(Hypertension. 1997;30:7-14.)
© 1997 American Heart Association, Inc.
Articles |
Safety of Nifedipine in Patients With Hypertension
A Meta-Analysis
From the Harvard School of Public Health (W.B.S.); MetaWorks, Inc (W.B.S., D.N., G.W.W., D.L., S.D.R., T.C.C.); Tufts University/New England Medical Center (C.H.S.); and Tufts University (T.C.C.), Boston, Mass.
Correspondence to William B. Stason, MD, MS, 29 Sandy Pond Rd, Lincoln, MA 01773.
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Abstract |
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Abstract Our objective was to compare cardiovascular event rates in patients with mild or moderate hypertension who received nifedipine with active drug controls. We performed a MEDLARS search using the MeSH heading "hypertension" and the text word "nifedipine" to identify all articles that were published between 1966 and August 1995 in English, French, German, Italian, and Spanish languages and that involved human subjects. The computerized search was supplemented by a manual search of article bibliographies. Review of 1880 citations revealed 98 randomized controlled clinical trials that met protocol criteria. Articles were extracted independently by two doctors who were blinded for author, institution, and treatment regimen, using a structured, pretested extraction form. Differences of opinion were resolved by consensus. Fourteen events occurred in 5198 exposures (0.27%) to nifedipine and 24 events in 5402 exposures (0.44%) to other active drug controls. Unadjusted odds ratios for nifedipine versus controls were 0.49 (95% confidence interval [CI], 0.22-1.09) for definitive events (death, nonfatal myocardial infarction or stroke, revascularization procedure) and 0.61 (95% CI, 0.31-1.17) for all events (definitive plus increased angina). The odds ratio for nifedipine monotherapy (sustained- or extended-release in 91% of exposures) was nonsignificantly higher for definitive and all events (odds ratio, 1.40; 95% CI, 0.49-4.03 and odds ratio, 1.39; 95% CI, 0.59-3.32, respectively). The odds ratio for nifedipine in combination with another drug was significantly lower for definitive and all events (odds ratio, 0.09; 95% CI, 0.01-0.66 and odds ratio, 0.15; 95% CI, 0.03-0.65, respectively). Differences in odds ratio for nifedipine monotherapy and combined therapy were statistically significant (P=.02 for definitive events and P=.001 for all events). Results support the safety of sustained- and extended-release nifedipine in the treatment of mild or moderate hypertension when it is used in combination with other drugs.
Key Words: nifedipine • meta-analysis • safety
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Introduction |
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Calcium channel blockers, including nifedipine, are widely used for the management of hypertension.1 2 Sustained- and extended-release nifedipine, alone or in combination with other agents, has been approved by the US Food and Drug Administration for the treatment of hypertension and has been endorsed in guidelines for the treatment of mild and moderate hypertension written by the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure.3
Two recent studies, however, have questioned the safety of calcium channel blockers in general and immediate-release nifedipine in particular. A meta-analysis of randomized controlled trials of nifedipine involving patients with myocardial infarction (9039 subjects in 12 trials) or unstable angina (1226 subjects in three trials) and subjects undergoing coronary angiography (425 subjects in one trial) concluded that the use of immediate-release nifedipine was associated with a significant, dose-related increase in mortality.4 A population-based case-control study of pharmacologically treated hypertensive patients enrolled in the Group Health Cooperative of Puget Sound (Seattle, Wash) found that the use of calcium channel blockers was associated with a statistically significant, dose-related increase in myocardial infarctions.5 On the basis of these findings, the authors recommended against the use of calcium channel blockers in patients with acute coronary syndromes and for restricted use in hypertensive patients until results are available from ongoing, large-scale clinical trials that are assessing cardiovascular outcomes of several antihypertensive agents, including calcium channel blockers.6 7 8 9
We performed a meta-analysis of published randomized controlled trials to assess the safety of nifedipine in hypertensive patients and to examine rates of adverse cardiovascular events in patients receiving nifedipine as monotherapy or in combination with other drugs compared with other active drugs. Outcomes of interest were definitive cardiovascular events (death, nonfatal myocardial infarction, nonfatal stroke, revascularization procedure during the study period) and episodes of new-onset or increased angina. We also examined other reasons for early withdrawal from studies.
