Combination Therapy of Trimetaridine with Diltiazem in Patients with Coronary Avtery Disease Samuel Levy, MD, and the Group of South of France Investigators The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with f) blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been stud- ied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oml diltiiem (60 mg three times daily). This was a multicenter, pla- &o-controlled study with a follow-up period of 6 months. Patients with stable angina and a positiie exercise electrocardiogmm before and after 15 days of diltiazem thempy were included. The 67 patients were randomized to dihiaxem plus placebo (group I, 35 patients) and diltiaxem plus trimetaxi- dine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physi- cal examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, de- fined as the time to 1 -mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of thempy in both groups showed that the ischemic threshold was significantfy prolonged (2 minutes 41 seconds; p <O.OOl) in group II. This was not the case for group I, which showed a 41 -second prolongation only (difference not significant). The work (LPM) produced at 1 -mm ST-segment depres- sion was also significantly increased in group II (1,445.9 kPM; p <O.OOl) compared with group I (563.7 kPM; p = 0.012). The difference in change between both groups was significant for each vari- able (respectively, p = 0.008 and p = 0.018). At peak exercise, the duration of effort and total work increased significantly in group II (50 seconds; p = 0.006; 570 kPM, p = 0.004) as opposed to group I (16 seconds, not significant; 22 1.2 kPM, not significant). The myocardial cost on exercise, ex- pressed as the rote-pressure product/workload at 1 -mm ST-segment depression, was significantly de- creased in grwp II (69.9, p <O.OOl), compared with group I (20.3, not significant). The difference between the 2 groups was significant (p <O.Ol). This study suggests that combination of dihiazem with trimetazidine in patients with stable angina and positive exercise test, despite diltiazem thempy, may favombly influence the exercise pammeters, particularly the ischemic threshokf, and lead to a decrease in myocardial cost on exercise. (Am J Cardiol 1995; 76: 128-l 68) I n recent years, the concepts underlying the management of coronary artery disease have evolved from the imbalance between myocar- dial oxygen supply and demand to the mechanisms of myocardial ischemia. A new concept of cytopro- tection by drugs acting at the cellular level has progressively emerged and supports the mecha- nism of action of a new class of antianginal agents. Trimetazidine represents an original antiangi- nal agent that has the unique property of counter- acting the deleterious effects of ischemia at the cellular level. It maintains phosphocreatine and adenosine triphosphatc levels’ and reduces cell acidosis calcium overload*-” and free radical- induced damage.4-s Little is known regarding the potential benefits of combining trimetazidine with From the Diwsion of Cardiology, HBpitol Nord, University of Marseille School of Medicine, Marseille, France. This work was supported by a grant from the Laboratoires Biophormaceutiques de France. Address for reprints: Samuel Levy, MD, HBpitol Nord, Division of Cardiology, University of Marseille School of Medicine, Marseille, France. diltiazem, a widely used calcium antagonist, in patients with coronary artery disease. The purpose of this study was to evaluate the effect of combination therapy of oral trimetazidine and diltiazem using bicycle ergometer exercise testing in patients with coronary artery disease and a positive exercise test despite the use of oral diltiazem. METHODS This trial was a prospective, multicenter, double- blind, placebo-controlled study. The inclusion crite- ria were as follows: male patients with stable angina pectoris and coronary artery disease proven either by coronary angiography or a history of myocardial infarction of >3 months, a positive maximal exercise test or positive thallium imaging scintigraphy, and informed consent. The protocol was approved by the Ethical Committee. The design of the study included for each patient 15 days of treatment with oral diltiazem I80 mg daily (60 mg, 3 times daily). After this period, a 126 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 AUGUST 24, 1995
Transcript
Combination Therapy of Trimetaridine with Diltiazem in Patients with Coronary
Avtery Disease Samuel Levy, MD, and the Group of South of France Investigators
