Diltiazem hydrochloride is a calcium antagonist

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1 The Treatment of Exercise-Inducible Chronic Stable Angina with Diltiazem* Effect on Treadmill Exercise Peter E. Pool, M.D., F.C.C.P.; t Shirley C. Seagren;! Joseph A. Bonanno, M.D., F.C.C.P.; Antone F. Salel, M.D., F.CC.P.;U and George W. Dennish, M.D., F.C.C.P. Although diltiazem has been shown to alleviate vasospastic angina pectoris, its effect on exercise-inducible chronic stable angina has not been objectively studied. Accordingly, the effect of diltiazem was studied in this condition with a placebo controlled double-blind randomized cross-over protocol at three dose levels (0, 180 and 0 mg/day) during graded treadmill exercise. Three eud-points were evalnated: 1) time to onset of angina or fatigue if angina were eliminated; ) time to 1 mm ST segment depression or fatigue if ST depression were eliminated; and 3) time to termination of exercise (+ angina or fatigue). All end-points were prolonged at all dose levels. At the highest dose of 0 mg/day, time to onset angina or termination was prolonged from a placebo time of 8.0 ± 0.9 to 9.8 ± 0.9 minutes (p = <.001); time to ST depression or termination was prolonged from 7.8 ± 0.9 to 9.1 ± 0.8 minutes (p =.007); and time to termination was prolonged from 9.9 ± 0.9 to 10.8 ± 0.8 minutes (p =.0). Diltiazem hydrochloride is a calcium antagonist and coronary vasodilator which appears to differ in its mode of action from traditional antianginal drugs. In the past, it has been effective in alleviating vasospasm-induced angina pectoris. Its usefulness in other forms of angina pectoris, however, has been documented chiefly by angina history studies. In fact, many have doubted that the calcium antagonist drugs would be effective in traditional angina pectoris, because their most popular known effect has been coronary vasodilatation. However, other effects of diltiazem have been demonstrated which at least raise the possibility that it might be effective in traditional forms of angina. Diltiazem has 'been shown to minimize the consequences of acute ischemia in the experimental animal by effects which may not be limited to coronary vasodilatation; 1 it has also been shown to have some negative inotropic and chronotropic effects," as well as peripheral vasodilating effects;3 and it is reasonable to surmise that exercise-inducible chronic stable angina involving fixed atherosclerotic coronary lesions may also have a signifi- From the Cardiopulmonary Laboratory Scripps Memorial Hospital (Encinitas), Encinitas California. tassociate Clinical Professor ;:; Medicine, University of California, San Diego and Director of Cardiology, Scripps Memorial Hospital-Encinitas. tchief, Cardiopulmonary Laboratory. Assistant Clinical Professor of Medicine, University of California, San Diego. UChief of Medicine, Scripps Memorial Hospital-Encinitas. Reprint requests: Dr. Pool, 1087 Deoonah're Drioe, No. 300, EncinltaB, CaU/omitJ 90 3 POOL ET At cant vasospastic component.' Accordingly, the effect of diltiazem on exercise-inducible chronic stable angina was tested over a six-week period in a double-blind randomized cross-over study, using three dose levels and comparing diltiazem with placebo during graded treadmill exercise. METHODS The study included 15 patients, men ages 8 to 75 years and 3 women ages 0 to 66 years, all of whom gave appropriate informed consent in writing. All had a typical history of angina pectoris which had been stable in occurrence rate for at least six months. Eight had had prior myocardial infarctions and five had had coronary artery bypass surgery (two both). Of the remaining four, all had had coronary arteriography. Two patients, both women aged 0 and 66 years, had angiographically demonstrated vasospastic angina pectoris in the absence of atherosclerotic lesions. This was validated by the reproduction of their typical anginal attacks with vasospasm during cardiac catheterization, along with accompanying electrocardiographic signs. All patients had a classically positive treadmill exercise test with ST segment depression of a horizontal or downsloping type with a duration of at least.08 sec and with a magnitude of at least 1 mm below the PR segment in lead V G or avf. In all cases, treadmill exercise was accompanied by the production of the patient's typical angina pectoris. All patients had a normal serum potassium, and none was receiving other drugs known to influence either angina pectoris or the ischemic electrocardiographic response such as vasodilators, beta-blockers, digitalis, or psychotropic drugs. In addition, the angina pectoris experienced was in all cases responsive to the use of nitroglycerin at a sublingual dose of 0.3 or 0. mg. Both diltiazem hydrochloride in 30 mg tablets and an identical placebo tablet containing lactose, microcrystalline CHEST, 78: 1, JULY, 1980 SUPPLEMENT

