International Journal of Cardiology 41 (1993) 191-199
Effect of metoprolol and diltiazem on the total ischaemic burden in patients with chronic stable angina: a randomized controlled trial R.C. Ahujaa, N. Sinha*b, R. Ravi Kumara, R.K. Saranc ‘Department of Medicine, King George Medical College, Lucknonj, India bDepartment of Cardiology, Sanjay Gandhi PGIMS. PB No. 375, Lucknow, India 226001 ‘Department of Cardiology, King George Medical College, Lucknow, India
(Received 3 March 1993; accepted 25 June 1993)
Abstract
We conducted a randomised controlled trial to study the effects of metoprolol and diltiazem on the total ischaemic burden - sum of symptomatic and silent myocardial ischaemia, in 146 patients with stable angina pectoris. Onehundred thirty-four completed the study protocol. Sixty-eight patients received metoprolol(lO0 mg twice daily, n = 52. 50 mg twice daily, n = 16) while 66 received diltiazem (90 mg three times daily, n = 50, 60 mg three times daily, n = 16). The drugs were given for 4 weeks. The primary outcome variables were frequency and duration of total ischaemic burden, silent and symptomatic myocardial ischaemia. These were measured on 48 h of Halter monitoring. The reductions in duration and frequency of total ischaemic burden by metoprolol, 76% and 40%, respectively, were significantly higher than by diltiazem, 43% and 24%, respectively (P < 0.01 and P < 0.02). The frequency and duration of silent myocardial ischaemia, which constituted more than 80% of the total ischaemic burden in the two groups showed similar results. However, the reduction in frequency of symptomatic myocardial ischaemia only was significantly greater by metoprolol (63% than diltiazem (24%) as the difference in reduction of duration of symptomatic ischaemia was insignificant (85% vs. 75%; P > 0.05). Whether a greater reduction of total ischaemic burden by metoprolol as compared to diltiazem has any implications for prognosis in patients with chronic stable angina remains to be established. Key
worak Coronary artery disease; Randomized ischaemia; Metoprolol; Diltiazem
controlled
1. Introduction Silent myocardial ischaemia has been shown to independently influence the prognosis in terms of l
Corresponding author.
0167-5273/93/$06.00 0 1993 SSDI 0167-5273(93)01828-L
trial; Total ischaemic burden;
Silent myocardial
future events in coronary artery disease [ 1,2]. This influence extends to all the clinically important myocardial ischaemic syndromes viz. stable angina, unstable angina, post myocardial infarction angina and totally asymptomatic myocardial ischaemia [3-71. This has led to the concept of
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R.C. Ahuja rr al. /Inr. J. Cardiol. 41 (19931 191-199
192
total ischaemic burden - sum total of symptomatic and asymptomatic myocardial ischaemic time. Therefore the reduction and, if possible, the elimination of total ischaemic burden is considered the more desirable goal of antianginal therapy than symptomatic relief alone [S]. All the major groups of antianginal drugs - betablockers, calcium blockers and nitrates have been documented to reduce silent myocardial ischaemia in different clinical syndromes [9-141. The first two drug groups betablockers and calcium channel blockers (verapamil and diltiazem) - have been shown to be equally effective in the control of symptomatic myocardial ischaemia in patients with chronic stable angina pectoris in controlled clinical trials [ 15- 171. However, no definitive randomised controlled trial is available regarding their comparative efficacy for reduction of total ischaemic burden in patients with chronic stable angina. Hence, the present study was designed and conducted with these aims in mind.
STABLE ANGINA (Treadmill,
diagnostic / familiarisation)
n = 227 GTNS/L,SOS x 2 weeks I Control Treadmill test STJ, >Imm and angina
No = 43
I n= 164 angina S 3 /week (diary) No = 23 silent myocardial lschaemia (Holter) Z 2146 hours I n = 161 Consent
No = 15
I n = 146 + Aandomisation
Fig. I. The patient
selection.
