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