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Efficacy of diltiazem for control of symptoms of coronary arterial spasm
Efficacy of Diltiazem for Control of Symptoms of Coronary Arterial Spasm STEVEN J. ROSENTHAL, MD ROBERT GINSBURG, MD IRENE H. LAMB, RN DONALD S. BAIM, MD JOHN S. SCHROEDER, MD, FACC Stanford, California
To evaluate the efficacy of the calcium antagonist diltiazem for therapy of active coronary arterial spasm, 13 patients with clinical variant angina attributed to documented coronary arterial spasm compieted a prospective randomized double-blind crossover trial of diltlatem (120 and 240 mg/ day) versus placebo. Response was assessed with the diary technique measuring frequency of angina, consumption of nitroglycerin and percent of pain-free days. When 120 mg of diitiazem/day was compared with the paired placebo period there was a significant increase in percent of pain-free days (from 43 to 71 percent [p = 0.03]), but no significant decrease in frequency of angina (p = 0.06) or consumptfon of nitroglycerin (p = 0.32). When 240 mg of dlftlazem/day was compared with the paired placebo period there was a significant increase in percent of pain-free days (from 50 to 79 percent [p = 0.031) and a signifkant decrease in both frequency of angina (from 1.6 to 0.4 episodes/day [p = 0.031) and consumption of nftrogiycerin (from 1.3 to 0.4/day [p = 0.011). Diltiazem was found to be a highly effective drug for control of symptoms of active coronary arterial spasm, without side effects and with excellent patient tolerance.
Variant angina is a manifestation of coronary arterial spasm with or without obstructive coronary artery disease.‘,* Long-acting nitrates have been the traditional prophylactic therapy for attacks of variant angina. Calcium antagonists are a new class of drugs that interfere with contraction of coronary arterial vascular smooth muscle.3 Limited trials with four calcium antagonists (diltiazem, nifedipine, perhexilene and verapamil) in the therapy of variant angina have been very encouraging.4-27 However, fluctuations in disease activity demand randomized trials. In this report we describe the results of a prospective double-blind outpatient study, using the new calcium antagonist diltiazem for the control of symptoms of coronary arterial spasm. Methods
From the Cardiology Division, Stanford University
Medical Center, Stanford, California. This study was supported in pad by MarionLaboratories, Inc.. Kansas City, Missouri. Manuscript received May 19, 1980; revised manuscript received July 7, 1980, accepted July 11, 1980. Address for reprints: John S. Schroeder, MD, Cardiology Division, Stanford University Medical Center, Stanford, California 94305.
Study patients: Sixteen patients of either sex participated in the study between February and December 1979. All patients had symptoms of nonexertional angina responsive to sublingual nitroglycerin. Patients were referred to this institution for evaluation and therapy of either suspected or confirmed coronary arterial spasm. Coronary arterial spasm was considered to be documented either electrocardiographically or angiographically. Electrocardiographic confirmation required spontaneous or ergonovine maleate-induced S-T segment elevation of 0.1 mV or more above baseline in association with typical angina. Angiographic confirmation required spontaneous or ergonovine maleate-induced focal coronary arterial spasm reducing the vessel diameter by 50 percent or more compared with that in its resting ~tate.~ All patients had coronary arteriography performed a mean of 9.6 f 11.2 months (4~standard deviation) before entry into the study. Informed consent was obtained from all participants in the study. Experimental design: Before entry into the study, administration of cardiac-related medications including long-acting nitrates, alpha and beta adrenergic blocking agents and other calcium antagonists was tapered and discon-
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tinued. Sublingual nitroglycerin for relief of acute angina was the only cardiac medication allowed during the study. Patients entered an initial 14 day single-blind placebo period. Only those patients having five or more episodes of typical angina during this 14 day period entered the subsequent double-blind protocol consisting of four 14 day periods. During the first of these periods, therapy consisted of either 1 placebo or one 30 mg diltiazem tablet every 6 hours with crossover to other therapy for the second period. Therapy during the third period consisted of either two placebo or two 30 mg dilitiazem tablets every 6 hours with crossover to the other therapy for the fourth period. Tablets of dilitiazem or identical placebo were provided in bottles containing 150 tablets. The sequence of assigned bottles was random and unknown.
