REVIEWS Treatment of refractory angina in patients not suitable for revascularization Timothy D. Henry, Daniel Satran and E. Marc Jolicoeur Abstract | A growing number of patients, particularly those with advanced, chronic coronary artery disease, experience symptoms of angina that are refractory to treatment with β‑blockers, calcium-channel blockers, and long-acting nitrates, despite revascularization. The management of patients with refractory angina who are unsuitable for further revascularization is strikingly different across the world, and is contingent on local resources and available expertise. Mortality in this patient population has decreased, but enhancing quality of life remains a challenge. New treatment principles are emerging in current practice, such as metabolic modulation, therapeutic angiogenesis, and novel interventional techniques (coronary in-flow redistribution and approaches to chronic total occlusion). The contemporary management of refractory angina encourages individualized, patient-centred care in interdisciplinary, specialized clinics. Global initiatives are required to address complex clinical problem-solving for patients with refractory angina. In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development. Henry, T. D. et al. Nat. Rev. Cardiol. 11, 78–95 (2014); published online 24 December 2013; corrected online 14 January 2014; doi:10.1038/nrcardio.2013.200
Introduction
Cedars-Sinai Heart Institute, 127 South San Vicente Boulevard, AHSP, A3100, Los Angeles, CA 90048, USA (T. D. Henry). Park Nicollet Heart and Vascular Center, 6500 Excelsior Boulevard, St Louis Park, MN 55426, USA (D. Satran). Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger East Street, Montreal, Québec H1T 1C8, Canada (E. M. Jolicoeur). Correspondence to: T. D. Henry [email protected]
An increasing number of patients, particularly those with advanced, chronic coronary artery disease (CAD), have severe symptoms of angina despite optimal medical therapy. When further revascularization options are limited, these patients are frequently described as being ‘no option’, and as having refractory angina.1–6 The care of these patients is challenging, and the guidance available from national practice guidelines is limited.4,6–8 Over 10 years ago, the ESC Joint Study Group on the Treatment of Refractory Angina defined this condition 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 evidence of ischaemia.3 Patients can be suboptimal candidates for revascularization for many reasons, including having unsuitable coronary anatomy (severe diffuse atherosclerosis, or the absence of targets or lack of graft conduits for CABG surgery), the presence of substantial comorbidities (severe left ventricular dysfunction, peripheral artery disease, or chronic kidney disease), or because Competing interests T. D. Henry declares associations with the following companies and organizations: Abbott Vascular, Baxter, Cytori, Gilead, Neovasc, and the NIH Cardiovascular Cell Therapy Research Network. E. M. Jolicoeur declares associations with the following companies and organizations: Baxter, the Canadian Institutes for Health Research, la Fondation de l’Institut de Cardiologie de Montréal, les Fonds la Recherche du Québec en santé, Gilead, Neovasc, and Servier. See the article online for full details of the relationships. D. Satran declares no competing interests.
78 | FEBRUARY 2014 | VOLUME 11
of advanced age. The term refractory angina can also encompass patients with microvascular angina and lessextensive CAD. We previously described a classification scheme to help to characterize this complex population of patients.5 The interaction between clinical symptoms, myocardial perfusion abnormalities (or lack thereof), and coronary anatomy is complicated in these individuals.4,5,7,8 In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development.
