Amlodipine (Norvasc 5 mg $53; 10 mg $73), bepridil, diltiazem (generic XR 180 $33; Cartia XT 120 mg; 180 mg $38; 240 mg; 300 mg $63; Taztia XT 180 $42; Tiazac ER 120; 180 $60; 240; 300; 360 $98 (generic $73), felodipine, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil belong to the group of medicines called calcium channel blocking agents.

Mortality Reduced by Diltiazem: In ten randomised, controlled trials that assessed the effects of calcium channel blockers (CCBs) on cardiovascular events in patients with hypertension, six enrolled a relatively small number (< 1500), whereas four of the studies were much larger (> 4500 patients). The smaller studies produced mixed findings, especially those trials where CCBs were compared with diuretics. The results from the four larger studies produced a consistent message: long-acting CCBs such as nifedipine GITS, nitrendipine and diltiazem, reduce CV morbidity and mortality. The effects of calcium channel blockers on cardiovascular outcomes: a review of randomised controlled trials. De Leeuw PW, et al. University Hospital Maastricht, The Netherlands. p.deleeuw@intmed.unimaas.nl. Blood Press 2002;11(2):71-8.

NORDIL Study Finds Distiazem In the Nordic Diltiazem (NORDIL) Study comparing 10,881 hypertensives (DB>100) ages 50-74 on diltiazem or diuretic/beta-blocker-based treatment, systolic blood pressure (SBP) and DBP were decreased by 20.3/18.7 mmHg in the diltiazem group and by 23.3/18.7 mmHg in the diuretic/beta-blocker group - a significant difference in SBP (P < 0.001). The incidence of the total of cardiovascular death, cerebral stroke and myocardial infarction was similar for the two treatments. Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 patients in the conventional treatment group [relative risk (RR) 0.80, P = 0.040], whereas there was a non-significant inverse tendency with respect to all myocardial infarction. There were more myocardial infarctions in those with heart rate less than 74 beats/min (n = 5303, RR 1.13, P = 0.040). Influence of age, sex and blood pressure on the principal endpoints of the Nordic Diltiazem (NORDIL) Study. Kjeldsen SE, et al. Ullevaal University Hospital, Oslo, Norway. J Hypertension 2002 Jun;20(6):1231-7.

Calcium Channel Blockers: Some Safe: Two 1995 studies linked high doses of short-acting nifedipine with an increased risk of heart attack and death. A more recent European study of 6,300 people ages 55 to 80 with blood pressures higher than 150/95 mm Hg or systolic BPs over 160 with at least one additional cardiovascular risk factor were randomized to either 30 mg/day of long-acting nifedipine or a diuretic combination (25 mg hydrochlorothiazide plus 2.5 mg amiloride). After about three years, both groups had the same average BP (138/82 mm Hg), and a similar proportion of each group (6%) had died from cardiovascular disease, had a heart attack, suffered a stroke, or developed heart failure. Nearly 40% of nifedipine users withdrew because of such side effects as swollen legs and skin flushing, compared with 33% of diuretic users. But more diuretic users suffered severe adverse effects, such as impaired kidney function. In another study, nearly 11,000 people aged 50 to 74 with diastolic BPs of 100 mm Hg or higher were assigned to diltiazen 180 to 360 mg or diuretics, beta-blockers, or both. Diltiazem users had slightly fewer strokes than those taking diuretics, beta-blockers, or both. Lancet. 2000;356:352-3, 359-65. 

Calcium Channel Blockers Inferior: A meta-analysis of larger long-term studies of hypertension found nine eligible trials included 27,743 participants. Calcium antagonists and other drugs achieved similar control of both systolic and diastolic blood pressure. Compared with patients assigned diuretics, beta-blockers, angiotensin-converting-enzyme inhibitors, or clonidine (n=15,044), those assigned calcium antagonists (n=12,699) had a significantly higher risk of acute myocardial infarction (odds ratio 1.26, p=0.0003), congestive heart failure (1.25, p=0.005), and major cardiovascular events (1.10, p=0.018). The treatment differences were within the play of chance for the outcomes of stroke (0.90 [0.80-1.02], p=0.10) and all-cause mortality (1.03, p=0.54). The longer-acting calcium antagonists cannot be recommended as first-line therapy for hypertension. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials. Pahor M, Psaty BM, et al. Wake Forest University. Lancet. 2000 Dec 9;356(9246):1949-54

