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From the Division of Cardiology and the Division of General Internal
Medicine, Department of Medicine, Duke University Medical Center and Health
Systems, Durham, NC.
Correspondence to Robert M. Califf, MD, Director, Duke Clinical Research Institute, 2024 W Main St, Durham, NC 27705.
Hundreds
of thousands of patients around the world have been treated with drugs
that antagonize the function of calcium channels. The development of
these drugs was based on the remarkable scientific discovery of calcium
channels, the identification of methods to antagonize their effects,
and the development of compounds to block
them.1 2 As concepts of the pathophysiology and
treatment of hypertension and atherosclerosis evolved
in parallel with the science of calcium channels, an approach to
determining whether these therapies have clinical benefit was
developed.
In the treatment of hypertension, the strategy for therapeutic
evaluation has been based on the simple concept that lowering blood
pressure will result in a decrease in the incidence of stroke,
myocardial infarction, renal failure, and death.2
In the treatment of angina, a more complex set of concepts has
prevailed. Three factors have formed the framework for evaluating
therapies for angina: (1) the role of coronary vasospasm in the
production of myocardial
ischemia,3 (2) the belief that reduction
in myocardial ischemia over a specified time interval or
improvement in exercise time on a treadmill provided strong evidence of
an overall health benefit,4 and (3) more
difficult extrapolations related to preservation of cellular function
during myocardial ischemia.5 The
synthesis of these factors has led to the acceptance of a
reduction in frequency of angina or an improvement in exercise time as
adequate evidence of a desirable clinical benefit of a therapy for
angina.
On the basis of these constructs, a variety of compounds were developed
that had disparate properties but the common action of antagonizing
calcium channels. Regulatory authorities in the United States and other
countries approved these agents for clinical use on the basis of their
pathophysiological constructs, relying on evidence
that they lowered blood pressure or improved exercise time. Hundreds of
small, carefully conducted, randomized trials of these compounds have
been completed, but many of them (especially those with negative
results6) have never been reported in the medical
literature. The vast majority of these studies evaluated uncomplicated
patients who could reasonably be expected to complete the trial without
clinical events or poor outcomes related to comorbidity. When released
for clinical use, the drugs contained careful labeling restricting them
to the populations and indications for which they had been shown to be
effective. Aided by the opinions of influential thought
leaders,7 clinicians have attempted to
extrapolate the findings of these small, carefully controlled studies
to more general populations, including patients with complex, high-risk
coronary disease and multiple comorbidities.
Only after the early calcium channel blocking agents had been marketed
for some time did an initial warning signal come from several
publications. An association was reported between short-acting
nifedipine and an increased incidence of adverse myocardial
ischemic events;8 this concern was
reinforced by regulatory authorities.9 A
systematic overview of postinfarction therapies echoed their
concern.1 Several studies subsequently
demonstrated that these agents carried significant risk in patients
with left ventricular
dysfunction.10 11 Despite these publications,
short-acting nifedipine continued to be widely prescribed,
other calcium channel blockers were broadly used in patients with left
ventricular dysfunction, and no action was taken to
restrict them. Then, after a hiatus, a case-control
study12 raised the possibility that calcium
channel blockers could result in substantial mortality and morbidity in
a general population with hypertension, especially in contrast to other
logical therapeutic choices. Since then, a substantial public
controversy has erupted,13 14 raising questions
about medical practice, science, business, and the role of government
in the regulation of therapies for chronic, life-threatening illnesses.
Many interesting questions have arisen about whether all these agents
produce the same clinical outcomes and the mechanisms by which their
effects on clinical outcomes differ. A critical question with
implications far beyond the specific use of calcium channel blockers is
why well-intentioned physicians continue to prescribe a class of drug
to thousands of patients every year in the absence of a clear
understanding of their effects on the health of the patients for whom
they are prescribed.
The most recent study, by Michels and
colleagues,15 in conjunction with other recent
publications,16 points out the complexity of the
evidence that we must consider before deciding whether calcium channel
blockers as a class, or any individual calcium channel blocker, are
deleterious or beneficial to the overall health of patients. In 14 617
nurses participating in the Nurses' Health Study who had a diagnosis
of hypertension, those taking calcium channel blockers had higher rates
of death and myocardial infarction than nurses prescribed another class
of drug. However, the group of nurses on calcium channel blockers were
also more likely to have diagnosed coronary disease, diabetes,
prior myocardial infarction, and prior stroke.
