Calcium channel blockers inferior to cheaper drugs
BMJ 2000; 321 doi: https://doi.org/10.1136/bmj.321.7261.590 (Published 09 September 2000) Cite this as: BMJ 2000;321:590
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Your NEWS article (BMJ 2000;321:590) "Calcium channel blockers
inferior to cheaper drugs" seems to have been taken directly from the
press release by the investigators from the Wake Forest University School
of Medicine. Nowhere is the lesser incidence of stroke with CCBs and the
equality of total mortality between CCBs and other drugs mentioned.
Moreover, the inappropriate inclusion of flawed data in this meta-analysis
should be contrasted with the more careful and complete meta-analysis
presented by S. MacMahon and B. Neal at the International Society of
Hypertension on 24 August 2000. Since it was not hyped by press releases,
Ms. Johnson probably was unaware of their balanced results.
But Deborah Johnson went even further. She falsely accuses CCBs as
being inferior to other antihypertensives in elderly patients with
diabetes and systolic hypertension, referring incorrectly to two papers.
The first, by Tuomilehto et al (N Eng J Med 1999;340:677-684) shows
exactly the opposite: CCBs in the Syst-Eur trial provided better
protection than did diuretics in the SHEP trial. The second paper (Curb et
al JAMA 1996;276:1886-1892) is the SHEP data with nary a CCB in sight.
At the least, you should insist on as much accuracy in your NEWS as
in your articles.
Norman M Kaplan, MD
Professor of Medicine
The University of Texas, Southwestern Medical Centre, 5323 Harry Hines
Blvd., J4, 134/Dallas, Texas
Email: ronald.victor@email.swmed.edu
Competing interests: No competing interests
Editor
We read with concern the article by Deborah Josefson in the news
section of the recent BMJ entitled "Calcium channel blockers inferior to
cheaper drugs" 1, which highlighted the belief that calcium channel
blockers may be less effective in elderly patients with diabetes and
systolic hypertension. We are particularly worried that not only was the
article inaccurate, but that it may be misinterpreted by the lay press, as
has happen previously 2, leading to widespread concern among patients and
sometimes discontinuation of antihypertensive treatment without proper
medical supervision and advice.
Both diabetes and isolated systolic hypertension (ISH) are associated
with a high risk of cardiovascular events. Two recent placebo-controlled
studies have shown, unequivocally, that reduction of blood pressure in
elderly patients with ISH reduces cardiovascular morbidity and mortality.
The first of these, the SHEP study, used a diuretic-based regime and the
second, the Syst-Eur trial, the long-acting dihydropyridine calcium
channel blocker nitrendipine. In her article, Deborah Josefson
incorrectly sates that calcium channel blockers are less effective in
patients with diabetes and systolic hypertension and references a subgroup
analysis of the Syst-Eur study 3. As the Syst-Eur study was placebo-
controlled, it is impossible to draw any conclusions as to the relative
efficacy of calcium channel blockers compared with other agents in older
patients with ISH. Moreover, the subgroup analysis actually demonstrated
a greater reduction in cardiovascular mortality amongst the 492 diabetic
patients included in the trial 3. Interestingly, a similar observation
was also made in the SHEP study, which included 583 diabetic patients, who
had a 34% reduction in cardiovascular disease compared with the placebo
group 4.
To date, there have been no comparative studies of antihypertensive
therapy in elderly patients with ISH, with or without diabetes mellitus.
However, the STOP-2 trial 5, which studied a large cohort of elderly
patients with hypertension, defined as a systolic pressure >180 and/or
diastolic >105 mmHg, compared a conventional (diuretic/b blocker)
regime against "modern" therapy with an angiotensin converting enzyme
inhibitor or a calcium channel blocker. At the end of the study there was
no significant difference in the primary endpoint of cardiovascular
mortality between the two groups.
