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Asian Cardiovasc Thorac Ann 1999;7:84-89
© 1999 Asia Publishing EXchange Pte Ltd

ORIGINAL CONTRIBUTION

Myocardial Ischemia After Coronary Bypass: Comparison of Trimetazidine and Diltiazem

Erkan Kuralay, MD, Ufuk Demirkiliç, MD, Ertugrul Özal, MD, Mehmet Uzun, MD,1, Harun Tatar, MD

Department of Cardiovascular Surgery
1 Department of Cardiology
Gülhane Military Medical Academy
Ankara, Turkey
For reprint information contact: Erkan Kuralay, MD Tel: 90 312 326 3855 Fax: 90 312 435 4732 email: ekural{at}gata.edu.tr Gülhane Lojmanlari Pamir Apt. No. 15, Etlik, Ankara 06010, Turkey.

   Abstract
TOP
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The aim of this prospective randomized study was to evaluate the effect of trimetazidine and diltiazem on persistent myocardial ischemia, mostly silent myocardial ischemia, after coronary artery bypass graft surgery. Sixty patients were divided into three groups of 20 each and followed up for 12 months. Patients in all 3 groups received acetylsalicylic acid 100 mg per day, those in group 1 also had trimetazidine 60 mg per day, and those in group 2 had diltiazem 90 mg per day. Each patient had coronary angiography during the first 3 weeks after surgery, 24-hour ambulatory monitoring every month, and cardiac scintigraphy at 3 weeks, 6 months, and 12 months. Ischemic episodes had resolved at 27 weeks in group 1, at 35 weeks in group 2 and at 51 weeks in group 3 (p < 0.05). Perfusion defects had resolved in the trimetazidine group at 6 months. At 12 months, perfusion defects had resolved in the diltiazem group but not in the group receiving only acetylsalicylic acid (p < 0.05). At these doses, trimetazidine and diltiazem were effective in decreasing silent myocardial ischemia following coronary artery bypass grafting. Trimetazidine appeared to be superior to diltiazem at 6 months on 24-hour ambulatory electrocardiogram monitoring and myocardial scintigraphy.


   Introduction
TOP
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Coronary artery bypass grafting (CABG) is the reference method to eliminate the vascular cause of myocardial ischemia. It is therefore indicated in patients whose symptoms are severe in spite of intensive medical treatment.1–4 Myocardial revascularization by CABG provides excellent symptomatic relief and improvement in exercise capacity, as documented by exercise testing.3,5 However, recent studies have shown that myocardial ischemia, whether spontaneous or exercise-induced, may recur in up to 33% of patients after CABG.6–9 In this post-CABG period, most of the ischemic episodes (77%) are silent during exercise testing.10 The exact mechanism of this silent ischemia is unknown but it may involve graft occlusion, progression of coronary artery disease, or incomplete revascularization diagnosed by a control angiography. Unknown factors with a neurogenic basis or resulting from a reduction in the amount of jeopardized myocardium may also be involved.6 In the first 9 months after CABG, silent myocardial ischemia is a good predictor of cardiac events; there is a 50% incidence of events in patients with silent ischemia compared to 8% in patients with no silent ischemia.8,11–13 It appears appropriate to treat such patients with silent myocardial ischemic episodes. The purpose of this open placebo-controlled prospective study was to assess the efficacy of diltiazem and trimetazidine in patients with silent myocardial ischemia after CABG.


