European Heart Journal – Cardiovascular Pharmacotherapy (2016) 2, 266–272 REVIEW doi:10.1093/ehjcvp/pvv051

Coronary artery disease Theroleoftrimetazidineincardiovascular disease: beyond an anti-anginal agent Downloaded from https://academic.oup.com/ehjcvp/article-abstract/2/4/266/2197104 by guest on 20 September 2018 Cian P. McCarthy1*, Kieran V. Mullins1, and David M. Kerins2

1Department of Medicine, University College Cork, Cork, Ireland; and 2Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland

Received 8 October 2015; accepted 30 November 2015

With evidence for efficacy in such diverse clinical settings such as stable , reperfusion injury, and contrast-induced ne- phropathy, trimetazidine (TMZ) is novel among cardiovascular agents. In spite of this and almost half a century of clinical experience with the drug, it remains licensed only as an adjunct in the management of pectoris in patients who are inadequately controlled by or intolerant to first-line therapies. Although no single pharmacological mechanism has been hitherto universally accepted, TMZ is known to target deranged cellular energetics particularly in ischaemic myocardial tissue. Mechanistically, this separates the drug from conventional anti-anginal therapies, namely beta-adrenergic antagonists, calcium channel blockers, and nitrates. Moreover, a haemodynamically neutral side-effect profile should make TMZ a much more attractive therapeutic agent in this setting. Such ostensibly beneficial pharmacodynamics notwithstanding, the drug has a limited role in angina pectoris treatment algorithms. Concerns regarding a potential for new onset movement disorder further complicate its use and have led to a licensing revocation in some jurisdictions for the treatment of vestibular disorders. In this review article, we examine the pertinent literature and assess the evidence base for TMZ as a viable treatment option in a number of clinical settings. ------Keywords Trimetazadine † Angina † † Reperfusion injury † Contrast-induced nephropathy † Peripheral arterial disease

Introduction in , and examine the evidence with regard to a concerning association with a movement disorder. Despite being licensed as an anti-anginal medication in Europe for over 40 years,1 trimetazidine (TMZ) has played only a limited role in cardiovascular medicine and its therapeutic utility remains a Mechanistic considerations source of significant debate among the cardiology community. Cur- rently, the European Cardiology Society advocates this medication Inhibition of free fatty acid b-oxidation as a second-line therapy in patients with stable angina.2 However, Free fatty acid oxidation is the primary energy source of cardiomyo- the drug has not gained such acceptance in the USA and without cytes, accounting for 60–90%, the remainder derived from glucose FDA approval it remains outside the armamentarium of cardiovas- metabolism.3 Unfortunately, despite producing the same quantity of cular drugs available to clinicians there. adenosine triphosphate, free fatty acid oxidation requires an add- Recent evidence suggests that TMZ may play an important role in itional 10–15% of oxygen, which represents a significant disadvan- cardiovascular disease beyond the treatment of angina, in such di- tage under ischaemic conditions.4 Trimetazidine, widely considered verse clinical situations such as in the management of heart failure, to be a cytoprotective agent, acts as a metabolic regulator, promot- peripheral arterial disease, contrast-induced nephropathy, and ing more efficient glucose oxidation in cardiomyocytes through in- reperfusion injury. However, concerns over an association with hibition of partial fatty acid oxidation (Table 1).5 It inhibits the parkinsonism may limit its utility. In the current article, we will re- enzymatic activity of long-chain 3-ketoacyl CoA thiolase, which is view the relevant pharmacology of TMZ, the evidence for its use responsible for the last stage of fatty acyl beta-oxidation (Figure 1).4

* Corresponding author. Tel: +353 862591133, Fax: +353 214904059, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected] The role of trimetazidine in cardiovascular disease 267