Therefore, in agreement with the authors of the Syst-Eur study, we
believe that the current evidence does not support the hypothesis that the
use of long-acting calcium channel blockers is deleterious in elderly
hypertensives. However, we would agree that the important issue of
potential differences in efficacy between antihypertensive drugs in the
elderly and patients with diabetes does deserve specific attention in
future large, randomised, controlled trials.
JR Cockcroft
Senior Lecturer
Wales Heart Research Institute, UWCM,
Cardiff.
IB Wilkinson
Senior Lecturer
Dept Clinical Pharmacology, Addenbrooke's,
Cambridge.
Reference List
1. Josefson D. Calcium channel blockers inferior to cheaper drugs.
Br.Med.J 2000;321:590.
2. Leonard, S. 1M Take 'wrong' high blood pressure drug. Times
Sunday, March 19. 2000.
3. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R,
Bulpitt CJ et al. Effects of calcium-channel blockade in older patients
with diabetes and systolic hypertension. N.Engl.J Med. 1999;340:677-84.
4. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H
et al. Effect of diuretic-based antihypertensive treatment on
cardiovascular disease risk in older diabetic patients with isolated
systolic hypertension. JAMA 1996;276:1886-92.
5. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B
et al. Randomised trial of old and new antihypertensive drugs in elderly
patients: cardiovascular mortality and morbidity the Swedish Trial in Old
Patients with Hypertension-2 study. Lancet 1999;354:1751-6.
Competing interests: No competing interests
Author's reply
The literature on calcium channel blockers and the optimal
pharmaceutical
treatment for hypertension is long and contentious and a full analysis of
the
literature is beyond the scope of a regular news piece and of this reply.
Clearly antihypertensive therapy is complex and dependent on the side
effect
profiles of various medications as well as concurrent patient disease, and
patient lifestyle.
Dr Kaplan should realize that in my role as a reporter, I was merely
reporting on a study and not necessarily promoting or defending any result
of
the study. Moreover, I have no interest, vested or otherwise, in the study
results. Since the Wake Forest study had not yet been published ( it was
presented at a meeting) and I lacked a paper to scrutinize, I was
admittedly
limited in my ability to analyze the data, and based my report on an
interview with Dr Pahor and the press release.
Nonetheless, a look at the literature on Calcium channel blockers
(CCB's)reveals multiple studies showing them inferior to other
antihypertensives in preventing some of the cardiovascular complications
of
hypertension, and moreover, concern has been raised that a financial
incentive may be at work because they are heavily promoted over cheaper
and
arguably at least equally effective if not more effective blood pressure
medications. (N Engl J Med 1998;338:101-6.)
Some of these studies single out short acting CCB's and
dihydropyridine
deriviatives as the culprits. Most people agree that CCB's are effective
antihypertensives and superior to placebo in reducing blood pressure and I
would not mean to suggest that patient on them abandon their therapy.
However, many meta-analyses have shown that when compared with other
antihypertensives, such as ACE-Inhibitors, B-blockers , thiazides and loop
diuretics, patients on them have a higher relative risk of events such as
heart attacks and stroke.
(EG At an American Heart Association meeting, Psaty et al. presented
a
case-control study assessing the association between myocardial infarction
and antihypertensive therapies. ( Psaty BM, Heckbert SR, Koepsell TD, et
al.
The risk of incident myocardial infarction associated with anti-
hypertensive
drug therapies. Circulation 1995;91:925. As compared with diuretics and
beta-blockers, short-acting calcium-channel blockers were associated with
a
60 percent increase in the risk of myocardial infarctions) The ABCD trial
compared Nisoldipine, a CCB ,with the ACE Inhbitor Enalapril in patients
with
both NIDDM and hypertension and also found a greater incidence of heart
attack with them. The MIDAS study suggested that the CCB isradapine is
associated with more strokes and cardiovascular complications than
hydrochlorothiazide.The abstracts for these studies are below.
