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(Circulation. 1995;92:1074-1078.)
© 1995 American Heart Association, Inc.

Articles

Nifedipine in Ischemic Heart Disease

Robert A. Kloner, MD, PHD

Correspondence to Robert A. Kloner, MD, PhD, The Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017.


Key Words: editorials • heart diseases • nifedipine • angina


*    Introduction
up arrowTop
 *Introduction
down arrowReferences
 
Until the 1980s, Prinzmetal's variant angina was difficult to treat—nitrates and ß-blockers usually did not control symptoms or signs of ischemia. In 1980, Antman et al1 reported the first clinical experience in the United States of the use of nifedipine in patients with Prinzmetal's angina. They used nifedipine capsules to treat 127 patients with Prinzmetal's angina, which reduced the weekly occurrences of angina from 16 to 2, reduced nitroglycerin requirements, completely controlled angina in 63% of patients, and reduced the frequency of angina by at least 50% in 87% of cases. Since that time, a number of trials with different calcium channel blockers, including nifedipine, diltiazem, verapamil, amlodipine, and others, have consistently shown that these agents are efficacious in reducing the morbidity of Prinzmetal's variant angina.2

Additional studies showed that calcium channel blockers, including nifedipine, were effective in patients with chronic stable angina pectoris3 ; they not only reduced symptoms but also reduced objective evidence of ischemia on exercise treadmill tests,4 5 reduced ST-segment changes on ambulatory ECG monitoring,6 increased coronary artery blood flow,7 8 9 and improved ventricular dysfunction associated with ischemia.10 Numerous studies showed that the calcium channel blockers were effective as antihypertensive agents and lacked many of the side effects of diuretics and ß-blockers.11

Of course, all drugs have limits, and not all cardiovascular drugs are appropriate for all cardiovascular situations. Calcium channel blockers are no exception. In 1984, Muller et al11 showed for the first time that nifedipine capsules did not reduce the size of myocardial infarction (MI) and did not prevent patients with threatened MIs from infarcting. Patients who received nifedipine capsules in the setting of myocardial infarction had a higher 2-week mortality (7.5%) versus placebo (2.3%) but 6-month mortality was similar between nifedipine-treated (10.8%) and control (11.4%) patients. Muller et al12 also showed that nifedipine offered no advantage over other conventional therapy for patients with unstable angina (other groups, however, actually showed that nifedipine was beneficial in the treatment of unstable angina13 ).

As a result of the study of Muller,11 which is now more than one decade old, and studies such as the Multicenter

Diltiazem Postinfarction Trial (MDPIT),14 which raised the concern that some patients with heart failure may do worse in the setting of MI when diltiazem is administered, cardiologists in the United States in general do not routinely prescribe short-acting calcium blockers after MI, prescribe them for secondary prevention, or prescribe them as first-line therapy for unstable angina. The meta-analysis15 in this issue of Circulation adds to existing knowledge of the use of nifedipine capsules in acute coronary syndromes. The study uses standard meta-analysis techniques, and the basic approach appears to be valid. It should be noted that the meta-analysis essentially reanalyzes the same studies from the 1980s included in a previous meta-analysis.16 Of the 16 studies listed in the Table,15 15 were presented in their former meta-analysis.16 The major differences in results between the present study15 and the previous one16 is the focus on the subgroup of patients receiving only nifedipine capsules and the relation between dose and outcome. The meta-analysis shows that high doses of nifedipine capsules (80 mg) are more likely to be associated with mortality. A potentially important implication is that in the subgroups studied, lower doses of nifedipine appear to be safer.

There are several limitations in the interpretation and discussion of the meta-analysis.15 One deals with the patient populations that were studied. Meta-analysis data are most useful when the populations of patients are homogeneous. The patients with coronary artery disease who were analyzed cannot be considered a homogeneous group of patients. They include patients with MI, patients with unstable angina, and a small number of patients with stable angina (some of whom had MI and some did not). The meta-analysis did not study a general population of patients with coronary artery disease but rather specific subgroups of patients with acute coronary syndromes.15 The findings that high doses of nifedipine capsules were deleterious in patients with MI and unstable angina may not be applicable to the broader population of patients with chronic stable angina and Prinzmetal's angina.

A second concern deals with the time at which patients were analyzed in relation to the MI. Interpretation of meta-analysis data of subgroups of patients is sensitive to certain assumptions that are not always clarified. The most impressive finding in the present meta-analysis15 is the relative risk of death of 2.8 in the four trials that used 80 mg/day of nifedipine capsules—this was the only dose for which the confidence intervals did not cross unity. The authors chose to study the incidence of death in one of the four studies (Muller et al [Reference 14 of the meta-analysis]) over 14 days but not over 6 months. During the 14-day period, there were 7 deaths in the nifedipine group and 2 deaths in the placebo group. However, had the authors chosen to study the data over 6 months, they would have reported 10 deaths in the nifedipine capsule group and 10 deaths in the placebo group, which are far less striking results. The relative risk of the use of nifedipine capsules increasing mortality would then have dropped to below 2 and would no longer have been statistically significant. Choosing the earlier time point over the later time point may thus have biased the results.

