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(Circulation. 1995;92:1326-1331.)
© 1995 American Heart Association, Inc.

Articles

Nifedipine

Dose-Related Increase in Mortality in Patients With Coronary Heart Disease

Curt D. Furberg, MD, PHD; Bruce M. Psaty, MD, PHD; Jeffrey V. Meyer, MS

From the Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC (C.D.F., J.V.M.), and the Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle (B.M.P.).

Correspondence to Dr Curt D. Furberg, Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1063.

	Abstract

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Background The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur.

Methods and Results We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P=.01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects.

Conclusions In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

Key Words: coronary disease • dihydropyridine • nifedipine • meta-analysis • mortality

	Introduction

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The first meta-analysis of the clinical trials of calcium antagonists in myocardial infarction and unstable angina reported all-cause mortality and initial or recurrent infarction among 19 000 patients in 28 randomized trials.¹ The findings suggested a slightly unfavorable effect of calcium antagonists. In the trials of myocardial infarction, for instance, the risk ratio (RR) for mortality was 1.06 (95% CI, 0.96 to 1.18). The small increase in mortality was present not only in trials in which intervention was started early and continued for a short or long time but also in trials in which it started later and continued for a long time. According to the combined data from the trials in unstable angina, 14 deaths occurred among 591 patients allocated to calcium antagonist treatment and 9 deaths among 578 control subjects. A 1991 update² added findings from a Danish trial of verapamil and from two large angiographic trials of stable angina in which half of the patients had a history of myocardial infarction. In this analysis, a difference was noted among the various calcium antagonists, although the difference was not statistically significant; the RR for mortality in the trials using dihydropyridines, such as nifedipine, that increase heart rate was 1.16 (0.99 to 1.35), whereas it was 0.95 (0.82 to 1.09) for the calcium antagonists verapamil and diltiazem, which slow heart rate. The RRs for these two agents individually were 0.91 (0.76 to 1.10) and 0.99 (0.80 to 1.24). Thus, there is no clinical trial evidence that any of the three main groups of calcium antagonists improves survival in coronary patients. Two additional meta-analyses have recently been published.^{3 4} Combining the results from all trials of dihydropyridines, Held and Yusuf³ found a statistically significant excess in all-cause mortality; RR, 1.17 (1.01 to 1.36). Previous meta-analyses have not addressed the issue of dose. The purpose of this report is not only to analyze the mortality data by the dose level of nifedipine that investigators selected for use in the randomized trials but also to review the mechanisms of action that are likely to lead to an increased risk of mortality. Our primary hypothesis was that high doses would be associated with an increased risk of mortality.

	Methods

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Since data on the equipotency of various calcium antagonists are limited, we restricted the dose-response analysis to trials that used nifedipine, which is the most extensively evaluated calcium antagonist. The dose-response analysis of nifedipine includes the results of the 16 randomized secondary-prevention clinical trials for which mortality data are available.^{5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21} Twelve trials randomized patients with myocardial infarction,^{6 7 8 9 10 11 12 13 14 15 16 17} three trials included patients with unstable angina,^{18 19 20} and one trial evaluated patients with stable angina, one third of whom had a history of prior infarction.²¹ About 8350 patients were studied, and the doses of nifedipine ranged from 30 to 120 mg/d. Capsules were used in 11 of the 16 trials; information on the formulation was lacking for the remaining trials.

We used standard methods of meta-analysis.²² In short, the analysis is stratified on trial so that comparisons between intervention and placebo always involve patients within the same trial. To estimate the RR for mortality, the CIs, and the tests for heterogeneity, we used maximum-likelihood methods for the stratified analysis of cumulative incidence.²³ The effect of nifedipine on mortality was assessed both within each dose category and across all trials combined. Formal tests of dose response were also conducted according to standard methods.^{22 24} In this analysis, the natural logarithm of the RR of mortality was used as the dependent variable in a linear regression model weighted by the inverse of the variance of the RR, and the dose of nifedipine was entered as the independent variable.²² All tests of significance were two-sided.

	Results

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Dose-Response Analysis
The Table summarizes the results of the 16 trials according to dose. Overall, the use of nifedipine was associated with a statistically significant adverse effect on mortality. For all trials combined, the RR was 1.16, with a 95% CI of 1.01 to 1.33. There was no statistical evidence of heterogeneity among the results of these 16 trials (P=.30). The summary estimate, however, fails to draw attention to an important dose-response relationship.

