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Efficacy and safety of sustained-release diltiazem as replacement therapy for beta blockers and diuretics for stable angina pectoris and coexisting essential hypertension: A multicenter trial
Efficacyand Safety of Sustained-Release Diltiazemas ReplacementTherapyfor Beta Blockersand Diuretics for StableAnginaPectorisand CoexistingEssential Hypertension:A MulticenterTrial DAVID
T.
KAWANISHI,
MD, ROBERT B. LEMAN, MD, CRAIG and ROBERT A. O’ROURKE, MD.
To determine if a sustained-release form of the calcium entry blocker diltiazem would be a satisfactory substitute for the combination of P-adrenergic blocking agent and thiazide diuretic in the treatment of systemic hypertension and angina pectoris, 38 patients were studied in a 4-center trial. Blood pressure and heart rate were measured in the supine position, immediately after and 5 minutes after standing. Modified Bruce protocol treadmill tests were performed to determine the time to onset of 1 mm ST-segment depression, time to onset of chest pain and time to terminaton of exercise. Diltiazem monotherapy resulted in equivalent blood pressure control in 28 of 38 patients (74% ). In the remaining patients, blood pressure control was achieved with resumption of the diuretic. Blood pressure with fl blocker plus diuretic compared with diltiazem were, in the supine position 137 f 22/82 f 7 (III 1 standard deviation) versus 139 f 22/82 f 8 mm Hg, immediately after standing 131 f 20/84 f 9 versus 133 f 21182 f 10 mm Hg and after stand-
T
he calcium entry blocking drug diltiazem is effective as an antianginal agent as measured by reduction in angina frequency and improvement of treadmill exercise performance1-4 and has been at least as effective as propranolol in the treatment of patients with
From the Section of Cardiology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California, Medical University of South Carolina, Charleston, Baylor College of Medicine, Houston, and the University of Texas Health Science Center/San Antonio, San Antonio, Texas. Address for reprints: David T. Kawanishi, MD, Section of Cardiology, University of Southern California, School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033.
M.
PRATT,
MD,
ing for 5 minutes 134 f 19/85 f 8 versus 137 f 18/85 f 9 mm Hg (difference not significant for each). The heart rate with diltiazem was higher supine (67 f 11 versus 60 f 11 beats/min), standing (73 f 13 versus 64 f 14 beats/min) and 5 minutes after standing (73 f 14 versus 63 f 14 beats/min, p
stable exertional angina. 5,6Diltiazem is an arterial vasodilator and its efficacy in the treatment of hypertension has been well documented.8sgIt has been substituted for hydrochlorothiazide and found to have an equivalent antihypertensive efficacy in low doses.10A sustained-release capsule preparation of diltiazem has been evaluated and found to be as effective as nifedipine in the treatment of patients with both angina and hypertensionll We investigated whether the sustained-release form of diltiazem provides effective and safe replacement therapy for the combination of a P-adrenergic blocking agent and diuretic in the treatment of patients who have both stable exertional angina pectoris and essential hypertension. 291
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TABLE I
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Patient Characteristics Age (years) Sex (M/F) Evidence for CAD Coronary arteriography Prior myocardial infarction (definite or possible) Thallium perfusion defect
59 f 7 24114 33 16 7
CAD = coronary artery disease.
Materialand Methods Study group: Thirty-eight patients aged 59 f 7 years (& 1 standard deviation] [range 42 to 69) were included in the study. These patients were enrolled at 4 centers; the number of patients enrolled at each center ranged from 7 to 14. There were 24 men and 14 women (Table I]. Patients were considered for the study if they fulfilled the entry criteria, which were: (1) a stable pattern of angina with regard to frequency, duration and intensity for at least 3 months (symptoms of chest pain were considered to be angina if they were a precordial sensation of pressure or distress lasting between 2 and 10 minutes and brought on by exertion or emotional stress, with relief by rest, removal of the emotional stress or nitroglycerin]; (2) evidence of coronary artery disease by one of the following: >70% reduction in diameter of at least 1 major coronary artery by arteriography, prior (>3 months] myocardial infarction based on at least 2 of the following criteriaa classic history of prolonged chest pain, new and persistent Q waves and/or ST-T wave changes on the electrocardiogram or an elevated CPK with positive MB fraction with a subsequent decrease to at least one-half of the peak values or a documented exercise thallium test showing a fixed perfusion defect and/or a reversible defect; (31a medical regimen that included only propranolol at a dose of 80 to 240 mg daily or another ,&adrenergic blocking agent at an equivalent dose plus a thiazide diuretic; (41 ST-segment depression of at least 1 mm below the baseline (2 mm if the associated R wave in that lead was 120 mm] and a total exercise time varying by <20% on 2 successive exercise tests during p blocker plus diuretic therapy; (51a documented history of mild-to-moderate hypertension with supine diastolic pressure of 190 mm Hg but supine systolic pressure no higher than 240 mm Hg; (61 a supine diastolic blood pressure with the P-adrenergic blocking agent plus diuretic therapy no higher than 95 mm Hg and a resting supine diastolic pressure varying by 110 mm Hg on 4 successive visits. Exclusion criteria included: (1) left bundle branch block, right bundle branch block, preexcitation conduction defect with QRS duration X.12 second or any other condition that resulted in interference with interpretation of ST-segment changes during angina, and (21valvular heart disease, impaired renal function with serum creatinine >2 mg/dl, greater than firstdegree heart block or sick sinus syndrome or any disorder aside from hypertension or ischemic heart disease that would interfere with exercise duration.
Study protocol: The study consisted of 3 phases. There was an optional lead-in period (phase 0) of 4 weeks, which allowed patients who were potential candidates for the study to be titrated to a /3-adrenergic blocking agent plus thiazide diuretic in appropriate doses if they were previously taking other antianginal or antihypertensive medications (Fig. 1). Patients who were already taking a P-adrenergic blocking agent and diuretic in the appropriate doses were entered into the study at phase 1, provided supine diastolic pressure was <120 mm Hg and supine systolic pressure was 5240,mm Hg. During the 3 weeks of phase 1 (weeks A, B and C), the patient was given a placebo capsule to be taken twice daily in addition to their fl-adrenergic blocking agent plus diuretic. Blood pressure was measured weekly. In addition, patients underwent a syniptom-limited exercise treadmill test at some time during both the second and the third week. In order to advance to phase 2 (weeks 1 through 61,the patient must ‘have had chest pain and at least 1 mm of ST-segment depression from the baseline level, in the same lead on both the treadmill tests, and the time to termination of exercise must have varied by
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DRUGS
BETA-
Titratr
BIGCKER
<2‘fOmq/day of Propranold* lus Thiaridr Iiuretic only
DIURETIC
to
LJ
Placebo
SUSTAINEDRELEASE DILTIAZEM
m
120 5 day
240 to 360 mg/doy
Titration 240 - 360 mg /day
ETT
f3-f
ETT
r----------1
PHASE
i O(Optional) L----------J
1 1 1 a
b
1 I
11
c
0
d
Iz
I (Control)
j
1 11 A
0
C
11 1
2
11 3
III
I
4
11 5
6
7
1
1 ’
1
8
IO
9
WEEKS *or equivalent
dose of other
beta-blocker
FIGURE 1. Study design. An optional 4-week phase was permitted to adjust medications so that all patients were taktng a standard combination of fl blocker and diuretic before addition of a placebo capsule. Phase 1 = 3 weeks of j3 blocker plus diuretic plus placebo therapy and 2 positive exercise test results with total time varying by <20%; phase 2 = 6 weeks with placebo replaced by diltiaxem; withdrawal of j3 blocker and diuretic over the initial 2 weeks and diltiazem dose adjusted over the next 4 weeks; phase 3 = 4 weeks with a stable dose of diltiazem with or without a diuretic. Modified Bruce protocol exercise treadmill tests (ElT) were performed at the times indicated.