Epidemiology With only limited data available from small, observational studies, the ESC Joint Study Group recognized “an urgent need to clarify the epidemiology of this condition [refractory angina]”.3 The Joint Study Group estimated the incidence of refractory angina at between 5% and 10% of patients undergoing cardiac catheterization.3 On the basis of coronary anatomy, symptoms, and myocardial perfusion, the incidence of patients with ‘no option’ was 11.8% in a series from the 1990s.9 In a subsequent series, 29% of 493 consecutive patients undergoing cardiac catheterization had incomplete revascularization, including 16% of patients who were not candidates for revascular ization.10 No data are available from national registries, such as Medicare; no specific claims codes exist for this complex group of patients, and standardized definitions are challenging. Currently, >500,000 Canadians and up to 1.8 million individuals from the USA are estimated to have refractory angina.4
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Refractory angina is an increasingly prevalent clinical syndrome characterized by ongoing ischaemic symptoms despite optimal medical management in patients for whom traditional revascularization is not an option ■■ Data indicate that up to 10–15% of patients undergoing cardiac catheterization fit the clinical description for refractory angina, and that prognosis is improving, with an annual mortality of only 3–4% ■■ The primary focus is on improving quality of life for patients with refractory angina ■■ Traditional treatment for myocardial ischaemia involves increasing coronary blood in-flow, increasing blood oxygen-carrying capacity, and decreasing oxygen consumption; new treatments involve modulating myocyte metabolism and redistributing coronary flow ■■ Emerging therapies include novel interventional techniques (percutaneous coronary intervention for chronic total occlusions, and the coronary sinus occluder), angiogenesis with cell therapy, shockwave therapy, and neuromodulation ■■ Implementation of interdisciplinary, specialized clinics with advanced clinical care, as well as investigational options (including psychological and selfmanagement approaches), could be important advances for patients with refractory angina
Box 1 | Summary of practice guidelines for refractory angina Novel pharmacological agents The ESC guidelines now consider ivabradine, nicorandil, or ranolazine on a par with long-acting nitrates as a second-line therapy for patients with persistent angina, according to heart rate, blood pressure, and tolerance (class IIa, level of evidence B).8 Trimetazidine is also recommended as a second-line therapy, but its use is less well established (class IIb, level of evidence B).8 The US guidelines consider ranolazine useful when prescribed as a substitute for β‑blockers for relief of symptoms in patients where the initial treatment with β‑blockers led to unacceptable adverse effects, or was ineffective, or if initial treatment with β‑blockers is contraindicated (class IIa, level of evidence B).7 Ranolazine can be used in combination with β‑blockers when prescribed for relief of symptoms when initial treatment with β‑blockers is not successful (class IIa, level of evidence A).7 Ivabradine, nicorandil, and trimetazidine are not available in the USA and are not addressed in the practice guidelines.7 The Canadian guidelines put an emphasis on the need for robust randomized, controlled trials focusing on patients with refractory angina before ivabradine, nicorandil, ranolazine, and trimetazidine can be definitively recommended in patients with refractory angina.4
Invasive treatment The Canadian and US guidelines weakly support the use of PMLR for reduction in the perceived severity of angina pain symptoms (weak recommendation with moderate-quality evidence,4 and class IIb, level of evidence B,7 respectively). The ESC guidelines do not support the use of PMLR or transmyocardial laser revascularization (class III, level of evidence B).8 According to all three practice guidelines, spinal-cord stimulation can be considered for reducing the perceived severity of angina pain symptoms and for improving exercise capacity (class IIb, level of evidence B; weak recommendation in both instances with moderate-quality evidence).4,8,7
Noninvasive treatment The Canadian and US guidelines propose that EECP can be considered to improve quality of life and severity of angina symptoms (weak recommendation with low-quality evidence,4 and class IIb, level of evidence B,7 respectively), whereas the ESC guidelines support the use of EECP for symptom relief in patients with refractory angina (class IIa, level of evidence B).8 According to the Canadian guidelines, patient self-management training can be considered for the reduction of angina symptoms and associated use of sublingual nitrates, and to improve health-related quality of life (weak recommendation, moderate-quality evidence).4 Abbreviations: EECP, enhanced external counterpulsation; PMLR, percutaneous myocardial laser revascularization.
Data on prognosis in refractory angina are conflicting. In a study from the 1990s, 1‑year mortality was 16.9%, but was calculated on the basis of only 59 patients.11 A wide range of 1‑year mortality figures (1–22%) has been reported from randomized clinical trials involving patients with refractory angina.12–19 Contemporary data on 1,200 patients from a specialized refractory angina clinic at the Minneapolis Heart Institute, MN, USA is much more encouraging, with a mortality of 3.9% at 1 year and 28.4% at 9 years.20 Survival with refractory angina seems to have improved over time, which is likely to be a result of the widespread adoption of standard medical therapy, aggressive riskfactor modification, and innovative revascularization techniques. Systematic evaluation in a specialized clinic might also improve long-term outcome. With improved survival, quality of life becomes the focus of therapy.