View this table: [in this window] [in a new window]   Table 1. Mortality in Trials of Nifedipine in Myocardial Infarction and Unstable Angina

In trials that used doses between 30 and 50 mg/d, the mortality experience was similar in the nifedipine and control groups. The RRs were 1.01, 1.09, and 1.03 for daily doses of 30, 40, and 50 mg, respectively. For trials that used 60 mg/d, the RR for mortality was 1.18 (0.93 to 1.50)—higher than for any of the low-dose trials. Since two of these four 60-mg trials were stopped before their scheduled termination as a result of a trend toward increased mortality during the early phase in one trial⁴ and a doubling of the rate of reinfarction in the other,¹⁸ this analysis may underestimate the adverse mortality effect of the 60-mg dose.

In trials that used 80 mg/d, nifedipine almost tripled the risk of mortality. Within these 80-mg trials, there was no statistical evidence of heterogeneity (P=.28), and the RR was 2.83 (1.35 to 5.93). Among trials that used 100 mg/d, the combined RR of mortality was also elevated (RR, 2.2), although the 95% CI was wide and included 1.0. For the 80-mg trials, the RR of 2.83 differed significantly not only from the null but also from the combined estimate for the 30- to 50-mg trials (RR, 1.06; 95% CI, 0.89 to 1.27).

In the formal dose-response analysis, the risk of mortality was strongly associated with the dose of nifedipine (P=.01). Although there was no statistical evidence of lack of fit of the linear model (P=.45), the Figure suggests that the risk of mortality rises sharply in trials that used 80 mg of nifedipine per day.

View larger version (18K): [in this window] [in a new window]   Figure 1. Graph showing risk of mortality according to daily dose of nifedipine. RR indicates risk ratio.

Potentially Harmful Mechanisms
Although important differences clearly exist among the 35 calcium antagonists in clinical use around the world, these agents also have mechanisms in common, or class effects. For calcium antagonists, the principal mechanisms of action are peripheral and coronary vasodilation. The relative potency of the pharmacological actions varies among calcium antagonists; thus, their clinical effects may be different. These differences, however, are likely to be differences of degree rather than kind. Therefore, this review of the mechanisms of action that might increase mortality included clinical trials of any calcium antagonist. There is a remarkable sparsity of outcome data in the literature of calcium antagonists. The five potentially harmful effects discussed here may or may not apply to other types of calcium antagonists. From a public health viewpoint, it is the sum of these effects that matters. The potentially most harmful clinical effect of nifedipine is that attributed to proischemia—an effect not expected in an anti-ischemic agent.

Proischemic Effect
Waters²⁵ described proischemia as "the potential of an antianginal drug to occasionally worsen ischemia in an unpredictable and dangerous manner." The most common form of proischemia is an increase in anginal symptoms. The first report linking nifedipine to increased angina was published in 1978.²⁶ Reporting on a cohort study, Stone and collaborators²⁷ concluded that "nifedipine was associated with an increase of angina frequency in 13% to 29% of the 716 patients. This increase was most frequently observed in those with no evidence of vasospasm." In a double-blind randomized crossover trial, Egstrup and Andersen²⁸ found that the ischemic effect of nifedipine in patients with stable angina depends on the presence or absence of coronary collateral flow. In patients with poor or no collateral flow, nifedipine reduced ischemic episodes. But in patients with good collateral flow, nifedipine significantly increased ischemic episodes. A proischemic effect in isolated cases has also been reported for nicardipine and isradipine.²⁵

In certain instances, severe proischemia occurs and may precipitate major coronary events. The "coronary steal" phenomenon described by Egstrup and Andersen may also explain the unfavorable effect of nisoldipine in patients with stable angina.²⁹ Four of the 137 nisoldipine-treated patients developed unstable angina, and 2 others died during 2 weeks of treatment, compared with no coronary events in 48 control subjects (P=.16). Both deaths were sudden and occurred in the high-dose (10 mg BID) group. In a crossover trial, Scheidt and coworkers³⁰ reported seven cardiac events (acute myocardial infarction, increased angina, and exertional hypotension) in 66 stable angina patients being treated with nicardipine compared with one (acute infarction) in patients given placebo. In another crossover trial, Gheorghiade et al³¹ noted six events (unstable angina and non–Q-wave infarction) in 46 patients on nicardipine but none on placebo.

