Metabolic agents in the protection of patients who undergo revascularization



by Y. Chen, China

Yundai CHEN, MD, PhD Department of Cardiology Chinese PLA General Hospital Beijing, CHINA

In clinical practice, metabolic agents, including trimetazidine, ranolazine, and glucose-insulin-potassium, often play an adjunctive role in the treatment of angina pectoris. With the worldwide use of percutaneous coronary intervention, especially stent implantation, doctors have come to realize that some patients still suffer from angina, percutaneous coronary intervention– related complications, or poor quality of life. For such reasons, researchers have used metabolic agents to treat patients who have undergone percutaneous coronary interventions, and some progress has been observed in this area. In this review article, we mainly discuss the protective role of three widely used agents: trimetazidine, ranolazine, and glucose-insulin-potassium in patients with coronary artery disease, with a particular focus on patients who have undergone percutaneous coronary intervention. Aside from these three, there are other metabolic agents requiring further investigation to confirm their benefits for patients undergoing revascularization.

In recent years, evidence-based medicine has demonstrated that revascularization can save lives in patients with acute coronary syndrome (ACS) and improve their quality of life. Research has shown that some metabolic agents could further benefit those patients and reduce ischemia-reperfusion injury or percutaneous coronary intervention (PCI)-related injury. Metabolic agents proven to be useful in patients who undergo revascularization include trimetazidine, ranolazine, L-carnitine, glucose-insulin-potassium (GIK), ribose, dichloroacetate, and perhexiline, of which trimetazidine, ranolazine, and GIK were the most evaluated in recent years.

Metabolic agents as adjunctive therapy in patients undergoing PCI

Trimetazidine
Trimetazidine, a piperazine derivative, has a long history of research, especially with regard to cardiac protection. Used worldwide as an adjunctive therapy for stable angina, trimetazidine’s protective effect in patients that undergo PCI has become a research focus.

In a small (n=20), randomized, double-blind, placebo-controlled trial, Kober et al found that trimetazidine treatment during percutaneous transluminal coronary angioplasty (PTCA) decreases intervention-related myocardial ischemia.1 Polonski et al reported that pretreatment with trimetazidine appears to be cardioprotective, helping to prevent myocardial ischemia during PTCA.2 In a study by Steg and his colleagues, patients with acute myocardial infarction (AMI) were prescribed intravenous trimetazidine as an adjunctive therapy to primary angioplasty. The authors demonstrated that trimetazidine was safe and led to earlier resolution of ST-segment elevation. 3 Later, in a prospective study, Labrou et al demonstrated that pretreatment with trimetazidine minimizes myocardial reperfusion injury during PCI and improves global and regional wall motion at 1 and 3 months after PCI.4 This result was further supported by a multicenter, randomized, and controlled study aiming to evaluate the myocardial protection of trimetazidine during PCI; the results suggested that perioperative trimetazidine therapy can reduce the frequency of angina attacks and myocardial damage during PCI and improve left ventricular function during follow-up after PCI.5 A study specifically aimed at the effect of trimetazidine on recurrent angina and left ventricular structure in elderly multivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation also found that adjunctive therapy with trimetazidine had a beneficial effect in these patients.6

For elective PCI patients, pretreatment with trimetazidine is a reasonable option; but what about acute PCI patients? To answer this question, Bonello et al carried out a study focusing on the protective effect of an acute oral loading dose of trimetazidine on myocardial injury induced by PCI. The results suggested that preprocedural acute oral trimetazidine administration significantly reduces PCI-induced myocardial injury.7 Aside from patients undergoing PCI, researchers also studied trimetazidine’s effect on ischemic injury and reperfusion in patients undergoing coronary artery bypass graft (CABG) surgery, with the same result.8,9

Cardioprotective mechanism
A number of investigations have looked into the mechanism involved in the cardioprotection afforded by trimetazidine. Tritto et al showed us that trimetazidine protects the post-ischemic heart from neutrophil-mediated injury.10 In an ischemia-injury rat model, Khan et al found that trimetazidine administered at the onset of reperfusion ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling.11 In a recent study, Yang et al revealed that by upregulating microRNA-21 (miR-21) expression, trimetazidine counteracts the apoptotic effect of hypoxia/ reperfusion.12 Consistent with previous studies, Senturk et al found that combination of N-acetylcysteine and trimetazidine effectively decreases oxidative stress, infarct area, and apoptotic activity in a rat model of ischemic reperfusion.13 Trimetazidine also improves endothelium-dependent relaxation in patients with ischemic cardiomyopathy, owing to its antioxidant properties.14 A recent experimental study suggested that trimetazidine ameliorates intracellular calcium (Ca2+) homeostasis via a switch from lipid metabolism to glucose metabolism, thereby producing its cardioprotective effect and reducing damage to hypoxic cardiomyocytes.15

