Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: A critical analysis based on 100 studies

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Abstract

Recently, serious concerns have been expressed about the long-term safety of the calcium channel blockers (CCBs) as a group. Safety and efficacy are, however, ultimately linked to each other; therefore both must be evaluated especially in the therapy of angina and hypertension, the main clinical indications for CCBs. The structural, functional, and pharmacokinetic heterogeneity of CCBs means that the efficacy and dangers of one subclass, such as the short-acting dihydropyridines (DHPs), in one situation, such as unstable angina, do not necessarily apply in other clinical situations. One hundred studies are reviewed according to their methods of data collection: case series, case control, cohort, randomized controlled trials (RCTs), and meta-analyses. Large, well-designed RCTs and the meta-analyses based on these trials remain the gold standard. Observational studies, though potentially less reliable sources of information because of selection bias, may nevertheless produce hypotheses that must then be tested in RCTs. Regarding safety, both observational studies and RCTs suggest that adverse effects of CCBs may be linked to short-acting agents, specifically short-acting nifedipine. Two good studies favor the safety of verapamil, even in short-acting form. Incomplete but increasing overall evidence favors the safety of longer-acting DHPs. Heart failure remains a class contraindication to the use of all CCBs, with some exceptions. Regarding efficacy, there are positive results of RCTs with CCBs in 2 specific clinical situations, namely, verapamil in postinfarct protection in the absence of pre-existing heart failure, and 2 outcome studies on hypertension with longer acting DHPs. These results cannot automatically be applied to other clinical situations and to other CCBs. For example, there is no evidence for the safety or efficacy of DHPs used without β blockers in postinfarct patients. In diabetic hypertensives, 2 relatively large RCTs show that the blood pressure can be reduced by DHP-based therapy in diabetics, with a reduction in hard end points. To achieve current blood pressure goals, combination therapy is almost always necessary, and in diabetics there is strong evidence that 1 essential component should be an angiotensin converting enzyme inhibitor. The future aim with CCBs must be to obtain a large database gathered from RCTs, which will give the same certainty about efficacy and safety that already holds for use of the diuretics in hypertension, β-blockers in postmyocardial infarction patients, and the angiotensin converting enzyme inhibitors in heart failure. Copyright © 2000 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 43, No. 2 (September/October), 2000: pp 171-196

Section snippets

Safety and efficacy

A hierarchy exists for the significance of end points, the most important being prolongation of life, with secondary end points being reductions in morbidity, relief of symptoms such as anginal pain, or other measures of the quality of life. Surrogate end points are those that improve neither the quantity nor quality of life but which are theoretically expected to prevent disease by reducing risk factors. Examples of surrogate end points are treating arterial hypertension or lowering elevated

Proposed hierarchy of evidence in the evaluation of safety

Safety is not well defined but could be regarded as the absence of significant adverse effects when the drug is used with due regard for its known contraindications (Table 1). Safety implies the added assurance that there are no hidden dangers in the legitimate use of the drug. Evidence for safety, like evidence for efficacy, can come from a variety of sources. We propose that there is a hierarchy of evidence, starting from anecdotal case reports that are the least reliable, followed by case

RCTs of CCBs in chronic stable effort angina

There are only 2 relatively small outcome RCTs comparing CCBs with β-blockers in effort angina, neither trial having a placebo arm (Table 4).In the Angina Prognosis Study in Stockholm (APSIS) study,15 slow-release verapamil was compared with metoprolol, whereas in the Total Ischaemic Burden European Trial (TIBET)16 slow-release nifedipine was compared with atenolol. In both cases safety and efficacy were approximately equal.17 The real problem is that the incidence of major end points such as

RCTs in unstable angina

With the collapse of the vasospastic hypothesis for unstable angina, there is no special case for the use of CCBs.26 In the case of unstable angina, there is a difference in the safety profile of the DHPs and non-DHPs when they are tested against short-term, 48-hour end points. Of the DHPs, only short-acting nifedipine has been well tested with an adverse outcome in 2 trials. In the Holland Inter-University Nifedipine (HINT) study,27 which used the end points of recurrent ischemia or myocardial

Early-Phase acute myocardial infarction

There is no good evidence for benefit of DHPs in early-phase acute myocardial infarction (AMI), when starting within some hours of the onset; rather, short-acting nifedipine may increase mortality rates.[28], [35] Results of 2 studies of threatened or diagnosed AMI revealed that short-acting nifedipine increased mortality rates in early-phase AMI.[29], [35] The short-term mortality rate was 46/587 versus 28/590 for controls (P = .04, 2-tailed chi-squared test; Table 5).These data reinforce the

