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Calcium Channel Antagonists: Morbidity and Mortality--What's the Evidence?

ROBERT J. STRAKA, PHARM.D., and AMY L. SWANSON, PHARM.D.

University of Minnesota College of Pharmacy, Minneapolis, Minnesota

DAVID PARRA, PHARM.D.,

Veterans Affairs Medical Center, West Palm Beach, Florida

Recent studies have shown an association between the use of calcium channel antagonists for the treatment of hypertension and an increased risk of myocardial infarction, gastrointestinal hemorrhage and cancer. The interpretation of the results of these studies and their application to clinical practice requires an understanding of study design constraints, conflicting results and limitations in extrapolating study findings to other dosage strengths, formulations or agents within the calcium channel antagonist class. A review and critique of these studies provides background information on the controversial subject of using calcium channel antagonists for the treatment of hypertension. Despite the limitations of these studies, clinicians may want to select other classes of agents, including diuretics and beta blockers, as first-line therapy until the morbidity and mortality effects related to the use of calcium channel antagonists are clearly known.

Reports have suggested that calcium channel blockers, especially at higher dosages, may be associated with an increased risk of myocardial infarction and mortality.

During the past decade, calcium channel antagonists have become one of the most widely used classes of drugs in the treatment of angina and hypertension.¹ This wide usage has occurred despite the lack of demonstrated clinical benefit in terms of reducing morbidity and mortality associated with hypertension. Currently, the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI)² advocates the use of beta blockers and diuretics as first-line therapy. This position is largely based on the fact that these are the only classes of drugs that have demonstrated benefits in morbidity and mortality when used to treat patients with hypertension. Characteristics of the commonly used calcium channel antagonists are given in Tables 1³ and 2.

TABLE 1 Pharmacology of Calcium Channel Blocking Agents Agent Heart rate Myocardial contractility* Cardiac output Peripheral vascular resistance Nifedipine/SR Verapamil Diltiazem/SR to 0 0 to Felodipine ± Amlodipine ± Isradipine ± 0 Nicardipine 0 Nisoldipine ± 0 0 Nimodipine N/A N/A N/A N/A Bepridil 0 or =pronounced effect; or =moderate effect; or =slight effect; ±=negligible effect; N/A=not applicable. *--Direct effects may be counteracted by reflex activity. Adapted with permission from Drug Facts and Comparisons. St. Louis, Mo.: Lippincott, 1998:149-149a.

TABLE 2 Comparison of Approved Calcium Channel Blockers Agent Formulation FDA-approved indications Dosage forms (mg) Initial dosage Maximum dosage Dosing comments Mibefradil Immediate release Hypertension, angina 50-, 100-mg tablets 50 mg daily 100 mg daily Take with or without food Verapamil Immediate and sustained release Hypertension, supraventricular tachycardia, angina Immediate release: 40-, 80-, 120-mg tablets; sustained release: 120-, 180-, 240-mg tablets or caplets Immediate release: 40 mg three times daily; sustained release: 120 to 180 mg daily* Immediate release: 480 mg daily; sustained release: 240 mg twice daily or 480 mg daily* Immediate release: take with or without food; sustained release: take with food or at bedtime* Diltiazem Immediate and sustained release Hypertension, angina Immediate release: 30-, 60-, 90-, 120-mg tablets; sustained release: 60-, 90-, 120-, 180-, 240-, 300-, 360-mg capsules Immediate release: 30 mg four times daily; sustained release: 120 or 180 mg daily* Immediate release: 360 mg daily; sustained release: 360, 480 or 540 mg daily* Immediate release: take before meals; sustained release: take with or without food or on empty stomach* Nifedipine Immediate and sustained release Hypertension, angina Immediate release: 10-, 20-mg capsules; sustained release: 30-, 60-, 90-mg tablets Immediate release: 10 mg three times daily; sustained release: 30 mg daily Immediate release: 180 mg daily; sustained release: 90 or 120 mg daily* Immediate release: take with or without food; sustained release: take with or without food or on empty stomach* Amlodipine Immediate release Hypertension, angina 2.5-, 5-, 10-mg tablets 5 mg daily (in rare cases, 2.5 mg daily) 10 mg daily Take with or without food Felodipine Extended release Hypertension 2.5-, 5-, 10-mg tablets 5 mg daily 10 mg daily Bioavailability doubles when taken with grapefruit juice Isradipine Immediate release Hypertension 2.5-, 5-mg capsules 2.5 mg twice daily 20 mg daily Take with or without food Nicardipine Immediate and sustained release Immediate release: angina; sustained release: hypertension Immediate release: 20-, 30-mg capsules; sustained release: 30-, 45-, 60-mg capsules Immediate release: 20 mg three times daily; sustained release: 30 mg twice daily Immediate release: 90 mg daily; sustained release: 120 mg daily Take on empty stomach Nisoldipine Extended release Hypertension 10-, 20-, 30-, 40-mg tablets 20 mg daily 60 mg daily Avoid taking with high-fat meal Nimodipine Immediate release Subarachnoid hemorrhage 30-mg capsules 60 mg four times daily 60 mg four times daily Liquid-filled capsule; may go down nasogastral tube Bepridil Immediate release Angina 200-, 300-, 400-mg tablets 200 mg daily 400 mg daily May take with food *--Depending on brand used.

