American Journal of Therapeutics 0, 1–15 (2015)

Newer Therapies for Management of Stable Ischemic Heart Disease With Focus on Refractory Angina Mukesh Singh, MD, MRCPI* and Rohit Arora, MD, FACC

Ischemic heart disease remains a major public health problem nationally and internationally. Stable ischemic heart disease (SIHD) is one of the clinical manifestations of ischemic heart disease and is generally characterized by episodes of reversible myocardial demand/supply mismatch, related to ischemia or hypoxia, which are usually inducible by exercise, emotion, or other stress and reproducible—but which may also be occurring spontaneously. Improvements in the treatment of acute coronary syndromes along with increasing prevalence of cardiovascular risk factors, including diabetes and obesity, have led to increasing population of patients with SIHD. A significant number of these continue to have severe angina despite medical management and revascularization procedures performed and may progress to refractory angina. This article reviews the newer therapies in the treatment of SIHD with special focus in treating patients with refractory angina. Keywords: newer therapies, refratory angina

BACKGROUND Ischemic heart disease (IHD) remains a major public health problem nationally and internationally. It is estimated that 1 in 3 adults in the United States (approximately 81 million) has some form of cardiovascular disease, including .17 million with coronary heart disease and nearly 10 million with angina pectoris.1,2 Among persons 60–79 years of age, approximately 25% of men and 16% of women have coronary heart disease, and these figures rise to 37% and 23% among men and women $80 years of age, respectively.2 IHD also accounts for the majority of mortality and morbidity of cardiac disease. Each year, .1.5 million patients have a myocardial infarction (MI). Many more are hospitalized for unstable angina and for evaluation and treatment of stable chest pain syndromes. Beyond the need for hospitalization, many patients with chronic Department of Cardiology, Chicago Medical School, Rosalind Franklin University of Medicine and Sciences, North Chicago, IL. The authors have no conflicts of interest to declare. *Address for correspondence: Department of Cardiology, Mt Sinai Hospital, 1500 South California Avenue, Chicago, IL 60608. E-mail: [email protected]

chest pain syndromes are temporarily unable to perform normal activities for hours or days and thus experience a reduced quality of life. Among patients enrolled in the Bypass Angioplasty Revascularization Investigation study,3 approximately 30% never returned to work after coronary revascularization and 15%–20% of patients rated their own health as “fair” or “poor” despite revascularization. Similarly, observational studies of patients recovering from an acute myocardial infarction (AMI) demonstrated that 1 in 5 patients, even after intensive treatment at the time of their AMI, still suffered angina 1 year later.4 These data confirm the widespread clinical impression that IHD continues to be associated with considerable patient morbidity despite the decline in cardiovascular mortality rate. Stable ischemic heart disease (SIHD) is one of the clinical manifestations of IHD and is generally characterized by episodes of reversible myocardial demand/ supply mismatch, related to ischemia or hypoxia, which are usually inducible by exercise, emotion, or other stress and reproducible—but which may also be occurring spontaneously. Such episodes of ischemia/hypoxia are commonly associated with transient chest discomfort (angina pectoris). SIHD also includes the stabilized, often asymptomatic, phases that follow an acute

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coronary syndrome (ACS).5 Unlike the different ACSs, stable angina is not immediately life threatening.6 However, there is risk of progression to a more severe form of the disease, and this risk alone merits a robust treatment strategy consistent with current scientific knowledge.6,7 With improving treatment modalities for ACSs and, thus, outcomes, more patients survive the acute event and their disease state changes into a chronic phase. Also with increasing survival of patients with primary coronary events after revascularization procedures, the number of patients presenting with coronary artery disease (CAD) unsuitable to further revascularization techniques and symptoms refractory to medical therapy also continues to rise.8 In addition, the increasing incidence of cardiovascular risk factors, such as diabetes mellitus and obesity, combined with the increasing number of revascularization procedures and decreased cardiac mortality rate have transformed the demographic of patients with IHD into a steadily increasing population of patients with chronic, and occasionally, refractory angina (RA) pectoris. This article reviews the newer therapies in the treatment of SIHD with special focus in treating patients with RA.

REFRACTORY ANGINA RA is a debilitating disease characterized by severe unremitting cardiac pain,9,10 resistant to all conventional treatments of CAD.9,10 RA was initially defined in 2002 by European Society of Cardiology (ESC) Joint Study Group9 as “a chronic condition (.3 months) characterized by the presence of angina caused by coronary insufficiency in the presence of CAD, which is not amenable to a combination of medical therapy, angioplasty, or coronary bypass surgery” in patients with objective evidence of ischemia. This definition was modified in 2009 by Canadian Cardiovascular Society (CCS) as “Refractory angina is a persistent, painful condition characterized by the presence of angina caused by coronary insufficiency in the presence of CAD which cannot be controlled by a combination of medical therapy, angioplasty/percutaneous interventions, and coronary bypass surgery. Although the presence of reversible myocardial ischemia must be clinically established to be the root cause, the pain experienced may arise or persist with or without this ischemia. Chronic is defined as persisting for more than 3 months.” This definition is commensurate with the understanding that both ischemic and persistent pain mechanisms underlie the problem.11 The mortality rate of patients living with RA is not known but is thought to be in the range of approximately 3%.12 These individuals suffer severely American Journal of Therapeutics (2015) 0(0)

