Microvascular
angina: a new potential target for trimetazidine?
Dr Pierre Sabouret
Department of Cardiology, Hôpital Pitié-Salpétrière, Paris, France
A 66-year-old female patient presented to the hospital
with 18 min of chest pain and was admitted to the cardiac emergency
ward.
The patient had a history of non-insulin-dependent diabetes mellitus, diagnosed
8 years earlier, and type 2b dyslipidemia (hypercholesterolemia with elevated
low-density and very-low-density lipoproteins associated with hypertriglyceridemia,),
discovered 7 years earlier. She was currently being treated with an oral sulfonylurea
and fenofibrate.
On arrival, the patient received intravenous nitroglycerin, aspirin, low molecular
weight heparin and an oral beta-blocker. Her chest pain resolved, and, on physical
examination, this mildly/moderately obese patient was in no apparent distress.
The 12-lead ECG showed a pattern of ST-segment elevation in the anteroseptal
and apical regions. The creatinine phosphokinase-MB peak was 460 UI/l and troponin
Ic was 2 mg/l (normal value <0.5). Over 4 days, the ST-segment and T-wave
abnormalities resolved.
On coronary angiography, moderate anteroseptal and apical hypokinesis were
seen, consistent with the electrocardiographic diagnosis of a non-Q-wave infarction.
However, the patient had no significant coronary stenosis. The ergotamine test
was negative. Despite this, the etiology of the myocardial infarction was presumed
to be vasospastic in origin and atenolol was replaced by sustained-release
verapamil 240 mg.
Before discharge, an exercise stress test was found positive and accompanied
by exercise-limiting chest pain at 150 W with a maximal heart rate of 154 bpm
(100% of the MPHR) (Figure 1).
Figure 1. Treadmill test no. 1 (treatment with verapamil
alone).
To improve the persistent and activity-limiting
anginal symptoms and improve the patient’s exercise tolerance,
she was started on trimetazidine 20 mg t.i.d.
At the follow-up visit 1 month later, the patient described a marked decrease
in the frequency of her anginal attacks. A second exercise stress test carried
out the same day showed no ischemic ST-T changes. The patient had no chest
pain even at a maximal workload of 150 w and a peak heart rate of 143 bpm (93%
of MPHR) (Figure 2).
Figure 2. Treadmill test no. 2 (treatment with verapamil
and trimetazidine).
Discussion
Epidemiology of coronary heart disease
(CHD) in women
Although young women are relatively immune to cardiovascular disease (CVD),
at least in part because of their hormonal status, CVD has become the major
cause of death in women in developed countries.[1] Coronary
heart disease (CHD) accounts for much of this and occurs on average 7–10 years
later in women than in men.[2,3] Although the frequency of
CHD increases exponentially with age, the rates observed in women are still
lower than those in men. This trend may change somewhat in the future in light
of the increasing number of young female smokers.[4,5]
Although the principal risk factors are the same in both sexes, the prevalence
differs somewhat and the absolute mortality risk associated with each risk
factor is generally lower in women than in men, with the exception of diabetes
mellitus.[6–8]
Diagnosis and clinical pattern of CHD
in women
The clinical presentation and natural history of angina pectoris often differ
between women and men, and the diagnosis in women may be more difficult to
make.[7,9] The Framingham study reported that women are more
likely than men to experience an unrecognized, or silent, myocardial infarction
(MI).[7]
The exercise stress test has been shown to have a lower accuracy for the identification
of coronary artery disease in women than in men, although the basis for this
remains unclear.[10,11] Myocardial perfusion imaging has
also been found to be less specific for the diagnosis of coronary artery disease
in women than in men, largely due to breast attenuation.[12,13]
Furthermore, women are more likely to have syndrome X, defined as the presence
of clinically typical anginal chest pain, as well as evidence of ischemia on
the exercise stress test, in the absence of significant coronary artery disease.[14] Such
was the case for the patient in this report.