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Methods |
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This study used techniques for meta-analysis of randomized, controlled trials described by Sacks et al.10 A prospectively designed study protocol defined the objectives of the study, eligibility criteria for the inclusion of trials, key data elements to be extracted, and analytical methods to be used. To be included, a study had to (1) be a randomized, controlled trial enrolling patients with mild or moderate hypertension, (2) be published in a peer-reviewed journal or supplement to such a journal, (3) enroll a minimum of 10 patients, (4) compare any nifedipine formulation, either as monotherapy or in combination with other agents, with a nondihydropyridine active drug or placebo control, and (5) monitor and report adverse clinical events and report them by treatment group. Eligible studies could be of either parallel or crossover design.
Studies were identified by a MEDLARS search using the MeSH heading "hypertension" and by searching for "nifedipine" as a text word. The search extended from 1966 through August 1995 and included articles published in English, French, Italian, German, and Spanish languages. CD-ROM Current Contents was searched independently. Computer-based searches were supplemented by manual searches of bibliographies of retrieved articles to detect other potentially acceptable studies. Retrieved abstracts and studies were screened by research analysts to exclude animal studies, nonqualifying languages, and nonrandomized clinical trials. Final eligibility was determined by the consensus of two independent physician reviewers.
Selected studies were blinded as to source, authors, and treatment groups.10 Each article was then extracted independently by two physicians or doctors of pharmacology using a pretested, standardized extraction form. Differences in opinions were resolved by consensus. The same reviewers assessed each study for quality using the scoring systems of Chalmers et al11 and Jadad et al.12 Administrative and treatment regimen data were extracted unblinded by an independent reviewer. Data were entered into Excel spreadsheets, verified by two research analysts, and downloaded as ASCII files for analysis with SAS software.13
Deaths, nonfatal myocardial infarctions, nonfatal strokes, and revascularization procedures that occurred during the study were classified as definitive cardiovascular events. Episodes of increased angina that led to withdrawal from the study were combined with definitive events in analyses of all cardiovascular events. Definitions of increased angina varied among studies and included unstable angina, crescendo angina, angina at rest, new angina, and increased frequency of chest pain.
Study withdrawals were classified as being due to adverse drug reactions (ADRs) or other causes. Withdrawals for ADRs included drug-related symptoms such as edema or headache as well as the cardiovascular events described above. Withdrawals for other causes included protocol violations, lost to follow-up, and inadequate therapeutic efficacy.
Because the majority of studies had no events in either the treatment or control arm, we could not compute within-study estimates of treatment effects. Heterogeneity statistics and random effects estimates could not be calculated for the same reasons.14 Incidence rates and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from the total number of events comparing nifedipine study arms with corresponding other active drug arms in the same studies. An OR less than 1.0 favors nifedipine. Placebo arms were excluded from the analysis because of the small numbers of subjects and events. We compared our results with those obtained by application of the Peto method, which discards trials in which no event occurred in any study arm.15 Results were similar. In fact, unweighted pooling and Peto's method can be shown to give equivalent OR estimates when no more than one event occurs during a study and the OR equals 1.0. The two methods give approximately equal results when the odds differ by no more than a factor of 3.0. In any event, all of these methods rely on asymptotic approximation, which is more nearly satisfied when small numbers of events are added together.
Analyses of cardiovascular events were stratified by type of nifedipine formulation (immediate-release [three or four times a day], sustained-release [twice a day], or extended-release [once a day] and by whether nifedipine was prescribed as monotherapy or in combination with other drugs (combotherapy). To test whether the unadjusted ORs differed between the type of formulation and monotherapy versus combotherapy, we fitted two logistic regression models, each including a term for type of drug (nifedipine versus other), one of the stratification factors (type of formulation or monotherapy/combotherapy), and an interaction term. The interaction term was used to determine whether the OR for drug type differed by the stratification factor.
To investigate whether treatment effects were confounded with study-level covariates, we fit multiple logistic regression models and computed the adjusted ORs for treatment.16
Covariates and rationales for their inclusion were (1) drug run-in before randomization—a proxy for case severity that indicates the reluctance of the investigator to take subjects off all active medications; (2) duration of treatment—a longer duration would be expected to be associated with an increased risk of adverse events; (3) parallel or crossover study design—carryover effects between phases of crossover studies might obscure differences between treatment regimens; (4) quality scores—a higher quality score may indicate more complete recording of adverse events and reasons for withdrawals; (5) date of publication (1987 or earlier versus 1988 or later)—a break point that coincides with the introduction of both Good Clinical Practices (GCPs) in Europe and longer-acting nifedipine formulations; and (6) study location (Europe or other versus United States) since differences in study designs, data collection strategies, or reporting conventions may influence study outcomes.