On the basis of these findings, Kim et al analyzed data from the Korean Acute Myocardial Infarction Registry and found that trimetazidine improves clinical outcomes in AMI patients by significantly reducing all-cause mortality and major adverse cardiac events (MACEs) over 12 months.16 For specific patients, such as diabetic patients with renal dysfunction undergoing elective PCI, a study demonstrated that trimetazidine administered before elective PCI decreases the incidence of contrast-induced nephropathy (CIN).17

Our team also demonstrated that long-term treatment with trimetazidine after stent implantation reduced in-stent restenosis and MACE in a 1-year follow-up study.18 In this study, 768 patients were enrolled and randomized into a trimetazidine group (n=384) or a control group. After drug-eluting stent implantation, all patients were treated with regular medication.

In the trimetazidine group, 20 mg trimetazidine was administered three times a day for at least 30 days. All patients received follow-up angiography 9-13 months after discharge. The final analysis included 635 patients (trimetazidine group, n=312; control group, n=323). Stent restenosis occurred in 49 (7.7%) patients. The trimetazidine group had a lower incidence of stent restenosis than the control group (4.2% vs 11.1%; P=0.001). At the 30-day follow-up, the trimetazidine group exhibited a higher left ventricular ejection fraction than the control group (65.4±10.7 vs 63.1±10.4; P=0.006). The incidence of major adverse cardiac and cerebrovascular events (MACCEs) was also lower in the trimetazidine group at the 1-year follow-up (6.1% vs 10.8%; P=0.032). Further multivariate analysis revealed that trimetazidine treatment was a predictor for stent restenosis (odds ratio, 0.376; 95% confidence interval, 0.196-0.721; P=0.003). This result was also supported by a Sprague-Dawley rat model experiment that demonstrated that trimetazidine inhibits the proliferation and migration of vascular smooth muscle cells and promotes the proliferation of human umbilical vein endothelial cells.19

Aside from these benefits for the heart, trimetazidine also protects the artery from PCI-related injury. Yoon et al reported that trimetazidine effectively accelerates re-endothelialization after carotid balloon injury.20 Recent studies have also demonstrated that trimetazidine significantly lessens endothelial dysfunction in the radial artery after catheterization.21,22 In a recent meta-analysis, the authors concluded from nine studies involving a total of 778 patients that adjunctive therapy with trimetazidine in patients undergoing PCI may reduce myocardial injury during the procedure and improve cardiac function. 23

Other protective effects
Besides the protective effect on the cardiovascular system, recent studies suggest that trimetazidine may have potential for use in prevention of CIN. In one meta-analysis including three randomized controlled trials in the final analysis, the addition of trimetazidine treatment significantly decreased the incidence of CIN in patients that underwent coronary angiography. 24 The authors pointed out that care should be taken in the interpretation of this result, taking into account the small sample size.

Final comments about trimetazidine
Collectively, these studies provide sufficient reason to believe that for elective PCI patients, pre- or perioperative treatment with trimetazidine reduces PCI-related myocardial and vascular injury and improves heart function; and that for ACS patients, an acute oral loading dose of trimetazidine or longterm treatmentwith trimetazidine after stent implantation would also benefit these patients; however, the use of trimetazidine for preventing CIN is not recommended as first-line therapy and still needs to be assessed in more clinical trials.

Ranolazine
Ranolazine is another drug used as an adjunctive therapy for angina in symptomatic patients who are inadequately controlled with first-line antianginal therapies.25,26 Among diabetic patients that have chronic angina despite treatment with up to two agents, ranolazine was found to reduce angina and sublingual nitroglycerin use and to be well tolerated.27 A systematic review of randomized controlled trials included seven studies and concluded that ranolazine reduces anginal symptoms among patients with symptomatic chronic stable angina pectoris28 and is probably cost effective.29 Recent studies have shown additional benefits of ranolazine in patients with coronary heart disease. Some experimental studies have demonstrated that ranolazine reduces myocardial infarct size and improves left ventricular function.30,31 It also markedly reduces ventricular arrhythmias induced by ischemia and ischemia-reperfusion, indicating a protective role in PCI in patients with ACS.32 Possible mechanisms involved in these phenomena include reduction in Ca2+ overload and oxidative stress and improvement in mitochondrial integrity.33-35 On the basis of these findings, some clinical research focused on the role of ranolazine in post-revascularization atrial fibrillation (POAF). Tagarakis et al found a protective role for oral ranolazine when administered preoperatively at a moderate dose in patients undergoing on-pump CABG surgery. Their findings suggest that perioperative treatment with ranolazine effectively reduces the incidence of POAF,36 a result that has been supported by further studies.37-39 In patients that underwent PCI, ranolazine has been found to reduce recurrent ischemic events and improve quality of life.40,41