The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with f) blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been stud- ied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oml diltiiem (60 mg three times daily). This was a multicenter, pla- &o-controlled study with a follow-up period of 6 months. Patients with stable angina and a positiie exercise electrocardiogmm before and after 15 days of diltiazem thempy were included. The 67 patients were randomized to dihiaxem plus placebo (group I, 35 patients) and diltiaxem plus trimetaxi- dine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physi- cal examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, de- fined as the time to 1 -mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of thempy in both groups showed that the ischemic threshold was significantfy prolonged (2 minutes 41 seconds; p <O.OOl) in group II. This was
not the case for group I, which showed a 41 -second prolongation only (difference not significant). The work (LPM) produced at 1 -mm ST-segment depres- sion was also significantly increased in group II (1,445.9 kPM; p <O.OOl) compared with group I (563.7 kPM; p = 0.012). The difference in change between both groups was significant for each vari- able (respectively, p = 0.008 and p = 0.018). At peak exercise, the duration of effort and total work increased significantly in group II (50 seconds; p = 0.006; 570 kPM, p = 0.004) as opposed to group I (16 seconds, not significant; 22 1.2 kPM, not significant). The myocardial cost on exercise, ex- pressed as the rote-pressure product/workload at 1 -mm ST-segment depression, was significantly de- creased in grwp II (69.9, p <O.OOl), compared with group I (20.3, not significant). The difference between the 2 groups was significant (p <O.Ol). This study suggests that combination of dihiazem with trimetazidine in patients with stable angina and positive exercise test, despite diltiazem thempy, may favombly influence the exercise pammeters, particularly the ischemic threshokf, and lead to a decrease in myocardial cost on exercise.
(Am J Cardiol 1995; 76: 128-l 68)
I n recent years, the concepts underlying the management of coronary artery disease have evolved from the imbalance between myocar-
dial oxygen supply and demand to the mechanisms of myocardial ischemia. A new concept of cytopro- tection by drugs acting at the cellular level has progressively emerged and supports the mecha- nism of action of a new class of antianginal agents.
Trimetazidine represents an original antiangi- nal agent that has the unique property of counter- acting the deleterious effects of ischemia at the cellular level. It maintains phosphocreatine and adenosine triphosphatc levels’ and reduces cell acidosis calcium overload*-” and free radical- induced damage. 4-s Little is known regarding the potential benefits of combining trimetazidine with
From the Diwsion of Cardiology, HBpitol Nord, University of Marseille School of Medicine, Marseille, France. This work was supported by a grant from the Laboratoires Biophormaceutiques de France.
Address for reprints: Samuel Levy, MD, HBpitol Nord, Division of Cardiology, University of Marseille School of Medicine, Marseille, France.
diltiazem, a widely used calcium antagonist, in patients with coronary artery disease.
The purpose of this study was to evaluate the effect of combination therapy of oral trimetazidine and diltiazem using bicycle ergometer exercise testing in patients with coronary artery disease and a positive exercise test despite the use of oral diltiazem.
METHODS This trial was a prospective, multicenter, double-
blind, placebo-controlled study. The inclusion crite- ria were as follows: male patients with stable angina pectoris and coronary artery disease proven either by coronary angiography or a history of myocardial infarction of >3 months, a positive maximal exercise test or positive thallium imaging scintigraphy, and informed consent. The protocol was approved by the Ethical Committee.
The design of the study included for each patient 15 days of treatment with oral diltiazem I80 mg daily (60 mg, 3 times daily). After this period, a
126 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 AUGUST 24, 1995
12 lead electrocardiogram (ECG) and a bicycle ergometer exercise test were obtained. Patients who had a positive exercise test were randomized to diltiazem 60 mg, 3 times daily and trimetazidine 20 mg, 3 times daily or to diltiazem 60 mg, 3 times daily and placebo (3 times daily). The treatment was given for 6 months, and an exercise test and 12 lead ECG were obtained at 3 and 6 months following randomization. Other antianginal agents-including long-acting nitrates, p blockers, calcium antagonists, or amiodarone-were not al- lowed (interruption 3 months before the study inclusion was required); allowed were diuretics, digoxin, antiarrhythmic agents, antiplatelet therapy, and sublingual 0.2 mg spray of nitroglycerin.