blood pressure were made 1 minute apart and averaged, and the pulse was again counted for 30 seconds. Treadmill test: The exercise treadmill tests were performed at approximately the same time of day, 4 hours after the last dose of medication. A modified Bruce exercise protocoP was used that consisted of an initial 3-minute stage at a speed of 1.7 mph and an incline of 5%. The next stage, 1.7 mph and 10% incline, was equivalent to stage 1 of the standard Bruce protocol and all subsequent 3-minute stages followed the standard protocol. The test was terminated at the occurrence of ischemic symptoms such as chest pain, severe dyspnea or ST-segment depression 11 mm above resting values. At the week B and C tests, it was required that both chest pain and ST-segment depression of 21 mm occurred, but not in any particular order. More than 20% variation in time to termination between these 2 tests resulted in disqualification of the patient from the study. During any test, continuation of the test beyond 1 mm ST-segment depression was at the investigator’s discretion. Statistics: Group data are expressed as mean f standard deviation. The paired t test was used to make pairwise comparisons between control, week 6 and week 10 values and differences were considered significant at a level of p <0.05. The subgroup of patients who required the addition of diuretic was compared with the subgroup that received only diltiazem using the &sample t test, analysis of variance and the Wilcoxon rank sum test.
Results Hypertension control: For the entire group of 38 patients, blood pressure control after 4 weeks of sus-
tained-release diltiazem was not significantly different from that seen with ,f3-adrenergic blocking agent plus thiazide diuretic in the supine position (137 f 22/ 82 f 7 versus 139 f 22/82 f 8 mm Hg), immediately after standing (131 f 20/84 f 9 versus 133 f21/82 f 10 mm Hg) and after 5 minutes of standing (134 f 19/85 f 8 versus 137 f 18/85 f 9 mm Hg) (Fig. 2A, Table II]. Further, there were no significant changes in pressures after 4 additional weeks of diltiazem therapy. After these 4 weeks, i.e., at the end of the study, 14 patients were receiving 240 mg daily of sustained-release diltiazem and 24 were receiving 360 mg daily with a mean dose of 316 mg daily. Of the latter 24 patients, 10 had also been given hydrochlorothiazide; 3 were taking 25 mg daily, 6 were taking 50 mg daily and 1 was taking 125 mg daily. Of the 38 patients, 28 (74701had both systolic and diastolic pressures that were not significantly different while taking the sustained-release diltiazem alone compared with combined therapy with ,&adrenergic blocking agent and diuretic. The only difference between pressures on the 2 regimens was that the diastolic pressure immediately after standing was slightly lower while the patients were taking diltiazem compared with the combination (82 f 9 versus 79 f 9 mm Hg, p = 0.04) (Table III]. Ten of 38 patients (26%) required hydrochlorothiazide in addition to diltiazem. In these patients, the diastolic pressure in the supine position while taking diltiazem alone tended to be higher than while taking the combination; however, the difference was not significant (86 f 8 versus 88 f 7 mm Hg, p = 0.30) (Table III]. The systolic pressure in these 10 patients was significantly higher immediately after standing with dil-
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tiazem alone (138 f 20 versus 151 f 22 mm Hg, p = 0.031, and both the systolic and diastolic pressures were higher 5 minutes after standing (144 f 21 versus 155 f 15 mm Hg, p = 0.02, and 88 f 8 versus 94 f 8 mm Hg, p = 0.005, respectively). Following the addition of the thiazide diuretic, there was no significant difference between either systolic or diastolic pressures compared with combination of /%adrenergic blocking agent plust diuretic. Heart rate: There was a significant increase in heart rate with the substitution of sustained-release diltiazem for the /3-adrenergic blocking agent plus diuretic combination (Fig. 2B, Table II). This was true for each position: supine (60 f 11 versus 67 f 11 beats/ min, p = O.OOOl),immediately after standing (64 f 14 versus 73 f 13 beats/min, p = 0.0001) and after 5 min-
cl SY6TOLlC
DIASTWC isi PMOSURL
PRESSURE
A.
SUPINE
STAND1 NO
1605 140j
120-
:
!OO-
$
60-
;
60-
0 8 d
4020o-
CONTRQ
8.
SUSTAINEB SUSTAIWLDN&EASE RELEASE OILTIAZEM DILTIAZEM I WEEK 61 (WEEK IO01
CONTR(X
STANDING
SUPINE t
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SUSTAIWED- SlSlAUP RELEASE DILTIAZEY DILTIAZEY (WEEK 6) (WEEK (0)
1
,
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f
T
utes of standing (63 f 14 versus 73 f 14 beats/min, p = 0.0001). This difference was observed both 4 weeks after substitution of diltisizem for the combination therapy as well as after 8 weeks of diltiazem therapy. The addition of hydrochlorothiazide to the sustainedrelease diltiazem did not further increase the heart rate except for immediately after standing, when the heart rate with diltiazem monotherapy was 72 f 15 beats/min; this increased further to 76 f 16 beats/min, p = 0.007, with the add i tion of the diuretic (Table III]. Although the heart rate increased on assuming upright posture with diltiazem, with or without a concomitant diuretic, no patients required discontinuation because of orthostatic hypotension. Exercise treadmill: The substitution of sustainedrelease diltiazem monotherapy for combination therapy resulted in an improvemeiit in exercise treadmill performance [Fig. 3, Table II). The time to onset of 1 mm ST-segment depression increased from 402 f 177. to 453 f’l94 seconds (p = 0.03), the time to onset of chest pain increased from 441 f 189 to 517 f 210 seconds (p = 0.002) and the total exercise time increased from 536 f 153 to 581 f 176 seconds (p = 0.009), after 4 weeks. The total exercise time increased further after an additional 4 weeks of diltiazem therapy to 608 f 167 seconds (p = 0.003 compared with total exercise time at 6 weeks). There was no improvement in exercise performance in the 10 patients who required the addition of diuretic to the maximum dosage of diltiazem when the paired t test was used to test for significance (Table III]. The time to onset of 1 mm ST-segment depression (345 f 131 versus 356 f 216 seconds], the time to onset of chest pain (429 f 142 versus 423 f 166 seconds) and the total exercise time (494 f 115 versus 520 f 145 seconds] were not different when compared with the values seen during the p-adrenergic blocking agent and diuretic combination therapy. Although this suggests that
L
TIME TO Imm ST DEPRESSION
TIME TO TERMINATION
L
%LSTAINED- SUSTAINEDRELEASE RELEASE DILTIAZEM DILTIAZEM (WEEK 6) (WEEK IO)
IAZEM EK 6)
FIGURE 2. A, blood pressure response. Results are mean f 1 standard deviation. Sustained-release dlltiazem monotherapy resulted in equivalent blood pressure control when substituted for the combination of B blocker and thiazide diuretic in both supine position (/eff) and standing for 5 minutes (right) after 4 (week 6) and 6 (week 10) weeks of diltiarem therapy in 26 of 36 patients. In 10 of 26 patients, thiazide diuretic was given In addition to the diltiazem. B, heart rate response. The change in heart rate In the supine position after substitution of sustained-release diltiazem for /3 blocker Is shown on the leff. A significant increase in heart rate was seen both 4 and 6 weeks after the substitution. A similar increase in heart rate was seen 5 minutes after standing when diltiazem was substituted for B blocker.
