FACT SHEET 2

METOPROLOL: Questions and Answers about the COMMIT/CCS-2 results

Q	What are the main results from COMMIT/CCS-2 for metoprolol?
A	Giving three intravenous doses of 5 mg metoprolol within 24 hours of the onset of a heart attack, followed by 200 mg daily oral doses in hospital, significantly reduced the relative risk of repeat heart attack or 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). On average, in absolute terms, the overall balance of these different effects was about even, with no clear reduction in hospital mortality for any particular type of patient. Moreover, for patients at increased risk of developing cardiac shock (such as those with evidence of severe heart failure and patients aged over 70), the hazards of early intravenous metoprolol appeared to outweigh any benefits.
Q	What are the main implications of the metoprolol results?
A	Early after a heart attack, the benefits and hazards with this intravenous then oral metoprolol regimen tended to counter-balance 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. There was already compelling evidence that long-term use of beta-blockers after a heart attack benefited patients, and the finding of clear reductions in repeat heart attacks and ventricular fibrillation in COMMIT/CCS-2 reinforces this evidence.
Q	What has COMMIT/CCS-2 told us that we did not know before – were the results in line with what was expected?
A	During the 1970s and 1980s, about two dozen randomized studies investigated the use of intravenous then oral beta-blocker for the emergency treatment of heart attacks, typically among relatively low risk patients. Overall, this treatment appeared to reduce the relative risks of death, repeat heart attacks and cardiac arrest by about 15-20% during the first week. The much larger COMMIT/CCS-2 study confirms these reductions of about 15-20% in the relative risks of repeat heart attacks and ventricular fibrillation (although not of other types of cardiac arrest). But, by contrast with those previous studies, there was no good evidence that this beta-blocker regimen reduced mortality for any particular type of patient (including those who were at low risk of death, or presented within only a few hours of symptom onset, or received fibrinolytic therapy), chiefly because it tended to increase the risk of death from cardiac shock.
Q	How important do you rate the findings?
A	Even though current guidelines advise the prompt administration of a beta-blocker during a heart attack (unless there are contraindications), there has been considerable uncertainty about its value (especially on top of current standard therapies). Perhaps as a consequence, there is about 100-fold variation between countries in the use of intravenous beta-blocker during a heart attack: ranging, for example, from less than 1% in the UK to about 20% in the US and over 50% in Sweden. The much larger COMMIT/CCS-2 study now provides clear guidance for doctors that it may generally be prudent to wait until after a heart attack patient has become stable before initiating beta-blocker therapy (and then continuing it long-term).
Q	Are these results for metoprolol definitive?
A	The large numbers of deaths and relevant non-fatal events on which these results are based make the COMMIT/CCS-2 findings extremely reliable and definitive. It may be, however, that the balance of benefits and risks would have differed with a different regimen (e.g. starting with an oral rather than intravenous dose) and/or with exclusion of patients at particular risk of developing cardiac shock (e.g. those with evidence of heart failure).
Q	Were there any disappointments with the metoprolol findings?
A	It was disappointing not to be able to identify any particular type of patient who obtained a clear mortality benefit from the use of intravenous then oral metoprolol during a heart attack. On the other hand, the findings of clear reductions in repeat heart attacks and ventricular fibrillation reinforce the value of starting beta-blocker therapy when heart attack patients are stable and continuing this treatment long-term in order to reduce the risk of these life-threatening complications.
Q	Were there any differences between the findings for metoprolol in men and women?
A	No. The efficacy and safety findings for metoprolol were consistent in men and women.
Q	Did the results reveal any types of patients that are definitely not suitable for metoprolol?
A	Patients who were already in cardiac shock, or who were thought to be at increased risk of developing it (such as those with persistently very low blood pressure [e.g. systolic pressure <100mmHg] or very slow heart beat [e.g. <50 beats/min]) were excluded from the study. Metoprolol appeared to produce similar relative and absolute reductions in the risks of repeat heart attacks and ventricular fibrillation in the different types of patient studied. But, among older individuals and those who presented with evidence of heart failure, the excess of cardiac shock with metoprolol outweighed the reductions in repeat heart attacks and ventricular fibrillation.
Q	Metoprolol was started by giving 3 intravenous injections of 5 mg each over the first 15 minutes, followed by 200 mg oral metoprolol daily. Is it possible that starting with oral treatment rather than injections might avoid the early excess of cardiac shock?
A	We cannot be sure, but it is of note that the excess of cardiac shock with this metoprolol regimen was observed chiefly during the first day or so after initiating therapy, whereas the beneficial effects on repeat heart attack and on ventricular fibrillation emerged more gradually during the treatment period in hospital. It may be, therefore, that starting beta-blocker therapy more gradually – particularly in high-risk patients – would help to reduce the excess risk of shock while still retaining much of the benefit.
