IJCA-15500; No of Pages 4

International Journal of Cardiology xxx (2012) xxxxxx

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Efcacy of trimetazidine on functional capacity in symptomatic patients with stable

exertional angina The VASCO-angina study
Cristiana Vitale a, Ilaria Spoletini a, Walter Malorni b, c, Pasquale Perrone-Filardi d,
Maurizio Volterrani a, Giuseppe M.C. Rosano a,
a

Department of Medical Sciences, IRCCS San Raffaele Pisana, Rome, Italy

Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanit, Rome, Italy
San Raffaele Institute, Sulmona, L'Aquila; Italy
d
Department of Cardiology, Universit Federico II, Napoli, Italy
b
c

a r t i c l e

i n f o

Article history:
Received 12 July 2012
Received in revised form 29 October 2012
Accepted 1 November 2012
Available online xxxx
Keywords:
Trimetazidine
Myocardial ischemia
Angina
Exercise performance
Heart disease
Exercise testing

a b s t r a c t
Background/objectives: Trimetazidine (TMZ) is a metabolic agent of proven efcacy in improving myocardial
ischemia and angina. VASCO, a randomised double-blinded, placebo-controlled trial, assessed anti-anginal efcacy and safety of standard and high dose of modied-release TMZ (70 mg/d and 140 mg/d) in symptomatic and asymptomatic patients with chronic ischemic heart disease receiving background atenolol 50 mg/d
on exercise test parameters.
The VASCO-angina study assessed the efcacy of the two doses of TMZ on total exercise duration (TED) and
time to 1-mm ST segment depression (T1), in symptomatic patients with chronic stable angina receiving
background atenolol treatment.
Methods and results: In the all cohort of chronic stable angina patients TMZ signicantly improved TED compared to baseline and to placebo. Both doses of TMZ signicantly increased TED (p = 0.0044 and p = 0.0338
for TMZ 140 mg/d and TMZ 70 mg/d, respectively). A greater TED improvement was observed in TMZ
140 mg/d than in TMZ 70 mg/d, although the difference was not signicant. Amongst patients with limiting
angina during exercise test, both doses of TMZ signicantly improved both T1 and TED. No difference in serious adverse events was noted between TMZ and placebo.
Conclusions: The VASCO-angina gives evidence for the efcacy and tolerability of standard and high dose of
TMZ in improving effort-induced myocardial ischemia and functional capacity in patients with chronic stable
angina receiving background beta-blockers.
2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Trimetazidine (TMZ) is an inhibitor of free fatty acids (FFA) oxidation that shifts cardiac and muscle metabolism from FFA to glucose
utilisation resulting into a greater production of high-energy phosphates and into an anti-ischemic effect [13]. Earlier studies have
shown that TMZ improves myocardial ischemia, exercise performance
and symptoms in patients with coronary artery disease and in those
with peripheral arterial disease [48]. Placebo-controlled studies have
proven the anti-ischemic effect of TMZ at the dose of 20 mg tid or

Authors take responsibility for all aspects of the reliability and freedom from bias of
the data presented and their discussed interpretation.
Corresponding author at: Centre for Clinical & Basic Research, IRCCS San Raffaele
Pisana, via della Pisana, 235, 00163 Rome, Italy. Tel.: + 39 06 52252409; fax: + 39 06
52252465.
E-mail address: giuseppe.rosano@sanraffaele.it (G.M.C. Rosano).