Finally, I
acknowledge a mixup wabout the Tuomileto paper - but Dr Kaplan is equally
befuddled, as he accuses me of citing the SHEP trial by Curb et al(JAMA
1996:
276:1886-1892) when I made no mention of it. He seems to have confused
this
citation with that of the MIDAS trial. Moreover, Dr Kaplan fails to point
out
that in the work done by Tuomilheto et al. nitredipine therapy is not
completely segregated from HCTZ and ACEI therapy - so that many of the
patients analyzed are on both the CCB and enalapril and /or
hydrochlorothiazides and thus the results may be confounded.
Deborah Josefson, M.D., ABIM, ABPath
Abstracts below
--------------------------------------------------------------------------
----
Raymond O. Estacio, Barrett W. Jeffers, William R. Hiatt, Stacy L.
Biggerstaff, Nancy Gifford, Robert W. Schrier
Abstract
Background. It has recently been reported that the use of calcium-channel
blockers for hypertension may be associated with an increased risk of
cardiovascular complications. Because this issue remains controversial, we
studied the incidence of such complications in patients with
non-insulin-dependent diabetes mellitus and hypertension who were randomly
assigned to treatment with either the calcium-channel blocker nisoldipine
or
the angiotensin-converting-enzyme inhibitor enalapril as part of a larger
study.
Methods. The Appropriate Blood Pressure Control in Diabetes (ABCD)
Trial is a
prospective, randomized, blinded trial comparing the effects of moderate
control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with
those of intensive control of blood pressure (target diastolic pressure,
75
mm Hg) on the incidence and progression of complications of diabetes. The
study also compared nisoldipine with enalapril as a first-line
antihypertensive agent in terms of the prevention and progression of
complications of diabetes. In the current study, we analyzed data on a
secondary end point (the incidence of myocardial infarction) in the
subgroup
of patients in the ABCD Trial who had hypertension.
Results. Analysis of the 470 patients in the trial who had
hypertension
(base-line diastolic blood pressure, greater than or equal to 90 mm Hg)
showed similar control of blood pressure, blood glucose and lipid
concentrations, and smoking behavior in the nisoldipine group (235
patients)
and the enalapril group (235 patients) throughout five years of follow-up.
Using a multiple logistic-regression model with adjustment for cardiac
risk
factors, we found that nisoldipine was associated with a higher incidence
of
fatal and nonfatal myocardial infarctions (a total of 25) than enalapril
(total, 5) (risk ratio, 9.5; 95 percent confidence interval, 2.3 to 21.4).
Conclusions. In this population of patients with diabetes and
hypertension,
we found a significantly higher incidence of fatal and nonfatal myocardial
infarction among those assigned to therapy with the calcium-channel
blocker
nisoldipine than among those assigned to receive enalapril. Since our
findings are based on a secondary end point, they will require
confirmation.
(N Engl J Med 1998;338:645-52.)
Final outcome results of the Multicenter Isradipine Diuretic
Atherosclerosis
Study (MIDAS). A randomized controlled trial.
Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M,
Carr AA,
Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG
Department of Internal Medicine, School of Medicine, University of
California
at Davis, USA.
OBJECTIVE: To compare the rate of progression of mean maximum intimal
-medial
thickness (IMT) in carotid arteries, using quantitative B-mode ultrasound
imaging, during antihypertensive therapy with isradipine vs
hydrochlorothiazide. DESIGN: Randomized, double-blind, positive-controlled
trial.
SETTING: Nine medical center clinics. POPULATION: A total of 883
patients with baseline mean +/- SD systolic and diastolic blood pressure
(SBP
and DBP, respectively) of 149.7 +/- 16.6 and 96.5 +/- 5.1 mm Hg, age of
58.5
+/- 8.5 years, and maximum IMT of 1.17 +/- 0.20 mm.
INTERVENTIONS: Twice
daily doses of isradipine (2.5-5.0 mg) or hydrochlorothiazide (12.5-25
mg).