Evaluation of novel therapies Designing clinical trials to evaluate therapeutic options in patients with refractory angina is challenging. The cyclical nature of angina, combined with a prominent placebo effect—particularly for invasive therapies (such as transmyocardial laser revascularization, spinal-cord stimulation [SCS], or novel revascularization techniques), which cannot easily be placebo-controlled—has led to scepticism and low rates of uptake. Few treatments for refractory angina achieve a strong recommendation when assessed using contemporary level-of-evidence measures.21 Novel therapies have been developed, but despite their initial promise, placebo-controlled trials have shown only modest improvements in exercise treadmill time and symptoms of angina. Prominent placebo effects have obscured results from potentially innovative approaches and must be taken into consideration when discussing the beneficial effects of novel therapies. In the 2012 Canadian Cardiovascular Society (CCS) practice guidelines for the management of patients with refractory angina, all nonpharmacological options received a weak recommend ation for use (Box 1).4 The majority of novel antianginal treatments have been studied in patients with stable CAD, rather than formally evaluated in patients with advanced CAD that is refractory to conventional therapy.1,2 Angina is traditionally treated with risk-factor modification and antianginal medications, as well as revascularization by percutaneous coronary intervention (PCI) or CABG surgery. Improved understanding of myocardial ischaemia has led to new therapeutic principles, including metabolic modulation, oxygen sparing, and coronary flow redistribution (Figures 1 and 2). To manage these challenging patients successfully, clin icians must address the ischaemic component of angina, as well as other factors in dynamic cardiac pain, such as the neurogenic or psychogenic components.
Novel pharmacological agents The mainstay of medical treatment for angina involves β‑blockers, long-acting nitrates, and calcium-channel blockers. These traditional antianginal agents exert their effect by reducing heart rate, myocardial contractility,
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | FEBRUARY 2014 | 79 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Intermittent thrombolytics
Hb
FiO2
O2-carrying capacity
Blood rheology
Allopurinol
Trimetazidine
Perhexiline
Oxidative stress reduction
3-KAT inhibition
CPT1/2 inhibition
O2 sparing
Metabolic modulation ?
Coronary flow redistribution
Ranolazine Supply
Demand
Coronary sinus reduction
INa inhibition
Heart rate Contractility LV wall tension
Coronary blood in-flow
? Angiogenesis Cell therapy Gene therapy
? EECP
PCI
CABG surgery
Nitrates Nicorandil
β-Blockers
Ivabradine
Calcium-channel Nitrates blockers Nicorandil
Figure 1 | Therapeutic principles of myocardial ischaemia. The classic treatment of myocardial ischaemia has traditionally relied on three principles: reduction in LV oxygen consumption, augmentation of coronary arterial blood inflow, and maximized oxygen-carrying capacity of the blood. Novel therapies and devices have allowed refinement of these principles and the rise of novel treatment strategies, such as oxygen sparing, metabolic modulation, and redistributing the coronary blood flow. Nonpharmacological options are displayed in blue boxes, whereas pharmacological therapies are displayed in yellow boxes. Abbreviations: 3‑KAT, mitochondrial long-chain 3‑ketoacyl‑CoA thiolase; CPT1/2, carnitine O‑palmitoyltransferase 1 and 2; EECP, enhanced external counterpulsation; FiO 2, fraction of inspired oxygen; Hb, haemoglobin; LV, left ventricular; PCI, percutaneous coronary intervention.
