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

ROBERT J. STRAKA; AMY L. SWANSON; DAVID PARRA

ROBERT J. STRAKA, PHARM.D., AMY L. SWANSON, PHARM.D., AND DAVID PARRA, PHARM.D.

Am Fam Physician. 1998;57(7):1551-1560

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.

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.

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

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

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

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.

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)

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.

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

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 comorbidities 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.

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.

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.

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.

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 non-fatal 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

Manolio TA, Cutler JA, Furberg CD, Psaty BM, Whelton PK, Applegate WB. Trends in pharmacologic management of hypertension in the United States. Arch Intern Med. 1995;155:829-37.

JNC VI. The sixth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-45.

Drug Facts and Comparisons. St. Louis, Mo.: Lippincott, 1998:149.

Psaty BM, Heckbert SR, Koepsell TD, Siscovick DS, Raghunathan TE, Weiss NS, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA. 1995;274:620-5.

Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation. 1995;92:1326-31.

National Heart, Lung, and Blood Institute. New analyses regarding the safety of calcium-channel blockers: a statement for health professionals from the National Heart, Lung, and Blood Institute. Statement issued Sept. 1, 1995.

Pahor M, Guralnik JM, Furberg CD, Carbonin P, Havlik R. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet. 1996;347:1061-5.

Pahor M, Guralnik JM, Ferrucci L, Corti MC, Salive ME, Cerhan JR, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet. 1996;348:493-7.

Epstein M. Calcium antagonists should continue to be used for first-line treatment of hypertension. Arch Intern Med. 1995;155:2150-6.

Kloner RA. Nifedipine in ischemic heart disease. Circulation. 1995;92:1074-8.

Wagenknecht LE, Furberg CD, Hammon JW, Legault C, Troost BT. Surgical bleeding: unexpected effect of a calcium antagonist. BMJ. 1995;310:776-7.

Egstrup K, Andersen PE. Transient myocardial ischemia during nifedipine therapy in stable angina pectoris, and its relation to coronary collateral flow and comparison with metoprolol. Am J Cardiol. 1993;71:177-83.

Ruzicka M, Leenen F. Relevance of intermittent increases in sympathetic activity for adverse outcome on short-acting calcium antagonists. In: Laragh J, Brenner B, eds. Hypertension: pathophysiology, diagnosis, and management. New York: Raven, 1995:2815–25.

Stone PH, Muller JE, Turi ZG, Geltman E, Jaffe AS, Braunwald E. Efficacy of nifedipine therapy in patients with refractory angina pectoris: significance of the presence of coronary vasospasm. Am Heart J. 1983;106:644-52.

Thadani U, Zellner SR, Glasser S, Bittar N, Montoro R, Miller AB, et al. Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris. Circulation. 1991;84:2398-408.

Packer M. Pathophysiological mechanisms underlying the adverse effects of calcium channel-blocking drugs in patients with chronic heart failure. Circulation. 1989;80:IV59-67.

Roine RO, Kaste M, Kinnunen A, Nikki P, Sarna S, Kajaste S. Nimodipine after resuscitation from out-of-hospital ventricular fibrillation. A placebo-controlled, double-blind, randomized trial. JAMA. 1990;264:3171-7.

Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med. 1991;324:1225-31.

Gore JM, Sloan M, Price TR, Randall AM, Bovill E, Collen D, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, Phase II, pilot and clinical trial. Circulation. 1991;83:448-59.

Lubbe WF, Podzuweit T, Opie LH. Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. J Am Coll Cardiol. 1992;19:1622-33.

Bigger JT, Coromilas J, Rolnitzky LM, Fleiss JL, Kleiger RE. Effect of diltiazem on cardiac rate and rhythm after myocardial infarction. Multicenter Diltiazem Postinfarction Trial Investigators. Am J Cardiol. 1990;65:539-46.

Waters D. Proischemic complications of dihydropyridine calcium channel blockers. Circulation. 1991;84:2598-600.

Carboni GP, D'Ermo M, Mattioli M, Lioy E, Biffani G. The response of the coronary collateral circulation to acute administration of nifedipine: an angiographic and ergometric study. Int J Cardiol. 1986;11:25-36.

