medical faculty of oporto university medical faculty of oporto university biostathistic and medical...

Medical Faculty of Medical Faculty of

Oporto UniversityOporto University Biostathistic and Medical Informatics Department

Introduction to Medicine – 1st Year

Head teacher: Prof. Doutor Altamiro da Costa PereiraSupervisor: Dra. Filipa Almeida

2006/2007

CCLINICALLINICAL OUTCOMES OF OUTCOMES OF DRUG-ELUTING STENTS DRUG-ELUTING STENTS

VERSUS UNCOATED STENTS VERSUS UNCOATED STENTS IN ACUTE CORONARY IN ACUTE CORONARY

DISEASEDISEASE

a meta-analysis of randomized controlled trialsa meta-analysis of randomized controlled trialsSummary

IntroductionIntroduction

Acute coronary artery disease (CAD) is an obstruction of the normal blood flow caused by accumulation of lipids in the coronary artery with resultant myocardial ischemia(1).

Acute Coronary Acute Coronary Artery DiseaseArtery Disease

(1) WebMD [homepage on the Internet]. c1996-2006.

Available from: http://www-emedicine.com/med/topic1567.htm

Drug-eluting vs uncoated stents

(2) Braunwald E. Unstable angina: a classification. Circulation 1989; 80: 410

(3) Scirica BM, et al. Prognosis in the trombolysis in myocardial ischemia III registry according to the Braunwald unstable angina pectoris classification. JACC 2002; 90:821

Clinical Syndromes (2, 3)

The acute coronary artery disease (CAD) can be divided according to the degree of the obstruction and the extent of the myocardial ischemia into:

• Unstable Angina

• Non-ST Elevation Myocardial Infarction

• ST Elevation Myocardial Infarction.


Severe chest pain with radiation to the upper side of the body (shoulder, neck and arm) – lasting 20 min or more;Chest discomfort;Nausea and vomiting;Other symptoms: profound weakness,

dizziness, palpitations, cold perspiration, sense of impending doom, lost of conciseness.

Symptoms: (4,5)

(4) Zipes, D.P., Libby, P., Barow, R.O., Braunwald, E. Braunwald’s Heart Disease: A textbook of Cardiovascular Medicine. 7th Edition. Philadelphia: Elsvier Saunders. P. 1155.(5) Lee TH. Evaluation of the patient with acute chest pain. NEJM 2000; 34:125


The management of patients presenting with acute coronary syndrome is induce reperfusion of the affected vessel.

Two different reperfusion therapies are available (6):

FibrinolysisInvasive strategy

ManagemenManagementt

(6) Antman EM et al. ACC/AHA Guidelines for the management of patients with ST elevation myocardial infarction JACC 2004; 12: 1458.


An invasive strategy is generally preferred if: (7)

Skilled PCI lab available with surgical backupHigh risk patients with cardiogenic shock or acute pulmonary edema Contraindications to fibrinolysis including increased risk of bleedingSymptom onset more than 3 hours agoDiagnosis of acute coronary syndrome in doubt

(7) Hamm CW et al. Acute cornary syndrome: Implementation of new guidelines. Lancet 2001; 358: 1533

Management – Invasive Management – Invasive StrategyStrategy


Angioplasty is the most frequent mechanical treatment used in this disease, being the percutaneous transluminal coronary angioplasty (PTCA), which uses an insufflable balloon, the most common.

The efficiency of this treatment is improved by the implantation of stents. (8)

Management – Invasive Management – Invasive StrategyStrategy

(8)Christian Spaulding, M.D., Patrick Henry, M.D., Ph.D., Emmanuel Teiger, M.D., Ph.D., Kevin Beatt, M.B., B.S., Ph.D., Ezio Bramucci, M.D. et al. Sirolimus-Eluting versus Uncoated Stents in Acute Myocardial Infarction. N Eng J Med. Sept 14, 2006 number 11; 355:1093-1104


StentsStentsA stent is a vascular endoprothesis of

tubular form and reduced size (microprothesis) that is introduced through a peripheral catheter in the coronary artery after an angioplasty. (9)

Its implantation aims to prevent restenosis, the most frequent life threatening complication of PCI.

(9) Manila, L, et al. João Alves Falcato (adapt and rev). Dicionário Médico. 2nd Edition. Lisboa: CMILPSI; 2001. P. 561.


