were randomized to the ‘polypill-
based strategy’ received a polypill containing aspirin 75 mg,
simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg
or hydrochlorothiazide 12.5 mg. Participants randomized to
‘usual care’ continued with separate medications and doses
as prescribed by their physician. Primary outcomes were self-
reported adherence to medications, systolic blood pressure
and total cholesterol. After a median of 18 months, patients
randomized to the polypill presented a significantly higher
adherence than those receiving usual care (70% vs 47%, p<0.001).
The study found no significant differences in BP or LDL-C
between both groups, possibly due to limited power of the study.
The FOCUS (Fixed Dose Combination Drug for Secondary
Cardiovascular Prevention) study was the first to prove the
benefits of a polypill strategy in secondary prevention. FOCUS
was fully funded by the FP7 EC programme and consisted
of a cross-sectional study (Phase 1) of 2118 post MI patients
recruited in Argentina, Brazil, Italy, Paraguay, and Spain, aimed
to elucidate factors that interfere with appropriate adherence
to CV medications for secondary prevention after an AMI [37].
Additionally, 695 patients from phase 1 were randomized into
a controlled clinical trial (Phase 2) to test the effect of Fuster-
CNIC-Ferrer CV polypill (a polypill containing aspirin 100 mg,
simvastatin 40mg and ramipril 2.5, 5 or 10 mg) compared to
the three drugs given separately on adherence, blood pressure
(BP) and low density lipoprotein cholesterol (LDL-C), as well as
safety and tolerability over a period of 9 months of follow-up.
Primary end-point in phase 2 was adherence to the treatment
measured at the final visit by the self-reported Morisky-Green
Adherence Questionnaire (MAQ) and pill count (patients had to
meet both criteria for adherence at the in-person visit in order
to be considered adherent). The results of phase 1 showed a very
low overall CV medication adherence of 45.5%. In a multivariable
regression model, the risk of being non-adherent was associated
with younger age, depression, being on a complex medication
regimen, poorer health insurance coverage, and a lower level of
social support, with consistent findings across countries. In Phase
2, the polypill group showed improved adherence compared to
the group receiving separate medications after 9 months follow
up: 50.8% vs 41% (p=0.019; intention-to-treat population) and
65.7% vs 55.7% (p=0.012; per protocol population) when using
the primary endpoint, attending the final visit with MAQ and
high pill count (80–110%) combined, to assess adherence.
Adherence was also higher in the FDC group when measured by
MAQ alone (68% vs. 59%, p=0.049). No treatment difference was
found at follow-up in mean SBP (129.6 vs 128.6 mmHg), mean
LDL-C levels (89.9 vs 91.7 mg/dL), serious adverse events (23
[6.6%] vs. 21 [6%]) or death (1, 0.2% in each group). In consonance
with other clinical trials, compared with the three drugs given
separately, the use of a polypill strategy met the primary
endpoint for adherence – self-reported and direct measured
medication – for post-MI secondary prevention.
Ongoing clinical trials
Several large, ongoing studies are testing the ability of different
polypills to reduce the occurrence of new CV events in real-world
practice. TIPS-3, HOPE-3, Poly-Iran, and HOPE-4 are currently
underway testing different combination pills against placebo.
TIPS-3 will evaluate a preparation of the Polycap without aspirin
(either the doses used in the first TIPS trial or enhanced doses
based on results of the TIPS-K trial) versus placebo over 5 years
in 5,000 individuals without CVD and with an estimated risk of
major CVD of 1%/year in India and China. The ongoing HOPE-3
trial is evaluating the concept of combined BP and cholesterol
lowering medications in individuals without vascular disease
and with average BP and cholesterol levels [38] in 22 countries in
North and South America, Europe, Africa, Asia, and Australia and
will soon complete enrollment of 12,500 individuals at moderate
CV risk (men age 55 years, with women over 65 years with 1
risk factor or women over 60 years with 2 risk factors). Patients
are randomized to rosuvastatin 10 mg/day alone, a FDC of
candesartan 16 mg/hydrochlorothiazide 12.5 mg/day alone, both,
or neither (2×2 factorial design) for 5 years. The main outcomes
will include major CVD events and changes in cognitive and
renal function. The PolyIran study is seeking to determine the
effects of a PolyPill (a FDC of 2 anti-hypertensive medications,
atorvastatin, and aspirin) on primary and secondary prevention
of CVD in Iranian adults older than 50 years [39]. This ambitious
trial will divide the cohort in 3 arms: 3,500 randomly selected
participants will receive the PolyPill once daily and minimal care
(which consists of direct education and a pamphlet on CV risk
reduction, biannual follow-ups and BP measurements); 3,500
will receive only minimal care as described above; and 24,000
participants will receive usual care (standard primary health care
provided by the local physicians and Community Health Workers
for the whole participants of Golestan Cohort study, consistent
with the current Iranian Health Care System guidelines). The
first and second arms will be compared via a 2-armed open-
labeled cluster RCT. The comparisons between arm 3 and the
other 2 arms will be performed by means of a cohort multiple
RCT design. Endpoints will include major CV events (death and
hospitalization). HOPE-4 is a community cluster RCT that will
evaluate an evidence-based program for CVD risk assessment,
S12 J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14
treatment, and control involving simplified screening and
treatment algorithms implemented by non-physician health
workers coupled with lifestyle counseling and combination-
pill therapy [40]. The initial risk factor phase of the study will
assess BP and cholesterol changes in Colombia and Malaysia (50
communities), with plans to expand to 190 communities in 8
countries to evaluate CVD events over 6 years.
The SECURE trial: comparing the efficacy of the Fuster-CNIC-Ferrer CV Polypill vs. usual care in reducing major adverse cardiovascular events during secondary prevention.
The SECondary prevention of cardiovascUlaR disease in the
Elderly (SECURE; EudraCT: 2015-002868-17; NCT0259612)
study is a multicenter, international, randomized trial designed
to evaluate the potential benefit of the Fuster-CNIC-Ferrer CV
polypill, containing aspirin 100 mg, ramipril 2.5, 5 or 10 mgs
and atorvastatin 40mg as a component of a cost-effective,
globally available and comprehensive treatment strategy for
secondary CV prevention. SECURE will enroll a total of 3206
patients >65 years old within 8 weeks of a MI to compare the
efficacy of this polypill in reducing major cardiovascular events
(cardiovascular death, nonfatal MI, nonfatal ischemic stroke,
and urgent revascularization) after a minimum of 2 years
follow-up. The SECURE trial is funded by the European Union
Horizon 2020 Research Support Program and coordinated by
the Centro Nacional de Investigaciones Cardiovasculares (CNIC)
in Spain. SECURE will start enrolling patients soon in in seven
EU countries: Spain, Italy, Germany, France, Poland, Hungry and
Czech Republic.
Polypill as a cost effective strategy in cardiovascular prevention
Considering the rising healthcare costs and their impact on
the economy, it is critical to understand what the future might
hold for CVD prevalence and cost. Currently, CVD is the leading
cause of death and in the United States it already constitutes
17% of overall national health expenditures. Projections show
that between 2010 and 2030, real total direct medical costs of
CVD are projected to triple, from $272.5 billion to 818.1 billion
[5] (Figure 1). Part of the huge economic burden of CVD falls
on the limited effectives of pharmacological treatment due to
non-adherence to medication. In fact, direct and indirect costs
of non-adherence to chronic treatments have been calculated
between $100billion and $289billion annually in the US [41,42].
Non-adherence leads up to €1.25 billion in annually within
the European Union with poor adherence to CVD medication
accounting for 9% of all European CVD events [43]. Therefore,
efforts to promote adherence are gathering worldwide attention
from patients, providers, payers and regulators. A variety of
interventions have been proposed, and range from blister
packaging, case management, education with behavioral
support, reminder calls, pharmacist-led, multicomponent inter-
ven tions, education with behavioral support, collaborative
care, shared decision making. Not all interventions, however,
provided evidence of benefit [44]. Complex interventions
are generally believed to be more effective that simple ones,
however little is known about potential trade-off between their
increased costs and the cost saving that might be reduced from
increased adherence. Moreover, complex interventions that may
show effectiveness in a high income settings are generally non
applicable to limited resource settings, where the burden of CVD
is highest. For this reason, there has been a tremendous effect
in analyzing the potential cost effectiveness of a CV polypill in
various resource settings.
The cost-effectiveness of a polypill regimen for patients at
high risk for CVD specifically in the setting of LMIC has also
been tested. Gaziano et al. [26] performed a pharmacoeconomic
study assessing 2 combination regimens, 1 for primary preven-
tion (which included aspirin, a calcium channel blocker, an
angiotensin-converting enzyme inhibitor, and a statin) and
another for secondary prevention (which included the same
combination of drugs in group 1 but substituted a beta-blocker for
the calcium channel blocker). The incremental cost-effectiveness
ratio for the secondary regimen was between $306 and $388 per
quality-adjusted life-year indicating a cost-effective intervention
for patients with CVD in all developing regions, even in low-
income countries.
The results of a Markov-model-based cost-effectiveness
analysis of the use of a polypill in the UK for secondary CVD
prevention from improved adherence, have been recently
published [27]. The model compared the use of Trinomia (Fuster-
CNIC-Ferrer polypill brand name containing 100 mg aspirin, 20
mg atorvastatin and 2.5, 5, or 10 mg ramipril) with multiple
monotherapy. Outcome measures were CV events prevented per
1000 patients; cost per life-year gained; and cost per quality-
adjusted life-year (QALY) gained. The model estimates that for
each 10% increase in adherence, an additional 6.7% fatal and
non-fatal CV events can be prevented. In the base case, over
10 years, the polypill would improve adherence by ~20% and
thereby prevent 47 of 323 (15%) fatal and non-fatal CV events
per 1000 patients compared with multiple monotherapy, with
an incremental cost-effectiveness ratio (ICER) of £8200 per
QALY gained. Probabilistic sensitivity analyses for the base-
case assumptions showed an 81.5% chance of the polypill being
cost-effective at a willingness-to-pay threshold of £20,000 per
QALY gained compared with multiple monotherapy. In scenario
analyses that varied structural assumptions, ICERs ranged
between cost saving and £21,430 per QALY gained. Based on
this model, the polypill appears to be a cost-effective strategy
to prevent fatal and non-fatal CV events in the UK. Furthermore,
assuming that some 450,000 adults are at risk of MI, a 10
percentage point uptake of the polypill could prevent 3260 CV
events and 590 CV deaths over a decade [27].
