 |
Clinical value of combined hemodynamic and metabolic agents in the treatment of stable anginaI. Holban, T. Hénane
Introduction Table I: comparative studies of combined hemodynamic
therapy over monotherapy.  Rationale for the use of metabolic agents Trimetazidine: evidence-based efficacy
Based on results
that showed an improvement in ergometric parameters and
clinical signs (Figures 1 and 2), the authors concluded that
“in patients with angina not sufficiently controlled with propranolol,
a better antianginal efficacy was observed with the addition
of
trimetazidine than with the addition of isosorbide dinitrate.”
This can easily be explained by the purely metabolic mechanism
of action of trimetazidine, which is fully additive to that of
the hemodynamic agent.
REFERENCES
Management of stable angina pectoris. Recommendations of the Task Force of the European Society of Cardiology. [No authors listed] Publication Types:
Management of patients with chronic stable angina at low risk for serious cardiac events. Thadani U. Cardiovascular Department, University of Oklahoma-HSC, Oklahoma City 73104, USA. Successful management of the patient with chronic stable angina requires correct stratification by assessing the risk of future coronary events. Patients at low risk for such events have a relatively good prognosis; revascularization procedures (balloon angioplasty or surgery) offer no benefit over medical management. Such patients should be offered medical therapy as their first option. The goals in management of chronic stable angina are (1) treatment of other conditions that may worsen angina; (2) treatment with aspirin and modification of risk factors for coronary artery disease (CAD) to improve outcome; and (3) effective relief of anginal symptoms. Most patients with stable angina will have CAD. It is well established that treatment with aspirin and modification of risk factors for CAD are beneficial in reducing cardiovascular mortality and morbidity. Blood pressure reduction, lowering of blood cholesterol level, and smoking cessation are interventions of proven value and appear to correct defects (at least partially) in the endothelial function of the coronary blood vessels. Other interventions that are helpful are estrogen replacement treatment in postmenopausal women, and low-dose aspirin therapy-which is recommended for all patients who can tolerate it. For controlling symptoms and improving angina-free walking time, nitrates, beta blockers, and calcium channel antagonists are efficacious as first-line monotherapy for chronic stable angina in this group of patients. Nitrates may be of special use in patients with impaired left ventricular function, overt congestive heart failure, intermittent coronary vasoconstriction, or coronary artery spasm. In patients with concomitant hypertension or supraventricular tachycardia, beta blockers are helpful. Calcium channel antagonists may be useful in patients with chronic obstructive pulmonary disease, peripheral vascular disease, or hypertension. When optimal monotherapy with a given class of drug fails to control symptoms, alternative monotherapy with a different class of agent should be tried before combination therapy. Combination therapy with 2 or 3 agents is not always superior to optimal monotherapy. Patients who fail to respond to adequate medical therapy should be considered for a revascularization procedure. Publication Types:
Comment on:
The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ. Royal Brompton Hospital, London, UK. OBJECTIVES: To determine the effects of atenolol, nifedipine and their combination on exercise parameters and ambulatory ischaemic activity in patients with mild chronic stable angina. SETTING: Multicentre, multinational study involving 608 patients from 69 centres in nine countries. DESIGN: Placebo washout followed by double-blind parallel-group study comparing atenolol 50 mg bd, nifedipine SR 20 mg bd, and their combination. Patients underwent maximal exercise testing using either a bicycle (n = 289) or treadmill (n = 319) and 48 h of ambulatory ST segment monitoring outside the hospital environment at the end of the placebo washout period and after 6 weeks of active therapy. RESULTS: Both medications alone and in combination caused significant improvements in exercise parameters and significant reductions in ischaemic activity during daily activities, when compared with placebo. There were, however, no significant differences between groups, for any of the measured ischaemic parameters although combination therapy resulted in a greater fall in resting systolic and diastolic blood pressure than either treatment alone. CONCLUSIONS: In the management of mild chronic stable angina there appears to be little advantage gained from using combination therapy for ischaemia reduction. Publication Types:
Comment in:
Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated? Lopaschuk GD. Cardiovascular Research Group, University of Alberta, Faculty of Medicine and Dentistry, Edmonton, Canada. gary.lopaschuk@ualberta Optimizing energy metabolism in the heart is a novel approach for the management of ischaemic heart disease, especially in conjunction with optimizing or restoring coronary flow. In particular, promoting myocardial glucose metabolism can enhance heart function, lessen injury to tissue, or both. Several pharmacological agents that directly stimulate myocardial glucose oxidation or indirectly stimulate glucose oxidation secondary to inhibition of oxidation of fatty acids are now available. Trimetazidine is the first compound in the class of 3-ketoacyl-coenzyme A thiolase inhibitors to see wide-spread clinical use. This agent increases glucose metabolism in the heart secondary to a direct inhibition of fatty acid metabolism. Considering results of experimental and clinical studies on other agents, it is clear that metabolic agents may provide a new approach to treating cardiovascular disease that should complement and improve existing therapies. Publication Types:
Comment in:
Trimetazidine: a new concept in the treatment of angina. Comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Saint-Luc University Hospital, Brussels, Belgium. 1. Trimetazidine has a direct anti-ischaemic effect on the myocardium without altering the rate x pressure product or coronary blood flow. 2. The effects of trimetazidine (20 mg three times daily) were compared with those of propranolol (40 mg three times daily) in a double-blind parallel group multicentre study in 149 men with stable angina. 3. Reproducibility of exercise performance was verified during a 3 week run-in placebo washout period. All patients had > 1 mm ST-depression on exercise test. 4. After 3 months, similar anti-anginal efficacy was observed between the trimetazidine (n = 71) and propranolol (n = 78) groups. No significant differences were observed between trimetazidine and propranolol as regards anginal attack rate per week (mean difference P-TMZ: 2; 95% CI: -4.4, 0.5) and exercise duration (mean difference P-TMZ: 0 s; 95% CI: -33, 34) or time to 1 mm ST segment depression (mean difference P-TMZ: 13 s; 95% CI: -24, 51). Heart rate and rate x pressure product at rest and at peak exercise remained unchanged in the trimetazidine group but significantly decreased with propranolol (P < 0.001 in all cases). With both drugs there was a trend to decreased ischaemic episodes in the 46% patients who experienced ambulatory ischaemia on Holter monitoring. Six patients stopped trimetazidine and 12 propranolol. Of these, five in each group were withdrawn because of deterioration in cardiovascular status. 5. The results suggest that trimetazidine and propranolol at the doses studied have similar efficacy in patients with stable angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS) Publication Types:
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:
12. Michaelides AP, Spiropoulos K, Dimopoulos K, Athanasiades
D, Toutouzas P. Clin Drug Invest. 1997;13:8–14. |
Figure
1: Significant improvement in exercise test results with trimetazidine.
Figure
2: Trimetazidine significantly reduces the mean number of angina
attacks per week.
Figure
3: Reduction in the mean number of angina attacks per week with
trimetazidine (TIGER study).
the publisher or the sponsor is not responsible for the continued currency of the information,
for any errors or omissions, or for any consequence arising therefrom.
© 2010 Les Laboratoires Servier