Clinical Cardiology: New Frontiers
Cardiovascular medicine is undergoing extraordinary and
rapid transformation. Circulation intends to keep its
readership at the forefront of advances in our knowledge. Hence, in
this issue, we introduce a section entitled "Clinical
Cardiology: New Frontiers." Approximately once per
month, we will engage topics of a clinically relevant nature to
integrate new discoveries and knowledge into the armamentarium of the
clinical practitioner. We intend that these articles will
be helpful in influencing the thinking and clinical practice of
physicians. Our primary goal is to provide useful information and
practical advice on the management of contemporary clinical problems.
Eligible topics will be drawn from a wide range of areas, including
pathophysiology, diagnostic methods,
epidemiology, natural history, and therapy.
Because we aim to provide mechanistic insights and evaluate areas of
controversy and uncertainty, we will generally invite two key opinion
leaders to write articles in this section. Readers will note, however,
that they will be from different institutions so as to achieve both
diversity and balance. We welcome feedback on this new initiative.
Cardiovascular and Renal Advisory Panel of the
FDA
The Cardiovascular and Renal Advisory Panel of the FDA met on
October 23 and 24, 1997, to discuss the broad issue of evaluation of
active-control trials and to consider the platelet antagonist
clopidogrel.
Although the traditional basis for drug approval has included
demonstration of superiority to placebo in two trials, it is
increasingly recognized that under some circumstances, a
placebo-controlled trial is not feasible. In a half-day workshop,
issues related to conduct and analysis of active-control trials were
discussed. Placebo-controlled trials are usually designed to
demonstrate superiority over placebo, and lack of rigor in a
placebo-controlled trial generally reduces the chance of finding a
significant difference between treatment and placebo. Therefore, there
is a great incentive to conduct placebo-controlled trials rigorously.
By contrast, active-control trials may be designed to demonstrate
superiority or equivalence of a new treatment against a standard
treatment; demonstration of equivalence in an active-control trial may
arise because the two drugs are in fact equally effective or because
the trial was not designed or executed in a sufficiently rigorous
fashion to detect differences. Implicit in the design of active-control
trials are assumptions about the efficacy (and confidence intervals
[CIs] around that efficacy) of the comparator active drug.
Calculation of these values allows the investigators to estimate the
outcome that would be expected with a putative placebo in an
active-control trial. Under some circumstances, this estimate of the
outcome with a putative placebo may be used to estimate the efficacy of
the new treatment. However, the CIs for that estimate may be quite
wide. For these and other reasons, active-control trials may require
very large numbers of patients to demonstrate efficacy or superiority
to standard therapies. Although in theory it would be possible with
this methodology to find a treatment better than placebo but worse than
standard therapy, such a finding is unlikely, given the CIs around the
point estimates of the various outcomes.
The discussion of clopidogrel centered around many of the same issues,
because the primary basis for the new drug application was the results
of CAPRIE, a single trial involving more than 19 000 patients with
various forms of vascular disease randomly assigned to clopidogrel (75
mg/d) or to aspirin (325 mg/d).1 In CAPRIE, there was an
8.7% reduction in the incidence of the combined end point of ischemic
stroke, myocardial infarction, or vascular death (P=.043).
Patients who entered the trial because of myocardial infarction did
better with aspirin, whereas those entering with peripheral vascular
disease and stroke did better with clopidogrel. However, despite the
size of the trial, there was not enough power to be certain about the
reliability or generalizability of a differential treatment effect in
these subgroups. After discussion related to these issues, to the
questions of active-control trials outlined above, and to concerns
regarding the exact status of some patients at the end of the trial,
the committee decided, in a split vote, to recommend approval for the
use of clopidogrel in patients with vascular disease. The committee
further voted that despite the marginally significant P
value for the benefit of clopidogrel over aspirin, the evidence that
clopidogrel is actually superior to aspirin is not sufficient to be
confident. Conversely, the recommendation for approval was based on the
certainty that clopidogrel is better than placebo and meets all
reasonable criteria for being at least equivalent to aspirin.
References
© 1998 American Heart Association, Inc.
Cardiovascular News
Cardiovascular News
This article has been cited by other articles:
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  D. M. Roden and R. Temple The US Food and Drug Administration Cardiorenal Advisory Panel and the Drug Approval Process Circulation, April 5, 2005; 111(13): 1697 - 1702. [Full Text] [PDF]
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