Q |
What is COMMIT/CCS-2? |
A |
It is the ClOpidogrel and Metoprolol in Myocardial Infarction
Trial/Second Chinese Cardiac Study – the largest clinical
study ever conducted in China and the world's second largest
clinical study of the emergency treatment of heart attacks (acute
myocardial infarction or MI). This randomised trial has
investigated the effects of adding the oral anti-platelet drug
clopidogrel to aspirin, and of starting the beta-blocker
metoprolol, within 24 hours of the onset of a heart attack. |
Q |
When did the study start and when did it end? |
A |
The first patients were recruited in October 1999. Within a
year more than 800 patients a month were entering the study, and
this recruitment level was maintained until the study closed on 9
February 2005. |
Q |
Where was the study undertaken and how many
patients took part? |
A |
The study was carried out in China, and 45,852 patients from
1,250 collaborating hospitals took part in the study. |
Q |
Who carried out the study? |
A |
It was a joint Chinese-British venture. The international
coordinating centre was at the Clinical Trial Service Unit (CTSU)
of Oxford University, UK, which worked in close collaboration
with the national coordinating centre at the Fuwai Hospital,
Chinese Academy of Medical Sciences, Beijing, China. |
Q |
Why was clopidogrel studied? |
A |
The use of aspirin for the emergency treatment of heart
attacks had been shown previously by the Oxford research team to
reduce the risk of death and repeat heart attacks by about one
quarter. As a consequence of that research, aspirin is now used
routinely during, and after, a heart attack. The objective of
COMMIT/CCS-2 was to see whether adding clopidogrel to aspirin
during a heart attack might be even more effective at preventing
death or a repeat heart attack than is aspirin alone. |
Q |
What do aspirin and clopidogrel do? |
A |
Aspirin is an anti-platelet drug that prevents blood clots.
Specifically, it irreversibly inhibits an enzyme complex called
cyclooxygenase, blocking the formation of thromboxane A2, a
potent agent that makes platelet cells in the blood stick
together. Clopidogrel is also an anti-platelet drug, introduced
in 1998, which works through a different mechanism from aspirin.
It inhibits an energy storage molecule called adenosine
diphosphate, which also makes platelets stick together. The
study's objective is to discover whether blocking these two
pathways simultaneously by using an aspirin/clopidogrel
combination produces a greater clinical effect than blocking the
aspirin pathway alone. |
Q |
What doses of aspirin and clopidogrel were
studied? |
A |
All patients received 162mg oral aspirin daily. Half were
randomly allocated to receive 75mg oral clopidogrel daily for up
to 4 weeks (or prior hospital discharge), and the other half were
allocated to receive matching placebo (“dummy”)
tablets. |
Q |
Why was metoprolol studied? |
A |
The use of beta-blockers in the years after a heart attack
had been shown previously to reduce the risk of death and repeat
heart attacks, and such treatment is now used routinely. But,
despite the use of intravenous beta-blockers for the emergency
treatment of heart attacks having been investigated in about two
dozen clinical studies during the 1970s and 1980s, its value
remains uncertain (especially on top of current standard
therapy). So, such use of beta-blockers is limited, even though
current guidelines advise their prompt administration during a
heart attack unless there are contraindications. COMMIT/CCS-2
aimed to establish whether starting intravenous and then oral
metoprolol during a heart attack could cut deaths and reduce the
risk of repeat heart attacks and cardiac arrest. |
Q |
What does metoprolol do? |
A |
Metropolol is a beta-blocker, introduced in 1975, which
blocks the action of adrenaline (epinephrine) and noradrenaline
(norepinephrine), two chemicals that increase the heart rate and