Syndrome X
The increased prevalence of syndrome X in women, as well as its reported association
with the menopause, has led to the theory of a hormonal trigger, possibly estrogen
deficiency, which could in turn lead to an imbalance in vasomotor tone involving
the coronary arteries. However, syndrome X is likely a clinical entity of diverse
etiologies and pathophysiological mechanisms. A subset of patients may have
coronary artery disease limited to only small arteries, so-called microvascular
angina. On the initial studies using electron microscopy of coronary biopsies
in patients with syndrome X,[14] many endothelial nuclei
in capillaries were found to be swollen, with an irregular narrowing of the
arterioles and small vessels and proliferating and deformed smooth muscle cells.
Although the pathophysiology of syndrome X is unclear, it is a common problem
for which therapies are needed. One approach to therapy, which we used with
success in this patient, is the metabolic approach using a metabolic agent.
The metabolic approach in stable angina
and syndrome X
A number of recent studies have shown that the metabolic agent, trimetazidine,
is an effective treatment for stable angina pectoris.[15–21] By
specifically inhibiting the long-chain 3-ketoacyl-coenzyme A thiolase, trimetazidine
causes a partial inhibition of fatty acid beta-oxidation.[22] This
leads to an optimization of cardiac metabolism during ischemia and reperfusion,
reducing acidosis and preserving energy production for contractility.
The metabolic approach with trimetazidine in monotherapy has been shown to
be as effective as a beta-blocker (propranolol) in patients with chronic stable
angina.[15] Other studies have demonstrated the value of
adding trimetazidine to another agent (beta-blocker, calcium channel blocker
or long-acting nitrate).[17–21] For example, in combination
with a beta-blocker, trimetazidine has been shown to be more effective than
the combination of a beta-blocker and a long-acting nitrate (isosorbide dinitrate).[17] The
association of trimetazidine with diltiazem is also useful and well tolerated.[18,19] Such
an additive benefit could be anticipated from the distinct mechanism of action
of trimetazidine from the hemodynamic drugs. Furthermore, this benefit occurs
without incurring any unwanted hemodynamic side effects.
Thus, the efficacy of trimetazidine in stable angina pectoris has been well
documented in controlled studies. Trimetazidine may also be beneficial in the
setting of syndrome X, as was the case for this patient. Two recent studies
have reported positive results.
The first study included 35 patients with microvascular angina.[23]
Microvascular angina was defined as typical exertional chest pain and positive
exercise test results (>1 mm ST-segment depression and typical chest pain)
with a completely normal coronary angiogram. None of the patients had hypertension,
left ventricular hypertrophy, cardiomyopathy, coronary artery spasm or conduction
disturbances. The effects of trimetazidine (60 mg daily) were investigated
in a double-blind study comprising two 4-week treatment periods. After a 1-week
washout period, patients received placebo for 4 weeks; after another week of
washout, patients received trimetazidine for 4 weeks. No other drug was prescribed.
Exercise testing was performed at the end of the placebo and trimetazidine
treatment periods. Patients were also studied with the ambulatory ECG monitoring
test before treatment and at the end of both treatment periods. The number
of anginal attacks at the second week and thereafter was significantly decreased
with trimetazidine compared with placebo (P < 0.0001). On treadmill testing,
the time to 1 mm ST-segment depression and total exercise time were significantly
longer in the trimetazidine group, and the maximum ST depression was significantly
less (P < 0.0001, P < 0.0001, P < 0.0005, respectively). Rogacka and
colleagues[24] found similar benefit with trimetazidine on
clinical symptoms and exercise tolerance in 28 patients with syndrome X.
The exact role of trimetazidine in patients with syndrome X remains to be determined,
but there is evidence that trimetazidine may be as beneficial in these patients
as it is in patients with chronic stable angina and coronary artery disease.
CONCLUSION
Even if the precise pathophysiology of microvascular angina remains unclear
and without consensus on its treatment, many investigators believe that coronary
microvascular dysfunction and intracellular metabolic changes are the main
etiologic factors. The metabolic approach with trimetazidine, which is highly
effective in reducing symptoms and improving exercise capacity in chronic stable
angina, may also be useful in certain patients with syndrome X.