Reports have suggested that calcium channel antagonists may be associated with an increase in the risk of myocardial infarction and mortality in patients with hypertension or coronary artery disease. Furthermore, this association is especially strong in patients taking higher daily dosages of these agents, particularly immediate-release nifedipine.^4,5 In response to these reports,⁶ the National Heart, Lung, and Blood Institute issued a statement recommending that "short-acting nifedipine should be used with great caution (if at all), especially at higher doses in the treatment of hypertension, angina and myocardial infarction." In addition, recent reports suggest that calcium channel antagonists may increase the risk of gastrointestinal hemorrhage and cancer in the elderly.^7,8

TABLE 3 Possible Mechanisms of Action Behind the Alleged Adverse Effects of Calcium Channel Antagonists Mortality/myocardial infarction Reflex increase in sympathetic activity (specifically for shorter-acting formulations) Proischemic effects (coronary steal phenomenon) Negative inotropic effects (specifically verapamil and diltiazem) Arrhythmogenic effects Activation of renin-angiotensin system Potentiation of catecholamine-induced arrhythmias Increased production of mineralocorticoids resulting in potassium depletion Prohemorrhagic effects Prevention of calcium influx in response to several platelet activators Gastrointestinal hemorrhage Cancer Inhibition of apoptosis (programmed cell death)

Speculative mechanisms of action behind these effects are listed in Table 3, and there is evidence to both support and refute these mechanisms as potential causes of the alleged detrimental effects of calcium channel antagonists.^5-36 A critical evaluation of recently published studies and their findings is necessary to allow clinicians to make rational, informed decisions regarding the proper use of calcium channel antagonists in the treatment of hypertension in a clinical practice setting.

Association with Myocardial Infarction

The first of several recent studies investigating potential detrimental effects of calcium channel antagonists was conducted by Psaty and associates.⁴ This case-control study was designed to evaluate the possible association between a first incident of myocardial infarction and the use of antihypertensive agents. Patients with hypertension who had sustained a myocardial infarction were compared with matched control patients with hypertension who had not sustained a myocardial infarction. This initial analysis⁴ involved only patients without cardiovascular disease who were prescribed beta blockers, calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors or vasodilators, as monotherapy or in combination with diuretics. A second analysis⁴ included only those patients with or without cardiovascular disease who were prescribed either calcium channel antagonists or beta blockers for treatment of hypertension. Results of these two analyses are shown in Table 4. The authors concluded that patients taking a short-acting calcium channel antagonist for the treatment of hypertension were at greater risk for the development of a myocardial infarction than those taking beta blockers. In addition, they concluded that the risk increased as the dosage of the calcium channel antagonist increased.

Today's standard of care strongly favors the use of long-acting preparations in the treatment of both hypertension and angina.

Although the study by Psaty and colleagues⁴ showed an association between the use of calcium channel antagonists and myocardial infarction, it had several limitations. The first of these limitations involves the nature of the study design. The investigation was a retrospective, case-control study in which subjects were chosen for participation because they had pharmacologically treated hypertension. The reasons that patients may have been prescribed a calcium channel antagonist rather than an agent from a different class of drugs (lack of randomization) are not known. Without knowledge of the patients' past medical history, including co-morbidities and severity of hypertension, it becomes difficult to ascribe the occurrence of the myocardial infarction to the use of calcium channel antagonists. Furthermore, since diabetes is a known risk factor for the development of myocardial infarction,³⁷ interpretation of this study is confounded by the fact that there was a statistically significant higher percentage of patients with diabetes among those receiving calcium channel antagonists compared with those receiving beta blockers.