raise the blood pressure. Metoprolol has been shown to be of
value for treating hypertension, certain arrhythmias and heart
failure, as well as for preventing further heart attacks during
the years after a heart attack. The study's objective is to
discover whether slowing the heart rate and reducing the force of
the heartbeat, thus reducing the workload on the heart and
preventing life-threatening arrhythmias early after the onset of
a heart attack, is beneficial. |
Q |
What dose of metoprolol was studied? |
A |
Half of the patients were randomly allocated to receive up to
15 mg intravenous metoprolol over about 15 minutes followed by
200mg oral metoprolol daily for up to 4 weeks (or prior hospital
discharge), and the other half were allocated to receive matching
placebo injections and tablets. |
Q |
What type of study was it? |
A |
A randomised double-blind placebo-controlled clinical trial
– that is, one in which patients were randomly allocated to
receive the study treatments or matching “dummy”
placebo (in addition to all the standard treatments for a heart
attack), but neither the patients nor their doctors knew which
they were receiving. |
Q |
How was the study able to assess clopidogrel as
well as metoprolol? |
A |
It used what is known as a factorial (2X2) design:
- 1/4 of patients received active clopidogrel and active
metoprolol
- 1/4 of patients received active clopidogrel and placebo
metoprolol
- 1/4 of patients received placebo clopidogrel and active
metoprolol
- 1/4 of patients received placebo clopidogrel and placebo
metoprolol
The assessment of clopidogrel involved comparison of outcome in
the two quarters that received active clopidogrel versus that in
the two quarters that received placebo clopidogrel. Similarly,
the assessment of metoprolol involved comparison of the two
quarters that received active metoprolol versus the two quarters
that received placebo metoprolol. (N.B. All patients were
allocated active aspirin, with all other treatments at the
discretion of the patients’ own doctors.) |
Q |
Previous studies have already shown that
clopidogrel and metoprolol are effective in treating heart
disease. How could you justify using placebo? |
A |
Adding clopidogrel to aspirin had previously been shown to be
beneficial for people who had unstable angina or were undergoing
percutaneous coronary intervention [PCI] balloon angioplasty, but
there was no good evidence for its use during a heart attack. For
metoprolol, 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. Entry to the study was guided by the
“uncertainty principle”: that is, each patient was to
be considered for inclusion in the study only when their
responsible doctors were substantially uncertain as to whether
the study treatments were clearly indicated or clearly
contraindicated for that particular patient. |
Q |
What percentage of acute MI patients receive these
drugs already? |
A |
Clopidogrel is becoming increasingly used as long-term
therapy for unstable angina or during coronary artery procedures
(such as PCI or stenting), but its use during a heart attack is
low, presumably because there is no clear evidence about the
balance of benefits and risks in this setting. The use of
intravenous beta-blocker during a heart attack varies widely
between countries: for example, there is about 100-fold variation
in Europe, ranging from less than 1% in the UK to over 50% in
Sweden. |
Q |
Who was eligible for the study? |
A |
Patients were eligible if they presented with:
- suspected acute heart attack within 24 hours of the onset of
symptoms;
- ST elevation or other ischemic abnormality on their
electrocardiogram; and
- no clear indication for, or contraindication to, any of the
study treatments
and they then provided their informed consent to
participate. |
Q |
Who might have been excluded? |
A |
Patients were to be excluded if there was thought to be:
- an increased risk of possible adverse effects of the study
