How effective can trimetazidine be in preventing myocardial and renal revascularization injury?



by Y. Lopatin, Russia

Yury LOPATIN, MD, PhD, FHFA Volgograd Medical State University Volgograd Regional Cardiology Centre, Volgograd RUSSIA

Currently, percutaneous coronary intervention is considered one of the key treatment strategies for the management of occlusive coronary artery disease. Even with the technical advances in percutaneous coronary intervention that have made the procedure safe, with a minimal rate of complications, myocardial revascularization procedures per se still cause myocardial or renal injuries. Lately, particular attention has been paid to such complications, including periprocedural myocardial injury and contrast-induced nephropathy. These complications can occur frequently and are associated with a worse prognosis. In this regard, the search for strategies that prevent the development of these periprocedural injuries seems very important. Results of experimental and clinical studies suggest promising potential for trimetazidine in the prevention of periprocedural myocardial and renal injuries.

Trimetazidine is an anti-ischemic metabolic modulator that has been approved worldwide for symptomatic treatment of chronic stable angina. Moreover, there is sound evidence to consider appropriate the use of this agent in patients with heart failure of ischemic etiology.1 In the past few years, several randomized clinical trials (RCTs) have demonstrated that therapy with trimetazidine after percutaneous coronary intervention (PCI) reduces the incidence of major adverse cardiac events, recurrent angina pectoris, and stent restenosis, and that it improves cardiac function.2-4

At the same time, evidence continues to accumulate that myocardial revascularization procedures per se cause myocardial or renal injuries, which can be associated with worse clinical outcomes.

How effective can the use of trimetazidine be in prevention of myocardial and renal revascularization injury?

Periprocedural myocardial injury during percutaneous coronary intervention

In about one-third of patients undergoing coronary revascularization by PCI, the  procedure itself causes myocardial injury (termed periprocedural myocardial injury, PMI),5,6 which has been associated with an increased rate of major adverse cardiac events, including death.7,8

PMI during PCI is often clinically silent; however, it can be detected if the level of serum cardiac enzymes increases above the 99th percentile upper reference limit (ULR). The Joint European Society of Cardiology (ESC)/American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/ World Heart Federation (WHF) Task Force Universal Definition of Myocardial Infarction 20129 defined PMI during PCI as an elevation of cardiac troponin (cTn) level above the 99th percentile URL after PCI, assuming a normal baseline troponin value. This document also noted that in patients undergoing PCI with normal (≤99th percentile URL) baseline cTn concentrations, elevations of cTn greater than 5 x 99th percentile URL occurring within 48 hours of the procedure plus ischemic, angiographic, or imaging findings are already defined as PCIrelated myocardial infarction (MI) (type 4a). The document also clarifies that when a cTn value is less than or equal to 5 x 99th percentile URL after PCI and if the cTn value was normal before PCI—or when the cTn value is greater than 5 x 99th percentile URL in the absence of ischemic, angiographic, or imaging findings—the term “myocardial injury” should be used.

Herrmann5 in his review classified the key factors that might determine the incidence and magnitude of PMI into three groups: patient-related, lesion-related, and procedure-related. The most frequently reported among these are older age; multivessel diffuse coronary artery disease (CAD); pre-existing renal impairment; presence of anemia; plaque burden; number of lesions; presence of bifurcation lesions; tortuosity of coronary arteries; suboptimal stenting; and multiple stents. Of course, the assessment of these factors before the intervention allows risk stratification for PMI. The most common mechanisms of myocardial injury during PCI are distal embolization and side branch occlusion; others are dissection, thrombus, no reflow/slow flow, or coronary perforation.6

Several strategies to protect from PMI during PCI have been applied in clinical practice. Babu et al6 have divided them into three subgroups: strategies to prevent side branch occlusion, strategies to prevent distal embolization and microvascular coagulation, and strategies of protecting the myocardium itself against PMI (cardioprotection).

Regarding prevention of side branch occlusion, the current ESC/European Association forCardiothoracic Surgery (EACTS) Guidelines on myocardial revascularization10 favor stent implantation in the main vessel only, followed by provisional balloon angioplasty with or without stenting of the side branch rather than routine stenting of both vessels. Several stents, designed specifically for treatment of bifurcation lesions, have undergone extensive evaluation. Strategies to prevent distal embolization and microvascular coagulation include administration of antiplatelet and antithrombotic agents, use of distal protection devices, or direct stenting of the coronary lesion without predilatation.6

Strategies for protecting the myocardium against PMI are based on pharmacological and nonpharmacological interventions. Among these interventions, the most discussed ones are a high dose of statins,11,12 intracoronary b-blocker or adenosine administration,13-17 trimetazidine,18 cyclosporine A,19,20 and remote ischemic preconditioning.21,22 However, the ability of some of these interventions to provide effective cardioprotection has not been confirmed in all RCTs.

