Efficacy of diltiazem in angina on effort: A multicenter trial

Efficacy of Diltiazem in Angina on Effort: A Multicenter Trial

KENNETH F. HOSSACK, MD PETER E. POOL, MD, FACC PETER STEELE, MD MICHAEL H. CRAWFORD, MD, FACC ANTHONY N. DeMARIA, MD, FACC LAWRENCE S. COHEN, MD, FACC THOMAS A. PORTS, MD, FACC with the biostatistical assistance of LORI SKALLAND, MS Seattle, Washington Davis, Encinitas, San Francisco, California Denver, Colorado San Antonio, Texas Kansas City, Missouri

From the University of Washington, seattle, Washington; ScrippsMemorial Hospital,Encinitas, California; Veterans Administration Hospital, Denver. Colorado; University of Texas, San Antonio, Texas;Universityof California, Davis, California; Menorah Medical Center, Kansas City, Missouri; Universityof California, San Francisco, California. Address for reprints: Kenneth F. Hossack,MD, Department of Medicine, Division of Cardiology, RG-20, University of Washington, Seattle, Washington 98195.

During a multicenter study 57 patients with exercise-induced angina were evaluated with serial exercise testing to assess the efficacy of diltiazem, a calcium slow channel blocking agent, compared with a placebo. The study consisted of a 1 week single-blind placebo stabilization period followed by a double-blind triple crossover between diltiazem and placebo. Three dose levels were tested (120, 180 and 240 rag/day) in each patient. For the three time-related variables there was a significant dose-related response, with 240 rag/day being the most effective. The increases, over the washout placebo stabilization values, of the time-related variables for the 240 rag/day week compared with the corresponding placebo week were total duration of exercise 1.87 versus 1.05 minutes (p <0.002), time to onset of angina 1.81 versus 1.17 minutes (p <0.01) and time to appearance of 1 mm S-T segment depression 1.81 versus 1.01 minutes (p <0.002). Analysis of exercise variables indicated a significant reduction in heart rate, diastolic blood pressure, and pressure-rate product at submaximal exercise after administration of diltiazem. Diastolic blood pressure was significantly reduced at maximal exercise. Heart rate and pressure-rate product were unchanged at maximal exercise. Systolic blood pressure was unchanged at rest during submaximal or maximal exercise. Submaximal and maximal exercise S-T depression was not significantly altered by diltiazem. The reduction in pressure-rate product at submaximal exercise was a possible mechanism for the drug's beneficial effect in enhancing the three Ume-related variables.

Diltiazem, a benzothiazephine derivative, possesses pharmacologic properties of a calcium slow channel blocking agent. 1,2 The efficacy of the drug in patients with angina due to coronary arterial spasm has been established, 3-5 and studies from other countries suggested that the agent was beneficial in treating patients with angina due to fixed coronary artery disease. 6,7 The compound was developed in Japan and recently the United States Food and Drug Administration allowed the drug to be evaluated in a limited number of patients with angina. This report presents data gathered from a multicenter trial conducted in patients with angina on effort due to fixed coronary artery disease. The efficacy of oral diltiazem at three dose levels was compared with placebo. The study was organized and funded by Marion Laboratories, Kansas City, Missouri. Methods

Patient selection: For entry into the study, each patient was required to have symptoms of typical angina pectoris 5 to 15 times/week, and to manifest 1 mm of S-T depression and experience angina during a preliminary symptom-limited treadmill exercise test. Patients with recent myocardial infarction (within 6 months of the study), valvular heart disease or serious noncardiac medical conditions were excluded. Each person gave informed consent. Patients: Five women aged 40 to 66 years (mean 53.6) and 52 men, aged 36 to 75 years (mean 56.3), were studied. Thirty-two patients had a history of prior