treatments; or
- only a small likelihood of worthwhile benefit from the study
treatments (e.g. unconvincing evidence of a heart attack or
undergoing primary percutaneous coronary intervention [PCI]
balloon angioplasty)
|
Q |
What possible adverse effects of study treatment
might warrant exclusion? |
A |
Examples would include:
- previous allergy to aspirin or any of the study drugs
- active bleeding or history of bleeding disorder
- persistent very low blood pressure (e.g. systolic pressure
<100mmHg)
- persistent very slow heart beat (e.g. <50 beats/min)
- third degree heart block(complete loss of electrical signals
between upper and lower heart chambers) or need for a
pacemaker
- cardiac shock (a condition in which the heart muscle is so
severely damaged that it is unable to pump sufficient blood to
the body)
|
Q |
What was the age range of the patients? |
A |
There was no age limit for inclusion in the study. The
youngest participant was 15 years of age and the oldest was 100,
with a mean age of 61 years, and about 12,000 patients were aged
70 or over. So, the findings should be relevant not only for
middle-aged heart attack victims but also for older people who
are often not included in clinical studies, and are less likely
to be given other emergency treatments (such as
“clot-busting” fibrinolytic therapy) for their heart
attacks. |
Q |
How many men and how many women? |
A |
There were 33,082 men (72%) and 12,760 women (28%). |
Q |
Why were there many more men than women in the
study |
A |
Because women tend to have a much lower incidence of heart
attack in early and late middle age than do men. |
Q |
What were other characteristics of patients in the
study? |
A |
By age:
Under 60 |
42% |
60-69 |
32% |
70 or over |
26% |
By time from onset of symptoms to study entry
0-6 hrs |
34% |
7-12 hrs |
33% |
13-24 hrs |
33% |
By systolic blood pressure (mmHg)
under 120 |
34% |
120-139 |
35% |
140-159 |
20% |
160 & over |
11% |
By heart rate (beats/min)
under 70 |
22% |
70-89 |
49% |
90-109 |
22% |
110 and over |
7% |
|
Q |
How long were patients in the study? |
A |
Following admission to hospital with a suspected heart
attack, patients were scheduled to continue study treatment and
follow-up for up to four weeks or until prior hospital discharge.
In practice, the average duration of the hospital stay and study
treatment was 16 days. |
Q |
Did all randomised patients complete their
allocated study treatment? |
A |
Both study treatments are well tolerated. For the clopidogrel
comparison, 93% of patients completed their scheduled study
clopidogrel/placebo tablets and there was no difference between
the clopidogrel and placebo groups in the numbers who stopped
these tablets prematurely. For the metoprolol comparison,
intravenous study treatment was stopped more commonly in the
metoprolol group than the placebo group (10% versus 4%), and so
too was the oral treatment (14% versus 8%), chiefly due to
persistent lower blood pressure and slower heart rate. |
Q |
Did you have to unblind any patients? If so,
why? |
A |
A 24-hour telephone service was available to deal with any
relevant medical queries, but the study treatment of only about a
dozen patients needed to be “unblinded” (i.e. active
or placebo nature of the allocated study treatment disclosed) for
various medical conditions throughout the whole study
period. |
Q |
Were patients also given other therapies while
taking part in the study? |
A |
Yes, the patients’ doctors were free to use any other
treatments in hospital that they considered necessary. So, as
well as all patients being given aspirin, they received:
fibrinolytic agents |
55% |
anticoagulants |
68% |
ACE inhibitors |
74% |
anti-arrhythmics |
23% |
diuretics |
23% |
calcium antagonists |
12% |
nitrates (oral or iv) |
94% |
The level of use of these treatments in this study in China was
similar to that found in similar situations in the US or Europe.