Trimetazidine for the prevention of periprocedural myocardial injury in patients undergoing coronary intervention

The first clinical trial on this issue was the open-label, randomized, controlled, two parallel groups study trial performed by Polonski et al,23 in which 22 patients with one-vessel CAD received oral trimetazidine, 60 mg daily, at least 4 days before percutaneous transluminal coronary angioplasty. It was found that, compared with the control group (22 patients) pretreatment with trimetazidine reduced not only angina, rhythm disturbances, and ischemic ST-T changes on the electrocardiogram during the procedure, but also demonstrated a nonsignificant trend to lower levels of cardiac troponin I (cTnI) 6 and 12 hours after the procedure.

Later, two independent groups from France and Greece received more clear evidence of the ability of trimetazidine to prevent periprocedural myocardial injury in patients undergoing coronary interventions. The single-center, prospective, randomized evaluation study of Bonello et al24 included 206 stable angina patients with one-vessel CAD. Patients who underwent more than one inflation procedure during PCI were excluded from the study. Half of the patients received an acute loading dose of trimetazidine (60 mg) starting 30 min before recanalization, after which the operator was allowed to proceed with angioplasty. The main outcome of this study was the frequency and the increase in the level of cTnI after a successful PCI. cTnI levels were measured before and 6, 12, 18, and 24 hours after PCI. It was found that there were no statistically significant differences in the frequency of cTnI levels between the trimetazidine group and the control group. However, postprocedural cTnI levels were significantly reduced in the trimetazidine group at all time points (mean [standard deviation] for control vs trimetazidine group, respectively: at 6 hours, 4.2 ng/mL [0.8] vs 1.7 ng/mL [0.2], P<0.001; at 12 hours, 5.5 ng/mL [1.5] vs 2.3 ng/mL [0.4], P<0.001; at 18 hours, 9 ng/mL [2.3] vs 3 ng/mL [0.5], P<0.001; and at 24 hours, 3.2 ng/mL [1.2] vs 1 ng/mL [0.5], P<0.001). Moreover, the total amount of cTnI released after PCI, as assessed by the area under the curve of serial measurements, was significantly reduced in the trimetazidine group (P<0.05) (Figure 1).

Figure 1. Time course of cardiac troponin I release. Mean circulating cardiac troponin I concentrations (error bars showing standard deviation) are indicated for control (open symbols; n=130) and trimetazidine (closed symbols; n=136) groups. The arrow indicates the time of PCI. ***P<0.001. Abbreviations: cTnI, cardicac troponin I; PCI, percutaneous coronary intervention. From reference 24: Bonello et al. Heart. 2007;93:703-707. © 2007, BMJ Publishing Group Ltd.

In the other trial, Labrou et al25 included 52 patients hospitalized for acute coronary syndromes. Coronary angiography was performed in all patients, and more specifically, after 6 days of hospitalization in patients with MI. Patients who had undergone primary PCI were excluded from this study. All patients received bare metal stents; drug-eluting stents were not used in the study. In addition to conventional antianginal therapy, 27 patients received 20 mg oral trimetazidine every 8 hours, starting 15 days before PCI and continuing for 3 months after the procedure. The other 25 patients were included in the placebo group. For each patient, serum cTnI and creatine kinase-MB (CK-MB) levels were measured before PCI, then at 6, 24, and 48 hours after the procedure. Serum cTnI and CK-MB measurements were considered negative for myocardial damage when levels were lower than 0.2 ng/mL and lower than 5 ng/mL, respectively. It was observed that 24 hours after PCI, cTnI levels were higher than 1 ng/mL in 7 of 27 patients (26%) in the trimetazidine group and in 11 of 25 patients (44%) in the placebo group. Forty-eight hours after the procedure, cTnI levels remained elevated in 15% of patients receiving trimetazidine and in 32% of patients in the placebo group. Twenty-four hours after PCI, CK-MB levels were above 5 ng/mL in 22% of patients in the trimetazidine group and 40% of patients in the placebo group. The authors concluded that trimetazidine can reduce myocardial reperfusion injury during PCI. They also stressed the need for further studies with inclusion of more patients.