REFERENCES
1. World Health Statistics Annuals 1982–1994. Geneva: World
Health Organization, 1982–1994.
-
Comment in:
Contribution of trends in survival and coronary-event
rates to changes in coronary heart disease mortality: 10-year results from
37 WHO MONICA project populations. Monitoring trends and determinants in
cardiovascular disease.
Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H,
Ruokokoski E, Amouyel P.
Cardiovascular Epidemiology Unit (MONICA Quality Control Centre for Event
Registration), University of Dundee, Ninewells Hospital and Medical School,
UK. h.tunstallpedoe@dundee.ac.uk
BACKGROUND: The WHO MONICA (monitoring trends and determinants in cardiovascular
disease) Project monitored, from the early 1980s, trends over 10 years in
coronary heart disease (CHD) across 37 populations in 21 countries. We aimed
to validate trends in mortality, partitioning responsibility between changing
coronary-event rates and changing survival. METHODS: Registers identified
non-fatal definite myocardial infarction and definite, possible, or unclassifiable
coronary deaths in men and women aged 35-64 years, followed up for 28 days
in or out of hospital. We calculated rates from population denominators to
estimate trends in age-standardised rates and case fatality (percentage of
28-day fatalities=[100-survival percentage]). FINDINGS: During 371 population-years,
166,000 events were registered. Official CHD mortality rates, based on death
certification, fell (annual changes: men -4.0% [range -10.8 to 3.2]; women
-4.0% [-12.7 to 3.0]). By MONICA criteria, CHD mortality rates were higher,
but fell less (-2.7% [-8.0 to 4.2] and -2.1% [-8.5 to 4.1]). Changes in non-fatal
rates were smaller (-2.1%, [-6.9 to 2.8] and -0.8% [-9.8 to 6.8]). MONICA
coronary-event rates (fatal and non-fatal combined) fell more (-2.1% [-6.5
to 2.8] and -1.4% [-6.7 to 2.8]) than case fatality (-0.6% [-4.2 to 3.1]
and -0.8% [-4.8 to 2.9]). Contribution to changing CHD mortality varied,
but in populations in which mortality decreased, coronary-event rates contributed
two thirds and case fatality one third. INTERPRETATION: Over the decade studied,
the 37 populations in the WHO MONICA Project showed substantial contributions
from changes in survival, but the major determinant of decline in CHD mortality
is whatever drives changing coronary-event rates.
Publication Types:
PMID: 10334252 [PubMed - indexed for MEDLINE]
-
Risk factors for cardiovascular disease
in women.
Holdright DR.
Department of Cardiology, The Middlesex Hospital, London, UK.
Publication Types:
PMID: 9819013 [PubMed - indexed for MEDLINE]
-
Comment in:
Prognosis after the onset of coronary heart disease.
An investigation of differences in outcome between the sexes according
to initial coronary disease presentation.
Murabito JM, Evans JC, Larson MG, Levy D.
Framingham Heart Study, MA 01701.
BACKGROUND. Differences exist between men and women in prognosis after the
onset of coronary heart disease (CHD). METHODS AND RESULTS. All Framingham
Heart Study subjects with the onset of clinically apparent coronary disease
from 1951 through 1986 were studied to compare prognosis in men and women
according to CHD presentation. Coronary disease presentations included angina,
coronary insufficiency (unstable angina), recognized myocardial infarction,
unrecognized myocardial infarction, and coronary death. Less than 1% of subjects
were lost to follow-up for overall mortality. Cox modeling was used to examine
the sex differences in outcome for each coronary presentation. New nonfatal
coronary disease developed in 750 men (mean age, 63 years) and 583 women
(mean age, 67 years). After onset of angina, men were at greater risk than
women for myocardial infarction (hazards ratio [HR], 2.20; 95% confidence
interval [CI], 1.45 to 3.34) and coronary death (HR, 2.11; 95% CI, 1.32 to
3.36) after adjustment for age and coronary disease risk factors. After a
recognized myocardial infarction, there was a trend toward greater risk for
overall mortality in women than men after adjustment for age and risk factors
(HR, 0.75; 95% CI, 0.53 to 1.08). In contrast, after an unrecognized myocardial
infarction, men were at increased risk for death compared with women (HR,
2.01; 95% CI, 1.28 to 3.15). CONCLUSIONS. Women fare at least as poorly as
men after recognized myocardial infarction, whereas women have a more favorable
outlook than men after the onset of angina or unrecognized myocardial infarction.
