IJCA-15500; No of Pages 4

International Journal of Cardiology xxx (2012) xxx–xxx

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International Journal of Cardiology

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

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

a r t i c l e i n f o a b s t r a c t

Article history: Background/objectives: Trimetazidine (TMZ) is a metabolic agent of proven efficacy in improving myocardial
Received 12 July 2012 ischemia and angina. VASCO, a randomised double-blinded, placebo-controlled trial, assessed anti-anginal ef-
Received in revised form 29 October 2012 ficacy and safety of standard and high dose of modified-release TMZ (70 mg/d and 140 mg/d) in symptom-
Accepted 1 November 2012 atic and asymptomatic patients with chronic ischemic heart disease receiving background atenolol 50 mg/d
Available online xxxx
on exercise test parameters.
The VASCO-angina study assessed the efficacy of the two doses of TMZ on total exercise duration (TED) and
Keywords:
Trimetazidine
time to 1-mm ST segment depression (T1), in symptomatic patients with chronic stable angina receiving
Myocardial ischemia background atenolol treatment.
Angina Methods and results: In the all cohort of chronic stable angina patients TMZ significantly improved TED com-
Exercise performance pared to baseline and to placebo. Both doses of TMZ significantly increased TED (p = 0.0044 and p = 0.0338
Heart disease for TMZ 140 mg/d and TMZ 70 mg/d, respectively). A greater TED improvement was observed in TMZ
Exercise testing 140 mg/d than in TMZ 70 mg/d, although the difference was not significant. Amongst patients with limiting
angina during exercise test, both doses of TMZ significantly improved both T1 and TED. No difference in se-
rious adverse events was noted between TMZ and placebo.
Conclusions: The VASCO-angina gives evidence for the efficacy 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 35 mg modified release (MR) bid either in monotherapy or in combina-

Trimetazidine (TMZ) is an inhibitor of free fatty acids (FFA) oxida-
tion that shifts cardiac and muscle metabolism from FFA to glucose
utilisation resulting into a greater production of high-energy phos-
phates and into an anti-ischemic effect [1–3]. 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 [4–8]. 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).
tion with common anti-anginal drugs [5,9–16]. Previous meta-analyses
[4,17–19] have confirmed 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 ef-
fect of TMZ 20 mg, evidence on the efficacy of TMZ 35 mg MR in pa-
tients 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 ap-
proved for the treatment of angina, based on bioequivalence with the
doses of 20 mg.
The VASCO study was a 12-week randomised double-blind, placebo-
controlled trial aimed at assessing the anti-anginal efficacy 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 efficacy 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, Efficacy 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
2 C. Vitale et al. / International Journal of Cardiology xxx (2012) xxx–xxx

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

VASCO-angina study VASCO trial

TMZ MR 70 mg/day TMZ MR 140 mg/day Placebo All patients All patients
(n = 249) (n = 260) (n = 136) (n = 645) (n = 1962)

Age (years) 59.9 ± 8.2 59.7 ± 8.2 59.6 ± 8.2 59.7 ± 8.2 60.4 ± 8.2
Gender (male) 225 (90.4%) 218 (83.9%) 120 (88.2%) 563 (87.3%) 1685 (85.9%)
Body mass index 27.3 ± 3.4 28.0 ± 3.5 27.9 ± 3.8 27.7 ± 3.5 27.5 ± 3.4
Physical activity (regular/occasional) 221 (88.8%) 239 (91.9%) 117 (86.0%) 577 (89.5%) 1701 (86.7%)
Smoking habit 50 (20.1%) 60 (23.1%) 23 (16.9%) 133 (20.6%) 354 (18.0%)
Diabetes mellitus 37 (14.9%) 36 (13.9%) 24 (17.7%) 97 (15.0%) 303 (15.4%)
Duration of angina pectoris (months) 68.8 ± 74.5 59.7 ± 67.2 58.2 ± 56.3 62.9 ± 68.1 57.9 ± 61.6
Mean number of angina attacks/week 5.3 ± 4.8 6.2 ± 6.4 5.8 ± 6.8 5.8 ± 6.0 5.2 ± 6.6
Mean number of SAN/week 3.1 ± 4.4 3.6 ± 5.3 3.4 ± 6.5 3.4 ± 5.3 3.2 ± 5.7
Time to angina onset during ETT (s) 295.2 ± 103.3 271.9 ± 97.8 318.4 ± 111.3 290.7 ± 104.3 305.0 ± 107.4
HR at rest 67.9 ± 12.0 67.7 ± 11.1 67.8 ± 11.6 67.8 ± 11.5 68.1 ± 11.3
HR at peak of exercise (bpm) 119.8 ± 17.6 117.7 ± 15.6 122.2 ± 16.6 119.5 ± 16.7 122.4 ± 16.7
RPP at rest (bpm.mm Hg) 8506.2 ± 1665.4 8553.2 ± 1617.3 8653.3 ± 1836.3 8556.2 ± 1682.2 8640 ± 1685
RPP at peak exercise(bpm.mm Hg) 19293.1 ± 3824.3 18947.8 ± 3695.0 20345.0 ± 4156.8 19376.4 ± 3875.8 20126 ± 4098
Maximum ST depression (mm) −1.56 ± 0.42 −1.55 ± 0.39 −1.53 ± 0.43 −1.55 ± 0.41 −1.61 ± 0.47
Total exercise duration (s) 402.1 ± 113.2 375.0 ± 109.5 420.3 ± 107.1 395.0 ± 111.7 420.1 ± 114.3
Time to 1-mm ST segment depression (s) 337.7 ± 113.1 313.0 ± 103.7 354.4 ± 108.8 331.3 ± 109.5 343.5 ± 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]. Briefly, 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
stratified on the following factors: country, documentation of the coronary artery dis-
ease or not, age (≤ or >65 years), presence of diabetes or not, and ventricular dysfunc-
tion (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 De-
partment of Pharmacology of the Istituto Superiore di Sanità – was aimed at assessing
the effect of TMZ 70 and 140 mg/d in the pre-specified patients fulfilling 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 require-
ment of a minimal number of angina attacks as inclusion criterion, for this study chron-
ic stable angina was defined 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 reflected in an a priori ap-
proval by the San Raffaele human research committee. The authors of this manuscript
have certified that they comply with the Principles of Ethical Publishing in the Interna-
tional Journal of Cardiology [22].
2.1. Assessment of efficacy
Efficacy was assessed by ETT using the Bruce protocol as reported in detail else-
where [19]. The assessment of efficacy of the VASCO-angina complies with the Guide-
line for the clinical investigation of anti-anginal medicinal products in stable angina
pectoris of the European Medicines Agency (CPMP/EWP/234/95 1996) that recom-
mends exercise capacity, measured by total exercise duration (TED), as main evalua-
tion criterion. Total exercise duration was therefore chosen as primary efficacy
criterion, and expressed as the change between last value and baseline. Time to
1-mm ST segment depression (T1) was chosen as secondary efficacy criterion. Time
to angina was defined as the time to onset of angina during ETT and time to limiting
angina was defined 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 pa-
tients 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 fulfilled 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. Demo-
graphic 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 significant
difference between groups in the occurrence of adverse events.
Separate ANOVAs showed significant 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 Significant Difference (PLSD) further clarified
that the group allocated to TMZ 140 mg/day significantly 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 per-
centage 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 significantly 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 significantly improved TED and T1
compared to placebo. Time to angina onset highly correlated with