Xu et al26 in a single-center, prospective, randomized, controlled study again demonstrated that trimetazidine reduced post-PCI cTnI release in patients with unstable angina pectoris. A total of 106 patients who underwent successful elective PCI and drug-eluting stent implantation were randomized to a trimetazidine group (n=51, 60 mg trimetazidine oral loading dose 0.5-1.0 hour before PCI followed by 20 mg three times daily after PCI on top of standard therapy) or a control group (standard therapy without trimetazidine, n=55). cTnI level was measured before and 16-18 hours after PCI. It was found that cTnI levels after PCI were higher than before the procedure in both groups of patients (P<0.01). However, postprocedural cTnI levels increased from 0.02 mg/L (95% CI, 0.01-0.03)] at baseline to 0.11 mg/L (95% CI, 0.07-0.13)] (P<0.05) at 16-18 hours in the trimetazidine group, whereas in the control group, it increased from 0.02 mg/L (95% CI, 0.01-0.03)] to 1.31 mg/L (95% CI, 0.44-2.31)] (P<0.05). The proportion of patients in the trimetazidine group who showed a postprocedural cTnI level elevation of greater than 0.10 mg/L was lower than that in the control group (P<0.01).

Recently Zhang et al18 have published a meta-analysis that covered data from 9 RCTs with a total of 778 patients having undergone PCI. It was shown that additional use of trimetazidine in the periprocedural period of PCI significantly improved left ventricular ejection fraction, reduced elevated cTnI level (relative risk [RR], 0.69; 95% confidence interval [CI], 0.48- 0.99), angina attacks during PCI (odds ratio [OR], 0.16; 95% CI, 0.07-0.38), and ischemic ST-T changes on the electrocardiogram during PCI (RR, 0.76; 95% CI, 0.59-0.98).

It should be noted that this meta-analysis is in line with another meta-analysis27 that also showed a cardioprotective effect of trimetazidine in patients that underwent coronary artery bypass graft surgery. The authors of both meta-analyses have noted the superiority of trimetazidine over conventional therapy during revascularization procedures. However, the authors also emphasize that new clinical trials with large samples and rigorous designs are needed.

Several mechanisms are responsible for the prevention of ischemic reperfusion injury; one of these is the ability of trimetazidine to inhibit the opening of mitochondrial permeability transition pores, a crucial event in cardiomyocyte death after myocardial ischemia-reperfusion.28

Contrast-induced nephropathy following percutaneous coronary intervention

Contrast-induced nephropathy (CIN) or contrast-induced acute kidney injury is a common but underdiagnosed complication of coronary diagnostic and interventional procedures that is associated with increased in-hospital morbidity and mortality, prolonged hospital stay, and raised health care costs.29-33 CIN is the third most common cause of hospital-acquired acute renal failure.34

It is known that the administration of contrast media (CM) rapidly induces intense renal vasoconstriction and subsequent reduced blood perfusion. This can lead to ischemic and hypoxic damage of the renal medulla and the production of oxygen free radicals, inducing tubular epithelial damage.35 Additional factors such as hypotension, microembolization of atheromatous debris, or bleeding complications can also be responsible for the development of CIN.36

In spite of the growing importance of this complication, there is a lack of consensus on how to define CIN. According to the most recognized definition, CIN is an absolute (≥0.5 mg/dL; ≥44 mmol/L) or relative (≥25%) increase in baseline serum creatinine (SCr) levels 48-72 hours after an exposure to iodinated CM.

Generally, the incidence of CIN in individuals with normal renal function who undergo PCI is low (<3%).37 However, it rises remarkably in patients with chronic kidney disease (CKD) (up to 40% and even more).29,37 Besides pre-existing CKD, other predisposing factors for CIN are diabetes, congestive heart failure, hypotension, hypertension, preprocedure shock, recent MI, anemia, female sex, advanced age, and concomitant use of nephrotoxic agents.29,38 Procedure-related risk factors for the development of CIN include high volume of CM, as well as its high osmolarity, intra-arterial injection, and multiple CM exposures within the past 72 hours.38 There is no specific treatment for CIN after PCI—prevention remains the most effective strategy. The first step in the prevention of CIN is the identification of patients at high risk. The most commonly used scoring system is the Mehran score.39 Preventive strategies for CIN include the limitation of CM volume; use of preheated (37°C) iso-osmolar CM; pre-PCI hydration with normal saline; use of N-acetylcysteine, sodium bicarbonate, and statins; and stopping nephrotoxic drugs 48 hours before and after CM exposure.40-42 The search continues for new pharmacologic and nonpharmacologic interventions for the prevention of CIN in patients undergoing coronary diagnostic and interventional procedures.

