Review

Angiology
2015, Vol. 66(3) 204-210
Trimetazidine and Cardioprotection: ª The Author(s) 2014
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Facts and Perspectives DOI: 10.1177/0003319714530040
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Konstantinos Tsioufis, MD, FESC1,

George Andrikopoulos, MD, FESC2,
and Athanasios Manolis, MD, FESC3

Abstract
Trimetazidine (TMZ) is a metabolic agent used in cardiology for more than 40 years. Several studies assessed the cardioprotective
effects of TMZ in patients with chronic coronary heart disease (CHD) as well as in patients with heart failure (HF). In light of the
inclusion of TMZ in the current guidelines on the management of stable CHD, we reviewed the published literature on TMZ,
focusing mainly its effects on patients with stable angina and HF. According to the published literature, there is sufficient evidence
to support the addition of this agent in the treatment of symptomatic patients with stable angina.

Keywords
trimetazidine, stable angina, coronary heart disease, heart failures

Introduction The oxygen-sparing effect of TMZ leads to reduced intracellu-

Trimetazidine (TMZ), a metabolic agent with several proper-
ties, is included in current European Society of Cardiology
(ESC) 2013 guidelines on the management of stable coronary
heart disease (CHD).1 Trimetazidine has been used in cardiol-
ogy for >40 years and recently reaccredited for the use as add-
on therapy for symptomatic treatment of patients with stale
angina, not adequately controlled with first-line therapy.2-4
Trimetazidine is available in the European Union as 20 or 35
mg tablets. Several studies assessed the cardioprotective effects
of TMZ not only in patients with CHD and stable angina but
also in patients with heart failure (HF). The majority of these
studies were conducted with TMZ 20 mg.5-13 In light of the
inclusion of TMZ in the current guidelines on the management
of stable CHD, we review the literature on TMZ, focusing
mainly on its effects in patients with CHD and HF.
Mechanism of action of TMZ
Fatty acid oxidation represents the major source of energy to
the myocardium while glucose metabolism is mainly a comple-
mentary source.14 However, b-oxidation requires more oxygen
in contrast to glucose metabolism to produce the same amount
of adenosine triphosphate (ATP). Trimetazidine (1-[2,3,4-tri-
methoxybenzyl] piperazine dihydrochloride) acts mainly by
inhibiting the enzyme 3-ketoacyl coenzyme A thiolase,15 the
terminal enzyme in b-oxidation pathway, shifting the energy
substrate metabolism, and enhancing glucose metabolism.
Thus, TMZ maintains energy production with less oxygen con-
sumption, an effect required in case of myocardial ischemia.
lar acidosis and intracellular calcium concentration while also
reducing the release of lactate dehydrogenase concentration
exerting cytoprotective effects on cardiac myocytes.16 In addi-
tion, TMZ, by enhancing glucose metabolism, preserves
energy metabolism in myocytes and prevents a decrease in
ATP intracellular levels, ensuring the function of ionic pumps
and preserving cellular homeostasis.17 Trimetazidine also has
other effects; these include improved endothelial function by
increasing nitric oxide production,18,19 reducing cell damage
(necrosis and apoptosis), and acting as a potent antioxidant.19
Treatment of Chronic CHD and Stable Angina:
What do the ESC Guidelines Suggest?
Current ESC guidelines suggest the use of either a b-blocker or
nondihydropyridine calcium channel blocker (CCB) along with
the use of short-acting nitrates as first-line therapy to relieve
symptoms and control heart rate in patients with stable CHD.1
If symptoms continue, it is advised to switch to the other option
(CCB or b-blocker) or to combine a b-blocker with a dihydro-
pyridine CCB (especially in case of low heart rate). Other heart
1
First Cardiology Clinic, Hippokration Hospital, University of Athens, Greece
2
Cardiology Department, Henry Dunant Hospital, Athens, Greece
3
Cardiology Department, Asklepeion General Hospital, Athens, Greece
Corresponding Author:
Konstantinos Tsioufis, First Cardiology Clinic, Hippokration Hospital,
University of Athens, 114, Vassilisis Sofias Ave. 11527 Athens, Greece.
Email: ktsioufis@hippocratio.gr