Patients were evaluated in an outpatient clinic on entry into the study, at each time a bottle was changed and on completion of the study. At every clinical evaluation the following were completed: measurement of weight, assessment of vital signs, physical examination, review of patient diary and pill bottle, interview to assess any adverse reactions, electrocardiogram and determination of plasma level of diltiazem obtained approximately 1 hour subsequent to the last dose of the completed 14 day period. On entry into the study and on completion of the routine serum chemistry determinations, blood and platelet counts and urinalysis were obtained. Patient compliance was assessed from pill counts and plasma levels of diltiazem. Grouped patient response was assessed from the diary of angina1 events and consumption of nitroglycerin and calculated percent of pain-free days. Response for individual patients was assessed by analysis of reduction of pain frequency during active drug periods in comparison with the paired placebo periods. Complete response was arbitrarily defined as a reduction of 90 percent or greater, partial response as 50 to 89 percent reduction and no response as less than 50 percent reduction. Disease attenuation was determined with analysis of reduction of frequency of pain during double-blind placebo periods in comparison with the single-blind placebo period on entry into the study. Disease attenuation was defined as a reduction in average pain frequency to fewer than 0.25 episodes/day and to less than 50 percent of the frequency of pain recorded on entry into the study. The study was designed to prevent any possible risks of prolonged periods of severe symptoms while on placebo medication. Early blinded crossover to the subsequent double-blind period was allowed if pain was of such frequency and severity as to be unacceptable to both the investigators and the patient. Blood samples of plasma levels of diltiazem were obtained with standard venipuncture technique with use of a heparinized glass tube that was immediately centrifuged. The supernatant plasma was then immediately frozen and stored. All samples were subsequently analyzed by gas chromatography2g at Bio-Research Laboratory, Senneville, Quebec,
Canada or Marion Laboratories, Kansas City, Missouri. Statistics: When paired data for assessing drug effects were compared, the two-tailed Fisher’s paired randomization test was applied. When paired data of laboratory values were compared, the two-tailed Student’s t test for paired data was applied. Results
sodes of pain and one refused to cooperate with the study design. One patient who completed the doubleblind protocol was withdrawn from study analysis because of the patient’s irregularities in handling study medication.* A profile of the 13 remaining patients is presented in Table I. Eight patients were women and five were men. Their ages ranged from 46 to 71 years (average 54 f 7 [f standard deviation]). Historical duration of symptoms before entry into the study ranged from 0.5 to 107 months (average 79 f 32). Twelve patients described angina at rest, 11 described nocturnal angina and 8 described exertional angina. All patients smoked cigarettes, five had systemic hypertension requiring pharmacologic therapy and 11 consumed more than 4 ounces of alcohol/week. Prior therapy for variant angina was long-acting nitrates in all patients, alpha adrenergic blocking agents in four, beta adrenergic blocking agents in six and calcium antagonists in two. All patients but one (Case 5) were deemed refractory to prior medical therapy. Documentation of coronary arterial spasm: Two patients (Cases 5 and 13) had obstructive coronary artery disease with 50 percent or greater reduction of a major vessel diameter. Two patients (one with obstructive coronary artery disease [Case 131 and one with normal coronary arteries [Case 121) had prior myocardial infarction. Of nine patients having coronary arterial spasm at the time of arteriography, one (Case 11) had spontaneous spasm and eight had spasm provoked by intravenous administration of ergonovine maleate. Of eight patients having S-T segment elevation of 0.1 mV or more above baseline in association with typical angina, five had spontaneous electrocardiographic change and three had electrocardiographic change provoked by intravenous administration of ergonovine maleate. Evidence of ventricular arrhythmia or atrioventricular conduction disturbance was not systematically sought. Three patients demonstrated ventricular tachycardia with angina and one of these three patients additionally demonstrated complete heart block with angina. To prevent any possible risks of prolonged periods of severe symptoms while on possible placebo medication 14 single- or double-blind periods were shortened in five patients for early crossover (Table II). Findings Details of each patient’s single-blind placebo period and double-blind crossover periods are reported in Table II. Group responses: When the single-blind placebo period was compared with each of the double-blind placebo periods, or when the double-blind placebo periods were compared with each other, the percent of pain-free days, frequency of pain and consumption of nitroglycerin were statistically equal. When 120 mg of A majorairline strike prohibitedthis patient from attendingthe clinic and necessitated mail transfer of pill bottles. The patient switched pill bottles as instructad but without permission switched back to the earlier bottle after several days to alleviate angina. If thesa two uninterpretable bottles are excludedfrom analysis (first cfossover pair), the patient was a complete responder at the higher dosage (240 mg/day). l
Clinical Features Sixteen patients entered the initial 14 day singleblind placebo period. Two patients did not qualify for the double-blind period; one had fewer than five epi-
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TABLE I Clinical Characteristics of 13 Patients Characteristics of Angina
Age (yr) & Sex
Duration (mo)
Z 4
50F 46F 57M 60M
:; 107 12
Yes Yes No
Yes No Yes Yes
p blocking agent CI blocking agent p blocking agent None
lrreg RCA lrreg LAD Normal lrreg RCA. LAD. LCx
5
53F
22
Yes
No
50% LAD
6 :
64
Yes
9
48F 54F 71M 54F
11 10
Case 1
Sleep
Yes
Exertion
Nonnitrate Before Angina1 Treatment
1
55F 51M
:;
No Yes Yes Yes
Yes Yes No No No Yes
12
51F
18
Yes
Yes
(Y and fi blocking agents, verapamil p blocking agent (Y blocking agent None None None p blocking agent, perhexilene None
13
48M
84
Yes
Yes
a and p blocking agents
Yes
;;
Method of Diagnosis
Coronary Arteriograms
lrreg LAD, lrreg Diag lrreg RCA, lrreg RCA. lrreg RCA, Normal
LCx LAD, LCx LAD, LCx LAD, Diag
Normal (Ml 6/1978, 311979) 70% LAD, 100% LCx & OM (MI 1976)
(E) ECG 0.3 mV S-T II Ill aVF Monitor 1.2 mV S-T 1 , VT (E) Marked RCA spasm (E) Marked LAD, Diag, LCx, OM spasm: ECG 0.2 mV S-T? Vl-3 (E) Marked R A spasm: Monitor 0.7 mV S-T F VT (E) 80 % LAD’ spasm Monitor 0.5 mV S-T?. VT, CHB (E) Marked RCA. LAD soasm (E) 50% LAD, 95% RCA spasm Monitor 0.7 mV S-T? Spontaneous 70 % LAD spasm; (E) Monitor 2.5 mV S-Tt (E) 70% RCA, 80% LAD spasm; (E) 1 mV S-T? II Ill aVF (E) Marked LAD spasm
N = alpha; fl= beta; CHB = complete heart block; LCx = circumflex coronary artery: Ofg = diagonal coronary artery: (E) = ergonovine maleate Provocation; lrreg = minor irregularity of less than 50 percent d&meter reduction: LAD = left anterior descending coronary artery: Marked = greater than or equal to 90 percent reduction in vessel diameter compared with its resting state: LCx = left circumflex coronary artery: MI = myocardial infarction: OM = obtuse marginal coronary artery: RCA = right coronary artery: S-T? = S-T segment elevation: VT = ventricular tachycardia.