1i 5
IllL :ONTNOL S;;SWD*
:
MLTIAZEM (WEEK61
C (
‘AlNEDEASE ;(o”:
rAINED- SUS REL EASE AZEM DILT EK6) (WE
FIGURE 3. Results of exercise ireadmill testlng. Sustained-release diltiarem resulted in improvement of exercise parameters, time to onset of 1 mm ST-segment depression (/eff) and total exercise time (right) when substituted for the combination of j3 blocker and dluretic. Further improvement in exercise time was seen between weeks 6 and 10. The improvement was not observed in the 10 patients requiring maximum diltiazem dosage plus diuretic (see text). * p = 0.03; l * p
December
14, 1967
patients who had the addition of hydrochlorothiazide had a smaller improvement in exercise performance after treatment with diltiazem than the subgroup who did not require the diuretic, a direct comparison between these subgroups using analysis of variance and the Wilcoxon rank sum tests showed that they did not differ significantly.
Discussion Diltiazem has been shown to be an effective substitute, when used in low doses, for hydrochlorothiazide
TABLE II
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as a single agent in the treatment of mild hypertension.*O A slow-release form of diltiazem in dosages ranging from 180 to 270 mg daily was comparable to a slow-release form of nifedipine, 40 to 60 mg daily, in control of hypertension.g A reduction of diastolic blood pressure, compared with placebo, of X0% was obtained in 53% of patients given diltiazem and in 78% given nifedipine. Diltiazem was associated with an 8% reduction in heart rate at rest, while no change was seen during nifedipine treatment. In a different study, sustained-release diltiazem in graded doses (60, 120
Results for All Patients (n = 38) Sustained-Release Diltiazem (week 6)
Control (week C) Blood pressure (mm Hg) Supine, systolic Supine, diastolic Immediate standing, systolic immediate standing, diastolic 5 minutes standing, systolic 5 minutes standing, diastolic
137 62 131 64 134 65
Heart rate (beatslmin) Supine Immediate standing 5 minutes standing
f f f f f
22 7 20 9 19
139 f 63 f 133 f 62f 137 f 65 f
f a
60f 64f 63%
Exercise treadmill testing (seconds) Time to 1 mm ST-segment 1 Time to onset of chest pain Time to termination of exercise
1 14 14
Sustained-Release Diltiazem (week 10)
22 6 21 10
136 f 60 f 130 f 64% 135 f 64 f
ia
9
67f II” 73 f 13* 73 f 14’
402 f 177 441 f 169 536 f 153
67f 73 f 72 i
453 f 194’” 517 f 210” 561 f 176’
TABLE Ill Results in 28 Patients Who Required Sustained-Release Diuretic to Achieve Blood Pressure Control Sustained-Release
Control Blood pressure (mm Hg) Supine, systolic Supine, diastolic Immediate standing, systolic Immediate standing, diastolic 5 minutes standing, systolic 5 minutes standing, diastolic Heart rate (beatslmin) Supine Immediate standing 5 minutes standing treadmill time (seconds) to 1 mm ST-segment 4 to onset of chest pain exercise time
131 61 129 62 130 64
60f 64f 63f
f f f f f f
17 6 20 9 16 7
12 14 15
423 f 166 446 f 206 551 f 164
Diltiazem (week 6)
132 f
16 7 127 f 17 79 f 9 130 f 14
60f
61f6 66f 73 f 73 f
11 12” 15””
469 f 177’ 551 f 217”’ 602 f 164”’
Diltlazem
19 7 17 10 17
a
11” 12’ 13”
476 f 176’ 540 f 210’ 606 f 167’t
All values are mean f 1 standard deviation. = p
Exercise Time Time Total
OF CARDIOLOGY
p = 0.003.