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myocardial infarction. Medications used for prophylaxis against angina before patients entered the study included beta receptor blocking agents in 13 patients, long-acting nitrates in 9 patients and a combination of both in 25 patients. Ten patients used only sublingual nitroglycerin. Beta receptor blocking agents and long-acting nitrates were discontinued; sublingual nitroglycerin was used if needed. Study design: A 1-week single-blind placebo (one tablet four times daily) stabilization period was followed by a randomized double-blind triple crossover study of diltiazem and placebo. Each crossover phase consisted of two 7 day periods. Diltiazem in 30 mg tablets and placebo tablets of identical appearance were supplied. In the first crossover period, patients received one tablet four times daily (placebo or 120 mg of diltiazem). In the second crossover period, they received two tablets three times daily (placebo or 180 mg of diltiazem) and in the third crossover period, patients received two tablets four times daily (placebo or 240 mg of diltiazem). Evaluation: Serial exercise testing on a treadmill was performed at weekly intervals and the responses were used to evaluate the efficacy of diltiazem. The treadmill was started at 1.7 miles/h and 0 percent grade for 3 minutes, and then the regular stages of the Bruce protocols were used. Heart rate, blood pressure measured with a cuff sphygmomanometer and electrocardiographic S-T segment depression were recorded at rest and during the last minute of each exercise stage. The time to awareness of angina, the occurrence of I mm of persistent S-T depression, and the total duration of exercise was noted. Medication compliance was checked by tablet count in returned bottles. Hematologic and biochemical profiles and urinalysis were carried out at entry and at the end of weeks 4 and 7. Patients were questioned about their awareness of possible adverse effects. Statistical analysis: The variables analyzed included: (1) total duration of exercise (minutes); (2) time from start of exercise to first awareness of angina or termination of exercise (minutes); (3) time from start of exercise to onset of I mm S-T depression or termination of exercise (minutes); (4) heart rate at rest and at submaximal* and end of exercise (beats/min); (5) systolic blood pressure at rest and at submaximal and end of exercise (mm Hg); (6) diastolic blood pressure at rest and at submaximal and end of exercise (mm Hg); (7) systolic pressure-rate product at submaximal and end of exercise (units); (8) magnitude of S-T depression at submaximal, and end of exercise (mm). For each variable analyzed, the value of the corresponding variable for the poststabilization evaluation (end of week 1) was subtracted from that of each posttreatment week. Thus, negative values indicated a decrease from the poststabilization period. Because the study had a triple crossover design, each patient had six values for each variable (one valve each at the end of weeks 2, 3, 4, 5, 6 and 7). The analysis was carried out in the same way regardless of which variable was investigated. The steps taken in the analysis included: Determining by two way analysis of variance if the three placebo values remained stable over time, and performing a nonparametric two period crossover analysis at each dosage level, s During each crossover phase, random allocation to one of two sequences of test medication was used: (1) diltiazem followed by placebo (D:P), or (2) pla* The submaximal work load was obtained for individual patients from their exercise test with the shortest total duration. The exercise stage before the stage during which that test terminated was defined as the submaximal work load. The respective values at this same stage were then analyzed for the 7 weeks.

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cebo followed by diltiazem (P:D). Residual effects of treatments, direct effects of treatments, and period effects of treatments were tested in terms of Wilcoxon rank sum statistics calculated on appropriate within-patient linear functions of observations. Residual effects (first medication remaining within the system and affecting symptoms associated with the second medication administered) were tested by applying the Wilcoxon rank sum test to the sums of the two consecutive within-patient observations. If residual effects were not significant, direct effects (diltiazem versus placebo) were tested by applying the Wilcoxon rank sum test to the differences between the two consecutive within-patient observations. Period effects (the mean response in the first period being statistically different from the mean response in the second period, independent of treatment) were tested by applying the Wilcoxon rank sum test to the crossover differences. The crossover differences were observation 1 minus observation 2 for each patient in the D:P sequence group, and observation 2 minus observation 1 for each patient in the P:D sequence group. Direct effects, residual effects and period effects were analyzed using a two-tailed test of significance. A two way analysis of variance using only diltiazem data was performed to determine if there was a difference in response to treatment with diltiazem depending on the dosage administered. If there was a significant dosage effect, Tukey's multiple comparison procedure 1° was used to determine which dosages differed. Results

Effects on time-related variables: T h e mean values + s t a n d a r d error of the mean for the three time-related variables m e a s u r e d from the start of exercise for the 7 weeks of s t u d y were d e t e r m i n e d (Fig. 1). T h e mean difference between the results obtained with the exercise test at the end of the single-blind placebo washout