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impaired health-related quality of life, with recurrent and sustained pain, poor general health status, psychological distress, impaired role functioning, activity restriction, and inability to self-manage.13–16 As a result of above-mentioned factors, the global prevalence of RA is increasing.9,10,17,18 Currently available estimates suggest that RA affects between 600,000 and 1.8 million people in the United States.10 The major challenge for these patients is not high mortality but persistent angina and poor quality of life. Reasons for being a poor candidate for further revascularization include diffuse atherosclerosis, unsuitable anatomy, multiple prior procedures—percutaneous coronary intervention or coronary artery bypass graft (CABG)—lack of conduits, absence of reasonable targets for bypass surgery, significant comorbidities such as severe left ventricular (LV) dysfunction, chronic kidney disease, carotid artery disease, and advanced age. It is noteworthy to mention that sometimes a patient who is labeled as “not suitable candidate for revascularization” might undergo revascularization by another operator. Therefore, the potential for revascularization should be carefully evaluated before labeling the diagnosis of RA. Patients with RA either have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III or IV). Before diagnosing a patient with RA, repeated attempts at “optimizing” medical treatment and lifestyle modification (initiation of an exercise program and discontinuation of tobacco) should be made. Additionally, all secondary causes of angina, such as anemia and uncontrolled hypertension, should be excluded.19

MANAGEMENT OF SIHD Myocardial ischemia occurs because of a mismatch between myocardial oxygen supply and demand. The main determinants of myocardial oxygen consumption are heart rate, myocardial contractility, wall stress, and fatty acid uptake.20,21 The aims of the management of SIHD are to reduce symptoms and improve prognosis. First step in the management is to determine and treat secondary causes of angina, such as hypertension, hyperthyroidism, anemia, hypoxia, and continued tobacco use in addition to optimizing the medical management. The management encompasses lifestyle modification (smoking cessation, healthy diet, physical activity, and weight management), control of risk factors [lipid management, blood pressure (BP) control, diabetes management, influenza vaccination, and psychosocial factors like anxiety and/ or depression management], evidence-based www.americantherapeutics.com

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Management of Stable Ischemic Heart Disease

pharmacological therapy, and patient education.5,22,23 There is considerable evidence that lifestyle changes and pharmacological treatment may reduce the progression of atherosclerosis and stabilize plaque in patients with SIHD. Therefore, risk factor modification should be the central component of management.24 Relief of angina symptoms Rapidly acting formulations of nitroglycerin are able to provide immediate relief of the angina symptoms once the episode has started or when the symptom is likely to occur (immediate treatment or prevention of angina). Not only anti-ischemic drugs but also lifestyle changes, regular exercise training, patient education, and revascularization all have a role to play in minimizing or eradicating symptoms over the long term (long-term prevention). To prevent the occurrence of cardiovascular events Efforts to prevent MI and death in coronary disease focus primarily on reducing the incidence of acute thrombotic events and the development of ventricular dysfunction. These aims are achieved by pharmacological or lifestyle interventions, which (1) reduce plaque progression; (2) stabilize plaque by reducing inflammation; and (3) prevent thrombosis, should plaque rupture or erosion occurs. In patients with severe lesions in coronary arteries supplying a large area of jeopardized myocardium, a combined pharmacological and revascularization strategy offers additional opportunities for improving prognosis by improving heart perfusion or providing alternative perfusion routes.5 Current evidence from multiple clinical trials indicates that aspirin, beta-blockers, statins, and angiotensin converting enzyme inhibitors should be used in nearly all patients with IHD who do not have specific contraindications. This is especially true for patients with a history of MI. It has been estimated that up to 85% of recurrent events in patients with coronary disease could be prevented or delayed with the use of these medications.25,26 It is likely that outcomes could be improved by adding lifestyle modifications, such as exercise and dietary changes, to the medication regimens (secondary prevention). Most conventional antianginal agents act by altering cardiovascular hemodynamics, such as a reduction in systemic vascular resistance or coronary vasodilation or negative inotropism, resulting in improved balance in myocardial oxygen supply and demand. Three major classes of anti-ischemic drugs are currently used in the medical management of angina pectoris: beta-blockers, nitrates (short and long acting), and calcium channel antagonists (Table 1). All 3 have been shown to prolong the duration of exercise before the www.americantherapeutics.com

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onset of angina and ST-segment depression and to decrease the frequency of angina.