Figure 2. Serum creatinine levels in control group and trimetazidine group. Abbreviation: TMZ, trimetazidine. Adapted from reference 43: Onbasili et al. Heart. 2007;93:698-702. © 2007, BMJ Publishing Group Ltd.

Trimetazidine for the prevention of contrast-induced nephropathy in patients undergoing coronary interventions

Onbasili et al43 were the first to clinically evaluate the efficacy of trimetazidine in the prevention of CIN in patients with high SCr levels undergoing coronary angiography or PCI. A total of 82 patients with basal SCr levels between 1.2 and 2.5 mg/dL were enrolled in a prospective double-blind, randomized, controlled trial. Indications of the coronary interventions were acute coronary syndrome, stable angina, dilated cardiomyopathy, and preoperative assessment. Of all patients, 19 had diabetes mellitus (all of them type 2). In this study, patients were randomized into a trimetazidine group (20 mg three times daily, orally, for 72 hours starting 48 hours before the procedure) or a control group. The standard parenteral hydration protocol was applied to patients in both groups. SCr levels were measured before the procedure, 48 hours, and 7 days after the procedure. An increase in SCr level exceeding 0.5 mg/day or one-quarter of the baseline value was considered as CIN. It was found that SCr levels in the control group increased significantly 2 days after the procedure (P<0.05) and returned to the baseline values on the seventh day (Figure 2). On the other hand, they did not change significantly on the second day, and they even significantly decreased on the seventh day in the trimetazidine group (P<0.05). CIN developed in 2.5% (1/ 40) of patients in the trimetazidine group and in 16.6% (7/42) of patients in the control group (P<0.05).

Later, Rahman et al44 in a large prospective randomized, controlled trial again confirmed the ability of trimetazidine to prevent CIN after coronary angiogram or PCI. A total of 400 patients were enrolled in this study; in contrast to the study performed by Onbasili et al,43 patients with diabetes were excluded. Of the 400 enrolled, 200 patients were treated with trimetazidine plus hydration with normal saline and 200 patients (control group) were given hydration with normal saline only. The dose of trimetazidine was 35 mg twice daily for 96 hours starting 48 hours before the procedure. It was found that the incidence of CIN was significantly reduced by administration of trimetazidine with saline in comparison with saline alone (4% vs 14%; P<0.05).

While the two above-mentioned trials43,44 enrolled nondiabetic or a mixture of diabetic and nondiabetic patients with CKD, the study performed by Shehata45 evaluated the effect of periprocedural administration of trimetazidine on the incidence of PCI-induced myocardial injury and CIN in high-risk patients with diabetes and mild-to-moderate renal dysfunction. The primary end point of the study was the development of CIN 72 hours after PCI. A total of 100 consecutive diabetic patients with chronic stable angina and mild-to-moderate CKD were randomized into a trimetazidine group (35 mg of agent twice daily for 72 hours starting 48 hours before the procedure) and a control group (without trimetazidine). The standard parenteral hydration protocol was applied to all included patients. Additionally, N-acetylcysteine (1200 mg) was given to patients in both groups 24 hours before and after the procedure. There was no statistically significant difference between the two groups in terms of the preliminary angiographic findings and procedural characteristics. However, postprocedural mean cTnI level was significantly higher in the control group than in the trimetazidine group (6 hours: 8±0.3 vs 16±0.2 pg/mL, P<0.001; 12 hours: 13±0.9 vs 24±0.8 pg/mL, P<0.001; and 24 hours: 7±0.7 vs 14±0.3 pg/mL, P<0.001). The SCr level in the control group significantly increased 3 days after PCI and decreased on the tenth day. On the other hand, no significant change was observed in the trimetazidine group. Mean cTnI levels as well as mean SCr levels in both study groups are graphically presented in Figures 3 and 4. CIN was noted in 6 patients (12%) of the trimetazidine group, whereas it occurred in 14 patients (28%) of the control group (P<0.05). Thus, the study performed by Shehata45 was the first one to evaluate both the anti-CIN and the anti-PMI effects of trimetazidine in diabetic patients with CKD undergoing elective PCI.