Nifedipine No Decrease in Death: In the DB PC ACTION study of 7665 patients, 52% were hypertensive. Some 80% were on a beta blocker; hypertensives were more often treated with other blood pressure-lowering drugs. Mean baseline blood pressure was 122/74 mmHg among normotensives and 151/85 mmHg among hypertensives. Follow-up blood pressures were reduced by nifedipine (P < 0.001) on the average by 3.9/2.4 and 6.6/3.5 mmHg among normotensives and hypertensives, respectively. Authors emphasize that nifedipine GITS (P < 0.05) reduced the combined incidence of all-cause mortality, myocardial infarction, refractory angina, heart failure, stroke and peripheral revascularization by 13% in hypertensives only. However, nifedipine did not affect all-cause death, cardiovascular death and myocardial infarction in either normo- or hypertensives, but increased the need for peripheral revascularization. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trial. Lubsen J, Wagener G, et al. Erasmus Medical and Bayer Healthcare AG, Wuppertal, Germany. J Hypertens. 2005 Mar;23(3):641-8

Diatiazem XT Did Well at Bedtime: In a DB study of 261 hypertensive adults, diltiazem XR  (240 mg titrated to 360 mg and to 540 mg) or ramipril each evening (5 mg titrated to 10 mg and to 20 mg), 76% of patients were titrated to the highest possible dose. After 10 weeks of treatment, reductions in early morning BP by diltiazem ER tablets were significantly greater (-18/-15 mm Hg) than reductions by ramipril (-13/-8 mmHg, P <.005 for systolic BP and P <.001 for diastolic BP). Diltiazem ER tablets also led to greater reductions in morning heart rate and the heart rate-pressure product compared to ramipril. Effects of graded-release diltiazem versus ramipril, dosed at bedtime, on early morning blood pressure, heart rate, and the rate-pressure product. White WB, et al. University of Connecticut. wwhite@nso1.uchc.edu. Am Heart J 2004 Oct;148(4):628-34.

In a DB study, once a night graded-release diltiazem (360 mg titrated to 540 mg after 6 weeks) had a greater benefit to morning blood pressure than morning (8 am) amlodipine 10 mg in 262 African American individuals with hypertension. The diltiazem showed significantly greater DBP reductions of 3.5 mm Hg (P < .0049) and 3.2 mm Hg (P < .0019) during the first 4 h after awakening and between 6 am and 12 noon respectively, as well as comparable reduction for the 24-h mean DBP. The SBP reductions during the morning periods were comparable, but the reduction in the 24-h mean SBP was 3.4 mm Hg greater (P < .0022) for amlodipine. Mean reductions in HR and RPP (heart rate x SBP) were significantly greater (P < or = .0008) for GRD during all intervals; amlodipine increased whereas diltiazem reduced HR with mean differences of 6.7 to 9.3 beats/min. Antihypertensive efficacy of night-time graded-release diltiazem versus morning amlodipine in African Americans. Wright JT Jr., et al. Case Western Reserve. jxw20@po.cwru.edu. Am J Hyperten 2004 Sep;17(9):734-42.

Elderly: A meta-analysis of treating patients over 80 has suggested that a reduction in stroke events of 36% may have to be balanced against a 14% increase in total mortality. In the Hypertension in the Very Elderly Trial (HYVET) study of 1283 patients over 80 with a sustained blood pressure of 160-219/90-109 mmHg allocated randomly to one of three treatments: a diuretic-based regimen (usually bendroflumethiazide; n = 426), an angiotensin-converting enzyme inhibitor regimen (usually lisinopril; n = 431) or no treatment (n = 426). The procedure permitted doses of the drug to be titrated and diltiazem slow-release to be added to active treatment. Target blood pressure was < 150/80 mmHg and mean follow-up was 13 months. In the combined actively treated groups, the reduction in stroke events relative hazard rate (RHR) was 0.47 and the reduction in stroke mortality RHR was 0.57. However, the estimate of total mortality supported the possibility of excess deaths with active treatment (RHR 1.23, 95% CI 0.75 to 2.01). Results of the pilot study for the Hypertension in the Very Elderly Trial. Bulpitt CJ, et al. Imperial College London, UK. c.bulpitt@ic.ac.uk. J Hypert 2003 Dec;21(12):2409-17.