Only and 10 Patients Who Required Both Dlltiarem
and
Diuretic Added to Sustained-Release Diltiazem
Diltiazem
Diltiazem (week IO)
135 60 130 63 132 63
f
16
f a
f 17 f 6t f 16 f a
67 f 72f 72 f
IO”’ 11”” 12”
504 f 166”” 556 f 216” 630 f 169”“tt
Control
152 66 136 67 144
f f f f f
159 f 25 86f 7 151 f 22” 90 f a 155 f 15” 94 f a**
IO 13 13
64f 10 72 f 15” 72 f 15”
67 f 12”’ 76 f 16tt 74 f 16””
356 f 216 423 f 166 520 f 145
396 f 133 465 f 164 539 f 146
345 f 131 429 f 142 494 f 115
All values are mean f 1 standard deviation. * p <0.05 versus control; * * p SO.01 versus control: 7 p SO.05 versus week 6; tt p
Diltiazem Plus Diuretic (week IO)
26 7 20 6 21
66f 8
60f 64f 63f
Diltiazem (week 6)
147 62 131 66 141 67
f f f f f f
24 6tt 1677 9 17tr 9tt
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A SYMPOSIUM:
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and 180 mg twice daily) was found to have efficacy comparable to graded doses of propranolol (80, 160 and 240 mg twice daily] in patients with mild to moderate hypertension.15J6 In our study of patients with both hypertension and angina, sustained-release diltiazem given orally in a range of 240 to 360 mg daily (2 or 3 60 mg capsules twice daily) resulted in: (1) blood pressure control equivalent’ to the combination of propranolol, up to 240 mg daily (or equivalent other fi-adrenergic blocking agent) and a thiazide diuretic in 28 of 38 (74%] patients; and (2) an improvement in angina control that was objectively documented by increase in time to onset of both 1 mm ST-segment depression and chest pain as well as increase of total exercise time. In the remaining 10 patients, equivalent control of hypertension required the resumption of thiazide diuretic. With the substitution of sustained-release diltiazem for p-adrenergic blocking agent plus thiazide, the heart rate at rest increased significantly in every position: supine, immediately after standing and after 5 minutes of standing. The heart rate change was most probably due to withdrawal of the /3 blockade as there was no significant further change in heart rate in those 10 patients in whom thiazide diuretic was resumed except for a small further increase in heart rate immediately after standing. A possible explanation for this finding is a reduction of blood volume due to the diuretic, which, in addition to the vasodilation produced by the diltiazem, may have resulted in an orthostatic effect. Diltiazem monotherapy has been shown effective in patients with exertional angina in doses of 24013and 360 mg daily,2 resulting in an increase of exercise duration. When compared with propranolol alone, diltiazem monotherapy produced an equivalent improvement in exercise time in such patients.536Propranolol produced a decrease in heart rate and double-product at peak exercise but diltiazem did not. In patients with both angina and systemic hyper-. tension, diltiazem has been compared with nifedipine.*l Both reduced standing blood pressure, exercise time and exercise diastolic pressure compared with placebo. Diltiazem was associated with a reduction of standing heart rate at rest from 88.5 f 14.4 to 79.7 f 17.9 beats/min (p
erance through reduction of, or delay in, the aug mentation of myocardial oxygen consumption during exercise.ll Our results in patients with both hypertension and angina in whom angina is already controlled with a combination of P-adrenergic blocking agent and diuretic suggest that exercise tolerance may increase to a greater extent with the substitution of sustained-release diltiazem. This was a somewhat unexpected result because previous observations had suggested that, even in doses up to 360 mg daily, the short-acting form of diltiazem increases exercise time similarly to that seen with propranolol alone in patients with angina without systemic hypertension5p6 Although a greater improvement in exercise time with the sustained-release form of diltiazem compared with propranolol was previously demonstrated in patients with hypertension, l4 it has not been observed before in patients with both hypertension and angina. In our study, the heart rate at rest with diltiazem was higher despite similar blood pressures compared with the P-blocker regimen. Thus, the improvement in exercise tolerance with substitution of sustained-release diltiazem may have been due to a delayed augmentation of the blood pressure-heart rate product (an indirect measure of M%‘O,] during exercise, an increase in myocardial blood flow through coronary artery dilation as has been suggested by other studies5 or a combination of factors. A precise definition of the causal mechanism is beyond the scope of this clinical investigation.
ClinicalImplications In this study of patients with both systemic hypertension and angina pectoris, sustained-release diltiazem monotherapy was found to produce hypertension control equivalent to the combination of P-adrenergic blocking agent and diuretic in 28 of 38 patients (74%) In the remaining patients, the addition of a diuretic to sustained-release diltiazem resulted in control of hy pertension similar to the /3-adrenergic blocking agent plus diuretic combination. Despite an increase in heart rate at rest and equivalent blood pressure at rest, the diltiazem regimen resulted in an increase of exercise duration, time to ST depression and time to chest pain when compared with the P-blocker regimen. Therefore, in patients with both systemic hypertension and angina, sustained-release diltiazem should be considered as replacement for the combination of /3-adrenergic blocking agent and thiazide diuretic. Diltiazem controls hypertension, increases the duration of exercise necessary to produce myocardial ischemia and results in a simplified medication schedule in the majority of patients, which would be expected to improve compliance. Acknowledgmenti University of Southern California, Cheryl Reid, MD, Yolie Amisola, RN; Medical University of South Carolina, Peter. C. Gazes, MD, Patti Leman; University of California at San Francisco, Elaine Der, RN, MSN; Baylor College of Medicine,
December
Saul Silver, MD, Terry Hohmann, RN; Michael Reese Hospital, Andrew C. Eisenhauer, MD, Robert Roth, MD, Patricia Bailey-Eisenhauer, PhD; Steven Walker, MS, Barbara J. Geiger, RN, BSN.
References 1. Lindenberg BS, Weiner DA, McCabe CH, Cutter SS, Ryan TJ, Klein MD. Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris. JACC 1983;2:1129-1133. 2. Petru MA, Crawford MH, Sorensen SG, Chaudhuri TK, Levine S, O’Rourke RA. Short and long-term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: a placebo-controlled, randomized double-blind crossover study. Circulation 1983;68:139-147. 3. Crawford MH. Effectiveness of diltiazem for chronic stable angina pectoris. Acta Pharmacof Toxicol 1985;57:suppl II:44-48. 4. Bala Subramanian V, Khurmi NS, Bowles MJ, O’Hara M, Raftery EB. Objective evaluation of three dose levels of diltiazem in patients with chfonic stable angina. [ACC 1983;2:1144-1153. 5. Hung J, Lamb IH, Connolly SJ. Jutzy KR, Goris ML, Schroeder JS. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort ongina: a double-blind, randomized, placebo-controlled study. Circulation 1983: 68:560-567.
6. Schroeder JS,Hung J,Lamb II-I, Connolly SJ,Jutzy KR, Goris ML. Diltiazem and propranolol, alone arid in combination, on exercise performance and left ventricular function in patients with stable effort angina: a double-blind,
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randomized, and placebo-controlled study. Acta Pharmacol Toxic01 1985;57: suppl
rr:55-60.
7. Bourassa MG. Haemodynamic and efectrophysiologic effects of diltiazem. Acta Pharmacol Toxicol 1985;57:suppl 112-30. 8. Amodeo C, Kobrin I, Ventura HO, Messerli FH, Frohlich ED. Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension. Circulation 1986;73:108-113. 9. Schulte KL, Meyer-Sabellek WA, Haertenberger A, Thiede HM, Roecker L, Distler A, Gotzen R. Antihypertensive and metabolic effects of diltiazem and nifedipine. Hypertension 1986;8:859-865. 10. Inouye IK, Massie BM, Benowitz N, Simpson P, Loge D. Antihypertensive therapy with diltiazem and comparison with hydrochlorothiazide. Am J CardioI 1984;53:1588-1592. 11. Frishman WF, Charlap S, Goldberger J, Kimmel B, Stroh J, Dorsa F, Allen L, Strom J. Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am 1 Cardiol 1985;56:41H-46H. 12. Brqce RA, Hornsten TR. Exercise stress testing in evaluation of patient with ischemic heart disease. Prog Cardiovasc Dis 1969;11:371-390. 13. Hossack KF, Pool PE, Steele P, Crawford MH, DeMaria AN, Cohen LS, Ports TA. Efficacy of diltiazem in angina on effort: a multicenter trial. Am r Cardiol 1982;49:567-572. 14. Szlachnic J, Hirsch AT, Tubau JF, Vollmer C, Henderson S, Massie BM. Diltiazem versus propranofol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity. Am J Cardiol 1987;59:393-399. 15. Massie BM. Antihypertensive therapy with calcium blockers: comparison with beta blockers. Am f Cardiol 1985;56:97H-ltJ0H. 16. Frishman WH, Stroh JA, Greenberg SM, Suarez T, Karp A, Peled HB. Calcium-channel blockers in systemic hypertension. Curr Prob Cardiol 1987;12:287-346.