Negative Inotropic Effect
It is well established that the class of calcium antagonists has a negative inotropic effect and that this action varies among agents. Packer³² proposed that the cardiodepressant action in long-term use "can be more readily explained by the capacity of calcium channel blockers to activate endogenous neurohormonal systems, especially the renin-angiotensin system." Regardless of underlying mechanisms, when given specific calcium antagonists, many patients in chronic heart failure experience worsening of their symptoms.^{32 33 34} Subgroup analysis in the Multicenter Diltiazem Post Infarction Trial (MDPIT) showed that a diltiazem-induced increased risk of new or worsening congestive heart failure was closely related to ejection fraction.³⁵ This adverse effect was most apparent in patients with ejection fractions <25% and 25% to 34%. In patients with an ejection fraction <0.40, late congestive heart failure appeared in 12% of 326 placebo patients and in 21% of 297 diltiazem-treated patients (P=.004). In addition to the negative inotropic effect, diltiazem caused a statistically significant increase in cardiac mortality and recurrent cardiac events among patients in MDPIT with pulmonary congestion at baseline.³⁶ Elkayam and coworkers³³ reported that administration of nifedipine alone or in combination with isosorbide dinitrate compared with isosorbide dinitrate alone resulted in a statistically significant worsening of congestive heart failure and that this adverse effect could not be predicted by resting ejection fraction.

Both the Physicians' Desk Reference and the package inserts of all approved calcium antagonists in the United States advise against use of these compounds in patients with congestive heart failure. The wording is more guarded for the new dihydropyridine amlodipine. A recently reported trial of amlodipine in patients with congestive heart failure showed a mortality benefit only in the small subgroup of patients with underlying dilated cardiomyopathy.³⁷ The lack of benefit in the large subgroup of patients with underlying coronary disease could perhaps be explained by a proischemic effect of amlodipine offsetting a favorable vasodilatory effect on failure-related mortality. It is not clear whether the findings in the cardiomyopathy group are applicable to other patient populations.

Effects on Rhythm
Short-acting calcium antagonists not only increase sympathetic stimulation and catecholamines but also activate the renin-angiotensin system. Packer³² suggested that "activation of the renin-angiotensin system may also predispose to the occurrence of complex ventricular tachyarrhythmias, either by potentiating the development of catecholamine-induced arrhythmias or by increasing the production of mineralocorticoids, which may exacerbate diuretic-induced potassium depletion."

No large clinical trial of a calcium antagonist has been conducted in coronary patients with ventricular arrhythmias.³⁸ Based on the hypothesis that calcium antagonists may exert a cerebroprotective effect, two major randomized clinical trials evaluated the effect of calcium antagonists in survivors of cardiac arrest.^{39 40} Although the purpose of both trials was the prevention of severe ischemic cerebral injury, they also reported the mortality rates and the rates of rearrest.

In the Finnish study, 155 patients resuscitated after out-of-hospital ventricular fibrillation were randomized to nimodipine (10 mg/kg IV initially followed by infusion of 0.5 mg · kg^-1 · min^-1 for 24 hours) or placebo.³⁹ During the first 24 hours, when nimodipine was being given intravenously, 10 of 75 nimodipine-treated patients died, compared with 2 of 80 placebo-treated patients (P=.01). No mortality difference was present at 3 months. It appears that nimodipine in this population induces rearrests.

In the second trial, lidoflazine (1 mg/kg initially, followed by two doses of 0.25 mg/kg, at 8 and 16 hours after resuscitation) or placebo was given to 516 comatose survivors of cardiac arrest.⁴⁰ This drug, which is no longer in use, was not found to be beneficial. A significantly higher proportion of lidoflazine-treated patients suffered a second nonfatal cardiac arrest or hypotension, 69% versus 60%, during the first 24 hours (P<.02). The number of rearrests was 26% higher in the lidoflazine group, 91 of 258 versus 72 of 254 (P=.09).