Bedtime Dosing Better for Morning Hypertension: The efficacy and safety of a chronotherapeutic, graded-release diltiazem HCl extended-release (GRD) 120-, 240-, 360- and 540-mg dose administered once-daily at bedtime (10 PM) were evaluated in a 7-week randomized, double-blind comparison to placebo and to GRD 360 mg administered once-daily at 8 AM in 478 patients with moderate-to-severe essential hypertension. Bedtime doses of GRD showed dose-related mean reductions in trough DBP that were significant for GRD doses of 240 mg and higher. Bedtime GRD 360 mg was associated with a significantly greater reduction in mean DBP between 6 AM and 12 noon compared to morning GRD 360 mg with a least squares mean for treatment difference of -3.3 mm Hg (P =.0004). Similar dose-related and significant reductions in systolic BP (SBP) and heart rate (HR) were obtained. Incidence of adverse events (AEs) for all GRD groups (44.5%) was less than that obtained for the placebo group (49.3%). The 540-mg group showed an incidence of AEs (43.5%) similar to that observed for the 240-mg group (42.6%).  Efficacy and safety of a once daily graded-release diltiazem formulation in essential hypertension. Glasser SP, et al. University of Minnesota. glasser@epi.umn.edu. Am J Hypertens 2003 Jan;16(1):51-8.

Diatiazem Better Tolerated Than Amlodipine: In a DB study of 67 patients of once-daily diltiazem (240 mg to 360 after 2 weeks) vs. amlodipine (5 mg to 10 mg after 2 weeks) in patients with stable angina, both treatments gave significant increases in time to 1-mm ST segment depression. Diltiazem, 360 mg/day, gave a significant decrease in rate pressure product. There were no significant treatment differences in any of the exercise test parameters. Both treatments reduced incidence of angina attacks and use of glyceryl trinitrate spray. The incidence of edema was significantly less in patients receiving diltiazem. A randomized, double-blind comparison of the efficacy and tolerability of once-daily modified-release diltiazem capsules with once-daily amlodipine tablets in patients with stable angina. Chugh SK, et al. Northwick Park Hospital, Harrow, Middlesex, UK. J Cardiovasc Pharm 2001 Sep;38(3):356-64. Similar: Tek Arkh 2001;73(9):42-6.

Diltiazem Said Safer than Nifedipine: In a DB crossover study of 20 angina patients of controlled-release diltiazem vs. sustained-release nifedipine, Diltiazem CR significantly reduced heart rate at rest and equivalent exercise and incidence of angina and nitroglycerin use compared with nifedipine SR. Exercise duration time to angina and time to 1-mm ST-segment depression (but not maximal ST-segment depression) were all significantly improved by diltiazem CR. Diltiazem CR also caused significantly fewer adverse events than nifedipine SR. Calcium antagonists with negative chronotropic effects (eg, diltiazem CR) are safer and more efficacious as monotherapy in chronic stable angina than dihydropyridines (eg, nifedipine SR) even when a long-acting formulation of the latter is used. Improved efficacy and safety of controlled-release diltiazem compared to nifedipine may be related to its negative chronotropic effect. Basu SK, et al. Northwick Park Hospital, Harrow, Middlesex, United Kingdom. Am J Ther 2000 Jan;7(1):17-22.

Epidemiologic evidence suggests that an elevated heart rate (HR) is an adverse and independent prognostic factor in arterial hypertension and other cardiovascular diseases. Although diltiazem is characterized as an HR-lowering calcium antagonist, no studies have quantified the magnitude of HR changes in patients with angina or hypertension. HYPOTHESIS: The study was undertaken to explore the magnitude of proportional HR reduction at varying levels of resting HR with the sustained-release formulation of diltiazem (SR diltiazem) at the usual clinical doses of 200 or 300 mg once daily. METHODS: This meta-analysis was conducted on six comparative double-blind studies including 771 patients with angina or hypertension in which SR diltiazem 200-300 mg once daily was compared either with placebo or with other agents known not to influence HR (angiotensin-converting enzyme inhibitors, diuretics). Sustained-release diltiazem decreases elevated baseline HR, with an increasing effect at higher initial rates. RESULTS: Multiple comparisons by baseline HR category showed a significant difference between both groups for baseline HR of 74-84 beats/min and > or = 85 beats/min (p = 0.001). Sustained-release diltiazem had no significant HR-decreasing effect on baseline HR < or =74 beats/min but appears to have a genuine regulating effect on HR: it reduces tachycardia without inducing excessive bradycardia. These findings are in contrast to those with dihydropyridine calcium antagonists, which tend to increase HR and have been associated with an adverse outcome in acute cardiovascular conditions. At the same time, there is evidence to suggest that HR-lowering calcium-channel blockers decrease cardiovascular event rates following myocardial infarction. CONCLUSION: When calcium antagonists are indicated for use in patients with angina or hypertension, an HR-lowering agent, that is, diltiazem rather than dihydropyridine, should be recommended. Heart rate-lowering and -regulating effects of once-daily sustained-release diltiazem. Boden WE, et al. State University of New York, Syracuse. Clin Cardiol 2001 Jan;24(1):73-9.