The place of metabolic agents in contemporary coronary artery disease guidelines



by L . H. W. Gowdak, Brazil

Luis Henrique Wolff GOWDAK, MD, PhD, FESC Laboratory of Genetics & Molecular Cardiology and Chronic Coronary Artery Unit, Heart Institute (InCor) University of São Paulo Medical School, São Paulo, BRAZIL

In the healthy human heart, free fatty acids (FFAs) supply approximately 60% to 90% of the energy used to synthesize adenosine triphosphate (ATP); 10% to 40% comes from glucose and lactate. During ischemia, reduced delivery of oxygen to cardiomyocytes leads to a decrease in ATP formation by oxidative phosphorylation, an increase in the rate of glycolysis, and a high rate of conversion of pyruvate to lactate. This metabolic disturbance yields a disruption in cell homeostasis (with accumulation of lactate and H+ ions), a fall in intracellular pH, and a reduction in contractile work. A metabolic shift by direct inhibition of FFA oxidation in the mitochondria with trimetazidine results in a decrease in the frequency of angina attacks, increased exercise tolerance, improvement in quality of life, enhanced myocardial contractility in patients with left ventricular dysfunction, and reduced myocardial damage during myocardial revascularization procedures. The European Society of Cardiology guidelines on stable angina indicate that trimetazidine may be considered second- line for the treatment of angina/relief of ischemia in patients already receiving a β-blocker and/or calcium channel antagonist to control symptoms. With a different view, the Brazilian guidelines on stable angina recommend trimetazidine for symptom relief as an add-on therapy right after β-blockers, but before long-acting nitrates (unless there is a need for better blood pressure control, in which case calcium channel antagonists are preferable).

When William Heberden first named and described angina pectoris in 1772, its treatment appeared the stuff of far-off dreams: “(…) With respect to the treatment of this complaint, I have little or nothing to advance: nor indeed is it to be expected we should have made much progress in the cure of a disease, which has hitherto hardly had a place or a name in medical books.”1 How times have changed. Since the description more than 250 years ago of the clinical presentation of an entity of which William Heberden could “not recollect any mention among medical authors,”1 and for which he “had little or nothing to advance” regarding its treatment, the modern cardiologist now faces a completely different challenge: that of devising an adequate therapeutic strategy for patients with stable angina using the many options available, which include antianginal drugs and myocardial revascularization procedures (percutaneous or surgical). But for physicians of the past the treatment scenario was very different: it took almost a century after Heberden’s description before the Scottish physician Sir Thomas Brunton 2 first used amyl nitrite in the treatment of angina pectoris in 1867. “In angina pectoris we wish a drug which will relax spasm of the vessels very quickly, but as a rule we do not require the relaxation to be prolonged,” said Brunton of the type of pharmacological effect he thought would be useful.3 While Brunton was using amyl nitrite, another British physician, William Murrell, began using nitroglycerine in the treatment of angina pectoris.4 After almost a century during which the use of nitrates had gained wide popularity as the only medical treatment for angina, there were two important new arrivals in the twentieth century: β-blockers5 (early-1960s) and calcium channel antagonists6 (late-1960s to mid-1970s). These drugs formed the new medical management basis for symptom relief in patients with stable angina; they could either be used alone or in combination, as tolerated, in the absence of contraindications to their use.

Although many patients certainly benefited from a combination of these so-called hemodynamic agents, it later became apparent that others remained symptomatic despite the use of maximally tolerated doses of these drugs. Moreover, even after an increase in the use of myocardial revascularization procedures, including a boom in the number of percutaneous coronary interventions (PCIs), patients would remain free of angina for different lengths of time, only to return a couple of years later complaining of angina again. In the randomized trial MASS (Medicine, Angioplasty, or Surgery Study) II,7 for example, in patients with nonlimiting angina, multivessel disease, and preserved left ventricular function at baseline, 45% of those initially assigned to optimal medical therapy (a combination of β-blockers and/or long-acting nitrates and/or calcium channel antagonists) were still symptomatic after 5 years of followup; however, it should be noted that even for those who were assigned to a myocardial revascularization procedure, the prevalence of angina was 22% (PCI group) and 25% (surgical group). In the COUrAGE (Clinical Outcomes Utilizing revascularization and AGgressive drug Evaluation) trial,8 in which optimal medical therapy with or without PCI was offered to patients with stable angina, about 40% of patients were still complaining of angina after only 3 years of follow-up, regardless of the therapeutic strategy assigned. These observations, which are not unique in the literature, raised the question, “When it comes to offering optimal symptom control, what is true ‘optimal medical therapy’ in patients with stable angina?” This led to an intensive search for drugs with alternative mechanisms of action to hemodynamic modulation to be added to the therapeutic armamentarium for the management of patients with ischemic heart disease (IHD).

