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Three Part Question

In [patients suspected to have unstable angina] is [the use of clopidogrel plus asprin better than asprin alone] at [improving cardiovascular outcome]

Clinical Scenario

A 55 year old man, known to have angina, presents to the Emergency Department with new-onset typical ischaemic rest pain that is not relieved by his nitrate spray at home. His ECG shows ST depression in V3-V6. He is haemodynamically stable. You treat him with oxygen, aspirin, nitrates, beta-blockers and heparin, after which he becomes pain free. You also give him clopidogrel 300 mg because you have heard that patients with unstable angina and non ST-elevation MI have a better cardiovascular outcome when treated with a combination of clopidogrel and aspirin versus aspirin alone. You wonder whether there is any evidence to support this.

Search Strategy

Medline 1966–11/2005 using the OVID interface
Embase 1980–2005 week 47
The Cochrane Library Issue 4 2005
Medline:[{unstable angina.mp.OR exp Angina, Unstable/OR acute coronary syndrome.mp. OR non-ST elevation MI.mp. OR non-ST elevation infarction.mp. OR non-ST elevation myocardial infarction.mp OR ACS.mp.} AND {exp Platelet Aggregation Inhibitors/OR exp Ticlopidine/OR exp Adenosine Diphosphate/OR clopidogrel.mp. OR adenosine 5'-diphosphate antagonist.mp. OR plavix.mp. OR Thienopyridines.mp.} AND {aspirin.mp. OR exp ASPIRIN/ OR ASA.mp. OR exp Aminosalicylic Acids/}] LIMIT to Human AND English
Embase:[{exp unstable angina pectoris/OR unstable angina.mp. OR acute coronary syndrome.mp. OR non-ST elevation MI.mp. OR non-ST elevation infarction.mp. OR non-ST elevation myocardial infarction.mp OR ACS.mp. OR non-STEMI.mp.} AND {platelet aggregation inhibitor$.mp. OR exp Ticlopidine/ OR exp Adenosine Diphosphate/ OR adenosine 5'-diphosphate antagonist.mp. OR plavix.mp. OR exp clopidogrel/ OR Thienopyridines.mp} AND { aspirin.mp. OR exp Acetylsalicylic Acid/ OR exp Aminosalicylic Acid Derivative/}] LIMIT to Human AND English and Clinical Queries "treatment – high specificity" (190 papers)
Cochrane:[Angina, Unstable {MeSH explode all trees} AND clopidogrel {All fields} OR Platelet Aggregation Inhibitors/TU {MeSH this term only, therapeutic use} OR adenosine NEXT diphosphate {All fields} OR Ticlopidine {MeSH explode all trees} AND Aspirin {MeSH explode all trees} OR Aminosalicylic Acids/TU {MeSH explode all trees, therapeutic use}] (47 papers)