The protocol used for the bicycle ergometer included progressive steps starting at 30 W for 3 minutes and increasing by 30 W every 3 minutes. A test was defined as positive when l-mm ST- segment depression evaluated 0.06 seconds after the J point was observed. Only patients with a maximal heart rate (HR) 280% of the predicted maximal HR (220 beats/min minus age), were included. The following parameters were evalu- ated; at rest: HR, systolic blood pressure and rate-pressure product (RPP); at l-mm ST-segment depression: the percentage of maximal HR, time in seconds/workload, in watts, work in kilopound- meters (kPM), RPP, and myocardial cost on effort, defined as the RPP/workload ratio; at peak exer- cise: ST-segment depression (duration in seconds) and the same parameters as at l-mm ST-segment depression.
The tolerance of the combination therapy in- cluded monitoring of HR, systolic blood pressure, 12 lead ECG, and search for side effects.
Comparison of the 2 groups used Student’s paired t test or covariance analysis of parameters at entry and at 6 months.
RESULTS A total of 67 patients were included in this trial:
32 were randomized to diltiazem plus trimetazi- dine and 35 to diltiazem plus placebo. The 2 groups were not statistically different in terms of age (61 2 1 versus 62 + 1 years), clinical history of myocardial infarction (16 versus 12), coronary angiography (24 versus 24), or extent of coronary artery disease (Table I). Similarly, the 2 groups were not statistically different in terms of ergomet- ric parameters assessed at the onset of the study (Table II) at rest and at l-mm ST-segment depres- sion, except for the duration of exercise, workload, and total work, which was lower in the trimetazi-
TABLE I Clinical Variables in the 2 Groups, Trimetazidine with
Diltiazem and Placebo with Diltiozem, When Entering the Study
Clmcol Vorlable
No. patients
Age (yr; meon -t SD)
HIstory of myocordlol InfarctIon (n)
Coronoly a”glogrom (n)
No slgmflcont (< 70%) leston (n)
One vessel (n)
Two vessels (n)
Three vessels (n)
Cl~mcol hIstory and fmdlngs (n)
Tnmetorldine
Group
32
61 -t 1
16
24
2
13
6
3
4
PlOC&O Group
35
62 + I
12
24
2
14
6
2
9
TABLE II Ergometric Variables in the 2 Groups at Rest, at 1 -mm
ST-Segment Depression, and at Peak Exercise When Entering the
dine group, and the myocardial cost, which was higher in the trimetazidine group, reflecting the fact that the trimetazidine group was more severely affected in terms of coronary insufficiency. This was also the case concerning the basal values at peak exercise. Thus, a covariance analysis was used for comparison of changes over 6 months.
Ergometric variables al 6 months: The change in the duration of exercise was not significantly different between the 2 groups. However, in the trimetazidine group, the duration of exercise in- creased significantly compared with the control value.
The increase in time to l-mm ST-segment depression was significantly more important (p = 0.008) in the trimetazidine group compared
A SYMPOSIUM: MANAGEMENT OF MYOCARDIAL ISCHEMIA 138
TABLE III Ergometric Voriobles ot 6 Months
p Value Tmnetortdine Group Placebo Group
Ergometric Between Vanable TO T6 TO T6 TMZ PlClC&O Groups
At peak exercise
Durotlon (5) 557 607 644 661 0 006 NS NS
(26) (251 (27) (28) Total work (kPM) 3,637 4,207 4.678 4,899 0.004 NS NS
(17) 113) (20) (121 Numbers 8” porenthsrss = no of sub,sctr TO = baselme, T6 = 6 month &to, TMZ = trometazldme. other abbrewotmnr 01 m Tobte II
with the placebo group (Figure 1). Similarly, the DISCUSSION work performed at l-mm ST-segment depression was significantly increased in the trimetazidine group compared with the placebo group (p = 0.018; Figure 2). The changes in the myocardial cost on effort at l-mm ST-segment depression were signifi- cantly more important in the trimetazidine group compared with the placebo group (p ~0.001). It was not significantly modified in the placebo group, but significantly decreased (p <O.OOl) in the tri- metazidine group (Figure 3).