Q	Given the size of this trial, are any further studies of metoprolol necessary?
A	COMMIT/CCS-2 provides clear evidence about the balance of benefits and risks of starting intravenous then oral metoprolol early after the onset of a heart attack in a range of different types of patient. Further studies of the effects of starting more gradually with oral doses of beta-blocker, in order to minimise the risks of developing cardiac shock, would be of value.
Q	Were you concerned about possible interactions between metoprolol and other drugs used by patients having heart attacks?
A	The doctors of patients in the study were free to use any other treatments in hospital that they considered necessary. There was no evidence that the risks of cardiac shock with metoprolol were materially increased in the presence of any other treatments. Nor was there any evidence that the reductions in the risks of repeat heart attacks or ventricular fibrillation with metoprolol were materially influenced by the use of any other treatments (including the other study drug, clopidogrel).
Q	Do you think the dosage of metoprolol used in COMMIT/CCS-2 was optimal?
A	The initial intravenous regimen of 15 mg metoprolol given over about 15 minutes, followed by 200 mg oral daily, had been studied in previous studies of the emergency treatment of heart attacks (including the 6,000 patient MIAMI trial), and is known to achieve complete beta-blockade rapidly. It may be prudent, however, to avoid very rapid beta-blockade during a heart attack unless the patient is stable and not at high risk of developing cardiac shock.
Q	Were there any side-effects of metoprolol that particularly concerned you?
A	Metoprolol is generally contraindicated in patients who are already in cardiac shock, so such patients were excluded from COMMIT/CCS-2. But, the study now shows that the use of intravenous then oral beta-blocker early after the onset of a heart attack can increase the risk of developing cardiac shock, especially during the first day or so when the patient’s condition is unstable. In order to minimise the risk of causing cardiac shock, it may generally be prudent to wait until the patient’s condition has stabilised following a heart attack before starting beta-blocker therapy (and then continuing it long-term).
Q	Are the findings from this study in China applicable to other populations?
A	Yes. There is no evidence that the nature of heart attacks is materially different in China than elsewhere, or that Chinese patients react differently to metoprolol than do other populations. Furthermore, the concomitant therapies used in hospital in the study were very similar to those typically used in other countries.
Q	Previous studies have already shown that beta-blocker therapy is effective in treating heart disease. How could you justify using placebo?
A	Although over two dozen studies had previously assessed the effects of starting intravenous then oral beta-blocker therapy during a heart attack, substantial uncertainties remained about the balance of any benefits and hazards of such therapy when added to current standard treatments for a heart attack. Moreover, entry to the study was guided by the “uncertainty principle”: that is, each patient was eligible for inclusion in the study only when their responsible doctors were substantially uncertain as to whether metoprolol was clearly indicated or clearly contraindicated.
Q	Are these results for metoprolol likely to be applicable to any other type of beta-blocker?
A	COMMIT/CCS-2 shows that metoprolol reduces the relative risk of repeat heart attack and ventricular fibrillation by about 15-20%, but this treatment increases the relative risk of cardiac shock early after a heart attack by about 30%. It seems likely that similar results would be observed with other intravenous then oral regimens using different beta-blockers (but starting more gradually after a heart attack with an oral beta-blocker when patients are stable may help to avoid this excess of cardiac shock).
Q	Is metoprolol expensive? Will this treatment be affordable in less developed countries as well as in more developed countries?
A	Metoprolol is an old drug and is relatively inexpensive (as is also the case with several other beta-blockers, such as atenolol), so treatment for only about 2 weeks is likely to be affordable for most patients – even in less well developed countries. Indeed, with a non-patented beta-blocker, the cost of long-term treatment following a heart attack in order to prevent repeat heart attack and death due to arrhythmias would be widely affordable.
Q	Are you going to follow the patients long-term to assess outcomes, or is day of discharge from hospital the final outcome?
A	The study aimed to assess outcome during the scheduled treatment period of 4 weeks or prior hospital discharge, and there is currently no plan to follow patients longer-term.
Q	The findings on metoprolol are mixed. What is the most important 'take home' message for doctors for this drug?
A	Following a heart attack, it may generally be prudent to wait until the patient's condition has stabilised before starting beta-blocker therapy.
Q	Do these findings suggest that changes are needed to the current guidelines for the use of beta-blockers during a heart attack?
A	The current guidelines generally recommended the prompt use of beta-blocker therapy early after the onset of a heart attack. The present findings now indicate that such treatment should generally be avoided in patients at high risk of developing cardiac shock (such as those who already have evidence of heart failure or who are elderly), and initiated only when the patient’s condition is stable.