NOVEL THERAPEUTIC STRATEGIES Despite the increasing success of conventional medical treatment and the continued development and improvement of mechanical revascularization approaches, a significant number of patients continue to have severe angina. The prevalence of this syndrome of RA is not well established, but data from registries suggest that approximately 10% of patients referred for angiography for symptomatic SIHD have coronary anatomy that is not amenable to revascularization.11,27,28 For this patient group, various novel pharmacological and nonpharmacological approaches have been investigated to improve the balance in myocardial oxygen demand and supply. These include metabolic modulation by inhibiting fatty acid metabolism, ionic channel modulation, reducing reactive oxygen species generation, intracellular signaling modulation, and nitric oxide generation. Major novel antianginal agents are mentioned in Table 2 and are described below.

Table 1. Goals of therapy and modalities to achieve goals in RA. Goal of therapy

Therapeutic strategies

Symptom control

(1) Traditional agents: betablockers, calcium channel blockers, short- and longacting nitrates (2) Novel agents: ranolazine, nicorandil, ivabradine, trimetazidine, perhexiline, allopurinol, L-arginine, and fasudil (1) Cardiovascular risk factor Stabilization of reduction: healthy atherosclerosis and lifestyle changes, prevention of recurrent including dietary events modification, smoking cessation, exercises, weight loss, control of hypertension, and dyslipidemia (2) Drug therapy: antiplatelet agents, beta-blocker, angiotensin converting enzyme inhibitor, and HMG CoA reductase inhibitor (statins) RA, refractory angina.

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Singh and Arora

Table 2. Novel antianginal agents.

Agent Ranolazine

Ivabradine

Nicorandil

Allopurinol

Trimetazidine

Perhexiline

L-Arginine

Fasudil

Molsidomine Testosterone and Estrogen

Pharmacological properties and mechanism of action Prevention of calcium overload and the subsequent increase in diastolic tension because of inhibition of late inward sodium channel Glycometabolic and antiarrhythmic effects Hepatic clearance with t1/2 of 2 h Heart rate–lowering agent via If ion channel blockade in sinoatrial node Hepatic clearance Nitrate-like vasodilation K ATP channel activation Inhibition of fatty acid oxidation Hepatic clearance Improves endothelium-dependent vasodilation Reduces xanthine oxidase–derived reactive oxidative stress Inhibition of lipid peroxidation, heat shock factor expression, and calcium sensitizing Metabolic modulator increasing myocardial glucose utilization and inhibiting oxidation of fats via 3-ketoacyl coenzyme A thiolase inhibition Renal clearance Inhibition of fatty acid oxidation

Endothelium-dependent vasodilator as a substrate For nitric oxide (NO) synthase and increased NO Hepatic clearance Rho kinase inhibitor thus modulating vascular smooth muscle contractile response NO-donating vasodilator Improves endothelial function

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Dose and side effects

Food and Drug Administration approval for angina

500 mg twice daily to 1 g twice daily

Yes

Constipation, dizzy, nausea, asthenia, QT interval prolongation, hepatic dysfunction 2.5–7.5 mg twice daily

No

Visual disturbance, bradycardia, headache, abdominal discomfort 10–30 mg twice daily May use 5 mg twice daily in patients prone to headache Headache, gastrointestinal distress Dose for angina not established

No

No

Nausea, diarrhea, hypersensitivity reaction, rash

20 mg 3 times per day with meals

Gastrointestinal intolerance Start with 100 mg/d and may adjust at 2- to 4-wk intervals; maximum dose: 300–400 mg/d Hepatotoxicity, peripheral neuropathy Dose for angina not established

No

No

No

Hypotension, hyperkalemia

Investigational agent

No

Investigational agent Not recommended at present because of concern for adverse effects

No No

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Management of Stable Ischemic Heart Disease

NOVEL PHARMACOLOGICAL STRATEGIES Metabolic modulators are agents that exert their effect by increasing the energy available to cardiac cells and improving the metabolic use of cardiac substrates.29 Under normal conditions in the absence of ischemia, cardiomyocytes derive 60%–70% of their energy requirement from fatty acid oxidation because fatty acids produce more ATP than glucose oxidation, but this occurs at the expense of higher oxygen requirement. Glucose is usually a secondary source of energy for the myocardium. There is a unique inter-regulation between fatty acid and glucose metabolism. Fatty acid oxidation modulates the rate of glucose metabolism. Increased fatty acid oxidation increases NADH;NAD+ and acetyl CoA:CoA ratios. The shift in the ratios inhibits pyruvate dehydrogenase (PDH) phosphatase and activates PDH kinase resulting in net suppression of PDH and subsequent decreased glucose oxidation. Conversely, when fatty acid oxidation is reduced, ratios of NADH:NAD+ and acetyl CoA:CoA are reduced, resulting in increased glucose metabolism.30 During ischemia, oxygen delivery is impaired, inhibiting the electron transport chain. This results in reduced fatty acid b-oxidation and complete glucose oxidation. The primary source of energy is shifted to the anaerobic glycolytic pathway where glucose conversion to pyruvate generates ATP. Excess pyruvate is converted to lactate. It has been theorized that anginal symptoms arise from intracellular acidification from increased lactate production and concentrations along with proton production from ATP hydrolysis. Conceptually, metabolic regulators as antianginal agents control symptoms by reducing lactate formation through stimulation of glucose oxidation and increase in metabolic efficiency.30 Trimetazidine is a pure metabolic agent that improves cellular tolerance to ischemia by inhibiting fatty acid metabolism and secondarily by stimulating glucose metabolism, although the exact anti-ischemic mechanisms are unknown.31 In patients with chronic stable angina, this agent increases coronary flow reserve, delaying the onset of ischemia associated with exercise and reducing the number of weekly angina episodes and weekly nitroglycerin consumption.32,33 The anti-ischemic effects are not associated with changes in heart rate or systolic BP. Few data exist on the effect of trimetazidine on cardiovascular endpoints, mortality, or quality of life. The most frequently reported adverse events are gastrointestinal disorders, but the incidence is low. The agent is not available in the United States. The Trimetazidine in Angina Combination Therapy trial showed that trimetazidine in www.americantherapeutics.com