Figure 1. Temporal sequence of ischemic events during stress-induced myocardial ischemia. Note that after perfusion heterogeneity sets in, metabolic alteration appears before any detectable functional abnormality. Chest pain is usually the latest manifestation of ongoing myocardial ischemia. Abbreviation: ECG, electrocardiography. Copied from reference 10: Kim and Youn. J Cardiovasc Ultrasound. 2009;17(2):40-53.© 2009, Korean Society of Echocardiography.

Optimizing energy metabolism as a therapeutic target in patients with angina

Even though angina is regarded as the clinical hallmark of coronary artery disease (CAD), as so eloquently described by Heberden, myocardial ischemia cannot be considered an event precisely circumscribed by the onset and resolution of angina. In fact, the identification of an ischemic cascade of pathophysiologic events9 broadened not only our understanding of different clinical presentations of CAD, but also opened upopportunities for new therapeutic strategies. Figure 1 shows the temporal sequence of ischemic events during stress-induced myocardial ischemia.10

Basic concepts in heart metabolism
Because metabolic disturbances occur early on during myocardial ischemia, the clinician should bear in mind basic concepts related to heart metabolism. In the healthy human heart, free fatty acids (FFAs) supply approximately 60% to 90% of the energy used to synthesize adenosine triphosphate (ATP), whereas the remaining 10% to 40% of the energy comes from different energetic substrates, ie, glucose and lactate.11 Once in the mitochondrion, FFAs undergo b-oxidation, a complex multistep enzymatic process, to produce ATP for contractile work, calcium uptake by the sarcoplasmic reticulum, and ion homeostasis.12 Glucose is taken up by the myocardium and is either stored as glycogen or broken down by glycolysis to pyruvate in the cytosol of the cell. Pyruvate is oxidized to acetyl-CoA in the mitochondria by the enzyme pyruvate dehydrogenase. Oxidation of glucose and lactate is strongly inhibited by high rates of FFA oxidation in the heart (Figure 2).11

Heart metabolism during ischemia
Reduced oxygen delivery to cardiomyocytes during ischemia leads to mitochondrial metabolic dysfunction, resulting in a decrease in ATP formation by oxidative phosphorylation and an increase in the rate of glycolysis. Pyruvate produced by glycolysis is not so readily oxidized in the mitochondria, which allows a high rate of conversion of pyruvate to lactate in the cytosol and a consequent rise in tissue lactate levels.13 This metabolic disturbance seen during myocardial ischemia yields a dramatic disruption in cell homeostasis, with accumulation of lactate and H+ ions, a fall in intracellular pH, and a reduction in contractile work (Figure 3).11

Targeting FFA and carbohydrate oxidation in IHD
Direct inhibition of FFA oxidation in the mitochondria with the 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor trimetazidine results in an increase in the rates of glucose and/or lactate uptake and oxidation.14 The suppression of FFA oxidation and increased oxidation of pyruvate by pyruvate dehydrogenase in the mitochondria reduces ischemia-induced disruption of cardiac metabolism. In other words, inhibiting cardiac FFA oxidation and increasing the oxidation of pyruvate results in less lactate production and less of a fall in cell pH, resulting in clinical benefit for the ischemic patient. This direct metabolic approach is optimally suited to conditions in which there is sufficient residual oxygen delivery to the myocardium to support pyruvate oxidation in the mitochondria.15 In other words, it is important that there be a sufficient rate of acetyl-CoA oxidation and oxygen consumption so that increasing the rate of pyruvate oxidation has a meaningful effect on the rate of lactate production. This metabolic shift from FFA oxidation to glucose oxidation has proven effective in different scenarios in patients with IHD and/or heart failure.