T.
KAWANISHI,
MD, ROBERT B. LEMAN, MD, CRAIG and ROBERT A. O’ROURKE, MD.
To determine if a sustained-release form of the calcium entry blocker diltiazem would be a satisfactory substitute for the combination of P-adrenergic blocking agent and thiazide diuretic in the treatment of systemic hypertension and angina pectoris, 38 patients were studied in a 4-center trial. Blood pressure and heart rate were measured in the supine position, immediately after and 5 minutes after standing. Modified Bruce protocol treadmill tests were performed to determine the time to onset of 1 mm ST-segment depression, time to onset of chest pain and time to terminaton of exercise. Diltiazem monotherapy resulted in equivalent blood pressure control in 28 of 38 patients (74% ). In the remaining patients, blood pressure control was achieved with resumption of the diuretic. Blood pressure with fl blocker plus diuretic compared with diltiazem were, in the supine position 137 f 22/82 f 7 (III 1 standard deviation) versus 139 f 22/82 f 8 mm Hg, immediately after standing 131 f 20/84 f 9 versus 133 f 21182 f 10 mm Hg and after stand-
T
he calcium entry blocking drug diltiazem is effective as an antianginal agent as measured by reduction in angina frequency and improvement of treadmill exercise performance1-4 and has been at least as effective as propranolol in the treatment of patients with
From the Section of Cardiology, Department of Medicine, University of Southern California School of Medicine, Los Angeles, California, Medical University of South Carolina, Charleston, Baylor College of Medicine, Houston, and the University of Texas Health Science Center/San Antonio, San Antonio, Texas. Address for reprints: David T. Kawanishi, MD, Section of Cardiology, University of Southern California, School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033.
M.
PRATT,
MD,
ing for 5 minutes 134 f 19/85 f 8 versus 137 f 18/85 f 9 mm Hg (difference not significant for each). The heart rate with diltiazem was higher supine (67 f 11 versus 60 f 11 beats/min), standing (73 f 13 versus 64 f 14 beats/min) and 5 minutes after standing (73 f 14 versus 63 f 14 beats/min, p
stable exertional angina. 5,6Diltiazem is an arterial vasodilator and its efficacy in the treatment of hypertension has been well documented.8sgIt has been substituted for hydrochlorothiazide and found to have an equivalent antihypertensive efficacy in low doses.10A sustained-release capsule preparation of diltiazem has been evaluated and found to be as effective as nifedipine in the treatment of patients with both angina and hypertensionll We investigated whether the sustained-release form of diltiazem provides effective and safe replacement therapy for the combination of a P-adrenergic blocking agent and diuretic in the treatment of patients who have both stable exertional angina pectoris and essential hypertension. 291
301
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TABLE I
HYPERTENSION-THE
HEART AND KIDNEY
Patient Characteristics Age (years) Sex (M/F) Evidence for CAD Coronary arteriography Prior myocardial infarction (definite or possible) Thallium perfusion defect
59 f 7 24114 33 16 7
CAD = coronary artery disease.
Materialand Methods Study group: Thirty-eight patients aged 59 f 7 years (& 1 standard deviation] [range 42 to 69) were included in the study. These patients were enrolled at 4 centers; the number of patients enrolled at each center ranged from 7 to 14. There were 24 men and 14 women (Table I]. Patients were considered for the study if they fulfilled the entry criteria, which were: (1) a stable pattern of angina with regard to frequency, duration and intensity for at least 3 months (symptoms of chest pain were considered to be angina if they were a precordial sensation of pressure or distress lasting between 2 and 10 minutes and brought on by exertion or emotional stress, with relief by rest, removal of the emotional stress or nitroglycerin]; (2) evidence of coronary artery disease by one of the following: >70% reduction in diameter of at least 1 major coronary artery by arteriography, prior (>3 months] myocardial infarction based on at least 2 of the following criteriaa classic history of prolonged chest pain, new and persistent Q waves and/or ST-T wave changes on the electrocardiogram or an elevated CPK with positive MB fraction with a subsequent decrease to at least one-half of the peak values or a documented exercise thallium test showing a fixed perfusion defect and/or a reversible defect; (31a medical regimen that included only propranolol at a dose of 80 to 240 mg daily or another ,&adrenergic blocking agent at an equivalent dose plus a thiazide diuretic; (41 ST-segment depression of at least 1 mm below the baseline (2 mm if the associated R wave in that lead was 120 mm] and a total exercise time varying by <20% on 2 successive exercise tests during p blocker plus diuretic therapy; (51a documented history of mild-to-moderate hypertension with supine diastolic pressure of 190 mm Hg but supine systolic pressure no higher than 240 mm Hg; (61 a supine diastolic blood pressure with the P-adrenergic blocking agent plus diuretic therapy no higher than 95 mm Hg and a resting supine diastolic pressure varying by 110 mm Hg on 4 successive visits. Exclusion criteria included: (1) left bundle branch block, right bundle branch block, preexcitation conduction defect with QRS duration X.12 second or any other condition that resulted in interference with interpretation of ST-segment changes during angina, and (21valvular heart disease, impaired renal function with serum creatinine >2 mg/dl, greater than firstdegree heart block or sick sinus syndrome or any disorder aside from hypertension or ischemic heart disease that would interfere with exercise duration.
Study protocol: The study consisted of 3 phases. There was an optional lead-in period (phase 0) of 4 weeks, which allowed patients who were potential candidates for the study to be titrated to a /3-adrenergic blocking agent plus thiazide diuretic in appropriate doses if they were previously taking other antianginal or antihypertensive medications (Fig. 1). Patients who were already taking a P-adrenergic blocking agent and diuretic in the appropriate doses were entered into the study at phase 1, provided supine diastolic pressure was <120 mm Hg and supine systolic pressure was 5240,mm Hg. During the 3 weeks of phase 1 (weeks A, B and C), the patient was given a placebo capsule to be taken twice daily in addition to their fl-adrenergic blocking agent plus diuretic. Blood pressure was measured weekly. In addition, patients underwent a syniptom-limited exercise treadmill test at some time during both the second and the third week. In order to advance to phase 2 (weeks 1 through 61,the patient must ‘have had chest pain and at least 1 mm of ST-segment depression from the baseline level, in the same lead on both the treadmill tests, and the time to termination of exercise must have varied by
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DRUGS
BETA-
Titratr
BIGCKER
<2‘fOmq/day of Propranold* lus Thiaridr Iiuretic only
DIURETIC
to
LJ
Placebo
SUSTAINEDRELEASE DILTIAZEM
m
120 5 day
240 to 360 mg/doy
Titration 240 - 360 mg /day
ETT
f3-f
ETT
r----------1
PHASE
i O(Optional) L----------J
1 1 1 a
b
1 I
11
c
0
d
Iz
I (Control)
j
1 11 A
0
C
11 1
2
11 3
III
I
4
11 5
6
7
1
1 ’
1
8
IO
9
WEEKS *or equivalent
dose of other
beta-blocker
FIGURE 1. Study design. An optional 4-week phase was permitted to adjust medications so that all patients were taktng a standard combination of fl blocker and diuretic before addition of a placebo capsule. Phase 1 = 3 weeks of j3 blocker plus diuretic plus placebo therapy and 2 positive exercise test results with total time varying by <20%; phase 2 = 6 weeks with placebo replaced by diltiaxem; withdrawal of j3 blocker and diuretic over the initial 2 weeks and diltiazem dose adjusted over the next 4 weeks; phase 3 = 4 weeks with a stable dose of diltiazem with or without a diuretic. Modified Bruce protocol exercise treadmill tests (ElT) were performed at the times indicated.
