Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease

Cristiana Vitalea, Mauricio Wajngatena,b, Barbara Sposatoa, Otavio Gebaraa,b, Paola Rossinia, Massimo Finia, Maurizio Volterrania and Giuseppe M.C. Rosanoa,*

a Cardiovascular Research Unit, Department of Medical Sciences, San Raffaele — TOSINVEST SANITA', via della Pisana 235, 00139 Roma, Italy
b Department of Geriatric Cardiology, InCOR, University of Sao Paulo Medical School, Sao Paulo, Brazil

Received December 1, 2003; revised June 13, 2004; accepted June 17, 2004 * Corresponding author. Tel.: +39-3358097652/6-660581; fax: +39-6-66058300 (E-mail: giuseppe.rosano{at}sanraffaele.it).

See page 1765 for the editorial comment on this article (doi:10.1016/j.ehj.2004.08.019)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
AIM: Elderly patients have an increased incidence of ischaemic dilated cardiomyopathy often related to diffuse coronary artery disease. Trimetazidine protects ischaemic myocardium by improving the myocardial energy utilisation during myocardial ischaemia. Aim of the present study was to evaluate the effects of trimetazidine on left ventricular (LV) function in elderly patients with ischaemic heart disease and reduced LV function.

METHODS: Forty seven elderly patients (40 males and 7 females, mean age 78±3 years) were randomised to receive, in addition to standard therapy, either trimetazidine or placebo and were evaluated by echocardiography at baseline and after 6 months.

RESULTS: Trimetazidine and placebo had no effect on either blood pressure or heart rate (SBP 2±5 vs 4±6 mmHg, DBP –1±6 vs 3±4 mmHg, HR –3±7 vs 5±9 bpm, trimetazidine and placebo compared to baseline, respectively). At the end of the study patients randomised to trimetazidine showed a significant greater left ventricular function and smaller left ventricular diastolic and systolic diameters and volume indices compared to patients receiving placebo (LVEF: 34.4±2.3% vs 27±2.8%, p<0.0001; LVEDD: 58.6±1.9 mm vs 64±1.7 mm, p<0.0001; LVESD: 44.5±1.1 vs 50±0.8 mm, p<0.0001). A significant smaller wall motion score index was detected in trimetazidine-treated patients compared to those allocated to placebo (1.24±0.12 vs 1.45±0.19, p<0.01), the percentage change in LVEF compared to baseline was also significantly greater in trimetazidine-treated patients. Diastolic function significantly improved in the trimetazidine group while it remained unchanged in the placebo group. At follow-up evaluation, patients receiving trimetazidine showed a greater improvement in angina and NYHA class than patients allocated to placebo. Quality of life significantly improved in all patients treated with trimetazidine while remained unchanged in those allocated to placebo.

CONCLUSION: In elderly patients with ischaemic cardiomyopathy trimetazidine in addition to standard medical therapy has a beneficial effect on LV systolic and diastolic function, and improves quality of life.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The prevalence of coronary artery disease (CAD) increases with advancing age representing the major cause of mortality, morbidity and disability in the elderly.1 Compared to younger patients with CAD, elderly patients have a higher incidence of multi-vessel coronary disease, often with coronary stenotic lesion on distal arteries.2,3 Because of the diffuse distribution of coronary atherosclerosis and the diffuse reduction of coronary blood flow and reserve, elderly patients often show a decrease in left ventricular function or an inability to adjust left ventricular performance to meet the peripheral metabolic needs.3—5 Furthermore, because of the frequent presence of co-morbidities, elderly patients with coronary artery disease are often excluded from revascularisation procedures, leaving medical treatment as the only approach.6

Conventional anti-anginal therapy improves myocardial ischaemia through haemodynamic mechanisms and although haemodynamic drugs are often used in combination, there is conflicting evidence about superiority of efficacy of combination treatment over monotherapy.7—10 In the elderly, haemodynamic combination therapy is often associated with a higher risk of drug-interaction,11 and higher incidence of significant adverse effects that are dependent not only upon their haemodynamic action but also to altered pharmacokinetics, renal and hepatic function.11,12