   Patients and Methods
TOP
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
CABG was carried out in 2240 patients in our cardiovascular surgery department from 1994 to 1997. Left internal mammary artery (LIMA) grafting was routinely performed under standard general anesthesia and cardiopulmonary bypass using a single two-stage venous cannula and an aortic cannula. The distal anastomoses were made during a single period of aortic cross-clamping. St Thomas' Hospital no. 2 solution (10 mL•kg–1 at induction) and cold-blood cardioplegia at 20-minute intervals were used for myocardial preservation. Warm blood cardioplegia was infused via an aortic needle before removal of the cross-clamp. Ambulatory monitoring was performed during the first 3 postoperative weeks and 315 patients (14%) were found to have postoperative myocardial ischemia. Among these 315 patients, 287 (91%) did not experience anginal pain. The 287 patients with silent myocardial ischemia were eligible for this study. There were 66 patients with congestive heart failure who were in New York Heart Association functional class II or higher, they were excluded from randomization for group 2 because of the negative inotropic effects of diltiazem. Before randomization, the 287 patients underwent a myocardial scintigraphic study to assess their left ventricular function and to check for perfusion defects. Patients with non-insulin-dependent diabetes mellitus, those with diffuse atherosclerotic coronary vessels, and those who required preoperative endarterectomy were excluded.

Study Groups
We randomly selected 60 patients with silent myocardial ischemia after coronary artery bypass surgery and divided them into the 3 groups of 20 patients each because of the cost of follow-up. Acetylsalicylic acid 100 mg per day was administrated to all patients from the 2nd postoperative day. Patients in group 1 received trimetazidine (20 mg x 3 per day) while those in group 3 received diltiazem (30 mg x 3 per day). Patients in group 3 received only acetylsalicylic acid. During the first 3 months of treatment, each patient underwent angiography to check the coronary grafts. Those with a persisting vascular cause of myocardial ischemia were excluded from the study.

Holter Monitoring
Ambulatory electrocardiographic monitoring was performed every month after the 3rd postoperative week during the first year. Electrocardiographic monitoring for ST-segment analysis was performed with a Hewlett Packard Holter Analyzer model no. 43400B (Hewlett Packard, Andover, MA, USA) using a 2-channel recorder with a modified V3 lead for channel 1 and a V5 lead for channel 2. Patients were instructed to press an event button on the recording box if they experienced chest pain. The recordings were analyzed by a wave-mass program. The experienced Holter analyst was unaware of the patient's group within the study. Silent ischemia was defined as transient ST-segment shifts without accompanying angina pectoris. Holter findings such as transient ST-segment depression (defined as >= 1 mm of horizontal or downward ST-segment depression 80 msec after the J point) or transient ST-segment elevation (defined as >= 1 mm of ST-segment elevation at the J point) were considered to constitute a myocardial ischemic episode. An episode had to last at least 1 minute and at least 2 minutes of normalization of the ST segment were required to define 2 separate episodes.

Myocardial Scintigraphy
Myocardial scintigraphy was performed at 3 weeks and at 6 and 12 months postoperatively. Patients underwent a symptom-limited treadmill exercise test by the Bruce protocol. At peak exercise, 3 mCi of thallium-201 was injected and exercise was continued for 1 minute. At 5 minutes and at 3 hours after this injection, tomograms were obtained by means of a large-field-of-view camera with the patient in the supine position. Thirty-two projections were obtained (step by step) of 40 seconds each, through a 180-degree orbit, beginning with a 45-degree right anterior oblique position and ending with a 45-degree left posterior oblique position. Tomographic reconstruction was performed with a filtered back-projection algorithm and a Hann filter. Oblique orthogonal tomographic slices were used to reconstruct the left ventricle in the short-axis, horizontal long-axis, and vertical long-axis orientations.

Statistical Analysis
The baseline characteristics of the study patients were evaluated with Kolmogorov tests and chi-squared tests. Ischemic episodes were compared with the Mann-Whitney U test and the numbers of patients with ischemic episodes and scintigraphic defects were compared by chi-squared tests. A p value of less than 0.05 was considered significant. Groups 1 and 2 were compared with each other and with the control patients (group 3).


   Results
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Coronary angiography, performed in all patients during the first 3 months after the beginning of treatment, detected 4 patients who had occluded grafts; 1 patient each in groups 1 and 2, and 2 patients in group 3. These 4 patients were excluded from the study. Thus, results are provided for 19 patients in group 1, 19 patients in group 2, and 18 patients in group 3 who completed the study (Table 1Go). The three groups were homogenous for all variables when entering the study, except for the existence of congestive heart failure (p > 0.05). All patients suffered from chronic ischemia before the operation (electrocardiographic signs of ischemia for more than 3 months). Perioperative myocardial infarction occurred in 2 patients in group 1 and in one patient each in groups 2 and 3.