35 mg modied release (MR) bid either in monotherapy or in combination with common anti-anginal drugs [5,916]. Previous meta-analyses
[4,1719] have conrmed that the effect of TMZ is comparable to that of
common anti-anginal drugs both in monotherapy and in combination
with heart rate reducing agents.
Despite the wealth of data on the anti-anginal and anti-ischemic effect of TMZ 20 mg, evidence on the efcacy of TMZ 35 mg MR in patients with effort-induced myocardial ischemia receiving beta-blockers
is still lacking. Furthermore, it is not clear whether higher doses of
TMZ may exert a greater anti-ischemic effect than those currently approved for the treatment of angina, based on bioequivalence with the
doses of 20 mg.
The VASCO study was a 12-week randomised double-blind, placebocontrolled trial aimed at assessing the anti-anginal efcacy and safety of
2 doses of TMZ MR (TMZ 70 mg/d, TMZ 140 mg/d) in 1962 coronary
patients with and without angina receiving atenolol 50 mg/d [19]. The
VASCO-angina study assessed the efcacy of the two doses of TMZ in
the patients reporting effort-induced angina despite treatment with
atenolol.

0167-5273/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijcard.2012.11.001

Please cite this article as: Vitale C, et al, Efcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina The
VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001

C. Vitale et al. / International Journal of Cardiology xxx (2012) xxxxxx

Table 1
Baseline clinical features of patients from the VASCO-angina study and the VASCO trial.
VASCO-angina study

Age (years)
Gender (male)
Body mass index
Physical activity (regular/occasional)
Smoking habit
Diabetes mellitus
Duration of angina pectoris (months)
Mean number of angina attacks/week
Mean number of SAN/week
Time to angina onset during ETT (s)
HR at rest
HR at peak of exercise (bpm)
RPP at rest (bpm.mm Hg)
RPP at peak exercise(bpm.mm Hg)
Maximum ST depression (mm)
Total exercise duration (s)
Time to 1-mm ST segment depression (s)

VASCO trial

TMZ MR 70 mg/day
(n = 249)

TMZ MR 140 mg/day

(n = 260)

Placebo
(n = 136)

All patients
(n = 645)

All patients
(n = 1962)

59.9 8.2
225 (90.4%)
27.3 3.4
221 (88.8%)
50 (20.1%)
37 (14.9%)
68.8 74.5
5.3 4.8
3.1 4.4
295.2 103.3
67.9 12.0
119.8 17.6
8506.2 1665.4
19293.1 3824.3
1.56 0.42
402.1 113.2
337.7 113.1

59.7 8.2
218 (83.9%)
28.0 3.5
239 (91.9%)
60 (23.1%)
36 (13.9%)
59.7 67.2
6.2 6.4
3.6 5.3
271.9 97.8
67.7 11.1
117.7 15.6
8553.2 1617.3
18947.8 3695.0
1.55 0.39
375.0 109.5
313.0 103.7

59.6 8.2
120 (88.2%)
27.9 3.8
117 (86.0%)
23 (16.9%)
24 (17.7%)
58.2 56.3
5.8 6.8
3.4 6.5
318.4 111.3
67.8 11.6
122.2 16.6
8653.3 1836.3
20345.0 4156.8
1.53 0.43
420.3 107.1
354.4 108.8

59.7 8.2
563 (87.3%)
27.7 3.5
577 (89.5%)
133 (20.6%)
97 (15.0%)
62.9 68.1
5.8 6.0
3.4 5.3
290.7 104.3
67.8 11.5
119.5 16.7
8556.2 1682.2
19376.4 3875.8
1.55 0.41
395.0 111.7
331.3 109.5

60.4 8.2
1685 (85.9%)
27.5 3.4
1701 (86.7%)
354 (18.0%)
303 (15.4%)
57.9 61.6
5.2 6.6
3.2 5.7
305.0 107.4
68.1 11.3
122.4 16.7
8640 1685
20126 4098
1.61 0.47
420.1 114.3
343.5 112.1