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combination with standard therapy improved exercise duration.34 In the Trimetazidine in Poland II study, 426 patients were recruited with stable angina. Trimetazidine improved anginal symptoms and total exercise capacity and time to .1-mm ST-segment depression in patients already receiving metoprolol.35 A recent review of clinical studies, published in 2005, demonstrated that trimetazidine is an effective antianginal treatment.33 Marzilli and Klein32 performed a metaanalysis of 12 randomized studies and showed that trimetazidine reduces anginal frequency and a nonsignificant trend for increased exercise duration. It does not seem to have any negative inotropic or vasodilator activity.36 Ranolazine (approved recently by the US Food and Drug Administration) is a unique anti-ischemic drug that does not significantly affect hemodynamic parameters.37 It is a piperazine derivative, chemically related to trimetazidine. Its mechanism of action was initially thought to be similar to trimetazidine, acting as a metabolic regulator to improve efficiency of cardiomyocyte glucose metabolism.38,39 However, current evidence implies that it is a selective inhibitor of late sodium current indirectly reducing the sodium-dependent calcium current during ischemic conditions and leading to improvement in ventricular diastolic tension and oxygen consumption with anti-ischemic and metabolic effects.40,41 The ranolazine extended-release preparation reduces the frequency of angina, improves exercise performance, and delays the development of exercise-induced angina and ST-segment depression.42,43 Combination Assessment of Ranolazine in Stable Angina trial42 demonstrated that ranolazine therapy significantly improved exercise duration, time to angina attacks, and electrocardiographic changes indicative of ischemia versus placebo (P , 0.01). Ranolazine also significantly reduced the mean weekly anginal attacks and nitroglycerin consumption (P , 0.02). This trial showed that ranolazine provided additional antianginal and anti-ischemic efficacy in patients with chronic angina who were symptomatic despite the use of other commonly prescribed agents without affecting hemodynamic parameters. Similar results were observed in Monotherapy Assessment of Ranolazine in Stable Angina trial43 that investigated 3 doses of sustainedrelease ranolazine twice daily for 1 week at 500, 1000, or 1500 mg. Compared with placebo, all 3 doses of ranolazine produced a longer time to 1-mm ST-segment depression, increased exercise duration, and lengthened time between anginal attacks. In patients with previous chronic angina enrolled in the MERLIN trial,44 ranolazine reduced recurrent ischemia [hazard ratio (HR): 0.78; P , 0.002].45,46 In those studied after the coronary event, ranolazine reduced the incidence of newly increased HbA1c by 32%.45 In the recent TERISA study (Type 2 American Journal of Therapeutics (2015) 0(0)

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Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina), ranolazine reduced episodes of stable angina in 949 diabetes patients already receiving 1 or 2 antianginal drugs and led to less use of sublingual nitroglycerin and the benefits seemed more prominent in patients with higher rather than lower HbA1c levels. These results suggest that this drug can be added to other well-established antianginal drugs, in particular in patients with higher HbA1c levels, who may also more often rely on medical management.47 Ranolazine blocks the delayed rectifier potassium current and prolongs the QTc interval in a dose-related manner, resulting in a mean increase in QTc of approximately 6 milliseconds at maximal recommended dosing. Ranolazine does not require dose adjustment for age, sex, New York Heart Association class I–IV heart failure, or diabetes mellitus. Plasma concentrations of ranolazine are increased by up to 50% in patients with stage 4 chronic kidney disease (creatinine clearance , 30 mL/min).48 The drug is contraindicated in patients with clinically significant hepatic impairment because of increased plasma concentrations and QT prolongation. Ranolazine is well tolerated; the major adverse effects are constipation, nausea, dizziness, and headache. Ivabradine is a specific inhibitor of the If current of pacemaker cells in the sinoatrial node at concentrations that do not inhibit other cardiac currents.49 The rate of spontaneous depolarization in the sinoatrial pacemaker cells is controlled by f channels.50 Activation of f channels occurs through binding with cAMP allowing influx of Na+ and K+ ions into the cell. This ionic influx establishes the If current, increases depolarization rate, and thereby increases heart rate. Conversely, inactivation of channels results in heart rate reduction, prolonging diastole and thereby improving myocardial oxygen balance. This is in contrast with beta-blockers that decrease heart rate mainly by regulating cAMP concentration and thus indirectly inhibiting f channels. Ivabradine has no effect on BP, myocardial contractility, or intracardiac conduction parameters.51–53 Ivabradine has been shown to improve exercise capacity and reduce angina frequency in comparison with atenolol among patients with chronic stable angina.54,55 Ivabradine was as effective as atenolol or amlodipine in patients with SIHD; adding 7.5 mg ivabradine twice daily to atenolol therapy gave better control of heart rate and anginal symptoms.55,56 In 1507 patients with previous angina enrolled in the Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction (BEAUTIFUL) trial, ivabradine reduced the composite primary endpoint of cardiovascular death, hospitalization with MI and heart failure, and reduced hospitalization for MI. The effect was predominant in patients with American Journal of Therapeutics (2015) 0(0)