Please cite this article as: Vitale C, et al, Efficacy 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) xxx–xxx
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, ad-
justed for time to angina onset (ANCOVAs).
Characteristic TMZ 70 mg/day (n = 249) TMZ 140 mg/day (n = 260)
Total exercise duration (s) 0.053 ± 0.207 0.068 ± 0.251
Time to 1 mm ST depression (s) 0.085 ± 0.308 0.107 ± 0.351
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 significantly 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 significantly differed from the placebo group (p =0.0044),
and that the group allocated to TMZ 70 mg/day significantly differed
from the placebo group (p= 0.0338). The improvement in TED was
greater but not significantly different between TMZ 70 mg/day and
TMZ 140 mg/day. However, a significant trend towards a greater effect
of TMZ 140 was found.
Similarly to what observed for TED, TMZ significantly improved T1
compared to placebo. Both groups allocated to TMZ 140 mg/day and
70 mg/d significantly 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 significant difference be-
tween 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 efficacy of TMZ in patients with se-
vere effort angina, 574 patients with limiting angina (crescendo angi-
na 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 significantly im-
proved both TED and T1 and significant 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 significant (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.
Please cite this article as: Vitale C, et al, Efficacy 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
3
Placebo (n = 136) F-value(df = 2642) p-value
0.007 ± 0.055 5.392 0.0048
0.030 ± 0.168 2.898 0.0536
Trimetazidine significantly improved T1 compared to placebo.
Both TMZ groups (140 mg/day and 70 mg/day) significantly 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 significant 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 an-
gina receiving background therapy with atenolol, TMZ improves
both TED and T1. The study confirms the efficacy of MR TMZ com-
pared 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. Neverthe-
less, while in the pooled symptomatic and asymptomatic patients
with coronary artery disease the VASCO trial reported a significant
improvement in TED only with the high doses of TMZ, the
VASCO-angina study provides the first evidence of such efficacy of
TMZ at both standard and higher dose.
The clinical experience with TMZ dates back to the early 70s. The ev-
idence on the anti-ischemic and anti-anginal effect of TMZ consists of
studies conducted both in monotherapy and in combination with con-
ventional anti-anginal therapy. Although the earlier studies on the effi-
cacy of anti-anginals have enrolled predominantly male patients, the
more recent and larger size trials have included larger but still inade-
quate numbers of female and elderly patients. Similarly, the percentage
of female patients included was also low in the VASCO study. The stud-
ies conducted with TMZ in patients with coronary artery disease span
more than 30 years and for this reason the criteria used to assess effica-
cy differ between the oldest and the more recent studies. The
VASCO-angina has used TED as primary criterion for assessing the effi-
cacy of an anti-anginal drug as add-on to beta-blockers.
Trimetazidine at both standard and high doses significantly im-
proved both TED and T1 compared to placebo both in symptomatic pa-
tients with coronary artery disease and in those with more severe,
limiting angina. These improvements are dose-related with greater im-
provements 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.
4 C. Vitale et al. / International Journal of Cardiology xxx (2012) xxx–xxx
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, ad-
justed 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)
Total exercise duration (s) 0.038 ± 0.204 0.059 ± 0.249
Time to 1 mm st dep (s) 0.068 ± 0.309 0.098 ± 0.346
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 efficacy
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 appropri-
ate 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 meta-
bolic mechanism of action of TMZ [23,24]. Trimetazidine optimises
cardiac metabolism, leading to an increase in cellular tolerance to is-
chemia and a change in the oxygen supply-to-demand-ratio. Thus,
the benefits 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 anti-
oxidant 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-specified
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
beneficial effects of TMZ translate into decreased morbidity and
mortality in the long term in stable angina patients, as it has been ob-
served in patients with heart failure [26], requires further investiga-
tion 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 2009–2012).
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