2 i 0 "!11O S SINGLE BLIND 1ST ND 3AD PLACEBO CROSSOVER CROSSOVER CROSSOVER l ( is III O X o o o 1 3 WEEKS FIGURE 1. Format of study protocol. x = TREADMILL cellulose and magnesium stearate, were supplied by Marion Laboratories. The study was initiated by a one-week period of single-blind placebo administration which was terminated with a treadmill exercise test (Fig 1). In addition, prior to the single-blind placebo period, each patient had had at least two other treadmill exercise tests. Thus, at the initiation of the double-blind cross-over period, each patient had a past treadmill training experience of three treadmill tests. The subsequent six weeks were divided into three two-week periods devoted to three separate cross-over dosing periods of placebo and diltiazem, using progress ive doses of 0 mg/day (30 mg QID), 180 mg/day (60 mg TID), and 0 mg/day (60 mg QID). The order of drug administration during each two weeks was randomized so that a patient might receive either diitiazem or placebo during either oneweek dosing period. Each patient visit included a physical examination and resting electrocardiogram. The patients were questioned specifically concerning side-effects and reliability of dosing, and pill counts were made to ensure dosing compliance. In all cases, treadmill exercise testing was carried out following a three-hour fast and within a time period of 1.5 to 3.0 hours following administration of diitiazem. During the study, periodic laboratory evaluations were carried out including complete blood counts, urinalyses and standard chemistry panels. No abnormalities in these parameters were noted, nor were there any side-effects reported. Exercise testing was conducted using a modified Broce protoeol.s Exercise was terminated at + angina or fatigue. Time to the onset of angina and to 1 mm of ST segment depression was measured, as well as the amount of ST segment depression at end-exercise, heart rate and blood pressure at rest, and the double product (heart rate X systolic blood pressure) at end-exercise. From each treadmill test, three end-points were assessed: 1) ST depression of 1 mm or termination (the latter in the event that ST depression did not occur after a treatment), ) onset of angina or termination (if angina were obliterated); and 3) termination (determined by fatigue or + angina). Statistical comparisons were made using a t-test of paired samples.s REsuLTS All 15 patients who entered the study completed all three cross-over periods. In spite of the three treadmilltests performedby each patientpriorto the first cross-over period, a further training effect was clearly noted (Fig ). The three major end-points used, ST depression or termination, onset of angina or termination, or termination were each progressively prolonged during placebo administration periods. Since within each period the order of dosing (placebo or diltiazem) was randomized, the training effect itself had no effect on the final results. Resting heart rate and blood pressure immediately prior to treadmill exercise were not systematically affected by diltiazem. At end-exercise, there were no significant differences in heart rate or systolic blood pressure or their product. The individual patient data points are illustrated in Figures 3 through 5 and are summarized in Table 1. At the highest dose level of 0 mgtday, there was a significant prolongation of all end-points. Time to onset of angina or termination (Fig 3) was prolongedfrom to minutes, time to ST depression or termination (Fig ) increased from 7.8 ± 0.9 to 9.1 ± 0.8 minutes, and termination of exercise (Fig 5) from to 10.8 ± 0.8 minutes. At the lower doses of 0 mgtday and 180 mgtday, there was significant prolongation in time to ST depression or termination or termination TRAINING EFFECT ON PLACEBO (GROUP MEANS) 10 TERMINATION 9... Z ONSET ANGINA i- OR TERMINATION ILl 8 :. ST -!- OR TERMINAnON 7 6 1ST ND 3RD PERIOD PERIOD PERIOD FxcURE. Demonstration of end-point prolongation by training effect using placebo data. CHEST, 78: 1, JULY, 1980 SUPPLEMENT TREATMENT OF CHRONIC STABLE ANGINA WITIf DILTIAZEM 35