Cardiac metabolic agents directly modify the use of energy substrates in the heart. Amongst this class of drugs, trimetazidine improves angina and myocardial ischaemia either in monotherapy or in association with haemodynamic agents through an inhibition of cardiac fatty acid oxidation.13,14 In diabetic patients the improvement of cardiac energy production by trimetazidine improves myocardial contractile function in areas of myocardium with reduced perfusion leading to a global improvement of left ventricular function.15,16 However, at present, it is not clear whether the improvement in cardiac metabolism, seen with trimetazidine in patients with diabetic cardiomyopathy, also occurs in elderly patients with coronary artery disease or is just related to the improvement of myocardial glucose metabolism typical of diabetic patients. Therefore, the aim of the present study was to evaluate the effect of a 6 month therapy with trimetazidine in addition to standard cardiovascular therapy on left ventricular function and quality of life of elderly patients with coronary artery disease and reduced left ventricular function.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study population
The study population included 62 elderly patients (mean age 78±3) with chronic stable angina on optimal medical therapy. Recruited for the study were those aged 65 years or over, with proven coronary artery disease by either coronary angiography or previous myocardial infarction or hospitalisation for unstable angina, a good acoustic window, a left ventricular function <50%.

Patients with clinically significant findings on physical exam or presence of known disease that would interfere with study evaluation, recent (<3 months) unstable angina and/or acute myocardial infarction, arrhythmia (Lown IV), cardiac surgery, PCI, stroke or TIA in the previous 6 months, presence of cardiac conduction abnormalities that would prejudice the evaluation of regional left ventricular function as those with inadequately controlled arterial hypertension (blood pressure >160/95 mmHg), uncorrected hypokalemia, kidney or liver dysfunction (creatinine levels >3 mg/dl; AST, ALT and γGT levels not higher than three times normal values); primary valvular, myocardial, pericardial or endocardial disease were excluded from the study. Patients with history of intolerance or allergic response to the study drug and those unable to comply with the protocol or refusing the exam related to end-point and those scheduled to undergo myocardial revascularisation procedures were also excluded.

During the study period patients' therapies routinely used for the treatment of myocardial ischaemia (e.g. acetylsalicylic acid, anti-platelet drugs, anti-coagulants, hypolipidaemic agents, anti-anginal therapy) and heart failure were continued.

Study design
The study design was randomised, parallel, and placebo controlled. After a baseline evaluation of all inclusion and exclusion criteria and optimisation of medical therapy, all suitable patients entered a four week run-in phase to ensure clinical stability, at the end of which patients underwent a baseline echocardiogram and filled in a visual analogue scale of quality of life and entered the double-blind study and were randomised to receive either trimetazidine (20 mg t.d.s.) or matching placebo (t.d.s.) for 6 months, in addition to their baseline therapy.

The transthoracic echocardiogram and the quality of life questionnaire were obtained at the end of each treatment period. Patients received a diary card to report the occurrence of episodes of chest pain and use of GTN tablets.

Study of left ventricular function
All patients underwent transthoracic echocardiogram according to the guidelines of the American Society of Echocardiography, using the parasternal and the apical views to calculate dimensions and evaluate global and regional left ventricular function.

Image analysis. All echocardiograms were stored on videotape or into electronic files for subsequent off-line reading. The echocardiograms were analysed by two experienced investigators blinded to clinical data. In case of discrepancy, a third investigator analysed the exam.

Left ventricular end-diastolic and end-systolic diameters were obtained from the parasternal long-axis view. A biplane algorithm was used to calculate left ventricular volumes. Left ventricular end-diastolic volume and end-systolic volumes were obtained from the apical four- and two-chamber views using a modified Simpson's rule, from which ejection fraction was automatically calculated as the difference between end-diastolic volume and end-systolic volume normalised to end-diastolic volume. For patients in atrial fibrillation, the mean of six consecutive evaluations of ventricular diameters and volumes were used for analysis.

Regional left ventricular function was evaluated according to the guidelines of the American Echocardiographic Society using a 16-segment model. Each segment of interest was visually graded using a semi-quantitative scoring system, where 1=normal, 2=hypokinetic, 3=akinetic and 4=dyskinetic. A global wall motion score index (WMSI) was derived for the entire left ventricle using the sum of individual scores divided by the total number of analysed segments.

