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Three Part Question

In [patients about to undergo primary angioplasty for myocardial infarction] does [clopidogrel 600mg or 300mg] lead to [less adverse events and lower mortality]?

Clinical Scenario

A fifty year-old man has presented to the Emergency Department with chest pain. ECG shows 4mm anterior ST elevation with reciprocal ST depression in the inferior leads. You discuss the case with the on-call cardiology registrar, who accepts the patient for primary angioplasty. He asks for the patient to be given 600mg clopidogrel. You wonder if there is any evidence that this is superior to a 300mg loading dose.

Search Strategy

OVID Medline 1966 - Week 2 July 2005
OVID Embase 1980 - Week 29, 2005
The Cochrane Library Issue 2, 2005
Medline and Embase:
[clopidogrel.af. OR exp Ticlopidine/ OR (adenosine adj5 antagonist).mp. OR plavix.mp. OR thienopyridine$.mp.] AND [exp Angioplasty, Transluminal, Percutaneous Coronary/ OR exp Angioplasty/ OR angioplasty.af. OR PTCA.af. OR PCI.af. OR percutaneous coronary intervention.mp.] AND [exp Angina Pectoris/ OR exp Coronary Disease/ OR exp Myocardial Ischemia/ OR exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR acute coronary syndrome.mp. OR heart attack.mp. OR AMI.mp. OR MI.mp OR (myocard$ adj ischem$).mp. OR (myocard$ adj ischaem$).mp. OR (myocard$ adj infarct$).mp.] AND [exp Dose-Response Relationship, Drug/ OR dosage.af. OR 600mg.af.] limit to human and English language
Cochrane:
clopidogrel AND (MesH descriptors Angioplasy, Transluminal, Percutaneous Coronary OR Angioplasty OR Angioplasty, Balloon)

Search Outcome

Altogether 255 papers were identified using Embase, 73 using Medline and 99 using Cochrane. One paper, identified using Embase only, was relevant to the three part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Patti et al 2005 Italy	255 patients undergoing elective coronary angioplasty, randomised to receive either 600mg (n=163) or 300mg (n=166) clopidogrel, median 6 hours before angiography.	PRCT	Death, myocardial infarction or target vessel revascularisation at 30 days (primary endpoint)	4% high-dose v. 12% low-dose (p=0.041) (difference accounted for by the difference in periprocedural myocardial infarction)	High-dose group were younger (63+/-10 years v. 65+/- 10 years, p=0.027) No intention to treat analysis Study may be underpowered to detect differences in haemorrhagic complications between the groups.
			Elevation of CK-MB above upper normal limit post-procedure	14% high-dose v. 26% low-dose (p=0.036)
			Troponin I increase post-procedure	26% high-dose v. 44% low-dose (p=0.004)
			Haemorrhagic complications	No major bleeding in either group. 1 minor bleed in each group. Groin haematoma in 9 high-dose & 6 low-dose patients (p=0.56)

Comment(s)

The most common method of revascularisation during PCI is coronary stenting, a major complication of which is stent thrombosis. There is therefore a sound pathophysiological basis for investigating the utility of loading with antiplatelet agents ahead of PCI. The CREDO trial investigated the value of loading with clopidogrel 300mg in patients undergoing elective stenting (Steinhubl et al, 2002). Subgroup analysis suggested that the loading dose was effective if given over 6 hours before PCI but not when given later. Clopidogrel has been shown to achieve superior platelet inhibition when given at a dose of 600mg compared with 300mg (Gurbel et al, 2005). In addition, a 600mg loading dose of clopidogrel has been shown to be effective within 2 to 3 hours of administration, with no additional benefit to be gained from longer durations of pretreatment before PCI(Hochholzer et al, 2005; Kandzari et al, 2004). An observational study which compared clopidogrel 600mg with ticlopidine before PCI demonstrated superior outcome with clopidogrel, with no increase in haemorrhagic complications (Pache et al, 2002). The only randomised trial to compare clopidogrel 600mg with 300mg has shown a significant reduction in periprocedural MI with the higher dose with no evidence of an increase in complications.

Clinical Bottom Line

Clopidogrel 600mg is probably superior to 300mg before primary angioplasty and should be recommended.

References

1. Patti G; Colonna G; Pasceri V; Pepe LL; Montinaro A; Di Sciascio G Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 Study Circulation 2005; 111: 2099-2106
2. Gurbel PA; Bliden KP; Hayes KM; Yoho JA; Herzog WR; Tantry US The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting Journal of the American College of Cardiologists 2005; 45(9): 1392-1396
3. Hochholzer W; Trenk D; Frundi D; Blanke P; Fischer B; Andris K; Bestehorn HP; Buttner HJ; Neumann FJ Time dependence of platelet inhibition after a 600mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention Circulation 2005; 111: 2560-2564
4. Kandzari DE; Berger PB; Kastrati A; Steinhubl SR; Mehilli J; Dotzer F; ten Berg J; Neumann FJ; Bollwein H; Dirxchinger J; Schomig A; for the ISAR-REACT Study Investigators Influence of treatment duration with a 600mg dose of clopidogrel before percutaneous coronary revascularization Journal of the American College of Cardiology 2004; 44: 2133-2136
5. Pache J; Kastrati A; Mehilli J; Gawaz M; Neumann FJ; Seyfarth M; Hall D; Braun S; Dirschinger J; Schomig A Clopidogrel therapy in patients undergoing coronary stenting: value of a high-loading-dose regimen Catheterization and Cardiovascular Interventions 2002; 55: 436-441