Franz H Messerli St. Luke's-Roosevelt Hospital , Georg Noll University Hospital Zurich , Lars H Lindholm Umeå University , Hermann Haller Hannover Medical School , Luis M Ruilope 12 de Octubre Hospital , Massimo Volpe University of Rome , Luis M Ruilope 12 de Octubre Hospital

Recent evidence supports a central role for calcium channel blockers (CCBs), and in particular the dihydropyridine (DHP) agents, in the treatment of hypertension and cardiovascular disease (CVD). We review here the findings of recent trials, systematic reviews and meta-analyses that rebut those of the single, yet widely-publicised, earlier unfavourable meta-analysis. In these latest reports, CCBs emerge as effective and safe antihypertensive agents that markedly reduce the risk of cerebrovascular and cardiovascular events and also may have beneficial effects in the kidney. Thus, since most hypertensive patients need more than one agent to achieve recommended blood pressure (BP) targets, there are strong arguments often to include a CCB in the combination.

Antihypertensive Efficacy

Numerous comparative studies have demonstrated CCBs to be generally at least as effective as other classes of antihypertensive agents. Nifedipine gastrointestinal therapeutic system (GITS), for example, achieved BP reductions similar to those of co-amilozide in the Intervention as a Goal in Hypertension Treatment (INSIGHT) trial in hypertensive patients with at least one additional cardiovascular risk factor. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in a somewhat similar patient population, amlodipine, lisinopril and chlorthalidone all lowered BP to a similar extent: although the 5-year systolic BP levels were 0.8mmHg higher in the amlodipine than the chlorthalidone group (p=0.03), 5-year diastolic BP was significantly lower (0.8mmHg, p<0.001). In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) (amlodipine, adding perindopril as required versus atenolol, adding bendroflumethiazide as required), BP values were lower throughout the trial in patients receiving the amlodipine-based rather than the atenolol-based regimen.

In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, in hypertensive patients at high cardiovascular risk, amlodipine-based therapy was shown to be significantly more effective in controlling BP than that based on the angiotensin AII receptor blocker (ARB) valsartan. The amlodipine-based regimens achieved greater BP control within one month of starting therapy and, although a 24-hour ambulatory BP monitoring (ABPM) sub-study showed similar reductions in 24-hour BP after one year’s treatment with either treatment regimen, night-time BP during the last hours of the dosing interval tended to be lower with the CCB. The Blood Pressure Lowering Treatment Trialists’ Collaboration overview of 27 randomised trials also demonstrated comparable antihypertensive efficacy for CCBs versus other agents.

Patients with a high salt intake respond well to CCBs, due to their diuretic and natriuretic properties, in contrast to those on ACE inhibitors or ARBs. Nifedipine, at a dose of 90mg (as the sustained-release GITS preparation) was as effective as 50mg of hydrochlorothiazide in a cross-over study in a group of 10 mild hypertensives treated for a period of eight weeks. Probably, most patients in VALUE were not restricting their salt intake, which may explain the efficacy of amlodipine-based versus valsartan-based treatments in that study.

Effects on Stroke

Ever since the Syst-Eur study showed a dramatic 42% reduction in stroke rate versus placebo, CCBs have been identified as efficacious antihypertensive agents in patients with cerebrovascular disease. Compared with placebo, CCBs lower the relative risk of stroke by 38–39%. This reduction is considerably greater than the 19% achieved with beta blockers, which is half that expected from previous hypertension trials. Furthermore, although stroke incidence in the control group varied considerably between the individual trials, a trend towards a reduction with CCB treatment was observed in most of them, albeit reaching significance in only one, the NORDIL (Nordic diltiazem) study, with diltiazem versus a diuretic/beta blocker. However, all DHP agents studied consistently reduced stroke risk. In the randomised, double-blind, placebocontrolled A Coronary disease Trial investigating Outcome with Nifedipine GITS (ACTION) study in which nifedipine GITS was compared with placebo, significant reductions of 28% and 27% were seen the incidence of any stroke or transient ischaemic attack (TIA) in both the total population and the hypertensive subgroup, respectively. Moreover, in the hypertensive patients, nifedipine GITS significantly reduced by 33% versus placebo the incidence of debilitating stroke (see Table 1).

In contrast, verapamil, in both the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) study and Verapamil in Hypertension and Atherosclerosis Study (VHAS), was associated with an increased stroke incidence compared with the active comparator (atenolol/hydrochlorothiazide and chlorthalidone, respectively). It should be noted, however, that both CONVINCE and VHAS were inadequately powered and that the results of INternational VErapamil SR-Trandolapril Study (INVEST) (see below) demonstrated a reduction in the risk of stroke with verapamil-based versus betablocker-based therapy.