Quality of life
All patients were administered at baseline and, at follow-up examination, given a vertical visual analogue scale to test their quality of life. The visual analogue scale was a 10 cm line with a mark at each centimetre. Each mark was numbered from 0 to 10. Patients were asked to score with a cross on the line their present quality of life with 0 being the worst ever and 10 being the best ever. The site of the cross was then measured with a ruler in order to convert the visual analogue mark into a measure in mm.11

Statistical analysis
Values are given as mean±1SD or as percentages where appropriate. Differences in mean values between groups were assessed using either the two-tailed Student's t test (parametric variables) or Mann—Whitney U test (for non-parametric variables). The treatment in echocardiographic parameters relative to respective pre-treatment values between groups were analysed using the analysis of covariance for repeated measurements using baseline values as constant covariates. Primary end-points of the study were left ventricular ejection fraction and wall motion score index; secondary endpoints were quality of life left ventricular diastolic diameters and volumes and diastolic function. All calculated p values are two-tailed and considered as significant when <0.05.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
From a total of 62 elderly patients with CAD screened 47 (40 men, 7 women, mean age 78±3 years) met the inclusion criteria and entered the study. Nine patients were excluded because they were scheduled to undergo either percutaneous or surgical myocardial revascularisation procedures, three because of elevated liver enzymes, two because of the presence of a cardiac pacemaker and one because unable to attend the follow-up examination. Patients randomised to trimetazidine or placebo had similar clinical and angiographic characteristics (Table 1). The majority of patients had multi-vessel coronary atherosclerosis often with involvement of peripheral branches. Fourteen patients were taking statins at baseline examination, in eight of which it was necessary to either adjust the dose or change statin therapy, the remaining 33 patients were newly started on statin therapy. No difference in the adjustment of dose or new use of statins was found between patients allocated to trimetazidine or placebo (18 vs 23). Use of cardiovascular drugs at randomisation was similar in the two groups (Table 1). Baseline echocardiographic characteristics were also similar in the two groups (Table 2). Compared to the baseline evaluation treatment, trimetazidine and placebo did not affect blood pressure nor heart rate (SBP 2±5 vs 4±6 mmHg, DBP –1±6 vs 3±4 mmHg, HR –3±7 vs 5±9 bpm, trimetazidine vs placebo, respectively). Trimetazidine did not affect electrocardiographic parameters such as PR, QRS and QT intervals and was well tolerated throughout the study. Follow-up examination was performed in 44 patients, one patient in the trimetazidine group and two in the placebo group reported nausea after the administration of the study drug but all of them completed the study protocol after being instructed to take the drug after meals. Two patients allocated to placebo were not studied at follow-up because they were hospitalised because of cardiac causes at the time of scheduled follow-up study. One patient allocated to trimetazidine could not attend follow-up examination because of immobilisation following hip fracture. No patient reported significant side-effects during the study. During the study period, patients allocated to placebo had a higher incidence of cumulative cardiovascular events compared to patients receiving trimetazidine (Table 3).


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Table 1. Clinical features of study patients
 

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Table 2. Baseline and follow-up echocardiographic parameters in patients randomised to trimetazidine or placebo
 

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Table 3. Incidence of cardiovascular events and hospitalisation during study period in patients allocated to trimetazidine or placebo
 
After 6 months, symptomatic patients for angina treated with trimetazidine showed a significant improvement in the number of anginal episodes and a significant decrease in the number of nitroglycerin tablets used while no significant changes were observed in patients receiving placebo (Fig. 1). At the end of the study, patients randomised to trimetazidine showed a significant greater left ventricular function and smaller left ventricular diastolic and systolic diameters and volume indices compared to patients receiving placebo (LVEF: 34.4±2.3% vs 27±2.8%, p<0.0001; LVEDD: 58.6±1.9 mm vs 64±1.7 mm, p<0.0001; LVESD: 44.5±1.1 vs 50±0.8 mm, p<0.0001, Table 2).



