Commentary

The metoprolol arm of COMMIT is an example of a so called “negative” trial having a positive effect on clinical practice. Perhaps these results should not come as too much of a surprise. Firstly, the bulk of the data concerning β blocker use in AMI comes from the prefibrinolytic era. The largest trial from the “fibrinolytic era,” comparing immediate IV followed by oral β blockers versus deferred (6 d) oral β blockers, also showed no effect on mortality at 6 weeks but did show a lower risk of recurrent infarction.¹ Immediate β blocker use was believed to be safe, but the trial was about one thirtieth the size of COMMIT and thus could have underestimated adverse consequences. Secondly, haemodynamic stability is probably at play. As a corollary, despite the benefit of angiotensin converting enzyme (ACE) inhibitors in the setting of AMI, their early IV administration has been shown to mitigate this benefit. The Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) showed that early IV followed by oral enalapril was associated with non-significantly higher mortality than placebo.² Hypotension was significantly more common in the ACE inhibitor group (12% v 3%) and may have been the culprit. Similarly, hypotension induced by IV nitroglycerine can mitigate its favourable effect on left ventricular remodelling in AMI.³

That the addition of clopidogrel to aspirin in the setting of ST segment elevation AMI (STEMI) is modestly effective and safe also comes as no surprise. Similar magnitudes of benefit (about 10 composite events per 1000 treated at 1 mo) were shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial among patients with acute coronary syndromes.⁴ A slightly larger, albeit not statistically significant, effect (18 events prevented per 1000 treated by 30 d) was seen in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–Thrombolysis in Myocardial Infarction (TIMI) 28 study among patients with STEMI treated with aspirin and fibrinolytics.⁵ COMMIT supports those results, but it should be noted that it was done against a background of a very low rate of invasive procedures. Can one apply the COMMIT results widely and, in particular, to locales where a more “invasive” approach is the norm? I believe one can. Observational substudies of CLARITY and CURE showed that a greater absolute benefit with clopidogrel was seen among patients having PCI.^6,7 Moreover, benefit was seen to emerge between randomisation and PCI in both these studies.

Clopidogrel is expensive—will it have value for money? Using a back of the envelope approach, I suspect it will. Consider that tissue plasminogen activator is regarded as cost effective compared with streptokinase, based on 10 fewer deaths per 1000 treated (counterbalanced by 1 non-fatal but disabling and expensive to treat stroke) and a cost differential of about US $2500. Based on COMMIT, clopidogrel use would result in 6 fewer deaths (and fewer recurrent AMIs and no excess strokes) per 1000 treated and a cost differential over a month of perhaps US $100.

Routine early IV β blocker use in STEMI is potentially hazardous and should be avoided. Consideration of routine oral β blockers after the haemodynamics have stabilised is a more prudent approach. As most of the hazard occurs within the first day or so, it should be safe to initiate β blockers after that period in response to symptoms of recurrent ischaemia or for treatment of hypertension, ventricular ectopy, or congestive heart failure.

In the absence of bleeding concerns, clopidogrel should be given with aspirin in patients with STEMI whether the plan is to use fibrinolysis or to do direct PCI. I would use a 300 mg loading dose followed by 75 mg daily. While optimal duration of therapy is not known, I would continue clopidogrel for at least 9–12 months.^4,8