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3-KAT inhibition: a new approach to cardioprotectionCardiovascular disease represents a major health
care problem worldwide.[1,2] Coronary artery
disease (CAD) remains the leading cause of morbidity and mortality
in cardiovascular disease and its treatment remains challenging.
Figure 1. Trimetazidine increases the ischemic threshold on dobutamine echocardiography. In experimental studies, trimetazidine was shown
significantly to reduce acidosis during ischemia, preserve ATP
synthesis, and improve functional recovery during ischemic reperfusion.
These findings have been confirmed in numerous clinical studies.
Table I. Results at 2 months follow-up
(adapted from
Improvement in left ventricular function in coronary
patients treated with trimetazidine was also confirmed in a double-blind,
placebo-controlled crossover study by Lu et al19 (Figure 1). These
data clearly support the value of cardiac metabolism manipulation
with metabolic agents such as trimetazidine and offer new perspectives
for the management and the prognosis of patients with CAD.
Mechanisms and significance of cardiac ischemic pain. Maseri A, Crea F, Kaski JC, Davies G. Cardiovascular Research Unit, Hammersmith Hospital, London, UK. Publication Types:
4. The Bypass Angioplasty Revascularisation Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1996;335(4):217225.
Continuing evolution of therapy for coronary artery disease. Initial results from the era of coronary angioplasty. Mark DB, Nelson CL, Califf RM, Harrell FE Jr, Lee KL, Jones RH, Fortin DF, Stack RS, Glower DD, Smith LR, et al. Department of Medicine, Duke University Medical Center, Durham, NC 27710. BACKGROUND: Survival after coronary artery bypass graft surgery (CABG) and medical therapy in patients with coronary artery disease (CAD) has been studied in both randomized trials and observational treatment comparisons. Over the past decade, the use of coronary angioplasty (PTCA) has increased dramatically, without guidance from either randomized trials or prospective observational comparisons. The purpose of this study was to describe the survival experience of a large prospective cohort of CAD patients treated with medicine, PTCA, or CABG. METHODS AND RESULTS: The study was designed as a prospective nonrandomized treatment comparison in the setting of an academic medical center (tertiary care). Subjects were 9263 patients with symptomatic CAD referred for cardiac catheterization (1984 through 1990). Patients with prior PTCA or CABG, valvular or congenital disease, nonischemic cardiomyopathy, or significant (> or = 75%) left main disease were excluded. Baseline clinical, laboratory, and catheterization data were collected prospectively in the Duke Cardiovascular Disease Databank. All patients were contacted at 6 months, 1 year, and annually thereafter (follow-up 97% complete). Cardiovascular death was the primary end point. Of this cohort, 2788 patients were treated with PTCA (2626 within 60 days) and 3422 with CABG (3080 within 60 days). Repeat or crossover revascularization procedures were counted as part of the initial treatment strategy. Kaplan-Meier survival curves (both unadjusted and adjusted for all known imbalances in baseline prognostic factors) were used to examine absolute survival differences, and treatment pair hazard ratios from the Cox model were used to summarize average relative survival benefits. For the latter, a 13-level CAD prognostic index was used to examine the relation between survival and revascularization as a function of CAD severity. The effects of revascularization on survival depended on the extent of CAD. For the least severe forms of CAD (ie, one-vessel disease), there were no survival advantages out to 5 years for revascularization over medical therapy. For intermediate levels of CAD (ie, two-vessel disease), revascularization was associated with higher survival rates than medical therapy. For less severe forms of two-vessel disease, PTCA had a small advantage over CABG, whereas for the most severe form of two-vessel disease (with a critical lesion of the proximal left anterior descending artery), CABG was superior. For the most severe forms of CAD (ie, three-vessel disease), CABG provided a consistent survival advantage over medicine. PTCA appeared prognostically equivalent to medicine in these patients, but the number of PTCA patients in this subgroup was low. CONCLUSIONS: In this first large-scale, prospective observational treatment comparison of PTCA, CABG, and medicine, we confirmed the previously reported survival advantages for CABG over medical therapy for three-vessel disease and severe two-vessel disease. For less severe CAD, the primary treatment choices are between medicine and PTCA. In these patients, there is a trend for a relative survival advantage with PTCA, although absolute survival differences were modest. In this setting, treatment decisions should be based not only on survival differences but also on symptom relief, quality of life outcomes, and patient preferences. PMID: 8181125 [PubMed - indexed for MEDLINE]
Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. Publication Types:
Comment on:
Amphipathic metabolites and membrane dysfunction in ischemic myocardium. Corr PB, Gross RW, Sobel BE. Publication Types:
Comment in:
10. Detry JMR, Leclerc PJ, on
behalf of the TEMS Steering Committee. Trimetazidine European
Multicenter Study versus Propranolol in stable angina pectoris:
contribution of Holter electrocardiographic ambulatory monitoring.
