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Three Part Question

In [patients with acute ST-elevation MI] is [clopidogrel plus aspirin better than aspirin alone] at [reducing morbidity and mortality]?

Clinical Scenario

A 60 year old man presents to the Emergency Department (ED) with chest pain. The ECG shows an ST elevation MI. You give him oxygen, nitrates, aspirin and morphine and also start thrombolysis.

You wonder whether giving him clopidogrel as well would be beneficial.

Search Strategy

(OVID interface) Medline 1950-October week 3 2009

[{ exp myocardial infarct/ OR myocardial infarct*.mp. OR MI.mp OR AMI.mp}
AND {clopidogrel.mp. OR plavix.mp.}
AND {aspirin.mp OR exp aspirin/ OR aminosalicyl* acid.mp. OR ASA.mp}
AND {exp clinical trial/}]
LIMIT to English language and humans

Search Outcome

Altogether 209 papers were found, of which 206 were irrelevant or duplicate data. The three relevant papers are summarised in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Sabatine, MS et al (CLARITY study) 2005 Multi-national	3491 patients aged 18-75 years. <12 hours from onset STEMI. Clopidogrel 300mg loading dose then 75mg daily vs placebo. All patients received a fibrinolytic agent, aspirin, heparin (if appropriate). Angiography scheduled 48-192 hours after start of study drugs. 99.7% patients were thrombolysed and approximately 57% had PCI.	International Multi-centre Prospective Blinded RCT	Composite of occluded infarct-related artery at angiography, death from any cause before angiography, or recurrent myocardial infarction before angiography	262/1752 (15.0%) clopidogrel vs 377/1739 (21.7%) placebo. OR in favour of clopidogrel 0.64 (95% CI 0.53-0.76); p<0.001.	Results emphasised angiographic outcomes. Of the two primary patient oriented outcomes, recurrent myocardial infarction was reduced and all cause mortality was worse in the clopidogrel group, although neither was statistically significant. Stitistical significance was only found in angiographic results, or by looking at cardiovascular deaths as a subgroup.
			Death	45 (2.6%) clopidogrel vs 38 (2.2) placebo. OR 1.17 (95%CI 0.75-1.82); p=0.49.
			Recurrent myocardial infarction	44 (2.5) clopidogrel vs 62 (3.6) placebo. OR 0.70 (95% CI 0.47-1.04); p=0.08.
			Death from cardiovascular causes, recurrent myocardial infarction, recurrent ischaemia leading to need for urgent revascularisation	11.6% clopidogrel vs 14.1% placebo. OR 0.80 (95% CI 0.65-0.97); p=0.03.
			Major or minor bleeding at 30 days.	59 (3.4%) clopidogrel vs 46 (2.7%): p=0.24
COMMIT collaborative group 2005 China, UK	45,852 patients. No age limit. <24 hours from onset MI. Randomized to 75mg clopidogrel or placebo in addition to aspirin 162mg. Treatment until discharge or up to 4 weeks in hospital. 54% thrombolysed PCI patients excluded	Multi-centre Prospective Blinded RCT	Composite of death, reinfarction, or stroke	2121 (9.2%) clopidogrel vs 2310 (10.1%) placebo; p=0.002. A 9% (95% CI 3-14) proportional reduction in composite outcome from adding clopidogrel.	Exclusion criteria unclear. Some baseline characteristics not collected. Included patients (<7%) with non-ST elevation MI No post-discharge follow-up.
			Death during treatment period	1726 (7.5%) clopidogrel vs 1845 (8.1%) placebo; p=0.03. A 7% (95% CI 1-13) proportional reduction in outcome from adding clopidogrel.
			Composite of fatal haemorrhage, haemorrhage needing a blood transfusion, or cerebral bleed	134 (0.58%) clopidogrel vs 125 (0.55%) placebo; p=0.59
			Cerebral haemorrhage through the day after angiography	8 (0.5%0 clopidogrel vs 12 (0.7) placebo; p=0.38
Zeymer et al 2006 Germany	5886 patients with STEMI. No age limit. 2091 (35.5%) discharged on aspirin alone and 3795 (64.5%) discharged on aspirin and clopidogrel. 1445 (25.4%) had no early reperfusion therapy, 1734 (29.4%) were thrombolysed, and 2707 (45.2%) had PCI.	Review of data from a German multi-centre registry of acute coronary syndromes.	Mortality at 1 year after discharge	259 (12.4%) aspirin vs 139 (3.7%) aspirin plus clopidogrel; p<0.001. OR for death 0.27 (95% CI 0.22-0.33) by adding clopidogrel.	Not a randomised controlled trial. Clopidogrel treatment at discretion of physician, so there is a risk of selection bias. Patient baseline characteristics vary considerably between 2 groups. Patients in aspirin only group were older and sicker than those in aspirin plus clopidogrel group. Length of clopidogrel therapy unknown for approx 50% of patients.
			Non-fatal reinfarction	44/1828 (2.4%) aspirin vs 102/3147 (2.9%) aspirin plus clopidogrel; p=0.30.
			Non-fatal stroke	15/1818 (0.8%) vs 32/3301 (1.0%) aspirin plus clopidogrel; p=0.60.
			Incidence of composite of death, non-fatal reinfarction, and non-fatal stroke	15.4 aspirin vs 7.1 aspirin plus clopidogrel.

Comment(s)

The two large multi-centre randomized controlled trials (1, 2) both show significant benefits with the addition of clopidogrel to standard therapy in the emergency treatment of acute MI. Although CLARITY (1) found no improvement in the patient oriented outcomes of recurrent myocardial infarction and all cause mortality, COMMIT (2) did. It is difficult to compare size of effect in the two studies as both patient inclusion and outcome measures were different. The third study (3) shows similar trends, and is useful in that it looks at one year mortality, however, it is not a randomized controlled trial and so may be subject to selection bias. In terms of safety, neither of these studies showed an increased risk of bleeding for patients given clopidogrel. This is in contrast to the CURE study (4), which showed a significant increase in major (but not life threatening) bleeding , in patients treated with clopidogrel. Of particular interest to ED physicians, in the sub-group analysis of the COMMIT trial the benefits of giving clopidogrel began to emerge within 24 hours; a similar pattern was noted in the CURE study (looking at non-ST elevation MI), but not in CLARITY, perhaps because it was a smaller study, and more of the patients presented early. It was also observed in the COMMIT trial that the effects of clopidogrel were greatest in those who presented (and therefore received treatment) within 13 hours of onset of symptoms. These results suggest that clopidogrel should be given as part of the ED management of STEMI, rather than being left for specialists to give later, although since they are sub-group analyses the results must be interpreted with care.

Clinical Bottom Line

Patients with acute ST elevation myocardial infarction should be given clopidogrel in addition to current standard therapy.

References

1. Sabatine MS, Cannon CP, Gibson CM et al Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation The New England Journal of Medicine 2005; 352: 1179-89
2. COMMIT collaborative group Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. The Lancet 2005; 366: 1607-21
3. Zeymer U, Gitt AK, Junger C et al Effect of clopidogrel on 1-year mortality in hospital survivors of acuter ST-elevation myocardial infarction in clinical practice. Eur Heart J 2006; 27: 2661-6
4. 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: 494-502.