September 1, 1995
NEW ANALYSES REGARDING THE SAFETY OF CALCIUM-CHANNEL
BLOCKERS:  A STATEMENT FOR HEALTH PROFESSIONALS FROM
THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
During the late summer and fall, three scientific papers are
being published in medical journals reporting new analyses
regarding the safety of calcium-channel blocking drugs. 
Anticipating the release of these data, the National Heart,
Lung, and Blood Institute (NHLBI) convened an Ad Hoc Panel
on Calcium-Channel Blockers in early June, 1995.  Based on
the presentations and discussions at this meeting, the
Institute has prepared this brief statement to provide a
perspective on the new information.
BACKGROUND
The calcium-channel blockers (CCBs), also called calcium
entry blockers and calcium antagonists, are a class of
vasodilating drugs first introduced into U.S. clinical
practice in 1980.  The main labeled indications for their
use are the treatment of arterial hypertension and of
chronic angina pectoris.  Their potential effects in
preventing, ameliorating, or retarding the progression of
other major cardiovascular conditions have also been
studied.  There are three sub-classes of CCBs that are
chemically distinct and have pharmacologic differences:  the
dihydropyridines (prototype--nifedipine), benzothiazepines
(diltiazem), and phenylalkylamines (verapamil).  In
addition, several CCBs have both short-acting (requiring
multiple daily doses) and long-acting (once daily) dosage
forms.  The latter have been introduced only in recent
years.
Concerns about the safety of some CCB drugs first drew
attention following the publication of several meta-analyses
during 1989-91 (1,2,3).  Using statistical methods for
pooling results of randomized clinical trials conducted in
patients following myocardial infarction (MI) or with stable
or unstable angina, these analyses suggested that CCBs of
the dihydropyridine sub-class (short-acting nifedipine in
all but a few of the long-term trials) increased the risk of
mortality (by about 16 percent) and reinfarction (by 19
percent).  Non-dihydropyridine CCBs (diltiazem, verapamil)
were associated with neither increased nor decreased
mortality, but pooled results tended toward lower rates of
nonfatal MI.
NEW ANALYSES
A publication in the September 1 issue of "Circulation" (4)
extends the meta-analyses just described to address the
question of dose-response.  In order to do so without
attempting to equate doses of different drugs, these
analyses were confined to the 16 trials of nifedipine in
patients with clinical coronary disease, mostly with acute
ischemic syndromes.  The trials were divided into six groups
according to the dose used in those randomized to nifedipine
treatment.  A dose-response relationship was observed, and
mortality was higher in nifedipine-treated patients compared
to placebo in trials that employed a dose of 80 mg daily or
greater.
Another study, focused on CCBs in the treatment of
hypertension, was published in the August 23/30 issue of the
"Journal of the American Medical Association" (5).  This is
the observational (case-control) study first reported by
Psaty et al. at an American Heart Association conference in
March, 1995 that was widely discussed in the lay press.  As
in all observational studies, the choice of drug for each
patient was determined by the treating physician based on
relevant aspects of the patient's medical condition, likely
including risk factors for MI, the cardiovascular (CV)
outcome addressed by the study.  The investigators attempted
to extract information on such confounding factors from the
medical records and control for them in their analyses; in
retrospective studies there is always some question about
the success of such efforts.  Two main comparisons were
carried out:  CCBs versus diuretics in relationship to MI
risk in patients free of CV disease according to the medical
record; and CCBs versus beta-blockers in patients both
without and with diagnosed CV disease (but not a prior MI or
heart failure).  The results showed a higher risk of MI (by
about 60 percent) associated with CCB use compared either
with diuretic or with beta-blocker treatment.  Further, the
higher the CCB dose, the greater the relative risk of MI
compared to each of the other drugs.  The higher risk of
CCBs compared to beta-blockers was seen in patients with and
without diagnosed CV disease.  When individual CCBs were
compared to beta-blockers, the MI risks were higher for
each--for nifedipine (by 31 percent), for diltiazem (by 63
percent), and for verapamil (by 61 percent)--but the
increased risk was statistically significant only for the
latter two drugs.  All of the CCBs in this study were in
short-acting formulations.  Note that the results with
diltiazem and verapamil in this population are at odds with
those of randomized trials in a post-MI population, a group
at high risk for recurrent MI, in which diltiazem and
verapamil have had either no effect on events or have shown
a favorable trend.  The different results could reflect the
different populations or could reflect failure to adjust
fully for coronary risk factors.
The third new study will be published in the "Journal of the
American Geriatrics Society" in November (6).  Like the
study by Psaty, it is observational in nature, based on
records collected for other research purposes.  This study
was conducted by Pahor, Guralnik, Havlik, and colleagues at
the National Institute on Aging in a sample of elderly
patients.  The analyses focused on risk of mortality in
patients prescribed single-drug treatment for hypertension,
comparing individual CCBs with beta-blockers.  Risk was
significantly higher for nifedipine, increased but not
significantly so for diltiazem, and not increased for
verapamil.  Here also, the investigators adjusted for other
CV risk factors to the extent possible.  Again, all of the
CCBs were of the shorter-acting type.