was compared with the paired placebo period, there was a significant increase in the number of pain-free days (from 43 f 30 to 71 f 37 percent [k SD], p = 0.03) and a trend toward a significant decrease in the frequency of angina (from 2.2 f 2.7/day to 0.6 f l.O/day, p = 0.06), but no significant decrease in the consumption of nitroglycerin (p = 0.32). When the period of administration of 240 mg of diltiazem was compared with the paired placebo period there was a significant increase in the number of pain-free days (from
50 f 37 to 79 f 30 percent, p = 0.03) and a significant decrease in both frequency of angina (from 1.6 f S.O/day to 0.4 f 0.5/day, p = 0.03) and consumption of nitroglycerin (from 1.3 f l.l/day to 0.4 f O.G/day, p = 0.01). Individual responses: Responses in individual patients varied. When receiving 120 mg of diltiazemlday six patients demonstrated a complete response, one a partial response, three no response and three disease attenuation. When receiving 240 mg of diltiazemlday
diltiazemlday
TABLE ii Data of lndlvidual Patients During Periods of Single-Blind Placebo (Se), Double-Blind Low Dosage Placebo (Pl), Diltiarem (Dl), Hlgh Dosage Placebo (P2), 240 mg/day of Diitiatem (D2)
120 mg of
Average Frequency/Day Total Days of Period Case
SB
Pl
Dl
P2
Angina
Percent of Pain-Free Days
NTG Consumption
SB
Pl
Dl
P2
D2
SB
Pl
Dl
P2
02
SB
Pl
0.4
1.3
0.1
0.9
0.2
0.6
1.5
0.0
0.9
0.2
64
36
02
Dl
P2
D2
36
79
1
14
14
14
3
:s
::
:t
:t
14 :t
0.9 18
0.1 2.1
0.1
0.0 2.6
0.0
0.3 1.9
0.1 1.1
0.1
0.0 2.1
0.0
57
21
93 ::
100 21
100
5 6
14 1:
14 3
:: 14
:t5
14 9
0’9 412 2.1
:.: 0:9
i.2 2:8
:.: 1:l
0’03 0 0:s
0 2’14 50
0.6 ;‘:
0.3 1::
0.0 1.2
0.0 0.1
5;9
!“6 0
::
:: 29
1:: 43
: 9 10 ::
14 1: 14 :
:: 14 2 :t 7
14 7
14 :d
:t 14
1: 14
:t :: :t
:.: 114 2.2 3.9
1.9 K 0:9 2.4
0.0 :.A 0:o 2.4
0.6 2.6 70 0:2 3.1
0.0 0.7 00 0:o 1.2 1.4
2.1 7.9 0.1 :‘: 54
0.9 117 1.5 !‘t 217
0.0 1.9 0.0 0.0 2.4 1.8
f:: 2.1 1.5 0.2 0.6 3.1
::A 1.1 0.0 0.0 1:5 13
2: 29 29 14 8
f: 86 50 57 4:
10: 1:: 100 4:
640 0 79 0
100 64 100 100 0
13
14
:t
:t
::
::;
::2
&!I
I
0.1
0.8
0.2
0.0
0.2
0.4
50
79
100
:t
3:
13.2 2.0
12.4 4.0
13.3 1.7
1.2 1.9
2.7 2.2
0.6 1.0
2.0 1.6
0.4 0.5
2.5 2.4
2.4 1.9
1.0 1.8
1.3 1.1
0.4 0.6
23 27
30 43
;:
;;
Z
Mean fSD
11.8 3.1
:‘:7 415
NTG = nitroglycerin; SD = standard deviation.
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four patients demonstrated a complete response, two a partial response, three no response and four disease attenuation. Rebound phenomenon and delayed response: To evaluate for a rebound phenomenon to abrupt cessation of diltiazem therapy, placebo periods after periods of either dosage of diltiazem were analyzed. There was no significant difference in frequency of pain when any combination of the first 3 days of placebo was compared with the remaining days of the placebo periods. To evaluate for a delay in clinical response to the institution of diltiazem therapy, active drug periods after periods of placebo were analyzed. At neither dosage of diltiazem was there a significant difference in frequency of pain when any combination of the first 3 days of active drug was compared with the remaining days of the drug periods. Systemic effects: There was no change in weight, systolic* or diastolic+ blood pressures, electrocardiographic intervals (P-R, QRS, Q-T), routine serum chemistry values, complete blood and platelet counts and urinalysis during the study. There were no complications during the study, and no adverse reactions during the study were ascertained except in one patient who reported headaches during therapy with both the low dosage of diltiazem drug and with placebo. Discussion Diltiazem is a member of the new class of agents termed calcium antagonists.30 These agents act by blocking the influx of freely exchangeable or “extracellular” calcium through calcium channels presumably located in the cell membrane of vascular smooth muscle.a1J2 Pharmacologically, these agents demonstrate noncompetitive antagonism to vasoactive substances such as catecholamines, acetylcholine and histamine, and competitive antagonism to calcium.33*34 Studies with in vitro human coronary arteries have demonstrated that a wide variety of endogenous vasoactive substances are potentially involved in mediating coronary spasm.35 The resulting mechanical response of the coronary artery to calcium an~gonis~ is relaxation of its vascular smooth muscle and thus vasodilation. In vitro pharmacologic studies demonstrate that, although diltiazem can exert a negative inotropic action on careffect at diac ventricular muscle, 3e its preferential clinically used doses is on the coronary vascular smooth muscle.37 Diltiazem and other calcium antagonist drugs such as perhexiline, nifedipine and verapamil have been evaluated for therapy of coronary arterial spasm and have been reported to be remarkably effective. However, except for two short-term in-patient studies of calcium antagonists in patients with coronary artery * Systolic: 120 mg/day, 138 mm Hg; paired placebo, 135 mm Hg (p = 0.31); 240 mglday, 136 mm Hg; paired placebo, 133 mm Hg (p = 0.29). + Diastolic: 120 mglday, 81 mm Hg: paired placebo, 87 mm ti9 (p = 0.81); 240 mglday, 84 mm Hg; paired placebo, 87 mm Hg (p = 0.71).