Clinical benefits of trimetazidine in patients with stable angina

Back in the late 1960s, the use of trimetazidine in patients with angina pectoris had been proposed and successfully used in small series of patients, although the exact mechanism of action implicated in pain relief was not clear at that time.15,16 Later on, the effects of trimetazidine were compared with those of propranolol in a double-blind parallel group multicenter study in 149 men with stable angina.17 After 3 months, similar antianginal efficacy was observed between the trimetazidine and propranolol groups. No significant differences were observed between trimetazidine and propranolol as regards weekly number of angina attacks, exercise duration, or time to 1-mm ST-segment depression. Similar results were found when trimetazidine was compared to nifedipine.18 Moreover, trimetazidine can be effectively and safely combined with different antianginal drugs including calcium channel antagonists, 19,20 β-blockers,21,22 and long-acting nitrates.23 The combination of trimetazidine with a hemodynamic agent yielded subjective (a decrease in the frequency of angina attacks) and objective (increase in exercise tolerance assessed during a treadmill test) evidence for its role in the management of patients with stable angina not sufficiently controlled with a single hemodynamic agent.

Figure 2. Cardiac energy metabolism under normal aerobic conditions. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; SR, sarcoplasmic reticulum. Modified from reference 11: Stanley. Eur Heart J Suppl. 2001;3(suppl O):O2-O7. © 2001, The European Society of Cardiology.

Figure 3. Cardiac energy metabolism during ischemia of moderate severity. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, inorganic phosphate. Modified from reference 11: Stanley. Eur Heart J Suppl. 2001;3(suppl O):O2-O7. © 2001, The European Society of Cardiology.

Since most clinical trials of trimetazidine involved a limited number of patients, a recently published study looked at 13 randomized controlled trials comprising 1628 patients to determine the efficacy of trimetazidine combined with other antianginal drugs versus other antianginal drugs in the treatment of stable angina pectoris.24 Figure 4 (page 268) shows that the weekly mean number of angina attacks decreased (panel A) and exercise duration improved (panel B) in patients receiving trimetazidine on top of conventional antianginal therapy.24

Trimetazidine in patients with stable angina: what do the guidelines say?

The unequivocal benefits of trimetazidine in patients with stable IHD include: (i) a decrease in the frequency of angina attacks and in the need for short-acting nitrates for pain relief 24; (ii) increased exercise tolerance25; (iii) improvement in quality of life26; (iv) enhanced myocardial contractility in patients with left ventricular dysfunction27; and (v) a reduction in myocardial damage during myocardial revascularization procedures, such as angioplasty28 or bypass surgery.29 In terms of cardiovascular events, trimetazidine may decrease the risk of hospitalizations in patients with heart failure30; the use of trimetazidine has been linked to a lower risk of death in patients after an acute myocardial infarction31 and in patients with heart failure. 30,32 So, how do different medical societies value these benefits and incorporate trimetazidine in their guidelines on stable angina?

The European perspective
The most recent guidelines on stable angina issued by the European Society of Cardiology33 acknowledge trimetazidine as an anti-ischemic metabolic modulator with similar antianginal efficacy to propranolol and devoid of any discernible hemodynamic action. In June 2012, the European Medicines Agency (EMA) reviewed available data regarding its efficacy in effort-induced myocardial ischemia.34 A thorough analysis of the safety and effectiveness of trimetazidine carried out by the EMA concluded that the drug was safe, although movement disorders (including parkinsonism), which were uncommon and reversible after drug discontinuation, could not be excluded with the use of trimetazidine. Thus, in patients with angina pectoris, treatment with trimetazidine should be considered as an add-on to existing treatments in those who are not adequately controlled by, or who are intolerant to, other medicines for angina pectoris. Accordingly, the European guidelines stated that trimetazidine may be considered for the second-line treatment of angina/relief of ischemia in patients already receiving a β-blocker and/or calcium channel antagonist to control symptoms (class of recommendation: IIb; level of evidence: B).33

The North American perspective
Although trimetazidine is not marketed in the United States, its ability to improve cellular tolerance to ischemia, delay the onset of exercise-induced ischemia, and reduce angina episodes and nitroglycerin use has been recognized by US experts in the American College of Cardiology/American Heart Association guidelines on the management of patients with stable angina.35

The Brazilian perspective
Trimetazidine is marketed worldwide and, therefore, included in different national guidelines for the management of patients with stable CAD or stable angina. Because a detailed North American reference to its use is lacking, many countries around the world where trimetazidine is available follow the recommendations proposed by the European Society of Cardiology. The Brazilian Society of Cardiology, however, has taken a slightly different approach in its placement of trimetazidine in the treatment of patients with stable angina.

