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Three Part Question

In [patients following coronary arterial bypass grafting] is [the use of clopidogrel] of any benefit in terms of [prolonging event free suvival]?

Clinical Scenario

You are on a ward round seeing a 70 year old man who is 7 days post CABG having been admitted with unstable angina 3 weeks ago. He is now well and pain free, but he asks you why you are sending him home only on aspirin instead of clopidogrel. He tells you that when he came into hospital 3 weeks ago the consultant cardiologist told him that clopidogrel was like aspirin but was a much better drug to be on as it was 'stronger' and more modern. You are unable to answer him to your satisfaction and thus you resolve to see if there is any evidence for the benefit of clopidogrel over aspirin postoperatively.

Search Strategy

Medline 1966-Aug 2003 using the OVID interface and the Cochrane Central Register of Controlled Trials.
([exp coronary artery bypass OR CABG.mp OR exp thoracic surgery OR cardiopulmonary bypass.mp OR cardiovascular surgical procedures OR Cardiac Surgery.mp] AND [clopidogrel.mp OR plavix.mp]).

Search Outcome

A total of 220 papers were found of which 1 was directly relevant and 2 provided further interesting evidence. In addition the American Heart Association guidelines for Coronary Artery Bypass Graft Surgery were reviewed. These papers are presented in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bhatt DL et al, 2001 USA	Patients who had recent MI/stroke/PVD with previous history of cardiac surgery Randomised to receive clopidogrel 75mg /day (N=775) or aspirin 325 /day (N=705)	Subgroup analysis of a randomised, double blinded (2b)	Combined end point of vascular mortality, MI and ischaemic stroke	Aspirin vs clopidogrel 9.1% vs 5.8% event rate per year P=0.004 36.3% overall relative risk reduction (95% CI, 13.4-53.1)	Exact date of previous cardiac surgery unknown Proportion of patients receiving venou or arterial grafts unknown
			Vascular death	3.3% vs 2% RRR 43% (95% CI, 5-66)
			Myocardial infarction	3.9% vs 2.4% RRR 39% (95% CI, 2-62)
CAPRIE study group, 1996, USA	19 185 patients with recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease Randomised to clopidogrel 75mg od or aspirin 325mg od	Double blind PRCT (1b)	Annual risk of ischaemic stroke, myocardial infarction, or vascular death	Clopidogrel 5.32% versus aspirin 5.83% annual risk (p=0·043) Relative-risk reduction of 8·7% in favour of clopidogrel (95% CI 0·3–16·5)	Significant heterogeneity of effect between the three subgroups of recent stroke recent MI and peripheral arterial disease, indicating that the benefit may not be equal for each subgroup 1/3rd of all patients had had an MI within 30 days
			Bleeding risk clopidogrel to aspirin	Intracranial haemorrhage (0·33% vs 0·47%) and gastrointestinal haemorrhage (0·52% vs 0·72%)
Gerschutz GP and Bhatt DL, 2002, USA	12 562 patients with acute coronary syndrome without ST elevation Clopidogrel 300 mg loading dose followed by 75 mg daily vs placebo in addition to aspirin	Double blind PRCT (1b)	Death from cardiovascular causes, non-fatal MI or stroke	Clopidogrel 9.3% vs 11.4% in aspirin group P<0.001	21% of the clopidogrel group stopped the medication permanently during the study (and 18% of the placebo)
			Bleeding	Clopidigrel 3.7% vs aspirin 2.7% P<0.01
			In a subset of patients with a history of revascularisation: event rate	Clopidogrel and aspirin 8.4% vs 14.4% aspirin alone P<0.05
Eagle KA et al, 1999, USA	Systematic review of a wide range of issues in coronary arterial bypass grafting This review updated a previous review conducted in 1991	Systematic review (2a)	Antiplatelet therapy post CABG	Aspirin should be considered the first line drug but ticlopidine and clopidogrel are alternatives if aspirin is contraindicated This is a grade 1 recommendation	Search strategies not given

Comment(s)

Bhatt et al, in their subgroup analysis of the CAPRIE trial showed that clopidogrel was superior compared with aspirin for reducing recurrent ischaemic events in patients with a history of cardiac surgery and a recent myocardial infarction or recent stroke or symptomatic peripheral vascular disease (PVD). In these patients they found that 1 adverse event could be avoided for every 33 patients treated. However it must be realised that this is a substudy of a larger trial. The inclusion criteria for the CAPRIE study was recent MI, stroke or PVD and the finding that these patients had received cardiac surgery in the past was elicited retrospectively from their database. Thus Bhatt et al, could not state the details of the operation received, i.e. whether it was total arterial revascularisation, or how long ago the operation was performed prior to entry into the study. This is a very different group to those patients immediately post CABG. Thus caution should be taken when interpreting these results other than calling for further studies in this area. Bhatt et al is the only study that directly looks at clopidogrel vs aspirin post cardiac surgery. In the full study of which the Bhatt et al paper was a subset, the CAPRIE Trial, which enrolled over 19,000 patients found that clopidogrel had a significant but modest relative risk benefit over aspirin of only 8.7% of events per year avoided. In the other major study into clopidogrel, the CURE trial found that clopidogrel in addition to aspirin did provide a benefit in terms of risk reduction of major adverse events, but there was also a significant increase in the rate of bleeding side effects. Their paper did provide a sub-analysis of patients with a history of revascularisation finding that the adverse event rate was 8.4 % in the clopidogrel and aspirin group but 14.4% in the aspirin only group. They did however caution against putting too much weight on the importance of this sub-analysis as they performed multiple sub-analyses in finding these results. Thus in summary it is clear that clopidogrel as a substitute for aspirin is at least as efficacious, and can be safely started without an increased rate of bleeding. This is the recommendation from the American Heart Association for the use of clopidogrel post CABG. The paper by Bhatt et al is the first study to suggest that there may be an increased benefit and although there may be some support for this in the CURE trial, these studies were not PRCTs on patients immediately post CABG. In order to provide convincing evidence of the superiority of clopidogrel over aspirin, a double blinded, randomized controlled trial is required. Using the figures for event rates from the Bhatt et al study, a total of 2,100 patients would need to be recruited in total to have an 80% chance of finding a significant result.

Clinical Bottom Line

Clopidogrel is a safe alternative to aspirin if aspirin is not tolerated but there is no strong evidence that clopidogrel is superior to aspirin post CABG. However 2 papers that suggest that this might be the case should stimulate further research in this area.

References

1. Bhatt DL, Chew DP, Hirsch AT et al. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103:363-368.
2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee Lancet 1996;348:1329-1339.
3. Gerschutz GP, Bhatt DL. The CURE trial: using clopidogrel in acute coronary syndromes without ST-segment elevation. Cleve Clin J Med 2002;69:377-378.
4. Eagle KA, Guyton RA, Davidoff R. American College of Cardiology Guidelines for Coronary Artery Bypass Graft Surgery. J Am Coll Cardiol 1999;99:1262-1346.