A third limitation of the meta-analysis15 involves the inclusion of studies that start the treatment both early and late after MI with different doses and the drawing of conclusions about dose rather than about timing of drug administration. This is demonstrated by the SPRINT I and II studies, which are both included in the meta-analysis. In the SPRINT I study, lower doses of nifedipine given 7 to 22 days after MI did not increase mortality; however, in SPRINT II, higher doses given within the first few days of MI did increase mortality. Although the meta-analysis15 ascribes the increased mortality to dose, the observation might be due to giving the drug too early after MI and have nothing to do with dose.

A fourth concern is that not all of the control groups received the same types of medication. In some of the studies, control patients received placebo; in others, they received ß-blockers. This complicates the interpretation of the meta-analysis.

A fifth and perhaps most important limitation deals with the dosing formulation of nifedipine that was studied. The meta-analysis15 deals with short-acting nifedipine capsules, which in the 1990s can no longer be considered to be the optimal formulation of nifedipine. There are long-acting formulations of nifedipine available, including nifedipine gastrointestinal system (GITS) and nifedipine coat-core delivery system (CC). The former is approved by the Food and Drug Administration (FDA) for angina and hypertension; the later is approved only for hypertension; thus, I concentrate in the following discussion on the GITS system.

There are important differences in pharmacokinetics and hemodynamic effects between the short-acting nifedipine capsules (FDA approved for angina but not hypertension) that are dosed three- to four-times-a-day and the newer slow-release forms of nifedipine, such as the GITS formulation, which is administered once a day.

After administration of a nifedipine capsule, plasma drug concentration peaks rapidly (within 1 hour) to high levels and then falls rapidly. In contrast, plasma drug concentration of nifedipine GITS (which uses an osmotic pump system to deliver the drug in a steady infusion over 24 hours17 18 19 20 21 ) reaches a plateau slowly, at approximately 6 hours, and maintains a relatively constant drug level over the duration of the 24 hours. Nifedipine-CC uses an outer slow-release nifedipine coating and an inner fast-release drug core. This results in a first peak in plasma concentrations between 2.5 and 5 hours, a drop in levels, and a second peak at 6 to 12 hours after administration.

By administering intravenous doses, Kleinbloesem et al22 investigated the importance of the rate of increase in the plasma concentration of nifedipine in relation to the hemodynamic effect of the drug. Rapid administration of nifedipine increased heart rate immediately without significant effects on diastolic blood pressure, suggesting activation of the baroreceptor reflex. Gradual administration of the drug, achieving the same steady-state concentration but over 5 to 7 hours, did not change the heart rate, and diastolic blood pressure gradually lowered. The authors concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.22 Investigators have suggested that the occasional case of worsening angina seen with capsules may be related to the rapid hemodynamic effects associated with the TID to QID dosing regimen.23 Rapid changes in peripheral vascular resistance are associated with an increase in sympathetic activity and plasma norepinephrine levels, two factors which may contribute to cardiac events. Because nifedipine-GITS and the newer-generation dihydropyridine amlodipine have a slower onset of action without major fluctuations in peak-to-trough drug levels (in comparison to nifedipine capsules), these agents are not associated with sudden increases in heart rate, decreases in blood pressure, or increases in plasma norepinephrine levels. Parmley et al24 showed that in patients with chronic stable angina, heart rate increased by only 1.6 beats per minute in patients receiving nifedipine-GITS.

There also is evidence in the literature that patients' responses to angina and side effects differ when treated with nifedipine capsules versus the nifedipine-GITS system. In one cross-over study,25 angina frequency was significantly lower with the GITS system (0.8 episodes per week) compared with therapy with the capsules (1.3 episodes per week; P<.05). Also, the vasodilator side effects of flushing and dizziness were less common with the nifedipine-GITS system than with the capsules.26

Although the nifedipine-GITS system has been available since 1989, a literature search failed to reveal reports of definite "proischemic" effects of this drug formulation. The recent study by Parmley et al24 in patients with chronic stable angina showed that nifedipine-GITS reduced the weekly number of anginal episodes from 5.7 to 1.8 (P=.0001) and the number of ischemic events (assessed by ambulatory ECG monitoring) from 7.3 to 4 (P=.0001). The drug reduced ischemia over a 48-hour period either alone or in combination with a ß-blocker. Specifically, Parmley et al did not observe a proischemic effect (worsening of ischemia on ambulatory ECG monitoring) with this drug. Similar trials with amlodipine, a calcium channel blocker with a slow onset of action and intrinsically long half-life (30 to 50 hours), also revealed reduction in ischemic ST-segment changes on both ambulatory monitoring27 and exercise stress testing,28 29 and did not cause a change in heart rate in patients with coronary artery disease.

