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Three Part Question

In [patients with acute coronary syndromes about to undergo percutaneous coronary intervention] does [clopidogrel plus aspirin or aspirin alone] lead to [lower mortality]?

Clinical Scenario

A thirty-five year-old man has presented with 12 hours of chest pain. ECG shows widespread T wave inversion and troponin T is 1.0. In view of his ongoing chest pain and young age the cardiologists decide to perform immediate angioplasty. You have given aspirin, oxygen, nitrates and morphine. As he is about to go for angioplasty, you wonder if a loading dose of clopidogrel will still confer any added benefit.

Search Strategy

OVID Medline 1966 - Week 2 July 2005
The Cochrane Library 2005 Issue 2
Embase
[clopidogrel.af. OR (adenosine adj5 antagonist).mp. OR plavix.mp. OR thienopyridine$.mp.] AND [exp Angioplasty, Transluminal, Percutaneous Coronary/ OR exp Angioplasty/ OR angioplasty.af. OR PTCA.af. OR PCI.af. OR percutaneous coronary intervention.mp.] AND [exp Myocardial Ischemia/ OR exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR acute coronary syndrome.mp. OR heart attack.mp. OR AMI.mp. OR MI.mp OR (myocard$ adj ischem$).mp. OR (myocard$ adj ischaem$).mp. OR (myocard$ adj infarct$).mp.] limit to human and English language
Medline:
[clopidogrel.af. OR (adenosine adj5 antagonist).mp. OR plavix.mp. OR thienopyridine$.mp. OR exp Ticlopidine/] AND [exp Angina Pectoris/ OR exp Coronary Disease/ OR exp Angioplasty, Transluminal, Percutaneous Coronary/ OR exp Angioplasty/ OR angioplasty.af. OR PTCA.af. OR PCI.af. OR percutaneous coronary intervention.mp.] AND [exp Myocardial Ischemia/ OR exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR acute coronary syndrome.mp. OR heart attack.mp. OR AMI.mp. OR MI.mp OR (myocard$ adj ischem$).mp. OR (myocard$ adj ischaem$).mp. OR (myocard$ adj infarct$).mp.] limit to human and English language
Cochrane:
clopidogrel AND (MesH descriptors Angioplasy, Transluminal, Percutaneous Coronary OR Angioplasty OR Angioplasty, Balloon)

Search Outcome

891 and 397 papers were identified in Embase and Medline respectively, two of which were relevant to the three-part question.
Cochrane: 99 papers were identified, none of which were relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Mehta et al 2000 Canada	2658 patients with non-ST elevation acute coronary syndrome undergoing PCI (percutaneous coronary intervention) in the CURE study. Randomly assigned to treatment with clopidogrel 300mg (n=1313) or placebo (n=1345) for a median of 6 days before PCI. After PCI, both groups received open-label clopidogrel for 4 weeks, after which study drug was restarted for a mean of 8 months.	PRCT, double-blind	Myocardial infarction (MI) or refractory ischaemia before PCI	15.3% (placebo) vs. 12.1% (clopidogrel). Relative risk 0.76 (95% CI 0.62-0.93), p=0.008	Patients treated with thienopyridines prior to recruitment were not excluded. Thus 24.7% of patients in the placebo group also received open-label thienopyridines before PCI and were included in the intention to treat analysis. As such, the treatment effect of clopidogrel may have been underestimated. Cardiac enzyme levels were not routinely screened post-PCI. As such, event rates and thus the treatment benefit with clopidogrel may have been underestimated. More patients in the placebo group received intravenous glycoprotein IIb/IIa inhibitors during PCI (26.6% vs. 20.9%, p=0.001). Again, this may have led to underestimation of treatment benefit.
			MI before PCI	5.1% (placebo) vs. 3.6% (clopidogrel). Relative risk 0.68 (0.47-0.99), p=0.04
			Cardiovascular (CV) death, MI or urgent revascularisation from PCI to 30 days	6.4% (placebo) vs. 4.5% (clopidogrel). Relative risk 0.70 (0.50-0.97), p=0.03
			Overall results: CV death or MI from recruitment to end of study (mean 8 months)	12.6% (placebo) vs. 8.8% (clopidogrel). Relative risk 0.69 (0.54-0.87), p=0.002
			Any bleeding (major, minor or blood transfusion of 2 or more units)	No significant differences
Steinhubl et al 2002 United States	2116 patients undergoing elective coronary angiography with a view to percutaneous coronary intervention (PCI). Randomised to receive 300mg clopidogrel loading (n=1053) or placebo (n=1063). Following PCI, all patients received aspirin and clopidogrel for 28 days. The treatment group then received clopidogrel 75mg od until 12 months following PCI.	PRCT	Death, MI or urgent target vessel revascularisation within 28 days	6.8% treatment v. 8.3% placebo (p=0.23)	Use of glycoprotein inhibitors was more common in the treatment group (p=0.08).
			Death, MI or urgent target vessel revascularisation within 28 days according to time of clopidogrel loading	No benefit of clopidogrel loading if given 3-6 hours before PCI (n=893, p=0.60); Relative risk reduction 35.5% if clopidogrel loading administered >6 hours before PCI (p=0.09)
			Death, MI or stroke within 1 year	Relative risk reduction 26.9% in treatment group (p=0.02)

Comment(s)

There is currently no direct evidence of benefit for using a loading dose of clopidogrel immediately before primary angioplasty in acute ST-elevation myocardial infarction. As such, the most relevant question for physicians working in the Emergency Department remains unanswered. However, the PCI-CURE trial investigated the value of clopidogrel when given for a median of 6 days before PCI in patients with acute coronary syndromes. The findings suggest a definite benefit for the use of clopidogrel in this situation. This is despite the fact that several factors in the design of the trial may have tended to underestimate the treatment benefit of clopidogrel. While the CREDO trial included patients attending for elective coronary angioplasty, the results suggest that early clopidogrel loading is of benefit before PCI. Subgroup analysis suggested that it may be necessary to give clopidogrel 300mg at least 6 hours before PCI in order to gain benefit. As this is impractical in the emergency setting, the potential value of administering a higher loading dose to achieve earlier platelet inhibition should be investigated. Although these findings are not directly applicable to the Emergency Department population, we can confidently infer that it is safe and beneficial to prescribe a loading dose of clopidogrel to patients with non-ST elevation acute coronary syndromes who are to undergo PCI.

Clinical Bottom Line

Clopidogrel is safe and beneficial in patients with non-ST elevation acute coronary syndromes prior to percutaneous coronary intervention. It should be given as soon as possible.

References

1. Mehta SR; Yusuf S; Peters RJG; Bertrand ME; Lewis BS; Natarajan MK; Malmberg K; Rupprecht HJ; Zhao F; Chrolavicius S; Copland I; Fox KAA Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Lancet 2001; 358: 527-33
2. Steinhubl SR; Berger PB; Tift Mann J; Fry ETA; DeLago A; Wilmer C; Topol EJ; for the CREDO Investigators Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial JAMA 2002; 288: 2411-2420