2. Patients and methods 2.1. Selection of patients Two-hundred twenty-seven consecutive patients with chronic stable angina pectoris (typical effort angina of >60 days duration without change in frequency or threshold) attending outpatient clinics of participating consultants constituted our study population. On treadmill testing 184 patients had a horizontal or downsloping ST-depression and angina after 2 weeks of control observations on sublingual glyceryl trinitrite SOS. One-hundred sixty-one patients had a frequency of angina > 3 episodes per week and had at least 2 episodes of ambulatory ischaemia on 48 h of Holter monitoring. One-hundred forty-six consented to participate in the present study and constituted our study sample (Fig. 1).
daily and 90 mg three times daily, respectively, after 2 weeks. If there was adequate heart rate control i.e. resting heart rate < 55/min, the initial doses were continued. If the patient felt worse on higher doses he/she was asked to reduce the dose himself/herself. Each patient was asked to maintain a patient diary for recording the exact number of angina1 episodes and number of tablets of nitroglycerine consumed daily. Patients were also instructed not to take sublingual glyceryl trinitrite prophylactically before expected angina. The clinical evaluation, treadmill test and ambulatory monitoring were again done after 4 weeks of study medication (Fig. 2). The compliance to a drug was measured at each visit to the clinic by pill count. A patient was said to be compliant when the number of pills consumed during the preceding period was >90% at each clinic visit.
2.2. Study protocol 2.3. Methods One-hundred forty-six patients were randomised to receive either metoprolol 50 mg twice daily (n = 74) or diltiazem 60 mg three times daily (n = 72). The doses were increased to 100 mg twice
A. Treadmill stress test This was done on a STS -7OOOA system from Nihon Kohden employing a 3-channel real time
R. C. Ahuja et al. /Int. J. Cardiol. 41 (1993)
191-199
193
RANDOMISATION
I
,
. METOPROLOL xZWKS(n
60 mg bid
= 74)
DILTIAZEM
n=146
60 mg lid
x2WKS(n
= 72)
Titration of dose
.
+
CLINICAL EVALUATION
CLINICAL
100 mg bld (n = 53) I 2 WKS 6Omgbid(n = 16)x2WKS
66 “IS lad (tl = 61) x 2 WKS
EVALUATION1 “=I40
60 mg lld (” = 16) x 2 WKS
mm in any lead were scanned for cross checking and exclusion of artifactual recording. In addition, symptom periods as detailed in the patient diary were checked and finally a random check was carried out by the event search capability of the analyzer so as to be certain of not missing any period of myocardial ischaemia. Episodes of myocardial ischaemia were taken as at least 1.0 mm ST-segment depression lasting for more than one minute in at least one channel with two episodes being separated by at least 1 min. The episodes were labelled as silent or symptomatic according to the patients diary. 2.4. Outcome variables
b
b
CLINICAL EVALUATION
CLINICAL
TREADMILL
TREADMILL (rl= 66)
(ll=
+ HOLTER
66)
EVALUATION + HOLTEA
I
n=134
Fig. 2. The study protocol. Clinical evaluation consisted of history, patient diary records, physical examination and symptom assessment on the visual analog scale.
monitoring and analysis system using Shefftelds modification of Bruce protocol [ 181. Patients were exercised to an end point consisting of angina and ST segment depression of > 1 mm in any one lead. The time to onset of 1.0 mm ST-segment depression and time to onset of angina during exercise alongwith the recovery periods of ST depression and angina were recorded. After 4 weeks of drug therapy the patients were examined again 90 min after the last dose B. Holler monitoring
This was performed on a DMC 3000K system from Nihon Kohden for 48 consecutive hours with maintenance of a detailed patient diary regarding nature and level of activities and exact timing of symptoms. The above system employs a 3-channel real time ambulatory monitoring and fully meets the recommendation of American Heart Association [ 191. A modified lead system was used SO as to record leads V5, L2 and V2. The recorded cassettes were analyzed blindly. A complete STsegment level printout for the recorded duration was obtained and periods of ST-depression > 1
For studying ing outcome measurements knowledge of subjects.