Moreover, when patients who presented within 12 hours of symptom
onset with definite ischaemic ECG changes (ST segment elevation)
are considered separately, the use of fibrinolytic therapy
increased to 68% (and it increased further with restriction to
patients aged under 70). Typically in China, the fibrinolytic
agent used was urokinase, whereas tissue plasminogen activator in
the US and streptokinase in Europe are more commonly used. |
Q |
Didn't these other therapies affect the assessment
of the study treatments? |
A |
No, because the use of these other therapies tended to be
balanced between the study treatment and placebo groups in this
double-blind study. So, in principle, it provides an unbiased
assessment of the effects of adding clopidogrel and metoprolol to
currently standard treatments for a heart attack. |
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 these treatments 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 |
Why did the study have to be so large? |
A |
The study sought to determine the effects of treatment on
hospital mortality and other serious outcomes (such as repeat
heart attack, stroke or cardiac arrest) for which even quite
small improvements could be very worthwhile. Studying large
numbers of patients reduces the play of chance in the results. By
involving 40-50,000 patients, the study has good statistical
power to detect reductions in the risks of death or of other
major vascular events as small as 10 per 1000 (e.g. 10% dead
reduced to 9% dead). |
Q |
If the treatments produce only modest benefits is
this worthwhile? |
A |
Yes. Acute MI is a very common condition, with about 10
million heart attacks every year worldwide. Moreover, both
clopidogrel and metoprolol are simple to use, and 2-weeks of
treatment is not expensive. So, the reliable demonstration of
modest benefits in this common disease with such widely
applicable treatments could mean that thousands of patients avoid
death or serious non-fatal vascular events each year. |
Q |
Was it difficult to recruit patients? |
A |
Successful recruitment depended on the widespread
collaboration of many doctors and nurses throughout China. In
order to make it easier for them to collaborate, the study
procedures were streamlined by the coordinating centre, with only
essential data collected, no extra investigations and no
interference with the routine care of patients. Apart from giving
the study treatments, all other aspects of patient management
were entirely at the discretion of the patients’
responsible doctors. |
Q |
This huge study involved 1,250 hospitals thousands
of miles apart. How did you manage to ensure the study was
well-run and the results reliable? |
A |
Careful design at the beginning aimed to make it
straightforward for collaborating doctors and nurses to
participate in the study, with minimal extra work and without
disruption of their routine practice. The study treatments were
conveniently packaged, using calendar packing to facilitate
compliance, and were provided in packs with clear instructions
and brief study forms. A number of centralised quality control
checks were implemented throughout the course of the study,
including random testing of drug packs, extensive computerised
checks and validation of data, and regular monitoring of
recruitment patterns and patient characteristics in each
hospital. In addition, on-site auditing of medical notes was
performed at 350 of the fastest recruiting hospitals which
accounted for about two thirds of all randomised patients. |
Q |
How did you manage to persuade 1,250 hospitals to
take part in the study? |
A |
The key factor to persuading a large number of hospitals to
participate was to make the study attractive to clinicians, with
streamlined patient entry involving little or no extra testing or
examination, with collection only of essential data at entry and
follow up, with reimbursement for the small amount of extra work
involved, and with publication of the main study findings in the
name of the whole collaborative group (rather than just the study
organisers). Potential collaborating hospitals were identified in
various ways, including from personal contacts of the principal
investigators and experience in previous studies, as well as
national and regional hospital directories. |
Q |
What approval and patient consent procedures were
there for the study? |
A |
The study was approved by the Chinese Ministry of Health and
China State Drug Administration Bureau, as well as by national
and regional ethics or health research boards. Written informed
consent had to be obtained either from the patient or (if too ill
to give consent) from a close family member prior to entry of
each patient into the study. |
Q |
Were study doctors paid or did they receive any
other incentive to take part? |
A |
Collaborating doctors had their travel costs covered for
attending investigators’ meetings. They were also
reimbursed with a small amount of money (about $12 per patient)
to cover the costs of the minimal extra clinical time spent on
recruiting, treating and managing patients enrolled in the study.
No other fee or financial incentive was given to doctors or their
hospitals for participating in the study. |
Q |
How much did the study cost and who funded it? |
A |
It cost US$3 million [UK£1.6 million or 24.6 million
Chinese Yuan]. This cost was split between the manufacturers of
clopidogrel (Bristol-Myers Squibb and Sanofi-Aventis) and of
metoprolol (AstraZeneca). The British Heart Foundation and UK
Medical Research Council also provided core staff and
infrastructure support to the CTSU. |
Q |
Is the study independent of the funders? |
A |
Yes. The idea for this study came from the principal
investigators in CTSU, following close discussion with Chinese
colleagues. The funding was provided as grants to Oxford
University, and the pharmaceutical companies had no say in the
running of the study, the analysis of the data, or the way the
results are presented, published or publicised. |
Q |
Were any other steps taken to ensure the
independence of the research? |
A |
Yes. An independent data monitoring committee, which did not
include anyone involved in the study, has been examining interim
results in confidence during recruitment to ensure that there
were no safety concerns. As no such issues arose during the
study, it continued until its scheduled end. |