Conclusions
The concept of a polypill, composed of a combination of
medications that are known to effectively treat CVD, has been
proposed as a simple, cost effective and innovative public health
strategy to combat the CVD epidemic on a global scale. Several
studies have shown the polypill to be well tolerated and superior
in terms of adherence to standard of care.
Fig. 1. Projection of rise in cost of treating CVD in the US (in billions US) [5].
J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14 S13
Perhaps the best evidence for the polypill concept is in
secondary prevention of CVD where its use has the potential to
close the treatment gap that exists. Large CV clinical trials, such
as FREEDOM, BARI-2D, and COURAGE have demonstrated that
current treatment strategies for secondary prevention are not
effectively improving the risk profiles of patients with CVD [45].
Also, large epidemiological studies have shown CVD therapy
to vary across socioeconomic levels with the worst outcomes
in LMICs [12]. Polypills have emerged as a way to bridge this
treatment gap through simplifying treatment algorithms,
improving patient adherence, improving accessibility, and
reducing CV events and associated costs. The World Health
Organization, citing positive study results, has recognized the
polypill concept as a potential to bridge the treatment gap and
named it a “best buy for cardiovascular disease prevention and
control” in the setting of secondary prevention (post-MI and
stroke). This has led to regulatory approval of the Fuster-CNIC-
Ferrer CV Polypill in more than 20 countries to date and its
commercialization in 8 countries in Mexico, Central America,
South America and Europe under the brands of Trinomia® and
Sincronium®.
The results of various trials under way (SECURE, TIPS-3, and
HOPE-4) designed to show actual reductions in morbimortality
will provide the ultimate evidence for the global implementation
of this cardiovascular prevention strategy.
Conflict of Interest Statement
Drs. Fuster, Castellano and Bueno are PI, co-PI and scientific
coordinator, respectively, of the SECURE trial. No other conflicts
of interest to report.
References
[1] Organization WH. Global status report on noncommunicable diseases 2010.
Geneva, 2011. 2012.
[2] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.
Executive Summary: Heart Disease and Stroke Statistics—2015 Update A
Report From the American Heart Association. Circulation. 2015;131(4):434–41.
[3] Fuster V, Mearns BM. The CVD paradox: mortality vs prevalence. Nat Rev
Cardiol. 2009;6(11):669.
[4] Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in
Europe: epidemiological update. Eur Heart J. 2013;34(39):3028–34.
[5] Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz
MD, et al. Forecasting the future of cardiovascular disease in the United
States a policy statement from the American heart association. Circulation.
2011;123(8):933–44.
[6] Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Beaglehole R,
et al. Grand challenges in chronic non-communicable diseases. Nature.
2007;450(7169):494–6.
[7] Castellano JM, Copeland-Halperin R, Fuster V. Aiming at strategies for a com-
plex problem of medical nonadherence. Global Heart. 2013;8(3):263–71.
[8] Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovas-
cular disease: meta-analysis on 376,162 patients. Am J Med. 2012;125(9):882–
7. e1.
[9] Castellano JM, Sanz G, Peñalvo JL, Bansilal S, Fernández-Ortiz A, Alvarez L, et
al. A polypill strategy to improve adherence: results from the FOCUS project. J
Am Coll Cardiol. 2014;64(20):2071–82.
[10] Claxton AJ, Cramer J, Pierce C. A systematic review of the associations
between dose regimens and medication compliance. Clin Therapeutics.
2001;23(8):1296–310.
[11] Mendis S, Abegunde D, Yusuf S, Ebrahim S, Shaper G, Ghannem H, et al. WHO
study on Prevention of REcurrences of Myocardial Infarction and StrokE
(WHO-PREMISE). Bull World Health Organization. 2005;83(11):820–9.
[12] Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al. Use of
secondary prevention drugs for cardiovascular disease in the community in
high-income, middle-income, and low-income countries (the PURE Study): a
prospective epidemiological survey. Lancet. 2011;378(9798):1231–43.
[13] World Health Organization. Secondary prevention of noncommunicable dis-
ease in low and middle income countries through community-based and
health service interventions. (WHO-Wellcome Trust meeting report 1–3.).
2002. Geneva.
[14] Yusuf S. Two decades of progress in preventing vascular disease. Lancet.
2002;360(9326):2–3.
[15] Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than
80%. BMJ. 2003;326(7404):1419.
[16] Castellano JM, Sanz G, Fernandez Ortiz A, Garrido E, Bansilal S, Fuster V. A
polypill strategy to improve global secondary cardiovascular prevention: from
concept to reality. J Am Coll Cardiol. 2014;64(6):613–21.
[17] Study TIP. Effects of a polypill (Polycap) on risk factors in middle-aged indi-
viduals without cardiovascular disease (TIPS): a phase II, double-blind, ran-
domised trial. Lancet. 2009;373(9672):1341–51.
[18] Yusuf S, Pais P, Sigamani A, Xavier D, Afzal R, Gao P, et al. Comparison of Risk
Factor Reduction and Tolerability of a Full-Dose Polypill (With Potassium)
Versus Low-Dose Polypill (Polycap) in Individuals at High Risk of Cardiovascular
Diseases The Second Indian Polycap Study (TIPS-2) Investigators. Circulation:
Cardiovascular Quality and Outcomes. 2012;5(4):463–71.
[19] Patel A, Cass A, Peiris D, Usherwood T, Brown A, Jan S, et al. A pragmatic ran-
domized trial of a polypill-based strategy to improve use of indicated pre-
ventive treatments in people at high cardiovascular disease risk. European
journal of preventive cardiology. 2014:2047487314530382.
[20] Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al. Effects of
a fixed-dose combination strategy on adherence and risk factors in patients
with or at high risk of CVD: the umpire randomized clinical trial. JAMA.
2013;310(9):918–29.
[21] Selak V, Elley CR, Bullen C, Crengle S, Wadham A, Rafter N, et al. Effect of fixed
dose combination treatment on adherence and risk factor control among
patients at high risk of cardiovascular disease: randomised controlled trial in
primary care. BMJ. 2014;348.
[22] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovas-
cular prevention: rationale, selection of drugs and target population. Nat Clin
Prac Cardiovasc Med. 2009;6(2):101–10.
[23] Bautista LE, Vera-Cala LM, Ferrante D, Herrera VM, Miranda JJ, Pichardo R, et
al. A ‘polypill’aimed at preventing cardiovascular disease could prove highly
cost-effective for use in latin america. Health Affairs. 2013;32(1):155–64.
[24] Shroufi A, Chowdhury R, Anchala R, Stevens S, Blanco P, Han T, et al. Cost
effective interventions for the prevention of cardiovascular disease in low
and middle income countries: a systematic review. BMC Public Health.
2013;13(1):285.
[25] Ito K, Shrank WH, Avorn J, Patrick AR, Brennan TA, Antman EM, et al.
Comparative Cost-effectiveness of interventions to improve medication
adherence after myocardial infarction. Health Serv Res. 2012;47(6):2097–117.
[26] Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with
a multidrug regimen in the developing world: a cost-effectiveness analysis.
Lancet. 2006;368(9536):679–86.
[27] Becerra V, Gracia A, Desai K, Abogunrin S, Brand S, Chapman R, et al. Cost-
effectiveness and public health benefit of secondary cardiovascular disease
prevention from improved adherence using a polypill in the UK. BMJ Open.
2015;5(5).
[28] Xavier D, Pais P, Sigamani A, Pogue J, Afzal R, Yusuf S, et al. The need to test the
theories behind the Polypill: rationale behind the Indian Polycap Study. Nat
Clin Prac Cardiovasc Med. 2009;6(2):96–7.
[29] Malekzadeh F, Marshall T, Pourshams A, Gharravi M, Aslani A, Nateghi A, et
al. A pilot double-blind randomised placebo-controlled trial of the effects of
fixed-dose combination therapy (‘polypill’) on cardiovascular risk factors. Int J
Clin Prac. 2010;64(9):1220–7.
[30] Soliman EZ, Mendis S, Dissanayake WP, Somasundaram NP, Gunaratne PS,
Jayasingne IK, et al. A Polypill for primary prevention of cardiovascular dis-
ease: a feasibility study of the World Health Organization. Trials. 2011;12:3.
[31] Group PC, Rodgers A, Patel A, Berwanger O, Bots M, Grimm R, et al. An inter-
national randomised placebo-controlled trial of a four-component combi-
nation pill (“polypill”) in people with raised cardiovascular risk. PloS One.
2011;6(5):e19857.
[32] Ezzati M, Hoorn SV, Rodgers A, Lopez AD, Mathers CD, Murray CJ, et al.
Estimates of global and regional potential health gains from reducing multiple
major risk factors. Lancet. 2003;362(9380):271–80.
[33] Narayan KM, Mensah GA, Sorensen S, Cheng YJ, Vinicor F, Engelgau MM, et
al. Combination pharmacotherapy for cardiovascular disease prevention:
threat or opportunity for public health? Am J Preven Med. 2005;29(5 Suppl
1):134–8.
[34] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovas-
cular prevention: rationale, selection of drugs and target population. Nat Clin
Prac Cardiovasc Med. 2009;6(2):101–10.
[35] Yusuf S, Pais P, Sigamani A, Xavier D, Afzal R, Gao P, et al. Comparison of risk
factor reduction and tolerability of a full-dose polypill (with potassium)
versus low-dose polypill (polycap) in individuals at high risk of cardiovas-
cular diseases: the Second Indian Polycap Study (TIPS-2) investigators. Circ
Cardiovasc Qual Outcomes. 2012;5(4):463–71.
[36] Patel A, Cass A, Peiris D, Usherwood T, Brown A, Jan S, et al. A pragmatic ran-
domized trial of a polypill-based strategy to improve use of indicated pre-
ventive treatments in people at high cardiovascular disease risk. Eur J Prev
Cardiol. 2015;22(7):920-30.
[37] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, et
al. A polypill strategy to improve adherence: results from the FOCUS project. J
Am Coll Cardiol. 2014;64(20):2071–82.
S14 J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14
[38] Heart Outcomes Prevention Evaluation-3 (HOPE-3), available at http://clini-
caltrials.gov/show/NCT00468923
[39] Prevention of Cardiovascular Disease in Middle-aged and Elderly Iranians
Using a Single PolyPill (PolyIran) avaliable at http://clinicaltrials.gov/ct2/
show/NCT01271985
[40] HeartOutcomes Prevention and Evaluation 4(HOPE-4). http://www.clinical-
trials.gov/show/NCT01826019
[41] Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to
improve medication adherence. Am J Health Sys Pharm. 2003;60(7):657–65.