Tolemnce: There were 2 side effects detected in both groups. In the diltiazem plus trimetazidine group, 1 patient complained of myalgia and 1 patient of lower limb edema. In the diltiazem plus placebo group 1 patient complained of somnolence and 1 also of lower limb edema.
Trimetazidine is an interesting antianginal agent with an original mechanism of action. Unlike nitrates or calcium antagonists, it does not inter- fere with coronary blood flow. Unlike l3 blockers, it does not affect heart rate, myocardial contractility, or blood pressure,6 all maneuvers favorable to decrease myocardial oxygen demand.
In this study, the decrease of the myocardial cost on effort (defined as the RPP/workload ratio) at the ischemic threshold (l-mm ST-segment de- pression) assessed the reduction of the myocardial oxygen requirement in the presence of trimetazi- dine to perform the same work. The mechanism by which trimetazidine could achieve this change is mainly supported by a protection of the energy
Time to 1 mm ST segment depression
Seconds r
p = 0.00s’ I
*** u < 0.001 NS
so0
0 TO T6 TO T6
trimetazidine placebo (n = 32) (n - 35)
FIGURE 1. Time to 1 -mm ST-seg- mentdaprussion~i~the2sldy z-ps, trhetadme and pkt-
148 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 76 AUGUST 24, 1995
FIGURE 2. Work at 1 -mm ST-seg- ment depression in the 2 study cl-ps.
FIGURE 3. Myoawdic~l cost on ef- fort ot 1 -mm ST-segment depres- sion in both groups.
Work at 1 mm ST segment depression
Work (kpm) I 4ooo *** p < 0.001
p =0.01&J* I
** p = 0.012 -I-
0 TO T6 TO T6 trimetazidine placebo
(n = 32) (n - 35)
Myocardial cost on effort at 1 mm ST segment depression
RPPlcharge
400 I p < 0.001’
0 TO T6 TO T6 trimetazidine placebo
(n = 32) (n = 35)
metabolism by the myocardial cells and a limitation of intracellular acidosis.
The safety and beneficial effect of combination therapy of trimetazidine with nifedipinc has been tested. However, there have been no reports so far of the efficacy and tolerance of combination of trimetazidine with diltiazem in a controlled fash- ion. The present report suggests that combining trimetazidine with diltiazcm results in an improvc- ment of ergometric parameters with a delayed appearance of l-mm ST-segment depression and a decreased myocardial cost on effort. Of interest is the fact that this study dealt with a group of patients with coronary insufficiency who had a positive exercise test despite the use of diltiazem alone. These patients are not so common, as they currently undergo coronary revascularization using balloon angioplasty or coronary artery bypass graft- ing. The study is only possible at a multicenter level
and required the successful interplay between a university center with cardiologists in practice particularly motivated and trained in clinical re- search.
CONCLUSION This double-blind placebo-controlled study
shows that combination therapy of trimetazidine with diltiazem is well tolerated and associated with a bcncficial effect on ischemia, as shown by exer- cisc parameters.
APPENDIX Investigators who participated in the study: H.
Reboul, Aiw-en-Provence; J. Fabre, Avignon; J. M. Bouteau, Hy&-es; C. Aronzon, C. H. Avierinos, J. Charbit, J. D’Journo, M. Gaudy, M. Gay, D. Ghez, B. Jauffret, G. Jullien, R. Khalvadjian, J. C. Pas-
A SYMPOSIUM: MANAGEMENT OF MYOCARDIAL ISCHEMIA 158
carello, G. Rochette, J. P. Romano, J. Scemama, I. A. Trigano, Murseille; E. Blache, Mart&yes.
Acknowledgment: We thank Dr. D. Jalbert and C. Harpey for their help in preparing the manu- script.
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