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disease and vasospastic angina at rest,2Lp”7no doubleblind evaluations of any of the calcium antagonist drugs for coronary arterial spasm have been reported. Effect of diltiazem on angina due to coronary spasm: In our study, six patients given the lower dosage (120 mg/day) and four patients given the higher dosage (240 mgfday) of diltiazem had a complete resolution of their pain. Of the remaining six patients without disease attenuation, one had a partial response to the lower dosage, two a partial response to the higher dosage and three no response at either dosage. These findings may reflect one of four possibilities in the patients without a complete response: f 1) inadequate oral dosage possibly secondary to decreased bioavailability; (2) resistance to therapeutic levels of diltiazem; (3) fluctuations in disease activity rendering the patient selectively responsive at only specific periods in the course of the disease; and (4) inaccuracies in the diary technique in evaluating response. Plasma levels of diltiazem obtained in these patients without a complete response, similar to those in patients with a complete response, exclude the possibility of decreased bioavailability. Comparative drug trials would evaluate the possibility that subsets of patients with coronary arterial spasm may have selective responsiveness to a given class of drugs (for example, calcium antagonists versus nitrates) or a specific drug within a given class (for example, diltiazem versus nifedipine). Studies of longer duration would evaluate the possibility of fluctuation in drug response over time. More objective data evaluating outpatient drug efficacy by reduction of clinical and subclinical ischemic episodes might have been achieved with ambulatory monitoring.“* Although patient diaries allowed analysis of several measures of subjective clinical response to therapy, the frequency of subclinical ischemic episodes could not be ascertained nor could the angina1 origin of all reported episodes of chest pain be confirmed. Spontaneous attenuation of coronary spasm: Five of 13 patients demonstrated spontaneous attenuation of disease activity at one or both dosages despite demonstration of much greater disease activity during the single-blind placebo period on entry into the study. The natural history of the activity of variant angina is generally considered variable,sg-42 and pronounced fluctuation of any single measure of disease activity would not he unexpected. However, these five patients demonstrated an at~n~tion of a clinical measure of disease activity to an extent that partial or complete response to medication could be mimicked if the study was not of crossover design. These findings reinforce the importance of double-blind studies, with the inclusion of placebo periods in study design, to delineate therapeutic response from spontaneous disease attenuation. The possibility of any contribution of diltiazem administration to subsequent disease attenuation could not be assessed because of the small number of patients involved. There is always concern about possible areas of bias introduced by either the patient or the investigator when using the diary method of documenting episodes
Vofume 46
DILTIAZEM
of pain. The lack of adverse effects of diltiazem and the multiple crossover periods render it less likely that the patients knew whether they were taking drug or placebo at any given time. However, the patients were aware that the low dosage diltiazem period always preceded the high dosage period. Absence of rebound phenomenon or delay in clinical response: The failure to detect a difference in frequency of pain when comparing the initial with the remaining days of the placebo periods subsequent to periods of either dosage of diltiazem, suggests the absence of a rebound phenomenon secondary to an abrupt discontinuation of the drug. Bias tending to obscure such a phenomenon could be provided by those patients whose placebo periods were shortened because of angina of unacceptable frequency and severity. If withdrawal symptoms were occurring, shortening of the placebo period would not allow these patients to demonstrate
FOR CORONARY
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a reduction in frequency of pain. The failure to detect a difference in frequency of pain when comparing the initial with the remaining days of active drug periods subsequent to placebo periods suggests the absence of a delay in clinical response to the institution of diltiazem therapy. In summary, diltiazem is a safe and highly effective calcium antagonist for therapy of clinical symptoms of coronary arterial spasm. This drug is free of adverse effects and patient tolerance is excellent. There is no evidence for either a rebound phenomenon secondary to abrupt discontinuation of the drug or a delay in clinical response to the institution of drug therapy.
Acknowledgment We express our appreciation to Marie Hu for assistance in statistical analysis and to Jo Maddox for assistance in manuscript preparation.
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41.