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Tsioufis et al
rate-lowering agents such as ivabradine or metabolic agents
such as TMZ, nicorandil, and ranolazine are suggested as
second-line therapy or add-on therapy (for patients with symp-
toms not controlled with first-line therapy, or when first-line
therapy is contraindicated or not tolerated).1,20
Apart from studies showing the clinical effects of TMZ in
patients with stable angina, meta-analyses also provided rele-
vant information and valuable insight on the potential role of
this agent in cardiovascular therapeutics.
Trimetazidine monotherapy. Few studies compared monotherapy
TMZ versus placebo.21-24 In these studies, TMZ increased the
duration of exercise, total work performed, and improved elec-
trocardiographic signs of ischemia. In addition, when TMZ was
compared head to head with other heart rate-lowering antiangi-
nal agents (b-blockers or CCBs),5,25,26 TMZ presented similar
efficacy without, however, influencing heart rate.
A double-blind comparative study25 assessed the effects of
TMZ versus diltiazem on exercise performance in 116 patients
with stable angina. Patients were randomized to receive TMZ
(20 mg  3/d) or diltiazem (60 mg  3/d) for a 4-week treat-
ment period after a placebo washout period of 2 weeks. Both
TMZ and diltiazem presented similar results and decreased the
number of angina attacks, weekly nitrate consumption while
improving the recovery of anginal pain as well as maximal
ST-segment depression.
In a multicenter study (double-blind parallel group),26
which enrolled 149 patients with stable angina, TMZ (20 mg
3/d) was compared with propranolol (40 mg  3/d) in order
to assess the antianginal efficacy effect of both the drugs. After
3 months of treatment, both drugs presented similar antianginal
efficacy in terms of anginal attack rate per week, exercise dura-
tion, or time to 1-mm ST-segment depression.
Trimetazidine combination therapy. Several studies showed the
beneficial effect of TMZ in combination with heart rate-
lowering agents.
A double–blind, placebo-controlled study assessed the effi-
cacy and safety of TMZ addition in 426 patients with stable
angina on treatment with metoprolol. Those patients were allo-
cated on therapy with metoprolol 50 mg twice daily and TMZ
60 mg (20 mg 3 times daily) or metoprolol 50 mg twice daily
and placebo and followed up for 12 weeks.6 The addition of
TMZ significantly improved total of exercise time duration
(TED), time to 1-mm ST-segment depression (T1) as well as
time to onset of angina, and significantly decreased mean num-
ber of angina attacks and consumption of short-acting nitrates
per week with minor side effects. In an attempt to assess the
effect of TMZ in patients with history of percutaneous trans-
luminal coronary angioplasty or coronary artery bypass graft-
ing (CABG), a subgroup of 94 patients of the same study
with a history of revascularization for CHD was retrospectively
analyzed. Those patients were symptomatic after 6 months
despite revascularization and treatment with metoprolol (50
mg twice daily). They were assigned to receive in addition
TMZ (20 mg 3 times daily) or placebo for 12 weeks. The
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205
addition of TMZ improved TED by 57 seconds, T1 by 80 sec-
onds as well as time to onset of angina by 75 seconds, while
mean numbers of short-acting nitrates and angina attacks were
reduced.27
Another randomized, double-blind, placebo-controlled
study assessed the efficacy of TMZ addition in 223 patients
with stable angina, treated with atenolol.28 Those patients had
stable angina despite treatment for 2 months with atenolol.
Patients were randomized to receive TMZ (35 mg twice daily)
or placebo on top of atenolol treatment (50 mg once daily). The
addition of TMZ significantly improved T1 (increased by 44
seconds) and time to angina onset while there were no differ-
ences between placebo regarding safety parameters. Likewise,
the addition of TMZ on top of nondihydropyridine CCBs
showed beneficial effects in patients with stable angina.29,30
Two randomized clinical trials assessed the efficacy of TMZ
(60 mg/d) combination with diltiazem (180 mg/d,29 90 mg/
d30 respectively) in patients with angina pectoris. In those stud-
ies, the addition of TMZ improved significantly T1, time to
angina onset, as well as mean maximum work at peak exer-
cise29,30 irrespective of diltiazem dosage.
There are several studies assessing the antianginal effects of
TMZ in addition to other antianginal drugs. In the Trimetazi-
dine in Angina Combination Therapy (TACT) study,31 combi-
nation of TMZ with b-blockers or nitrates significantly
improved angina symptoms and TED while in the Trimetazi-
dine in Poland (TRIMPOL) study, the addition of TMZ to con-
ventional antianginal therapy (b-blockers, nitrates, or CCBs)
improved TED, T1, and time to angina onset while decreased
the frequency of anginal episodes and mean nitrate consump-
tion in coronary diabetic patients.32
The VASCO trial12 was the largest randomized, placebo-
controlled, double-blind study (phase III) conducted to assess
the additive effect of TMZ on top of atenolol in patients with
stable angina. Of 4755 patients, 1962 were randomized to
active treatment (add-on: TMZ [70 mg] 35 mg twice daily,
TMZ [140 mg] 2  35 mg twice daily, or placebo twice daily)
on top of 50 mg of atenolol every day and followed up for 12
weeks. Although there was a trend in favor of TMZ, the results
did not reach statistical significance on clinical parameters
compared with placebo. We have to underline however that
60% of the patients did not meet the stability criteria at the end
of the study (% of patients who improved or worsened at the
end of the study) while the population of this trial had few
symptoms probably because 20% of the patients did not report
an angina attack or short-acting nitrate use during the run-in
phase (there was no minimum incidence of weekly angina
attacks for inclusion in the trial). For this reason, a complemen-
tary (post hoc) analysis was performed on symptomatic
patients who will be described subsequently.
Trimetazidine meta-analysis, post hoc analysis. The Cochrane