Another limitation of this study was the use of short-acting calcium channel antagonists. Short-acting nifedipine and diltiazem are not approved for use in hypertension, which was their role in this study. Today's standard of practice strongly favors the use of the long-acting preparations for treating both hypertension and angina, and it is essential that the results of a study involving short-acting agents not be extrapolated to the long-acting calcium channel antagonists. The long-acting formulations are considered to be optimal for use in most patients, because they lack extreme variability in differences between peak and trough plasma concentrations, and have a lower incidence of profound hypotension and a decreased frequency of the reflex tachycardia that is associated with the immediate-release formulations. Compliance is also an issue when an agent must be taken three to four times a day compared with once a day.

In a meta-analysis conducted by Furberg and associates,⁵ similar results regarding a dose response between nifedipine and mortality were reported (Table 4). The authors found that nifedipine was associated with an increase in total mortality when data from all trials were combined. When the data were further analyzed, patients who were prescribed nifedipine at daily dosages greater than 80 mg were at an even greater risk of mortality than those prescribed lower daily dosages. The authors concluded that the use of higher dosages of short-acting nifedipine may cause an increase in total mortality in patients with various degrees of coronary artery disease.

TABLE 4 Summary of Pertinent Studies of Calcium Channel Blockers Risk factor Agent Relative risk 95% confidence interval Statistically significant Risk of myocardial infarction (Psaty, et al.4) Calcium channel antagonist alone Calcium channel antagonist with diuretics Nifedipine Diltiazem Verapamil Low-dose calcium channel antagonists Medium-dose calcium channel antagonists High-dose calcium channel antagonists 1.58 1.70 1.31 1.63 1.61 1.13 1.42 1.81 1.04 to 2.39 0.97 to 2.99 0.85 to 2.01 1.06 to 2.50 1.19 to 2.17 0.75 to 1.71 0.97 to 2.07 1.20 to 2.75 Yes No No Yes Yes No No Yes Risk of mortality (Furberg, et al.5) Nifedipine Nifedipine, 30 to 50 mg per day Nifedipine, 60 mg per day Nifedipine, 80 mg per day 1.16 1.06 1.18 2.83 1.01 to 1.33 0.89 to 1.27 0.93 to 1.50 1.35 to 5.93 Yes No No Yes Risk of gastrointestinal hemorrhage (Pahor, et al.7) ACE inhibitors Calcium channel antagonists 1.23 1.86 0.66 to 2.28 1.22 to 2.82 No Yes Risk of cancer (Pahor, et al.8) Calcium channel antagonists 1.72 1.27 to 2.34 Yes Risk of mortality (Pahor, et al.38) Verapamil Diltiazem Nifedipine ACE inhibitors Nifedipine, <=20 mg per day Nifedipine, > 20 mg per day 0.8 1.3 1.7 0.9 1.4 3.1 0.4 to 1.4 0.8 to 2.1 1.1 to 2.7 0.6 to 1.4 0.5 to 4.4 1.7 to 5.8 No No Yes No No Yes ACE=angiotensin-converting enzyme. Information from references 4, 5, 7, 8 and 38.

As with the previous study,⁴ the meta-analysis⁵ has several limitations. Patient populations in a meta-analysis should be as homogeneous as possible so that valid comparisons can be made between the separate studies analyzed. In the meta-analysis, patients with varying degrees of coronary artery disease, such as stable angina, unstable angina and myocardial infarction, were evaluated. This places certain groups at a different risk of death than others, regardless of the prescribed dosage of nifedipine, making the results of the study difficult to apply to a specific patient type.

Another limitation is the possible bias in criteria used for data selection. For example, the time frames in which patients were analyzed ranged from two weeks to as long as six months, depending on the study. Involving trials with similar durations of study periods may eliminate a source of bias, thus altering the findings. This study⁵ also included data solely on the short-acting formulation of nifedipine, which has inherent limitations, as described previously. Lastly, Furberg and associates⁵ conclude that other types of calcium channel antagonists may show similar findings. Verapamil, a phenylalkylamine, and diltiazem, a benzothiazepine, are structurally unrelated to nifedipine and have different effects on the cardiovascular system than nifedipine. Therefore, it would not be appropriate to extrapolate the findings related to nifedipine to verapamil and diltiazem.

Association with Gastrointestinal Hemorrhage

Calcium channel antagonists have been shown to have prohemorrhagic effects; specifically, they inhibit platelet aggregation. Pahor and colleagues⁷ conducted a study to determine whether an increased risk of gastrointestinal hemorrhage exists among patients who take calcium channel antagonists. This was a prospective cohort study of 1,636 patients more than 67 years of age who were prescribed either beta blockers, ACE inhibitors or calcium channel antagonists as monotherapy for hypertension. Hospital discharge diagnoses and death certificates were used to assess the incidence of gastrointestinal hemorrhage. A summary of results is shown in Table 4. The authors concluded that an association exists between the use of calcium channel antagonists and the risk of gastrointestinal hemorrhage in the elderly population.