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a heart rate $70 bpm.57 The most common adverse event, reported in 14.5% of patients, is phosphenes, described as a transient enhanced brightness in a limited area of the visual field that typically occurs within the first 2 months of treatment. Most of these luminous visual field disturbances (77%) resolve without discontinuing treatment. The drug is approved in Europe (not currently available in the United States) for the symptomatic treatment of chronic stable angina in patients with normal sinus rhythm with a contraindication or intolerance to beta-blockers.58 Nicorandil is a nicotinamide ester that confers benefits through a dual action: opening the mitochondrial potassium ATP channels leading to preconditioning of the myocardium and a nitrate-like effect. It activates adenosine triphosphate–sensitive potassium channels and promotes systemic venous and coronary vasodilation through a nitrate moiety.59 This dual action increases coronary blood flow, with reductions in afterload, preload, and oxidative injury.59 The agent does not exhibit effects on contractility or conduction.60,61 The antianginal efficacy and safety of nicorandil are similar to those of oral nitrates, beta-blockers, and calcium channel blockers.59,62,63 The prospective Impact of Nicorandil in Angina study, over a mean of 1.6 years in 5126 patients with SCAD, showed that the primary endpoint, a composite of coronary heart disease death, nonfatal MI, or unplanned hospital admission for cardiac chest pain, in patients treated with nicorandil was reduced by 17% [HR: 0.83; 95% confidence interval (CI), 0.72–0.97; P 5 0.014]. Furthermore, the rate of ACS was significantly lowered by 21% in the nicorandil-treated group (HR: 0.79; 95% CI, 0.64–0.98; P 5 0.028) and a 14% reduction in all cardiovascular events (HR: 0.86; 95% CI, 0.75–0.98; P 5 0.027).64 Long-term use of oral nicorandil may stabilize coronary plaque in patients with stable angina.65 Occasional side effects include oral, intestinal, and perianal ulceration. Investigational agents Fasudil is an investigational agent that inhibits an intracellular signaling molecule, rho kinase, that is involved in the vascular smooth muscle contractile response. In the cardiac system, rho pathway has been implicated in angiotensin II–induced cardiac hypertrophy, endothelial dysfunction, coronary artery spasm, and myocardial ischemia. Increased activation of rho kinase promotes cell contraction by permitting myosin light chain to remain phosphorylated. Conversely, rho kinase inhibition promotes cell relaxation, thus resulting in myosin to remain in a noncontractile state and, therefore, promote vasodilation.66 In a multicenter, double-blind placebo-controlled randomized trial in patients with stable angina, fasudil treatment was demonstrated to significantly increase www.americantherapeutics.com

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Management of Stable Ischemic Heart Disease

time to 1-mm ST-segment depression, at both peak and trough compared with placebo (172.1 vs. 44.0 seconds, P 5 0.001, and 92.8 vs. 26.4 seconds, P 5 0.02, respectively). Fasudil improved Seattle Angina Questionnaire scores. No significant differences in CCS class, time to angina, or frequency of angina or nitroglycerin use were noted between groups. Fasudil did not affect heart rate or BP and was well tolerated.67 Molsidomine is a direct nitric oxide–donating vasodilator that was shown to reduce the incidence of angina attacks, use of sublingual nitrates, and increased exercise capacity compared with placebo in patients with stable angina. Higher doses provided better protection from angina but caused hypotension. It has antiischemic effects similar to those of isosorbide dinitrate. The long-acting once-daily 16-mg formulation is as effective as 8 mg twice daily.68 Allopurinol, an inhibitor of xanthine oxidase that reduces uric acid in persons with gout, is also antianginal. There is limited clinical evidence, but in a randomized crossover study of 65 patients with SCAD, 600 mg/d allopurinol increased times to ST-segment depression and to chest pain.69 In renal impairment, such high doses may have toxic side effects. In optimally treated SIHD patients, allopurinol reduced vascular oxidative stress,70 whereas in heart failure patients, it conserved ATP.71 F-15845 {3-(R)-[3-(2-methoxyphenylthio-2-(S)methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate} is a newly described selective inhibitor of the persistent Na+ current, which has shown antiischemic properties and an ability to prevent ischemiainduced arrhythmias in animal models; it currently is being assessed in phase II clinical trials.72–74 Both testosterone and estrogen have been shown to improve coronary blood flow in humans. Testosterone acts by endothelium-independent mechanisms and may involve the ion channels on vascular smooth muscle cells,75,76 whereas estrogen improves endothelial function.77,78 Acute administration of estrogen has been shown to cause coronary vasodilation and reverse endothelial dysfunction within minutes in postmenopausal women with CAD.79–83 The addition of progesterone to estrogen may, however, attenuate the beneficial effects of estrogen on endothelial function and coronary vasodilation.84,85 Schulman et al86 conducted a study of 233 postmenopausal women with unstable angina treated with standard anti-ischemic therapy within 24 hours of symptom onset. In a double-blind fashion, subjects were randomized to receive intravenous followed by oral conjugated estrogen for 21 days, intravenous estrogen followed by oral conjugated estrogen plus medroxyprogesterone for 21 days, or placebo. Electrocardiographic ischemia did not differ www.americantherapeutics.com