Bpm, beats per minute; ETT, exercise test; HR, heart rate; RPP, rate pressure product; SAN, short-acting nitrates.
Results are expressed as mean standard deviation.
2. Methods
The methods of the VASCO trial are described in detail elsewhere [19]. Briey, 203
active centres located in 13 countries participated in the study. Of the 4755 patients
that attended the selection visit, 4705 were enrolled into the run-in period during
which they were treated with atenolol 50 mg/d, and 1962 patients were randomised
to the active treatment phase during which they were treated with add-on TMZ MR
70 mg (35 mg/d), TMZ MR 140 mg (70 mg/d), or placebo b.i.d.
A total of 1907 patients completed the study (633 in the TMZ MR 70 mg group,
641 in the TMZ MR 140 mg group, and 633 in the placebo group). A central
randomisation procedure was utilised, a stochastic minimisation following the Pocock
method [20,21] was also used. The randomisation was balanced between groups and
stratied on the following factors: country, documentation of the coronary artery disease or not, age ( or >65 years), presence of diabetes or not, and ventricular dysfunction (LVEF b or 40% or not available). Reasons for withdrawal were similar among
treatment groups: adverse event (n = 25), non-medical reason (n = 23) and protocol
deviation (n = 7). No difference in the occurrence of adverse events was observed
amongst groups.
The VASCO-angina study coordinated by the IRCCS San Raffaele and by the Department of Pharmacology of the Istituto Superiore di Sanit was aimed at assessing
the effect of TMZ 70 and 140 mg/d in the pre-specied patients fullling the current
therapeutic indication for TMZ, i.e. patients with chronic stable angina pectoris and,
in a further analysis, patients in which the reason for stopping the exercise test (ETT)
was angina (group with limiting angina). Since in VASCO study there was no requirement of a minimal number of angina attacks as inclusion criterion, for this study chronic stable angina was dened as that with a mean anginal attacks/week 1.
Informed consent was obtained from each patient. The study protocol conforms to
the ethical guidelines of the 1975 Declaration of Helsinki as reected in an a priori approval by the San Raffaele human research committee. The authors of this manuscript
have certied that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [22].
2.1. Assessment of efcacy
Efcacy was assessed by ETT using the Bruce protocol as reported in detail elsewhere [19]. The assessment of efcacy of the VASCO-angina complies with the Guideline for the clinical investigation of anti-anginal medicinal products in stable angina
pectoris of the European Medicines Agency (CPMP/EWP/234/95 1996) that recommends exercise capacity, measured by total exercise duration (TED), as main evaluation criterion. Total exercise duration was therefore chosen as primary efcacy
criterion, and expressed as the change between last value and baseline. Time to
1-mm ST segment depression (T1) was chosen as secondary efcacy criterion. Time
to angina was dened as the time to onset of angina during ETT and time to limiting
angina was dened as the time to angina of such a severity that the patient wished
to stop exercising.
2.2. Statistical analyses
The overall VASCO data-base was transferred to the two coordinating centres of
the VASCO-angina study. Data were independently analysed by expert investigators,
blinded on treatment allocation. Only patients with evidence of angina in the
4 weeks prior the inclusion and/or limiting angina during the exercise test were

included in the analysis. Comparisons amongst the three groups (placebo, TMZ
70 mg/d and TMZ 140 mg/d) for baseline values in TED and T1 were performed by
using a series of ANOVAs. Differences in TED and T1 between the pooled group of patients allocated to TMZ (i.e. both 70 mg/day or 140 mg/day) and the placebo group
were assessed by using t-tests. Between groups comparisons on the variation from
baseline values in TED and T1 were performed by using a series of ANCOVAs, adjusting
for time to angina onset. The latter was chosen as covariate as highly correlated with
the dependent variables.