Am J Cardiol. 1995;76:8B11B.
Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Levy S. Division of Cardiology, Hopital Nord, University of Marseille School of Medicine, France. The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with beta blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been studied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oral diltiazem (60 mg three times daily). This was a multicenter, placebo-controlled study with a follow-up period of 6 months. Patients with stable angina and a positive exercise electrocardiogram before and after 15 days of diltiazem therapy were included. The 67 patients were randomized to diltiazem plus placebo (group I, 35 patients) and diltiazem plus trimetazidine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physical examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, defined 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 therapy in both groups showed that the ischemic threshold was significantly prolonged (2 minutes 41 seconds; p < 0.001) in group II. This was not the case for group I, which showed a 41-second prolongation only (difference not significant). The work (kPM) produced at 1-mm ST-segment depression was also significantly increased in group II (1,445.9 kPM; p < 0.001) compared with group I (563.7 kPM; p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS) Publication Types:
Combination treatment with trimetazidine and diltiazem in stable angina pectoris. Manchanda SC, Krishnaswami S. Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India. OBJECTIVE: To assess antianginal efficacy and possible adverse haemodynamic effects of combination treatment with trimetazidine and diltiazem in patients with stable angina. DESIGN: Double blind, randomised, placebo controlled trial of four weeks duration. SETTING: Outpatient department of two Indian hospitals. SUBJECTS: 64 male patients with stable angina, uncontrolled on diltiazem alone. INTERVENTIONS: Diltiazem 180 mg and trimetazidine 60 mg, or diltiazem 180 mg and placebo daily. MAIN OUTCOME MEASURE: Change in exercise time to 1 mm ST segment depression. RESULTS: 33 patients (55%) had no exercise induced angina at 3 mm ST segment depression at inclusion in the study (silent ischaemia). Intention to treat analysis showed that of 32 patients in each treatment group, the number (%) of patients responding to trimetazidine compared to placebo was: for anginal attacks, 28 (87.5) v 15 (46.9), p < 0.001; for exercise time to 1 mm ST segment depression, 21 (65.6) v 9 (28.1), p < 0.003; for exercise time to angina, 12 (37.5) v 5 (15.6), p < 0.05; and for maximum work at peak exercise, 17 (53.1) v 8 (25), p < 0.02. Compared to placebo, there was net improvement with trimetazidine in mean anginal attacks of 4.8/ week (95% confidence interval (CI) 7.5 to 2.1; p < 0.002); in mean exercise times at 1 mm ST segment depression of 94.2 seconds (95% CI 182.8 to 5.6; p < 0.05), and at onset of angina of 113.1 seconds (95% CI 181.6 to 44.6; p < 0.02); and in mean maximum work at peak exercise of 1.4 metabolic equivalents (95% CI 2.4 to 0.3; p < 0.05). CONCLUSIONS: Patients with stable angina uncontrolled with diltiazem had a clinically important improvement after combination treatment with trimetazidine, without adverse haemodynamic events or increased side effects. Publication Types:
Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Szwed H, Sadowski Z, Elikowski W, Koronkiewicz A, Mamcarz A, Orszulak W, Skibinska E, Szymczak K, Swiatek J, Winter M. Department of Ischemic Heart Disease, National Institute of Cardiology, Warsaw, Poland. AIMS: To assess the antiischaemic efficacy and tolerability of the metabolic agent trimetazidine in combination with metoprolol in patients with stable effort angina. METHODS: This was a randomized, multicentre, double-blind, placebo-controlled parallel group study. A total of 426 male and female patients with stable, effort-induced angina and documented coronary artery disease received either placebo or trimetazidine 20 mg three times daily in addition