Prohemorrhagic Effects
Calcium antagonists are known to have varying degrees of antiplatelet effects. They prevent the influx of calcium in response to several platelet activators. In addition, they have a vasodilatory effect that in combination with the antiplatelet effect may prevent normal hemostasis. The incidence of intracerebral hemorrhage in the Thrombolysis in Myocardial Infarction Phase II trial, which randomized patients to recombinant tissue-type plasminogen activator (TPA), was almost four times higher in patients on calcium antagonists at study entry than in those not on these drugs, 1.5% versus 0.4% (P=.009).⁴¹ In a follow-up to this surprising finding, Becker et al⁴² observed in an animal model that prolonged use of diltiazem, with or without TPA, was associated with a fivefold increase in bleeding. According to a recent conference report from Japan, 2042 hypertensive patients were randomized to an angiotensin-converting enzyme (ACE) inhibitor or to either nifedipine or manidipine, both dihydropyridines. Even though the calcium antagonists produced a greater reduction in blood pressure than the ACE inhibitor, the reported numbers of cerebrovascular events were 15 in the calcium antagonist arm versus 5 in the ACE inhibitor arm, respectively (P<.02).⁴³ The excess events may be explained by a prohemorrhagic effect but also by an ischemic effect induced by marked hypotension. Until the full report appears, these data should be interpreted with caution.

Wagenknecht and colleagues⁴⁴ recently reported on a statistically significant increase in major bleeding after cardiac surgery in 149 patients with valvular heart disease. Ten nimodipine-treated patients and two placebo-treated patients (P=.01) suffered major bleeding, defined as either transfusion of 10 or more units or chest tube drainage exceeding 2400 mL during the first 24 hours after operation. Surgical bleeding was a direct or major contributing cause of the excess mortality among the nimodipine patients, 8 deaths versus 1 (P=.016).

Marked Hypotension
One of the primary therapeutic effects of calcium antagonists is lowering of blood pressure. Several forms of marked hypotension are also possible. First, it was recently reported⁴⁵ that nitrendipine in a 24-hour ambulatory monitoring trial accentuated the physiological lowering of blood pressure at night. Pronounced nocturnal hypotension may be linked to the onset of coronary events⁴⁶ and ischemic strokes. Second, sublingual nifedipine markedly reduces blood pressure in some patients with hypertensive crisis.⁴⁷ Hypoperfusion of the subendocardium accompanied by major ECG T-wave inversions is induced in 25% of the patients.⁴⁸ Several case reports⁴⁹ have described the development of acute myocardial infarction after sublingual nifedipine.

	Discussion

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If a drug exerts a harmful effect, one would expect to see such an association most clearly with high doses of the drug. As we hypothesized, the dose of nifedipine was directly and strongly related to the risk of mortality (P=.01). Compared with placebo, doses >60 mg/d almost tripled the risk of death, and the adverse effect differed not only from the null but also from the small adverse effect seen with the doses of 30 to 50 mg/d. High doses were clearly harmful. A visual inspection of the risks and doses in the Figure suggests the possibility of a threshold effect at these high doses. But because several of the 60-mg trials were stopped early, the RR of 1.18 may underestimate the mortality effect of the 60-mg doses. The use of moderate to high doses of short-acting nifedipine in survivors of an acute myocardial infarction and patients with stable or unstable angina should be avoided. Adequate outcome data are lacking for all doses of the long-acting formulations of nifedipine, the other dihydropyridines, and the nondihydropyridines.

Mechanisms of Action
The reflex increase in sympathetic activity induced by short-acting calcium antagonists may be the underlying mechanism of action behind the observed proischemic, negative inotropic, and arrhythmogenic effects of these compounds. Muller et al⁵⁰ hypothesized that the circadian variation in onset of acute cardiovascular events is associated with alterations in sympathetic activity that may lead to plaque rupture.

Ruzicka and Leenen⁵¹ reviewed the association between intermittent increases in sympathetic activity induced by dihydropyridines and adverse clinical outcomes. They conclude that intrinsic pharmacokinetic properties as well as various formulations of the same drug may influence plasma drug concentrations and fluctuations both in blood pressure and in sympathetic activity. The fast-absorbed drugs—nifedipine, nicardipine, felodipine, and isradipine—cause marked fluctuations in blood pressure even during chronic treatment. Blood-pressure fluctuations may disappear with some slow-release formulations but seem to persist with others. The authors emphasize that hemodynamic changes do not reflect the actual extent of sympathetic activity and call for more research.