MAIN OUTCOME MEASURE (PRIMARY END POINT): Rate of progression of mean
maximum
IMT in 12 carotid focal points over 3 years.
RESULTS: There was no
difference
in the rate of progression of mean maximum IMT between isradipine and
hydrochlorothiazide over 3 years (P=.68). There was a higher incidence of
major vascular events (eg, myocardial infarction, stroke, congestive heart
failure, angina, and sudden death) in isradipine (n=25; 5.65%) vs
hydrochlorothiazide (n=14; 3.17%) (P=.07), and a significant increase in
nonmajor vascular events and procedures (eg, transient ischemic attack,
dysrhythmia, aortic valve replacement, and femoral popliteal bypass graft)
in
isradipine (n=40; 9.05%) vs hydrochlorothiazide (n=23; 5.22%) (P=.02). At
6
months, mean DBP decreased by 13.0 mm Hg in both groups, and mean SBP
decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in
isradipine
(P=.002); the difference in SBP between the 2 groups persisted throughout
the
study but did not explain the increased incidence of vascular events in
patients treated with isradipine.
CONCLUSION: The rate of progression of
mean
maximum IMT in carotid arteries, the surrogate end point in this study,
did
not differ between the 2 treatment groups. The increased incidence of
vascular events in patients receiving isradipine compared with
hydrochlorothiazide is of concern and should be studied further.
Final outcome results of the Multicenter Isradipine Diuretic
Atherosclerosis
Study (MIDAS). A randomized controlled trial.
Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M,
Carr AA,
Kappagoda T, Rocco MV, Schnaper HW, Sowers JR, Bond MG
Department of Internal Medicine, School of Medicine, University of
California
at Davis, USA.
OBJECTIVE: To compare the rate of progression of mean maximum intimal
-medial
thickness (IMT) in carotid arteries, using quantitative B-mode ultrasound
imaging, during antihypertensive therapy with isradipine vs
hydrochlorothiazide. DESIGN: Randomized, double-blind, positive-controlled
trial.
SETTING: Nine medical center clinics. POPULATION: A total of 883
patients with baseline mean +/- SD systolic and diastolic blood pressure
(SBP
and DBP, respectively) of 149.7 +/- 16.6 and 96.5 +/- 5.1 mm Hg, age of
58.5
+/- 8.5 years, and maximum IMT of 1.17 +/- 0.20 mm.
INTERVENTIONS: Twice
daily doses of isradipine (2.5-5.0 mg) or hydrochlorothiazide (12.5-25
mg).
MAIN OUTCOME MEASURE (PRIMARY END POINT): Rate of progression of mean
maximum
IMT in 12 carotid focal points over 3 years.
RESULTS: There was no
difference
in the rate of progression of mean maximum IMT between isradipine and
hydrochlorothiazide over 3 years (P=.68). There was a higher incidence of
major vascular events (eg, myocardial infarction, stroke, congestive heart
failure, angina, and sudden death) in isradipine (n=25; 5.65%) vs
hydrochlorothiazide (n=14; 3.17%) (P=.07), and a significant increase in
nonmajor vascular events and procedures (eg, transient ischemic attack,
dysrhythmia, aortic valve replacement, and femoral popliteal bypass graft)
in
isradipine (n=40; 9.05%) vs hydrochlorothiazide (n=23; 5.22%) (P=.02). At
6
months, mean DBP decreased by 13.0 mm Hg in both groups, and mean SBP
decreased by 19.5 mm Hg in hydrochlorothiazide and 16.0 mm Hg in
isradipine
(P=.002); the difference in SBP between the 2 groups persisted throughout
the
study but did not explain the increased incidence of vascular events in
patients treated with isradipine.
CONCLUSION: The rate of progression of
mean
maximum IMT in carotid arteries, the surrogate end point in this study,
did
not differ between the 2 treatment groups. The increased incidence of
vascular events in patients receiving isradipine compared with
hydrochlorothiazide is of concern and should be studied further.
Competing interests: No competing interests