The favorable outcome in women after angina and unrecognized myocardial infarction
is due, in part, to greater misclassification of these coronary events in
women than in men.
PMID: 8252666 [PubMed - indexed for MEDLINE]
-
Comment in:
Relation between coronary risk and coronary mortality
in women of the Renfrew and Paisley survey: comparison with men.
Isles CG, Hole DJ, Hawthorne VM, Lever AF.
Dumfries and Galloway Royal Infirmary, UK.
Most epidemiological and intervention studies in patients with coronary artery
disease have focused on men, the assumption being that such data can be extrapolated
to women. However, there is little evidence to support this belief. We have
completed a fifteen-year follow-up of 15,399 adults, including 8262 women,
who lived in Renfrew and Paisley and were aged 45-64 years when screened
between 1972 and 1976. We identified 490 deaths from coronary heart disease
(CHD) in women and 878 in men. Women were more likely to have high cholesterol,
to be obese, and to come from lower social classes than men, but they smoked
less and had similar blood pressures. The relative risk--top to bottom quintile
(95% Cl)--of cholesterol for coronary death after adjustment for all other
risk markers was slightly greater in women (1.77 [1.45,2.16]) than in men
(1.56 [1.32, 1.85]), but absolute and attributable risk were lower. Thus,
women in the top quintile for cholesterol had lower coronary mortality (6.1
deaths per thousand patient years) than men in the bottom quintile (6.8 deaths
per thousand patient years). Moreover, it was estimated that there would
have been only 103 (21%) fewer CHD deaths in women, yet 211 (24%) fewer in
men, if mortality had been the same for women and men in the lowest quintiles
of cholesterol. Trends showing similar relative risks in these women, but
lower absolute and attributable risks than in men, were present for smoking,
diastolic blood pressure, and social class. There was no relation between
obesity and coronary death after adjustment for other risks. Our results
suggest that some other factors protect women against CHD. The potential
for women to reduce their risk of CHD by changes in lifestyle may be less
than for men.
PMID: 1347584 [PubMed - indexed for MEDLINE]
-
Coronary artery disease in women. Risk
factors, evaluation, treatment, and prevention.
Kuhn FE, Rackley CE.
Department of Medicine, Georgetown University Medical Center, Washington,
DC.
Cardiovascular disease is the leading cause of death in women. Unfortunately,
the problem of cardiovascular disease in women has been largely ignored as
women have been enrolled in limited numbers or excluded entirely from many
of the major trials on which treatment of cardiovascular disease have been
based. Furthermore, recent evidence suggests that a gender bias against aggressive
intervention and treatment of cardiovascular disease in women may exist.
This article reviews the risk factors, methods of identification, and treatment
of coronary artery disease in women, as well as the potential benefits of
postmenopausal estrogen.
Publication Types:
PMID: 8250659 [PubMed - indexed for MEDLINE]
7. Stokes JS, Kannel WB, Wolf
PA et al. The relative importance of selected risk factors for
various manifestations of cardiovascular disease among men and
women from 35 to 64 years old: 30 years’ follow-up in the Framingham
study. Circulation 1987; 75 (suppl V): 65–73.
-
Erratum in:
- BMJ 1998 Jun 20;316(7148):1881
Comparison of the prediction by 27 different factors
of coronary heart disease and death in men and women of the Scottish Heart
Health Study: cohort study.
Tunstall-Pedoe H, Woodward M, Tavendale R, A'Brook R,
McCluskey MK.
Cardiovascular Epidemiology Unit, Ninewells Hospital, and Medical School,
Dundee. h.tunstallpedoe@dundee.ac.uk
OBJECTIVE: To compare prediction by 27 different factors in men and women
of coronary heart disease events, coronary deaths, and deaths from all causes.
