ArticlesHealth outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials
Introduction
Placebo-controlled trials have established that the lowering of raised blood pressure with diuretics and β-blockers as first-line agents reduces the risk of major cardiovascular complications of hypertension.1 Observational studies have suggested that short-acting calcium antagonists are inferior to diuretics and β-blockers in decreasing the risks of these complications.2, 3 Findings of two large trials have suggested that what may be important is the type of drug used to lower high blood pressure.4, 5 The investigators of the Heart Outcomes Prevention Evaluation (HOPE) trial concluded that most of the benefit of ramipril is mediated through non-blood-pressure-lowering mechanisms.4 In ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), doxazosin was inferior to chlorthalidone for several cardiovascular outcomes.5 Moreover, several controlled trials of long-acting calcium antagonists, compared with other therapies, have shown similar blood-pressure-lowering potential but trends towards high event rates.6, 7
There are no data from individual trials to allow ranking of the currently available groups of antihypertensive drugs by their preventive effects. For millions of people receiving drug therapy for hypertension, the issue of drug selection is highly relevant. The most reliable information will come from controlled clinical trials of sufficient scope and duration, because the documentation of moderate treatment differences requires a very large number of events. As MacMahon and Neil pointed out lately, about 1000 events are needed for moderate treatment-group differences of 10–15% to be detectable.8 They also drew attention to the need for a meta-analysis.
The findings of observational studies2, 3 and the emerging evidence that the type of blood-pressure-lowering drug is important4, 5 emphasise the need to find out how the long-acting calcium antagonists as a group compare with other antihypertensive agents. The main objective of this meta-analysis was to find out whether the intermediate-acting and long-acting calcium antagonists used as first-line therapy are superior, equal, or inferior to other treatments in reducing the frequency of cardiovascular complications.
Section snippets
Methods
The criteria for studies to be included in the meta-analysis were: a randomised controlled trial published in a peer-reviewed journal; inclusion of patients with hypertension; comparison of a calcium antagonist with another antihypertensive drug; assessment of cardiovascular events; follow-up of 2 years or longer; and sample size of 100 or more. Studies were identified through PubMed searches of the MEDLINE database with the MeSH headings “calcium-channel blockers”, “hypertension”, and
Results
In the nine eligible trials the total number of participants was 27 743; 12 699 were assigned a calcium antagonist and 15 044 another antihypertensive drug (table 1). The follow-up duration ranged from 2 to 7 years with an estimated total follow-up experience of about 120 000 person-years. Two trials took place in the USA, six in Europe and Israel, and one in Japan. ABCD, INSIGHT, MIDAS, and NICS-EH were double-blinded, and VHAS was masked for only 6 months; the other four trials used an
Discussion
In comparative analyses of intermediate-acting or long-acting calcium antagonists versus other antihypertensive therapies, the combined results of the nine trials that met our inclusion criteria showed that calcium antagonists were associated with a significantly higher risk of major complications of hypertension, including acute myocardial infarction, congestive heart failure and combined major cardiovascular events. No significant differences were found for the outcomes of stroke and
References (27)
- et al.
Differences between blood-pressure lowering drugs
Lancet
(2000) - et al.
Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal In Hypertension Treatment (INSIGHT)
Lancet
(2000) - et al.
Randomised trial of effects of calcium antagonists compared with diuretics and ß-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study
Lancet
(2000) - et al.
Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 study
Lancet
(1999) - et al.
Role of cytokines in the mechanism of action of amlodipine: the PRAISE Heart Failure Trial (Prospective Randomized Amlodipine Survival Evaluation)
J Am Coll Cardiol
(1997) - et al.
Differential effects of enalapril and nitrendipine on the fibrinolytic system in essential hypertension
Am Heart J
(1999) - et al.
Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension
Lancet
(1997) - et al.
Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old
Lancet
(1996) - et al.
Calcium-channel blockade and incidence of cancer in aged populations
Lancet
(1996) - et al.
Rationale and design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial
Control Clin Trials
(1998)
Rationale and design for the Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial (ALLHAT)
Am J Hypertens
Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis
JAMA
The risk of myocardial infarction associated with antihypertensive drug therapies
JAMA
Cited by (360)
Synthesis, vasorelaxant activity and 2D-QSAR study of some novel pyridazine derivatives
2016, European Journal of Medicinal ChemistrySynthesis, biological evaluation and structure-activity relationships of new phthalazinedione derivatives with vasorelaxant activity
2014, European Journal of Medicinal ChemistryRational design, synthesis and QSAR study of vasorelaxant active 3-pyridinecarbonitriles incorporating 1H-benzimidazol-2-yl function
2013, European Journal of Medicinal ChemistryIs meta-analysis the "top of the evidence pyramid" in cardiology?
2024, Cardiovascular Therapy and Prevention (Russian Federation)Calcium channel blockers versus other classes of drugs for hypertension
2022, Cochrane Database of Systematic ReviewsEffect of Amlodipine in Stroke and Myocardial infarction: A Systematic Review and Meta-analysis
2021, Cardiology and Therapy