and blood pressure; all can be useful in patients with refractory angina.1,4,6–8 β‑Blockers have historically been favoured over calciumchannel blockers in patients unsuitable for revascular ization, because these individuals have often previously had a myocardial infarction (MI; β‑blockers reduce mortality after MI7) and have reduced left ventricular function (nondihydropyridine calcium-channel blockers have been associated with increased mortality in the setting of low left ventricular ejection fraction7). The dominance of these traditional agents has been questioned,22 and treatment of chronic stable angina is slowly moving beyond these drugs. The ESC and the National Institute for Health and Care Excellence in the UK now advocate the use of ivabradine, nicorandil, or ranolazine with the same level of recommendation as monotherapy with long-acting nitrates or in association long-acting nitrates, when neither β‑blockers nor calcium-channel blockers can be administered.6,8 Therapeutic choice is dependent on comorbidities, accessibility, costs, and potential adverse effects.1,4,6–8 To be clinically useful, alternative antianginal agents must be safe and effective in patients receiving traditional medical therapy. Many of the novel agents have limited negative chronotropic and hypotensive effects and are, therefore, appropriate for patients who do not tolerate traditional antianginal drugs for these reasons (Table 1).
Nicorandil Nicorandil is a nicotinamide ester comprising a nitratelike moiety, which vasodilates coronary arteries, and a cardioprotective moiety, which promotes the opening 80 | FEBRUARY 2014 | VOLUME 11
of the mitochondrial ATP-sensitive potassium channels (KATP), known to mimic ischaemic preconditioning (Figure 3).23 The results of the IONA trial24 demonstrated the cardioprotective effect of nicorandil among patients with chronic stable angina, with a reduction compared with placebo in the combined end point of cardio vascular death, nonfatal MI, and hospital admission for cardiac chest pain (13.1% versus 15.5%; P = 0.014). Nicorandil exerts an anti-ischemic effect similar to that of β‑blockers, calcium-channel blockers, and long-acting nitrates in patients with stable angina that occurs with physical exercise.23,25–29 Nicorandil has never been studied in patients with advanced CAD, where cardioprotective and antianginal effects might be most pronounced. Nicorandil seems particularly appealing as a substitute for long-actingnitrates, which can be associated with tachyphylaxis and tolerance. Nicorandil neither impairs endothelial function nor paradoxically exacerbates angina,30 as is often the case with long-acting nitrates.31 Nicorandil is available in Europe, but its availability is restricted by special-access programmes run by regulatory agencies in Canada and the USA.
Ivabradine Ivabradine has been shown to be noninferior to β‑blockers in reducing the number of angina attacks in patients with chronic stable angina.32 Ivabradine blocks If channels, which regulate the intrinsic chronotropic characteristics of the sinoatrial node. Unlike calcium-channel blockers and β‑blockers, ivabradine does not reduce blood pressure or exert negative bathmotropic or dromotropic effects.
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Narcotics Transplantation Angiogenesis
Experimental and palliative options
ESWT, sinus reduction O2 sparing: allopurinol Self-management training Nonpharmacological: EECP, SCS, TMLR Metabolic modulation: trimetazidine, perhexiline (?)
Therapies for refractory angina
Late Na current inhibition: ranolazine Coronary blood flow increase: PCI, CTO PCI, CABG surgery Coronary vasodilatation: nitrates, nicorandil, molsidonine (?) Heart rate and contractility reduction: β-blockers, calcium-channel blockers, ivabradine Treat hypertension, diabetes mellitus, dyslipidaemia Smoking cessation, regular exercise and rehabilitation, healthy lifestyle
Evidence-based therapies for stable angina Risk-factor reduction
Figure 2 | Treatment options for refractory angina. The treatment of refractory angina starts with the management of risk factors (yellow steps) and the implementation of evidence-based therapy for chronic stable angina (pink steps). Available options for refractory angina include medical therapies and devices (green steps). The blue and orange steps display experimental and palliative options, which should be considered after lower options have been attempted. Abbreviations: CTO, chronic total occlusion; EECP, enhanced external counterpulsation; ESWT; extracorporeal shockwave therapy; PCI, percutaneous coronary intervention; SCS, spinal-cord stimulation; TMLR, transmyocardial laser revascularization.