42.
to diltiazem in coronary arteries. Jpn J Pharmacol 1970;27: 330-3. Curry R. Pepine C, Con6 C. Ambulatory monitering to evaluate therapy results in variant angina pectoris (abstr). Circulation 1979:59,6O:Suppl ll:ll-190. Clpriano P, Koch F, Rosenthal S, Schroeder J. Clinical course of patients with coronary artery spasm demonstrated by angiography (abstr). Circulation 1979;59,6O:Suppl ll:ll-161. Johnson A, Stroud Ii, Vieweg W, Ross J. Variant angina pectoris: clinical presentations, coronary arteriographic patterns, and the results of medical and surgical management in 42 consecutive patients. Chest 1978;73:786-94. Pasternak R, Hulter A, DeSanctis R, JaRo M, Buckley M. Variant angina-clinical spectrum and results of medical and surgical therapy. J Thorac Cardiovasc Surg 1979;78:614-22. Sever1 S, Davies G, L’Abbate A, Maseri A. Long term prognosis of variant angina with medical management (abstr). Circulation 1979;59,6O:Suppl ll:ll-250.
Volume 48
To evaluate the efficacy of the calcium antagonist diltiazem for therapy of active coronary arterial spasm, 13 patients with clinical variant angina attributed to documented coronary arterial spasm compieted a prospective randomized double-blind crossover trial of diltlatem (120 and 240 mg/ day) versus placebo. Response was assessed with the diary technique measuring frequency of angina, consumption of nitroglycerin and percent of pain-free days. When 120 mg of diitiazem/day was compared with the paired placebo period there was a significant increase in percent of pain-free days (from 43 to 71 percent [p = 0.03]), but no significant decrease in frequency of angina (p = 0.06) or consumptfon of nitroglycerin (p = 0.32). When 240 mg of dlftlazem/day was compared with the paired placebo period there was a significant increase in percent of pain-free days (from 50 to 79 percent [p = 0.031) and a signifkant decrease in both frequency of angina (from 1.6 to 0.4 episodes/day [p = 0.031) and consumption of nftrogiycerin (from 1.3 to 0.4/day [p = 0.011). Diltiazem was found to be a highly effective drug for control of symptoms of active coronary arterial spasm, without side effects and with excellent patient tolerance.
Variant angina is a manifestation of coronary arterial spasm with or without obstructive coronary artery disease.‘,* Long-acting nitrates have been the traditional prophylactic therapy for attacks of variant angina. Calcium antagonists are a new class of drugs that interfere with contraction of coronary arterial vascular smooth muscle.3 Limited trials with four calcium antagonists (diltiazem, nifedipine, perhexilene and verapamil) in the therapy of variant angina have been very encouraging.4-27 However, fluctuations in disease activity demand randomized trials. In this report we describe the results of a prospective double-blind outpatient study, using the new calcium antagonist diltiazem for the control of symptoms of coronary arterial spasm. Methods
From the Cardiology Division, Stanford University
Medical Center, Stanford, California. This study was supported in pad by MarionLaboratories, Inc.. Kansas City, Missouri. Manuscript received May 19, 1980; revised manuscript received July 7, 1980, accepted July 11, 1980. Address for reprints: John S. Schroeder, MD, Cardiology Division, Stanford University Medical Center, Stanford, California 94305.
Study patients: Sixteen patients of either sex participated in the study between February and December 1979. All patients had symptoms of nonexertional angina responsive to sublingual nitroglycerin. Patients were referred to this institution for evaluation and therapy of either suspected or confirmed coronary arterial spasm. Coronary arterial spasm was considered to be documented either electrocardiographically or angiographically. Electrocardiographic confirmation required spontaneous or ergonovine maleate-induced S-T segment elevation of 0.1 mV or more above baseline in association with typical angina. Angiographic confirmation required spontaneous or ergonovine maleate-induced focal coronary arterial spasm reducing the vessel diameter by 50 percent or more compared with that in its resting ~tate.~ All patients had coronary arteriography performed a mean of 9.6 f 11.2 months (4~standard deviation) before entry into the study. Informed consent was obtained from all participants in the study. Experimental design: Before entry into the study, administration of cardiac-related medications including long-acting nitrates, alpha and beta adrenergic blocking agents and other calcium antagonists was tapered and discon-
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tinued. Sublingual nitroglycerin for relief of acute angina was the only cardiac medication allowed during the study. Patients entered an initial 14 day single-blind placebo period. Only those patients having five or more episodes of typical angina during this 14 day period entered the subsequent double-blind protocol consisting of four 14 day periods. During the first of these periods, therapy consisted of either 1 placebo or one 30 mg diltiazem tablet every 6 hours with crossover to other therapy for the second period. Therapy during the third period consisted of either two placebo or two 30 mg dilitiazem tablets every 6 hours with crossover to the other therapy for the fourth period. Tablets of dilitiazem or identical placebo were provided in bottles containing 150 tablets. The sequence of assigned bottles was random and unknown.
