Clopidogrel (ISCOVER, PLAVIX) reduces the rate of vascular complications in acute coronary syndrome (a-t 2001; 32: 91-2). On the other hand, the benefit in ST-elevation myocardial infarction (STEMI) had not been confirmed. Since combining fibrinolytics with aspirin reduces mortality in STEMI additively, it appears theoretically a rational choice to intensify platelet aggregation inhibition in STEMI. However, the incidence of haemorrhage is increased by glycoprotein IIb/IIIa blockers together with fibrinolytics and aspirin in acute myocardial infarction (MI) without a further reduction in mortality (a-t 2001; 32: 68 and 73) (1,2).

The randomised double-blind CLARITY* study (3) has now investigated the benefit of clopidogrel (loading dose 300 mg, then 75mg daily) compared to placebo in 3,491 patients with STEMI, who received fibrinolytic treatment within twelve hours after the onset of symptoms. In addition concomitant treatment with aspirin (150 mg to 325 mg per day) and unfractionated heparin was recommended, if fibrin-specific thrombolytics were used (e.g. LIQUEMIN N) (60 U/kg body weight as bolus, then 12 U/kg/hour as continuous intravenous infusion). Coronary interventions were not planned in the acute management.

The primary endpoint was a combination of angiographically confirmed occlusion of the infarct vessel on day 3 to 12 or death or reinfarction before the angiography or, if angiography is not performed, up to day 8 or until discharge. Clopidogrel started directly after the fibrinolysis and was continued until angiography or until day 8 or until discharge. If a stent was inserted during angiography, the patients received clopidogrel without blinding (loading dose 300 mg, then 75 mg/d).

On average, patients were 57 years old, 80% were men, 50% were smokers and 16% were diabetics. 43% were known to have hypertension, 33% had hyperlipidaemia and 9% had had a previous MI. 99.7% of the patients received fibrinolytic treatment according to protocol (31% streptokinase [STREPTASE], 69% fibrin-specific agents such as alteplase [ACTILYSE]) and 80% received concomitant heparin (fractionated and/or unfractionated). Angiography was performed as planned in 94% after 3.5 days on average, with subsequent angioplasty in 57%.

On clopidogrel 15% suffered a primary endpoint event compared to 21.7% on placebo (odds ratio [OR] 0.64; 95% confidence interval [CI] 0.53-0.76). Of the individual components of the primary endpoint, only the rate of angiographically confirmed infarct vessel occlusions was significantly lower (11.7% vs. 18.4%, OR 0.59; 95% CI 0.48-0.72). However, this is a surrogate endpoint. The mortality was numerically higher with clopidogrel (2.6% vs. 2.2%), and the reinfarction rate was lower than with placebo (2.5% vs. 3.6%).

Cerebral (1.3% vs. 1.1%) and other relevant haemorrhages (0.7% vs. 0.5%) did not differ significantly on clopidogrel and placebo. Cardiovascular deaths, MI or emergency revascularisations up to day 30 were reduced from 14.1% to 11.6% (OR 0.80 with 95% CI 0.65-0.97). It remains to be clarified whether this secondary combined endpoint was prespecified. Moreover, the results were obtained only by a telephone survey. The clopidogrel group was favoured in this period by the study design as patients in the placebo group in whom a stent was inserted during the angiography (57%, see above) received clopidogrel only after the procedure (4). However, clopidogrel must be given as a loading dose at least 6 hours before the intervention to prevent vascular events after coronary interventions (5,6).

Publication of another study, the chinese COMMIT/CCS-2** study with over 45,000 participants, is still pending. According to conference reports (7), clopidogrel is said to have resulted in a small (absolute 0.4%), but significant reduction in overall mortality in acute infarction However, the applicability of the results will have to be scrutinised, especially as only 50% of the patients received fibrinolysis and invasive procedures were a reason for exclusion.

	In the CLARITY study, clopidogrel (ISCOVER, PLAVIX) added to aspirin, fibrinolysis and possibly heparin (e.g. LIQUEMIN N) in acute myocardial infarction with ST-elevation (STEMI) reduced a combined endpoint consisting of the rate of infarct vessel occlusion, reinfarction and mortality.
	A particular shortcoming of the study is the fact that the primary endpoint consists of a surrogate parameter combined with clinically relevant events.
	The clinically relevant components of the primary endpoint are not improved, in contrast to the surrogate parameter.
	Furthermore, the reduction in cardiovascular events after 30 days appears not to be adequately confirmed from methodological points of view.
	The benefit of clopidogrel in STEMI remains unproven at present.

(R = randomised study)

1

TOPOL, E.J. et al.: Lancet 2001; 357: 1905-14

2

ASSENT-3-Investigators: Lancet 2001; 358: 605-13

3

SABATINE, M.S. et al.: N. Engl. J. Med. 2005; 352: 1179-89

4

LANGE, R.A., HILLIS, L.D.: N. Engl. J. Med. 2005; 352: 1248-50

5

STEINHUBL, S.R. et al.: JAMA 2002; 288: 2411-20

6

LANGE, R.A., HILLIS, L.D.: N. Engl. J. Med. 2004; 350: 277-80

7

http://www.medscape.com/viewarticle/501637

CLARITY = Clopidogrel as Adjunctive Reperfusion Therapy

COMMIT/CCS-2 = Clopidogrel and Metoprolol in Myocardial Infarction Trial - Second Chinese Cardiac Study