Coronary stents reduce the rates of abrupt closure, emergency coronary artery bypass graft surgery and restenosis, but do not prevent myocardial infarction or death at six months. (10)

Drug-eluting stents provide a fair single digit number for angiographic and clinical restenosis at 9 months(11).

(10)Warren J. Cantor, Eric D. Peterson et al. Provisional stenting strategies: systematic overview and implications for clinical decision-making. J Am Coll Cardiol, 2000; 36:1142-1151(11)Sigmund S. et al. Guidelines for Percutaneous Coronary Disease – The Task Force for Percutaneous Coronary Interventions for European Society for Cardiology. European Heart Journal. 2005. 26, 804-847.


There are two main types of stents: uncoated stents or bare-metal stents (BMS) and drug-eluting stents (DES).

In both cases, is required an anticoagulation regimen, usually with antiplatelet drugs (aspirin associated to ticlopidine or clopidogrel)(12).

However, the administration of clopidogrel or ticlopidine may be absent in uncoated stenting.

(12)Kasper, D.L., Braunwald, E., Fauci, A.S., Hauser, S.L., Longo, D.L., Jameson, J.L. Harrison’s – Principles of Internal Medicine. 16th Edition. EUA: McGraw-Hill (Medical Publishing Division). Vol. II, p.1461.


Metallic scaffolds inserted in a vessel segment covering its interior wall

High recommended use:patients contra-indicated to a prolongated administration of clopidogrel (i.e. major extratoraxic surgery planned soon)(11).

Uncoated StentsUncoated Stents

(11) Sigmund S. et al. Guidelines for Percutaneous Coronary Disease – The Task Force for Percutaneous Coronary Interventions for European Society for Cardiology. European Heart Journal. 2005. 26, 804-847.


Stents coated with antiproliferative agents or immunomodulary compounds released in a controlled fashion. (11)

The stent platforms for drugs releasing may present a polymer carrier. (13)

There are several different drug-eluting stents which contain different drugs.

Drug-eluting Stents (DES)Drug-eluting Stents (DES)

(11) Sigmund S. et al. Guidelines for Percutaneous Coronary Disease – The Task Force for Percutaneous Coronary Interventions for European Society for Cardiology. European Heart Journal. 2005. 26, 804-847.(13) Cohn LH, Edmund LH Jr., et al. Cardiac Surgery in The Adult. 2nd Ed, chapter 5. New York: McGraw-Hill, 2003:119185. chapter 5


Nowadays there are four DES CE-certificated and available in Europe: (14)

Cypher stent, releasing Sirulimus from a polymer;

Taxus stent, releasing Paclitaxel from a polymer;

V-Flex stent, releasing Paclitaxel without a polymer;

Dexamet stent, releasing Dexamethasone from a PC coating.

(14) Silber S. When are drug-eluting stents effective? A critical analysis of the presently available data[Article in German]. Z Kardiol. 2004 Sep;93(9):649-63.


NICE recommends stents that contain either sirolimus (Cypher) or paclitaxel (Taxus), because most of the research has been on these(15) and so far are the ones guaranteeing better patients’ outcomes(16).

(15) Silber S. When are drug-eluting stents effective? A critical analysis of the presently available data[Article in German]. Z Kardiol. 2004 Sep;93(9):649-63. (16) NICE (National Institute for Clinical Excellence), Coronary artery stents (No 71), replacing drug-eluting stents No 4). Available at http://www.nice.org.uk, 2004.


The application of many drugs in stenting was abandon because its use revealed harmfull or too weak clinical results.

These drugs prevent the excessive cellular proliferation of the injured tissues that results in in-stent restenosis(17).

Drug eluting lasts at least one year, period of special vulnerability for restenosis.

(17) Ryan, J., Cohen, D. J.. Are drug-eluting Stents Cost-Effective?: It Depends on Whom You Ask. Circulation 2006; 114: 1736-1744


The target artery is <3mm in calibre (internal diameter);

The lesion is >15mm longer.

Use of DES is recommended when: (18)

(18)Sigmund S. et al. Guidelines for Percutaneous Coronary Disease – The Task Force for Percutaneous Coronary Interventions for European Society for Cardiology. European Heart Journal. 2005. 26, 804-847.


Small vessels;Chronic total occlusions;Bifurcational/ostial lesions;Bypass stenoses;Insulin-dependent diabetes mellitus;Multi-vessel disease;Unprotected left main stenosis;In-stent restenosis.