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Fig. 1 Effect of 6-month therapy with trimetazidine or placebo on anginal episodes and number of nitroglycerin tablets used. Trimetazidine significantly reduced both the number of anginal episodes and the nitroglycerin consumption compared to both baseline examination and placebo. TMZ, trimetazidine; PBO, Placebo.

 
At the end of the study a significant smaller wall motion score index and a greater change from baseline was detected in trimetazidine-treated patients compared to those allocated to placebo (1.24±0.12 vs 1.45±0.19, p<0.01 and –0.1±0.06 vs +0.06±0.09 p<0.01)

Furthermore, compared to placebo, a significant difference in the change of left ventricular end-diastolic volume and end-systolic volume indices were found in patients allocated to trimetazidine (–3.9+2.1 ml/m2, vs +2.3±0.8 ml/m2 p<0.001 and –2.4+0.8 ml/m2, vs +0.45±0.2 ml/m2 p<0.005, respectively). Fig. 2 shows individual changes in LVEF in patients allocated to trimetazidine or placebo. No difference in the improvement in left ventricular systolic and diastolic function was noted between patients with or without a previous myocardial infarction. Also, the improvement in LVEF after trimetazidine was similar in all NYHA classes and in quartiles of baseline LVEF. Left ventricular diastolic function was significantly improved by trimetazidine compared to placebo (Table 4). The treatment effect of trimetazidine compared to placebo on LVEF, WMSI and left ventricular diameters is shown in Fig. 3.



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Fig. 2 Effect of 6-month therapy with trimetazidine or placebo on top of usual medical care in elderly patients with ischemic cardiomyopathy. Trimetazidine significantly improved left ventricular ejection fraction while a trend towards a decline in left ventricular function was noted in patients taking placebo.

 

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Table 4. Doppler parameters of left ventricular diastolic function at baseline and follow-up examination in patients allocated to trimetazidine or placebo
 


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Fig. 3 Treatment effect of 6-month therapy with trimetazidine or placebo on % change in LVEF, WMSI and left ventricular diameters. The treatment effect is shown as median together with 25—75% Confidence Intervals.

 
At follow-up evaluation, patients receiving trimetazidine showed a greater improvement in angina and NYHA class than patients allocated to placebo (Table 5). Quality of life was assessed by the visual analogue scale in all patients attending last follow-up exhamination and significantly improved in all patients treated with trimetazidine (n=22) while remained unchanged in those (n=22) allocated to placebo (Fig. 4).


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Table 5. Change in NYHA and Canadian classes between baseline and follow-up examination in patients allocated to trimetazidine or placebo
 


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Fig. 4 Effect of 6-month therapy with trimetazidine or placebo on quality of life in elderly patients with ischaemic cardiomyopathy. A significant improvement in the visual-analogue self-report on quality of life was detected in patients receiving trimetazidine while no change was noted in patients allocated to standard care and placebo.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The present study shows that the adjunct of trimetazidine to standard optimal medical therapy improves reverse remodelling of chronically dysfunctional myocardium and improves cardiac symptoms and quality of life in elderly patients with coronary artery disease. We believe that our data suggest that the adjunct of targeted cardiac metabolic therapy to usual anti-ischaemic care improves the mechanical efficiency of areas of viable myocardium.

The effects seen in patients receiving trimetazidine are most probably related to an improved efficiency of myocardial cells suffering from chronic hypoperfusion because of the anatomic and metabolic features of coronary artery disease in elderly patients. Indeed, in the elderly, coronary artery disease is more likely to be diffuse and severe and left ventricular performance may be reduced on the basis of regionally ischaemic or hibernating myocardium rather than irreversibly infarcted myocardium. The structural and metabolic alterations of myocardial cells consequent to chronic reduction in blood flow may be reversed by the trimetazidine-induced improvement of glucose utilisation even in the presence of chronic reduction of blood flow. Indeed, the anti-ischaemic effect of trimetazidine is obtained at the cellular level by shifting the energy substrate from fatty acid to glucose. This effect, obtained trough an inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase,13 leads to a reduction of myocardial ischaemia and to an improvement in cardiac efficiency.14

