958-92 A Randomized, Double-Blind, Placebo-Controlled Trial of Zatebradine and Diltiazem SR in Chronic Stable Angina: Efficacy and Safety

Abstract

Zatebradine is a memberof a new class of compounds, sinus node inhibitors, that may be useful for the management of chronic stable angina. To test this concept, 188 pts with mild to moderate angina in 17 Canadian centers were enrolled in a parallel-design trial with placebo and diltiazem comparison groups; 143 of them completed a placebo run-in period that required reproducible exercise-induced angina and ST depression. They were then randomized to placebo, zatebradine or diltiazem SA. Study drugs were uptitrated (2.5, 5 and 7.5 mg BID for zatebradine and 60, 90 and 120 mg BID for diltiazem SR) at weekly intervals if the exercise test remained positive. The highest dose was reached by 24 of 47 zatebradine pts and 28 of 49 diltiazem pts. Pts took no other anti-anginal drugs except sublingual NTG to relieve angina. The primary endpoint of the trial was the change from baseline in total exercise time, measured at 12 hours post-dose, after at least 2 weeks at the optimum dose. The table lists the differences from baseline, ± 1 SD: Placebo Zatebradine Diltiazem Completed Pts 49 47 47 Total exercise time (sec) 43 ± 56 56 ± 69 79 ± 56 * Time to angina (sec) 30 ± 82 63 ± 76 * 76 ± 65 * Time to ↓ ST (sec) 12 ± 94 59 ± 87 * 60 ± 90 * Heart rate at rest (bpm) 0 ± 10 -13 ± 11 * -6 ± s 10 * * p < 0.05 versus placebo The improvement in exercise time with diltiazem, but not with zatebradine, was significantly better than with placebo. The number of responders, defined as pts whose total exercise time improved by >20% or by >60 sec, was higher with diltiazem (p < 0.01), but not with zatebradine, compared to placebo. Both drugs improved time to angina and time to 1 mm ST depression. Visual phenomena, described as wavy lines or flashes in peripheral visual fields, were reported by 26% of the zatebradine pts. Although zatebradine has anti-anginal efficacy, as shown in this trial, visual adverse effects will limit its clinical utility for this indication. However, drugs like zatebradine that slow heart rate but have no other cardiac effects may playa role in the management of angina.