However, as presented at the 2015 American Heart Association (AHA) Scientific Sessions, the RIVER-PCI study (Ranolazine for Incomplete Vessel Revascularization) showed no incremental benefit in angina or quality of life measures from adding ranolazine treatment in an angiographically-identified population.42 Furthermore, an overall analysis of this study revealed that ranolazine did not reduce the composite rate of ischemia-driven revascularization or hospitalization without revascularization in patients with a history of chronic angina who had incomplete revascularization after PCI.43

Final comments about ranolazine
In our opinion, despite a confirmed role for ranolazine in angina frequency and in quality of life, further investigation—welldesigned clinical trials, especially—are warranted to evaluate its effect in CAD patients undergoing PCI. The use of ranolazine in patients that are to undergo PCI should not be encouraged for now.

Glucose-insulin-potassium
GIK has been used as metabolic therapy in practice for many years. Earlier studies found that GIK improves hemodynamic performance and is associated with reduced troponin I release after on-pump CABG surgery.44,45 It also improves myocardial perfusion after revascularization and lessens the LV remodeling observed at follow-up.46,47 These results are supported by other experimental research.48,49 However, a 1-year follow-up study found that GIK therapy offers no clinical benefit in patients with ST-elevated myocardial infarction (STEMI) without signs of heart failure.50 Further meta-analysis also suggested that GIK does not reduce mortality in patients with AMI.51 Despite these negative results, some important studies were carried out to determine the effect of GIK on patients with CAD. In the IMMEDIATE randomized controlled trial (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care), Selker et al found that in patients with suspected ACS, out-of-hospital treatment with GIK did not reduce progression to MI and although it did not improve 30-day survival, it was associated with lower rates of the composite outcome comprising cardiac arrest and in-hospital mortality.52 Similar results were found in a 1-year follow-up of this study, whereas in those with STEMI, the composite of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or hospitalization for heart failure within 1 year, were significantly reduced. This benefit might be limited to AMI patients.53 A further meta-analysis also revealed that administration of GIK in ACS patients did not significantly reduce mortality after the onset of symptoms.54

Final comments about GIK
On the basis of the above, we believe that presently we do not have enough evidence to support the first-line use of GIK in patients undergoing PCI. Studies to further investigate the role of GIK in these patients are needed.

Other metabolic agents
L-Carnitine is another adjunctive therapy for angina pectoris and has been shown to attenuate left ventricular dilation during the first year after an AMI, resulting in smaller left ventricular volumes at follow-up.55 In the stent era, L-carnitine has also been used in patients undergoing PCI, with inconsistent results. Xue et al found that L-carnitine as an adjunctive therapy to PCI was associated with a reduced level of cardiac markers in patients with non-STEMI.56 A later systematic review and meta-analysis found that, compared with placebo or control, L-carnitine was associated with a 27% reduction in all-cause mortality, a 65% reduction in ventricular arrhythmias, and a 40% reduction in anginal symptoms in patients experiencing an AMI.57 However, these findings were not consistent with results from another meta-analysis in which the authors concluded that there was no significant marginal benefit in terms of all-cause mortality, heart failure, unstable angina, or myocardial reinfarction in the setting of AMI for oral L-carnitine maintenance doses of 2 g or greater per day.58 A possible reason behind the differing results of these two studies may involve the different number of trials included in the metaanalyses (13 vs 5 respectively). On the basis of these inconsistent findings, we suggest that clinical trials—well-designed randomized controlled trials, especially—are needed to further determine the effect of L-carnitine treatment in patients with CAD, especially those planned to undergo PCI.

Recent studies have demonstrated that the metabolic agent dichloroacetate improves cardiac contractile dysfunction after ventricular fibrillation59 and also prevents restenosis in preclinical animal models of vessel injury.60 However, until more evidence is available, care should be exercised when considering its clinical use in patients undergoing PCI.

Additional metabolic agents, such as perhexiline, ribose, and others, still need further investigation to confirm their roles in patients with CAD, especially for those undergoing PCI.

Conclusions

There are a number of metabolic agents widely used in adjunctive therapy for anginal pectoris. Their use in patients that have undergone PCI has been under investigation for some time, with differing levels of support available for the various agents. With regard to the agents discussed in this article, we believe a sufficient amount of evidence has accumulated in support of a protective role for trimetazidine, though its use in preventing CIN should be further investigated. In our opinion, ranolazine, GIK, and L-carnitine, among other metabolic agents briefly touched on here, require further investigation regarding their use in patients undergoing revascularization.

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