3. Results
A total of 645 patients fullled the inclusion criteria for this study
and were analysed. Patients were distributed in the 3 treatment
groups as follows: 249 patients in the TMZ MR 70 mg/day group,
260 in the 140 mg/day group and 136 in the placebo group. Demographic and baseline clinical characteristics of patients from the
VASCO-angina study and those of the main VASCO trial as reported
in Table 1. Baseline clinical features of patients allocated to TMZ
groups and placebo group were similar. Trimetazidine treatment
was well tolerated throughout the study and there was no signicant
difference between groups in the occurrence of adverse events.
Separate ANOVAs showed signicant differences in baseline
values of TED and T1 amongst groups (TED: F = 8362; df = 2642,
p-value = 0.0003; T1: F = 7189; df = 2642, p-value = 0.0008).
Fisher's Protected Least Signicant Difference (PLSD) further claried
that the group allocated to TMZ 140 mg/day signicantly differed
from the placebo group (TED: p = 0.0001; T1: p = 0.0003) and from
the group allocated to TMZ 70 mg/day (TED: p = 0.0057; T1: p =
0.0105). Therefore, in order to eliminate the confounding of different
baseline values we analysed the variation after treatment, i.e. the percentage of change from baseline for both TED and T1.
3.1. Effect of trimetazidine in patients with chronic stable angina
Compared to baseline, in the overall cohort of patients with chronic
stable angina TMZ signicantly improved both TED (TMZ: 6% 23%;
placebo: 0.7% 5%; t-value: 2.689; p-value: 0.0074) and T1 (TMZ:
9.6%33%; placebo: 3% 16.8%; t-value: 2.265; p-value: 0.0239).
Similar results were observed in the pooled TMZ (70 and 140 mg;
n= 509) and in each of the two TMZ groups but not in the placebo
group.
Comparisons between the two TMZ groups and placebo group are
shown in Table 2. Trimetazidine signicantly improved TED and T1
compared to placebo. Time to angina onset highly correlated with

Please cite this article as: Vitale C, et al, Efcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina The
VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001

C. Vitale et al. / International Journal of Cardiology xxx (2012) xxxxxx

Table 2
Comparisons among TMZ 70 mg/day; TMZ 140 mg/day and placebo groups for post-treatment variation in total exercise duration and time to 1 mm ST segment depression, adjusted for time to angina onset (ANCOVAs).
Characteristic

TMZ 70 mg/day (n = 249)

TMZ 140 mg/day (n = 260)

Placebo (n = 136)

F-value(df = 2642)

p-value

Total exercise duration (s)

Time to 1 mm ST depression (s)

0.053 0.207
0.085 0.308

0.068 0.251
0.107 0.351

0.007 0.055
0.030 0.168

5.392
2.898

0.0048
0.0536

Bold = p-value b0.05; Italics = p-value b0.1. Results are expressed as mean standard deviation.

TED and T1 baseline values (respectively: r = 0.835, p b 0.001; r =

0.799; p b 0.001) and was therefore chosen as covariate.
The improvement in TED was signicantly different amongst the
three treatment groups, with mean values progressively increasing
from placebo to the group allocated to TMZ 70 mg/day, and to the
group allocated to TMZ 140 mg/day. The group allocated to TMZ
140 mg/day signicantly differed from the placebo group (p =0.0044),
and that the group allocated to TMZ 70 mg/day signicantly differed
from the placebo group (p= 0.0338). The improvement in TED was
greater but not signicantly different between TMZ 70 mg/day and
TMZ 140 mg/day. However, a signicant trend towards a greater effect
of TMZ 140 was found.
Similarly to what observed for TED, TMZ signicantly improved T1
compared to placebo. Both groups allocated to TMZ 140 mg/day and
70 mg/d signicantly differed from the placebo group (F = 5.453;
df = 1381, p-value = 0.0200; and F = 5.479; df = 1381, p-value =
0.0198, respectively). Although a trend towards a greater effect of
TMZ 140 mg was observed, no statistically signicant difference between TMZ 70 mg/day and TMZ 140 mg/day was found (F = 0.064;
df = 1381, p-value = 0.7999).