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among the 3 randomized groups. The mean number of ischemic events per patient over 48 hours was 0.74 for estrogen, 0.86 for estrogen plus progesterone, and 0.74 for the placebo groups (P 5 0.87). The percentage of patients with ischemic events and the mean duration of ischemia did not differ between hormone- and placebo-treated groups. In-hospital and 6-month rates of adverse clinical events were also similar among the 3 randomized groups. Moreover, concerns exist regarding long-term therapy and side effects both with testosterone (prostate and hematologic effects) and estrogen (initial increase in cardiac events caused by estrogen therapy for females with CAD).87 Therefore, these are not the recommended therapies.

NONPHARMACOLOGICAL THERAPIES Although effective in many cases, antianginal medications are insufficient or have side effects in a significant number of patients with severe CAD. For these “nooption” patients with RA, the investigation of novel nonpharmacological therapies offers hope for improved quality of life by relieving angina symptoms. Some of the main approaches studied include enhanced external counterpulsation (EECP), neurostimulatory techniques [transcutaneous electrical nerve stimulation (TENS), spinal cord stimulation (SCS)], and angiogenesis through noninvasive techniques (extracorporeal cardiac shock wave myocardial revascularization) or invasive techniques, such as transmyocardial laser revascularization (TMR), percutaneous myocardial laser revascularization (PMR), or stem cell/gene therapy (preclinical or investigational). Table 3 lists various nonpharmacological therapies for patients with RA. Among nonpharmacological treatments, EECP therapy and neurostimulatory techniques have shown that they can ameliorate symptoms and improve quality of life, although convincing evidence regarding reduction in both ischemia burden and mortality is still lacking.5 Recent American College of Cardiology/American Heart Association (ACC/ AHA) guidelines7 have given EECP, TMR, and SCS as class IIb recommendation, whereas most recent ESC guidelines have given EECP as class IIa recommendation; SCS and TENS received class IIb recommendation, and TMR was given class III recommendation.5 EECP is approved by the Food and Drug Administration for the treatment of AMI, cardiogenic shock, congestive heart failure, and stable angina. Approval for the AMI and cardiogenic shock dates before thrombolytic therapy and percutaneous coronary intervention. EECP is a class IIb recommendation in most recent ACC/AHA guidelines,7 whereas it was given American Journal of Therapeutics (2015) 0(0)

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Table 3. Nonpharmacological therapies for RA (see text for EECP). Therapy TMR

TENS

SCS

Extracorporeal cardiac shock wave myocardial revascularization

Comments Invasive percutaneous procedure making 20–40 transmural channels using a high-energy carbon dioxide laser with brief manual compression of the epicardial surface to allow for closure of the epicardial opening sites It stimulates angiogenesis and may destroy nerve fibers to the heart, making patients numb to their chest pain Class IIa indication for RA as per ACC/AHA Clinical efficacy with 80% response rate in short term but long-term follow-up not known Used mainly in conjunction with CABG TENS involves applying a low-voltage electrical current via pads placed on the skin in the area of pain It stimulates large-diameter afferent fibers and inhibits input from small-diameter fibers in the substantia gelatinosa of the spinal cord An increased endorphin concentration in blood and cerebrospinal fluid has also been proposed Advantage: passive, noninvasive, and nonaddictive modality with no potentially harmful side effect SCS blocks pain by stimulating the dorsal columns, which inhibits transmission through the pain-conducting spinothalamic tract Possible benefits include the ease of use and portability of the device that allows patients to resume activities at home or at work Class IIb indication for treatment of RA as per ACC/AHA guidelines Epidural hematoma and infection occurring in approximately 1% of patients SCS may interfere with pacemakers and implantable defibrillators by possible false inhibition of the pacemaker function, but this risk may be lowered by programming both devices in bipolar mode and setting the stimulator frequency to 20 Hz Ultrasound-guided shock wave therapy to ischemic areas identified by SPECT. Shock waves, created by a special generator, are focused using a shock wave applicator device. This induces localized stress on cell membranes and causes nonenzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide. It also upregulates VEGF in ischemic myocardium in vivo that causes angiogenesis The treatment is guided by standard echocardiography equipment The shock waves are delivered in synchronization with the patient’s R-wave to avoid arrhythmias