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  		Table 1. Baseline Characteristics of the Study Patients
 
Results of the monthly follow-up studies with ambulatory 24-hour monitoring are summarized in Tables 2 and 3GoGo. The first Holter monitoring in the 3rd postoperative week revealed that 5 patients had ST-segment elevation in group 1, 6 in group 2, and 6 in group 3. Ischemic episodes in the second Holter examination involved 2 patients with ST-segment elevation; one each in groups 2 and 3. A total of 18 ST-segment elevations was recorded in these 2 patients. In the group-2 patient, the ST-segment elevations had resolved one month later but they were still present in the group-3 patient. Intergroup differences were observed throughout the study period as shown in Tables 2 and 3GoGo.


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  		Table 2. Number of Ischemic Episodes on Ambulatory Holter Monitoring
 

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  		Table 3. Number of Patients with Ischemic Episodes on Ambulatory Holter Monitoring
 
Myocardial scintigraphy was repeated in the 6th and 12th months postoperatively. No perfusion defects were found in the patients in group 1, except in infarcted areas. Various degrees of perfusion defects were detected in groups 2 and 3 at the 6-month scintigraphic examinations. Perfusion defects in the diltiazem group resolved completely but infarcted areas were still present at the 12–month scintigraphy examinations. Perfusion defects in group 3 were still present at the 12-month scintigraphic examinations (p < 0.05). These results are summarized in Table 4Go.


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  		Table 4. Number of Patients with Scintigraphic Perfusion Defects
 

   Discussion
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Myocardial revascularization by CABG is usually considered to be very effective in providing symptomatic relief for patients with angina pectoris.3 The quality of myocardial revascularization has been documented by an improvement in exercise capacity.5 However, recent studies have shown that transient myocardial ischemia can be detected in up to 33% of patients after CABG.6,7,9,10 In our study, myocardial ischemic episodes were silent in 91% of patients. Recently, evidence has accumulated that during the post-CABG period, a remarkably high proportion of patients have asymptomatic myocardial ischemia.14,15 Ribeiro and colleagues14 advised that even when graft patency is established, it is not necessarily indicative of physiologic relief of transient myocardial ischemia. Their study using regional myocardial perfusion positron emission tomography and ambulatory electrocardiography, showed that relief of angina symptoms after CABG could be attributed to 3 different mechanisms: relief of transient ischemia; perioperative myocardial infarction; and conversion of angina pectoris to silent myocardial ischemia.

It has been shown that 70% of ischemic episodes are silent during exercise testing in the postoperative period.10 This high proportion of silent episodes of post-CABG myocardial ischemia might be related to their etiology. The absence of pain associated with these ischemic episodes has been ascribed to various mechanisms.16,17 However, the determinant etiology of silent ischemia after CABG remains speculative. Incomplete myocardial revascularization can be an important cause of postoperative myocardial ischemia but the patients usually suffer angina pectoris and only a few of them have silent ischemia preoperatively. In this study, we excluded patients with incomplete myocardial revascularization. Although several investigators have documented that disturbed regional myocardial perfusion accompanies episodes of transient ST-segment depression detected after CABG, Kennedy and colleagues6 excluded angiographically definable stenotic vessels as the dominant mechanism in the early years after CABG. Perhaps presurgical abnormalities of elevated coronary vascular resistance, or acquired abnormal vasodilator flow reserve of the microcirculation due to endothelial or pre-arteriolar abnormalities after CABG, or both of these factors, account for the silent ischemia.18,19 In one study, the existence of a coronary spasm was suspected in only one patient out of 19 with complete myocardial revascularization.7