blood pressure were made 1 minute apart and averaged, and the pulse was again counted for 30 seconds. Treadmill test: The exercise treadmill tests were performed at approximately the same time of day, 4 hours after the last dose of medication. A modified Bruce exercise protocoP was used that consisted of an initial 3-minute stage at a speed of 1.7 mph and an incline of 5%. The next stage, 1.7 mph and 10% incline, was equivalent to stage 1 of the standard Bruce protocol and all subsequent 3-minute stages followed the standard protocol. The test was terminated at the occurrence of ischemic symptoms such as chest pain, severe dyspnea or ST-segment depression 11 mm above resting values. At the week B and C tests, it was required that both chest pain and ST-segment depression of 21 mm occurred, but not in any particular order. More than 20% variation in time to termination between these 2 tests resulted in disqualification of the patient from the study. During any test, continuation of the test beyond 1 mm ST-segment depression was at the investigator’s discretion. Statistics: Group data are expressed as mean f standard deviation. The paired t test was used to make pairwise comparisons between control, week 6 and week 10 values and differences were considered significant at a level of p <0.05. The subgroup of patients who required the addition of diuretic was compared with the subgroup that received only diltiazem using the &sample t test, analysis of variance and the Wilcoxon rank sum test.
Results Hypertension control: For the entire group of 38 patients, blood pressure control after 4 weeks of sus-
tained-release diltiazem was not significantly different from that seen with ,f3-adrenergic blocking agent plus thiazide diuretic in the supine position (137 f 22/ 82 f 7 versus 139 f 22/82 f 8 mm Hg), immediately after standing (131 f 20/84 f 9 versus 133 f21/82 f 10 mm Hg) and after 5 minutes of standing (134 f 19/85 f 8 versus 137 f 18/85 f 9 mm Hg) (Fig. 2A, Table II]. Further, there were no significant changes in pressures after 4 additional weeks of diltiazem therapy. After these 4 weeks, i.e., at the end of the study, 14 patients were receiving 240 mg daily of sustained-release diltiazem and 24 were receiving 360 mg daily with a mean dose of 316 mg daily. Of the latter 24 patients, 10 had also been given hydrochlorothiazide; 3 were taking 25 mg daily, 6 were taking 50 mg daily and 1 was taking 125 mg daily. Of the 38 patients, 28 (74701had both systolic and diastolic pressures that were not significantly different while taking the sustained-release diltiazem alone compared with combined therapy with ,&adrenergic blocking agent and diuretic. The only difference between pressures on the 2 regimens was that the diastolic pressure immediately after standing was slightly lower while the patients were taking diltiazem compared with the combination (82 f 9 versus 79 f 9 mm Hg, p = 0.04) (Table III]. Ten of 38 patients (26%) required hydrochlorothiazide in addition to diltiazem. In these patients, the diastolic pressure in the supine position while taking diltiazem alone tended to be higher than while taking the combination; however, the difference was not significant (86 f 8 versus 88 f 7 mm Hg, p = 0.30) (Table III]. The systolic pressure in these 10 patients was significantly higher immediately after standing with dil-
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tiazem alone (138 f 20 versus 151 f 22 mm Hg, p = 0.031, and both the systolic and diastolic pressures were higher 5 minutes after standing (144 f 21 versus 155 f 15 mm Hg, p = 0.02, and 88 f 8 versus 94 f 8 mm Hg, p = 0.005, respectively). Following the addition of the thiazide diuretic, there was no significant difference between either systolic or diastolic pressures compared with combination of /%adrenergic blocking agent plust diuretic. Heart rate: There was a significant increase in heart rate with the substitution of sustained-release diltiazem for the /3-adrenergic blocking agent plus diuretic combination (Fig. 2B, Table II). This was true for each position: supine (60 f 11 versus 67 f 11 beats/ min, p = O.OOOl),immediately after standing (64 f 14 versus 73 f 13 beats/min, p = 0.0001) and after 5 min-
cl SY6TOLlC
DIASTWC isi PMOSURL
PRESSURE
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SUPINE
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1605 140j
120-
:
!OO-
$
60-
;
60-
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CONTRQ
8.
SUSTAINEB SUSTAIWLDN&EASE RELEASE OILTIAZEM DILTIAZEM I WEEK 61 (WEEK IO01
CONTR(X
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SUPINE t
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SUSTAIWED- SlSlAUP RELEASE DILTIAZEY DILTIAZEY (WEEK 6) (WEEK (0)
1
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f
T
utes of standing (63 f 14 versus 73 f 14 beats/min, p = 0.0001). This difference was observed both 4 weeks after substitution of diltisizem for the combination therapy as well as after 8 weeks of diltiazem therapy. The addition of hydrochlorothiazide to the sustainedrelease diltiazem did not further increase the heart rate except for immediately after standing, when the heart rate with diltiazem monotherapy was 72 f 15 beats/min; this increased further to 76 f 16 beats/min, p = 0.007, with the add i tion of the diuretic (Table III]. Although the heart rate increased on assuming upright posture with diltiazem, with or without a concomitant diuretic, no patients required discontinuation because of orthostatic hypotension. Exercise treadmill: The substitution of sustainedrelease diltiazem monotherapy for combination therapy resulted in an improvemeiit in exercise treadmill performance [Fig. 3, Table II). The time to onset of 1 mm ST-segment depression increased from 402 f 177. to 453 f’l94 seconds (p = 0.03), the time to onset of chest pain increased from 441 f 189 to 517 f 210 seconds (p = 0.002) and the total exercise time increased from 536 f 153 to 581 f 176 seconds (p = 0.009), after 4 weeks. The total exercise time increased further after an additional 4 weeks of diltiazem therapy to 608 f 167 seconds (p = 0.003 compared with total exercise time at 6 weeks). There was no improvement in exercise performance in the 10 patients who required the addition of diuretic to the maximum dosage of diltiazem when the paired t test was used to test for significance (Table III]. The time to onset of 1 mm ST-segment depression (345 f 131 versus 356 f 216 seconds], the time to onset of chest pain (429 f 142 versus 423 f 166 seconds) and the total exercise time (494 f 115 versus 520 f 145 seconds] were not different when compared with the values seen during the p-adrenergic blocking agent and diuretic combination therapy. Although this suggests that
L
TIME TO Imm ST DEPRESSION
TIME TO TERMINATION
L
%LSTAINED- SUSTAINEDRELEASE RELEASE DILTIAZEM DILTIAZEM (WEEK 6) (WEEK IO)
IAZEM EK 6)
FIGURE 2. A, blood pressure response. Results are mean f 1 standard deviation. Sustained-release dlltiazem monotherapy resulted in equivalent blood pressure control when substituted for the combination of B blocker and thiazide diuretic in both supine position (/eff) and standing for 5 minutes (right) after 4 (week 6) and 6 (week 10) weeks of diltiarem therapy in 26 of 36 patients. In 10 of 26 patients, thiazide diuretic was given In addition to the diltiazem. B, heart rate response. The change in heart rate In the supine position after substitution of sustained-release diltiazem for /3 blocker Is shown on the leff. A significant increase in heart rate was seen both 4 and 6 weeks after the substitution. A similar increase in heart rate was seen 5 minutes after standing when diltiazem was substituted for B blocker.