In addition to heart-rate reduction, ivabradine might allow vasodilatation beyond that achieved by β‑blockers, possibly through unmasked α‑adrenergic vasoconstriction in the coronary circulation.33 In the ASSOCIATE trial,34 889 patients with stable angina despite taking atenolol 50 mg daily were randomly allocated to either ivabradine up to 7.5 mg twice daily or placebo for 4 months. Total exercise time increased by 24.3 ± 65.3 s with ivabradine, compared with 7.7 ± 63.8 s with placebo (P
Introduction
Cedars-Sinai Heart Institute, 127 South San Vicente Boulevard, AHSP, A3100, Los Angeles, CA 90048, USA (T. D. Henry). Park Nicollet Heart and Vascular Center, 6500 Excelsior Boulevard, St Louis Park, MN 55426, USA (D. Satran). Department of Medicine, Montreal Heart Institute, Université de Montréal, 5000 Belanger East Street, Montreal, Québec H1T 1C8, Canada (E. M. Jolicoeur). Correspondence to: T. D. Henry [email protected]
An increasing number of patients, particularly those with advanced, chronic coronary artery disease (CAD), have severe symptoms of angina despite optimal medical therapy. When further revascularization options are limited, these patients are frequently described as being ‘no option’, and as having refractory angina.1–6 The care of these patients is challenging, and the guidance available from national practice guidelines is limited.4,6–8 Over 10 years ago, the ESC Joint Study Group on the Treatment of Refractory Angina defined this condition 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 evidence of ischaemia.3 Patients can be suboptimal candidates for revascularization for many reasons, including having unsuitable coronary anatomy (severe diffuse atherosclerosis, or the absence of targets or lack of graft conduits for CABG surgery), the presence of substantial comorbidities (severe left ventricular dysfunction, peripheral artery disease, or chronic kidney disease), or because Competing interests T. D. Henry declares associations with the following companies and organizations: Abbott Vascular, Baxter, Cytori, Gilead, Neovasc, and the NIH Cardiovascular Cell Therapy Research Network. E. M. Jolicoeur declares associations with the following companies and organizations: Baxter, the Canadian Institutes for Health Research, la Fondation de l’Institut de Cardiologie de Montréal, les Fonds la Recherche du Québec en santé, Gilead, Neovasc, and Servier. See the article online for full details of the relationships. D. Satran declares no competing interests.
78 | FEBRUARY 2014 | VOLUME 11
of advanced age. The term refractory angina can also encompass patients with microvascular angina and lessextensive CAD. We previously described a classification scheme to help to characterize this complex population of patients.5 The interaction between clinical symptoms, myocardial perfusion abnormalities (or lack thereof), and coronary anatomy is complicated in these individuals.4,5,7,8 In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development.
Epidemiology With only limited data available from small, observational studies, the ESC Joint Study Group recognized “an urgent need to clarify the epidemiology of this condition [refractory angina]”.3 The Joint Study Group estimated the incidence of refractory angina at between 5% and 10% of patients undergoing cardiac catheterization.3 On the basis of coronary anatomy, symptoms, and myocardial perfusion, the incidence of patients with ‘no option’ was 11.8% in a series from the 1990s.9 In a subsequent series, 29% of 493 consecutive patients undergoing cardiac catheterization had incomplete revascularization, including 16% of patients who were not candidates for revascular ization.10 No data are available from national registries, such as Medicare; no specific claims codes exist for this complex group of patients, and standardized definitions are challenging. Currently, >500,000 Canadians and up to 1.8 million individuals from the USA are estimated to have refractory angina.4