DESIGN: Cohort study. SETTING: Scottish population study. SUBJECTS: In 1984-7
random sampling of residents aged 40-59 produced 11,629 men and women who
generated survey clinic questionnaires, examination findings, and blood and
urine specimens. MAIN OUTCOME MEASURES: Subsequent death, coronary artery
surgery, and myocardial infarction. Risks were calculated for each category
of factor or fifth of continuous variables. 27 factors were ranked by descending
age adjusted hazard ratio of the top to bottom class in each factor, by sex
and end point. RESULTS: Follow up averaged 7.6 years, during which the 5754
men had 404 coronary events, 159 coronary deaths, and 383 deaths and the
5875 women 177, 47, and 208 respectively. The rankings for factors for the
three end points were mainly similar in men and women, although hazard ratios
were often higher in women. Classical risk factors ranked better for predicting
coronary risk than newer ones. Yet strong prediction of coronary risk was
no guarantee of significant prediction of all cause mortality. Findings included
an anomalous coronary protective role for type A behaviour in women; raised
plasma fibrinogen as a strong predictor of all end points; and an unexpectedly
powerful protective relation of dietary potassium to all cause mortality.
CONCLUSIONS: These initial unifactorial rankings and comparisons must be
interpreted with caution until potential interaction, confounding, and problems
of measurement and causation are further explored.
PMID: 9314758 [PubMed - indexed for MEDLINE]
-
Comment in:
The evaluation of chest pain in women.
Douglas PS, Ginsburg GS.
Harvard-Thorndike Laboratory, Cardiovascular Division, Beth Israel Hospital,
Boston, MA 02215, USA.
Publication Types:
PMID: 8609950 [PubMed - indexed for MEDLINE]
-
Significant sex differences in the correlation
of electrocardiographic exercise testing and coronary arteriograms.
Sketch MH, Mohiuddin SM, Lynch JD, Zencka AE, Runco
V.
Two hundred fifty-one patients (195 male and 56 females) referred for evaluation
of chest pain were studied by multistage submaximal stress testing and selective
coronary arteriography. In men with positive exercise tests the incidence
rate of true positive exercise test results--that is, positive tests associated
with 75 percent of greater coronary stenosis--was 89 percent in contrast
to a 33 percent incidence rate of true positive exercise test results in
women. The incidence rate of false positive excercise test results--that
is, positive tests associated with no coronary stenosis or less than 50 percent
stenosis--was 8 percent in men in contrast to 67 percent in women. Conversely,
the incidence rate of false negative exercise test results (that is, negative
exercise tests associated with 75 percent or greater coronary stenosis) was
higher in men (37 percent) than in women (12 percent). It is concluded that
in men a positive multistage stress test is useful in predicting the presence
of significant coronary artery disease although a negative stress test cannot
be relied upon to rule out the presence of significant disease. In women,
a positive exercise test is of little value in predicting the presence of
significant coronary artery disease, whereas a negative test is quite useful
in ruling out the presence of significant disease. New criteria should be
developed for stress testing of women.
PMID: 1155337 [PubMed - indexed for MEDLINE]
-
Diagnostic value of history and maximal
exercise electrocardiography in men and women suspected of
coronary heart disease.
Detry JM, Kapita BM, Cosyns J, Sottiaux B, Brasseur
LA, Rousseau MF.
PMID: 912834 [PubMed - indexed for MEDLINE]
-
Exercise thallium-201 myocardial scintigraphy
in women: correlation with coronary arteriography.
Friedman TD, Greene AC, Iskandrian AS, Hakki AH, Kane
SA, Segal BL.
PMID: 7081050 [PubMed - indexed for MEDLINE]
-
Comment in:
Differences in the use of procedures between women and
men hospitalized for coronary heart disease.
Ayanian JZ, Epstein AM.
Department of Medicine, Brigham and Women's Hospital, Boston, MA.