meta-analysis,33 which included 23 randomized trials (1378
patients with stable angina), showed that TMZ improved T1
and reduced the number of weekly angina attacks as well as
weekly nitroglycerin tablet consumption compared with
206
placebo. Likewise, another large meta-analysis that assessed
218 trials (19 028 patients) including the VASCO trial12
showed similar results with improvement in T1, TED, and time
to angina onset.
As mentioned earlier, the VASCO trial had several queries
regarding patient’s symptoms. Thus a post hoc analysis was
performed on symptomatic patients with chronic stable angina
(mean angina attacks/week  1). In both the groups, the addi-
tion of TMZ (TMZ [70 mg] 35 mg twice daily, TMZ [140 mg]
2  35 mg twice daily) showed significant improvement in
TED, T1, and time to angina onset compared with placebo.34
Trimetazidine in patients with acute ischemic conditions. Pretre-
atment or concomitant treatment with TMZ seems to have a
cardioprotective effect in patients undergoing CABG or percu-
taneous coronary intervention (PCI) with less incidence of con-
trast induced nephropathy.35-38 According to these studies,
TMZ administration (even when TMZ was included in the car-
dioplegic solution) decreases myocardial damage and improves
left ventricular function several months after the procedure.39-44
In addition, adjunctive therapy with TMZ after drug-eluding
stent implantation improved the incidence and the severity
of angina pectoris as well as silent ischemia in elderly patients
with multivessel CHD and diabetes mellitus.45
Further results are expected from randomized double-blind
controlled studies46 that are in progress and will assess the effi-
cacy and safety of TMZ in patients treated for 2 to 4 years with
angina pectoris, having been treated by PCI.
Trimetazidine versus other antianginal agents. According to sev-
eral meta-analyses,12,33 the antianginal efficacy of TMZ is sim-
ilar to that of nonheart rate-lowering alternatives (nicorandil,
ranolazine, long-acting nitrates, and dihydropyridines). In a
large meta-analysis that assessed 218 trials (19 028 patients),12
the differences in TED, T1, and time to angina onset as well as
other clinical criteria between TMZ and other antianginal agents
(mentioned earlier) were small and did not reach statistical sig-
nificance. Similar results were found in the Cochrane meta-
analysis33 which included mainly nitrates and dihydropyridines.
Clinical application. The rational of TMZ inclusion in the current
guidelines is mainly based on the fact that there is a long expe-
rience of TMZ administration in patients with stable angina, as
well as sufficient evidence to support the addition of this agent
in the treatment of symptomatic patients with angina, inade-
quately controlled by or intolerant to first-line antianginal
therapies. An overview of the clinical studies with TMZ in
angina pectoris is presented in Table 1.
Heart failure
Since 1939,47 there was the concept that the failing heart pre-
sents an impaired energy metabolism. Current treatment with
b-blockers,48,49 angiotensin-converting enzyme inhibitors,50,51
or angiotensin II blockers52,53 aims to also tackle this issue
since energy-sparing treatment in patients with HF improves
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Angiology 66(3)
morbidity and mortality. Several studies assessed the efficacy
of TMZ on patients with HF54-64 since metabolic modulation
of failing myocardium represents an interesting topic.
Single-center studies on TMZ in patients with HF. Addition of TMZ
to standard medical therapy seems to improve left ventricular
volumes and ejection fraction as well as functional class and
symptoms. In patients with HF of ischemic origin, TMZ
improves TED, T1, and time to angina onset.17,24,54-59 How-
ever, the majority of these studies had a small sample of
patients and a short follow-up period.
Trimetazidine meta-analysis—retrospective studies. In a meta-
analysis of randomized controlled trials in patients with HF
treated with TMZ, which included 17 trials (955 patients), the
addition of TMZ to standard medical therapy improved left
ventricular (LV) ejection fraction (LVEF), LV volumes, and
functional class while reduced cardiovascular events, hospitali-
zations, and total mortality.60 Improvement in LVEF and LV
volumes as well as in functional class was also observed in
other 2 meta-analyses,61,62 while in a retrospective study13 and
in a post hoc analysis63 that evaluated the long-term effect of
TMZ on morbidity and mortality in patients with HF, addition
of TMZ was associated with a reduction in mortality and event-
free survival in those patients. Meta-analysis—retrospective
studies with TMZ in HF are shown in Table 2.
Trimetazidine and Mortality
In the Korean Acute Myocardial Infarction Registry (KAMIR)
study,62 a retrospective analysis that explored the effect on
clinical outcomes of adding TMZ to standard treatment in
patients with acute myocardial infarction (AMI), 13 733 regis-
tered patients with AMI from 2005 to 2008 were retrospec-
tively assessed. The addition of TMZ during their in-hospital
management period significantly decreased all-cause mortality
and major adverse cardiac events (MACEs) over 12 months.
Over 12 months, the relative risk of all-cause death decreased
by 59% (event rate 2.3% vs 6.4%; hazard ratio (HR) 0.41,
95% confidence interval [CI] 0.18-0.97, P < .05) and the rela-
tive risk of MACE decreased by 76% (event rate 2.3% vs 9.5%;
HR 0.24, 95% CI 0.10-0.56, P ¼ .001) in the TMZ group com-
pared with those without TMZ addition.
Other studies showed that addition of TMZ decreases total
and cardiovascular mortality in patients with CHD and/or
HF.13,57,60,63,66,67 In the study of Zhang et al, TMZ addition did
not affect all-cause mortality, but it improved clinical and
echocardiographic parameters.65 Overall, the effect of TMZ
on mortality requires further investigation with large scale ran-
domized controlled clinical trials. Studies assessing the effect
of TMZ on mortality are shown in Table 3.
Limitations
Published data were obtained by only searching PubMEd and
Scopus.
Tsioufis et al 207