In doing so, it causes a shift in cardiomyocyte energy derivation to- Table 1 Mechanisms of action of trimetazidine wards more efficient glycolytic biochemical pathways thereby main- 4 Mechanism References taining energy production while conserving oxygen...... Inhibition of b-oxidation of free fatty acid 3 Increased pyruvate dehydrogenase activity 3,5,6 Enhancement of pyruvate dehydrogenase Increasing sarcolemma mechanical resistance 8,9 activity 10 Inhibiting apoptosis by increased miR-21 expression Trimetazidine is known to increase the activity of pyruvate dehydro- 11 Reduced cardiac fibrosis by decreasing connective genase, a component of the pyruvate dehydrogenase complex.4,6,7 tissue growth factor (CTGF) expression in cardiac Through this mechanism, it facilitates the transformation of pyruvate fibroblasts

to acetyl Co-A, thereby linking glycolysis with the citric acid cycle Downloaded from https://academic.oup.com/ehjcvp/article-abstract/2/4/266/2197104 by guest on 20 September 2018 with the subsequent release of energy via nicotinamide adenine

Figure 1 Trimetazadine effect on the fatty acid b-oxidation pathway. 268 C.P. McCarthy et al. dinucleotide hydride. Other researchers posit an effect on cardiac period of 2 weeks. Both medications produced similar and statistic- mitochondria promoting adenosine triphospate synthesis via altera- ally significant decreases in anginal attacks and nitrate consumption tions in mitochondrial calcium metabolism to account for at least per week, while also improving the recovery from anginal pain and some of TMZ pharmacological effect.8 maximal ST-segment depression on exercise treadmill testing.15 However, while diltiazem caused a slight prolongation of PR and Inhibition of reperfusion injury QRS durations (P ¼ 0.039) on ambulatory ECG, this effect was 15 Recently, TMZ has been shown to increase microRNA-21.9 not seen in the TMZ subgroup. Increased microRNA-21 expression up-regulates the activity of In another multicentre study (double-blind parallel group), involv- Akt signalling resulting in a decrease in the ratio of bax/bcl-2 and ing 149 patients with stable angina, TMZ (20 mg three times daily), also the expression of caspase-3, the ultimate effect being a reduc- compared with propranolol (40 mg three times daily), produced simi- 9 lar anti-anginal efficacy in terms of anginal attack rate per week, exer-

tion in hypoxia/reperfusion-induced apoptosis. Additionally, TMZ Downloaded from https://academic.oup.com/ehjcvp/article-abstract/2/4/266/2197104 by guest on 20 September 2018 16 may protect cardiomyocytes from reperfusion injury following cise duration, and time to 1 mm ST-segment depression. acute (MI) via enhancement of the mechanical resistance of the sarcolemma.10,11 Following restoration of blood Trimetazidine combination therapy flow in acute MI, the sarcolemma is exposed to significant mechan- The use of TMZ as an adjunctive therapeutic agent has proved an ical stress secondary to soft tissue oedema. By increasing sarcolem- attractive option in patients whose symptom control is suboptimal mal resistance, TMZ protects cells from potential apoptosis and the when managed with first-line agents or in those with significant resultant ventricular dysfunction.10,11 haemodynamic disturbances. The efficacy of TMZ as add-on therapy has been investigated with both beta-blockers and calcium channel Inhibition of cardiac fibrosis blockers. Trimetazidine is thought to directly inhibit cardiac fibrosis. The drug reduces accumulation, connective tissue growth factor ex- Trimetazidine combined with beta-blockers pression in cardiac fibroblasts, nicotinamide adenine dinucleotide The Trimetazidine in Angina Combination Therapy (TACT) study phosphate-oxidase levels, and the production of reactive oxygen was a randomized, multicentre, placebo-controlled study involving species.12 Such mechanisms are thought to explain the beneficial 177 patients with stable angina to assess the efficacy and acceptabil- effects of this agent in the setting of congestive cardiac failure. ity of TMZ in combination with haemodynamic agents (beta- blockers or long-acting nitrates).17 Patients were randomly