CLINICAL TRIALS IN HYPERTENSION
The last two studies described above are observational and
thus subject to all the potential biases of such study
designs.  Therefore, it is important to consider evidence
from randomized controlled trials in hypertensive patients. 
Unfortunately, the completed trials comparing CCBs to other
antihypertensive drugs or to placebo, such as the Treatment
of Mild Hypertension Study (7) and the Veterans
Administration Monotherapy Trial (8), included only 100-200
patients per treatment group, and therefore were not large
enough to reliably detect or exclude a beneficial or harmful
effect on MI rate or other CV events.  Reported but as-yet-
unpublished results from the Multicenter Isradipine Diuretic
Atherosclerosis Study (MIDAS), with about 450 patients in
each group, showed (with a small number of total events) a
trend toward a higher rate of CV events in the isradapine (a
dihydropyridine) compared to the diuretic group (9).
The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT) is a large-scale, long-term
randomized clinical trial to determine if the rate of
coronary heart disease death or nonfatal MI is reduced by
antihypertensive treatment with a CCB (amlodipine, an
inherently long-acting dihydropyridine), an angiotensin-
converting-enzyme inhibitor (lisinopril), or an alpha-1-
blocker (doxazosin) compared to a diuretic (chlorthalidone)
(10).  ALLHAT is sponsored by the NHLBI, in collaboration
with the Department of Veterans' Affairs and with support
from the pharmaceutical industry.  Enrollment of a study
population of 40,000 older men and women (approximately half
African American) is currently 25 percent complete. 
Followup is scheduled through the year 2002.
Other large trials involving CCBs are underway in Europe and
elsewhere.  Only two of these, centered in Scandinavia
(11,12), are comparing CCBs to other classes of
antihypertensive drugs and have largely enrolled their study
populations.  One involves shorter-acting dihydropyridine
CCBs (11); the other employs diltiazem (12).  These trials
differ from ALLHAT in other important respects, such as the
absence of a double-blind design.
POSSIBLE MECHANISMS OF ADVERSE EFFECTS
There are a number of mechanisms by which CCBs could
theoretically increase the risk of adverse CV outcomes in
some clinical situations.  The shorter-acting drugs can
cause reflex sympathetic stimulation, leading to increased
myocardial oxygen demand and potentiating arrythmogenesis
(13).  All CCBs are known to have negative inotropic effects
(14).  Some CCBs have anti-platelet actions, an effect that
has generally been viewed as likely to reduce MI risk. 
However, this action, together with vasodilatation, could
have led to the excess of hemorrhagic complications in a
recent trial in cardiac surgery patients (15).  Finally,
there is evidence for differential arterial vasodilation in
the setting of advanced coronary artery disease leading to a
redistribution of blood flow to smaller collateral vessels
(16).
CONCLUSIONS
Calcium-channel blockers are used in many millions of
patients in the United States and other countries.  They are
effective in relief of certain cardiac disorders--angina
pectoris (especially variant angina) and some arrhythmias,
and they are effective, well-tolerated agents for blood
pressure reduction.  Like most drugs, however, CCBs have
multiple effects.  As such, it is important to establish
whether the known benefits are accompanied by significant
risks, or conversely whether major morbidity and mortality
are reduced.  At present, the following conclusions seem
prudent and consistent with available information:
1)  With recognition of the likely biases of observational
studies, the apparent concordance of findings from
observational studies of hypertensive patients and
randomized trials in primarily acute MI and unstable angina
patients suggests that short-acting nifedipine should be
used with great caution (if at all), especially at higher
doses, in the treatment of hypertension, angina, and MI.
2)  Whether this conclusion should be generalized to any
other classes of CCBs, to other short-acting
dihydropyridines such as isradipine, or to longer-acting
dosage forms of nifedipine or other dihydropyridines is
unclear.  Verapamil and diltiazem were associated with
significantly increased MI risk in the University of
Washington case-control study in patients with hypertension,
but not in other studies, including well-designed clinical
trials in patients with MI, a group at high risk of
recurrent MI.
3)  The results of ongoing and possibly additional large-
scale randomized clinical trials in people with hypertension
are absolutely essential to the ultimate resolution of these
extremely important issues of safety and efficacy.  For
example, in ALLHAT a risk as large as that seen with CCBs in
the study by Psaty et al. could, if present, be detected
after only a few years of followup.
4)  Practitioners should be reminded that there are drugs
with unequivocal survival and other benefits in the post-
infarction and hypertensive settings.  Certain beta-blockers
in post-MI patients (17) are known to reduce mortality and
reinfarction;  in contrast, controlled trials of adequate
size of CCBs have not revealed such a benefit, and there is
no reason to use them in the post-infarction setting except
to treat symptoms.  Similarly, diuretics and beta-blockers
have reduced major cardiovascular events and mortality in
well-controlled trials in hypertension, while other agents
have not been adequately tested, leading "The Fifth Report
of the Joint National Committee on Detection, Evaluation,
and Treatment of High Blood Pressure" to recommend diuretics
and beta-blockers as preferred drugs for treating
hypertension (18).