Patients were evaluated in an outpatient clinic on entry into the study, at each time a bottle was changed and on completion of the study. At every clinical evaluation the following were completed: measurement of weight, assessment of vital signs, physical examination, review of patient diary and pill bottle, interview to assess any adverse reactions, electrocardiogram and determination of plasma level of diltiazem obtained approximately 1 hour subsequent to the last dose of the completed 14 day period. On entry into the study and on completion of the routine serum chemistry determinations, blood and platelet counts and urinalysis were obtained. Patient compliance was assessed from pill counts and plasma levels of diltiazem. Grouped patient response was assessed from the diary of angina1 events and consumption of nitroglycerin and calculated percent of pain-free days. Response for individual patients was assessed by analysis of reduction of pain frequency during active drug periods in comparison with the paired placebo periods. Complete response was arbitrarily defined as a reduction of 90 percent or greater, partial response as 50 to 89 percent reduction and no response as less than 50 percent reduction. Disease attenuation was determined with analysis of reduction of frequency of pain during double-blind placebo periods in comparison with the single-blind placebo period on entry into the study. Disease attenuation was defined as a reduction in average pain frequency to fewer than 0.25 episodes/day and to less than 50 percent of the frequency of pain recorded on entry into the study. The study was designed to prevent any possible risks of prolonged periods of severe symptoms while on placebo medication. Early blinded crossover to the subsequent double-blind period was allowed if pain was of such frequency and severity as to be unacceptable to both the investigators and the patient. Blood samples of plasma levels of diltiazem were obtained with standard venipuncture technique with use of a heparinized glass tube that was immediately centrifuged. The supernatant plasma was then immediately frozen and stored. All samples were subsequently analyzed by gas chromatography2g at Bio-Research Laboratory, Senneville, Quebec,
Canada or Marion Laboratories, Kansas City, Missouri. Statistics: When paired data for assessing drug effects were compared, the two-tailed Fisher’s paired randomization test was applied. When paired data of laboratory values were compared, the two-tailed Student’s t test for paired data was applied. Results
sodes of pain and one refused to cooperate with the study design. One patient who completed the doubleblind protocol was withdrawn from study analysis because of the patient’s irregularities in handling study medication.* A profile of the 13 remaining patients is presented in Table I. Eight patients were women and five were men. Their ages ranged from 46 to 71 years (average 54 f 7 [f standard deviation]). Historical duration of symptoms before entry into the study ranged from 0.5 to 107 months (average 79 f 32). Twelve patients described angina at rest, 11 described nocturnal angina and 8 described exertional angina. All patients smoked cigarettes, five had systemic hypertension requiring pharmacologic therapy and 11 consumed more than 4 ounces of alcohol/week. Prior therapy for variant angina was long-acting nitrates in all patients, alpha adrenergic blocking agents in four, beta adrenergic blocking agents in six and calcium antagonists in two. All patients but one (Case 5) were deemed refractory to prior medical therapy. Documentation of coronary arterial spasm: Two patients (Cases 5 and 13) had obstructive coronary artery disease with 50 percent or greater reduction of a major vessel diameter. Two patients (one with obstructive coronary artery disease [Case 131 and one with normal coronary arteries [Case 121) had prior myocardial infarction. Of nine patients having coronary arterial spasm at the time of arteriography, one (Case 11) had spontaneous spasm and eight had spasm provoked by intravenous administration of ergonovine maleate. Of eight patients having S-T segment elevation of 0.1 mV or more above baseline in association with typical angina, five had spontaneous electrocardiographic change and three had electrocardiographic change provoked by intravenous administration of ergonovine maleate. Evidence of ventricular arrhythmia or atrioventricular conduction disturbance was not systematically sought. Three patients demonstrated ventricular tachycardia with angina and one of these three patients additionally demonstrated complete heart block with angina. To prevent any possible risks of prolonged periods of severe symptoms while on possible placebo medication 14 single- or double-blind periods were shortened in five patients for early crossover (Table II). Findings Details of each patient’s single-blind placebo period and double-blind crossover periods are reported in Table II. Group responses: When the single-blind placebo period was compared with each of the double-blind placebo periods, or when the double-blind placebo periods were compared with each other, the percent of pain-free days, frequency of pain and consumption of nitroglycerin were statistically equal. When 120 mg of A majorairline strike prohibitedthis patient from attendingthe clinic and necessitated mail transfer of pill bottles. The patient switched pill bottles as instructad but without permission switched back to the earlier bottle after several days to alleviate angina. If thesa two uninterpretable bottles are excludedfrom analysis (first cfossover pair), the patient was a complete responder at the higher dosage (240 mg/day). l
Clinical Features Sixteen patients entered the initial 14 day singleblind placebo period. Two patients did not qualify for the double-blind period; one had fewer than five epi-
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DILTIAZEM FOR CORONARY ARTERIAL SPASM-ROSENTHAL
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TABLE I Clinical Characteristics of 13 Patients Characteristics of Angina
Age (yr) & Sex
Duration (mo)
Z 4
50F 46F 57M 60M
:; 107 12
Yes Yes No
Yes No Yes Yes
p blocking agent CI blocking agent p blocking agent None
lrreg RCA lrreg LAD Normal lrreg RCA. LAD. LCx
5
53F
22
Yes
No
50% LAD
6 :
64
Yes
9
48F 54F 71M 54F
11 10
Case 1
Sleep
Yes
Exertion
Nonnitrate Before Angina1 Treatment
1
55F 51M
:;
No Yes Yes Yes
Yes Yes No No No Yes
12
51F
18
Yes
Yes
(Y and fi blocking agents, verapamil p blocking agent (Y blocking agent None None None p blocking agent, perhexilene None
13
48M
84
Yes
Yes
a and p blocking agents
Yes
;;
Method of Diagnosis
Coronary Arteriograms
lrreg LAD, lrreg Diag lrreg RCA, lrreg RCA. lrreg RCA, Normal
LCx LAD, LCx LAD, LCx LAD, Diag
Normal (Ml 6/1978, 311979) 70% LAD, 100% LCx & OM (MI 1976)
(E) ECG 0.3 mV S-T II Ill aVF Monitor 1.2 mV S-T 1 , VT (E) Marked RCA spasm (E) Marked LAD, Diag, LCx, OM spasm: ECG 0.2 mV S-T? Vl-3 (E) Marked R A spasm: Monitor 0.7 mV S-T F VT (E) 80 % LAD’ spasm Monitor 0.5 mV S-T?. VT, CHB (E) Marked RCA. LAD soasm (E) 50% LAD, 95% RCA spasm Monitor 0.7 mV S-T? Spontaneous 70 % LAD spasm; (E) Monitor 2.5 mV S-Tt (E) 70% RCA, 80% LAD spasm; (E) 1 mV S-T? II Ill aVF (E) Marked LAD spasm
N = alpha; fl= beta; CHB = complete heart block; LCx = circumflex coronary artery: Ofg = diagonal coronary artery: (E) = ergonovine maleate Provocation; lrreg = minor irregularity of less than 50 percent d&meter reduction: LAD = left anterior descending coronary artery: Marked = greater than or equal to 90 percent reduction in vessel diameter compared with its resting state: LCx = left circumflex coronary artery: MI = myocardial infarction: OM = obtuse marginal coronary artery: RCA = right coronary artery: S-T? = S-T segment elevation: VT = ventricular tachycardia.