[42] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.
2005;353(5):487–97.
[43] Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, et al. Adherence
to cardiovascular therapy: a meta-analysis of prevalence and clinical conse-
quences. Eur Heart J. 2013;34(38):2940–8.
[44] Viswanathan M, Golin CE, Jones CD, Ashok M, Blalock SJ, Wines RC, et al.
Interventions to improve adherence to self-administered medications for
chronic diseases in the United States: a systematic review. Ann Intern Med.
2012;157(11):785–95.
[45] Farkouh ME, Boden WE, Bittner V, Muratov V, Hartigan P, Ogdie M, et al. Risk
factor control for coronary artery disease secondary prevention in large rand-
omized trials. J the Am Coll Cardiol. 2013;61(15):1607–15.
International Journal of Cardiology 201 S1 (2015) S15–S22
1. The Fuster-CNIC-Ferrer CV Polypill: making the leap from conceptual debate to worldwide reality
Moving from the theoretical proposal of a CV polypill to
the actual pharmaceutical development of a combination pill
presents several challenges. The selection of the medications
to include in the combination pill is a complex process. Wald
and Law suggested a pill composed of 6 different compounds
in order to maximize potential benefit [1]. Although the idea
of combining so many compounds into a single pill may seem
attractive for some patient populations, the reality is that the
difficulty of manufacturing a combination pill increases with each
component due to challenges related to the chemical properties
of each substrate (Figure 1). The concept of a CV polypill for
secondary prevention proposed by Fuster et al. resulted from
having a clear picture of the global burden of cardiovascular
disease (CVD) [2]. The effectiveness of the drugs included in a
polypill are generally well understood, and the principles behind
using pharmacotherapy at a population level are that the drugs
themselves should have a well-known risk/benefit ratio and
should be supported by an evidence-based efficacy and safety in
secondary CV prevention. On the other hand, a polypill is simple
to administer and is an effective option to increase adherence in
order to reduce CV events on top of the promotion of lifestyle
changes for multiple risk factor control [3].
The Fuster-CNIC-Ferrer CV polypill (commercialized under
Trinomia®, Sincronium® and Iltria® brand names) was developed
within a very clear conceptual framework: to provide
accessibility of treatment to as many patients worldwide for the
longest periods of time so as to prevent recurrence of events and
death, by simplifying treatment in a cost effective way [2,4]. At
the core of this concept lies the decision of including guideline
recommended therapy for secondary prevention, namely,
blood pressure control and prevention of the LV remodeling
process that accompanies cardiac dysfunction after myocardial
infarction (MI), cholesterol lowering, plaque stabilization and
use of antiplatelet drugs to prevent further CVD events, all of
which are known to be effective in secondary prevention [5,6].
From a clinical standpoint, each additional drug presents the
possibility for more adverse effects (AEs) and thus using too
many components could limit the potential patient population.
Furthermore, when choosing the components of the pill, the
target population of the therapy must be considered because
the benefit for some of the drugs varies with respect to use in
primary and secondary prevention of CVD. For example, a polypill
that targets secondary prevention might favor the inclusion of
an antithrombotic agent, a statin and blood pressure lowering
agents (an angiotensin-converting enzyme (ACE) inhibitor and
beta-blocker (BB) over a calcium channel blocker (CCB)) given
the known mortality benefit of the former medications in post-
MI patients. The Fuster-CNIC-Ferrer CV polypill does not include
K E Y W O R D S
Trinomia®
Sincronium®
Iltria® cardiovascular polypill
Ramipril
Atorvastatin
Simvastatin
Aspirin
Secondary prevention
A B S T R A C T
During the last decade, there has been a tremendous effort to develop different cardiovascular
polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological
development of such a strategy has proven to be extremely complex from a formulation standpoint.
Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them.
Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically
compatible with the other components of the pill.
The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to
be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the
pharmacological properties of its three components, including the clinical evidence supporting their
use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse
effects, drug interactions and contraindications.
© 2015 Elsevier Ireland Ltd. All rights reserved.
The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular prevention
Juan Tamargoa, José M. Castellanob,c,d, Valentín Fusterb,d,*
a Department of Pharmacology, School of Medicine, Universidad Complutense, 28040, Madrid, Spainb Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainc HM Hospitales, Hospital Universitario Montepríncipe, Madrid, Spaind Mount Sinai Cardiovascular Institute, New York, USA
* Corresponding author at: Mount Sinai Heart, One Gustave L. Levy Place,
Box 1030 New York City, NY 10029. Tel.: 212.241.3852; fax: 212.423.9488.
E-mail address: [email protected] (V. Fuster).
0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Contents lists available at ScienceDirect
International Journal of Cardiology
j our na l homepage: www.e lsev ie r.com/ loca te / i j card
S16 J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22
a BB in their combination pill, based on clinical and technical
aspects. Clinically, beta-blockers appropriately titrated are
indicated in patients with STEMI, NSTE-ACS and LV dysfunction
with or without signs of heart failure [7,8]. In stable coronary
heart disease (CHD), there is solid evidence to show that BB
effectively relieve anginal symptoms and improve myocardial
ischemia, and are therefore recommended as first-line agents
for symptom relief in both U.S. [9] and European [10] guidelines.
However, the evidence base for the use of BB to improve
prognosis in asymptomatic patients, who represent about
80% of the stable CHD population [11], is less robust and not
supported by data from an appropriately powered randomized
trial [12]. Additionally, a recent report from the REACH registry
has demonstrated that BB usage in patients with stable CHD
was not associated with a reduced rate of CV death, nonfatal MI,
nonfatal stroke, hospitalization for an atherothrombotic event,
or revascularization, even in patients with previous MI [13].
While guidelines currently recommend 3 years of BB treatment
after presentation with acute coronary syndrome (ACS) [9],
should side effects occur there is no definitive evidence to
insist on continued treatment citing concerns about needing to
increase the number of formulations of the pill to allow for dose
adjustments in order to limit side effects.
The concern about limiting the number of formulations of
the combination pill is well founded because from a technical
standpoint there is an almost linear relationship between the
number of active components in the polypill and the difficulty
of formulation (Figure 1). The difficulty of formulation relates
to the different characteristics of each component with respect
to chemical and physical stability. Combining compounds
with differing solubility and sensitivity to heat and moisture
requires significant development time and cost. The dosages
of the different components of the polypill also complicate
the development process. The use of certain components in
very low doses (such as ramipril at 2.5 mg) combined with
another compound at a much higher dose (such as ASA at 100
mg) causes technical problems with the analytical methods
used in purification and bioanalytics. The formulation of a
combination polypill also has illustrated the potential for drug
incompatibilities and issues with bioavailability.
The Fuster-CNIC-Ferrer CV Polypill has been developed by
a technologic platform patented by Ferrer. The combination of
different active ingredients in a single capsule has been achieved
avoiding the physico-chemical incompatibilities conserving
at the same time the biopharmaceutical and pharmacokinetic
properties of every one of its components (Figure 2).
The combination of atorvastatin, rampiril and acetylsalicylic
acid (ASA) shows a clear chemical incompatibility between the
three active ingredients. The employed technology achieves the
stabilization of all of them inside one single pharmaceutical
form, a capsule.
At the same time, some of the components show a very
high pharmacokinetic variability which difficults enormously
the bioequivalence achievement. The Fuster-CNIC-Ferrer CV
polypill technology has allowed the administration of a single
pharmaceutical form to be equivalent to the concomitant
use of every one of the single active ingredient individually
administered.
The Fuster-CNIC-Ferrer CV polypill includes ASA (100 mg),
ramipril (in doses of 2.5, 5, or 10 mg) and Atorvastatin 20 mg.
2. Pharmacological characteristics of Trinomia®
Extensive controlled, randomised studies have demonstrated
that treatment with the proposed dosages of ASA, atorvastatin,
and ramipril decrease mortality in patients with established
CVD [14–16]. There is also extensive experience with the
combination therapy of these medications in free combinations
for CV prevention, with an adequate risk/benefit ratio, in clinical
practice.
2.1. In vivo and in vitro studies with Trinomia®
2.1.1 In vitro: biopharmaceutical studies
A battery of comparative in vitro dissolution studies between
the biobatch for the fixed-dose combination (test) and the
reference products for ASA (Aspirine N® 100mg), Ramipril
10mg (Acovil®), and atorvastatin (Cardyl® 20 mg) used in the
bioequivalence studies, found that there is a similar in vitro
dissolution profile between the biobatch and the reference
products used in the bioequivalence study [17].
2.1.2 In vivo: biopharmaceutical studies: bioequivalence study
Ferrer Internacional, S.A. (Barcelona, Spain) performed a
randomised, open-label, two-period, two-sequence, controlled,
cross-over, bioequivalence study of single-dose atorvastatin 20
mg, ramipril 10 mg, and ASA 100 mg fixed-dose combination
capsule vs. equivalent doses of Cardyl® 20 mg film-coated
tablets + Acovil® 10 mg tablets + Aspirin N® 100 mg tablets
(reference formulations), in order to establish the rate and
extent of absorption of Trinomia® compared to the individual
components. The study was carried out under fasting conditions
(bioequivalence studies in fasting conditions are considered
Fig. 1. Relationship between the number of drugs in a polypill and the formulation
challenges, patentability, and clinical value. Adapted from Guglietta A, and
Guerrero M. (reprinted with permission, license number: 3640791509009).
Fig. 2. The Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®, Iltria®)
technology.
J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22 S17
to be the most sensitive condition to detect a potential
difference between formulations). Even though there are no
relevant interactions with food for any of the components, it
is recommended to take the Fuster-CNIC–Ferrer CV polypill
after meals in order to improve tolerability mainly related to
aspirin. In accordance with the Guideline on the Investigation
of Bioequivalence [18], this study confirms the bioequivalence of
Trinomia as the geometric 90% confidence intervals for the log-
transformed results of the area under the plasma concentration-
time curve from time 0 to the last sampling time [AUC(0t)
] and
peak plasma concentrations (Cmax
) within the acceptable interval
of 80% to 125% for aspirin, atorvastatin, and ramipril (Table 1).
Thus, the Fuster-CNIC–Ferrer CV polypill is the first-in-class
polypill that has been found bioequivalent as compared with the
individual components of the polypill.