Compared with the long-acting formulations of nifedipine that have more recently become available, both the regular nifedipine capsule and tablet are relatively short-acting formulations. If the intermittent reflex increases in sympathetic activity associated with these short-acting formulations are responsible for the increased risk of mortality, then it is possible that the long-acting versions may be entirely safe. If, on the other hand, the coronary steal phenomenon associated with vasodilation is responsible for the increased risk of mortality, then the long-acting formulations, by increasing patient compliance, may be even more dangerous than the short-acting formulations. Whether these formulations differ in terms of their effects on mortality and major disease end points is an empirical question that deserves further study. Furthermore, if the coronary steal phenomenon is important, older adults, many of whom have subclinical coronary disease, may be a population particularly vulnerable to the coronary steal effect of calcium antagonists. Again, these issues are empirical questions that can only be answered by properly designed clinical trials.

Among the potential causes of the excess mortality, the proischemic and negative inotropic effects are well established, and appropriate warnings are included with the package inserts. The proarrhythmic effect is more speculative and is based on observations in a special high-risk population. Serious surgical bleeding attributed to nimodipine was an unexpected finding in a trial of patients with valvular disease. Confirmations are required before firm conclusions regarding a causal relationship can be drawn. It is known that a small proportion of hypertensive patients respond to calcium antagonist with marked hypotension and that those patients are at risk of developing clinical events.

Clinical Implications
The clinical implications of the findings reported here could be potentially far-reaching. The mortality data from randomized clinical trials of short-acting nifedipine are alarming. The twofold to threefold increase in all-cause mortality associated with high doses is similar to that reported for encainide and flecainide in the Cardiac Arrhythmia Suppression Trial.⁵² Regulatory agencies ought to consider whether moderate to high doses of nifedipine capsules should be excluded from the approved labeling.

The literature review strongly suggests that the problem may go beyond short-acting nifedipine. Other short-acting dihydropyridines that also induce intermittent increases in sympathetic activity are likely to be similar to nifedipine in their effects. Extrapolation to slow-release dihydropyridines and nondihydropyridines represents a greater leap.

The findings appear to go beyond myocardial infarction, unstable angina, and stable angina. In the presence of subclinical atherosclerosis, short-acting dihydropyridines may exert proischemic effects. In the Multicenter Isradipine Diuretic Atherosclerosis Study, a randomized trial in 883 hypertensive patients with carotid artery disease, the number hospitalized for angina was higher (11 versus 3, RR 3.66; P=.04) in the isradipine-treated group than in the diuretic group according to a conference report.⁵³ Ruzicka and Leenan⁵¹ conclude that "so far, dihydropyridines are clearly not the treatment of choice for regression of left ventricular hypertrophy and as monotherapy are likely to be detrimental for outcome in patients with (sub)clinical forms of coronary artery disease."

The effects of nifedipine on morbidity and mortality remain untested in the setting of hypertension. The assumption that the findings for a drug in one patient population do not apply to the same drug used in another patient population seems to us to be unreasonable and potentially hazardous. We would simply argue that because a drug has been shown to cause harm in one patient population, this same drug should not be used in another patient population unless or until that drug has been proved not only effective but also safe in that population.

It has been suggested that the addition of a ß-blocker to a calcium antagonist may offset any adverse effects associated with increased sympathetic activity. In a cohort study of coronary patients, those receiving ß-blockers with or without calcium antagonists had a lower risk of mortality than those receiving calcium antagonists alone.⁵⁴ The only trial data¹⁸ of this drug combination lend support to this hypothesis, which needs to be tested in large-scale clinical trials before it forms the basis for treatment decisions.

The clinical dilemma is the lack of adequate documentation of long-term safety. Clinicians have several options. They may view the relief of symptoms as more important than the emerging data that suggest a link between the use of nifedipine, as well as possibly other short-acting dihydropyridines, and an excess of cardiovascular events. Or they can restrict their use of these drugs until adequate safety information is available. Alternative and proven treatment options such as the use of ß-blockers are available and, if tolerated, have established records of efficacy and safety. The latter approach seems prudent to us, since it carries no unnecessary risks. In general, we favor compliance with treatment guidelines issued by independent organizations and evidence-based medicine.

Received January 18, 1995; revision received July 18, 1995; accepted July 18, 1995.

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