The improvement of LV function with trimetazidine seen in the present study may be related to the effect of this drug towards a more efficient utilisation of glucose in areas of myocardium with reduced oxygen availability as also suggested by the improvement of the wall motion index score. In the present study, the improvement in reverse remodelling was similar in patients with or without limiting angina suggesting that the effect we found is to be related more to a direct improvement in glucose utilisation and consequent increase in contractility than to an improvement in angina. Our data are in agreement with those of Belardinelli et al.17 and those of Lu et al.,18 that found an acute improvement of left ventricular function of chronically dysfunctional myocardium during dobutamine test in patients with ischaemic cardiomyopathy treated with trimetazidine, but neither of the two studies have evaluated the chronic effect of trimetazidine on left diastolic ventricular function of elderly coronary patients. The importance of fatty acid inhibition in the improvement of left ventricular function is also supported by recent findings of Sabbah et al., which found that ranolazine, another metabolic modulator increased left ventricular ejection fraction without increasing myocardial oxygen demand in a chronic ischaemic dog model.19

The acute and chronic effect of trimetazidine on reverse remodelling seen in the present as in other studies 15—18 are most probably also related to the anti-ischaemic effect of trimetazidine.20—23 Since the anti-ischaemic effect achieved by trimetazidine is independent of changes in the oxygen supply-to-demand-ratio no significant changes in heart rate or blood pressure have been observed in this as in other studies with this drug.15,23

An important finding of the present study is the improvement of diastolic function after chronic trimetazidine. The natural aging process coupled with coronary artery disease and LV dysfunction alters diastolic function and progressively decreases ventricular compliance.4,24—26 In the elderly, left ventricular diastolic dysfunction is highly prevalent and has prognostic importance as it is generally associated with high morbidity and incidence of heart failure even in the presence of preserved left ventricular systolic function.24—26

In the present study the improvement of left ventricular function was paralleled by a similar improvement in left ventricular diastolic compliance as assessed by Doppler flow parameters. This effect on left ventricular diastolic function of trimetazidine may also be related to the metabolic anti-ischaemic effect of trimetazidine on chronically hypoperfused myocardium.

The effect of trimetazidine on left ventricular reverse remodelling in elderly patients may have prognostic implications as left ventricular systolic function is one of the most important determinants of long-term outcome in patients with coronary artery disease 27 and abnormalities in left ventricular diastolic filling are independently predictive of future development of congestive heart failure in elderly subjects even without clinically evident coronary artery disease.28 Although the present study was not designed to assess the incidence of clinical events, a trend towards a decrease in cumulative cardiovascular events and need of hospitalisation was noted in patients treated with trimetazidine.

The effect of trimetazidine on reverse remodelling may explain its effect on quality of life. The improvement in ventricular performance may cause a reduction in symptoms and an improvement in functional capacity and quality of life while, the absence of systemic haemodynamic effects, explain the elevated compliance to study. The quality of life may have been positively affected by the effect of trimetazidine on diastolic function since patients with diastolic dysfunction have a marked limitation in exercise tolerance because of the limited ability to use the Frank-Starling mechanism. The improvement of diastolic function reduces effort-induced dyspnoea and increases functional capacity. Another mechanism through which trimetazidine may improve quality of life is the increase in muscle strength related, in part, to the improved haemodynamic conditions and in part to a direct effect of the drug on skeletal muscle.

One major limitation of the present study is the lack of follow-up data on plasma BNP levels but, while the role of BNP in the diagnosis of heart failure is well established, its importance for monitoring the effectiveness of therapy has been suggested only recently and was not clear when the study was planned. However, the present study was designed to evaluate the effect of therapy on echocardiographic parameters and quality of life that are independent from the variations of BNP levels.

In conclusion, adjunctive therapy with trimetazidine to standard care of elderly patients with ischaemic cardiomyopathy improves reverse remodelling and quality of life suggesting that metabolic therapy may be particularly useful in these patients. Longer-term trials are necessary to determine whether trimetazidine will be effective in reducing cardiovascular event rates and incidence of heart failure in elderly patients with coronary artery disease.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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