the efficacy of the drug the followvariables were measured. These were made blindly without the the randomisation status of the
A. Primary outcome variables (i) Duration and frequency of total ischaemic burden. The duration of total ischaemic burden
(minutes per 48 h) equalled the sum of durations of silent and symptomatic myocardial ischaemia on 48 h of Holter monitoring. Frequency of total ischaemic burden was also similarly calculated. (ii) Duration and frequency of symptomatic and silent myocardial ischaemia. ST-segment depres-
sion with corresponding entry of angina in patient diary was labelled as symptomatic myocardial ischaemia. The remaining episodes of myocardial ischaemia on Holter as defined above were labelled as silent myocardial ischaemia. B. Secondary outcome variables (i) Antianginal response rates.
This was calculated from the diary records of angina1 episodes during 4 weeks on drug therapy maintained by patients and the subjective change on a visual analog scale (rating from 0 to 100) studied at the beginning and end of study. The patients having 50% reduction in frequency of angina per week together with >50% improvement on a visual analog scale were labelled as responders. (ii) Time to angina on treadmill. This was taken
194
as the time to onset of angina or the total exercise time when angina was absent during the post drug treadmill exercise test. (iii) Heart rate. The heart rates (beats per minute) at rest maximum achieved during daily activities and during treadmill exercise were calculated from electrocardiogram records. 2.5. Sample size calculation For a two tailed alpha error equal to 0.05, power i.e. 1 - beta = O&20% difference in change in total ischaemic burden in two groups (i.e. metoprolol and diltiazem) being clinically important and the assumed attrition rate due to loss to followup or lack of compliance being lo%, a total of 146 patients (73 in each group) had to be randomized.
R.C. Ahuja et al. /Inr. J. Cardiol.41 (1993) 191-199 Table 1 Baseline clinical characteristics in the two groups Characteristic
1. Age (years) 2. Previous infarction (n) 3. Diabetes (n) 4. Duration of symptoms (years) 5. Heart rates (beats/min) Resting Peak exercise Peak ambutatory 6. Blood pressure (mmHg) Systolic Dystolic 7. Total exercise time (mm) 8. 2-D Echo ejection fraction (%)
Metoprolol group (n = 68) 56 zt 5.1 5 9 3.2 f 1.6
Diltiazem group (n = 66) 57.4 * 6 10 3.0 f
6
1.7
81 135 121
ztll f 22 f 20
.79 l 8 132 f 24 123 f 19.5
137 84 5.8 52.3
f 18 *15 zt 3.2 zt 6
136 82 6.0 51.7
f 19.5 f 14 f 3.3 f 6.8
2.6. Analysis As the mean frequency and duration of total ischaemic burden, silent ischaemia and angina in our patients were positively correlated with the variance i.e. greater means were accompanied by greater variances we transformed our values into common logarithms. For testing the significance of difference of effects of metoprolol and diltiazem on these variables the unpaired t-test for the difference in means was applied to these transformed values. For other continuous variables namely heart rates and time to angina the unpaired t-test for the difference in means was used. For testing the statistical significance of difference in percentage reduction of duration and frequency of total ischaemic burden, silent myocardial ischaemia and angina in the two groups the Z-test for significance of difference in proportions was used. For testing the statistical significance of response rates in the two groups Pearsons x2 test was used 3. Results One-hundred thirty-four patients completed the study protocol (126 males, eight females; age, 56.9 f 5.7 years). Of these 68 received metoprolol and 66 were on diltiazem (Fig. 2). Fifty-two patients on metoprolol received 100 mg twice daily