Regarding safety, the results of this bioequivalence study also
confirmed that there is no difference in tolerance and safety
between the two treatment groups.
2.2. Pharmacodynamic properties of the components of Trinomia®
Long-term, controlled, randomised studies have demonstrated
that treatment with the dosages of ASA, atorvastatin, and
ramipril contained in the Fuster-CNIC-Ferrer CV polypill decrease
mortality in patients with established CVD. There is also extensive
experience with the combination therapy of these medications
in free combinations for CV prevention, with an adequate risk/
benefit ratio, in clinical practice [10].
2.2.1. Ramipril
This angiotensin converting enzyme inhibitor (ACEI) decreases
plasma and tissular levels of angiotensin II (Figure 3A) [19]. The
maximum inhibition of plasma ACE activity (>90%) appeared
within 1–4 hours and persisted inhibited by 80% after 24 hours.
Epidemiological studies have consistently demonstrated that
high blood pressure levels correlate with the risk of CVD and
cerebrovascular accidents [20] and antihypertensive drugs reduce
the risk of both conditions, not only in hypertensive patients, but
also in those who have a high CVD risk and normal blood pressure.
Present ESC guidelines recommend ACEIs in hypertensives with
LV hypertrophy, HF or LV dysfunction, myocardial infarction (MI),
diabetes, peripheral artery disease, chronic kidney disease or
microalbuminuria, metabolic syndrome and atherosclerosis [21].
The Heart Outcomes Prevention Evaluation (HOPE) trials showed
that in high risk patients ≥55 years of age with evidence of CVD
or diabetes plus a CV risk factor ramipril (10 mg/day over 5 years)
significantly reduced the rates of death, MI, and cerebrovascular
accidents [22]. A similar benefit was reproduced in diabetic
patients. In this study, ramipril also significantly reduced the
development of HF in patients without known low LV ejection
fraction or HF and in elderly patients reduced the risk of major
CV events, CV deaths, MI, and cerebrovascular accidents.
A meta-analysis of the HOPE, the European trial on Reduction
Of cardiac events with Perindopril among patients with stable
coronary Artery disease (EUROPA), and the Prevention of Events
with ACE inhibition (PEACE) trials found that ACEIs significantly
reduce serious vascular events in patients with atherosclerosis
without known evidence of HF or LV systolic dysfunction [23].
Similarly, ACEIs reduce total mortality and major CV end points
in patients who have CHD and no LV systolic dysfunction or
HF [24]. In patients with MI the Acute Infarction Ramipril
Efficacy (AIRE) Study [15] showed that ramipril produces a 27%
risk reduction (RR) in mortality compared with placebo. This
benefit persisted in patients taking aspirin. Interestingly, ACEIs
were effective when administered with antiplatelet and lipid-
lowering agents. In the Ramipril Efficacy in Nephropathy (REIN)
trial ramipril reduced the glomerular filtration rate decline more
than expected from the blood pressure drop [25]. Therefore,
present AHA/ACC and ESC guidelines recommend ACEIs for all
patients with an EF £40% to reduce the risk of HF hospitalization
and the risk of premature death [6,9] and in all patients after an
ACS in the absence of contraindications [10].
2.2.2. Atorvastatin
This selective and competitive inhibitor of the (3-hydroxy-
3-methyl-glutaryl-CoA (HMG-CoA) reductase reduces the
hepatic synthesis of cholesterol (Figure 3B). In patients with
hypercholesterolemia or with mixed hyperlipidemia, ator-
vastatin dose-dependently (10–80 mg daily) decreases total
cholesterol (30–46%), LDL-C (37–55%), apolipoprotein B (34–
50%) and triglycerides (14–33%) plasma levels, and produces
variable increases in HDL-C (2–12%) [26].
Statins are effective in the primary prevention and secondary
prevention of CV diseases [27]. In a meta-analysis of 27 trials
(n=174,149), a 1 mmol/L (40 mg/dL) reduction in LDL-C levels
by statin therapy results in a 21% RR in major vascular events
(MI, coronary death, coronary revascularization, or stroke) and
a 12% RR in vascular mortality [28]. In the GREek Atorvastatin
and Coronary-heart-disease Evaluation (GREACE) study, long-
term treatment of CHD with atorvastatin (mean dose 24 mg/day)
significantly reduced the relative risk, in comparison to usual
care, of all-cause (RRR 43%), coronary mortality (RRR 47%) and
morbidity (RRR 54%) and stroke (RRR 47%) [14]. In a cohort study,
statin therapy produced a 40% RRR in hospitalisation for acute
MI; the 20 mg daily of atorvastatin was equipotent to 80 mg
of pravastatin, 160 mg of fluvastatin, and 40 mg of simvastatin
[29]. Furthermore, early atorvastatin therapy (20 mg/day
within 48 hours) reduced long-term major adverse cardiac and
cerebrovascular events (MACCE) as compared with placebo.
(30) A review of 52 clinical studies recommended 20 mg of
atorvastatin as the standard initial dose in patients requiring a
LDL-C reduction of 35-50% [31]. In the NICE Guideline 2014 Lipid
modification [32] a daily 20 mg dose of atorvastatin reduces
LDL-C to a similar extent (43%) than 10 mg of rosuvastatin and
80 mg of simvastatin, and more than 40 mg of pravastatin and
40 mg of simvastatin. This guideline recommends atorvastatin
20 mg for the primary prevention of CVD to people with or
without type 2 diabetes who have a 10% or greater 10-year risk of
developing CVD, for the secondary prevention of CVD to people
with chronic kidney disease (CKD) and for people ≥85 years to
reduce the risk of non-fatal MI. Because 20 mg atorvastatin dose
presents a good overall balance between efficacy and safety, this
dose was selected for Trinomia®.
Table 1Results of bioequivalence studies comparing components of the
Fuster-CNIC-Ferrer CV Polypill to monocomponents
Drug Parameter 90% CI
Acetyl salycilic acid
AUC0–t
96.92–104.47 BE
Cmax
84.51–95.78 BE
Ramipril
AUC0–t
108.13–120.11 BE
Cmax
91.51–112.62 BE
Atorvastatin
AUC0–t
95.50–105.93 BE
Cmax
94.58–116.14 BE
The upper and lower CL (confidence level) demonstrate that the ratio
and corresponding 90% confidence interval of the relative AUC0-t
and Cmax
geometric least square means of the Test to Reference formulation are in the
pre-specified 80.00 to 125.00% bioequivalence range for all components of the
fixed combination.
AUC 0-t
area under the curve. Cmax:
maximun plasma concentration. CI:
confidence interval. BE: bioequivalence
S18 J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22
2.2.3. Aspirin
Aspirin inhibits platelet aggregation by irreversibly inhibiting
the enzyme cyclooxygenase-1 (Figure 3C) and its antiplatelet
effect last for the duration of platelet life (~10 days) [33]. In
randomised, controlled trials in patients with one or more major
CV risk factors or who have suffered a MI have demonstrated the
efficacy of low-doses of aspirin in the prevention of CV deaths and
total cerebrovascular accidents [34]. Interestingly, the efficacy of
low doses of aspirin (up to 325 mg/day) in preventing the risk of
MI or stroke is greater than with higher doses. A meta-analysis of
287 randomised trials confirmed that long-term treatment with
aspirin (75–125 mg/day) for secondary prevention in a wide
range of patients with high CV risk (patients with a history of MI,
stroke or transient ischemic attacks, or some major CV events)
achieved a RRR of 32% in the incidence of new cardiovascular
events, with no apparent adverse effect on non-cardiovascular
deaths whereas the RRR for the same outcomes was a 26% for
the dose range from 160–325 mg and only of 19% with doses
ranging from 500 mg to 1500 mg [35]. Because of its favorable
benefit-risk ratio, lifelong low-doses of aspirin (75–125 mg) are
the cornerstone for the secondary prevention of MI and death in
patients with coronary artery disease and other atherosclerotic
cardiovascular disease unless contraindicated [6,9,36].
The Fuster-CNIC-Ferrer CV polypill contains 100 mg of ASA,
dose included in the most favourable recommended dosage
range by the current prevention guidelines [6].
2.3. Pharmacokinetic properties of the components of
Fuster-CNIC-Ferrer CV Polypill (Table 2)
2.3.1. Ramipril
It is rapidly absorbed, reaching peak plasma concentrations
(Cmax
) within 1 h. The rate, but not the extent, of absorption
is delayed with food.(19) Ramipril is almost completely
biotransformed in the gut wall and the liver into its metabolite
ramiprilat, which has about 6 times the ACE inhibitory activity
of ramipril and reaches its Cmax
within 2–4 h and steady-state
plasma levels after 4 days. The Cmax
and the 24-hour AUC for
ramiprilat are linear at doses of ramipril between 2.5 and 10 mg
[37]. Ramipril and ramiprilat bind to plasma proteins and are
widely distributed, reaching higher concentrations in kidneys
and lungs than in blood [37]. Ramipril and its metabolites are
excreted in urine (60%, but <2% as unchanged ramipril) and
faeces. After multiple daily doses of 5 and 10 mg of ramipril, the
half-life of ramiprilat is 13–17 hours. ACEIs can cause fetal and
neonatal morbidity and death when given to pregnant women
(Pregnancy Category D). There is no information on the use of
ramipril during breastfeeding.
2.3.2. Atorvastatin
It is rapidly orally absorbed, but presents low oral bioavailability
due to high pre-systemic clearance. Food can decrease the rate
and extent of drug absorption, but does not modify the reduction
Fig. 3. Mechanism of action of (A) ramipril, (B) atorvastatin and (C) acetylsalicilic acid. ACE: angiotensin-converting enzyme. COX: cyclo-oxigenase. ET-1: endothelin-1. GI:
gastrointestinal. NO: nitric oxide. ROS: reactive oxygen species. PGs: prostaglandins. PP: pyrophosphate.
J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22 S19
on LDL-C. Atorvastatin highly binds to plasma proteins and
presents a large volume of distribution; thus, hemodialysis does
not increase drug clearance [38]. Atorvastatin is a substrate of
the hepatic uptake transporter OATP1B1 and is predominantly
metabolised by cytochrome P450 3A4 (CYP3A4) into metabolites
that are responsible for 70% of its LDL-C lowering effects, undergo
further metabolism via glucuronidation and are eliminated in
bile. The Cmax
and AUC of atorvastatin are 4- and 11-fold greater
in patients with Childs-Pugh A and B disease, respectively. Thus,
Fuster-CNIC-Ferrer CV Polypill® is contraindicated in patients
with severe liver failure. Conversely, since <2% of the dose is
excreted in urine, dose adjustment are not necessary in patients
with mild-moderate CKD [39]. The half-life of atorvastatin is
~14 hours, but the half-life of the inhibitory activity for HMG-
CoA reductase is 20-30 hours due to its active metabolites. This
explains why LDL-C reduction is the same regardless the time
the drug is administered. Atorvastatin use is contraindicated in
pregnancy (Pregnacy Category X), but it is unknown whether the
drug or its metabolites are excreted in human breast milk [19].