1i 5
IllL :ONTNOL S;;SWD*
:
MLTIAZEM (WEEK61
C (
‘AlNEDEASE ;(o”:
rAINED- SUS REL EASE AZEM DILT EK6) (WE
FIGURE 3. Results of exercise ireadmill testlng. Sustained-release diltiarem resulted in improvement of exercise parameters, time to onset of 1 mm ST-segment depression (/eff) and total exercise time (right) when substituted for the combination of j3 blocker and dluretic. Further improvement in exercise time was seen between weeks 6 and 10. The improvement was not observed in the 10 patients requiring maximum diltiazem dosage plus diuretic (see text). * p = 0.03; l * p
December
14, 1967
patients who had the addition of hydrochlorothiazide had a smaller improvement in exercise performance after treatment with diltiazem than the subgroup who did not require the diuretic, a direct comparison between these subgroups using analysis of variance and the Wilcoxon rank sum tests showed that they did not differ significantly.
Discussion Diltiazem has been shown to be an effective substitute, when used in low doses, for hydrochlorothiazide
TABLE II
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as a single agent in the treatment of mild hypertension.*O A slow-release form of diltiazem in dosages ranging from 180 to 270 mg daily was comparable to a slow-release form of nifedipine, 40 to 60 mg daily, in control of hypertension.g A reduction of diastolic blood pressure, compared with placebo, of X0% was obtained in 53% of patients given diltiazem and in 78% given nifedipine. Diltiazem was associated with an 8% reduction in heart rate at rest, while no change was seen during nifedipine treatment. In a different study, sustained-release diltiazem in graded doses (60, 120
Results for All Patients (n = 38) Sustained-Release Diltiazem (week 6)
Control (week C) Blood pressure (mm Hg) Supine, systolic Supine, diastolic Immediate standing, systolic immediate standing, diastolic 5 minutes standing, systolic 5 minutes standing, diastolic
137 62 131 64 134 65
Heart rate (beatslmin) Supine Immediate standing 5 minutes standing
f f f f f
22 7 20 9 19
139 f 63 f 133 f 62f 137 f 65 f
f a
60f 64f 63%
Exercise treadmill testing (seconds) Time to 1 mm ST-segment 1 Time to onset of chest pain Time to termination of exercise
1 14 14
Sustained-Release Diltiazem (week 10)
22 6 21 10
136 f 60 f 130 f 64% 135 f 64 f
ia
9
67f II” 73 f 13* 73 f 14’
402 f 177 441 f 169 536 f 153
67f 73 f 72 i
453 f 194’” 517 f 210” 561 f 176’
TABLE Ill Results in 28 Patients Who Required Sustained-Release Diuretic to Achieve Blood Pressure Control Sustained-Release
Control Blood pressure (mm Hg) Supine, systolic Supine, diastolic Immediate standing, systolic Immediate standing, diastolic 5 minutes standing, systolic 5 minutes standing, diastolic Heart rate (beatslmin) Supine Immediate standing 5 minutes standing treadmill time (seconds) to 1 mm ST-segment 4 to onset of chest pain exercise time
131 61 129 62 130 64
60f 64f 63f
f f f f f f
17 6 20 9 16 7
12 14 15
423 f 166 446 f 206 551 f 164
Diltiazem (week 6)
132 f
16 7 127 f 17 79 f 9 130 f 14
60f
61f6 66f 73 f 73 f
11 12” 15””
469 f 177’ 551 f 217”’ 602 f 164”’
Diltlazem
19 7 17 10 17
a
11” 12’ 13”
476 f 176’ 540 f 210’ 606 f 167’t
All values are mean f 1 standard deviation. = p
Exercise Time Time Total
OF CARDIOLOGY
p = 0.003.
Only and 10 Patients Who Required Both Dlltiarem
and
Diuretic Added to Sustained-Release Diltiazem
Diltiazem
Diltiazem (week IO)
135 60 130 63 132 63
f
16
f a
f 17 f 6t f 16 f a
67 f 72f 72 f
IO”’ 11”” 12”
504 f 166”” 556 f 216” 630 f 169”“tt
Control
152 66 136 67 144
f f f f f
159 f 25 86f 7 151 f 22” 90 f a 155 f 15” 94 f a**
IO 13 13
64f 10 72 f 15” 72 f 15”
67 f 12”’ 76 f 16tt 74 f 16””
356 f 216 423 f 166 520 f 145
396 f 133 465 f 164 539 f 146
345 f 131 429 f 142 494 f 115
All values are mean f 1 standard deviation. * p <0.05 versus control; * * p SO.01 versus control: 7 p SO.05 versus week 6; tt p
Diltiazem Plus Diuretic (week IO)
26 7 20 6 21
66f 8
60f 64f 63f
Diltiazem (week 6)
147 62 131 66 141 67
f f f f f f
24 6tt 1677 9 17tr 9tt
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A SYMPOSIUM:
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and 180 mg twice daily) was found to have efficacy comparable to graded doses of propranolol (80, 160 and 240 mg twice daily] in patients with mild to moderate hypertension.15J6 In our study of patients with both hypertension and angina, sustained-release diltiazem given orally in a range of 240 to 360 mg daily (2 or 3 60 mg capsules twice daily) resulted in: (1) blood pressure control equivalent’ to the combination of propranolol, up to 240 mg daily (or equivalent other fi-adrenergic blocking agent) and a thiazide diuretic in 28 of 38 (74%] patients; and (2) an improvement in angina control that was objectively documented by increase in time to onset of both 1 mm ST-segment depression and chest pain as well as increase of total exercise time. In the remaining 10 patients, equivalent control of hypertension required the resumption of thiazide diuretic. With the substitution of sustained-release diltiazem for p-adrenergic blocking agent plus thiazide, the heart rate at rest increased significantly in every position: supine, immediately after standing and after 5 minutes of standing. The heart rate change was most probably due to withdrawal of the /3 blockade as there was no significant further change in heart rate in those 10 patients in whom thiazide diuretic was resumed except for a small further increase in heart rate immediately after standing. A possible explanation for this finding is a reduction of blood volume due to the diuretic, which, in addition to the vasodilation produced by the diltiazem, may have resulted in an orthostatic effect. Diltiazem monotherapy has been shown effective in patients with exertional angina in doses of 24013and 360 mg daily,2 resulting in an increase of exercise duration. When compared with propranolol alone, diltiazem monotherapy produced an equivalent improvement in exercise time in such patients.536Propranolol produced a decrease in heart rate and double-product at peak exercise but diltiazem did not. In patients with both angina and systemic hyper-. tension, diltiazem has been compared with nifedipine.*l Both reduced standing blood pressure, exercise time and exercise diastolic pressure compared with placebo. Diltiazem was associated with a reduction of standing heart rate at rest from 88.5 f 14.4 to 79.7 f 17.9 beats/min (p
erance through reduction of, or delay in, the aug mentation of myocardial oxygen consumption during exercise.ll Our results in patients with both hypertension and angina in whom angina is already controlled with a combination of P-adrenergic blocking agent and diuretic suggest that exercise tolerance may increase to a greater extent with the substitution of sustained-release diltiazem. This was a somewhat unexpected result because previous observations had suggested that, even in doses up to 360 mg daily, the short-acting form of diltiazem increases exercise time similarly to that seen with propranolol alone in patients with angina without systemic hypertension5p6 Although a greater improvement in exercise time with the sustained-release form of diltiazem compared with propranolol was previously demonstrated in patients with hypertension, l4 it has not been observed before in patients with both hypertension and angina. In our study, the heart rate at rest with diltiazem was higher despite similar blood pressures compared with the P-blocker regimen. Thus, the improvement in exercise tolerance with substitution of sustained-release diltiazem may have been due to a delayed augmentation of the blood pressure-heart rate product (an indirect measure of M%‘O,] during exercise, an increase in myocardial blood flow through coronary artery dilation as has been suggested by other studies5 or a combination of factors. A precise definition of the causal mechanism is beyond the scope of this clinical investigation.