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Refractory angina is an increasingly prevalent clinical syndrome characterized by ongoing ischaemic symptoms despite optimal medical management in patients for whom traditional revascularization is not an option ■■ Data indicate that up to 10–15% of patients undergoing cardiac catheterization fit the clinical description for refractory angina, and that prognosis is improving, with an annual mortality of only 3–4% ■■ The primary focus is on improving quality of life for patients with refractory angina ■■ Traditional treatment for myocardial ischaemia involves increasing coronary blood in-flow, increasing blood oxygen-carrying capacity, and decreasing oxygen consumption; new treatments involve modulating myocyte metabolism and redistributing coronary flow ■■ Emerging therapies include novel interventional techniques (percutaneous coronary intervention for chronic total occlusions, and the coronary sinus occluder), angiogenesis with cell therapy, shockwave therapy, and neuromodulation ■■ Implementation of interdisciplinary, specialized clinics with advanced clinical care, as well as investigational options (including psychological and selfmanagement approaches), could be important advances for patients with refractory angina
Box 1 | Summary of practice guidelines for refractory angina Novel pharmacological agents The ESC guidelines now consider ivabradine, nicorandil, or ranolazine on a par with long-acting nitrates as a second-line therapy for patients with persistent angina, according to heart rate, blood pressure, and tolerance (class IIa, level of evidence B).8 Trimetazidine is also recommended as a second-line therapy, but its use is less well established (class IIb, level of evidence B).8 The US guidelines consider ranolazine useful when prescribed as a substitute for β‑blockers for relief of symptoms in patients where the initial treatment with β‑blockers led to unacceptable adverse effects, or was ineffective, or if initial treatment with β‑blockers is contraindicated (class IIa, level of evidence B).7 Ranolazine can be used in combination with β‑blockers when prescribed for relief of symptoms when initial treatment with β‑blockers is not successful (class IIa, level of evidence A).7 Ivabradine, nicorandil, and trimetazidine are not available in the USA and are not addressed in the practice guidelines.7 The Canadian guidelines put an emphasis on the need for robust randomized, controlled trials focusing on patients with refractory angina before ivabradine, nicorandil, ranolazine, and trimetazidine can be definitively recommended in patients with refractory angina.4
Invasive treatment The Canadian and US guidelines weakly support the use of PMLR for reduction in the perceived severity of angina pain symptoms (weak recommendation with moderate-quality evidence,4 and class IIb, level of evidence B,7 respectively). The ESC guidelines do not support the use of PMLR or transmyocardial laser revascularization (class III, level of evidence B).8 According to all three practice guidelines, spinal-cord stimulation can be considered for reducing the perceived severity of angina pain symptoms and for improving exercise capacity (class IIb, level of evidence B; weak recommendation in both instances with moderate-quality evidence).4,8,7
Noninvasive treatment The Canadian and US guidelines propose that EECP can be considered to improve quality of life and severity of angina symptoms (weak recommendation with low-quality evidence,4 and class IIb, level of evidence B,7 respectively), whereas the ESC guidelines support the use of EECP for symptom relief in patients with refractory angina (class IIa, level of evidence B).8 According to the Canadian guidelines, patient self-management training can be considered for the reduction of angina symptoms and associated use of sublingual nitrates, and to improve health-related quality of life (weak recommendation, moderate-quality evidence).4 Abbreviations: EECP, enhanced external counterpulsation; PMLR, percutaneous myocardial laser revascularization.
Data on prognosis in refractory angina are conflicting. In a study from the 1990s, 1‑year mortality was 16.9%, but was calculated on the basis of only 59 patients.11 A wide range of 1‑year mortality figures (1–22%) has been reported from randomized clinical trials involving patients with refractory angina.12–19 Contemporary data on 1,200 patients from a specialized refractory angina clinic at the Minneapolis Heart Institute, MN, USA is much more encouraging, with a mortality of 3.9% at 1 year and 28.4% at 9 years.20 Survival with refractory angina seems to have improved over time, which is likely to be a result of the widespread adoption of standard medical therapy, aggressive riskfactor modification, and innovative revascularization techniques. Systematic evaluation in a specialized clinic might also improve long-term outcome. With improved survival, quality of life becomes the focus of therapy.