8

$ 6 *5 E H 4

-

a O3

E O

2-

o • Total Duration [3 • Time to Angina z~ • Time to Imm ST Depression

0

Washout Placebo Diltiazem Placebo Diltiazem Placebo Dilttozem Placebo 120mcj/day 180me/day 24Omg/day

I-

FIGURE 1. Mean 4- standard error of the mean of the three time-related variables, time to onset of 1 mm of S-T depression, time to angina and total exercise duration from the start of stage I are shown in minutes for the 7 weeks of the study. For each variable there was a significant increase associated with the administration of diltiazem. However, there was also a nonspecific increase in each variable parameter as the study progressed. Open symbols = placebo; closed symbols = diltiazem.

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TABLE I

Mean Difference From Placebo Washout for Time Related Variables p Value

Total duration of exercise (min) Time to onset of angina (min) Timeto 1 mm of S-T depression (min)

p Value

PI

Dilt 120 mg

R

D

P

0.55

0.99

NS

<0.02

0.82

1.04

NS

0.69

1.21

NS

p Value

PI

Dilt 180 mg

PI

Dilt 240 mg

R

D

P

R

D

P

NS

0.79

1.21

NS

<0.1

NS

1.05

1.87

NS

<0.002

NS

NS

NS

0.91

1.48

NS

<0.01

NS

1.17

1.81

NS

<0.01

NS

<0.02

NS

0.70

1.21

NS

<0.1

NS

1.01

1.81

NS

<0.002

NS

D = direct effect; D i l t = diltiazem; NS = not significant; p = probability; P = period effect; PI = placebo; R = residual effect.

week and the results from the other tests performed at the end of the study weeks are shown in Table I. For the three crossover periods, results of the statistical analysis for residual effect, direct effect and period effect are shown. The increase in total duration of exercise was significantly greater while patients were receiving 120 and 240 mg/day of diltiazem than in the corresponding placebo weeks. The increase was greatest (1.87 minutes) with the 240 mg/day dosage. This increase was significant at the p <0.01 level when compared with the increase after 120 (0.99 minutes) and 180 (1.21 minutes) mg/day. Analysis of the placebo data indicated a significant increase in exercise duration as the study progressed. The increase in time to onset of angina was significantly greater after diltiazem at the 180 mg and 240 mg dosage levels than in the corresponding placebo weeks (1.49 versus 0.91 minutes and 1.81 versus 1.17 minutes, respectively). There was a significant dose-related effect when the 240 mg/day dosage was compared with the 120 rag/day dosage (p <0.01). When time to onset of 1 m m of S - T segment depression was analyzed, there was a significant direct effect after diltiazem at the 120 and 240 mg dosage levels. The mean increase after 240 mg/day of diltiazem was significantly greater than the increase after either 180, or 120 mg/day (p <0.05). At 180 mg/day diltiazem was given in three divided doses, which may account for the lack of effect at this dose level. H e a r t rate: The mean values for heart rate at rest and at submaximal and end of exercise for each period are shown in Figure 2. Table II shows the mean differences from the placebo washout period for heart rate and gives the results of Koch's analysis for residual, direct and period effects. Two way analysis of variance of the placebo values indicates that they were stable at all periods of observation. Analysis of resting and maximal heart rate data indicated no significant difference between the effects of placebo and diltiazem. In contrast, diltiazem at the 180 and 240 mg/day levels resulted in a significantly lower submaximal heart rate than that in the corresponding placebo periods (p <0.01, p <0.001, respectively). The effect of 240 mg/day of diltiazem on heart rate was significantly greater than that recorded with 180 or 120 mg/day (p <0.01).