5)  Uncertainties about the choice of drugs for the
treatment of hypertension should not detract from efforts to
achieve optimal blood pressure control, because it is clear
that lowering blood pressure is an effective strategy for
preventing stroke, MI, and other CV sequelae of
hypertension.
__________________________________________________
REFERENCES
1.  Held PH, Yusuf S, Furberg CD.  Calcium channel blockers
in acute myocardial infarction and unstable angina:  an
overview.  Br Med J. 1989;299:1187-1192.
2.  Yusuf S, Held P, Furberg.  Update of effects of calcium
antagonists in myocardial infarction or angina in light of
the second Danish Verapamil Infarction Trial (DAVIT-II) and
other recent studies.  Am J Cardiol. 1991;67:1295-1297.
3.  Glasser SP, Clark PI, Lipicky RJ, Hubbard JM, Yusuf S. 
Exposing patients with chronic, stable, exertional angina to
placebo periods in drug trials.  JAMA. 1991;265:1550-1554.
4.  Furberg CD, Psaty BM, Meyer JV.  Nifedipine: dose-
related increase in mortality in patients with coronary
heart disease.  Circulation. 1995; (in press).
5.  Psaty BM, Heckbert S, Koepsell T, Siscovick DS,
Raghunathan TE, Weiss NS, Rosendaal FR, Lemaitre RN, Smith
NL, Wahl PW, Wagner EH, Furberg CD.  The risk of myocardial
infarction associated with antihypertensive drug therapy. 
JAMA. 1995;274:620-625.
6.  Pahor M, Guralnick JM, Corti MC, Foley DJ, Carbonin P,
Havlik RJ.  Longterm survival and use of antihypertensive
medications in older persons.  J Am Geriatr Soc. 1995; (in
press).
7.  Neaton JD, Grimm RH Jr, Prineas RJ, Stamler J, Grandits
GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald
R, Lewis CE, Liebson PR; for the Treatment of Mild
Hypertension Study Research Group.  Treatment of Mild
Hypertension Study: final results.  JAMA. 1993;270-713-724.
8.  Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED,
Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J,
Ramirez EA, Henderson WG; for the DVA Cooperative Study
Group on Antihypertensive Agents.  Single-drug therapy for
hypertension in men: a comparison of six antihypertensive
agents with placebo.  N Engl J Med. 1993;328:914-921.
9.  McClellan K.  Unexpected results from MIDAS in
atherosclerosis [summary of results presented at the 15th
Scientific Meeting of the International Society of
Hypertension in Melbourne, Australia, March 1994].  Inpharma
Wkly. 1994;932-4.
10.  Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT,
Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM,
Alderman MH, Ford CE, Oparil S, Francis C, Proschan M,
Pressel S, Black HR, Hawkins CM; for the ALLHAT Research
Group.  Rationale and design for the Antihypertensive and
Lipid Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT).  Am J Hypertension. 1995; (in press).
11.  Dahlf B, Hansson L, Lindholm LH, Schirstn B, Wester
P-O, Ekbom T, Hedner T, Faire U de.  STOP-Hypertension 2: a
prospective intervention trial of newer versus older
treatment alternatives in old patients with hypertension:
Swedish Trial in Old Patients With Hypertension.  Blood
Press. 1993;2:136-141.
12.  The NORDIL Group.  The Nordic Diltiazem Study (NORDIL):
a prospective intervention trial of calcium antagonist
therapy in hypertension.  Blood Press. 1993;2:314-321.
13.  Ruzicka M, Leenen FHH.  Relevance of intermittent
increases in sympathetic activity for adverse outcome on
short-acting calcium antagonists.  In: JH Laragh, BM Breener
(eds): Hypertension.  Pathophysiology, Diagnosis and
Management.  New York: Raven Press, 1995; 2815-2825.
14.  Francis GS.  Calcium channel blockers and congestive
heart failure.  Circulation. 1991;83:336-338.
15.  Wagenknecht LE, Furberg CD, Hammon JW, Legault C,
Troost BT.  Surgical bleeding: unexpected effect of a
calcium antagonist.  B Med J. 1995;310:776-777.
16.  Egstrup K, Anderson PE.  Transient myocardial ischemia
during nifedipine therapy in stable angina pectoris, and its
relation to coronary collateral flow and comparison with
metoprolol.  Am J Cardiol. 1993;71:177-183.
17.  Yusuf S, Peto R, Lewis J, Collins R, Sleight P.  Beta
blockade during and after myocardial infarction: an overview
of randomized trials.  Prog Cardiovasc Dis. 1985;27:335-371.
18.  Joint National Committee on Detection, Evaluation, and
Treatment of High Blood Pressure.  The Fifth Report of the
Joint National Committee on Detection, Evaluation and
Treatment of High Blood Pressure (JNC V).  Arch Intern Med.
1993;153:154-183.
.