A comprehensive review of Pfizer's clinical controlled database of the use of nifedipine GITS for angina did not reveal an increase in MI or death, relative to placebo (Dr Michael Gaffney, personal communication).

Finally, in a preliminary analysis of two of the largest hypertension trials of nifedipine-GITS and amlodipine, there were no deaths, and the incidence of MI was similar to that reported for diuretics and ß-blockers30 by Psaty et al.31

Thus, at least two types of long-acting dihydropyridines—nifedipine-GITS and amlodipine—have been shown to have primarily anti-ischemic properties, and significant proischemia has not been reported. This may be related to their slower, gradual reduction in blood pressure and lack of reflex tachycardia compared with nifedipine capsules.

Thus, the fifth limitation of the meta-analysis15 is that extrapolations and generalizations are made based on subgroups of patients receiving nifedipine capsules that may not be applicable to the newer longer-acting formulations of nifedipine or other calcium channel blockers.

The discussion in the meta-analysis15 postulates several mechanisms for why nifedipine capsules had a negative effect on patients with MI or unstable angina and why in some patients with stable angina the capsules appear to worsen ischemia. The first mechanism described is a "proischemic effect." The meta-analysis15 related the proischemic effect to "coronary steal." However, the evidence supporting the concept that nifedipine causes coronary steal in humans is speculative at best. The meta-analysis refers to the study of Egstrup and Anderson,32 which suggested that an increase in angina in patients receiving nifedipine was associated with the presence of coronary collaterals, and therefore coronary steal was the cause of ischemia. However, no measure of coronary flow or perfusion was provided to document coronary steal. Furthermore, another study by Carboni et al34 showed just the opposite findings. They observed that coronary artery disease patients with improved exercise tolerance after nifedipine were more likely to have coronary collaterals. Malacoff et al35 measured regional myocardial blood flow in patients with coronary artery disease with 133Xe and observed that nifedipine improved regional myocardial blood flow to ischemic segments. Melandri et al36 studied the effects of a sustained intravenous dose of nifedipine in patients with unstable angina. They titrated to a mean dose of 27 µg/min and observed an increase in coronary blood flow, a decrease in coronary vascular resistance, no change in coronary sinus norepinephrine levels, and an increase in myocardial lactate uptake, suggesting reduced ischemia. The patients experienced a significant reduction in episodes of angina with nifedipine. An important study of myocardial perfusion in patients with variant angina during exercise was reported by Kugiyama et al.37 They observed that nifedipine improved exercise duration and reduced the size of the perfusion defect on thallium imaging; propranolol shortened exercise duration and actually increased the size of the perfusion defect compared with placebo. Heusch et al38 demonstrated in a canine model (a species known to have coronary collaterals) that nifedipine improved poststenotic subendocardial blood flow during exercise and improved regional wall motion abnormalities induced by ischemia. Other studies have also failed to show that nifedipine causes a coronary steal phenomenon when coronary perfusion was assessed39 ; most suggest that it has a favorable effect on coronary perfusion in humans.40 In addition, studies have shown that nifedipine improves left ventricular dysfunction associated with ischemia in humans, a finding that argues against coronary steal.41 Thus, the concept that nifedipine causes a coronary steal in humans and that this causes proischemia remains speculative.

It is more likely that the patient who develops worsening angina with nifedipine capsules is either having a decrease in coronary perfusion pressure due to too rapid a drop in blood pressure, an increase in heart rate due to reflex tachycardia causing an increase in oxygen demand, or an increase in other sympathomimetic activities (including contractility) that could increase oxygen demand. This scenario is much less likely to develop with the slower-onset, longer-acting calcium blockers that lack large peak-to-trough fluctuations in drug levels.

The meta-analysis15 correctly points out that calcium channel blockers may exacerbate heart failure, although not all patients with heart failure decompensate on calcium blockers. It appears that agents such as amlodipine42 and felodipine will be less likely to result in heart failure.