Drug regimen characteristics (nifedipine versus control drugs and monotherapy versus combotherapy) and their interaction were included in all models. Dose relationships could not be explored because most studies that titrated doses did not report the distribution of doses patients received.
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Results |
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Study Characteristics
A total of 1880 citations were retrieved for nifedipine in the treatment of hypertension. Ninety-eight were accepted for the meta-analysis and are summarized in Table 1
.17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 These studies contained 230 study
arms (111 nifedipine, 106 other active drugs, 13 placebo),
9506 subjects, and 11 020 treatment exposures (5198 to
nifedipine, 5402 to other active drugs, 420 to placebo).
The majority of studies were of parallel group design (69%), had
run-in periods with placebo or active drug controls (92%), involved at
least one monotherapy arm (81%), were of relatively short duration
(active treatment 
12 weeks in 74%) and small size (47% enrolled
50 subjects), were performed in Europe (70%), and had been published
since 1987 (61%). Mean quality scores were 29.1 (range, 5 to 56) on
the Chalmers scale and 3.0 (range, 1 to 5) on the Jadad scale. These
quality scores are average compared with other randomized controlled
trials. Subjects were predominantly male (mean for all studies, 57%)
and had a mean age of 54.6 years (range of means, 42 to 74).
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Sustained- or extended-release formulations were used in 85% of study arms and 91% of treatment exposures, and immediate-release formulations were used in 15% of study arms and 9% of treatment exposures. Starting doses were titrated upward to achieve the desired clinical response in 40% of study arms and reached a maximum of greater than or equal to 80 mg/d in 39% of study arms with sustained- and extended-release nifedipine and 35% of study arms with immediate-release nifedipine. The proportion of subjects who actually received higher doses was rarely specified.
Frequency of Cardiovascular Events
Nifedipine Versus Other Active Drugs
A cardiovascular event was reported in 0.27% of
patients in nifedipine study arms (14 events in 5198 drug
exposures) and 0.44% of patients in active drug control arms (24
events in 5402 drug exposures) (see Table 2). Overall,
there were 28 definitive events (deaths, nonfatal myocardial
infarctions or strokes, or revascularization
procedures during the study period) and 10 episodes of new or increased
angina. One or more cardiovascular events were reported
in 21% of studies. Table 3 and the
Figure present the associations between drug regimen
and the incidence of cardiovascular events. Unadjusted
ORs were nonsignificantly lower during nifedipine therapy
than during other active drugs for definitive events (OR, 0.49; 95%
CI, 0.22-1.09) and all events (OR, 0.61; 95% CI, 0.31-1.17). ORs
adjusted for type of regimen and study-level covariates increased to
0.51 (95% CI, 0.23-1.13) for definitive events and decreased to 0.57
(95% CI, 0.29-1.11) for all events. Hence, there was no apparent
confounding of treatment effects by study-level covariates. Total study
duration was significantly associated with an increased risk of
definitive events. Total study duration, location of the study in the
United States, and higher study quality were independently and
significantly associated with an increased risk of all events
controlling for drug regimen.
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Nifedipine Monotherapy Versus Combotherapy
Nifedipine was used as monotherapy in two thirds of
drug exposures and as part of combotherapy in one third of drug
exposures. In subjects on combotherapy, nifedipine was
combined with diuretics in 56% of subjects, ß-blockers in
29%, angiotensin-converting enzyme inhibitors
in 6%, and with both ß-blockers and a diuretic in 9%.
During nifedipine monotherapy, the OR for definitive events
was 1.40 (95% CI, 0.49-4.03), and during nifedipine in
combotherapy, it was 0.09 (95% CI, 0.01-0.66). Corresponding ORs for
all events were 1.39 (95% CI, 0.59-3.32) for monotherapy and 0.15
(95% CI, 0.03-0.65) for combotherapy. Differences between monotherapy
and combotherapy were statistically significant for both definitive
events and all events (P=.02 and P=.001,
respectively).