and the fifty patients on diltiazem received 90 mg three times daily on completion of the study. The baseline clinical variables were comparable in both groups (Table 1). The duration and frequency of the total ischaemic burden (Table 2) were decreased significantly by metoprolol as compared to diltiazem (P c 0.01). While metoprolol reduced the duration of the total ischaemic burden by 76%, diltiazem reduced it by 43% (P < 0.01). Metopro101 reduced the frequency of total ischaemic burden by 40% while diltiazem reduced this by 24% (P c 0.02). The total abolition of the episodes of myocardial ischaemia, both symptomatic as well as silent, was observed in 11 patients on both drugs. The duration of silent myocardial ischaemia (Table 3) was significantly reduced by metoprolol as compared to diltiazem (P < 0.05). There was 43% reduction in the frequency of silent ischaemic episodes by metoprolol as compared to 27% by diltiazem (P < 0.02). The reduction in the duration of symptomatic ischaemia on 48 h ambulatory monitoring by metoprolol was not significantly different in comparison to diltiazem (P > 0.05). However the frequency of symptomatic episodes was more
R.C. Ahuja et al. /Int. J. Cardiol. 41 (1993)
191-199
195
Table 2 Effects of metoprolol Total ischaemic
and diltiazem
burden
A. Duration In minutes Logarithmic values
on total ischaemic
burden
(TIB)
Metoprolol
Difference (P-value)
Diltiazem
Control (mean =t SD.)
After therapy (mean f SD.)
Control (mean f S.D.)
After therapy (mean f SD.)
364 l 410 2.6 f 0.5
88 f 1.22 f
295 f 350 2.25 f 0.4
169 f 205 1.76 f 0.6
Mean percentage reduction
113 0.8
76
B. Frequency Episodes per 48 h Logarithmic values Mean percentage reduction
8.2 f 5.2 0.79 + 0.38
43
4.9 f 5.6 0.41 + 0.48
8.0 0.8
f 5.3 + 0.34
40.4
6.1 0.6
f f
5.9 0.45
24
favourably altered by metoprolol when compared to diltiazem (63% reduction by metoprolol versus 24% by diltiazem; P < 0.01) (Table 4). It may be emphasised that angina1 episodes constituted less than 20% of the total ischaemic burden at any time in the study period. On evaluation of subjective response to a drug as judged by patient diary and assessment on a visual analog scale, 63% patients responded to metoprolol while 54.5% patients responded to diltiazem with respect to their reduction in fre-
quency of angina. This difference was statistically not significant (P > 0.05). The time to ST depression and angina and total exercise time on treadmill increased to almost the same extent on metoprolol and diltiazem (Table 5). These differences were statistically not significant. The resting and peak heart rates during the exercise stress test and maximum heart rates achieved during ambulatory ischaemic episodes on metopro101 were 57.0 f 7, 99.2 A 13.4 and 97.2 f 12
Table 3 Effect of metoprolol
and diltiazem
Silent myocardial ischaemia
A. Duration In minutes Logarithmic values
on silent myocardial
Difference (P-value)
Diltiazem
Metoprolol Control (mean f SD.)
After therapy (mean * S.D.)
Control (mean f SD.)
After therapy (mean f SD.)
325 k 462 2.2 f 0.5
78.8 f 109.5 0.7 + 0.36
238 l 345 2.13 f 0.5
128 Zt 190 1.54 + 0.87
Mean percentage reduction B. Frequency Episodes per 48 h Logarithmic values Mean percentage reduction
ischaemia
75
7.1 f 0.71 f
4.8 0.36
46
4.2 0.4 43
f f
3.3 0.44
7.0 f 0.69 f
5.0 0.3
5.3 f 0.55 * 27
< 0.05
2.2 0.43
NS < 0.02
R.C. Ahuja et al. /Inr. J. Cardiol. 41 (1993) 191-199
196 Table 4 Effect of metoprolol and diltiazem on symptomatic myocardial ischaemia Symptomatic myocardial ischaemia
Metoprolol
Diltiazem
Difference (P-value)
Control (mean f S.D.)
After therapy (mean f SD.)