2.3.3. Aspirin
It is rapidly and almost completely absorbed in the stomach
and small intestine [41], reaches the Cmax
within 15–20 minutes
and platelet function is inhibited within 1 hour. Aspirin is
rapidly biotransformed by plasma and tissular esterases into
salicylic acid being undetectable 1–2 h after dosing (half-life
~15–20 min). Salicylic acid reaches the Cmax
within 1–2 h, binds
to plasma proteins (90–99%) and is widely distributed to all
tissues, crosses the blood-brain barrier and the placenta and is
excreted into breast milk. At low doses (<250 mg), salicylic acid is
glucoconjugated in the liver with glycin (salicyluric acid) and to
a lesser extent with glucuronic acid and presents an elimination
half-life of 2–4 hours [60]. Salicylic acid is excreted mainly in
urine, but its urinary excretion increases 10–20 times (from 5%
to more than 80%) when urine pH rises from 5 to 8 [42]. Pregnant
women (Pregnacy Category D) and those breastfeeding should
avoid taking aspirin unless specifically advised by their doctor.
2.4. Safety of the components of Fuster-CNIC-Ferrer CV Polypill
Acetylsalicylic acid, atorvastatin, and ramipril have been
marketed at the proposed dosages worldwide for decades,
with an established safety profile, and are available as generic
products. This extensive, long-term use of the three drugs in
clinical practice provides a large patient population for analysing
the safety of these three drugs. On the other hand, the dosage
regimen proposed for this polypill (once per day) is the same
as for all of the active components. Therefore, it is not expected
that changing from the concurrent use of the three individual
pills in free combination to the polypill will result in a potentially
different safety profile.
2.4.1. Ramipril
Adverse effects are mild and transient, and drug dis con-
tinuation due to AEs effects is observed in 3% of patients.
The most common AEs include hypotension, dry cough,
dizziness, headache, asthenia, nausea and gastrointestinal (GI)
disturbances [43]. Other AEs include a decrease in hemoglobin
or hematocrit, dermatological reactions (rash, urticaria, pruritus,
photosensitivity), neurologic reactions (headaches, blurred
vision) and impotence. Because ramipril decreases aldosterone
release, hyperkalemia can occur, particularly in patients with
renal failure.
Hypotension can be observed at the beginning of the treat-
ment, particularly in patients with HF post-MI, renal artery
stenosis, hyponatremia, hypovolemia or increased serum
creatinine (1.5–3 mg/dL or 135–265 mol/L). Ramipril produces
a preferential vasodilatation of glomerular efferent arterioles,
reduces the intraglomerular pressure and may increase serum
creatine levels at the beginning of treatment in patients with
hypotension, hyponatremia or renal insufficiency and in
hypertensive patients with unilateral or bilateral renal artery
stenosis. ACEIs can produce angioedema, particularly in blacks;
warning signs include facial swelling, unilateral facial or
periorbital oedema [44].
2.4.2. Atorvastatin
The most frequently described AEs are GI (anorexia, nausea,
flatulence, and constipation), headache, skin rashes, dizziness,
blurred vision, insomnia, and dysgeusia [45]. Myopathy,
characterised by myalgia and muscle weakness with increased
levels of creatine phosphokinase (CPK) >10 times the upper
limit of normal (ULN) has been reported, especially in patients
treated potent CYP3A4 inhibitors, cyclosporine, fibrates or
niacin (Table S1) [46,47]. Rhabdomyolysis is a very rare AE
(~1 per 100,000 patient-years); if suspected or diagnosed,
Table 2Pharmacokinetic profile of the components of the Fuster-CNIC-Ferrer CV Polypill
Drug Atorvastatin Aspirin Ramipril
Bioavailability (%) 14 68 Ramipril - 28
(30 metabolites) Ramiprilat - 44
Cmax
(h) 1–2 0.25–0.3 Ramipril - 0.1–1
Ramiprilat - 2–4
Tmax
(h) 5–7 0.33 Ramipril - 1–2
1–2 (salycilic acid) Ramiprilat - 3.0
PPB (%) ≥98 99 (salycilic acid) Ramipril - 73
Ramiprilat - 56
Vd (L/kg) 5.4 0.15 -
Metabolism Hepatic CYP450 3A4 Hepatic (multiple) Hepatic hydrolysis
Active metabolites yes yes Ramiprilat
Half-life (h) 14 15-20 min Ramipril - 5
2-4 h (low doses) Ramiprilat - 13-17
Excretion (%) Renal – 2 Renal – 5 Renal - 60
Feces - 98 Depend on urinary pH Feces - 40
Breast milk yes yes no
Abbreviations: Cmax
: peak plasma drug concentrations. h: horas. PPB: plasma protein binding. Tmax
: time to reach peak plasma levels or Cmax. Vd. Volume of
distribution
S20 J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22
atorvastatin should be discontinued immediately. Transaminase
elevations >3 times ULN occurs in 0.2%, 0.2%, 0.6% of patients
treated with atorvastatin 10, 20 and 40 mg, but serious liver
injury rarely occurs. Other reported AEs include amnesia,
increased weight, nightmares, paresthesia, peripheral edema
and thrombocytopenia. New-onset diabetes has been reported,
but the risk is low both in absolute terms and when compared
with the reduction in coronary events [48]. Treatment with
statins for 4 years resulted in 1 extra case of diabetes, whereas
5.4 coronary events (coronary death, non-fatal MI) are prevented
[49]. In postmarketing studies, rare and reversible AEs,
including hepatitis, pancreatitis, depression, bullous rashes and
hypersensitivity reactions, have been reported.
2.4.3. Aspirin
The most common AEs are GI (dyspepsia, nausea, and
diarrhea). (46) These AEs are usually mild, although in patients
a peptic ulcer severe GI hemorrhage may occur [50]. Aspirin
increases major (hemorraghic stroke) and minor bleeding
(epistaxis, hematuria, melena, bruising), but when used in
secondary prevention, the balance clearly favors benefit. In a
meta-analysis, aspirin (75–325 mg/day) increased the risk of
major GI bleeding and intracranial bleeding versus placebo [51],
but 769 patients (95% CI 500–1250) need to be treated to cause
1 additional major bleeding episode annually. The risk of GI
bleeding increases when aspirin is co-administered with other
NSAIDs, antiaggregants or anticoagulants [52]. In patients at
increased risk of GI bleeding, a proton pump inhibitor should be
used.
Others adverse effects include weakness, dizziness, tinnitus,
edema, hyperkalemia and deterioration of renal function. Allergic
responses (anaphylactic shock, skin rash, asthma) are rare
(<0.5%), but aspirin may precipitate bronchospasm in patients
with asthma or NSAID-precipitated bronchospasm. Aspirin has
been implicated in some cases of Reye syndrome, so it should not
be prescribed in children and adolescents under 18 years of age.
In recent decades, there has been concurrent use worldwide
of the three drugs for secondary prevention of CVD as a
free combination, which has provided solid evidence on the
appropriate risk/benefit ratio. This drug combination has not
been associated with an increased incidence of adverse effects.
The conclusions of the fixed-dose combination safety study
carried out by Yusuf et al. with Polycap with five components,
although carried out in primary prevention, confirmed that the
safety of the fixed-dose combination was similar to treatment
with each drug in monotherapy. The study found there were no
increases in adverse events specific to the drug [53].
The recent published FOCUS study with a polypill contain-
ing asprin, simvastatin and ramipril compared to the
monocomponents in 695 post MI patients also confirmed that
there were no differences in the occurrence of adverse events
between both groups whereas the polypill treated group showed
a significantly greater adherence rate compared to the control
group after 9 months of follow up [4].
2.5. Drug Interactions
The main drug interactions of ramipril, atorvastatin and
aspirin are summarized in Additional file 1 (Table S1).
A potential interaction between ACEIs and aspirin was
proposed as aspirin inhibits prostaglandin synthesis and causes
sodium and water retention which might potentially counteract
the blood pressure lowering effects of ramipril. However, the
evidence of this potential interaction came from clinical trials
not designed to examine this issue [54]. Indeed, several studies
and two meta-analysis confirmed the efficacy and safety of ACEIs
in patients treated with aspirin [55,56]. A meta-analysis of 6
long-term trials (22,060 patients) found that ACEIs significantly
reduced the risk of the major clinical outcomes, both among
in patients receiving (OR 0.80, 99% CI 0.73–0.88) or not aspirin
at baseline (0.71, 99% CI 0.62–0.81) [57]. In 96,712 patients
allocated to receive ACEIs or standard therapy in the acute phase
of MI (0–36 h from onset), ACEI therapy was associated with
similar reductions in 30-day mortality, irrespective of whether
or not aspirin was given [58]. Furthermore, in patients with CAD
and diagnosis of HF, the use of aspirin in conjunction with ACEIs
does not worsen long-term survival compared to the use of ACEIs
without aspirin [55]. Thus, there is no evidence of a decreased
efficacy of ACEIs when coadministered with low doses of aspirin
(up to 200 mg).
Interestingly, a synergy between statins and ACEIs has been
suggested [59]. In a post hoc analysis of the GREek Atorvastatin
and Coronary-heart-disease Evaluation (GREACE) trial in
high-risk patients with CAD treatment with statins and ACEIs
significantly reduced the cardiovascular events (all-cause and
coronary mortality, nonfatal MI and stroke) more than statins
alone and considerably more than ACEIs alone [60]. Moreover,
in the HOPE trial the benefit of ramipril was observed in patients
already treated with aspirin, beta-blockers, and statins [22].