Outcome studies with CCBs in vascular disease

Experimentally, CCBs inhibit atherogenesis. CCBs are not at present established as agents that prevent the progression of vascular disease,[55], [56], [57], [58] although several trials have had positive results[59], [60] (Table 6).In the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) study55 a small effect on arterial patency was annulled by a significant increase in mortality rates despite the relatively small sample size. In selected patients with peripheral occlusive

Cohort and case control studies: cardiovascular risk and mortality

There are 8 studies of hypertensives treated with CCBs with variable results (Table 7).tableIn the Framingham cohort,64 follow up of 3,539 hypertensives over 2 to 12 years showed a RR for mortality of 0.93 (not significant) for CCB users compared with nonusers. In the United Kingdom-based Department of Health Hypertension Care Computing Project (DHCCP),65 those treated with a CCB had a mortality RR of 1.03 (CI, 0.85 to 1.25) when compared with all other treatments.

Outcome in essential hypertension

There are now several

Congestive heart failure studies

There are several relatively small studies of CCBs in congestive heart failure (Table 9).Amlodipine, added to conventional therapy, had no overall benefit in the Prospective Randomized Amlodipine Survival Evaluation Group (PRAISE) study96 and some risk (6% v placebo 3%) of pulmonary edema. Subgroup data suggested that amlodipine unexpectedly lessened mortality rates in patients with nonischemic cardiomyopathy, providing a hypothesis not supported by the much larger PRAISE II study.97 The

Accepted indications for CCBs

Generally, accepted indications for the efficacy (but not safety) of CCBs are Prinzmetal's variant angina100 or other situations in which major vasoconstriction is strongly suspected, such as effort-induced ST segment elevation or Raynaud's phenomenon.

Case-Control studies and safety

The potential weakness of case control studies are several, including especially the problems of confounding factors such as diabetes mellitus76 and ignorance of the reason why a given drug was chosen for an individual patient. Statistical adjustment cannot be guaranteed to remove any residual bias. Often adherence to a drug regimen cannot be guaranteed. Data from case control studies in relation to mortality rates (Table 10) or cardiovascular risk (Table 7) with CCBs do not clearly support the

Cancer

Numerous studies have appeared since the 1997 review of CCBs by the World Health Organization.111 CCBs have been linked to cancer in the elderly,117 and one study with small numbers showed a link to breast cancer.118 Two other small studies suggest that there could be a high-dose effect.[118], [119] Much larger numbers in 5 other recent studies failed to show any cancer link.[120], [121], [122], [123], [124] Of special interest is the study by Jick,119 in which there was an overall neutral

Gastrointestinal hemorrhage

The non-DHPs have been linked to gastroin-testinal (GI) hemorrhage in the elderly cohort studied by Pahor et al.101 This association is regarded as weak by the World Health Organization-International Society of Hypertension Committee111 but supported by an observational study in the very elderly.14 In the case of verapamil, this possible risk did not alter the overall survival rate.13 Overall, the RR for GI hemorrhage in observational studies with CCBs is close to unity and therefore not

The requirement for further outcome studies

In many parts of the world, CCBs are the most commonly used drugs in cardiovascular disease. However, this frequency of use contrasts with the rather scanty data for the long-term efficacy and safety of CCBs based on hard end points such as mortality and morbidity rates, except for 3 well- designed RCTs: Syst-Eur,4 DAVIT II,41 and STOP-2.6 INSIGHT and NORDIL, soon to be published, are 2 large trials in hypertensives with outcome data on morbidity and mortality (see Addendum). This deficit in

Conclusions

The ideal cardiovascular drug is both efficacious in reducing hard end points and safe. Safety, not yet well defined, may be regarded as the absence of significant adverse effects when the drug is used with due regard for its known contraindications. For example, ACE inhibitors are a widely accepted safe drug class with established efficacy for treatment of heart failure. In the case of CCBs, there has been controversy regarding both efficacy and safety. A review of 100 reports leads to the

Addendum

Two important outcome trials will be published in The Lancet later this year: INSIGHT and NORDIL (Nordic Diltiazem Study). Between them they enrolled about 18,000 patients with hypertension.

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