3.2. Effect of trimetazidine in patients with limiting angina

In order to further clarify the efcacy of TMZ in patients with severe effort angina, 574 patients with limiting angina (crescendo angina as main reason for stopping the exercise test) were analysed (n =
217 receiving TMZ 70 mg/day; n = 233 receiving TMZ 140 mg/day;
n = 124 placebo group). Compared to baseline, TMZ signicantly improved both TED and T1 and signicant differences were observed
between the placebo and the pooled TMZ groups: TED (TMZ, 4.9%
5.2%; placebo, 0.6% 0.3%; F = 9.935, df = 1570, p-value = 0.0017)
and T1 (TMZ, 8.4% 32.9%; placebo, 2.8% 16.6%; F = 4.875, df =
1570, p-value = 0.0276) (Figs. 1 and 2).
Comparisons between the three groups show that the treatment
effect progressively increased from placebo to the group receiving
TMZ 70 mg/day, and to that receiving TMZ 140 mg/day (Table 3).
The comparison between the groups allocated to TMZ and placebo
was statistically signicant (p b 0.02).

Fig. 1. Percentages of post-treatment variations in total exercise duration in patients

with limiting angina allocated to the pooled TMZ (n = 450) or placebo (n = 124)
groups. *The value indicates standard error.

Trimetazidine signicantly improved T1 compared to placebo.

Both TMZ groups (140 mg/day and 70 mg/day) signicantly differed
in the improvement in T1 from the placebo group (F = 4.776; df =
1381, p-value = 0.0295, and F = 4.155; df = 1381, p-value = 0.0423,
respectively) while no signicant difference between the two doses
of TMZ was found (F = 0.108; df = 1381, p-value = 0.7422).
4. Discussion
The present study shows that, in patients with effort induced angina receiving background therapy with atenolol, TMZ improves
both TED and T1. The study conrms the efcacy of MR TMZ compared to placebo in addition to beta-blocker treatment, in improving
functional capacity, measured by TED at ETT. These results mirror
those obtained in earlier smaller studies with TMZ 20 mg. Nevertheless, while in the pooled symptomatic and asymptomatic patients
with coronary artery disease the VASCO trial reported a signicant
improvement in TED only with the high doses of TMZ, the
VASCO-angina study provides the rst evidence of such efcacy of
TMZ at both standard and higher dose.
The clinical experience with TMZ dates back to the early 70s. The evidence on the anti-ischemic and anti-anginal effect of TMZ consists of
studies conducted both in monotherapy and in combination with conventional anti-anginal therapy. Although the earlier studies on the efcacy of anti-anginals have enrolled predominantly male patients, the
more recent and larger size trials have included larger but still inadequate numbers of female and elderly patients. Similarly, the percentage
of female patients included was also low in the VASCO study. The studies conducted with TMZ in patients with coronary artery disease span
more than 30 years and for this reason the criteria used to assess efcacy differ between the oldest and the more recent studies. The
VASCO-angina has used TED as primary criterion for assessing the efcacy of an anti-anginal drug as add-on to beta-blockers.
Trimetazidine at both standard and high doses signicantly improved both TED and T1 compared to placebo both in symptomatic patients with coronary artery disease and in those with more severe,
limiting angina. These improvements are dose-related with greater improvements observed in patients receiving the higher doses of TMZ.

Fig. 2. Percentages of post-treatment variations in time to 1 mm ST segment depression

in patients with limiting angina allocated to the pooled TMZ (n=450) or placebo (n=
124) groups. *The value indicates standard error.

Please cite this article as: Vitale C, et al, Efcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina The
VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001

C. Vitale et al. / International Journal of Cardiology xxx (2012) xxxxxx

Table 3
Comparisons among TMZ 70 mg/day; TMZ 140 mg/day and placebo groups for post-treatment variation in total exercise duration and time to 1 mm ST segment depression, adjusted for time to angina onset (ANCOVAs) in patients with angina as main reason for stopping ETT.
Characteristic

TMZ 70 mg/day (n = 217)

TMZ 140 mg/day (n = 233)

Placebo (n = 124)

F-value
(df = 2571)

p-value

Total exercise duration (s)

Time to 1 mm st dep (s)

0.038 0.204
0.068 0.309

0.059 0.249
0.098 0.346

0.006 0.057
0.028 0.166

4.943
2.449

0.0074
0.0873

Bold = p-value b0.05; Italics = p-value b0.1. Results are expressed as mean standard deviation.