B l o o d p r e s s u r e : The mean values for systolic and diastolic blood pressure at rest and at submaximal and maximal exercise are plotted in Figure 3. Mean differences from the placebo washout period are shown in Table II. Analysis of variance of the placebo data indicate that values apart from systolicblood pressure at rest were stable. Residual effects were not present for either systolic or diastolic blood pressure at any of the stages or periods of observation. There was no significant effect of diltiazem at any of the doses tested on systolic blood pressure at rest or at submaximal or maximal exercise. Period effects were present for systolic blood pressure at submaximal exercise values at the 120 mg and 180 mg level crossover stages. Period effects were also present for maximal systolic blood pressure values at the 240 mg/day crossover stage. At rest and at submaximal exercise, diastolic blood pressure differences between diltiazem and placebo were significantly (p <0.005) lower with the 240 rag/day dose level. The magnitude of the differences was small (less than 10 mm in each case). Period effects were not present. At maximal exercise, differences between dil-

15('

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6c Washout 120mg/day 180mgldoy 240mglday Placebo Placebo Diltiazem Placebo Diltiazem Placebo Dilliazem FIGURE 2, Mean values 4- standard error of the mean (X 4- SE) of heart rate at rest (solid bars) and at submaximal (dolled bars) and maximal (hatched bars) exercise are shown for the 7 weeks of the study. There was no significant change in resting or maximal heart rate. There was a significant reduction in submaximal heart rate associated with the administration of diltiazem after the 180 and 240 mg/day dosage periods.

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TABLE II Mean Difference From Placebo Washout for Heart Rate and Blood Pressure p Value

Heart rate (beats/min) Resting Submaximal exercise Maximal exercise Systolic blood pressure (mm Hg) Resting Submaximal exercise Maximal exercise Diastolic blood pressure (ram Hg) Resting Submaximal exercise Maximal exercise Pressure-rate product X 10 -2 Submaximal exercise Maximal exercise

p Value

PI

Dilt 120 mg

Dilt 180mg

R

D

P

PI

- 1 --3 2

-2 -5 2

NS NS NS

NS <0.1 NS

NS NS NS

0 -3 2

-2 -7 0

NS NS NS <0.01 NS NS

1 -2 0

--3 -4 1

NS <0.05 NS --3 NS NS <0.05 --2 NS NS NS 2

--2 --3 2

NS NS NS

0 --3 0

-- 1 --4 --1

NS NS NS

NS NS <0.1

NS NS NS

-- 1 -4 0

--3 -5 --3

NS NS NS NS NS <0.01

--8 3

-10 4

NS NS

NS NS

NS NS

--7 7

--14 4

NS <0.01 NS NS

R

D

NS NS NS

p Value P

PI

Dilt 240 mg

R

D

NS NS NS

--2 --6 5

-5 --13 3

NS NS NS <0.001 NS NS

NS <0.001 NS

1 --3 1

--2 --6 --1

NS NS NS

NS, NS NS

1 --3 0

-2 --6 --3

NS <0.005 NS <0.01 NS <0.01

<0.05--13 NS 10

--25 3

NS NS NS

P NS NS NS NS NS <0.05 NS NS NS

NS <0.001 NS NS NS <0.01

Abbreviations as in Table I.

tiazem and placebo were significant (p <0.01) at the 180 and 240 mg/day levels. Period effects were not significant and a dose-related effect was not detected. Pressure-rate product: The values of this variable at submaximal and maximal exertion are plotted in Figure 4. Table II shows the mean differences between values in the diltiazem or placebo weeks and those in the placebo washout period. Placebo data were stable at both submaximal and maximal exercise. Residual effects were not significant at submaximal or maximal exercise. Submaximal pressure-rate product was significantly reduced by diltiazem with the 180 mg/day (p <0.01) and the 240 mg/day (p <0.001) dosages. A significant period effect was present with the 180 mg/day dosage. The effect of 240 mg/day was significantly greater than that of 180 or 120 mg/day (p <0.01). The maximal pressure-rate product was not influenced by

diltiazem. A period effect was significant (p <0.01) at the 240 mg/day level. Effect on S-T depression: Table III shows the mean differences between values in the diltiazem or placebo weeks and those in the placebo washout period for S-T depression at submaximal and maximal exercise. Analysis of variance indicated that placebo values were stable at both submaximal and maximal exercise. At submaximal exercise, residual, direct and period effects were not significant. At maximal exercise, residual and period effects were not significant; however, a direct effect was present (p <0.05) at the 180 mg day level but not at the 120 or 240 mg/day levels. Adverse effects: No abnormalities due to diltiazem were observed in the hematologic and biochemical profiles or urinalyses. The drug was remarkably free of adverse effects. Adverse effects reported while patients were taking diltiazem, but not necessarily attributed to diltiazem, included headaches (two), gastrointestinal