Although the discussion within the meta-analysis15 implies that the deleterious effect of nifedipine capsules may have been due to rhythm disturbances or bleeding disturbances, solid evidence to support this claim is lacking. The discussion extrapolates results from the use of nimodipine and lidoflazine, calcium channel blockers not used for angina and hypertension in this country, to other calcium blockers. Furthermore, Biggers et al43 evaluated patients in the MDPIT and failed to find a proarrhythmic effect of the calcium channel blocker diltiazem after infarction. Experimental studies have suggested that nifedipine has an antiarrhythmic effect (not proarrhythmic) in the setting of ischemia.44

The discussion section of the meta-analysis states that "alternative and proven treatment options such as the use of ß-blockers are available and, if tolerated, have established records of efficacy and safety."15 ß-Blockers are wonderful drugs; they are efficacious in stable angina and hypertension. However, the problem here is tolerability. Patients do not like feeling tired and depressed and being impotent. And although the discussion in the meta-analysis states "that ß-blocker therapy carries no unnecessary risks," ß-blockers can exacerbate heart failure, worsen coronary vasospasm,37 and cause bradycardia and conduction abnormalities, bronchospasm, and Raynaud's syndrome. ß-Blockers have been shown to reduce mortality when given chronically after MI. However, large numbers of postinfarction patients were excluded from these trials because of heart failure and left ventricular dysfunction, and these were primarily prethrombolytic era trials. Whether ß-blockers administered chronically after infarction will improve survival in the thrombolytic era is less certain.

Clinical judgment must be used when drugs are prescribed. Like all drugs, there are situations where calcium channel blockers are appropriate; there are situations where they are not appropriate. A "shotgun" approach is the wrong approach. At the present time, nifedipine capsules should not be routinely used for MI and probably not for unstable angina—again, this has been known for more than a decade. However, based on a meta-analysis of subgroups of nonhomogeneous coronary patients with MI and unstable angina from studies performed in the 1980s, lack of inclusion of mortality rates at 6 months in one of the key studies, variability in timing of administration of the drug in relation to infarction, use of older drug formulations, inclusion of control groups that received variable treatments, and extrapolations from nifedipine capsules to other formulations of nifedipine as well as other calcium blockers, we should not abandon calcium channel blockers for the treatment of patients with chronic stable angina, Prinzmetal's angina, and hypertension.

There are several areas where additional research is desperately needed to better guide the use of calcium channel blockers, and I strongly agree with the coauthors of the meta-analysis on this issue.15 The DAVIT II study suggested that verapamil after MI improved survival.45 Diltiazem reduced the incidence of reinfarction in patients with non–Q-wave infarction.46 It is conceivable that some of the newer slower-onset, longer-acting calcium channel blockers might still have benefits in patients with MI and unstable angina, such as reducing recurrent ischemia and infarction, reducing left ventricular dilation, and possibly reducing postinfarct remodeling. Boden et al47 are proposing a study with long-acting diltiazem to assess some of these issues, and additional studies are needed. The timing of administration of calcium channel blockers after MI is another area where research is needed. In the SPRINT II study, excess mortality primarily occurred within the first 6 days of infarction, especially in patients who had low blood pressure on admission.48 There may be a window in time during which calcium channel blockers should not be administered after an infarction, but perhaps later administration in some subgroups of patients will be safe. However, there have been few studies that have prospectively determined the effects of calcium channel blockers on reperfused infarcts in humans.49 50 In regard to timing of administration, there may be a parallel to some of the studies with angiotensin-converting enzyme inhibitors. Captopril was shown to improve survival when begun later after infarction (SAVE); however, in CONSENUS II, very early administration of enalapril after infarction did not improve survival, and some investigators postulated that administration of vasodilators too soon during an infarction may precipitate hypotension and decrease coronary perfusion.

Long-term, prospective, randomized-outcome studies are needed to assess the effects of the newer calcium channel blockers in patients with chronic stable angina, Prinzmetal's angina, syndrome X, and hypertension. One such study, the National Institutes of Health ALLHAT trial, is under way and will be assessing the effects of several of the newer antihypertensive agents (including the calcium channel blocker amlodipine) on morbidity and mortality in patients with chronic hypertension. It is likely that these large prospective trials will yield key data that will allow clinicians to prescribe drugs in a wiser fashion.

Finally, there are other cardiovascular disorders for which the calcium channel blockers show promise and for which additional studies are needed. Nifedipine was shown to delay the need for aortic valve replacement in patients with aortic regurgitation51 ; both nifedipine and diltiazem have shown promise in improving morbidity and mortality in patients with primary pulmonary hypertension—a disease that has been notoriously difficult to treat.52

Should we deny patients whose vasospastic angina, hypertension, chronic angina, pulmonary hypertension, and aortic regurgitation are well controlled on calcium blockers access to these medicines based on the meta-analysis?15 Each physician will have to judge for himself or herself, but each must take into account the positive as well as the negative studies in the literature, the strengths and limitations of meta-analysis, and advances in drug delivery and pharmacokinetics of the newer calcium channel blockers.


*    Acknowledgments
 
I thank the following individuals for their helpful comments and review of this editorial: Charles Hennekens, James Muller, Richard Nesto, and William W. Parmley. I thank Cathy Davisson for her excellent typing skills in preparing the manuscript.


*    Footnotes
 
Section of Cardiology, University of Southern California, Director of Research, Good Samaritan Hospital, Heart Institute (Los Angeles).


*    References
up arrowTop
 up arrowIntroduction
 *References
 

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