ACC/AHA, American College of Cardiology/American Heart Association; CABG, coronary artery bypass graft; RA, refractory angina; SCS, spinal cord stimulation; SPECT, single photon emission tomogrpahy; TENS, transcutaneous electrical neural stimulation; TMR, transmyocardial laser revascularization; VEGF, vascular endothelial growth factor.

class IIa status in recently released ESC guidelines for the management of stable CAD. EECP consists of the application of 3 pairs of pneumatic cuffs placed on the lower extremities, at the levels of the calves and lower and upper thighs. Cuff inflation and deflation are synchronized with the electrocardiogram. Electrocardiogramsynchronized sequential cuff inflation and deflation increase venous return and (analogous to intra-aortic balloon pump) decrease afterload. The early diastolic pressure is increased beyond the systolic, resulting in hyperperfusion of coronary, cerebral, and other proximal vascular beds. The usual EECP treatment regimen is 35 hours administered 1–2 h/d.88 EECP results in diastolic augmentation, increased coronary artery perfusion American Journal of Therapeutics (2015) 0(0)

pressure, and decreased LV work. It is associated with improved myocardial perfusion during stress testing, increased levels of nitric oxide and angiogenic growth factors, and improved endothelial function. Contraindications to EECP include arrhythmias that interfere with the triggering of the EECP system, bleeding diathesis or warfarin therapy with INR .3.0, current or recent (within 2 months) lower extremity thrombophlebitis, severe lower extremity vaso-occlusive disease, severe pulmonary hypertension (pulmonary artery mean pressure . 50 mm Hg), severe aortic insufficiency, and the presence of abdominal aortic aneurysm .5 cm.88 Uncontrolled hypertension and acute decompensated heart failure must be medically optimized and BP www.americantherapeutics.com

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Management of Stable Ischemic Heart Disease

controlled before initiation of EECP. Although the precise mechanism of action remains unclear, proposed hypothesis include enhanced diastolic flow, the possible collateralization of coronary vessels, and an improvement in endothelial function.89 The cuffs are inflated sequentially so that during early diastole, they cause retrograde blood flow in the aorta, increase coronary artery mean pressure, increase diastolic pressure, and increase venous return.90,91 When deflated at the end of diastole, the cuffs allow the blood vessels to return to their normal state and result in unloading of the left ventricle and decreased systolic BP.91 The increased cardiac output is related, in part, to increased venous return and augmentation of atrial preload that occurs with EECP.92 The effectiveness of this intervention for patients with RA has been investigated in a number of international studies over the last 3 decades. Several studies have demonstrated significant improvements in exercise tolerance, time to ST depression during treadmill exercise testing, angina, nitroglycerin use, myocardial perfusion, and quality of life.93–99 The Multicenter Study of EECP was a prospective, multicenter randomized controlled trial to assess the safety and efficacy of EECP in patients with stable angina.95 Patients were enrolled in the study if they had class I, II, or III angina; evidence of ischemia on an exercise treadmill test; and documented evidence of CAD. Patients with revascularization in the preceding 3 months, overt congestive heart failure or an LV ejection fraction #30%, significant valvular heart disease, uncontrolled hypertension, permanent pacemaker or implantable cardiac defibrillator, uncontrolled arrhythmias, and significant stenosis of the left main coronary artery without bypass were excluded. Health-related quality of life was assessed at baseline, immediately after EECP, and at 1 year. Compared with controls, patients in the active treatment arm had significant increase in time to $1-mm ST depression and a decrease in the frequency of angina along with significant improvements in all quality of life scales immediately after EECP that persisted at 1 year. However, there was no significant difference in exercise duration or in the amount of sublingual nitroglycerin used in this trial.96 In a meta-analysis of 13 observational studies involving 949 patients, anginal class was improved by .1 class (Canadian classification system) in 86% (95% CI, 82%–90%).100 The EECP Consortium reported results in 2289 consecutive patients undergoing EECP therapy at 84 participating centers, including a subgroup of 175 patients from 7 centers who underwent radionuclide perfusion stress tests before and after therapy.101 Treatment was associated with improved perfusion images and increased exercise duration. Similarly, the International EECP www.americantherapeutics.com