was compared with the paired placebo period, there was a significant increase in the number of pain-free days (from 43 f 30 to 71 f 37 percent [k SD], p = 0.03) and a trend toward a significant decrease in the frequency of angina (from 2.2 f 2.7/day to 0.6 f l.O/day, p = 0.06), but no significant decrease in the consumption of nitroglycerin (p = 0.32). When the period of administration of 240 mg of diltiazem was compared with the paired placebo period there was a significant increase in the number of pain-free days (from
50 f 37 to 79 f 30 percent, p = 0.03) and a significant decrease in both frequency of angina (from 1.6 f S.O/day to 0.4 f 0.5/day, p = 0.03) and consumption of nitroglycerin (from 1.3 f l.l/day to 0.4 f O.G/day, p = 0.01). Individual responses: Responses in individual patients varied. When receiving 120 mg of diltiazemlday six patients demonstrated a complete response, one a partial response, three no response and three disease attenuation. When receiving 240 mg of diltiazemlday
diltiazemlday
TABLE ii Data of lndlvidual Patients During Periods of Single-Blind Placebo (Se), Double-Blind Low Dosage Placebo (Pl), Diltiarem (Dl), Hlgh Dosage Placebo (P2), 240 mg/day of Diitiatem (D2)
120 mg of
Average Frequency/Day Total Days of Period Case
SB
Pl
Dl
P2
Angina
Percent of Pain-Free Days
NTG Consumption
SB
Pl
Dl
P2
D2
SB
Pl
Dl
P2
02
SB
Pl
0.4
1.3
0.1
0.9
0.2
0.6
1.5
0.0
0.9
0.2
64
36
02
Dl
P2
D2
36
79
1
14
14
14
3
:s
::
:t
:t
14 :t
0.9 18
0.1 2.1
0.1
0.0 2.6
0.0
0.3 1.9
0.1 1.1
0.1
0.0 2.1
0.0
57
21
93 ::
100 21
100
5 6
14 1:
14 3
:: 14
:t5
14 9
0’9 412 2.1
:.: 0:9
i.2 2:8
:.: 1:l
0’03 0 0:s
0 2’14 50
0.6 ;‘:
0.3 1::
0.0 1.2
0.0 0.1
5;9
!“6 0
::
:: 29
1:: 43
: 9 10 ::
14 1: 14 :
:: 14 2 :t 7
14 7
14 :d
:t 14
1: 14
:t :: :t
:.: 114 2.2 3.9
1.9 K 0:9 2.4
0.0 :.A 0:o 2.4
0.6 2.6 70 0:2 3.1
0.0 0.7 00 0:o 1.2 1.4
2.1 7.9 0.1 :‘: 54
0.9 117 1.5 !‘t 217
0.0 1.9 0.0 0.0 2.4 1.8
f:: 2.1 1.5 0.2 0.6 3.1
::A 1.1 0.0 0.0 1:5 13
2: 29 29 14 8
f: 86 50 57 4:
10: 1:: 100 4:
640 0 79 0
100 64 100 100 0
13
14
:t
:t
::
::;
::2
&!I
I
0.1
0.8
0.2
0.0
0.2
0.4
50
79
100
:t
3:
13.2 2.0
12.4 4.0
13.3 1.7
1.2 1.9
2.7 2.2
0.6 1.0
2.0 1.6
0.4 0.5
2.5 2.4
2.4 1.9
1.0 1.8
1.3 1.1
0.4 0.6
23 27
30 43
;:
;;
Z
Mean fSD
11.8 3.1
:‘:7 415
NTG = nitroglycerin; SD = standard deviation.
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The American Journal of CARDIOLOGY Volume 48
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DILTIAZEM FOR CORONARY ARTERIAL SPASM-ROSENTHAL
ET AL.