Whatever its etiology, silent myocardial ischemia has been found to be a predictor of cardiovascular mortality and morbidity in most studies.9 Egstrup8 compared cardiac events (such as cardiac death and angina pectoris) in 12 patients with silent myocardial ischemia and 24 patients without silent myocardial ischemia determined by ambulatory monitoring, without any restriction of exercise in the first 3 months after CABG. They found that cardiac events were more common (50%) in patients with silent myocardial ischemia. Cardiac death was seen to occur in the first 9 months after CABG. A smaller proportion (8%) of the cardiac events was found in patients without silent myocardial ischemia. Studies analyzing the prognostic significance of postoperative ischemia have produced conflicting results. In the Coronary Artery Surgery Study (CASS), which followed up patients for several years after CABG, the occurrence of silent myocardial ischemia during exercise testing predicted a reduced rate of survival.9,10 There is no consensus on the drug of choice for patients with silent ischemia, particularly for post-CABG patients, and especially for those without a remaining vascular cause of myocardial ischemia.

Some recent clinical studies have demonstrated that trimetazidine exerts a direct anti-ischemic effect at the cellular level, preventing ischemia-induced deterioration of energy production and reducing ischemia-induced acidosis. In maintaining the intracellular pH and adenosine triphosphate levels necessary for adenosinetriphosphatase-dependent ion pumps, trimetazidine prevents potassium leakage and sodium and calcium accumulation in the cell.20–24 Diltiazem works via a different mode of action; it increases coronary artery vasodilatation and reduces the myocardial oxygen demand by peripheral arterial vasodilatation and a negative inotropic effect. Comparing trimetazidine with diltiazem in patients with silent myocardial ischemia, we observed that ischemic episodes disappeared in 5 months with trimetazidine and in 8 months with diltiazem. These 24-hour Holter results were confirmed by the disappearance of the defects on cardiac scintigraphy at 6 months with trimetazidine and at 12 months with diltiazem. This might account for the better results obtained with an anti-ischemic agent acting at the cellular level (trimetazidine) than with a hemodynamic agent (diltiazem). Diltiazem was used in our study as a dose of 90 mg per day because of its negative inotropic effect at higher dosage. The superiority of trimetazidine may be due to the mechanism of post-CABG myocardial ischemia, which might be mediated mostly by ischemic cellular changes rather than vascular causes.25,26 Trimetazidine has no hemodynamic effects and therefore represents a valuable alternative for treating myocardial ischemia. Further double-blind trials with larger numbers are needed to establish the benefit of treating post-CABG silent ischemia with a metabolic agent, particularly in terms of morbidity and mortality.


   References
TOP
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Cosgrove DM, Loop FD, Sheldon WC. Results of myocardial revascularization: a 12-year experience. Circulation 1982;65(Suppl II):II-37–43.[Abstract]

  2. Braunward E. Effect of coronary artery bypass grafting on survival: implications of the randomized coronary artery study. N Engl J Med 1983;309:1181–4.[Medline]

  3. Rahimtoola SH. Coronary artery bypass for chronic angina–1981. A perspective. Circulation 1982;65:225–41.[Free Full Text]

  4. Loop FD, Sheldon WC, Lytle BW, Cosgrove DM, Proudfit WL. The efficacy of coronary artery bypass surgery. Am Heart J 1981;101:86–96.[Medline]

  5. Hassack KE, Bruce RA, Ivey TD, Kusumi F. Changes in cardiac functional capacity after coronary artery bypass surgery in relation to adequacy of revascularization. J Am Coll Cardiol 1984;3:47–54.[Abstract]

  6. Kennedy HL, Seiler SM, Spraque MK, Hamon SM, Whitlock JA, Kern MJ, et al. Relation of silent myocardial ischemia after coronary artery bypass grafting to angiographic completeness of revascularization and long-term prognosis. Am J Cardiol 1990;65:14–22.[Medline]

  7. Crea F, Kaski JC, Fragasso G, Hackett D, Stanbridge R, Taylor KM, et al. Usefulness of Holter monitoring to improve the sensibility of exercise testing in determining the degree of myocardial revascularization after coronary artery bypass grafting for stable angina pectoris. Am J Cardiol 1987;60:40–3.[Medline]