ClinicalImplications In this study of patients with both systemic hypertension and angina pectoris, sustained-release diltiazem monotherapy was found to produce hypertension control equivalent to the combination of P-adrenergic blocking agent and diuretic in 28 of 38 patients (74%) In the remaining patients, the addition of a diuretic to sustained-release diltiazem resulted in control of hy pertension similar to the /3-adrenergic blocking agent plus diuretic combination. Despite an increase in heart rate at rest and equivalent blood pressure at rest, the diltiazem regimen resulted in an increase of exercise duration, time to ST depression and time to chest pain when compared with the P-blocker regimen. Therefore, in patients with both systemic hypertension and angina, sustained-release diltiazem should be considered as replacement for the combination of /3-adrenergic blocking agent and thiazide diuretic. Diltiazem controls hypertension, increases the duration of exercise necessary to produce myocardial ischemia and results in a simplified medication schedule in the majority of patients, which would be expected to improve compliance. Acknowledgmenti University of Southern California, Cheryl Reid, MD, Yolie Amisola, RN; Medical University of South Carolina, Peter. C. Gazes, MD, Patti Leman; University of California at San Francisco, Elaine Der, RN, MSN; Baylor College of Medicine,
December
Saul Silver, MD, Terry Hohmann, RN; Michael Reese Hospital, Andrew C. Eisenhauer, MD, Robert Roth, MD, Patricia Bailey-Eisenhauer, PhD; Steven Walker, MS, Barbara J. Geiger, RN, BSN.
References 1. Lindenberg BS, Weiner DA, McCabe CH, Cutter SS, Ryan TJ, Klein MD. Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris. JACC 1983;2:1129-1133. 2. Petru MA, Crawford MH, Sorensen SG, Chaudhuri TK, Levine S, O’Rourke RA. Short and long-term efficacy of high-dose oral diltiazem for angina due to coronary artery disease: a placebo-controlled, randomized double-blind crossover study. Circulation 1983;68:139-147. 3. Crawford MH. Effectiveness of diltiazem for chronic stable angina pectoris. Acta Pharmacof Toxicol 1985;57:suppl II:44-48. 4. Bala Subramanian V, Khurmi NS, Bowles MJ, O’Hara M, Raftery EB. Objective evaluation of three dose levels of diltiazem in patients with chfonic stable angina. [ACC 1983;2:1144-1153. 5. Hung J, Lamb IH, Connolly SJ. Jutzy KR, Goris ML, Schroeder JS. The effect of diltiazem and propranolol, alone and in combination, on exercise performance and left ventricular function in patients with stable effort ongina: a double-blind, randomized, placebo-controlled study. Circulation 1983: 68:560-567.
6. Schroeder JS,Hung J,Lamb II-I, Connolly SJ,Jutzy KR, Goris ML. Diltiazem and propranolol, alone arid in combination, on exercise performance and left ventricular function in patients with stable effort angina: a double-blind,
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randomized, and placebo-controlled study. Acta Pharmacol Toxic01 1985;57: suppl
rr:55-60.
7. Bourassa MG. Haemodynamic and efectrophysiologic effects of diltiazem. Acta Pharmacol Toxicol 1985;57:suppl 112-30. 8. Amodeo C, Kobrin I, Ventura HO, Messerli FH, Frohlich ED. Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension. Circulation 1986;73:108-113. 9. Schulte KL, Meyer-Sabellek WA, Haertenberger A, Thiede HM, Roecker L, Distler A, Gotzen R. Antihypertensive and metabolic effects of diltiazem and nifedipine. Hypertension 1986;8:859-865. 10. Inouye IK, Massie BM, Benowitz N, Simpson P, Loge D. Antihypertensive therapy with diltiazem and comparison with hydrochlorothiazide. Am J CardioI 1984;53:1588-1592. 11. Frishman WF, Charlap S, Goldberger J, Kimmel B, Stroh J, Dorsa F, Allen L, Strom J. Comparison of diltiazem and nifedipine for both angina pectoris and systemic hypertension. Am 1 Cardiol 1985;56:41H-46H. 12. Brqce RA, Hornsten TR. Exercise stress testing in evaluation of patient with ischemic heart disease. Prog Cardiovasc Dis 1969;11:371-390. 13. Hossack KF, Pool PE, Steele P, Crawford MH, DeMaria AN, Cohen LS, Ports TA. Efficacy of diltiazem in angina on effort: a multicenter trial. Am r Cardiol 1982;49:567-572. 14. Szlachnic J, Hirsch AT, Tubau JF, Vollmer C, Henderson S, Massie BM. Diltiazem versus propranofol in essential hypertension: responses of rest and exercise blood pressure and effects on exercise capacity. Am J Cardiol 1987;59:393-399. 15. Massie BM. Antihypertensive therapy with calcium blockers: comparison with beta blockers. Am f Cardiol 1985;56:97H-ltJ0H. 16. Frishman WH, Stroh JA, Greenberg SM, Suarez T, Karp A, Peled HB. Calcium-channel blockers in systemic hypertension. Curr Prob Cardiol 1987;12:287-346.