Evaluation of novel therapies Designing clinical trials to evaluate therapeutic options in patients with refractory angina is challenging. The cyclical nature of angina, combined with a prominent placebo effect—particularly for invasive therapies (such as transmyocardial laser revascularization, spinal-cord stimulation [SCS], or novel revascularization techniques), which cannot easily be placebo-controlled—has led to scepticism and low rates of uptake. Few treatments for refractory angina achieve a strong recommendation when assessed using contemporary level-of-evidence measures.21 Novel therapies have been developed, but despite their initial promise, placebo-controlled trials have shown only modest improvements in exercise treadmill time and symptoms of angina. Prominent placebo effects have obscured results from potentially innovative approaches and must be taken into consideration when discussing the beneficial effects of novel therapies. In the 2012 Canadian Cardiovascular Society (CCS) practice guidelines for the management of patients with refractory angina, all nonpharmacological options received a weak recommend ation for use (Box 1).4 The majority of novel antianginal treatments have been studied in patients with stable CAD, rather than formally evaluated in patients with advanced CAD that is refractory to conventional therapy.1,2 Angina is traditionally treated with risk-factor modification and antianginal medications, as well as revascularization by percutaneous coronary intervention (PCI) or CABG surgery. Improved understanding of myocardial ischaemia has led to new therapeutic principles, including metabolic modulation, oxygen sparing, and coronary flow redistribution (Figures 1 and 2). To manage these challenging patients successfully, clin icians must address the ischaemic component of angina, as well as other factors in dynamic cardiac pain, such as the neurogenic or psychogenic components.
Novel pharmacological agents The mainstay of medical treatment for angina involves β‑blockers, long-acting nitrates, and calcium-channel blockers. These traditional antianginal agents exert their effect by reducing heart rate, myocardial contractility,
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | FEBRUARY 2014 | 79 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Intermittent thrombolytics
Hb
FiO2
O2-carrying capacity
Blood rheology
Allopurinol
Trimetazidine
Perhexiline
Oxidative stress reduction
3-KAT inhibition
CPT1/2 inhibition
O2 sparing
Metabolic modulation ?
Coronary flow redistribution
Ranolazine Supply
Demand
Coronary sinus reduction
INa inhibition
Heart rate Contractility LV wall tension
Coronary blood in-flow
? Angiogenesis Cell therapy Gene therapy
? EECP
PCI
CABG surgery
Nitrates Nicorandil
β-Blockers
Ivabradine
Calcium-channel Nitrates blockers Nicorandil
Figure 1 | Therapeutic principles of myocardial ischaemia. The classic treatment of myocardial ischaemia has traditionally relied on three principles: reduction in LV oxygen consumption, augmentation of coronary arterial blood inflow, and maximized oxygen-carrying capacity of the blood. Novel therapies and devices have allowed refinement of these principles and the rise of novel treatment strategies, such as oxygen sparing, metabolic modulation, and redistributing the coronary blood flow. Nonpharmacological options are displayed in blue boxes, whereas pharmacological therapies are displayed in yellow boxes. Abbreviations: 3‑KAT, mitochondrial long-chain 3‑ketoacyl‑CoA thiolase; CPT1/2, carnitine O‑palmitoyltransferase 1 and 2; EECP, enhanced external counterpulsation; FiO 2, fraction of inspired oxygen; Hb, haemoglobin; LV, left ventricular; PCI, percutaneous coronary intervention.
and blood pressure; all can be useful in patients with refractory angina.1,4,6–8 β‑Blockers have historically been favoured over calciumchannel blockers in patients unsuitable for revascular ization, because these individuals have often previously had a myocardial infarction (MI; β‑blockers reduce mortality after MI7) and have reduced left ventricular function (nondihydropyridine calcium-channel blockers have been associated with increased mortality in the setting of low left ventricular ejection fraction7). The dominance of these traditional agents has been questioned,22 and treatment of chronic stable angina is slowly moving beyond these drugs. The ESC and the National Institute for Health and Care Excellence in the UK now advocate the use of ivabradine, nicorandil, or ranolazine with the same level of recommendation as monotherapy with long-acting nitrates or in association long-acting nitrates, when neither β‑blockers nor calcium-channel blockers can be administered.6,8 Therapeutic choice is dependent on comorbidities, accessibility, costs, and potential adverse effects.1,4,6–8 To be clinically useful, alternative antianginal agents must be safe and effective in patients receiving traditional medical therapy. Many of the novel agents have limited negative chronotropic and hypotensive effects and are, therefore, appropriate for patients who do not tolerate traditional antianginal drugs for these reasons (Table 1).