175

250 F

X+-SE

"I"

E E

0

12E

20( SBPDBP 0 • Mox~mol

n

n

•

z~ •

l

I

Submox Resl

m

15(

75

Washout Placebo

Placebo

Diltiazem 12Omg/doy

Placebo

Ddhozem Placebo DiIhazem I 8Omg/doy 24Omg/doy

FIGURE 3. Mean values 4- standard error of the mean for systolic blood pressure (SBP) (open symbols) and diastolic blood pressure (DBP) (closed symbols) are shown at rest (triangles) and at submaxlmal (squares) and maximal (circles) exercise for the 7 weeks of the study. There were no significant direct effects of diltiazem on systolic blood pressure at any level or period of observation. Diltiazem reduced diastolic blood pressure at the 240 mg/day dose level at rest and at submaximal (Submax) and maximal exercise. The magnitude of this reduction was small.

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IO( Woshout 120rag/day I80mg/doy 240 mcJ/doy Placebo Placebo Diltiozem Placebo Diltiozem Placebo Diltiozem FIGURE 4. Mean values 4- standard error of the mean (X 4- SE) for pressure-rate product at submaximal (hatched bars) and maximal (sUppled bars) exercise are shown for the 7 weeks of the study. There was a significant reduction in submaximal (Submax) pressure-rate product associated with administration of 180 and 240 mg/day of diltiazem. There was no significant change in maximal pressure-rate product.

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TABLE III

Difference From Placebo Washout for S-T Depression Significance

S-T depression (mm) Submaximal exercise Maximal exercise

Significance

Significance

PI

Dilt 120 mg

PI

Dilt 180 mg

R

D

P

--0.15

~0.11

NS

NS

0.08

0.01

NS

NS

PI

Dilt 240 mg

R

D

P

R

D

P

NS

--0.17

--0.24

NS

NS

NS

--0.12

--0,19

NS

NS

NS

NS

0.11

--0.05

NS

<0.05

NS

0.08

--0.02

NS

NS

NS

Abbreviations as in Table I.

upset (one), edema of feet (one), blepharitis (one), fatigue (one) and ventricular ectopic beats during the exercise test (one). The ventricular ectopic beats occurred at the 120 rag/day level and were not present with 180 or 240 rag/day. Reported adverse effects while taking placebo included headaches (three), dizziness (three), gastrointestinal upset (three), fatigue (two), tinnitus (one), visual disturbance (one) and fever (one). All seven adverse effects reported during diltiazem therapy and the 14 adverse effects reported during placebo periods resolved without sequelae.

Discussion Effect on exercise performance: The results of this study confirm the initial data of previous reports 11-13 from three of the participating centers. All indicated a significant improvement in exercise capacity associated with the administration of diltiazem. The other timerelated variables of time to angina and time to onset of I mm S-T depression showed significant increases with diltiazem. The nonspecific increase of each variable as the study progressed is illustrated in Figure 1, and analysis of variance of the placebo data for total duration of exercise indicated that placebo values were not stable. The magnitude of increase in the three timerelated variables at each period of the study was similar. This finding suggests that the effect of the drug was to delay the onset of the signs and symptoms of myocardial ischemia but that, once they appeared, the duration of further possible exertion was relatively fixed. Tukey's analysis 1° of the diltiazem values clearly indicated a significant dose-related effect with 240 rag/day being the most effective dosage. With use of a previously reported regression equation 14 for estimating maximal oxygen uptake from exercise duration, the estimated mean maximal oxygen uptake for the placebo washout was 21 ml/kg body weight per min and for the final placebo and diltiazem crossover period 23 and 25 ml/kg per rain, respectively. This improvement on diltiazem represents just over a 1 MET increase in performance. Effect o n h e a r t rate: Analysis of the heart rate and blood pressure responses gives some insight into the possible mechanisms of action of diltiazem. The effect of diltiazem on heart rate in this study was variable. Neither resting nor maximal exercise heart rate was significantly altered by the drug; however, the mean value at submaximal exercise was significantly lower particularly with the 240 rag/day dosage. Some evidence suggests that diltiazem may have dose-related effects