It is fascinating to note that in such a highly educated patient
population, nurses with a higher risk of cardiovascular
events had a higher rate of use of calcium channel blockers than nurses
with a lower risk, despite extensive coverage of the controversy in the
medical literature. This finding of more calcium channel blocker use in
higher-risk nurses makes interpretation of the worse outcomes in the
nurses who were treated with calcium channel blockers difficult. The
authors appropriately conclude that investigators are unlikely to
resolve the question of whether short-acting calcium channel blockers
have deleterious effects with observational studies, despite their many
years of use in clinical practice, and that only with ongoing direct
comparative studies will the impact of these agents on important
clinical outcomes be determined.
This study raises the important question of why we have definitive
clinical outcome information about therapies in some conditions, such
as acute myocardial infarction, whereas we have almost no such
information about the overall health effects of most commonly used
therapies. Definitive information about the mortality effects of ACE
inhibitors and ß-blockers guides the clinician in the
treatment of ischemic heart disease, yet there is no reasonable
long-term information on medical outcomes from adequate randomized
trials about the treatment of type II diabetes, obesity, asthma,
depression, or comparative therapies for hypertension. In each of these
conditions, significant damage could be done by commonly used therapies
prescribed by well-intentioned physicians. The clinical benefit of
effective therapies, on the other hand, may be minimized by a lack of
adequate outcome data to present a compelling need for
treatment.
Whose responsibility is it to ensure that appropriate studies are done?
We believe that when physicians and other healthcare providers take the
lead in pointing out the need for adequate outcome data and in
providing the mechanisms to obtain these data, as the ISIS
investigators did with acute myocardial infarction
treatment,17 the other constituents will
collaborate to obtain the desired information.
An examination of the roles of the major participants in clinical
research provides considerable insight into the reasons for significant
progress toward knowledge of outcomes in some areas but not others.
Clinical research involving human experimentation has designated roles
for healthcare providers, regulatory authorities, and a sponsor,
usually either the government or the medical products industry. In
some situations it is considered the norm to conduct clinical trials
designed to determine the impact of the treatment on clinical outcomes,
including death and adverse events such as stroke and heart failure. In
other situations, such as the evaluation of calcium channel blockers in
the treatment of hypertension and angina, clinical investigation has
stopped with the measurement of pathophysiological
surrogates (blood pressure) or clinical measurements that reflect a
short-term outcome (exercise treadmill time).
When the regulatory process does not demand true clinical outcome
information before a therapy is marketed, two common misconceptions
ensue. The first is that government funding will be available through
the National Institutes of Health or the Agency for Health Care Policy
and Research to ensure that the therapy is beneficial. The second is
that physicians and patients will be able to discern that a treatment
is detrimental from their experience with its use in their personal
practices. Unfortunately, however, the government is unable to support
the amount of clinical research that needs to be done to determine
which therapies are beneficial and which are detrimental. And, as we
have learned the hard way, prophylactic therapies in
cardiovascular disease cannot be assessed by the
impressions of individual
practitioners.18 19 Even if an
adequate sample size existed in an individual
practitioner's office, and usually it does not, the
complexity of chronic disease outcomes makes it very unlikely that a
modest but clinically very important increase in mortality would be
discernible. The recent "fen-phen" diet drug problem is an
excellent example of the failure to detect a deleterious effect before
marketing. The harm was initially detected by astute observers because
of the severity of the defect it caused, but only after thousands of
patients had been treated.20
The medical products industry is appropriately concerned with
making a profit to report to its shareholders. This capitalistic
approach produces considerable reward for creative endeavor and should
be continued. If regulatory groups do not require long-term clinical
outcome data in the broad population of patients in whom the treatment
is likely to be used, industry is faced with a choice between
performing definitive and expensive clinical outcome studies and doing
less expensive, small, complicated studies addressing surrogates or
mechanisms. The clinical outcome study, such as a mortality trial or a
stroke prevention study, is attractive when it is positive, but a
negative trial creates a significant commercial risk. By comparison, a
series of small studies aimed at pathophysiology, coupled with support
of small research and educational programs by academic leaders, creates
a less definitive, less expensive, and less risky approach to
product development. These inadequate studies then leave the
academic community suspect when leaders advocate one therapy or another
without definitive clinical outcome
support.21
Why would regulatory authorities not demand definitive evidence
about whether a drug increases the risk of mortality or stroke when
prescribed for hypertension and angina? Regulatory authorities meet
historical standards, set by legislative bodies, for determining safety
and efficacy, and they are charged with labeling therapies for the
context in which they were studied. Most calcium channel blockers are
labeled to lower blood pressure in patients with hypertension or to
improve exercise tolerance in patients with angina. If they were not
studied in a trial large enough to produce reliable estimates about
their effect on mortality, they cannot be labeled to indicate whether a
mortality effect, positive or negative, is present. The fact that
this labeling leaves open the question of how to use the therapies in
the millions of patients with angina or hypertension and left
ventricular dysfunction or another comorbid condition
represents a flaw in the interface between the regulatory
system and the practice of medicine.