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Registry reported improvement of $1 angina class in 81% of patients immediately after the last treatment.102 SCS at the T1–T2 level has been advocated as a therapeutic option for patients with angina pectoris that is refractory to medical therapy and coronary revascularization. The efficacy of SCS has been evaluated in several observational and cohort studies.103,104 The published RCTs of SCS were small.105,106 These studies of SCS suggest that this technique might have some use as a method to relieve angina in patients with symptoms that are refractory to standard medical therapy and revascularization. However, there is a paucity of data on the mechanisms and long-term risks and benefits.7 The stimulation lead is inserted into the epidural space and is connected to a pulse generator implanted subcutaneously. A paresthetic stimulus is delivered in a continuous, cyclic, or intermittent manner. Although inhibition of pain transmission plays a role, some studies suggest that SCS also might reduce myocardial ischemia.107–109 Transcutaneous electrical neural stimulation (TENS) involves applying a low-voltage electrical current via pads placed on the skin in the area of pain. The technique primarily works via the “gate control” theory of pain. Stimulating large-diameter afferent fibers inhibits input from small-diameter fibers in the substantia gelatinosa of the spinal cord.110 The activation of an endogenous opioid pathway or an increased endorphin concentration in blood and cerebrospinal fluid may also be involved.111 This technique may induce mild secondary effects, such as skin irritation, paresthesiae, and pacemaker interaction. In a small series of patients with pacing-induced angina,112 TENS demonstrated an increased tolerance to pacing, improved lactate metabolism, and less-pronounced ST-segment depression. No data on the long-term efficacy have been reported. The benefits of TENS are that it is a passive, noninvasive, and nonaddictive modality with no potentially harmful side effects. It may be used as a test method for planned SCS implantation, to determine whether myocardial ischemia is really the cause of the patient’s pain and to evaluate whether the patient shows good enough compliance to handle a spinal cord stimulator.113 Thus, TENS is a potentially harmless technique that may be useful to ameliorate symptoms, although efficacy in the long term is unknown. TMR has been used as either a percutaneous or a surgical procedure concomitant with CABG or as a sole therapy in patients with angina refractory to medical therapy,114–117 although the mechanism by which it might be efficacious is unknown.118,119 Early studies of the percutaneous approach demonstrated no therapeutic benefit, and it was promptly abandoned.120 When used as sole therapy by a surgical approach, TMR is reserved for the patient with incapacitating American Journal of Therapeutics (2015) 0(0)

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medical RA and no other feasible therapeutic options. Proposed mechanisms of action include stimulation of microcirculation, creation of myocardial scarring, and denervation of ischemic myocardium.121 Various energy sources have been used, including carbon dioxide XeCl excimer and holmium:YAG lasers.122–124 There is no convincing evidence that one energy source is superior to the others. TMR also has been combined with cardiac denervation by thoracic sympathectomy.125 Numerous single-center and a few multicenter randomized trials have been published that compare TMR with medical therapy for relief of RA.126–129 Most have shown better angina relief with TMR but no survival benefit. The exception is a single multicenter trial that shows a survival benefit and better relief of angina at 5 years.130 TMR and PMR have been evaluated by the National Institute of Clinical Excellence.131 The evaluation of TMR included 10 randomized controlled clinical trials, involving a total of 1359 patients. Seven of the trials compared TMR with continued medical management, and in 2 trials, CABG was compared with a combination of TMR and CABG. It was demonstrated that although there was an improvement in the more subjective outcome measures (including exercise tolerance testing, angina score, and quality of life), this was counterbalanced by a higher risk of postoperative mortality and morbidity (including MI, heart failure, thromboembolic events, pericarditis, acute mitral insufficiency, and neurological events). In the same way, the evaluation of PMR included 5 randomized trials. As a conclusion, overall mortality was not increased. However, morbidity (MI, ventricular perforation and tamponade, cerebrovascular events, and vascular complications) was also increased by PMR. Based on these data, ESC guidelines recommend against TMR (class III recommendation).5 Extracorporeal shock wave myocardial revascularization is under investigation. This technology uses low-intensity shock waves (one-tenth the strength of those used in lithotripsy) that are delivered to myocardial ischemic tissue. Shock waves, created by a special generator, are focused using a shock wave applicator device. The treatment is guided by standard echocardiography equipment. The shock waves are delivered in synchronization with the patient’s R-wave to avoid arrhythmias. At first, the patient undergoes stress single photon emission tomogrpahy testing to identify the ischemic areas. After that, the same area is localized by the ultrasound device and the shock waves are focused on the ischemic area. Several treatments are required for optimal results. A small study (n 5 9 patients) has reported an improvement in symptoms and in functional class score.132 More data are needed before establishing a potential recommendation. American Journal of Therapeutics (2015) 0(0)

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CONCLUSIONS Because of advances in revascularization strategies and medical therapies, the survival of patients with atherosclerotic CAD has improved substantially over the past 2 decades. Thus, a growing number of patients with SIHD have RA, defined as multivessel CAD with ischemia and symptoms that cannot be controlled with medical therapy or surgical or percutaneous revascularization. The goals of therapy need to be individualized in each case, and optimal medical therapy and risk factor modification are the first step for prognostic and symptomatic benefit. A number of novel pharmacological and nonpharmacological approaches are promising modalities and, in future, may provide additional line of therapy to be considered in these patients with RA, in an effort to improve their symptom relief and quality of life.

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Newer Therapies for Management of Stable Ischemic Heart Disease With Focus on Refractory Angina.

Ischemic heart disease remains a major public health problem nationally and internationally. Stable ischemic heart disease (SIHD) is one of the clinic...
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