to metoprolol 50 mg twice daily. Treadmill exercise tests were performed at weeks (-1), 0, 4 and 12. RESULTS: After 12 weeks, there were significantly greater improvements in the metoprolol + trimetazidine group than in the metoprolol + placebo group in: time to 1 mm ST segment depression, total workload, time to onset of angina, maximum ST segment depression, mean weekly number of angina attacks, mean weekly nitrate consumption, and grade of anginal pain. There was no evidence of any development of tolerance to trimetazidine. The tolerability of trimetazidine was excellent. CONCLUSIONS: Therapy with trimetazidine plus metoprolol produced significant improvements in exercise stress tests and the symptoms of angina relative to metoprolol alone. With its metabolic effect, devoid of any haemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker. Copyright 2001 The European Society of Cardiology. Publication Types:
15. Szwed H, et al. Anti-ischemic efficacy and tolerability of trimetazidine in elderly patients with angina pectoris. Clin Drugs Invest. 2000;19(1):18.
The antiischemic effects and tolerability of trimetazidine in coronary diabetic patients. A substudy from TRIMPOL-1. Szwed H, Sadowski Z, Pachocki R, Domzal-Bochenska M, Szymczak K, Szydlowski Z, Paradowski A, Gajos G, Kaluza G, Kulon I, Wator-Brzezinska A, Elikowski W, Kuzniak M. National Institute of Cardiology, Warsaw, Poland. Diabetes mellitus, a disease with a wide prevalence, has major cardiovascular effects, being a risk factor for the development of ischemic heart disease and congestive heart failure. The aim of this open, multicenter study was to assess the antiischemic efficacy and tolerability of trimetazidine, a metabolic agent acting at the myocardial mitochondrial level, in diabetic patients with stable effort angina treated previously with a single conventional antianginal drug. Fifty diabetic patients (mean age 58 years) with proven coronary artery disease, stable effort angina for at least 3 months, and positive, comparable results of two initial treadmill exercise tests separated by a 1-week interval were included in the study. They continued their conventional antianginal monotherapy with a long-acting nitrate, beta-blocker, or calcium channel blocker. After stabilization, 4-week therapy with trimetazidine, three times daily, 20 mg was initiated in combination with previous treatment. The results showed a significant improvement in exercise tolerance (440.2 vs. 383.2 s; P < 0.01), time to 1-mm ST-segment depression (358.3 vs. 301.6 s; P < 0.01), time to onset of anginal pain (400.0 vs. 238.3 s; P < 0.01), and total work (9.39 vs. 8.67 metabolic equivalents, P < 0.01). Maximal ST-segment depression was attenuated compared with baseline (1.82 vs. 1.91 mm). Other findings included a significant decrease in the mean frequency of anginal episodes (3.06 vs. 4.79 per week; P < 0.01) and in mean nitrate consumption (2.29 vs. 4.2 doses/week). These results suggest that trimetazidine may be effective and is well tolerated as combination therapy for diabetic coronary artery disease patients uncontrolled with a single hemodynamic agent. Publication Types:
A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Steg PG, Grollier G, Gallay P, Morice M, Karrillon GJ, Benamer H, Kempf C, Laperche T, Arnaud P, Sellier P, Bourguignon C, Harpey C; LIST Study Group. Cardiologie, Hopital Bichat, 46 rue Henri Huchard, 75877 Cedex 18, Paris, France. gabriel.steg@bch.ap-hop-paris.fr BACKGROUND: Despite high patency rates, primary angioplasty for myocardial infarction does not necessarily result in optimal myocardial reperfusion and limitation of infarct size. Experimentally, trimetazidine limits infarct size, decreases platelet aggregation, and reduces leukocyte influx into the infarct zone. To assess trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction a prospective, double-blind, placebo-controlled pilot trial was performed. METHODS: 94 patients with acute myocardial infarction were randomized to receive trimetazidine (40 mg bolus followed