Varying response to nifedipine during treatment of stable exertional angina pectoris: Results of a double-blind, randomized, cross-over, placebo-controlled study

The studies were performed in 15 patients with angiographically-documented coronary artery disease. One patient, who developed unstable angina in the run-in phase, was withdrawn from the study; the remaining 14 had stable angina pectoris of at least six month's duration and incurred, reproducibly, ST-segment depression in the exercise ECG concomitant with anginal pain. After a four-week run-in period, two treatment phases of ten weeks each were carried out according to a randomized, cross-over, double-blind protocol with t.i.d. administration of 10 mg nifedipine or placebo. In each of the treatment phases, exercise testing at an identical, predetermined workload was performed at five and ten weeks. The workload for the individual was chosen as that at which angina could be predictably precipitated after three to six minutes. The incidence of anginal attacks as well as nitrate consumption were recorded by each patient in a protocol diary. In addition to calculation of mean values for the entire patient population, the patients were grouped with respect to the extent of changes affected by nifedipine on ST-segment depression with those demonstrating a reduction of more than 0.5 mm during at least one of the two workloads collectively designated as responders. Together, three hours after the last ingestion of 10 mg nifedipine the 14 patients showed a mean reduction in ST-segment depression at the initial workload from 1.3 to 0.8 mm (-36%, p < 0.01) and at the maximum workload from 2.5 to 2.1 mm (-17%, p < 0.01). Unequivocal anti-ischemic efficacy was observed, however, in only nine of the 14 patients who collectively demonstrated a mean reduction from 1.9 to 1.0 mm (-47%, p < 0.005). The latter patients were designated as responders. In contrast, five of the 14 patients showed no appreciable alteration in the amount of ST-segment depression and, accordingly, were classified as nonresponders. The ST-segment response at five weeks did not differ from that recorded at ten weeks. After nifedipine, the mean heart rate at rest as well as at the respective workloads did not differ significantly. Neither the responders nor the nonresponders showed a directional trend and in no case did the extent of the decrease or increase exceed more than 10 beats/min. Nifedipine led to a significant mean reduction in systolic blood pressure from 171.1 to 162.3 mm Hg (-5%, p < 0.025) only at the initial workload but not, however, at rest or at the maximum workload. Six of the nine responders showed a decrease of more than 10 mm Hg while the remaining three had no change or an increase; three of the five nonresponders demonstrated a clear decrease while the remaining two showed a slight increase. After nifedipine, the product of the heart rate and systolic blood pressure, both at rest and at the respective workloads, did not differ significantly from that of patients receiving placebo. Here, too, the mean was comprised of similarly distributed values. Thus, no relationship could be found between reduction of ST-segment depression and the circulatory response of heart rate, blood pressure or the heart rate-blood pressure procuct. For the entire population, nifedipine did not lead to a decrease in the rate of anginal attacks or nitrate consumption. Again, however, the nine responders registered a decrease in anginal attacks from 8.2 to 5.2 per week (-37%, p < 0.025) and in nitrate consumption from 10.7 to 5.1 tablets per week (-52%, p < 0.05) while these parameters remained unaffected in the five nonresponders. Adverse reactions to nifedipine were observed only at the initiation of treatment and consisted of headache in one patient, orthostatic complaints in one and evanescent flush in two patients. In the absence of a relationship between the reduction in exercise induced ST-segment depression and the response of heart rate and blood pressure, the anti-ischemic efficacy of nifedipine appears primarily attributable to an enhanced myocardial oxygen supply. Accordingly, nifedipine should be expected to elicit an effective response only if the capability for vasodilation at the stenotic site is rendered maintained by the morphology of the lesion. Since the latter is present only in a certain percentage of patients with fixed coronary arterial stenoses, they may account for the varying response affected by this agent.