treated with TMZ (20 mg three times daily) or placebo orally for 12 weeks. Trimetazidine as an anti-anginal After 12 weeks of therapy, exercise test duration increased by 89 s agent in the TMZ group vs. 23.6 s in the placebo group (P , 0.05). Time to 1 mm ST-segment depression increased by 90 s in the TMZ group The most well recognized and established role of TMZ in cardiovas- vs. 16.7 s in the placebo group (P , 0.05). Time to onset of anginal cular medicine is as an anti-anginal agent. Conventional anti- pain increased by 100 s in the TMZ group vs. 21.3 s in the placebo ischaemic agents such as beta-blockers, calcium channel blockers, group (P , 0.005). The mean number of anginal attacks per week and nitrates play an important role in clinical practice in their relief decreased from 5.6 + 0.6 to 2.7 + 0.5 in the TMZ group vs. of symptoms in patients with stable coronary artery disease. Unfor- 6.8 + 0.7 to 5.1 + 0.7 in the placebo group (P , 0.05), and mean tunately, these agents are not without side effects, impacting heart consumption short-acting nitrates per week decreased from rate and blood pressure to varying degrees. Owing to its unique 5.2 + 0.9 to 2.8 + 0.8 in the TMZ group vs. 5.5 + 0.8 to 4.1 + 13 mechanism of action, TMZ has very limited haemodynamic effects 0.9 in the placebo group.17 and thus may be the ideal agent for patients susceptible to changes in The TRIMetazidine in POLand (TRIMPOL) II study was a double- haemodynamic variables. A plethora of clinical trials have assessed blind, placebo-controlled study, involving 426 patients with stable the efficacy of TMZ both a mono-therapeutic agent and as part of angina.18 It found that the addition of TMZ (60 mg/day) to metopro- a combination regimen in the treatment of angina. lol (50 mg/day), over a 12-week period, significantly improved total exercise time duration (+20.1 s, P ¼ 0.023), time to 1 mm Trimetazidine monotherapy ST-segment depression (+33.4 s, P ¼ 0.003), time to onset of an- In a double-blind, placebo-controlled study undertaken by Passer- gina (+33.9 s, P , 0.001) , and significantly decreased the mean on14 involving 109 patients, TMZ caused a statistically significant re- number of angina attacks and consumption of short-acting nitrates duction in angina attacks from 8.1 + 0.3 to 2.9 + 0.5 a week. per week with only minor side effects.18 Furthermore, nitroglycerin consumption among participants over The largest trial, the VASCO-angina study, was a 12-week rando- a week decreased by over 50% from 9.1 + 0.6 to 3.1 + 0.5 tablets.14 mized double-blind, placebo-controlled trial aimed at assessing the In comparative trials with conventional anti-anginal agents, TMZ anti-anginal efficacy and safety of two doses of TMZ MR (TMZ has shown equivalent results. In a multicentre double-blind com- 70 mg/day, TMZ 140 mg/day) in 645 symptomatic patients with parative study conducted by Koylan et al.,15 the effects of TMZ chronic stable angina receiving background atenolol treatment.19 were assessed in comparison with diltiazem on exercise perform- Compared with baseline, in the overall cohort of patients with ance in 116 patients with stable angina. Patients were randomized chronic stable angina, TMZ significantly improved total exercise to receive TMZ (20 mg three times daily) or diltiazem (60 mg three duration (TMZ: 6 + 23%; placebo: 0.7 + 5%; t-value: 22.689; times daily) for a 4-week treatment period after a placebo washout P-value: 0.0074) with similar improvements in total exercise The role of trimetazidine in cardiovascular disease 269 duration seen in both TMZ treatment doses (TMZ 70 mg/day: the TMZ group, whereas the total amount of cardiac troponin I 5.3 + 20%, P ¼ 0.0338; TMZ 140 mg/day: 6.8 + 20%, P ¼ 0.0044).19 released after percutaneous intervention, as assessed by the area While a greater total exercise duration improvement was ob- under the curve of serial measurements, was also significantly served in TMZ 140 mg/day than in TMZ 70 mg/day, this was not reduced (P ¼ 0.05).32 significant.19 The benefit of TMZ during percutaneous intervention has also been investigated in the setting of acute MI. In a multicentre, rando- Trimetazidine in