A summary of the shortcomings of this study,⁷ along with a statement regarding the significance of each, can be found in Table 5.^2,7,8,38 However, two limitations to the study deserve specific mention. The influence of histamine H₂-receptor antagonists, proton pump inhibitors, sucralfate and antacids was not analyzed. Each of these agents may play an important role in the prevention and development of gastrointestinal hemorrhage. In addition, the cause of gastrointestinal hemorrhage was not given, although comorbidities were identified.

TABLE 5 Limitations of Selected Studies and Their Significance Limitation Significance Observational study design Inability to formulate a cause-and-effect relationship. Definition of hypertension Authors defined hypertension as any measured DBP >=90 mm Hg, any SBP >=140 mm Hg, or any similar self-reported measurement. JNC VI guidelines define hypertension based on the average of two or more readings taken at each of two or more visits after an initial screening. Medication exposure Relied on patients' self-report and memory of subjects with an average age of 75 years. Duration of therapy Measured only at baseline and three years after baseline. No information given on length of treatment, making a cause-and-effect relationship difficult to establish. Outcome measures Outcomes obtained from hospital discharge diagnoses and death certificates. Individual review of medical records would have been more accurate. DBP=diastolic blood pressure; SBP=systolic blood pressure; JNC VI=Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. Information derived from references 2, 7, 8 and 38.

Possible risk factors for gastrointestinal hemorrhage, among many, could include the use of thrombolytics, heparin, ethanol, NSAIDs and steroids, and trauma. Without knowledge of the underlying cause of the gastrointestinal hemorrhage, no definitive conclusion may be made that the use of calcium channel antagonists in the elderly increases the risk of gastrointestinal hemorrhage. It is important to remember that the antiplatelet effects of calcium channel antagonists may be beneficial in patients with certain cardiovascular diseases, so the risks of an association with an increased risk of gastrointestinal hemorrhage must be weighed against the benefits of treating diseases, such as hypertension and angina, when considering a patient for therapy with one of these agents.

Association with Cancer

Also recently published is a study⁸ to assess whether the long-term use of calcium channel antagonists is associated with an increased risk of cancer. The prospective cohort study design involved 5,052 people 71 years of age or older. Patients who were prescribed calcium channel antagonists for hypertension were compared with those who were not given such medication. Hospital discharge diagnoses and death certificates were used to assess the incidence of cancer. Results of this study are shown in Table 4. The authors concluded that an increased risk of cancer in the elderly was associated with the use of calcium channel antagonists.

Many of the limitations of the previous study by Pahor and associates⁷ (Table 5) are applicable to this study⁸ as well. A major issue is the difference between the two populations studied. In general, patients who were prescribed calcium channel antagonists had a statistically significant higher percentage of comorbidities, including coronary heart disease, heart failure, hypertension, stroke and diabetes. In addition, they had a statistically significant higher percentage of physical disabilities and a higher number of hospital admissions. Not only were the patients who were prescribed calcium channel antagonists sicker than those in the control group, but they may have had a greater likelihood of cancer detection since they had more frequent hospital admissions. This study, like the others, also involved mainly short-acting formulations of calcium channel antagonists, which have limited use today compared with the longer-acting preparations.

Increased Risk of Mortality in Elderly Patients

In a final study by Pahor and colleagues,³⁸ a prospective cohort study was used to determine whether a difference exists in the risk of mortality in older persons with hypertension treated with calcium channel antagonists and ACE inhibitors compared with those treated with beta blockers. The study included hypertensive persons 71 years of age or older, with no signs or symptoms of congestive heart failure. The major outcome variable was mortality resulting from all causes, as reported in Table 4. The authors' conclusion was that the association between mortality and hypertensive agents, specifically nifedipine, was greater in older hypertensive patients receiving short-acting nifedipine than in those receiving beta blockers.

This study,³⁸ not unlike the others previously cited,^7,8 also has limitations. As mentioned previously, no cause-and-effect relationships can be drawn from observational studies. Only associations between exposure to calcium channel antagonists and mortality can be made. Similar to the studies regarding the risks of gastrointestinal hemorrhage and cancer,^7,8 the present study³⁸ used the same methods of defining hypertension, evaluating drug exposure and obtaining outcome results. The problems associated with these techniques also hold true for this study. In addition, the nifedipine used in this trial was the short-acting formulation, not the longer-acting preparation more frequently prescribed today. Finally, the study population ranged in age from 71 to 96 years, making extrapolations of the findings to a younger population inappropriate.