Control (mean f SD.)
After therapy (mean f S.D.)
40.4 f 63 0.77 l 0.94
5.4 f I3 0.25 f 0.55
54.5 f 74 0.86 f 0.9
II.5 f 46 0.38 f 0.7
A. Duration
In minutes Logarithmic values Mean percentage reduction
85
15
NS NS
B. Frequency
Episodes per 48 h Logarithmic values Mean percentage reduction
1.2 f 0.15 l
1.7 0.25
0.44 f 0.6 0.025 f 0.05
1.0 f 0.14 f
1.7 0.25
63
0.75 f 0.12 f
2.4 0.27
24
while on diltiazem were 66.2 f 11.O, 117.5 f 17 and 114 f 11.5 beats/min, respectively. The decrease in these heart rates, from control rates, on metoprolol were significantly more than on diltiazem (P < 0.001). Eight of 68 (11%) patients on metoprolol reported minor side effects like fatigue or giddiness. In live of them these symptoms occured when the dose was increased to 100 mg b.i.d. On diltiazem 15% (10 of 66 patients) reported gastrointestinal symptoms (epigastric discomfort, constipation) while 5% reported giddiness. In six of them these symptoms appeared when the dose was increased to 90 mg t.i.d. No patient had a serious side effect necessitating withdrawal of either drug.
4. Discussion
The selection criteria in the present study ensured that our patients had ~90% probability of having significant obstructive coronary atherosclerotic disease. This was supported by the coronary arteriographic findings in 45 patients constituting 31% of our sample. The coronary angiograms showed L 70% luminal obstruction in all of them (one-vessel, 10; two-vessel, 16; threevessel, 19). The control frequency of total ischaemic burden in the present study (metoprolol group 8.2 A 5.2 per 48 h, diltiazem group 8.0 f 5.3 per 48 h) compares well with the frequency of 4, 3.6 f 3.4 and 3.3 per patient per
Table 5 Effect of metoprolol and diltiazem on time to st depression and angina and total exercise time Parameter
Time to ST depression (min) Time to angina (min) Total exercise time (min)
Metoprolol (n = 68)
P-value
Diltiazem (n = 66)
Control
After therapy
Control
After therapy
4.2 f 2.6 5.2 f 3.0
8.8 f 2.0 9.3 f 3.4
4.4 f 2.5 5.5 f 3.1
8.2 f 2.7 9.5 l 3.1
NS NS
5.8 f 3.2
9.5 f 3.3
6.0 zt 3.3
9.6 + 3.4
NS
R.C. Ahuja et al. /Int. J. Cardiol. 41 (1993)
191-199
24 h in studies by Rocco et al. [4], Deedwania et al. [3] and Yeung et al. [20]. Our study shows that metoprolol reduced the frequency and duration of total ischaemic burden significantly as compared to diltiazem in patients with stable angina. Two randomized crossover studies comparing atenolol and propranolol with diltiazem were available in literature when we started this work in 1989 [21,22]. Both were small trials with 14 patients only. The study period in one of them was only 5 days [22]. The subsequent study by Stone et al. included 56 patients who received propranolol or diltiazem in a randomized cross over design [23] The drugs were given for 2 weeks each. The authors reported that propranolol significantly reduced frequency as well as duration of total ischaemic burden in comparison to diltiazem. The reduction in frequency of total ischaemic burden of 57% for propranolol versus 17% for diltiazem in their study compares well with our findings of 40.4% and 24% on metoprolol and diltiazem, respectively. However the reduction in duration of total ischaemic burden in the study by Stone et al. was 87% for propranolol and nil for diltiazem. It is of interest to note that their mean dose of diltiazem was higher than that used in our study. Khurmi et al. reported an improvement of 44% in the frequency of total ischaemic burden in diltiazem treated patients at a dose of 60 mg three times a day [21], while Bonnetti et al. have reported 80% improvement in the frequency of total ischaemic burden on diltiazem [22]. The effect of drugs on duration of total ischaemic burden has not been given in these two reports. A recent placebo controlled double blind study of effects of diltiazem in 60 patients with stable coronary artery disease reported a 44% reduction in duration of total ischaemic burden [1 11. Silent myocardial ischaemia as expected constituted more than 80% (87% in the metoprolol group and 8 1% in the diltiazem group) of the total ischaemic burden in the control state in our study. The major reduction in both frequency and duration of total ischaemic burden was therefore due to different effects of metoprolol and diltiazem primarily on silent myocardial ischaemia. The studies by Stone et al. [23] and Khurmi et al. [21] did not analyze silent myocardial ischaemic episodes