The VASCO-angina study extends further the well-known efcacy

of TMZ to the dose of 70 and 140 mg/d. Since a greater improvement
in TED was observed in patients with limiting angina with higher
doses of TMZ, this suggests that higher doses may be more appropriate for those patients with more severe angina.
The observed improvements in exercise parameters observed in
the VASCO-angina study are to be related to the well-known metabolic mechanism of action of TMZ [23,24]. Trimetazidine optimises
cardiac metabolism, leading to an increase in cellular tolerance to ischemia and a change in the oxygen supply-to-demand-ratio. Thus,
the benets of TMZ here reported may be related to the mechanism
of the drug, as modulator of skeletal muscle FFA metabolism, and
are dose-dependent. Furthermore, we cannot rule out the possibility
that the protective activity of TMZ could be due to the complex
framework of intracellular events associated with cytoprotective antioxidant properties of the drug together with the activation of p38
mitogen-activated protein kinase and Akt signalling hindering cell
death [25].
A limitation of the study is that VASCO-angina is a pre-specied
sub-analysis of the main VASCO trial. The VASCO trial was the largest
study assessing the anti-ischemic effect of any anti-ischemic agent
and the VASCO-angina study was of a similar size of the more recent
studies conducted with Ranolazine. The difference between the
VASCO-angina study and the CARISA study with Ranolazine lies in
that in the VASCO-angina all patients were receiving background
treatment with atenolol while in the CARISA study only a subset of
patients received atenolol. In the VASCO-angina, as in all previous
studies conducted with TMZ there was no gender difference in the
anti-ischemic effect.
In conclusion, the VASCO-angina study suggests that metabolic
modulation exerted by TMZ may represent a new therapeutic option
in stable exertional angina patients to improve TED. Whether the
benecial effects of TMZ translate into decreased morbidity and
mortality in the long term in stable angina patients, as it has been observed in patients with heart failure [26], requires further investigation and it is currently being tested in a large multinational study.
Acknowledgement of grant support
The VASCO study was funded by the Institut de Recherches
Internationales SERVIER.
The independent VASCO-angina study was supported by a grant
from the IRCCS San Raffaele Pisana (Ricerca Corrente, Ministero
della Salute 20092012).
References
[1] Stanley WC, Marzilli M. Metabolic therapy in the treatment of ischaemic heart
disease: the pharmacology of trimetazidine. Fundam Clin Pharmacol 2003;17:
133-45.
[2] Rosano GM, Fini M, Caminiti G, Barbaro G. Cardiac metabolism in myocardial
ischemia. Curr Pharm Des 2008;14:2551-62.
[3] Kantor PF, Lucien A, Kozak R, Lopaschuk GD. 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. Circ Res
2000;86:580-8.