on heart rate.In a previously reported study of the acute effects of a single 120 m g oral dose of diltiazem no significant changes were found in resting, submaximal, maximal or recovery heart rates in a group of patients with coronary artery disease.Is Diltiazem can significantly influence atrioventricularnodal conduction both in h u m a n beings 16,17and in animal preparations, is Effect on blood pressure: In this study there were no significant effects of diltiazem on systolic blood pressure at any of the periods of observation; however, diastolicblood pressure was significantlyreduced at rest and at submaximal and maximal exercise at the 240 rag/day dosage. The magnitude of this reduction was small, but the reduction in diastolic blood pressure suggests that peripheral resistance was lowered as a result of diltiazem. Short-term studies with diltiazem using invasive measurements have confirmed the effect of diltiazem in lowering peripheral resistance. 15,19In the previously cited study, 15 a single 120 mg oral dose of diltiazem resulted in a highly significant decrease in mean intraarterial blood pressure. There are several possible explanations for the discrepancy in blood pressure effects of diltiazem between the short-term study and this study. The dosage of the drug was significantly higher for the short-term invasive study and the method for blood pressure measurement was different. The possibility of differences between short- and long-term administration also should be considered. The differences in blood pressure responses may also contribute to the different heart rate responses. A reflex tachycardia tends to occur as a result of afterload reduction. Thus, small doses of diltiazem may slow heart rate responses but do not cause a decrease in blood pressure, whereas larger doses cause a decrease in blood pressure but no net increase in heart rate as a result of the previously described small-dose negative chronotropic effect. The recently published animal study is showing dose-dependent effects on atrioventricular (A-V) conduction and hemodynamic effects supports this concept. Effect o n p r e s s u r e - r a t e p r o d u c t : Despite a lack of effect on systolic blood pressure, diltiazem administration was associated with a significant reduction in submaximal pressure-rate product. This is a noninvasire measure of myocardial oxygen demand. 2° The reduction of pressure-rate product associated with the use of diltiazem suggests that the drug enhances exercise duration and lengthens the time to the onset of signs and symptoms of myocardial ischemia by reducing myocardial oxygen demand at submaximal work loads.

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This may not, however, be the only mechanism for the drug's effect. Direct effects of diltiazem on coronary arterial tone may occur but this effect cannot be confirmed or denied by the noninvasive measurements of this study. Effect on exercise S-T depression: The amount of S-T depression at submaximal or maximal exercise was not significantly changed by diltiazem. This may have been because some patients at the submaximal work load chosen did not exhibit a significant degree of S-T depression. In the previously mentioned short-term study, 15 diltiazem was associated with a significant reduction in the amount of S-T depression during exercise and recovery. Methodologic considerations: This study was designed to test the efficacy of diltiazem compared with placebo in improving exercise capacity in patients with exercise-induced angina. An additional aim was to assess the efficacy of three different dosage schedules. The study was carried out over a short period of time that therefore necessitated weekly exercise testing. The frequency of such testing no doubt contributed to the nonspecific increase of the time-related variables during the placebo periods. In retrospect, a study design with

longer intervals between exercise tests m a y have some advantages: the dosages chosen were based on the Japanese experience with the drug, and it is clear that in most cases an initialdosage of 240 rag/day in four divided doses would be appropriate. There are reports of the drug being used in a total daily dosage of 360 rag.12 The small incidence of adverse effectsmay be due in part to the relatively low dosages of diltiazem employed, although the use of higher levels has also been remarkably free of adverse effects.12 Patients with more severe disease for w h o m a physician considered a placebo period unsafe were not enrolled in the study, but the drug m a y be of benefit to such patients. Clinical implications: This study demonstrated that diltiazem was effective in the treatment of persons with exercise-induced angina. It provided a modest increase in exercise capacity and, as such, is an appropriate drug in the treatment of angina due to fixed coronary artery disease. There is obviously a need for additional studies to test the long-term efficacy of the drug, assess the value of higher dose schedules, explore the value and safety of combining the drug with other antianginal agents and compare the efficacy of diltiazem with that of other antianginal agents.