BACKGROUND AND METHODS. Previous studies at individual hospitals have reported
differences in the use of major diagnostic and therapeutic procedures for
women and men with coronary heart disease. To assess whether these differences
can be generalized, we performed retrospective analyses of coronary angiography
and revascularization (coronary-artery bypass surgery or percutaneous transluminal
coronary angioplasty) in women and men hospitalized for coronary heart disease
in 1987, using abstract data on 49,623 discharges in Massachusetts and 33,159
discharges in Maryland. We used multiple logistic regression to estimate
the adjusted odds of the use of a procedure, controlling for principal diagnosis,
age, secondary diagnosis of congestive heart failure or diabetes mellitus,
race, and insurance status. RESULTS. The adjusted odds of undergoing angiography
were 28 percent and 15 percent higher for men than for women in Massachusetts
and Maryland, respectively (95 percent confidence intervals for the odds
ratios, 1.22 to 1.35 and 1.08 to 1.22). The respective adjusted odds of undergoing
revascularization were 45 percent and 27 percent higher for men than for
women (95 percent confidence intervals, 1.35 to 1.55 and 1.16 to 1.40). Because
these differences could be related to differing thresholds for hospital admission,
we performed a second analysis limited to patients with diagnosed acute myocardial
infarction (11,865 discharges in Massachusetts and 6894 discharges in Maryland),
a group in which all patients would be expected to receive hospital care.
The male-to-female odds ratios in both states remained similar in magnitude
and were statistically significant for angiography and revascularization.
CONCLUSIONS. These findings demonstrate that women who are hospitalized for
coronary heart disease undergo fewer major diagnostic and therapeutic procedures
than men. These differences may represent appropriate levels of care for
men and women, but it is also possible that they reflect underuse in women
or overuse in men. Further study should assess the cause of these differences
and their effect on patients' outcomes.
PMID: 2057022 [PubMed - indexed for MEDLINE]
14. Schlant RC, Alexander RW.
Diagnosis and management of patients with chronic ischemic heart
disease. In: Alexander W, Schlant R, Fuster V, eds. Hurst’s the
heart. 9th ed. New York: McGraw-Hill, 1998; 1275–1305.
-
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:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 8198938 [PubMed - indexed for MEDLINE]
-
-
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:
- Clinical Trial
- Randomized Controlled Trial
PMID: 9781975 [PubMed - indexed for MEDLINE]
17. Michaelides AP, Spiropoulos K, Dimopoulos K et al. Antianginal
efficacy of the combination of trimetazidine-propranolol compared with isosorbide
dinitrate-propranolol in patients with stable angina. Clin Drug Invest 1997;
13: 8–14.
-
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:
- Clinical Trial
- Randomized Controlled Trial
PMID: 9404250 [PubMed - indexed for MEDLINE]
-
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:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 7645522 [PubMed - indexed for MEDLINE]
20. Efficacy and tolerance of
trimetazidine in combination one of the antianginal drugs in
patients with stable effort angina. Diagnostyka i Leczenie w
Kardiologii 1997; 4: 237–247.
21. Szwed H, Sadowski Z, Pachocki R et al. Trimpol II — multicenter
study. Efficacy and safety of trimetazidine in patients with stable angina
pectoris under beta-blocker therapy. Preliminary results. Eur Heart J 1999;
20: 478.
-
Comment in:
The antianginal drug trimetazidine shifts cardiac energy
metabolism from fatty acid oxidation to glucose oxidation by inhibiting
mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD.
Cardiovascular Research Group and the Division of Pediatric Cardiology, University
of Alberta, Edmonton, Canada.
Trimetazidine is a clinically effective antianginal agent that has no negative
inotropic or vasodilator properties. Although it is thought to have direct
cytoprotective actions on the myocardium, the mechanism(s) by which this
occurs is as yet undefined. In this study, we determined what effects trimetazidine
has on both fatty acid and glucose metabolism in isolated working rat hearts
and on the activities of various enzymes involved in fatty acid oxidation.
Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL
insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain
lengths. Both glucose and fatty acids were appropriately radiolabeled with
either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and
fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption
or cardiac work under any aerobic perfusion condition used. In hearts perfused
with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the
rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1)
x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation
from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05).