In the most recent version of the Brazilian guidelines on stable angina,36 β-blockers have kept their position as the first-line treatment for the prophylaxis of angina attacks and shortacting nitrates remain the cornerstone treatment for the immediate relief of chest pain due to CAD. But for patients whose symptoms are poorly controlled with β-blockers, the Brazilian guidelines now recommend that physicians consider adding trimetazidine early on, provided blood pressure and heart rate have been controlled. However, if one needs better control of blood pressure calcium channel antagonists may be preferred.

There are a couple of studies that may support this approach. In these studies, the effects of early administration of trimetazidine on top of different background antianginal therapies were assessed. In one study, 53 patients with symptomatic stable angina receiving propranolol 40 mg tid were randomized to long-acting nitrates or trimetazidine as an add-on therapy for 6 weeks.37 Patients on the combination of a β-blocker + long-acting nitrates had a 30% reduction in the number of angina episodes per week compared to a 62% reduction seen in patients on the β-blocker + trimetazidine combination (P=0.001). A treadmill test revealed that the latter combination yielded a 6-fold increase in total exercise duration (95 s versus 16 s).


Figure 4. Forest plot for the aggregate weekly mean number of angina attacks (panel A) and exercise duration at peak exercise (panel B) in patients received trimetazidine combined with conventional antianginal agents in the treatment of stable angina pectoris, in comparison with conventional antianginal agents. Modified from reference 24: Peng et al. Int J Cardiol. 2014;177(3):780-785. © 2014, Elsevier Ireland Ltd.

In another study, investigators looked at the benefit of adding trimetazidine in 1213 highly symptomatic patients with stable angina being treated with different antianginal strategies, comprising β-blocker alone, β-blocker + long-acting nitrates, or β-blocker + calcium channel antagonist.38 The addition of trimetazidine significantly reduced the weekly number of angina attacks and consumption of short-acting nitrates in all patients, regardless of the treatment strategy used. But, maybe more importantly, the combination of long-acting nitrates or calcium channel antagonists with β-blockers did not provide any additional reduction in the number of angina attacks compared with patients receiving β-blocker + trimetazidine.

So, when the time came to review the Brazilian guidelines on stable angina, the committee decided to give trimetazidine a class IIa recommendation (level of evidence: B) for symptom relief as a second-line treatment, as an add-on therapy right after β-blockers (unless, as previously stated, there is a need for better blood pressure control, in which case calcium channel antagonists are preferable).

Another particular aspect of this document is that long-acting nitrates have been downgraded to a third-line treatment for angina control. The reason being that at least two studies have demonstrated that the long-term use of long-acting nitrates leads to an increase in the risk of cardiovascular events, including death, in healed myocardial infarction patients39 and in diabetes patients who underwent elective PCI.40 Worsening of endothelial dysfunction is a potential complication of longacting nitrates that may be linked to adverse outcomes.41

Conclusion

The benefits of trimetazidine in patients with cardiovascular disease have been demonstrated in several studies and metaanalyses, allowing for its incorporation into practice guidelines not only for stable angina, but also for heart failure. Although there is some consistency in the view of trimetazidine’s use as an add-on agent, there is a slight difference in perception about how soon trimetazidine should be added as a second-line treatment. The more traditional view—expressed by the European Society of Cardiology, for instance— recommends trimetazidine as a second-line agent for use only when a combination of conventional hemodynamic agents, such as β-blockers and calcium channel antagonists, has been unable to control symptoms satisfactorily. On the other hand, the less traditional view held by the Brazilian Society of Cardiology recognizes that trimetazidine, which possesses no major safety concerns, may be offered early on—before long-acting nitrates—in combination with any hemodynamic agent (β-blocker and/or calcium channel antagonist), as long as blood pressure and heart rate are properly controlled.

With this latter position, a different view emerges of the treatment of patients with stable IHD, one that widens the concept of “optimal medical therapy” and allows for the inclusion of trimetazidine before the commonplace “after everything else has failed” stance. This proposal may seem original and new, but it was, in fact, prophetically suggested almost 50 years ago by two British investigators, who said that “trimetazidine appears to have a place in the long term treatment of angina pectoris (…), and may be given to all cases of angina.” 16 It is never too late to do what we ought to have done.

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