Table 1. Clinical Studies With TMZ in Angina Pectoris.

Study No. of Patients/Group Evaluation Criteria Results

Trimetazidine monotherapy
Sellier et al22 TMZ 60 mg/d (18 pts) versus placebo (14 pts) Exercise capacity—clinical TW þ25%, TED þ14%, T1 þ11%,
criteria A/W 10%
Prasad et al23 TMZ 60 mg/d (20 pts) versus placebo (20 pts) Exercise capacity—clinical TW þ33%, A/W 27%
criteria
Passeron et al21 TMZ 60 mg/d (27 pts) versus placebo (27 pts) Exercise capacity—clinical TW þ37%, A/W 29%
criteria
Dalla-Volta et al5 Nif (40 mg/d)/TMZ (60 mg/d), 19 pts—TMZ (60 Exercise capacity—clinical ND in TED, T1, A/W, TW
mg/d)/Nif (40 mg/d) criteria
TTS study25 TMZ 60 mg/d (58 pts) versus diltiazem (58 pts) Exercise capacity—clinical ND in TED, T1, A/W, TW
criteria—Holter—ECG
Detry et al26 TMZ 60 mg/d (71 pts) versus propranolol (78 Exercise capacity—clinical ND in TED, T1, A/W
pts) criteria
Trimetazidine combination therapy
TRIMPOL II6 MTP (100 mg) þ TMZ (60 mg), 211 pts versus Exercise capacity—clinical TA þ15%, T1 þ16%, TW þ11%,
MTP (100 mg) þ placebo (215 pts) criteria TED þ9%
Sellier and ATE (50 mg) þ TMZ (70 mg), 117 pts versus Exercise capacity—clinical T1 þ44 seconds, TA þ20 seconds
Broustet28 ATE (50 mg) þ placebo (106 pts) criteria
Manchanda and DIL (180 mg) þ TMZ (60 mg), 32 pts versus DIL Exercise capacity—clinical A/W 27%, T1 þ77%
Krishnaswami29 (180 mg) þ placebo (32 pts) criteria
Manchanda30 DIL (90 mg) þ TMZ (60 mg), 25 pts versus DIL Exercise capacity—clinical A/W 65%, T1 þ51%
(90 mg) þ placebo (25 pts) criteria
TACT study31 CTþTMZ (60 mg), 90 pts—CT þ placebo (87 Exercise capacity—clinical TED þ89 seconds, T1 þ90 seconds,
pts) criteria TA þ100 seconds, A/W 51%
Trimetazidine meta-analysis—post hoc analysis
Ciapponi et al33 1378 patients Clinical criteria, ST-segment A/W –40%, TED þ23 seconds,
depression T1 þ33.8 seconds
Danchin et al12 19 028 patients Exercise capacity—clinical TED þ46 seconds, T1 þ55 seconds,
criteria TA þ54 seconds
VASCO-angina 645 patients Exercise capacity—clinical TED þ6%, T1 þ9.6%
study34 criteria
Abbreviations: TMZ, trimetazidine; ATE, atenolol; MTP, metoprolol; Nif, nifedipine; DIL, diltiazem; CT, conventional therapy; pts, patients; TED, total exercise
duration; T1, time to 1-mm ST-segment depression; TW, total work; A/W, angina per week; TA, time to angina; ND, no difference; pts, patients; TTS, Turkish
trimetazidine study; TRIMPOL, Trimetazidine in Poland; ECG, electrocardiogram.