by 60 mg/day intravenously for 48 h) (n=44) or placebo (n=50), starting before recanalization of the infarct vessel by primary angioplasty. Patients underwent continuous ST-segment monitoring to assess return of ST-segment deviation to baseline and presence of ST-segment exacerbation at the time of vessel recanalization. Infarct size was measured enzymatically from serial myoglobin measurements. Left ventricular angiography was performed before treatment and repeated at day 14. RESULTS: Blinded ST segment analysis showed that despite higher initial ST deviation from baseline in the trimetazidine group (355 (32) vs. 278 (29) microV, P=0.07), there was an earlier and more marked return towards baseline within the first 6 h than in the placebo group (P=0.014) (change: 245 (30) vs. 156 (31) microV respectively, P=0.044). There was a trend towards less frequent exacerbation of ST deviation at the time of recanalization in the trimetazidine group (23.3 vs. 42.2%, P=0.11). There was no difference in left ventricular wall motion at day 14, or in enzymatic infarct size. There was no side effect from treatment. Clinical outcomes were similar between groups. CONCLUSION: Trimetazidine was safe and led to earlier resolution of ST-segment elevation in patients treated by primary angioplasty for acute myocardial infarction. Publication Types:
Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Belardinelli R, Purcaro A. Department of Cardiology G.M.Lancisi, Ancona, Italy. BACKGROUND: There is evidence that trimetazidine, an anti-ischaemic agent with a direct cytoprotective effect on the myocardium, is effective in stable angina. However, it is not clear whether trimetazidine can improve the mechanical efficiency of chronically dysfunctional myocardium, and whether this potentially beneficial effect can translate into improvements in left ventricular function as well as functional capacity. METHODS: Thirty-eight patients (52.7 +/- 8 years) with post-necrotic left ventricular dysfunction (ejection fraction: 33 +/- 5%) and multivessel coronary artery disease were studied. Patients were randomized into two matched groups. Group A received trimetazidine (20 mg three times daily) for 2 months, while group B received a placebo during the same period. The usual antianginal medications were not altered during the study. At baseline and after 2 months, all patients underwent low-dose dobutamine echocardiography (5-20 microg x kg(-1) x min(-1)), and a symptom-limited cardiopulmonary exercise test. RESULTS: On initial evaluation, systolic wall thickening score index, heart rate, systolic blood pressure and rate pressure product were similar at rest and peak dobutamine in both groups. However, at 2 months, group A patients had significant improvements in the rest and peak systolic wall thickening score index (13% and 20.7%, P<0.001) and ejection fraction (19.7% and 14.1%, P<0.001) without concomitant changes in heart rate and blood pressure. Peak VO2 was also significantly increased in patients taking trimetazidine (15%, P=0.001 vs controls). CONCLUSIONS: In patients with ischaemic cardiomyopathy, trimetazidine improves the contractile response of chronically dysfunctional myocardium to dobutamine without haemodynamic changes. This effect was associated with improvements in left ventricular function and peak VO2. PMID: 11913478 [PubMed - in process]
Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Lu C, Dabrowski P, Fragasso G, Chierchia SL. Istituto Scientifico H. San Raffaele, Milan, Italy. We studied 15 patients with chronic coronary artery disease (13 men aged 62 +/- 8 years) undergoing dobutamine (5 to 40 microg/kg/min) echocardiography at the end of two 15-day treatment periods with placebo and trimetazidine (20 mg 3 times daily) given in random order, according to a double-blind, crossover design. Results show that trimetazidine improves resting left ventricular function and reduces the severity of dobutamine-induced ischemic myocardial dysfunction. Publication Types:
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