Malacoff RF, Lorell BH, Mudge GH, Holman BL, Idoine J, Bifolck L, et al. Beneficial effects of nifedipine on regional myocardial blood flow in patients with coronary artery disease. Circulation. 1982;65:I32-7.

Kugiyama K, Yasue H, Horio Y, Morikami Y, Fujii H, Koga Y, et al. Effects of propranolol and nifedipine on exercise-induced attack in patients with variant angina: assessment by exercise thallium-201 myocardial scintigraphy with quantitative rotational tomography. Circulation. 1986;74:374-80.

Bonaduce D, Muto P, Morgano G, Canonico V, Breglio R, Salvatore M, et al. Effect of nifedipine on dipyridamole thallium-201 myocardial scintigraphy. Clin Cardiol. 1986;9:285-8.

Hayward R, Hunter GJ, Swanton H. Effects of nifedipine on coronary perfusion; recent assessment by parametric digital subtraction. Eur Heart J. 1987;8:1-7.

Furberg CD, Pahor M, Psaty BM. The unnecessary controversy. Eur Heart J. 1996;17:1142-7.

Pahor M, Guralnik JM, Salive ME, Corti MC, Carbonin P, Havlik RJ. Do calcium channel blockers increase the risk of cancer?. Am J Hypertens. 1996;9:695-9.

Connor J, Sawczuk IS, Benson MC, Tomashefsky P, O'Toole KM, Olsson CA, et al. Calcium channel antagonists delay regression of androgen-dependent tissues and suppress gene activity associated with cell death. Prostate. 1988;13:119-30.

Juntti-Berggren L, Larsson O, Rorsman P, Ammala C, Bokvist K, Wahlander K, et al. Increased activity of L-type Ca2+ channels exposed to serum from patients with type I diabetes. Science. 1993;261:86-90.

Ray SD, Kamendulis LM, Gurule MW, Yorkin RD, Corcoran GB. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J. 1993;7:453-63.

Zacharski LR, Moritz TE, Haakenson CM, O'Donnell JF, Ballard HS, Johnson GJ, et al. Chronic calcium antagonist use in carcinoma of the lung and colon: a retrospective cohort observational study. Cancer Invest. 1990;8:451-8.

Pales J, Palacios-Araus L, Lopez A, Gual A. Effects of dihydropyridines and inorganic calcium blockers on aggregation and on intracellular free calcium in platelets. Biochim Biophys Acta. 1991;1064:169-74.

Blache D, Ojeda C. Comparative inhibitory effects of dihydropyridines on platelet aggregation, calcium uptake and cyclic AMP concentration. Pharmacology. 1992;45:250-9.

Berkels R, Klaus W, Boller M, Rosen R. The calcium modulator nifedipine exerts its antiaggregatory property via a nitric oxide mediated process. Thromb Haemost. 1994;72:309-12.

National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Circulation. 1994;89:1333-445.

Pahor M, Guralnik JM, Corti MC, Foley DJ, Carbonin P, Havlik RJ. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc. 1995;43:1191-7.

van Harten J, Burggraaf K, Danhof M, van Brummelen P, Breimer DD. Negligible sublingual absorption of nifedipine. Lancet. 1987;2:1363-5.

Grossman E, Messerli FH, Grodzicki T, Kowey P. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies?. JAMA. 1996;276:1328-31.

McAllister RG. Kinetics and dynamics of nifedipine after oral and sublingual doses. Am J Med. 1986;81:2-5.

Messerli FH, Kowey P, Grodzicki T. Sublingual nifedipine for hypertensive emergencies. Lancet. 1991;338:881.

Effect of verapamil on mortality and major events after acute myocardial infarction (The Danish Verapamil Infarction Trial II—DAVIT II). Am J Cardiol. 1990;66:779-85.

The Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988;319:385-92.

Rehnqvist N, Hjemdahl P, Billing E, Bjorkander I, Eriksson SV, Forslund L, et al. Effects of metoprolol vs verapamil in patients with stable angina pectoris. Eur Heart J. 1996;17(1):76-81.

Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med. 1996;335:1107-14.

Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation. 1997;96(3):856-63.

Saunders E. Recruitment of African-American patients for clinical trials—the Allhat challenges. Antihypertensive and Lipid-lowering Trial to Prevent Heart Attack. J Natl Med Assoc. 1995;87:627-9.