Search Outcome

676/47 /190 papers were identified. The CURE trial is the only RCT relevant to the question. It is also the only article in a systematic review which looked at the clinical and cost effectiveness of using clopidogrel in combination with aspirin in ACS.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
CURE Trial Investigators 2001 Multinational	12,562 patients presenting with chest pain within 24 hrs of onset of symptoms with either 1) ECG changes consistent with ischaemia (but not ST-elevation) or 2) raised serum cardiac enzymes to twice normal upper limit. Randomised to receive either clopidogrel (300mg loading followed by 75mg od) (n=6259) or placebo (n=6303) plus aspirin for 3-12 months.	Prospective, multi-centre placebo-controlled randomised trial	First primary composite outcome (CV death, MI or Stroke)	9.3% clopidogrel v/s 11.4% placebo (p,0.001) RR 0.80 CI 0.72-0.92	Patients were recruited from centres favouring conservative management of ACS. There is an increased incidence of bleeding in patients undergoing CABG within 5 days of receiving clopidogrel. In the initial study design patients over 60 years of age with no new ECG changes but a history of coronary artery disease were included. After recruiting the first 3000 patients, event rates were low (thus potentially rendering the trial underpowered) and this inclusion criteria was removed. Only patients with ECG changes or raised cardiac enzymes were treated, not all chest pain syndromes.
			Second primary outcome (CV death, MI , Stroke or Refractory ischaemia))	16.5% clopidogrel v/s 18.8% placebo (p<0.001) RR 0.86 CI 0.79-0.94
			Incidence of second primary outcome by 24 hours	1.4% clopidogrel v/s 2.1% placebo. RR 0.66 (0.51-0.86).
			Non-fatal myocardial infarction during follow-up period	5.2% clopidogrel v/s 6.7% placebo. RR 0.77 (0.67-0.89).
			All bleeding	8.5% clopidogrel v/s 5.0% placebo ( p<0.001) RR 1.69
			Major bleeding	3.7% clopidogrel v/s 2.7% placebo (p<0.001) RR 1.38
			Minor bleeding	5.1% clopidogrel v/s 2.4% placebo (p<0.001) RR 2.12
			Life-threatening bleeding	2.2% clopidogrel v/s 1.8% placebo (p=0.12).
Budaj A et al, 2002, Poland	12,562 patients presenting with symptoms within 24hrs of onset with either 1) ECG changes consistent with ischaemia (but not ST-elevation) or 2) raised serum cardiac enzymes or markers to twice the normal upper limit	Retrospective sub-group analysis of the CURE trial	Low-risk group (TIMI 0-2) primary outcome rates, RR and NNT (for 12mths, mean 9 mths) N=3276	4.1% v/s 5.7% (p<0.04) RR 0.71; CI 0.52-0.97, NNT 63	Retrospective subgroup analysis
			Intermediate-risk group (TIMI 3-4) primary outcome rates, RR and NNT (for 12mths, mean 9 mths) N=7297	9.8% v/s 11.4% (p<0.03) RR 0.85 CI 0.74-0.98, NNT 63
			High-risk group (TIMI 5-7) primary outcome rates, RR and NNT (for 12mths, mean 9 mths) N=1989	15.9% v/s 20.7% (p<0.004) RR 0.73; CI 0.60-0.90, NNT 21

Comment(s)

To date only one randomised controlled trial has been conducted to compare the effects of clopidogrel and aspirin versus aspirin alone in non-ST elevation acute coronary syndromes. This large trial, which included 12,562 patients, yielded promising results. It appears that clopidogrel decreases the 12-month cardiovascular event rate. Interestingly, there was a significant reduction in the incidence of the second primary outcome by 24 hours after starting therapy and there was evidence of separation of the cumulative hazard rate curves within as early as a few hours. This has significant implications for Emergency Medicine, suggesting that clopidogrel loading should commence as soon as possible following presentation. Analysis of the data from the CURE trial reveals that the number needed to treat (NNT) with clopidogrel to prevent the first primary outcome is 47. The number needed to harm (NNH) with clopdigrel to cause one major haemorrhage is 99. This means that, for every 100 patients with non-ST elevation acute coronary syndrome treated for 3-12 months, clopidogrel will prevent two cardiovascular deaths, MI's or strokes while causing one major haemorrhage. Subgroup analysis of the CURE trial demonstrates that patients who at high clinical risk (as judged by the TIMI risk score) gain particular benefit from clopidogrel therapy, although lower risk patients with non-ST elevation acute coronary syndromes may still stand to benefit. In low-risk patients, 16 patients would need to be treated (NNT) for 3-12 months to prevent one primary outcome, while treating 143 patients for the same period (NNH) would lead to one major haemorrhage. For intermediate-risk patients, NNT is 63 while NNH is 83. For high-risk patients, NNT is 21 while NNH is 100. As such, if 1,000 patients in each category were treated, 16 low-risk patients would be saved from a primary outcome, while 7 would have a major haemorrhage. For intermediate-risk patients, 16 would be saved while 12 would have a major haemorrhage. For high-risk patients, 48 would be saved while 10 would have a major haemorrhage. While the benefit of clopidogrel is maintained in all risk groups, the effect was most profound in the high-risk group. A careful risk-benefit consideration should be made before prescribing the drug for prolonged periods in low-risk patients.

Editor Comment

Abbreviations: NNT: Number needed to treat; NNH: Number needed to harm; CI: Confidence intervals; RR: Relative risk

Clinical Bottom Line

Clopidogrel should be given to patients with non-ST elevation acute coronary syndromes in the Emergency Department.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. The Clopidogrel in Unstable Angina To Prevent Recurrent Events Trial Investigators Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation New England Journal Of Medicine 2001; 345(7): 494-502.
2. Budaj A. Yusuf S. Mehta SR. Fox KA. Tognoni G. Zhao F. Chrolavicius S. Hunt D. Keltai M. Franzosi MG. in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Benefit of clopidogrel in patients with acute coronary syndromes without ST-segment elevation in various risk groups Circulation 2002; 106(13):1622-6.