Situations requiring further evidence-based evaluation: (11)

(11)Sigmund S. et al. Guidelines for Percutaneous Coronary Disease – The Task Force for Percutaneous Coronary Interventions for European Society for Cardiology. European Heart Journal. 2005. 26, 804-847.


DES are generally 3 to 4 times more expensive than BMS. (19)

If DES considerably reduce the number of patients undergoing coronary artery bypass graft (CABG) surgery (especially patients with multi-vessels disease and/or diabetes mellitus), there will be a significant reduction of cost in medical care(16).

(16) NICE (National Institute for Clinical Excellence), Coronary artery stents (No 71), replacing Drug-eluting stents No 4). Available at http://www.nice.org.uk, 2004.(19) Ryan, J., Cohen, D. J.. Are drug-eluting Stents Cost-Effective?: It Depends on Whom You Ask. Circulation 2006; 114: 1736-1744


Although there is a support for better outcome with the implantation of stents rather than balloon angioplasty alone(20), studies are inconclusive about advantage on the application of drug-eluting stents rather than uncoated ones.

(20)Spaulding C., et al. Sirolimus-Eluting versus Uncoated Stents in Acute Myocardial Infarction. N Eng J Med 2006; 355:1093-1104


To investigate whether routine use of drug-eluting stents rather than uncoated stents reduces mortality and improves clinical outcomes in patients with acute coronary artery disease.

Aim of the Aim of the study:study:


Systematic review Systematic review searching in medical searching in medical databases:databases:

PubMed’s; Cochrane’s online database.

Searching criteria:Searching criteria: From the earliest article available until our data acquisition.

MethoMethodsds


Pubmed’s QueryPubmed’s Query

("Myocardial Infarction"[MeSH] OR "acute coronary artery disease" OR "acute coronary syndrome" OR "obstructive coronary artery disease" OR "myocardial infarction" OR "coronary artery disease" OR "unstable angina")

AND

("uncoated stents" OR "bare metal stents" OR " drug-eluting stents" OR "sirolimus" OR "rapamycin" OR "paclitaxel" OR "taxol" OR "taxane")

NOT

(review OR letter)


("Myocardial Infarction" OR "acute coronary artery disease" OR "acute coronary syndrome" OR "obstructive coronary artery disease" OR "myocardial infarction" OR "coronary artery disease" OR "unstable angina")

AND

("uncoated stents" OR "bare metal stents" OR "

drug-eluting stents" OR "sirolimus" OR "rapamycin" OR "paclitaxel" OR "taxol" OR "taxane")

Cochrane’s Cochrane’s QueryQuery


Performed by six groups, composed of two reviewers, according to the inclusion criteria mentioned below:

1. Articles written in english, portuguese, spanish or french.

2. Randomized controlled trials

3. Articles which mention the methods used and results.

4. Articles that compare clinical outcomes of drug-eluting stents with

uncoated ones in acute coronary artery disease

5. Test subjects human.

Initial tracing (inclusion):Initial tracing (inclusion):Drug-eluting vs uncoated stents

• Performed by six groups, composed of two reviewers.

• Exclusion of the article is dependent on the agreement of the two elements, bearing in mind the exclusion criteria set.

Exclusion criteria:Exclusion criteria:


1. The articles aren't directly related to the review’s main subject.Clinical outcomes of drug-eluting stents versus uncoated stents in acute coronary artery disease.

2. The articles don't compare drug-eluting stents with uncoated ones in which concerns the percutaneous coronary intervention where they are used.

3. The articles have a maximum “n” (sample size) of one hundred individuals.

4. The endpoints of the included article don't include death or acute myocardial infarction.

5. The studies don't have a follow-up period of at least 6 months6. The articles don't have data about relative risk or odds ratio or

mean difference for one or more of the endpoints (or don't have enough data to allow them to be calculated).

Exclusion criteria:Exclusion criteria:


Mortality and composite endpoint of death and myocardial infarction.

Major adverse cardiac events, restenosis rate, late loss of arterial lumen diameter.

Bleeding complications needing blood transfusion or surgery.

OutcomesOutcomes::


(21) Jadad AR, Moore RA, Carroll D. Assessing the quality of reports of randomized controlled clinical trials. Control clinical trials. 1996; 17: 1-12.

Quality evaluation of the selected articles(21):

•Random allocation

•Blinding

•Blinded outcome assessment

•Full description of all losses of follow-up and withdrawals

•Loss of follow-up

An aditional point is given if:

Randomization is concealed

Double blinding appropriate

Utilization of the Jadad scoring system

According to this quality scale, 1 point is given for each of the following items:


•The acute CAD is an obstruction in the coronary arteries with resultant ischemia.