References 1. Sato M, Na9ao T, Yamaguchl J, NakaJlma H, Klyomoto A. Pharmacological studies on new 1,5-benzothiazepine derivative (CRD-401). 1. Cardiovascular actions. Arzneim Forsch 1971; 21:1338-43. 2. EIIrodt GE, Chew CYC, Singh BN. Therapeutic implications of slow channel blockade in cardiocirculatory disorders. Circulation 1980;62:699-72. 3. Nakamura M, Kolwaya Y. Beneficial effect of diltiazem, a new antianginal drug, on angina pectoris at rest. Jpn Heart J 1979; 20:613-21. 4. Yasue H, Omote S, Taklzawa A, Nagao M, Mlwa K, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetars variant angina: role of exercise-induced coronary arterial spasm. Circulation 1979;59:938-48. 5. Rosenthal SG, Glnsbur9 R, Lamb JH, Balm DS, Schrooder JS. Efficacy of diltiazem for control of symptoms of coronary arterial spasm. Am J Cardiol 1980;46:1027-32. 6. Kilborn JR, Battellocchl S, Larrlbaud J, Morselll PL. Preliminary clinical report on diltiazem in French patients suffering from angina. In: Bing RJ, ed. New Drug Therapy with a Calcium Antagonist. Diltiazem Hakone Symposium, 1978. Amsterdam: Excerpta Medica, 1979:129-38. 7. Kolwaya Y, Nakamura M, Mltsutake A, Tanaka S, Takoshlta A. Increased exercise tolerance after oral diltiazem, a calcium antagonist, in angina pectoris. Am Heart J 1981;101:143-9. 8. Bruce RA. Exercise testing of patients with coronary heart disease. Principles and normal standards of evaluation. Ann Clin Res 1971;3:323-32. 9. Koch GG. The use of nonparametric methods in the statistical analysis of the two-period changeover design. Biometrics 1972; 28:577-86. 10. Bancroft TA. Topics in Intermediate Statistical Methods. Ames, IA: Iowa State University Press 1968;1:100-8.

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11. Pool PE, Seagren SC, Bonanna JA, Salel AF, Dennish GW. The treatment of exercise Inducible chronic stable angina with diltiazem. Chest 1980 (Suppl);78:234-8. 12. Hoseack KF, Bruce RA. Improved exercise performance of persons with stable angina pactoris receiving diltiazem. Am J Cardiol 1981;47:95-101. 13. Starling MR, Crawford MH, O'Rouke RA. Beneficial effects of diltiazem on exercise performance in patients with coronary artery disease and angina pectoris. Int J Cardiol, in press. 14. Bruce RA, Kusuml F, Hosmor D. Maximal oxygen intake and nomographic assessment of functional aerobic impairment in cardiovascular disease. Am Heart J 1973;85:546-62. 15. Hossack KF, Bruce RA, Rltterman JB, Kusuml F, Trlmble S. Divergent effects of diltiazem in patients with exertional angina. Am J Cardiol 1982;49:538-46. 16. Hossack KF, Bruce RA, Stewart DK. Alteration of exercise hemodynamic responses with propranolol or diltiazem in hypertrophic cardiomyopathy. A comparison of 2 cases. J Cardiol Rehab 1981;1:171-8. 17. Rlfterman JS, Hossack KF, Bruce RA. Acute and chronic effects of diltiazem on A-V conduction at rest and during exercise. J Electrocardiography 1982;15:41-6. 18. FuJlmoto T, Peter T, Mandol WJ. Electrophysiologic and hemodynamic actions of diltiazem: disparate temporal effects shown by experimental dose-response studies. Am Heart J 1981;101: 403-7. 19. Debaisleux J, Theroux P, Waters DD, Mlzgala HF, Bourassa MG. Hemodynamic effects of nifedipine and diltiazem after acute myocardial infarction (abstr). Circulation 1979;60:Supp111:11-82. 20. Nelson RR, Gobel R, Jorgensen CR, Wang K, Wang Y, Taylor HL. Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 1974;50:1179-80.

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