combination with calcium channel mized, double-blind study by Steg et al., the investigators detected blockers an earlier and more complete return of the ST-segment toward In a double-blind, randomized, placebo-controlled trial of 4 weeks baseline in patients who were pretreated with TMZ for 48 h.33 duration, conducted by Manchanda et al.20 involving 64 patients This result was supported by another randomized trial, this time with stable angina uncontrolled with diltiazem, compared with by Labrou et al.,34 which found that TMZ minimized myocardial re- Downloaded from https://academic.oup.com/ehjcvp/article-abstract/2/4/266/2197104 by guest on 20 September 2018 placebo, there was net improvement with TMZ in mean anginal perfusion injury during percutaneous intervention and improved attacks of 4.8/week (P , 0.002); in mean exercise times to 1 mm global and regional wall motion at 1 and 3 months after percutan- ST-segment depression by 94.2 s (P , 0.05), in time to onset of eous intervention. However, both trials were limited by small pa- angina by 113.1 s (P , 0.02); and in mean maximum work at peak tient numbers. exercise of 1.4 metabolic equivalents (P , 0.05). In a subsequent Trimetazidine may also be useful in preventing reperfusion fol- studybythesameinvestigators,using a lower dose of diltiazem lowing coronary artery bypass grafting. In a recent meta-analysis (90 mg/day), similar benefits were demonstrated.21 Compared of six randomized controlled trials investigating the efficacy of pre- with placebo, there was an improvement with TMZ in mean exer- operative TMZ therapy on myocardial preservation in coronary ar- cise time to 1 mm ST-segment depression of 128 s (P , 0.01); in the tery bypass grafting patients, Zhang et al. found significantly lower mean duke treadmill score of 57.4% (P , 0.02); and in mean anginal postoperative levels of creatine kinase, creatine kinase-MB, Tropo- attacks of 5.1 per week (P , 0.01).21 nin T, and Troponin I in the TMZ-treated coronary artery bypass grafting patients relative to control coronary artery bypass grafting Meta-analyses patients. These results were consistent in both the ≤12 and .12 h 35 The results from monotherapy and combination therapy trials is post-coronary artery bypass grafting subgroup analyses. supported by meta-analyses. In a meta-analysis of 23 trials with 1378 patients with stable angina conducted by Ciapponi et al.,22 TMZ reduced the number of weekly angina attacks (P , 0.0001) Trimetazidine and and weekly nitroglycerin tablet consumption (P , 0.0001) and im- contrast-induced nephropathy proved exercise time to 1 mm ST-segment depression on the exer- cise test (P ¼ 0.0002), compared with placebo. In the largest The incidence of contrast-induced nephropathy in patients under- meta-analysis, conducted by Danchin et al.23 evaluating 218 trials going angiography is ,2% of the general population. However, with a total 19 028 patients, TMZ significantly improved exercise this figure can increase to up to 50% in patients with advanced kid- 36 tolerance, weekly angina episodes, and use of short-acting nitrates ney disease. Identification of renoprotective agents that can pre- when compared with placebo. vent contrast-induced nephropathy has proved a challenging area of research. Trimetazidine has shown some promise in tackling this issue in several clinical trials. Trimetazidine and reperfusion In one such trial undertaken by Onbasili et al.37 on 82 patients injury undergoing coronary angiography, the investigators assessed whether pretreatment of patients with TMZ (20 mg three times Over the last 30 years, thrombolytic therapy and percutaneous cor- daily) in addition to isotonic saline would reduce the incidence onary intervention have revolutionized the management of acute of contrast-induced nephropathy. Their results found contrast- MI, with resultant reduction in infarct sizes.24 Although overwhelm- induced nephropathy developed in 2.5% (1/40) of patients in the ingly beneficial, the abrupt restoration of blood flow unfortunately TMZ group and in 16.6% (7/42) of patients in the control group has been found to cause additional and accelerated myocardial in- (P , 