197
separately from total ischaemic burden. As 94% of total ischaemic burden in the study by Stone et al. was silent, the same would apply to their results too. It is of interest to note that in comparison with silent myocardial ischaemia, the effects of metopro101 and diltiazem on symptomatic ischaemia i.e. angina were not significantly different in two groups of our patients. This was apparent on analysis of subjective response rates as well as time to angina on the exercise stress test. Several clinical trials of various betablockers versus verapamil or diltiazem also report similar findings [ 15- 171. A finding which is contrary to the above in our study was that the decrease in frequency of angina on diltiazem during the 48 h period of recording of events while on Holter monitoring was significantly less than that of metoprolol during a comparable period of observation (24% for diltiazem versus 63% for metoprolol). In view of similar reductions in duration of symptomatic ischaemia during these period of observations, this would mean that patients on diltiazem were experiencing a greater number of angina1 episodes albeit of shorter duration. As this was not captured on the analysis of angina1 episodes per week during the 4-week, treatment period, it seems that these angina1 episodes of shorter duration do not bother the patient enough so as to be entered on the diary unless a patient is somehow sensitized to record these events during periods of Holter monitoring. Overall superiority of metoprolol in reducing frequency and duration of the total ischaemic burden vis a vis diltiazem in patients with stable angina seems to be related to its ability to better control resting, peak exercise and maximum heart rates achieved during daily activities. This is consistent with the fact that heart rate is not only the major determinant of symptomatic ischaemia but also silent myocardial ischaemia in patients with stable angina [24,25]. The prognostic value of elimination of total ischaemic burden in 16% of the patients by both the drugs, its reduction upto 76% by metoprolol and 33% extra benefit by metoprolol vis a vis diltiazem observed in the present study remains to be established. We did not find any published study addressing these questions as its primary ob-
R.C. Ahuja et al. /Int. J. Cardiol. 41 (1993) 191-199
198
jective. However, the study by Yeung et al. [20] failed to demonstrate any beneficial effect of elimination of monitored ischaemia in 18 patients for a mean period of 37 months on drugs as compared with those who did not have transient ischaemic episodes on ambulatory monitoring to begin with. The appropriate comparison group to answer the question of prognostic value of our observed results, however, would have been patients who had a similar degree of monitored ischaemia but in whom drugs failed to reduce it to a significant level. Betablockers have been widely documented to prevent future cardiac events associated with higher mortality and morbidity in patients with various clinical coronary syndromes [26,27]. Calcium channel blockers do not appear to provide these benefits on long term usage in the same settings [28]. As silent myocardial ischaemia is an independent predictor of future cardiac events, the superiority of metoprolol over diltiazem in significantly reducing silent myocardial ischaemia could be one of the explanations of their differential effects in prevention of future cardiac events in these patients. It is reassuring to note that metoprolol which is a cheaper drug compared to diltiazem and which also has a potential of offering prevention against clinically important future cardiac events, decreases the total ischaemic burden much more effectively in a randomized controlled trial in the dosages routinely used for managing patients with stable angina pectoris. 5. Acknowledgements The study was supported by an intramural research grant from the Sanjay Gandhi Post Graduate Institute of Medical Sciences. The work has not been supported by any pharmaceutical firm.
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