2.6. Posology
The Fuster-CNIC-Ferrer CV Polypill should be administered
once daily, preferably after food and accompanied by liquid to
reduce the risk of GI effects caused by the aspirin. The capsules
should not be opened, chewed, or crushed. For the prevention
of CV events, the recommended maintenance dose of ramipril
is 10 mg daily. In elderly patients, treatment should be initiated
with precaution due to the higher risk of adverse effects. In
patients with CKD the daily dose of Fuster-CNIC-Ferrer CV
Polypill should be based on creatinine clearance (crCl). When
the crCl is ≥60 mL/min, the maximum daily dose of ramipril
is 10 mg, if crCl is 30-60 mL/min the maximum daily dose of
ramipril is 5 mg, but the Fuster-CNIC-Ferrer CV Polypillis
contraindicated in patients in hemodialysis or with severe
kidney failure (CrCl <30 mL/min) (Table 3) [16]. Liver function
tests should be carried out in patients with liver disease before
beginning treatment with the Fuster-CNIC-Ferrer CV Polypill and
periodically afterwards. Patients who developed increased levels
of transaminases should be monitored until the abnormality
is resolved and the Fuster-CNIC-Ferrer CV Polypill should be
discontinued if the increase in transaminase is >3× the ULN. The
maximum daily dose of ramipril in this patient group is 2.5 mg.
2.7 . Contraindications
The main contraindications of the Fuster-CNIC-Ferrer CV
Polypill are a compilation of the ones described in the summary
of product characteristics of each of the single components and
are summarized in Table 3. The Fuster-CNIC-Ferrer CV Polypill
is therefore contraindicated in women who are pregnant, trying
to become pregnant, or suspected to be pregnant because it can
produce teratogenic effects [19]. It should also be avoided during
lactation as small amounts of statins and aspirin are found in the
mother’s milk and is contraindicated in children and adolescents
under 18 years of age [16].
3. Fuster-CNIC-Ferrer CV polypill marketing authorization
The Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®,
Iltria®) including aspirin (100 mg), ramipril (in doses of 2.5, 5,
or 10 mg to allow for titration) and atorvastatin 20 mg has been
J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22 S21
approved at present by the Medicine Agencies of 15 European
countries (Austria, Belgium, Bulgaria, Czech Republic, Finland,
France, Germany, Greece, Ireland, Italy, Poland, Portugal,
Rumania, Spain, Sweden) and Chile for its use in secondary
prevention of CV events. The indication for its use is for the
secondary prevention of CV events as substitution therapy in
adult patients adequately controlled with the monocomponents
given concomitantly at equivalent therapeutic dosages [13].
Currently it has been marketed in Spain, Portugal, Romania
and Germany under two different brand names: Trinomia® and
Sincronium®.
During the next years, it has been planned to launch the
Fuster-CNIC-Ferrer CV polypill in additional European countries
as well as worldwide.
4. Conclusions
The concept of a pill containing guideline recommended
therapy for secondary prevention, composed of aspirin, an
antihypertensive agent and a statin has been suggested for over
a decade to simplify treatment complexity, increase accessibility
to treatment and serve as a cost effective public health
strategy to improve pharmacological treatment worldwide.
In stark contrast to the simple concept of the cardiovascular
polypill itself (including three active principles in one pill) the
pharmacological development of such a strategy has proven to
be extremely complex from a formulation point of view. The
Fuster-CNIC-Ferrer CV Polypill has made the leap from this
conceptual debate to clinical reality and has become first in class
to achieve bioequivalence of all components, which in turn has
led to widespread approval by regulatory agencies.
Additional file
Additional file 1: Table S1 Drug interactions of the
components of the Fuster-CNIC-Ferrer CV Polypill (Trinomia®,
Sincronium®, Iltria®).
Financial disclosure
The authors have no financial disclosures or relationships to
report.
Conflict of Interest Statement
No conflict of interest to report.
References
[1] Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than
80%. BMJ. 2003;326(7404):1419.
[2] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovascu-
lar prevention: rationale, selection of drugs and target population. Nature Clin
Prac Cardiovasc Med. 2009;6(2):101-10.
[3] Castellano JM, Sanz G, Fuster V. Evolution of the polypill concept and ongoing
clinical trials. Can J Cardiol. 2014;30(5):520-6.
[4] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, et
al. A polypill strategy to improve adherence: results from the FOCUS project. J
Am Coll Cardiol. 2014;64(20):2071-82.
[5] Smith SC, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, et al.
AHA/ACCF secondary prevention and risk reduction therapy for patients with
coronary and other atherosclerotic vascular disease: 2011 update: a guide-
line from the American Heart Association and American College of Cardiology
Foundation endorsed by the World Heart Federation and the Preventive
Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432-46.
[6] Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren M, et al.
European Guidelines on cardiovascular disease prevention in clinical practice
(version 2012) The Fifth Joint Task Force of the European Society of Cardiology
and Other Societies on Cardiovascular Disease Prevention in Clinical Practice
(constituted by representatives of nine societies and by invited experts)
Developed with the special contribution of the European Association for
Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012:ehs092.
[7] Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, et al. ESC
Guidelines for the management of acute myocardial infarction in patients
presenting with ST-segment elevation. Eur Heart J. 2012:ehs215.
[8] Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines
for the management of acute coronary syndromes in patients presenting with-
out persistent ST-segment elevation. Eur Heart J. 2011;32(23):2999-3054.
[9] Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Douglas PS, et al.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and
management of patients with stable ischemic heart disease: a report of the
American College of Cardiology Foundation/American Heart Association
task force on practice guidelines, and the American College of Physicians,
American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and
Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.
[10] Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al.
2013 ESC guidelines on the management of stable coronary artery disease. Eur
Heart J. 2013;34(38):2949-3003.
[11] Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the risk
of recurrent cardiovascular events in outpatients with stable coronary heart
disease: the heart and soul study. Arch Intern Med. 2008;168(13):1423-8.
[12] Calhoun M, Cross LB, Cooper-DeHoff RM. Clinical utility of -blockers for
primary and secondary prevention of coronary artery disease. Expert Rev
Cardiovasc Ther. 2013;11(3):289-91.
Table 3Contraindications of the Fuster-CNIC-Ferrer CV Polypill [13]
• Hypersensitivity to the active substances, to any of the excipients, to other salicylates, to NSAIDs, to any other ACE inhibitor, or to tartrazine
• Hypersensitivity to soya or peanut
• History of previous asthma attacks or other allergic reactions to salicylic acid and other NSAIDSs
• Acute gastric and enteric ulcers
• Hemophilia and other clotting disorders
• Severe or active liver disease, or unexplained persistent elevations of serum transaminases ≥3× ULN
• Severe kidney failure (creatinine >221 mmol/L or eGFR £30 mL/min/1.73 m2) or haemodialysis
• Severe heart failure
• Concomitant treatment with methotrexate at a dosage ³15 mg per week
• Patients with nasal polyps associated to asthma induced or exacerbated by aspirin
• During pregnancy, lactation and in women of child-bearing potential not using appropriate contraceptive measures
• Concomitant treatment with tipranavir, ritonavir or cyclosporine due to the risk of rhabdomyolysis
• History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or ARBs).
• Extracorporeal treatments which involve blood contact with negatively charged surfaces
• Bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney
• Ramipril should not be administered to hypotensive or hemodynamically unstable patients.
• Children and adolescents below 18 years of age during episodes of fever-causing or viral illness
Abbreviations: ACE: angiotensin-converting enzyme. ARBs: angiotensin II receptor blockers. GFR: glomerular filtration rate. NSAIDs: non-steroidal anti-
inflammatory drugs. ULN: upper limit of normal
S22 J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22
[13] Bangalore S, Steg G, Deedwania P, Crowley K, Eagle KA, Goto S, et al. -Blocker
use and clinical outcomes in stable outpatients with and without coronary
artery disease. JAMA. 2012;308(13):1340-9.
[14] Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN,
Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol
Educational Program goal versus’ usual’care in secondary coronary heart dis-
ease prevention. Curr Med Res Opin. 2002;18(4):220-8.
[15] Cleland J, Erhardt L, Hall A, Winter C, Ball S, Investigators AS. Validation of
primary and secondary outcomes and classification of mode of death among
patients with clinical evidence of heart failure after a myocardial infarction: a
report from the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
J Cardiovasc Pharmacol. 1993;22:S22-7.
[16] Study TAIREA. Effect of ramipril on mortality and morbidity of survivors of
acute myocardial infarction with clinical evidence of heart failure. Lancet.
1993;342(8875):821-8.
[17] Trinomia®. Summary of Product Characteristics. http://www.hpra.ie/img/
uploaded/swedocuments/LicenseSPC_PA1744-002-001_09022015101132.pdf
[18] Tamboli A, Todkar P, Zope P, Sayyad F. An Overview on Bioequivalence:
Regulatory Consideration for Generic Drug Products. J Bioequiv Availab
2: 086-092. doi:10.4172/jbb.1000037. OMICS Publishing Group J Bioequiv
Availab ISSN; 2010.
[19] Warner GT, Perry CM. Ramipril. Drugs. 2002;62(9):1381-405.
[20] Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment
Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and
other blood-pressure-lowering drugs: results of prospectively designed over-
views of randomised trials. Blood pressure lowering treatment trialists’ col-
laboration Lancet. 2000;356(9246):1955-64.
[21] Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013
ESH/ESC guidelines for the management of arterial hypertension: the Task
Force for the Management of Arterial Hypertension of the European Society
of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood
Pres. 2013;22(4):193-278.
[22] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angi-
otensin-converting-enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation Study
Investigators. N Engl J Med. 2000;342(3):145-53.
[23] Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-
enzyme inhibitors in stable vascular disease without left ventricular systo-
lic dysfunction or heart failure: a combined analysis of three trials. Lancet.
2006;368(9535):581-8.
[24] Danchin N, Cucherat M, Thuillez C, Durand E, Kadri Z, Steg PG. Angiotensin-
converting enzyme inhibitors in patients with coronary artery disease
and absence of heart failure or left ventricular systolic dysfunction: an
overview of long-term randomized controlled trials. Arch Intern Med.
2006;166(7):787-96.
[25] Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G, et al. Renal
function and requirement for dialysis in chronic nephropathy patients on
long-term ramipril: REIN follow-up trial. Lancet. 1998;352(9136):1252-6.
[26] Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien P-J,
et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary
hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.
Arterioscler Thromb Vasc Biol. 1995;15(5):678-82.
[27] Stone NJ, Merz CNB, ScM F, Blum FCB, McBride FP, Eckel FRH, et al. 2013 ACC/
AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults. J Am Coll Cardiol. 2014;63(25):2889–934.
[28] Trialists CT. Efficacy and safety of cholesterol-lowering treatment: prospec-
tive meta-analysis of data from 90 056 participants in 14 randomised trials of
statins. Lancet. 2005;366(9493):1267-78.