Nicorandil Nicorandil is a nicotinamide ester comprising a nitratelike moiety, which vasodilates coronary arteries, and a cardioprotective moiety, which promotes the opening 80 | FEBRUARY 2014 | VOLUME 11
of the mitochondrial ATP-sensitive potassium channels (KATP), known to mimic ischaemic preconditioning (Figure 3).23 The results of the IONA trial24 demonstrated the cardioprotective effect of nicorandil among patients with chronic stable angina, with a reduction compared with placebo in the combined end point of cardio vascular death, nonfatal MI, and hospital admission for cardiac chest pain (13.1% versus 15.5%; P = 0.014). Nicorandil exerts an anti-ischemic effect similar to that of β‑blockers, calcium-channel blockers, and long-acting nitrates in patients with stable angina that occurs with physical exercise.23,25–29 Nicorandil has never been studied in patients with advanced CAD, where cardioprotective and antianginal effects might be most pronounced. Nicorandil seems particularly appealing as a substitute for long-actingnitrates, which can be associated with tachyphylaxis and tolerance. Nicorandil neither impairs endothelial function nor paradoxically exacerbates angina,30 as is often the case with long-acting nitrates.31 Nicorandil is available in Europe, but its availability is restricted by special-access programmes run by regulatory agencies in Canada and the USA.
Ivabradine Ivabradine has been shown to be noninferior to β‑blockers in reducing the number of angina attacks in patients with chronic stable angina.32 Ivabradine blocks If channels, which regulate the intrinsic chronotropic characteristics of the sinoatrial node. Unlike calcium-channel blockers and β‑blockers, ivabradine does not reduce blood pressure or exert negative bathmotropic or dromotropic effects.
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Narcotics Transplantation Angiogenesis
Experimental and palliative options
ESWT, sinus reduction O2 sparing: allopurinol Self-management training Nonpharmacological: EECP, SCS, TMLR Metabolic modulation: trimetazidine, perhexiline (?)
Therapies for refractory angina
Late Na current inhibition: ranolazine Coronary blood flow increase: PCI, CTO PCI, CABG surgery Coronary vasodilatation: nitrates, nicorandil, molsidonine (?) Heart rate and contractility reduction: β-blockers, calcium-channel blockers, ivabradine Treat hypertension, diabetes mellitus, dyslipidaemia Smoking cessation, regular exercise and rehabilitation, healthy lifestyle
Evidence-based therapies for stable angina Risk-factor reduction
Figure 2 | Treatment options for refractory angina. The treatment of refractory angina starts with the management of risk factors (yellow steps) and the implementation of evidence-based therapy for chronic stable angina (pink steps). Available options for refractory angina include medical therapies and devices (green steps). The blue and orange steps display experimental and palliative options, which should be considered after lower options have been attempted. Abbreviations: CTO, chronic total occlusion; EECP, enhanced external counterpulsation; ESWT; extracorporeal shockwave therapy; PCI, percutaneous coronary intervention; SCS, spinal-cord stimulation; TMLR, transmyocardial laser revascularization.
In addition to heart-rate reduction, ivabradine might allow vasodilatation beyond that achieved by β‑blockers, possibly through unmasked α‑adrenergic vasoconstriction in the coronary circulation.33 In the ASSOCIATE trial,34 889 patients with stable angina despite taking atenolol 50 mg daily were randomly allocated to either ivabradine up to 7.5 mg twice daily or placebo for 4 months. Total exercise time increased by 24.3 ± 65.3 s with ivabradine, compared with 7.7 ± 63.8 s with placebo (P