0.05), suggesting a clear benefit. These encouraging results jury beyond the region of ischaemia alone, in a process known as ‘re- were supported by a prospective, randomized, controlled trial perfusion injury’.25,26 With evidence to suggest that reperfusion undertakenbyRahmanet al.38 involving 400 patients, evaluating injury accounts for 50% of the final infarct size,26 several drugs aimed the efficacy of TMZ in the prevention of contrast-induced nephro- at tackling this phenomenon have been proposed. Following consist- pathy in patients with raised serum creatinine levels undergoing cor- ent evidence from elegantly performed animal studies demonstrat- onary angiogram. The investigators found that the incidence of ing the ability of TMZ to limit ischaemia–reperfusion injury,27 – 31 contrast-induced nephropathy was significantly (P , 0.05) reduced clinical trials on human subjects were undertaken. In one such ran- by TMZ administration with saline in comparison with saline alone domized prospective trial by Bonello et al.32 on 582 patients with in patients undergoing coronary angiography (4 vs. 14%).38 stable angina undergoing percutaneous intervention, patients were Another study by Shehata et al.39 evaluated the effect of peri- randomized to receive an acute loading dose of 60 mg of TMZ or no procedural administration of TMZ on the incidence of percutaneous treatment prior to intervention. The group found that post- intervention-induced myocardial injury and contrast-induced ne- procedural cardiac troponin I levels were significantly reduced in phropathy in the high-risk population of diabetic patients with 270 C.P. McCarthy et al. mild–moderate renal dysfunction. The trial found that peri- (RR 0.42, P , 0.00001) and overall mortality (RR 0.29, P , procedural treatment with TMZ (70 mg/day) for 72 h resulted in 0.00001).44 These findings were supported by a multicentre retro- an incidence of contrast-induced nephropathy of 12% in compari- spective trial by Fragasso et al.45 in 2013 involving 669 chronic heart son with 28% in the control group (P , 0.05).39 Cardiac troponin failure patients. This trial showed that the addition of TMZ to con- I levels were significantly reduced in the TMZ group at 6 h post- ventional therapy vs. conventional therapy alone was associated percutaneous intervention (8 + 0.3 vs. 16 + 0.2 pg/mL) 12 h post- with reduced cardiovascular hospitalization rate (adjusted hazard percutaneous intervention (13 + 0.9 vs. 24 + 0.8 pg/mL) and ratio [HR] 0.524, 95% CI 0.352–0.781, P ¼ 0.001), cardiovascular 24 h post-percutaneous intervention (7 + 0.7 vs. 14 + 0.3 pg/mL mortality (HR 0.072, 95% CI 0.019–0.268, P ¼ 0.0001), as well as P , 0.001).39 The evidence from this trial further endorses results overall mortality (HR 0.102, 95% CI 0.046–0.227, P ¼ 0.0001). from previous trials highlighting the benefit of TMZ in prevent- ing both myocardial injury and contrast-induced nephropathy in Downloaded from https://academic.oup.com/ehjcvp/article-abstract/2/4/266/2197104 by guest on 20 September 2018 patients undergoing percutaneous intervention. Trimetazidine and peripheral In a meta-analysis of randomized controlled trials, Nadkarni arterial disease et al.,40 investigated whether the addition of TMZ to normal saline A few studies have assessed the value of TMZ in the treatment of plus/minus N-acetylcysteine could reduce the incidence of peripheral arterial disease. In a study by Syrkin et al.,46 the authors contrast-induced nephropathy. The group found that TMZ signifi- demonstrated the ability of TMZ to extend the intermittent claudi- cantly reduced the incidence of contrast-induced nephropathy by 40 cation distance. More recently, in 2011, a double-blind study by 11% (P , 0.01). Vitale et al. randomized 100 patients with symptomatic peripheral arterial disease to TMZ or placebo. While the ankle brachial index Trimetazidine and heart failure values did not differ at a 3-month follow-up, the maximal walking distance increased by 23% in the TMZ vs. 14% in the placebo.47 It Over the past 30 years, much research interest has centred on an is important to note that these were small and underpowered stud- association between