3 ST! or Termination Onset Angina or Termination Termination 0mg ISO mg 0mg 0 mg lsomg 0mg 0mg lsomg 0mg Placebo 7.6± ± ± ± ± ±0.9 9.S± ± ±0.9 Diltiazem 8.7 ± ± ± ± ± ±0.9 1O.0±0.7 1O.± ±0.8 p.00.os.007 NS NS < alone; however, time to the onset of angina or termination was not significantly prolonged. At every dose level, however, every end-point was longer on the average following diltiazem administration than during the placebo period, whether achieving statistical significance or not (Table 1). In assessing the data on time to ODSet of angina or termination at the 0 and 180 mgtday dose levels, there was one patient's trend which appeared to be significantly disparate from that of the others. This patient can be identified in Figure 3 as the one with the highest time to ODSet of angina in the placebo column at 0 and 180 mgtday. The patient is a 0-year-old woman who has exercise-induced angina due to coronary spasm with no flxed atherosclerotic coronary lesion. In addition to her exercise-induced angina, she has relatively frequent angina without obvious cause. In an effort to determine the influence of this patient's data on the significance level of the remaining data, and recognizing the possibility that the two patients with demonstrated vasospastic angina might diher from the rest, the statistics were recalculated subtracting FIGURE 3. Individual patient data and group means ( ±SE) for end-point "time to onset angina or termination," (P = placebo; D =diltiazem ; 0 mg, 180 mg, and 0 mg = dose/day) Ẕ o the data of these two patients from all the dose levels for the end-point, time to onset of angina or termination. At the 0 mgtday level, subtraction of these data had essentially no effect and the differences remained statistically significant Subtraction of these patients' data from the 0 and 180 mgtday dose level results, however, changed the significance level of the 0 mgtday dose to p =.0 and that of the 180 mgtday dose to p =.0. Average end-point times at the 0 mg/day level, placebo versus diltiazem, were versus 8. ± 0.1 minutes, and at the 180 mg/day level versus minutes. DISCUSSION Diltiazem is known to be effective in the treatment of vasospastic angina pectoris. This has been demonstrated both in Prinzmetal's variant angina? and in vasospasm associated with ST segment depression.' It is known that coronary vasospasm may occur in conjunction with fixed lesion atherosclerotic coronary disease," and, in fact, most fixed-lesion coronary disease could involve some component of TIME TO ONSET ANGINA OR TERMIMAnON 0 MG 180 MG MQ...!. Jl..!. Jl..!..Il. /l N.S. N.S. 36 POOL ET AL CHEST, 78: 1, JULY, 1980 SUPPLEMENT.001

4 16 TIME TO ST OR TERMINATION" 0MG e MG ' e 0' -: 0MG e 0 Of------Oo -Z10 i8-6 i= o vasospasm. This also might be inferred from the clinical impression that long-standing severe, fixed lesion coronary disease may be associated with stable mild angina pectoris (perhaps with no vasospastic component) while more mild coronary Ii'.IGlJBE. Individual patient data and group means (±SE) for end-point "ST depression or termination" (see Fig 3 for abbreviations).007 disease involving only one coronary artery, for instance, may be associated with severe angina pectoris or myocardial infarction (perhaps with an active vasospastic component). In one study, the effect of diltiazem was examined in four patients TERMINATION 0MQ R 110MQ D 0MQ R.... FiGURE 5. Individual patient data and group means (± SE) for end-point "termination" (see Fig 3 for abbreviations). -Z 1 il -I. i=.0.0 CHEST, 78: 1, JULY, 1980 SUPPLEMENT TREATMENT OF CHRONIC STABLE ANGINA WITH DILTIAZEII 37

