Review: Nifedipine for hypertension may not increase the risk for adverse cardiovascular events
ACP J Club. 1998 Jan-Feb;128:2. doi:10.7326/ACPJC-1998-128-1-002
Stason WB, Schmid CH, Niedzwiecki D, et al. Safety of nifedipine in patients with hypertension. A meta-analysis. Hypertension. 1997 Jul;30:7-14.
To determine, using meta-analysis, the safety of nifedipine in patients with hypertension and to assess the adverse cardiovascular events in patients receiving nifedipine compared with other active drugs.
Studies identified with MEDLINE (1966 to August 1995) by using the terms hypertension and nifedipine, Current Contents, and bibliographies of relevant studies.
Randomized controlled trials that studied > 10 patients with mild or moderate hypertension, were published in peer-reviewed journals, compared any formulation of nifedipine with nondihydropyridine agents or placebo, and reported adverse events by study group.
Data were extracted on study quality, adverse events, study drugs, duration of treatment, and drug regimens. Definitive adverse events were death, nonfatal acute myocardial infarction, nonfatal stroke, and revascularization. The nondefinitive adverse event was increased angina.
98 trials were included with 9506 patients. Nifedipine was studied in 5198 treatment exposures (3451 monotherapy), other drugs in 5402 exposures (3617 monotherapy), and placebo in 420 exposures. Definitive adverse events were similar (9 events with nifedipine vs 19 with other agents). The results were similar for nifedipine used as monotherapy for all events (12 with nifedipine vs 9 with other agents) and for definitive events (8 with nifedipine vs 6 with other agents).
When nifedipine was used in combination therapy, both total events (2 with nifedipine vs 15 with other agents) and definitive events were decreased (1 with nifedipine vs 13 with other agents) (Table). Study withdrawals were higher in patients who received nifedipine. This pattern of withdrawal was similar when analysis was done for monotherapy or combination therapy.
When nifedipine is used as part of combination therapy for patients with hypertension, cardiovascular events are reduced, although withdrawal rates are higher. Events are not reduced when nifedipine is used as monotherapy.
Sources of funding: Pfizer, Inc.; US Pharmaceuticals Group; Bayer AG, Pharmaceutical Business Group.
For article reprint: Dr. W.B. Stason, 29 Sandy Pond Road, Lincoln, MA 01773, USA. FAX 617-636-8023.
Table. Definitive cardiovascular events associated with nifedipine plus other drugs vs other active drugs for hypertension*
|Nifedipine plus other drugs weighted EER||Other active drugs weighted CER||RRR||Weighted ARR||NNT (95% CI)|
|0.06%||0.66%||86%||0.6%||136 (153 to 369)|
*Abbreviations defined in Glossary; RRR, ARR, NNT, and CI calculated from data in article.
The meta-analysis by Stason and colleagues evaluated event reduction in patients treated with nifedipine alone or combined with other antihypertensive agents for a median of 8 weeks. It is questionable whether such short-term results can be extrapolated to a lifetime of antihypertensive therapy. The results suggested that combination therapy containing nifedipine was better than other comparison therapies. The blood pressure reduction was, however, not reported. If the other therapy resulted in less adequate blood pressure control, more events might be expected in the other group. Differences in blood pressure between groups is possible because many of these studies were designed to show the potency of nifedipine.
Most of the data on combination therapy were not directly comparable: 12 trials compared combination therapy, whereas 27 contained data on combination therapy in only some study groups. Because only 14 definitive cardiovascular events were found in the 39 combination therapy trials, the results may be spurious. A meta-analysis of trials that are larger and have longer follow-up periods would be more convincing.
Nifedipine, especially the short-acting formulations, causes reflex tachycardia by increasing sympathetic tone (1). High sympathetic tone is associated with increased mortality in patients with coronary syndromes and heart failure. This may be the reason that treating unstable angina with nifedipine (≥ 60 mg/d) was associated with increased mortality (2). In this study, for every 41 patients who were treated with nifedipine, 1 additional death occurred (number needed to harm) (CI 20 to 185). Because many of our patients with hypertension develop acute coronary syndromes, do we wish them to have high sympathetic tone?
We are free to choose antihypertensive therapy. We can choose antihypertensive treatments that decrease sympathetic tone, such as angiotensin-converting enzyme inhibitors. Nifedipine need not be first-line therapy.
Finally, these data do not apply to the heart rate-lowering calcium channel blockers mibefridil, diltiazem, and verapamil.
Christopher Rembold, MD
University of Virginia Health Science CenterCharlottesville, Virginia, USA