[29] Penning-van Beest FJ, Termorshuizen F, Goettsch WG, Klungel OH, Kastelein JJ,
Herings RM. Adherence to evidence-based statin guidelines reduces the risk
of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur
Heart J. 2007;28(2):154-9.
[30] Dohi T, Miyauchi K, Okazaki S, Yokoyama T, Yanagisawa N, Tamura H, et al.
Early intensive statin treatment for six months improves long-term clinical
outcomes in patients with acute coronary syndrome (Extended-ESTABLISH
trial): a follow-up study. Atherosclerosis. 2010;210(2):497-502.
[31] Smith MB, Lee NJ, Haney E, Carson S. Drug class review: Hmg-coa reductase
inhibitors (statins) and fixed-dose combination products containing a statin:
Final report update 5. Drug Class Reviews. 2009.
[32] Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardio-
vascular risk assessment for the primary and secondary prevention of cardio-
vascular disease: summary of updated NICE guidance. BMJ. 2014;349:g4356.
[33] Capone ML, Tacconelli S, Sciulli MG, Grana M, Ricciotti E, Minuz P, et al.
Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase
inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation.
2004;109(12):1468-71.
[34] Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE,
et al. Low-dose and high-dose acetylsalicylic acid for patients under-
going carotid endarterectomy: a randomised controlled trial. Lancet.
1999;353(9171):2179-84.
[35] Trialists’Collaboration A. Collaborative meta-analysis of randomised trials of
antiplatelet therapy for prevention of death, myocardial infarction, and stroke
in high risk patients. BMJ. 2002;324(7329):71-86.
[36] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.
Executive Summary: Heart Disease and Stroke Statistics—2015 Update A
Report From the American Heart Association. Circulation. 2015;131(4):434-41.
[37] Van Griensven J, Schoemaker R, Cohen A, Luus H, Seibert-Grafe M, Röthig H-J.
Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor
ramipril. Eur J Clin Pharmacol. 1995;47(6):513-8.
[38] Davidson MH, Robinson JG. Lipid-lowering effects of statins: a comparative
review. Expert Opin Pharmacother. 2006;7(13):1701-14.
[39] Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet.
2003;42(13):1141-60.
[40] Amir LH, Pirotta MV, Raval M. Breastfeeding: Evidence Based Guidelines for
the Use of Medicines. Austr Family Physician. 2011;40(9):684.
[41] Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA.
Use of nonsteroidal antiinflammatory drugs an update for clinicians: a
scientific statement from the American Heart Association. Circulation.
2007;115(12):1634-42.
[42] Dargan P, Wallace C, Jones A. An evidence based flowchart to guide the manage-
ment of acute salicylate (aspirin) overdose. Emerg Med J. 2002;19(3):206-9.
[43] Carré A, Vasmant D, Elmalem J, Thiéry P. Tolerability of ramipril in a mul-
ticenter study of mild-to-moderate hypertension in general practice. J
Cardiovasc Pharmacol. 1991;18:S141-S3.
[44] Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat
and enalapril in patients with hypertension: the Omapatrilat Cardiovascular
Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103-11.
[45] Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin
derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol.
2003;92(6):670-6.
[46] Law MR, Wald NJ, Rudnicka A. Quantifying effect of statins on low density
lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic
review and meta-analysis. BMJ. 2003;326(7404):1423.
[47] Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C.
ACC/AHA/NHLBI clinical advisory on the use and safety of statins12. J Am Coll
Cardiol. 2002;40(3):567-72.
[48] Ma T, Tien L, Fang C-L, Liou Y-S, Jong G-P. Statins and new-onset diabetes: a
retrospective longitudinal cohort study. Clin Therapeut. 2012;34(9):1977-83.
[49] Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins
and risk of incident diabetes: a collaborative meta-analysis of randomised sta-
tin trials. Lancet. 2010;375(9716):735-42.
[50] Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary preven-
tion of cardiovascular events: a summary of the evidence for the US Preventive
Services Task Force. Ann Intern Med. 2002;136(2):161-72.
[51] McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events
of low-dose aspirin and clopidogrel in randomized controlled trials. Am J
Med. 2006;119(8):624-38.
[52] Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug–drug interactions between
antithrombotic medications and the risk of gastrointestinal bleeding. Can
Med Assoc J. 2007;177(4):347-51.
[53] Study TIP. Effects of a polypill (Polycap) on risk factors in middle-aged indi-
viduals without cardiovascular disease (TIPS): a phase II, double-blind, ran-
domised trial. The Lancet. 2009;373(9672):1341-51.
[54] Peterson JG, Lauer MS. Using aspirin and ACE inhibitors in combination: why
the hullabaloo? Cleveland Clin J Med. 2001;68(6):569-73.
[55] Harjai KJ, Solis S, Prasad A, Loupe J. Use of aspirin in conjunction with angi-
otensin-converting enzyme inhibitors does not worsen long-term survival in
heart failure. Int J Cardiol. 2003;88(2):207-14.
[56] McAlister FA, Ghali WA, Gong Y, Fang J, Armstrong PW, Tu JV. Aspirin use and
outcomes in a community-based cohort of 7352 patients discharged after first
hospitalization for heart failure. Circulation. 2006;113(22):2572-8.
[57] Tea KK, Yusuf S, Pfeffer M, Kober L, Hall A, Pogue J, et al. Effects of long-term
treatment with angiotensin-converting-enzyme inhibitors in the presence or
absence of aspirin: a systematic review. Lancet. 2002;360(9339):1037-43.
[58] Latini R, Tognoni G, Maggioni AP, Baigent C, Braunwald E, Chen Z-M, et al.
Clinical effects of early angiotensin-converting enzyme inhibitor treatment
for acute myocardial infarction are similar in the presence and absence of
aspirin: systematic overview of individual data from 96,712 randomized
patients. J Am Coll Cardiol. 2000;35(7):1801-7.
[59] Krumholz HM, Chen Y-T, Wang Y, Radford MJ. Aspirin and angiotensin-con-
verting enzyme inhibitors among elderly survivors of hospitalization for an
acute myocardial infarction. Arch Intern Med. 2001;161(4):538-44.
[60] Athyros V, Mikhailidis D, Papageorgiou A, Bouloukos V, Pehlivanidis A,
Symeonidis A, et al. Effect of statins and ACE inhibitors alone and in com-
bination on clinical outcome in patients with coronary heart disease. J Hum
Hypertens. 2004;18(11):781-8.
Table S1Drug interactions of the components of the Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®, Iltria®)
Interacting drug(s) PD/PK consequence Clinical implications
Ramipril
• Antihypertensives
• Vasodilators (e.g. nitrates)
• Alcohol
• Anesthetic agents
• Antipsychotics
• Tricyclic antidepressants
Increase the antihypertensive response of
ramipril
Monitor blood pressure
ARBs, Beta-blockers, Heparin, K+-sparing diuretics, K+
supplements, Tacrolimus, Trimethoprim.
Increase the risk of hyperkalemia Monitor plasma potassium levels
Cyclosporine, NSAIDs, Vasopressor sympathomimetics Inhibit the antihypertensive response of ramipril Monitor blood pressure
NSAIDs May produce renal failure in the elderly or
dehydrated patients
Lithium salts Decreases lithium renal excretion and increases
plasma levels and toxicity.
Monitor lithium plasma levels
Oral antidiabetic agents or insulin Increase the risk of hypoglycaemia Monitor glucose plasma levels
Erythropoietin Higher doses of erythropoietin are needed in
dialysed patients
Aliskiren, ARBs Increased renal dysfunction Avoid the combination
Drugs eliminated by the kidney:
• Atenolol, Flecainide, Disopyramide, Nadolol,
Procainamide, Sotalol,
Ramipril decreases their renal clearance Monitor drug response
Temsirolimus Increased risk for angioedema With caution
Atorvastatin
Strong CYP3A4 inhibitors:
• Azole antifungals (Itraconazole, Ketoconazole,
Posoconazole, Voriconazole),
• Clarithromycin, Telithromycin
• HIV-protease inhibitors: Atazanavir, Darunavir,
Fosamprenavir, Indinavir, Lopinavir, Nelfinavir,
Ripanavir, Ritonavir, Saquinavir, Tipranavir
• Hepatitis C protease inhibitors: telaprevir
• Other: Ciclosporin, Delavirdine, Stiripentol
Significantly increased the Cmax
of atorvastatin
and the risk of myopathy
Atorvastatin should be used with caution and close
clinical monitoring is recommended.
Clarithromycin, itraconazole: caution at doses
>20 mg/day
HIV protease inhibitors: should be avoided if
possible. The dose of atorvastatin should not exceed
20 mg/day
Boceprevir
Moderate CYP3A4 inhibitors:
• Amiodarone, Erythromycin, Fluconazole, Fluoxetine,
Grapefruit juice, Lomipatide, Verapamil
They may increase the Cmax
of atorvastatin and
the risk of myopathy.
Starting dose: 10 mg/day
Ezetimibe, Fibrates, Fusidic acid, Gemfibrozil, Niacin Increased risk of myopathy and rabdomyolysis Avoid combination with gemfibrozil. Clinical
monitoring is recommended
CYP3A4 inducers:
• Carbamazepin, Eferivenz, Rifampin, St. John’s wort
Variable decrease in the plasma concentrations of
atorvastatin
OATP1B1 inhibitors: Cyclosporine It increases the Cmax
of atorvastatin Monitor clinical efficacy
Digoxin Plasma digoxin levels increase (20%) Monitor digoxin plasma levels
Colchicine Cases of myopathy and rhabdomyolysis, have
been reported
Caution when prescribing atorvastatin with
colchicine.