5 who manifested exercise-induced angina brought on by the performance of arm exercise on the catheterization table, albeit under rather select conditions," These patients had simultaneous coronary vasospasm on angiography. This study suggested that at least some patients have reproducible exercise-induced angina pectoris associated with vasospasm. Diltiazem relieved this exercise-induced angina, although the direct effect on vasospasm was not demonstrated Two of these four patients had fixed atherosclerotic disease as well. In the present study, all 15 patients had what can be considered to be typical, chronic, stable angina pectoris. As demonstrated on cardiac catheterization, two had no fixed atherosclerosis, but only coronary vasospasm. Thirteen had histories of prior typical myocardial infarction and/or catheterization evidence of diffuse atherosclerotic coronary disease. Three end-points were chosen, because it was possible in studying the effect of a drug on treadmill exercise performance that a chosen end-point such as angina pectoris or ST segment depression might be obliterated by the drug intervention. All patients had both ST segment changes and accompanying angina pectoris on their initial treadmill evaluation which was terminated at + angina. Subsequently, if the end-points of angina or ST segment changes were obliterated, termination of exercise due to fatigue became the end-point. Because three end-points were used at three different dose levels, there were nine possible comparisons between placebo and diltiazem. Of these, seven showed statistically significant improvement Because one patient demonstrated apparently whimsical angina pectoris and because she also had vasospastic disease, a separate treatment of the data was carried out eliminating this patient's data, along with that of the other patient with demonstrated vasospastic disease. When considered in this fashion, all nine comparison end-points reached statistical signi.6cance. The underlying mechanism responsible for the prolongation of exercise time by diltiazem remains to be determined Possibilities include an effect of diltiazem on myocardial metabolism, 1 a decrease in myocardial work-load due to peripheral vasodilatation, 3 dilatation of conductance coronary ar- teries" or inhibition of neurogenically-mediated coronary Vasospasm.8-10 It is an attractive speculation to implicate inhibition of associated coronary vasospasm simply because diltiazem has demonstrated effects on this process. Clearly, whatever mechanism is invoked, diltiazem improves exercise performance in patients with typical effortinduced angina. These results reached statistical signi.6cance even with a small patient sample. It is interesting that the least signi.6cant changes occurred at the 180 tug]day dose level which was the only dose level administered on a TID basis, rather than a QID basis. It is possible that cumulative active levels are higher on a QID dose regimen. At the highest dose level (0 tng]day) there was a highly signi.6cant effect of diltiazem on all three end-points and a greater prolongation of exercise time than at lower doses. It has yet to be determined whether even higher doses of diltiazem might induce greater improvement. REFERENCES 1 Weishaar R, Askikawa K, Bing RJ. Effect of diltiazem, a calcium antagonist, on myocardial ischemia. Am J Cardiol 1979; 3: Nabata H. Effects of calcium antagonistic coronary vuodilators on myocardial contractility and membrane potentials. Jpn J Pharmacoll977: 7: Kusukawa R, Kinoshita M, Shimoto Y, Tomonaga G, Hoshino T. Hemodynamic effects of a new anti-anginal drug, diltiazem hydrochloride. Arzneim Forsch 1977: 1: Yasue H, Omote S, Telcizawa A, Nagao M, Miwa K, Tanaka S. Exertional angina pectoris caused by coronary arterial spasm: effects of various drugs. Am J Cardiol 1979: 3: Bruce RA, Hornsten TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Progress Cardiovasc Dis 1969: 11: Ostle B. Statistics in research. Iowa City: Iowa State University Press, Yasue H, Ornote S, Taldzawa A, Nagao M, Miwa K, Kato H, Tanaka S, Akiyama F. Pathogenesis and treatment of angina pectoris at rest as seen from its response to various drugs. Jpn Circ J 1978: : FeigI EO. Sympathetic control of coronary circulation. Cire Res 1967: 0: MacRaven DR Mark AL, Abboud FM, Mayer HE. Responses of coronary vessels to adrenergic stimuli. J Clin Invest 1971: 50: Mudge GH Ir, Grossman W, Mills RM, Lesch M, BraunwaId E. Reflex increase in coronary vascular resistance in patients with ischemic heart disease. N EngI J Moo 1976: 95: POOL ET AL CHEST, 78: 1, JULY, 1980 SUPPLBMENT