EDITORIAL COMMENT
Metabolic Approach in Heart Failure
Rethinking How We Translate From Theory to Clinical Practice*
W.H. Wilson Tang, MD, FACC1,*
Department of Cardiovascular Medicine, the Cleveland Clinic, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. W. H. Wilson Tang, Department of Cardiovascular Medicine, the Cleveland Clinic, 9500 Euclid Avenue, F25, Cleveland, Ohio 44195. (Email: tangw{at}ccf.org).
The concept of metabolic modulation in the treatment heart failure has been extensively reviewed in several recent publications (1–3). Over the past decades, several dugs that have been shown to affect the metabolic processes in the failing heart, including carnitine palmitoyl transferase I and/or II inhibitors such as etomoxir (4) and perhexiline (5), late sodium current inhibitors such as ranolazine (6), and long-chain 3-ketoacyl coenzyme A thiolase inhibitors such as trimetazidine (7). Some of these drugs are believed to work by partially inhibiting the oxidation of fatty acids in ischemic myocytes. Because oxidation of glucose requires less oxygen per mole of adenosine triphosphate generated, glucose oxidation is preferable to fatty acid oxidation when oxygen availability is limited in underperfused cardiac tissue. However, unlike neurohormonal antagonism, this concept of supplying "better" fuel to improve myocardial efficiency has not received wide acceptance. Part of the issue is the lack of reliable assessment tools to identify the phenotype of metabolic distress, and part is due to the lack of large-scale clinical trials to support their use. Hence, the majority of these agents have found themselves going through a long and tedious regulatory approval process for the treatment of angina pectoris rather than heart failure.
Trimetazidine has been approved for the treatment of angina pectoris in most of Europe and Asia (but not in the U.S.), and in some countries trimetazidine is even available in generic forms. In this issue of the Journal, Fragasso et al. (8) reported the results of a prospective, open-label, parallel group, randomized study comparing add-on trimetazidine versus conventional therapy in 65 consecutive, mostly nondiabetic and well-treated patients with symptomatic chronic systolic heart failure. The investigators had previously conducted several studies in patients with ischemic cardiomyopathy, and took a further step to test the effects of trimetazidine on cardiac and exercise performance in a subset of patients suffering from non-ischemic dilated cardiomyopathy. The results are intriguing—trimetazidine was associated with significant improvement in functional capacity, quality of life, and plasma natriuretic peptide levels compared with conventional therapy; the improvement was equally apparent in patients with non-ischemic and ischemic cardiomyopathy. The mean improvement in left ventricular ejection fraction was 7%-U, which is consistent with prior observations (9) and comparable with that of beta-adrenergic blockers. As in previous studies, trimetazidine was well tolerated and provoked no hemodynamic dysfunction.
The observation that trimetazidine reverses left ventricular remodeling in patients with non-ischemic cardiomyopathy challenges the longstanding working hypothesis that trimetazidine counteracts the "metabolic switch" in the setting of myocardial ischemia. However, the findings may be consistent with recent work in animal models that suggests that there is a downregulation of fatty acid oxidation enzymes; the switch to carbohydrate oxidation may only be a late-stage phenomenon in the heart failure phenotype, and may not be present in otherwise chronic compensated states (10). Furthermore, it cannot be assumed that the mechanism of action of trimetazidine in patients with non-ischemic cardiomyopathy is solely attributable to modulation of the metabolic switch. On the other hand, subclinical regional myocardial ischemia can present in patients with nonstenotic epicardial coronary arteries, and abnormalities in positron emission tomography are commonly observed in the setting of non-ischemic cardiomyopathy (11,12). Whether trimetazidine acts as an anti-ischemic agent in patients without overt myocardial ischemia is still unclear.
This paper raises a more important conceptual question in an era when development of heart failure drug therapy is becoming more challenging (13). To date, reversal of left ventricular remodeling has been the most reliable and consistent surrogate marker for heart failure drugs that have demonstrated mortality benefits (14). Trimetazidine is an approved drug with longstanding clinical experience in treating angina in patients outside of the U.S. It has a good safety profile and is free of deleterious hemodynamic effects. Although there is still debate regarding its role in angina management, multiple clinical studies (all <100 subjects per study) have shown short-term and long-term improvement in left ventricular ejection fraction in patients with heart failure who were treated with trimetazidine (9,15–21). The exact phenotype for those who had a response to trimetazidine remain to be clearly identified. However, the prerequisite for drug approval in the U.S. mandates a thorough demonstration of hard end points (composed mainly of mortality benefits, or morbidity benefits combined with objective clinical improvement) in large clinical trials. This strategy is appropriate and absolutely necessary for newly discovered compounds coming along the research development pipeline to ensure public safety and to establish drug efficacy. However, one may wonder whether a widely used and well-tolerated agent (such as trimetazidine) must follow the same rigorous process. Unless we reconsider our approach, the promise of these types of medical therapies are likely out of reach because of the cost of performing large-scale pivotal trials and potential rejection from regulatory agencies.
Studies such as this give us an opportunity to reflect on how heart failure drugs work and how we should approach an established drug with a novel therapeutic mechanism in the challenging environment of drug approval. The risk/benefit profile of the intervention is already well recognized. One can easily make a list of criticisms toward single studies (open-label study, small sample size, single-center study, lack of clinical outcomes, and so on), and conclude that further studies are needed. The challenge is to translate decades of theory into clinical practice—does the answer lie in getting more evidence by conducting larger clinical trials, finding better ways to characterize the phenotype, or rethinking the way we determine how drugs should be made available? What is clear is that in the near future, trimetazidine will not likely become an option for treating heart failure in clinical practice in the U.S. It is difficult to reconcile the promise of such therapies with the reality that the barriers to their approval as heart failure drugs seems insurmountably high.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
1 Dr. Tang has previously received honorarium from CV Therapeutics, Inc. and previously served as a consultant to Amylin Pharmaceuticals and GlaxoSmithKline Pharmaceuticals. He is currently a member of the Speakers’ Bureau for Takeda Pharmaceuticals and is a consultant for F. Hoffman La-Roche.
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References
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