Oral contraceptives Increased AUC values for norethindrone and
ethinyl estradiol
Select the proper oralanticonceptive
Aspirin
• Alcohol
• Other antiaggregants
• Anticoagulants
• Systemic glucocorticoids
• Other NSAIDs/antirheumatics
• Platelet antiaggregants
• Selective serotonin and serotonin-norepinephrine
reuptake inhibitors
• Tositumomab
The risk of GI ulcers and bleeding increases Monitor for signs of external or internal bleeding
ACEIs, ARBs, beta-blockers, thiazides Aspirin can decrease their antihypertensive
effects
Monitor blood pressure
Antiacids Increase the renal excretion of aspirin Monitor drug response
COX-1 inhibitors: ibuprofen, naproxen) Can prevent the antiaggregant and
cardioprotective effects of aspirin
Avoid the combination
Ciclosporine NSAIDs may increase the nephrotoxicity of
ciclosporine
Careful monitoring of renal function
Digoxin Plasma digoxin levels increase (20%) Monitor digoxin plasma levels
Diuretics NSAIDs can cause acute renal failure in
dehydrated patients
Monitor hydratation of the patient
Methotrexate, tacrolimus Aspirin displace these drugs from plasma
proteins and decrease their renal excretion
Dose adjustment or more frequent monitoring of
renal function and hemogram
Oral antidiabetic agents or insulin Increase the risk of hypoglycaemia Monitor glucose plasma levels
Uric acid Aspirin inhibits kidneys’ ability to excrete uric
acid and reduce the effect of uricosuric drugs
With caution in patients with hyperuricemia, or
gout
Barbiturates, Lithium salts, Phenytoin, Zidovudine Aspirin increases their plasma levels. It decreases
the renal excretion of lithium
Monitor the patient’s response. Monitor plasma
lithium levels
Abbreviations: ACEIs: angiotensin converting enzyme inhibitors. ARBs: angiotensin receptor blockers. AUC: area under the plasma drug concentration-time
curve. Cmax
: peak plasma concewntrations. COX: cyclooxygenase. GI: gastrointestinal. NSAIDs. Non-steroidal anti-inflammatory drugs. OATP1B1: organic anion-
transporting polypeptide 1B1. PD/PK: pharmacodynamic/pharmacokinetic.
ScopeThe International Journal of Cardiology is a world journal of clinical cardiology. Articles relating to clinical cardiology and cardiovascular medicine in its widest sense are welcome. Articles relating purely to experimental or theoretical topics may be
fo stcepsa lla tneserp ot smia lanruoj ehT .ecnaveler lacinilc rieht fo srotide eht ecnivnoc ot deen lliw srohtua tub ,deredisnoc .snoitalupop ot seneg morf lacinilc eht ot ecnaveler fo enicidem ralucsavoidrac
Preference for publication will be given to articles reporting original observations or research. The journal commissions high quality review articles from distinguished authors; unsolicited reviews which pass the peer review process will also be accepted. Letters to the editor are welcome. Case reports can only be considered in the form of research letters.
Editor-in-ChiefProfessor Andrew J.S. Coats, The University of Sydney, NSW 2006 Australia, e-mail: [email protected]
Editorial ManagerDr. Louise Shewan, e-mail: [email protected]
Associate Editors
Affiliated with the International Societyfor Adult Congenital Heart Disease
Stefan D. Anker (Metabolic Cardiology)Yi-Jen Chen (Cell Pathways)Carlo Di Mario (Interventional Cardiology)Rob Doughty (Cardioendocrinology)Gerasimos S. Filippatos (Acute Cardiology)Darrel P. Francis (Mathematical and Computing)Abdel J. Fuenmayor (Electrophysiology and Arrhythmias)Nobusada Funabashi (Imaging)Michael A. Gatzoulis (Congenital Heart Disease)Finn Gustafsson (Transplant and Devices)Stephan von Haehling (Biomarkers)Michael Y. Henein (Echocardiography)Johan Herlitz (Epidemiology)Livia C. Hool (Cardiac Myocytes)Martin St. John Sutton (Functional Imaging) Anthony Keech (Clinical Trials)Ijaz A. Khan (Clinical Cardiology)Kwang Kon Koh (Coronary Artery Disease)Mitja Lainscak (Heart and Lung)
Yat-Yin Lam (Cardiac Interventions)Francisco Leyva (Cardiovascular Medicine)Roberto Lorusso (Cardiac Surgery)Harry C. Lowe (Cardiology in Practice)Gishel New (Women and Heart Disease)Massimo Piepoli (Preventive Cardiology)Giuseppe M.C. Rosano (Metabolism and Endothelium)Christopher Semsarian (Molecular Cardiology)Ashok Seth (Interventional Cardiology)Simon Stewart (Cardiovascular Nursing)Lip-Bun Tan (Cardiac Function)Dimitris Tousoulis (Atherosclerosis)Konstantinos Toutouzas (Interventional Cardiology)Darren Walters (Interventional Cardiology)Maria Wartenberg (Stem Cells)Xander H.T. Wehrens (Cardiomyopathy)Leon de Windt (Molecular Biology)Cheuk-Man Yu (Pacing and Resynchronization)
Enrico Agabiti-Rosei (Brescia, Italy)Joseph S. Alpert (Tucson, USA)Jeroen J. Bax (Leiden, The Netherlands)Bradford Berk (Rochester, USA)Luciano Bernardi (Pavia, Italy)Mike Bristow (Denver, USA)Morris Brown (Cambridge, UK)Isabel Coma-Canella (Pamplona, Spain)John Deanfield (London, UK)Kenneth Dickstein (Stavanger, Norway)Rainer Dietz (Berlin, Germany)Gary S. Francis (Cleveland, USA)Yoichi Goto (Osaka, Japan)Masayasu Hiraoka (Tokyo, Japan)Masatsugu Hori (Osaka, Japan)Kevin Jennings (Aberdeen, UK)Itsuo Kodama (Nagoya, Japan)Michel Komajda (Paris, France)Gregory Lip (Birmingham, UK)Giuseppe Mancia (Monza, Italy)
Barrie Massie (San Francisco, USA)William McKenna (London, UK)John McMurray (Glasgow, UK)Seibu Mochizuki (Tokyo, Japan)Kazuo Momma (Tokyo, Japan)Takeshi Motomiya (Tokyo, Japan)Ryozo Nagai (Gunma, Japan)Yasuyuki Nakamura (Shiga, Japan)Ali Oto (Ankara, Turkey)Milton Packer (New York, USA)Tom Quinn (Surrey, UK)Jean Rouleau (Toronto, Canada)Patrick Serruys (Rotterdam, The Netherlands)Norman Sharpe (Auckland, New Zealand)Kenji Sunagawa (Fukuoka, Japan)Nagara Tamaki (Sapporo, Japan)Eric Topol (La Jolla, USA)Richard Underwood (London, UK)Alec Vahanian (Paris, France)Frans van de Werf (Leuven, Belgium)
Editorial Board
International Consulting Editor for China: Tsung O. Cheng
International Consulting Editor for Japan:Chuichi Kawai
Instructions to authors: The instructions can be found on the World Wide Web: access under http://www.elsevier.com/locate/ijcard
All manuscripts should be submitted online: http://ees.elsevier.com/ijc
Affiliated with the International Societyfor Adult Congenital Heart Disease
Printed by Henry Ling Ltd, The Dorset Press, Dorchester, UK
The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper)
International Journal of Cardiology has no page charges
Publication information: International Journal of Cardiology (ISSN 0167-5273). For 2015, volume(s) 180–203 (24 issues) is (are) scheduled for publication. Subscription prices are available upon request from the Publisher or from the Elsevier Customer Service Department nearest you or from this journal’s website (http://www.elsevier.com/locate/IJCA). Further information is available on this journal and other Elsevier products through Elsevier’s website (http://www.elsevier.com). Subscriptions are accepted on a prepaid basis only and are entered on a calendar year basis. Issues are sent by standard mail (surface within Europe, air delivery outside Europe). Priority rates are available upon request. Claims for missing issues should be made within six months of the date of dispatch.
Orders, claims, and journal inquiries: please contact the Elsevier Customer Service Department nearest you:
St. Louis: Elsevier Customer Service Department, 3251 Riverport Lane, Maryland Heights, MO 63043, USA; phone: (800) 6542452 [toll free within the USA]; (+1) (314) 4478871 [outside the USA]; fax: (+1) (314) 4478029; e-mail: [email protected]
Oxford: Elsevier Customer Service Department, The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK; phone: (+44) (1865) 843434; fax: (+44) (1865) 843970; e-mail: [email protected]
Tokyo: Elsevier Customer Service Department, 4F Higashi-Azabu, 1-Chome Bldg, 1-9-15 Higashi-Azabu, Minato-ku, Tokyo 106-0044, Japan; phone: (+81) (3) 5561 5037; fax: (+81) (3) 5561 5047; e-mail: [email protected]
Singapore: Elsevier Customer Service Department, 3 Killiney Road, #08-01 Winsland House I, Singapore 239519; phone: (+65) 63490222; fax: (+65) 67331510; e-mail: [email protected]
USA mailing notice: International Journal of Cardiology (ISSN 0167-5273) is published semimonthly by Elsevier House (Brookvale Plaza, East Park, Shannon, Co. Clare, Ireland). Periodicals postage paid at Jamaica, NY 11431 and additional mailing offices.
USA POSTMASTER: Send change of address to International Journal of Cardiology, Elsevier Customer Service Department, 3251 Riverport Lane, Maryland Heights, MO 63043, USA.
AIRFREIGHT AND MAILING in USA by Air Business Ltd., c/o Worldnet Shipping Inc., 156-15, 146th Avenue, 2nd Floor, Jamaica, NY 11434, USA.
Author inquiries: You can track your submitted article at http://help.elsevier.com/app/answers/detail/a_id/89/p/8045/. You can track your accepted article at http://www.elsevier.com/trackarticle. You are also welcome to contact Customer Support via http://support.elsevier.com.
Advertising information: Advertising orders and inquiries can be sent to: USA, Canada and South America: Elsevier Inc.,360 Park Avenue South, New York, NY 10010-1710, USA; phone: (+1) (212) 633 3974; Europe and ROW: Chris Woods,32 Jamestown Road, London, NW1 7BY, UK; phone: +44 (0)207 424 4454; e-mail: [email protected]
Language (usage and editing services): Please write your text in good English (American or British usage is accepted, but not a mixture of these). Authors who feel their English language manuscript may require editing to eliminate possible grammatical or spelling errors and to conform to correct scientific English may wish to use the English Language Editing service available from Elsevier’s WebShop http://webshop.elsevier.com/languageediting/ or visit our customer support site http://support.elsevier.com for more information.
Electronic manuscripts: International Journal of Cardiology only accepts online submission: www.ijc.elsevier.com
Illustration services Elsevier’s WebShop (http://webshop.elsevier.com/illustrationservices) offers Illustration Services to authors preparing to submit a manuscript but concerned about the quality of the images accompanying their article. Elsevier’s expertillustrators can produce scientific, technical and medical-style images, as well as a full range of charts, tables and graphs. Image ‘polishing’ is also available, where our illustrators take your image(s) and improve them to a professional standard. Please visit the website to find out more.