four patients demonstrated a complete response, two a partial response, three no response and four disease attenuation. Rebound phenomenon and delayed response: To evaluate for a rebound phenomenon to abrupt cessation of diltiazem therapy, placebo periods after periods of either dosage of diltiazem were analyzed. There was no significant difference in frequency of pain when any combination of the first 3 days of placebo was compared with the remaining days of the placebo periods. To evaluate for a delay in clinical response to the institution of diltiazem therapy, active drug periods after periods of placebo were analyzed. At neither dosage of diltiazem was there a significant difference in frequency of pain when any combination of the first 3 days of active drug was compared with the remaining days of the drug periods. Systemic effects: There was no change in weight, systolic* or diastolic+ blood pressures, electrocardiographic intervals (P-R, QRS, Q-T), routine serum chemistry values, complete blood and platelet counts and urinalysis during the study. There were no complications during the study, and no adverse reactions during the study were ascertained except in one patient who reported headaches during therapy with both the low dosage of diltiazem drug and with placebo. Discussion Diltiazem is a member of the new class of agents termed calcium antagonists.30 These agents act by blocking the influx of freely exchangeable or “extracellular” calcium through calcium channels presumably located in the cell membrane of vascular smooth muscle.a1J2 Pharmacologically, these agents demonstrate noncompetitive antagonism to vasoactive substances such as catecholamines, acetylcholine and histamine, and competitive antagonism to calcium.33*34 Studies with in vitro human coronary arteries have demonstrated that a wide variety of endogenous vasoactive substances are potentially involved in mediating coronary spasm.35 The resulting mechanical response of the coronary artery to calcium an~gonis~ is relaxation of its vascular smooth muscle and thus vasodilation. In vitro pharmacologic studies demonstrate that, although diltiazem can exert a negative inotropic action on careffect at diac ventricular muscle, 3e its preferential clinically used doses is on the coronary vascular smooth muscle.37 Diltiazem and other calcium antagonist drugs such as perhexiline, nifedipine and verapamil have been evaluated for therapy of coronary arterial spasm and have been reported to be remarkably effective. However, except for two short-term in-patient studies of calcium antagonists in patients with coronary artery * Systolic: 120 mg/day, 138 mm Hg; paired placebo, 135 mm Hg (p = 0.31); 240 mglday, 136 mm Hg; paired placebo, 133 mm Hg (p = 0.29). + Diastolic: 120 mglday, 81 mm Hg: paired placebo, 87 mm ti9 (p = 0.81); 240 mglday, 84 mm Hg; paired placebo, 87 mm Hg (p = 0.71).
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disease and vasospastic angina at rest,2Lp”7no doubleblind evaluations of any of the calcium antagonist drugs for coronary arterial spasm have been reported. Effect of diltiazem on angina due to coronary spasm: In our study, six patients given the lower dosage (120 mg/day) and four patients given the higher dosage (240 mgfday) of diltiazem had a complete resolution of their pain. Of the remaining six patients without disease attenuation, one had a partial response to the lower dosage, two a partial response to the higher dosage and three no response at either dosage. These findings may reflect one of four possibilities in the patients without a complete response: f 1) inadequate oral dosage possibly secondary to decreased bioavailability; (2) resistance to therapeutic levels of diltiazem; (3) fluctuations in disease activity rendering the patient selectively responsive at only specific periods in the course of the disease; and (4) inaccuracies in the diary technique in evaluating response. Plasma levels of diltiazem obtained in these patients without a complete response, similar to those in patients with a complete response, exclude the possibility of decreased bioavailability. Comparative drug trials would evaluate the possibility that subsets of patients with coronary arterial spasm may have selective responsiveness to a given class of drugs (for example, calcium antagonists versus nitrates) or a specific drug within a given class (for example, diltiazem versus nifedipine). Studies of longer duration would evaluate the possibility of fluctuation in drug response over time. More objective data evaluating outpatient drug efficacy by reduction of clinical and subclinical ischemic episodes might have been achieved with ambulatory monitoring.“* Although patient diaries allowed analysis of several measures of subjective clinical response to therapy, the frequency of subclinical ischemic episodes could not be ascertained nor could the angina1 origin of all reported episodes of chest pain be confirmed. Spontaneous attenuation of coronary spasm: Five of 13 patients demonstrated spontaneous attenuation of disease activity at one or both dosages despite demonstration of much greater disease activity during the single-blind placebo period on entry into the study. The natural history of the activity of variant angina is generally considered variable,sg-42 and pronounced fluctuation of any single measure of disease activity would not he unexpected. However, these five patients demonstrated an at~n~tion of a clinical measure of disease activity to an extent that partial or complete response to medication could be mimicked if the study was not of crossover design. These findings reinforce the importance of double-blind studies, with the inclusion of placebo periods in study design, to delineate therapeutic response from spontaneous disease attenuation. The possibility of any contribution of diltiazem administration to subsequent disease attenuation could not be assessed because of the small number of patients involved. There is always concern about possible areas of bias introduced by either the patient or the investigator when using the diary method of documenting episodes
Vofume 46
DILTIAZEM
of pain. The lack of adverse effects of diltiazem and the multiple crossover periods render it less likely that the patients knew whether they were taking drug or placebo at any given time. However, the patients were aware that the low dosage diltiazem period always preceded the high dosage period. Absence of rebound phenomenon or delay in clinical response: The failure to detect a difference in frequency of pain when comparing the initial with the remaining days of the placebo periods subsequent to periods of either dosage of diltiazem, suggests the absence of a rebound phenomenon secondary to an abrupt discontinuation of the drug. Bias tending to obscure such a phenomenon could be provided by those patients whose placebo periods were shortened because of angina of unacceptable frequency and severity. If withdrawal symptoms were occurring, shortening of the placebo period would not allow these patients to demonstrate
FOR CORONARY
ARTERIAL SPASM-ROSENTHAL
ET AL.
a reduction in frequency of pain. The failure to detect a difference in frequency of pain when comparing the initial with the remaining days of active drug periods subsequent to placebo periods suggests the absence of a delay in clinical response to the institution of diltiazem therapy. In summary, diltiazem is a safe and highly effective calcium antagonist for therapy of clinical symptoms of coronary arterial spasm. This drug is free of adverse effects and patient tolerance is excellent. There is no evidence for either a rebound phenomenon secondary to abrupt discontinuation of the drug or a delay in clinical response to the institution of drug therapy.
Acknowledgment We express our appreciation to Marie Hu for assistance in statistical analysis and to Jo Maddox for assistance in manuscript preparation.
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