Last year Nadkarni et al46 published a meta-analysis that pooled data from the three above-mentioned RCTs, which altogether included 582 patients with CKD and SCr levels ranging from 1.26 to 2 mg/dL. It was shown that in patients undergoing coronary angiography, administration of trimetazidine in conjunction with normal saline and/or oral N-acetylcysteine was associated with a significant reduction in the incidence of CIN by 11% (risk difference 0.11; 95% CI, 0.16-0.06; P<0.01) when compared with the control group. The number needed to treat to prevent 1 episode of CIN was 9. The authors concluded that trimetazidine could be considered a potential tool for prevention of CIN in patients with renal dysfunction. On the other hand, Nadkarni et al46 emphasized that considering the small sample size of these studies and the level of evidence being 1C, decision making about the use of trimetazidine should be individualized to each patient and each clinical context.

 

Recently Liu et al47 have confirmed once again the renoprotective effect of trimetazidine on CIN in patients with mild-tomoderate renal dysfunction who undergo coronary angiography or PCI. In this single-center prospective, randomized controlled clinical trial, 132 patients with renal dysfunction undergoing coronary angiography or PCI (more than half of all patients) were divided into a control group (n=70) and a trimetazidine group (n=62). Trimetazidine was administered orally 48 hours before and 24 hours after the procedure. Standard hydration was used in all included patients.

Figure 3. Graphic presentation showing changes in mean cardiac troponin I levels in control group and trimetazidine group. Abbreviation: PCI, percutaneous coronary intervention. Adapted from reference 45: Shehata. Am J Cardiol. 2014;114:389-394. © 2014, Elsevier Inc. All rights reserved.

Figure 4. Graphic presentation showing changes in mean serum creatinine levels in control group and trimetazidine group. Abbreviation: PCI, percutaneous coronary intervention. Adapted from reference 45: Shehata. Am J Cardiol. 2014;114:389-394. © 2014, Elsevier Inc. All rights reserved.

Postoperative SCr concentration was significantly lower in the trimetazidine group than in the control group at 48 hours but not at 24 hours (P=0.026 and P=0.056, respectively), whereas postoperative cystatin C level was significantly lower in the trimetazidine group both at 24 and 48 hours than in the control group (P=0.000 and P=0.025, respectively). Trimetazidine significantly reduced the incidence of CIN (8% vs 20% in control; P=0.034). Moreover, the incidence of adverse events within 12 months of follow- up was significantly lower in the trimetazidine group than in the control group (9.6% vs 22.8%; P=0.043). The Kaplan-Meier survival curves of adverse events showed that the incidence of adverse events significantly decreased in the trimetazidine group compared with the control group (log rank P=0.035) (Figure 5). A significant correlation between the adverse events and the incidence of CIN was also noted.

Figure 5. Kaplan-Meier survival curve of the timing of adverse events during the followup period. Abbreviation: TMZ, trimetazidine. Adapted from reference 47: Liu et al. Am J Med Sci. 2015;350:398-402. Copyright © 2015 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Akgüllü et al48 explain the renoprotective properties of trimetazidine against CIN by its antioxidant properties. In an experimental study, the authors showed significantly higher levels of malondialdehyde and lower levels of superoxide dismutase activity in a CM alone group than in a CM plus trimetazidine group. Moreover, histopathological analysis demonstrated a significant expansion of Bowman’s capsule, tubule epithelium degeneration, tubule epithelium necrosis, and interstitial infiltration in the CM group compared with the CM plus trimetazidine group. Interestingly, none of the histopathological scores differed significantly between the CM plus trimetazidine group and the control group (without CM). It is important to mention that the potent antioxidant effect of trimetazidine has been demonstrated not only in myocardial and renal, but also hepatic, pulmonary, intestinal, and testicular ischemia-reperfusion injuries.49-53 This allows us to consider trimetazidine a promising agent that can prevent development of ischemia-reperfusion injuries during revascularization procedures. However, several issues are still to be clarified. First of all, it is necessary to identify the optimal duration of the pre- and post-procedural administration of trimetazidine. The question regarding the optimal dose of trimetazidine also remains open. Moreover, new studies are needed to evaluate not only the efficacy but also the safety of trimetazidine in different patient populations having undergone revascularization procedures. For example, this agent is contraindicated when creatinine clearance is below 30 mL/min. The dose of trimetazidine that will be most effective in the context of prevention of ischemia-reperfusion injury in patients with creatinine clearance of 30-60 mL/min is still to be defined as well. Largescale studies are required to answer these questions.

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