Study Withdrawals
Study withdrawal rates were significantly higher during
nifedipine than active drug controls for both ADRs (OR,
1.74; 95% CI, 1.49-2.05) and all causes (OR, 1.33; 95% CI, 1.17-1.5).
ADR withdrawal rates were significantly higher than controls for both
nifedipine monotherapy and nifedipine
combotherapy and were higher during nifedipine
monotherapy than nifedipine combotherapy. ORs were 2.36
(95% CI, 1.89-2.95) for monotherapy and 1.27 (95% CI, 1.00-1.60) for
combo-therapy. The higher ADR withdrawal rates for
nifedipine were primarily due to edema and symptoms related
to sympathetic stimulation (tachycardia, palpitations,
symptoms due to vasodilatation, dizziness, headache, and sweating).
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Discussion |
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This meta-analysis of nifedipine in the treatment of hypertension demonstrates a nonstatistically significant lower risk of cardiovascular events in subjects treated with nifedipine compared with control subjects who received other active drugs. The risk is significantly lower in patients treated with nifedipine in combination with diuretics or ß-blockers. The explanation of the latter finding may lie either in the greater efficacy of combotherapy or in an enhanced safety of using nifedipine in combination with other agents.
Our findings differ from those of the case-control study of Psaty et al5 that found increased rates of myocardial infarction in hypertensive patients treated with calcium channel blockers compared with control subjects treated with diuretics (risk ratio, 1.62) or ß-blockers (risk ratio, 1.57). In that study, the increased risk was dose related and statistically significant for diltiazem and verapamil but not for nifedipine and was present when calcium channel blockers were given as monotherapy or in combination with diuretics. One possible explanation for the differences in results lies in the shorter period of observation in our analysis—a mean of less than 12 weeks compared with a minimum of 1 year in the case-control study. Adverse effects in the latter, therefore, are more likely to reflect progression of coronary artery disease and less likely to result solely from short-term effects of the drug. Another possibility is that uncontrolled confounding by differences in case severity between cases and controls in the study of Psaty et al may influence the results. Patients treated with diuretic monotherapy in a clinical setting are likely to have less-severe hypertension and less symptomatic coexisting arteriosclerotic disease than those treated with nifedipine alone or in combination with other drugs. Finally, differences in results may reflect the fact that patients who remain on a drug regimen for a year or more are a selected population in the sense that they remain in care and are able to tolerate any side effects of their drug regimens.
Early withdrawals from studies may be due to ADRs, lack of efficacy, or protocol violations. Study withdrawal rates for ADRs were higher in subjects on both nifedipine monotherapy and nifedipine as part of combotherapy. They were more than twofold higher during nifedipine monotherapy than active drug controls. During both regimens, the symptoms that led to withdrawal reflected sympathetic stimulation or vasodilatation.
A major strength of our meta-analysis is the inclusion of the universe of relevant, published, randomized, controlled trials. The effects are to increase the generalizability of results and to minimize the likelihood of case-mix differences between study arms. Other strengths are the use of rigorous meta-analytic methods for screening studies; the blinding for author, institution, and treatment regimen of the doctors before extraction of the articles; dual extraction of articles by two physicians or doctors of pharmacology; and thorough exploration of the resulting database, including multiple logistic regression and substantiation of results by application of the fixed effects meta-analytic method proposed by Peto (Yusuf et al15 ).
Limitations relate to the relatively small number of cardiovascular events on which analyses are based; the relatively short duration of studies; the inability to adjust per-person rates for the duration of drug treatment because available information did not permit us to determine the timing of events relative to the initiation of treatment; the inability to explore dose relationships to adverse events because most studies did not provide information on actual doses received; and the paucity of patient-level data to permit case-mix adjustment across studies.
The results of our meta-analysis lend support to the safety of sustained-release and extended-release formulations of nifedipine in the treatment of hypertension, especially when they are used in combination with diuretics or ß-blockers. Evidence from the controlled clinical trials that are in progress will be required, however, to verify these conclusions.6 7 8 9
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Acknowledgments |
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This work was supported by grants from Pfizer, Inc; US Pharmaceuticals Group; and Bayer AG, Pharmaceutical Business Group.
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Footnotes |
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1 Deceased.
Received March 3, 1996; first decision March 25, 1997; accepted March 25, 1997.
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