Perhaps this gap would be much smaller if physicians and other
healthcare providers became more knowledgeable about these issues with
regard to therapies that are commonly prescribed. Our willingness to
accept short-term measures of outcome in narrowly focused patient
populations and to broadly extrapolate them to much more diverse
patient populations has created a situation in which most of the
therapies for chronic diseases have never been assessed for their
overall health outcomes. Until the past decade, the concept of large
outcome studies would have been considered a dream. The advent of
global communication through computers and the development of large,
simple trial methodology have provided a realistic possibility for
adequate studies by allowing the rapid enrollment of patients around
the world to achieve adequate sample sizes to assess clinical
outcomes.
The remaining impediments to the implementation of adequate clinical
trials measuring outcomes fall into two categories: cultural and
financial. Until recently, clinical investigation was regarded as an
endeavor for specialists in academic settings, and the concept of
randomizing patients in practice seemed unreasonable. The ISIS
investigators22 and
others23 have demonstrated both the desirability
and the feasibility of changing this culture. Practitioners
gain a different perspective when they recognize that prescribing a
therapy in the absence of knowledge about its potential for benefit or
harm is an irresponsible experiment compared with encouraging a patient
to participate in a randomized trial that will provide that
information. If practitioners incorporated clinical
research into their clinical practices in hopes of creating a system to
constantly improve the understanding of therapies and the diseases they
were designed to treat, the cost of doing clinical trials would
diminish, and both patients and practitioners would be much
better off. The continuing acceptance of common nomenclature
and clinical information systems provides a mechanism to dramatically
reduce the cost of trials. Such an approach would have the further
benefit of identifying therapies that could be discarded for lack of
effectiveness, leaving more funding for therapies that are truly
beneficial to patients.
Patients expect their doctors to know whether the therapy they
recommend will be helpful or harmful. Doctors can no longer claim that
the methodology to determine the overall health effects of a given
therapy is not feasible. Large, randomized trials assessing therapies
for common chronic diseases such as hypertension need to happen sooner
rather than later in the development of new therapies, and these same
types of trials are needed to identify the older therapies that are
truly beneficial. Fortunately, several such trials are now ongoing in
the field of hypertension. Given our current knowledge of the fallacy
of surrogate outcome measures and the difficulty of interpreting
confounded observational analyses, it is imperative for
practitioners to become producers of the evidence for
evidence-based medicine and not just consumers of the evidence. In this
modern era, in which the possibilities for medical care exceed
society's willingness to pay, it is vital to the interest of our
patients that we admit that gaining definitive knowledge about the
therapies we prescribe is our professional responsibility. Until we
shoulder that responsibility, our patients will suffer needlessly from
damage done by the overuse of detrimental but inadequately understood
therapies and the underuse of beneficial but inadequately understood
therapies. In the case of calcium channel blockers, many years and
thousands of patients later we still do not know which problem, overuse
or underuse, we have created.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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Editorials
What Have We Learned From the Calcium Channel Blocker Controversy?
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