[4] Marzilli M, Klein WW. Efcacy and tolerability of trimetazidine in stable angina: a
meta-analysis of randomized, double-blind, controlled trials. Coron Artery Dis
2003;14:171-9.
[5] Szwed H, Sadowski Z, Elikowski W, et al. Combination treatment in stable effort
angina using trimetazidine and metoprolol: results of a randomized, doubleblind, multicentre study (TRIMPOL II). TRIMetazidine in POLand. Eur Heart J
2001;22:2267-74.
[6] Vitale C, Marazzi G, Pelliccia F, et al. Trimetazidine improves exercise performance
in patients with peripheral arterial disease. Pharmacol Res 2011;63:278-83.
[7] Rosano GM, Marazzi G, Patrizi R, et al. Comparison of trimetazidine plus sildenal
to chronic nitrates in the control of myocardial ischemia during sexual activity in
patients with coronary artery disease. Am J Cardiol 2005;95:327-31.
[8] Rosano GM, Vitale C, Sposato B, Mercuro G, Fini M. Trimetazidine improves left
ventricular function in diabetic patients with coronary artery disease: a
double-blind placebo-controlled study. Cardiovasc Diabetol 2003;2:16.
[9] Chaitman BR. Efcacy and safety of a metabolic modulator drug in chronic stable
angina: review of evidence from clinical trials. J Cardiovasc Pharmacol Ther
2004;9(Suppl. 1):S47-64.
[10] Dalla-Volta S, Maraglino G, Della-Valentina P, Viena P, Desideri A. Comparison of
trimetazidine with nifedipine in effort angina: a double-blind, crossover study.
Cardiovasc Drugs Ther 1990;4(Suppl. 4):853-9.
[11] Detry JM, Sellier P, Pennaforte S, Cokkinos D, Dargie H, Mathes P. Trimetazidine: a
new concept in the treatment of angina. Comparison with propranolol in patients
with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin
Pharmacol 1994;37:279-88.
[12] Levy S. Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Am J Cardiol
1995;76:12B-6B.
[13] Manchanda SC, Krishnaswami S. Combination treatment with trimetazidine and
diltiazem in stable angina pectoris. Heart 1997;78:353-7.
[14] Michaelides AP, Spiropoulos K, Dimopoulos K, Athanasiades D, Toutouzas P.
Antianginal efcacy of the combination of trimetazidinepropranolol compared
with isosorbide dinitratepropranolol in patients with stable angina. Clin Drug
Investig 1997;13:814.
[15] Passeron J. Effectiveness of trimetazidine in stable effort angina due to chronic
coronary insufciency. A double-blind versus placebo study. Presse Med
1986;15:1775-8.
[16] Sellier P, Broustet JP. Assessment of anti-ischemic and antianginal effect at trough
plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, double-blind, placebo-controlled study. Am J
Cardiovasc Drugs 2003;3:361-9.
[17] Abu-Amara M, Gurusamy KS, Hori S, Glantzounis G, Fuller B, Davidson BR. Pharmacological interventions versus no pharmacological intervention for ischaemia
reperfusion injury in liver resection surgery performed under vascular control.
Cochrane Database Syst Rev 2009:CD007472.
[18] Ciapponi A, Pizarro R, Harrison J. Trimetazidine for stable angina. Cochrane Database Syst Rev 2005:CD003614.
[19] Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efcacy comparison of
trimetazidine with therapeutic alternatives in stable angina pectoris: a network
meta-analysis. Cardiology 2011;120:59-72.
[20] Freedman L, White S. On the use of Pocock and Simon's method for balancing
treatment number over prognostic factors in the controlled clinical trials. Biometrics 1976;32:691-4.
[21] Pocock S, Simon R. Sequential assignment with balancing for prognostic factors in
the controlled clinical trials. Biometrics 1975;31:103-15.
[22] Coats AJ, Shewan LG. Statement on authorship and publishing ethics in the international journal of cardiology. Int J Cardiol 2011;153:239-40.
[23] Fragasso G, Palloshi A, Puccetti P, et al. A randomized clinical trial of trimetazidine,
a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll
Cardiol 2006;48:992-8.
[24] Fragasso G, Salerno A, Spoladore R, Cera M, Montanaro C, Margonato A. Effects of
metabolic approach in diabetic patients with coronary artery disease. Curr Pharm
Des 2009;15:857-62.
[25] Khan M, Meduru S, Mostafa M, Khan S, Hideg K, Kuppusamy P. Trimetazidine,
administered at the onset of reperfusion, ameliorates myocardial dysfunction
and injury by activation of p38 mitogen-activated protein kinase and Akt signaling. J Pharmacol Exp Ther 2010;333:421-9.
[26] Fragasso G, Rosano G, Baek SH, et al. Effect of partial fatty acid oxidation inhibition
with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int J Cardiol in press. http://
dx.doi.org/10.1016/j.ijcard.2012.09.123.

Please cite this article as: Vitale C, et al, Efcacy of trimetazidine on functional capacity in symptomatic patients with stable exertional angina The
VASCO-angina study, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.11.001