Table 2. Meta-analysis: Retrospective Studies With Trimetazidine in Heart Failure.

Study No. of Patients/Group Evaluation Criteria Results

60
Gao et al 955 patients Clinical (NYHA) LVEF þ7.37% (ischemic HF)
Echocardiographic parameters LVEF þ8.72% (nonischemic HF)
All-cause morbidity LVESV 10.37 mL
NYHA class 0.41
Exercise duration þ30.26 seconds
Hu et al61 545 patients Echo-radionuclide ventriculography LVEF þ6.88%
LVESV 11.58 mL
Zhang et al65 884 patients Clinical (NYHA) LVEF þ6.46%
Echocardiographic parameters LVESD 6.67 mm
All-cause mortality LVEDD 6.05 mm
Cardiac morbidity NYHA class 0.57
Total exercise duration þ63.75 seconds
Fragasso et al13 720 patients Cardiovascular morbidity All-cause mortality 11% (P ¼ .015)
All-cause/cardiovascular mortality CVD mortality 8.5% (P ¼ .050)
Hospitalization rate 10.4% (5 years)
Hospitalization-free survival þ7.8 months
Abbreviations: LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; LVESD, left ventricular end-systolic diameter; LVEDD, left
ventricular end-diastolic diameter; NYHA class, New York Heart Association class; CVD, cardiovascular disease; HF, heart failure.

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208 Angiology 66(3)

Table 3. Studies Assessing the Effect of TMZ on Mortality.

No. of Patients/
Study Group Evaluation Criteria Results

Fragasso et al13 720 patients Cardiovascular morbidity All-cause mortality 11% (P ¼ .015)
All-cause/cardiovascular mortality CVD mortality 8.5% (P ¼ .050)
Hospitalization rate 10.4% (5 years; P < .0005)
Hospitalization-free survival þ7.8 months
Gao et al60 955 patients Clinical (NYHA) Reduction all-cause mortality (RR 0.29; P < .00001)
Echocardiographic parameters Reduction CVD events and hospitalizations (RR 0.42;
All-cause morbidity P < .00001)
All-cause mortality
Zhang et al65 884 patients Clinical (NYHA) Reduction all-cause mortality (RR 0.47; P ¼ .27)
Echocardiographic parameters Reduction hospitalizations for cardiac causes (RR 0.43;
All-cause mortality P ¼ .03)
Cardiac morbidity
METRO study67 353 patients 6-months post Discharge for MI All-cause Reduction OR all-cause mortality 0.36 (0.15-0.86;
mortality P ¼ .022)
KAMIR study62 13 733 patients All-cause mortality RR of all-cause death 59% (P < .05)
Major adverse cardiac event RR of MACE 76% (P ¼ .001)
Over 12 months
Abbreviations: OR, odds ratio (95% CI); NYHA class, New York Heart Association class; CVD, cardiovascular disease; MI, myocardial infarction; RR, relative risk;
MACE, major adverse cardiac events; CI, confidence interval.

Conclusions 4. Questions and answers on the review of medicines containing tri-

Trimetazidine is a drug used in cardiology for >40 years. There
is evidence from several meta-analyses and post hoc analyses
that the addition of TMZ presents favorable effects with few
adverse effects at least in patients with stable angina while
there are promising results in patients with HF. Further inves-
tigation with large-scale randomized controlled clinical trials is
needed to assess the effects of this agent on mortality in
patients with cardiomyopathy.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: G. Andrikopoulos has no disclosures to declare in relation to
trimetazidine. However, he has received research grants and honoraria
for participating in lectures and advisory boards focusing on ivabra-
dine and ranolazine.
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
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