Diltiazem

Abstract: ContextMany patients with chronic angina experience anginal episodes despite revascularization and antianginal medications. In a previous trial, antianginal monotherapy with ranolazine, a drug believed to partially inhibit fatty acid oxidation, increased treadmill exercise performance; however, its long-term efficacy and safety have not been studied in combination with β-blockers or calcium antagonists in a large patient population with severe chronic angina.ObjectivesTo determine whether, at trough levels, ranolazine improves the total exercise time of patients who have symptoms of chronic angina and who experience angina and ischemia at low workloads despite taking standard doses of atenolol, amlodipine, or diltiazem and to determine times to angina onset and to electrocardiographic evidence of myocardial ischemia, effect on angina attacks and nitroglycerin use, and effect on long-term survival in an open-label observational study extension.Design, Setting, and PatientsA randomized, 3-group parallel, double-blind, placebo-controlled trial of 823 eligible adults with symptomatic chronic angina who were randomly assigned to receive placebo or 1 of 2 doses of ranolazine. Patients treated at the 118 participating ambulatory outpatient settings in several countries were enrolled in the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial from July 1999 to August 2001 and followed up through October 31, 2002.InterventionPatients received twice-daily placebo or 750 mg or 1000 mg of ranolazine. Treadmill exercise 12 hours (trough) and 4 hours (peak) after dosing was assessed after 2, 6 (trough only), and 12 weeks of treatment.Main Outcome MeasuresChange in exercise duration, time to onset of angina, time to onset of ischemia, nitroglycerin use, and number of angina attacks.ResultsTrough exercise duration increased by 115.6 seconds from baseline in both ranolazine groups (pooled) vs 91.7 seconds in the placebo group (P = .01). The times to angina and to electrocardiographic ischemia also increased in the ranolazine groups, at peak more than at trough. The increases did not depend on changes in blood pressure, heart rate, or background antianginal therapy and persisted throughout 12 weeks. Ranolazine reduced angina attacks and nitroglycerin use by about 1 per week vs placebo (P<.02). Survival of 750 patients taking ranolazine during the CARISA trial or its associated long-term open-label study was 98.4% in the first year and 95.9% in the second year.ConclusionTwice-daily doses of ranolazine increased exercise capacity and provided additional antianginal relief to symptomatic patients with severe chronic angina taking standard doses of atenolol, amlodipine, or diltiazem, without evident adverse, long-term survival consequences over 1 to 2 years of therapy.

Abstract: The Multicenter Diltiazem Postinfarction Trial (MDPIT) reported no consistent diltiazem effect on new or worsened congestive heart failure (CHF) during 12-52 months' follow-up after acute myocardial infarction. This was puzzling in light of the observation that patients with findings suggesting left ventricular dysfunction (LVD) at baseline on diltiazem had more cardiac events (cardiac mortality or recurrent nonfatal infarction) than such patients on placebo. We hypothesized that diltiazem increased the frequency of late CHF as well as of cardiac events, but only in patients predisposed by LVD. Using the same characterizing variables as the primary MDPIT analysis, we found that patients with pulmonary congestion, anterolateral Q wave infarction, or reduced ejection fraction (EF) at baseline were more likely to have CHF during follow-up than those without these markers of LVD. CHF was particularly frequent in the patients with LVD who were randomized to diltiazem. Among those with a baseline EF of less than 0.40, late CHF appeared in 12% (39/326) receiving placebo and 21% (61/297) receiving diltiazem (p = 0.004). Life table analysis in patients with an EF of less than 0.40 confirmed more frequent late CHF in those taking diltiazem (p = 0.0017). In addition, the diltiazem-associated rise in the frequency of late CHF was progressively greater with increasingly severe decrements in baseline EF. This diltiazem effect was absent in patients with pulmonary congestion at baseline but an EF of 0.40 or more, suggesting a unique association between diltiazem-related late CHF and systolic LVD.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Calcium influx blockers, diltiazem, nicardipine, nifedipine, niludipine, and nimodipine, which possess coronary vasodilator activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human K562 myelogenous leukemia. The extent of enhancement was different among the drugs, and up to a 50- to 70-fold increase in VCR cytotoxicity occurred in P388/VCR cells with nontoxic or marginally toxic concentrations of diltiazem and nicardipine. A 50- to 100-fold enhancement occurred in VCR-resistant human K562 myelogenous leukemia cells with diltiazem, nicardipine, niludipine, and nimodipine. VCR resistance of these cell lines was circumvented completely by these blockers. Calcium influx blockers also enhanced the cytotoxicity of Adriamycin in P388 leukemia cells and especially in its Adriamycin-resistant subline. The extent of enhancement, however, was lower than that which occurred in VCR-resistant tumor lines with VCR. An approximately 10- to 30-fold increase in Adriamycin cytotoxicity occurred in P388 Adriamycin-resistant subline cells with diltiazem, nicardipine, niludipine, and nimodipine. Although VCR alone at 10 to 200 micrograms/kg did not confer a significant therapeutic effect in P388/VCR-bearing mice, calcium influx blockers in doses of 30 to 125 mg/kg administered daily for 10 days with VCR enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. A maximum of approximately a 40 to 50% increase in life span occurred with diltiazem, nicardipine, niludipine, and nimodipine. The calcium influx blockers also enhanced the therapeutic effect of Adriamycin in P388 Adriamycin-resistant subline-bearing mice, although the extent of enhancement was smaller than that observed with VCR in P388/VCR-bearing mice.