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QUESTION: In patients with hypertension, are calcium antagonists (CAs) as first line treatment superior, equal, or inferior to other antihypertensive drugs for reducing major cardiovascular events?
Studies were identified by searching Medline up to September 2000, the US National Library of Medicine clinical trials database, and the Cochrane Library; by reviewing reference lists of identified articles; and by contacting colleagues.
Studies were selected if they were randomised controlled trials published in peer reviewed journals that included >100 patients with hypertension who were allocated to first line treatment with a CA or other antihypertensive agent and who were followed for ≥2 years for the assessment of cardiovascular events.
Data were extracted on drug type and dose, patient characteristics, and main outcomes. Summary data were pooled.
9 trials involving 27 743 patients with about 120 000 person years of follow up met the selection criteria. CAs and other antihypertensive agents led to similar reductions in blood pressure. Patients assigned to diuretics, β blockers, angiotensin converting enzyme (ACE) inhibitors, or clonidine (n=15 044) had a lower risk for myocardial infarction (MI), congestive heart failure, and major cardiovascular events than those allocated to CAs (n=12 699) (table). No statistically significant differences were found for stroke or all cause mortality (table).
In patients with hypertension, initial treatment with calcium antagonists leads to higher risks for myocardial infarction, congestive heart failure, and major cardiovascular events than treatment with other antihypertensive agents.
Bottom line interpretations of these 2 meta-analyses will vary depending on previous beliefs. For methodological purists and fans of CAs, the data neither prove nor refute the choice of CAs as first line agents for adults with hypertension or those at high risk for cardiovascular disease. For those of us who are already wary of using CAs as a first line treatment, the data support our practice of avoiding these agents. Many of us, regardless of our previous beliefs, may now question whether we should either begin reserving or using CAs specifically for people who have high risk for stroke. Such a decision would be premature for at least 2 reasons. Firstly, we cannot reliably determine whether an individual is likely to have a stroke and no cardiac outcomes. Secondly, the important meta-analyses summarised here are limited and complicated.
The meta-analyses have limited power to precisely assess stroke and cardiac outcomes because few large, long term trials exist that directly compare the effects of different antihypertensive agents. They are complicated because they combine data from trials characterised by either discontinuation of initial antihypertensive drug treatments or the addition of second and third antihypertensive agents. They make comparisons by grouping all drugs within a class together (eg, CAs) as well as by grouping drugs across classes together (eg, diuretics and β blockers). This method is dicey because all antihypertensive drugs have actions other than that of lowering blood pressure, and mechanisms by which a drug lowers blood pressure probably have effects independent of the blood pressure lowering effect.1 Moreover, mechanisms of action and effects may vary among antihypertensive drugs within classes as well as across classes.
The reviews include trials that involved various groups of patients with different risks for cardiovascular disease. Pathways that lead people with diabetes, renal disease, hypertension, or CAD to experience cardiovascular outcomes may differ. Antihypertensive agents may have specific effects on causal pathways unique to particular groups of patients. Generalising the results of meta-analyses that are based on few trials is potentially misleading: 1 or 2 large trials that tested a specific drug in a particular population could drive the results. The determinants of cause specific outcomes, such as stroke and CAD, probably differ, even among people who share common risk factors (eg, patients with hypertension). Although such drugs as CAs may differentially affect pathways that lead to strokes from those that lead to CAD, meta-analyses based on few trials cannot easily disentangle specific from class effects of antihypertensive drugs. Finally, the reviews are limited because they do not address the side effects and costs of different drugs.
Regardless, both meta-analyses are important summaries of accumulating evidence. Some diuretics, β blockers, ACE inhibitors, and CAs have proven morbidity and mortality benefits for some people with hypertension or some who are at high risk for cardiovascular disease. Knowledge about the relative benefits and harms of the different drugs in particular groups of patients is murky but will probably become clearer in the next 5 years as larger trials that directly compare antihypertensive agents become available.
Source of funding: not stated.
For correspondence: Professor M Pahor, Sticht Center on Aging, Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Fax + 1 336 713 8588.