Article Text

Addition of clopidogrel to aspirin, but not early use of metoprolol, improved overall outcome in acute myocardial infarction
1. David Massel, MD, FRCPC
1. T London Health Sciences Centre  London, Ontario, Canada

## Statistics from Altmetric.com

Q In patients hospitalised within 24 hours of suspected acute myocardial infarction (AMI), does the addition of clopidogrel to aspirin and the early use of metoprolol improve outcomes?

Clinical impact ratings IM/Ambulatory care ★★★★★★★ Internal medicine ★★★★★★☆ Cardiology ★★★★★★★ Emergency medicine ★★★★★★☆

## METHODS

### Design

randomised placebo controlled trial with 2 × 2 factorial design (Clopidogrel and Metoprolol in Myocardial Infarction Trial [COMMIT]).

concealed.*

### Blinding

blinded {clinicians, patients, and outcome assessors}.*

until first hospital discharge or 28 days.

### Setting

1250 hospitals in China.

### Patients

45 852 patients (mean age 61 y, 72% men) hospitalised within 24 hours (mean 10 h) of onset of symptoms of AMI, with ST elevation (87%), left bundle branch block (6%), or ST depression (7%) and no clear indication for or against the study medications. Those with moderate heart failure were eligible. Patients scheduled for primary percutaneous coronary intervention (PCI) and those with small likelihood of benefit or high risk for adverse effects were excluded.

### Interventions

clopidogrel, 75 mg once daily (n = 22 961), or placebo (n = 22 891); all patients also received aspirin, 162 mg once daily. Intravenous (IV) metoprolol, 5 mg, up to 3 doses given over 2–3 minutes and spaced 2–3 minutes apart (provided heart rate >50 beats/min and systolic blood pressure >90 mm Hg), then oral metoprolol, 50 mg every 6 hours for 2 days, followed by oral controlled release metoprolol, 200 mg once daily (n = 22 929), or placebo (n = 22 923). 54% of patients also received fibrinolytic therapy.

### Outcomes

clopidogrel study: composite end point (death, reinfarction, or stroke), all cause mortality, reinfarction, stroke, and life threatening bleeding (haemorrhagic stroke or major non-cerebral bleeding). Metoprolol study: composite end point (death, reinfarction, or cardiac arrest), all cause mortality, reinfarction, ventricular fibrillation, other cardiac arrest, and cardiogenic shock.

>99.99% (100% in intention to treat analyses).

## MAIN RESULTS

Clopidogrel study: Clopidogrel plus aspirin reduced risk of the composite end point and the single end points of death and reinfarction more than aspirin alone (table 1). Groups did not differ for stroke alone or life threatening bleeding (table 1). For the composite end point, the efficacy of clopidogrel increased with shorter interval between onset of symptoms and study entry, but did not differ by days since study entry, patient age, use of fibrinolytic therapy, or allocation to metoprolol.

Table 1

. Clopidogrel (Clop) plus aspirin v aspirin alone for acute myocardial infarction at up to 28 days*

Metoprolol study: Metoprolol and placebo did not differ for the composite end point (table 2). Metoprolol reduced risk of reinfarction and ventricular fibrillation; it increased risk of cardiogenic shock (table 2). Risk of shock was elevated on the first 2 days but not subsequently. Combining the composite end point and shock, there was no overall net benefit or harm of metoprolol (table 2), but this result varied by time since study entry: harm on day 0, no net effect on day 1, and benefit from day 2 onward. Risk of harm with metoprolol was higher in patients ⩾70 years of age, rated as Killip class III, or with systolic blood pressure <120 mm Hg or heart rate ⩾110 beats/min.

Table 2

. Metoprolol (Met) v placebo for acute myocardial infarction at up to 28 days*

## CONCLUSIONS

In patients hospitalised within 24 hours of suspected acute myocardial infarction, adding clopidogrel to aspirin (and other standard treatments) reduced risk of the composite end point of death, reinfarction, or stroke and did not increase the risk of major bleeding. Early intravenous then oral metoprolol did not reduce risk of the composite end point of death, reinfarction, or cardiac arrest; it increased risk of cardiogenic shock, especially in the first 2 days after admission, but reduced the risk of reinfarction and ventricular fibrillation.

Abstract and commentary also appear in ACP Journal Club.

# 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

## References

View Abstract

## Footnotes

• * See glossary

• Information provided by author.

• For correspondence: Dr Z Chen, Clinical Trial Service Unit, Oxford, UK. zhengming.chen{at}ctsu.ox.ac.uk

• Sources of funding: Sanofi-Aventis; Bristol-Myers Squibb; AstraZeneca.

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