heart failure and derangements in cellular en- ies. Thus, larger trials are necessary before any judgements concern- ergy derivation.41 Trimetazidine via metabolic modulation4 and ing the true efficacy of this agent in peripheral arterial disease can be through inhibition of cardiac fibrosis12 has emerged as an attractive made. agent. There is now a substantial evidence base to suggest that TMZ can not only improve symptoms of chronic heart failure but also ef- fect an improvement in cardiac ejection fraction (EF) in this patient Trimetazidine adverse effects cohort. As far back as 1990, a small double-blind, placebo- controlled study carried out on 20 patients, comparing the addition Unlike other conventional anti-anginal agents, TMZ has a contrast- of TMZ vs. placebo to standard therapy for patients with ischaemic ing side-effect profile. Generally, treatment-related side effects are and NYHA class III/IV found that at 6 months, all mild and well tolerated mostly comprising gastrointestinal distur- 48 TMZ-treated patients were free from angina.42 Moreover, dyspnoea bances such as nausea and vomiting and minor headaches. How- was improved in all those in the TMZ-treated group in comparison ever, much more concerning is an association with a parkinsonism, with only one placebo-treated patient, while EF increased by 9.3% in which led to the de-licensing of this agent as a treatment option in the TMZ group and decreased by 15.6% in the placebo group (P , the management of vertigo and tinnitus by the European Medicines 49 48 0.018).42 More recently, a trial by Fragasso et al., though again with Agency. In a study by Marti Masso et al., 56 of the 130 patients small study numbers, demonstrated that the addition of TMZ to who were treated with TMZ (43%) reported adverse motor func- conventional therapy in heart failure patients led not only to im- tion. Drug-induced parkinsonism was detected in 20 patients, gait provement in the NYHA HF class (P , 0.0001) and left ventricular disturbances in 15 subjects, and 9 experienced tremor, while 12 end-diastolic volume (from 98 + 36 to 81 + 27 mL; P ¼ 0.04) and of the patients who had a pre-existing diagnosis of Parkinson’s dis- 48 but also to a significantly improved left ventricular EF (from 36 + 7 ease exhibited a worsening of symptoms. However, and perhaps to 43 + 10%; P ¼ 0.002) while the same parameters deteriorated more telling, examination of post-marketing analysis reveals the in- among the placebo-treated group.43 cidence of this side effect to be very low, with an incidence of 0.36/ The clinical utility of any drug is ultimately judged on its overall 100 000 person-years. In the majority of patients, symptoms resolve impact on disease mortality. Crucially, we now have data demon- within 4 months of discontinuation of the medication. The European strating a mortality benefit among patients with chronic heart failure Medicines Agency recommends referral to a neurologist only if the 49 treated with TMZ. In a meta-analysis by Gao et al.,44 involving 17 symptoms persist beyond 4 months. Nonetheless, patients must randomized studies from the period between 1966 and May 2010 be advised of the potential risk and of the early signs of the condition and including a total of 955 patients with chronic heart failure, in while in those with pre-existing Parkinson’s disease, the drug should comparison with placebo, TMZ treatment was associated with in- be considered contraindicated. creased exercise tolerance (weighted mean difference 30.26 s; P , 0.01), NYHA class reduction (weighted mean difference 0.41; Conclusion P , 0.01), improved left ventricular EF in ischaemic heart failure (weighted mean difference 7.37%; P , 0.01), and non-ischaemic Trimetazidine, a unique and undervalued anti-anginal medication, is heart failure patients (weighted mean difference 8.72%; P , 0.01). an attractive and potentially advantageous alternative to conven- Moreover, their analysis showed that TMZ reduced hospitalizations tional agents, especially among those patients with disturbed The role of trimetazidine in cardiovascular disease 271 haemodynamic profiles. 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