In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210%
increase in glucose oxidation rates. In both aerobic and ischemic hearts,
glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine
on glucose oxidation were accompanied by a 37% increase in the active form
of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation.
No effect of trimetazidine was observed on glycolysis, glucose oxidation,
fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was
substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting
that trimetazidine directly inhibits long-chain fatty acid oxidation. This
reduction in fatty acid oxidation was accompanied by a significant decrease
in the activity of the long-chain isoform of the last enzyme involved in
fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity
(IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess
of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain
forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown
that inhibition of fatty acid oxidation and stimulation of glucose oxidation
can protect the ischemic heart. Therefore, our data suggest that the antianginal
effects of trimetazidine may occur because of an inhibition of long-chain
3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid
oxidation and a stimulation of glucose oxidation.
PMID: 10720420 [PubMed - indexed for MEDLINE]
-
The Effect of Trimetazidine in the Treatment
of Microvascular Angina.
Nalbantgil S, Altintiğ A, Yilmaz H, Nalbantgil
I I, Onder R.
Ege University Medical School, Cardiology Department, Izmir, Turkey
Although the pathophysiology of microvascular angina is unclear, intracellular
metabolic changes are believed to be the main factors. Trimetazidine has
an intracellular metabolic effect in coronary insufficiency. The effect of
trimetazidine in microvascular angina is unknown. Thirty-five patients (8
men, 27 women, age 36-57 years, mean 43.9 +/- 6.4 years) with microvascular
angina were included in this study. The effects of trimetazidine (60 mg daily)
were investigated in a placebo-controlled, double-blind study consisting
of two 4-week treatment periods. Patients were assessed by symptom-limited
exercise testing (Bruce protocol). Heart rate and systolic blood pressure
at rest, peak exercise, and the time of 1 mm ST segment depression were not
significantly different between placebo and trimetazidine treatment. Trimetazidine
prolonged total exercise time and time to 1 mm ST depression compared with
placebo. Maximum ST depression was less in patients with trimetazidine therapy
than those with placebo. It is concluded that trimetazidine has a beneficial
effect in cases with microvascular angina.
PMID: 9826407 [PubMed - as supplied by publisher]
-
Effects of trimetazidine on clinical symptoms
and tolerance of exercise of patients with syndrome X: a
preliminary study.
Rogacka D, Guzik P, Wykretowicz A, Rzezniczak J, Dziarmaga
M, Wysocki H.
Department of Internal Medicine, University School of Medical Sciences, Poznan,
Poland.
BACKGROUND: Trimetazidine diminishes angina and improves tolerance of exercise
of patients with ischemic heart disease, and has no influence on blood pressure
and heart rate. OBJECTIVE: To determine the effect of trimetazidine on angina
symptoms and exercise tolerance in patients with syndrome X. METHODS: We
investigated the effect of trimetazidine on the clinical symptoms and tolerance
of exercise of 34 patients (20 women and 14 men, aged 32-60 years) with syndrome
X (angina pectoris, positive result of exercise test, and normal coronary
angiogram). The exercise test was performed before initiation of oral administration
of trimetazidine therapy (20 mg three times a day) and 1 and 6 months thereafter.
RESULTS: We obtained negative results of exercise treadmill tests for four
patients (11.76%) after 1 month and five patients (14.71%) after 6 months
of trimetazidine treatment. There was also a decrease in the incidence of
effort angina after 6 months of treatment (26 patients or 76.47% before treatment
versus 13 patients or 38.23% after 6 months of treatment). The drug had no
significant influence on the heart rate and blood pressure. The duration
for which patients could exercise was significantly prolonged by 1 month
(652.9 +/- 206.2 versus 563.4 +/- 190.4 s, P = 0.0047) and 6 months (650.3
+/- 207.8 s, P = 0.0094) of treatment with trimetazidine. CONCLUSION: Treatment
with trimetazidine decreases signs of angina during exercise and improves
tolerance of exercise of patients with syndrome X.
Publication Types:
PMID: 10758819 [PubMed - indexed for MEDLINE]
|