•A stent is a tubular microprothesis which is placed in the injured vessel, reinforcing it’s wall.

•There are two types of stents: bare metal stents (BMS) and drug-eluting stents (DES).

•DES release drugs that inhibit the proliferation of tissues and the imune response to the lesion.

Aim of the study:

To investigate whether routine use of drug-eluting stents rather than uncoated stents reduces mortality and improves clinical outcomes in patients with acute coronary artery disease.


Summary:

Flow Flow ChartChart

• Methods description:


1. Written in english, portuguese,

spanish or french.

2. RCT’s.

3. Mention the methods used and

results.

4. Compare clinical outcomes of DES

with BMS in ACAD.

5. Test subjects human.

Inclusion criteria:


1. Not directly related to the review’s main subject.

2. Don't compare DES with BMS in which concerns the PCI where they are used.

3. n < 100

4. Don't include death or acute myocardial infarction as endpoints

5. Follow-up inferior to 6 months

6. Don’t have data about relative risk or odds ratio or mean difference for one or more of the endpoints

Exclusion criteria:


• Articles selection


Systematic review phase

Results

Pubmed’s Query 466 articles61 not excluded

21 included

Cochrane’s Query 67 articles5 repeated

24 not excluded9 included

Substudies 13 excluded

Total included articles 15 articles


• Patients inclusion criteria•Intervention description•Objective outcomes•Randomization - description of the process•Blinding•Populational demographic characteristics•Data presented intables.

The included articles respect the quality criteria (22,23)

evaluated.

(22) David Moher, MSc; Kenneth F. Schulz, PhD, MBA; and Douglas G. Altman, DSc. The CONSORT Statement: Revised Recommendations for Improving the Quality of Reports of Parallel-Group Randomized Trials. Ann Intern Med. 2001;134:657-662.(23) Peter Juni, Douglas G Altman, Mathias Egger. Systematic reviews in health care – Assessing the quality ofcontrollled clinical trials. BMJ. 2001; 323: 42-6.

.


n

Total %

N_participants 15 7514

N_men 15 5410 72,0

N_diabetics 15 1493 19,9

N_hipertension 13 3775 50,3

N_hiperlipidemia 12 4033 53,7

Prior_miocardial_infarction 13 1889 25,1

n Total %

Missing_followup 13 207 2,8

N_deaths 14 81 1,1

N_baremetal 15 3855 51,3

N_drugeluting 15 3650 48,6

Bare_diabetics 11 543 7,2

Drug_diabetics 11 592 7,9


Baseline Characteristics

n Total %

1 month

cardiac death 8 71.1 1.0AMI 7 71.9 1.0Trombosis 8 13.3 0.2

MACE 2.1

6 months

cardiac death 5 6.0 0.1AMI 5 44.0 0.6Trombosis 4 4.0 0.1MACE 0.7

12 months

cardiac death 6 13.3 0.2AMI 7 41.2 0.6trombosis 5 25.9 0.3MACE 1.1

n Total %

1 month


6 months


12 months

cardiac death 7 18.7 0.3AMI 7 53.0 0.7

trombosis 5 27.9 0.4MACE 1.3

BMS

DES


OUTCOMES

bare metal

drug-eluting

N 3855 3650

Diabetics 14,1 16,2

1 month

cardiac death 1,8 0,8

AMI 1,9 2,6

trombosis 0,3 0,4

MACE 4,1 3,8

6 months


AMI 1,1 1,3

trombosis 0,1 0,3

MACE 1,4 1,8

12 months


AMI 1,1 1,5

trombosis 0,7 0,8

MACE 2,1 2,7

•Qui-square test (95%)p = 0,01

•H0 is rejected.

% %


MeanStd. error

CI 95%

Age in years (n=15) 62,50 2,38 57,8 67,2

Time_follow-up in mounths (n=12) 11,43 4,30 3,0 19,9

Reference_diameter in mm (n=8) 2,41 0,13 2,2 2,7

Lesion_lenght in mm (n=8) 14,05 5,32 3,6 24,5


Baseline Characteristics

Turma Turma 7 7

Ana Carvalho Gustavo Vidal

Ana Menezes Inês Teles

Ana Amado Jaime Rodrigues

Bruno Mendes Marta Costa

Diana Santos Sara Camões

Érico Costa Tiago Rodrigues


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