  8. Egstrup K. Asymptomatic myocardial ischemia as a predictor of cardiac events after coronary artery bypass grafting for stable angina pectoris. Am J Cardiol 1988;61:248–52.[Medline]

  9. Weiner DA, Ryan TJ, Parsons L, Fisher LD, Chaitman BR, Sheffield LT, et al. Prevalence and prognostic significance of silent and symptomatic ischemia after coronary artery bypass: a report from the Coronary Artery Surgery Study (CASS) randomized population. J Am Coll Cardiol 1991;18:343–8.[Abstract]

  10. Weiner DA. Significance of silent myocardial ischemia after coronary artery bypass surgery. Am J Cardiol 1992;70:33F–8F.

  11. Deanfield JE, Selwyn AP, Chierchia S, Maseri A, Riberia P, Krikler S, et al. Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1983;2:753–8.[Medline]

  12. Chierchia S, Lazzari M, Freedman B, Bunnelli C, Maseri A. Impairment of myocardial perfusion and function during painless myocardial ischemia. J Am Coll Cardiol 1983;1:924–30.[Abstract]

  13. Cohn PF, Brown EJ Jr, Wynne J, Holman BL, Atkins HL. Global and regional left ventricular abnormalities during exercise in patients with silent myocardial ischemia. J Am Coll Cardiol 1983;1:931–3.[Abstract]

  14. Ribeiro P, Shea M, Deanfield JE, Oakley CM, Sapsford R, Jones T, et al. Different mechanism for the relief of angina after coronary bypass surgery. Physiological versus anatomical assessment. Br Heart J 1984;52:502–9.[Abstract/Free Full Text]

  15. Quyyumi AA, Wright CA, Mockus LJ, Yacoup M, Fox KM. Effects of myocardial revascularization in patients with effort angina and those with effort and nocturnal angina. Br Heart J 1985;54:537–61.

  16. Gottlieb SO, Weisfeldt ML, Ouyang P, Mellits ED, Gerstenblith G. Silent myocardial ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N Engl J Med 1986;314:1214–9.[Abstract]

  17. Schwartz JN, Kong Y, Hackel DB, Bartel AG. Comparison of angiographic and postmortem finding in patients with coronary artery disease. Am J Cardiol 1975;36:174–8.[Medline]

  18. Gould KL. Identifying and measuring severity of coronary artery stenosis: quantitative coronary arteriography and positron emission tomography. Circulation 1988;78:237–45.[Free Full Text]

  19. Brush JE, Cannon RO, Schenke WH, Bonow RO, Leon MB, Maron BJ, et al. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med 1988;319:1302–7.[Abstract]

  20. Lavanchy N, Martin J, Rossi A. Anti-ischemic effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart. Arch Int Pharmacodyn Ther 1987;286:97–110.[Medline]

  21. Harpey C, Clauser P, Labrid C, Freyria JL, Proirer JP. Trimetazidine, a cellular anti-ischemic agent. Cardiovasc Drug Rev 1986;6:292–312.

  22. Renaud JF. Internal pH, Na+ and Ca2+ regulation by trimetazidine during cardiac cell acidosis. Cardiovasc Drugs Ther 1988;1:677–86.[Medline]

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  24. Maupoil V, Rochette L, Tabard A, Clauser P, Harpey C. Direct measurement of free radical generation in isolated rat heart by electron paramagnetic resonance spectroscopy: effect of trimetazidine. In: Emerit I, editor. Antioxidants in therapy and preventive medicine. New York: Plenum Press, 1990:373–6.

  25. Kober G, Pennaforte S, Buck T, Sievert H, Vallbracht C. Myocardial cytoprotection during percutaneous transluminal coronary angioplasty. Eur Heart J 1993;14(Suppl G):6–11.

  26. Fabiani JN, Farah B, Vuilleminot A, Lecompte T, Emerit I, Chardigny C, et al. Chromosomal aberrations and neutrophil activation induced by reperfusion in the ischaemic human heart. Eur Heart J 1993;14(Suppl G):12–7.





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