Avoidance of Sublingual Nifedipine for Hypertensive Emergencies

Another important issue related to the use of calcium channel antagonists involves the administration of sublingual nifedipine in the management of hypertensive emergencies and urgencies. Although the practice has been widespread, clinical data attesting to the safety or efficacy of this intervention is lacking. In contrast, evidence exists showing that nifedipine is poorly absorbed through the buccal mucosa, and reports of serious adverse effects with sublingual or oral nifedipine are numerous in the literature.^39-42 Furthermore, in 1985 the U.S. Food and Drug Administration Cardiorenal Advisory committee reviewed the data regarding the safety and efficacy of sublingual nifedipine in hypertensive emergencies and concluded that dose-response information, as well as assessment of the true risk of a cataclysmic complication from this form of dosing, was lacking and that the practice should be abandoned because it was neither safe nor efficacious.⁴²

Data Suggesting No Increased Risk of Mortality

Several large trials have shown no increase in the risk of death associated with the use of calcium channel antagonists, including the Danish Verapamil Infarction Trial II (DAVIT II),⁴³ the Multicenter Diltiazem Postinfarction Trial Research Group,⁴⁴ the Shanghai Trial of Nifedipine in the Elderly (STONE)¹⁴ and the Angina Prognosis Study in Stockholm (APSIS).⁴⁵ More randomized controlled trials are needed to evaluate the claims related to the use of calcium channel antagonists for treating hypertension.

Sublingual nifedipine is potentially harmful and should not be used in hypertensive urgencies or emergencies.

Long-term morbidity and mortality data for calcium channel antagonist therapy are being evaluated in several studies, including the recently published Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial⁴⁶ and V-HeFT III.⁴⁷ The PRAISE trial assessed the effect of amlodipine in patients with severe chronic heart failure. Results from this trial showed that the cardiovascular mortality rate in patients treated with amlodipine was 16 percent lower than that of the placebo group. Although this reduction in mortality was not statistically significant, a PRAISE II study is underway to examine a subset of this population. The V-HeFT III trial showed no increased risk of death with felodipine.

The Antihypertensive and Lipid-lowering Trial to Prevent Heart Attack (ALLHAT)⁴⁸ is currently in progress to assess whether the use of amlodipine, lisinopril, doxazosin or chlorthalidone, in the treatment of hypertension, is associated with a decreased incidence of fatal coronary heart disease or nonfatal myocardial infarction. The Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial, developed to assess the effects of a once-daily formulation of verapamil and a beta blocker and/or diuretic, is expected to be completed in 2001. Several other trials to study the effects of calcium channel antagonists also are under way.

Final Comment

The trials involving calcium channel antagonists have several limitations, and the results are conflicting. The increased risk of mortality found in these trials was associated with the use of short-acting calcium channel antagonists and not the longer-acting preparations more commonly used today. In addition, the use of sublingual nifedipine for the treatment of hypertensive emergencies is potentially harmful and should be avoided. Until results from the previously mentioned trials are obtained, clinicians should cautiously interpret data such as that described above. They should weigh the risks or potential risks of treating hypertensive patients with calcium channel antagonists versus other agents, such as diuretics and beta blockers, which are currently recommended as first-line agents by the JNC VI guidelines.²

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

This article exemplifies the AAFP 1997-98 Annual Clinical Focus on prevention and management of cardiovascular disease.

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The Authors

ROBERT J. STRAKA, PHARM.D.,
is an associate professor at the University of Minnesota College of Pharmacy, Minneapolis. He also practices as a clinical pharmacist at Regions Hospital in St. Paul, Minn. Dr. Straka received a doctor of pharmacy degree from the University of Minnesota, Minneapolis, and served a fellowship at the University of Tennessee in Memphis.

AMY L. SWANSON, PHARM.D.,
is a pharmacy associate at the University of Minnesota College of Pharmacy. She received a doctor of pharmacy degree from the University of Minnesota and is serving a fellowship in cardiovascular pharmacotherapy.

DAVID PARRA, PHARM.D.,
is currently a clinical specialist in the Department of Cardiology at the Veterans Affairs Medical Center, West Palm Beach, Fla. He received a doctor of pharmacy degree from the University of Minnesota and completed a two-year residency and fellowship in cardiovascular pharmacotherapy.

Address correspondence to Robert J. Straka, Pharm.D., University of Minnesota College of Pharmacy, 7-148 Weaver-Densford Hall, 308 Harvard St., S.E., Minneapolis, MN 55455. Reprints are not available from the authors.

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