Adding the anti-platelet drug clopidogrel to aspirin for the emergency treatment of heart attacks could save thousands of lives a year worldwide and prevent thousands of repeat heart attacks and strokes, according to new research presented at the American College of Cardiology annual conference.
The study also established that giving the beta-blocker metoprolol as an emergency treatment for heart attacks cuts the risks of repeat heart attacks and of ventricular fibrillation. But, early use of beta-blocker treatment raises the risk of cardiac shock in the immediate aftermath of a heart attack, and these early benefits and hazards tend to cancel each other out.
The findings are from the 45,852-patient COMMIT/CCS-2 randomised study – the largest ever conducted in China and the second largest study of emergency heart attack treatment in the world. This five-year joint Chinese/British venture involving 1,250 hospitals was organised by the Fuwai Hospital, Chinese Academy of Medical Sciences, Beijing, China, and the Clinical Trial Service Unit (CTSU) of Oxford University, UK.
Aspirin and clopidogrel are anti-platelet drugs that prevent blood clots through different mechanisms. The use of aspirin for the emergency treatment of heart attacks had been shown previously to reduce the risk of death and repeat heart attacks by about one quarter. The objective of COMMIT/CCS-2 was to see whether adding clopidogrel to aspirin might be even more beneficial than aspirin alone.
Beta-blockers are proven effective long-term treatment in the years after a heart attack. But, their value as emergency treatment is uncertain and such use is limited, although current guidelines advise prompt administration unless there are contraindications. COMMIT/CCS-2 aimed to establish whether using intravenous then oral metoprolol during a heart attack could cut deaths and reduce the risk of repeat heart attacks and cardiac arrest.
Dr Zhengming Chen of the CTSU, the study's principal investigator, told the ACC's 54th Annual Scientific Session in Orlando, Florida, that adding 75 mg of oral clopidogrel daily to aspirin significantly reduced the relative risk of death in hospital by 7% and the risk of death, repeat heart attack or stroke by about 10%, without any significant increase in serious bleeds. These benefits were additional to those of standard heart attack treatments, and were seen even in older patients and those presenting several hours after the onset of symptoms (who do not typically receive "clot busting" fibrinolytic therapy for their heart attack).
He said: "This means that, on average, adding clopidogrel to current therapies benefits one out of every 100 patients. So, for every million patients having a heart attack, giving this simple additional treatment for about two weeks would save 5,000 lives and prevent another 5,000 repeat heart attacks or strokes. As there are an estimated 10 million heart attacks in the world every year, the findings from this study – if implemented appropriately widely – would make an important contribution to saving lives and reducing disability."
Professor Rory Collins, co-chair of the study's steering committee and co-director of the CTSU, told the conference that giving three intravenous doses of 5 mg metoprolol during a heart attack, followed by 200 mg daily oral doses in hospital, reduced the relative risk of repeat heart attacks and ventricular fibrillation by 15–20%, but increased the relative risk of cardiac shock by about 30% (chiefly during the first day or so of treatment). In absolute terms, the overall balance of these different effects was about even, and there was no clear reduction in hospital mortality for any particular type of patient.
He emphasised that there was already compelling evidence that long-term use of beta-blockers after a heart attack benefited patients. "Our finding of clear reductions in repeat heart attacks and ventricular fibrillation reinforces this evidence," he said. "Early after a heart attack, however, the benefits and hazards with intravenous then oral metoprolol counter-balanced each other. So, to maximise the benefits and minimise any potential hazard, it may generally be prudent to wait until a heart attack patient's condition has stabilised before starting beta-blocker therapy."
Professor Liu Lisheng of the Fuwai Hospital, co-chair of the study's steering committee, emphasised the value of such international collaboration. "The findings from this large collaborative study in China should help to improve the treatment of many millions of people around the world who have heart attacks each year."
The study’s cost of UK£1.6 million (US$3 million) was split between the manufacturers of clopidogrel (Sanofi-Aventis/Bristol-Myers Squibb) and of metoprolol (AstraZeneca). The British Heart Foundation and UK Medical Research Council also supported the Oxford coordinating centre. However, the trial was designed, conducted, analysed, interpreted and presented by the researchers entirely independently of the funders.