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Canadian Journal of Cardiology

Management of Patients With Refractory Angina: Canadian Cardiovascular Society/Canadian Pain Society Joint Guidelines

      Abstract

      Refractory angina (RFA) is a debilitating disease characterized by cardiac pain resistant to conventional treatments for coronary artery disease including nitrates, calcium-channel and β-adrenoceptor blockade, vasculoprotective agents, percutaneous coronary interventions, and coronary artery bypass grafting. The mortality rate of patients living with RFA is not known but is thought to be in the range of approximately 3%. These individuals suffer severely impaired health-related quality of life with recurrent and sustained pain, poor general health status, psychological distress, impaired role functioning, and activity restriction. Effective care for RFA sufferers in Canada is critically underdeveloped. These guidelines are predicated upon a 2009 Canadian Cardiovascular Society (CCS) Position Statement which identified that underlying the problem of RFA management is the lack of a formalized, coordinated, interprofessional strategy between the cardiovascular and pain science/clinical communities. The guidelines are therefore a joint initiative of the CCS and the Canadian Pain Society (CPS) and make practice recommendations about treatment options for RFA that are based on the best available evidence. Concluding summary recommendations are also made, giving direction to future clinical practice and research on RFA management in Canada.

      Résumé

      L'angine de poitrine réfractaire (APR) est une maladie débilitante caractérisée par une douleur cardiaque résistant aux traitements traditionnels de la maladie coronarienne incluant les nitrates, le canal calcique et le blocage des récepteurs β-adrénergiques, les agents vasculoprotecteurs, les interventions coronariennes percutanées et le pontage aortocoronarien. Le taux de mortalité des patients vivant avec une APR n'est pas connu, mais est présumé se situer à environ 3 %. Ces individus souffrent sévèrement de leur qualité de vie liée à leur santé déficiente, dont une douleur récurrente et soutenue, un mauvais état de santé général, une détresse psychologique, un déficit de fonctionnement et une restriction d'activité. Au Canada, l'efficacité des soins offerts aux patients souffrant d'une APR est dramatiquement sous-développée. Ces lignes directrices s'appuient sur un énoncé de position de la Société canadienne de cardiologie (SCC) 2009 qui déterminait que le problème sous-jacent de la gestion de l'APR est le manque de stratégies interprofessionnelles, coordonnées et formalisées, entre les communautés clinique et scientifique dans les domaines cardiovasculaire et de la douleur. Les lignes directrices sont par conséquent une initiative conjointe de la SCC et de la Société canadienne de la douleur (SCD) et font des recommandations pratiques sur les options de traitement de l'APR qui sont basées sur les meilleures preuves disponibles. Des recommandations sont aussi faites, donnant une direction à la pratique clinique future et à la recherche sur la gestion de l'APR au Canada.
      Refractory angina (RFA) is a debilitating disease characterized by severe, unremitting cardiac pain,
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Bhatt A.B.
      • Stone P.H.
      Current strategies for the prevention of angina in patients with stable coronary artery disease.
      resistant to all conventional treatments for coronary artery disease (CAD).
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Bhatt A.B.
      • Stone P.H.
      Current strategies for the prevention of angina in patients with stable coronary artery disease.
      The mortality rate of patients living with RFA is not known but is thought to be in the range of approximately 3%.
      • Henry T.D.
      A new option for the “no-option” patient with refractory angina?.
      These individuals suffer severely impaired health-related quality of life (HRQL), with recurrent and sustained pain, poor general health status, psychological distress, impaired role functioning, activity restriction, and inability to self-manage.
      • Brorsson B.
      • Bernstein S.J.
      • Brook R.H.
      • Werko L.
      Quality of life of patients with chronic stable angina before and four years after coronary revascularisation compared with a normal population.
      • McGillion M.
      • Watt-Watson J.
      • LeFort S.
      • Stevens B.
      Positive shifts in the perceived meaning of cardiac pain following a psychoeducation program for chronic stable angina.
      • Erixson G.
      • Jerlock M.
      • Dahlberg K.
      Experiences of living with angina pectoris.
      • McGillion M.H.
      • Watt-Watson J.H.
      • Kim J.
      • Graham A.
      Learning by heart: a focused group study to determine the self-management learning needs of chronic stable angina patients.
      The global prevalence of RFA is increasing;
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Bhatt A.B.
      • Stone P.H.
      Current strategies for the prevention of angina in patients with stable coronary artery disease.
      • Chow C.M.
      • Donovan L.
      • Manuel D.
      • et al.
      Regional variation in self-reported heart disease prevalence in Canada.
      • Thadani U.
      Recurrent and refractory angina following revascularization procedures in patients with stable angina pectoris.
      available estimates suggest that RFA affects between 600,000 and 1.8 million people in the United States
      • Bhatt A.B.
      • Stone P.H.
      Current strategies for the prevention of angina in patients with stable coronary artery disease.
      with as many as 50,000 new cases each year, and 30,000-50,000 new cases per year in continental Europe.
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Bhatt A.B.
      • Stone P.H.
      Current strategies for the prevention of angina in patients with stable coronary artery disease.
      • Thadani U.
      Recurrent and refractory angina following revascularization procedures in patients with stable angina pectoris.
      Canadian Community Health Survey (2000-2001) data (www.statcan.gc.ca) suggest that approximately 500,000 Canadians are living with unresolved angina. The proportion of these patients living with true RFA is not known.
      • Chow C.M.
      • Donovan L.
      • Manuel D.
      • et al.
      Regional variation in self-reported heart disease prevalence in Canada.
      The incidence and prevalence of RFA will continue to rise as CAD-related survival rates increase and populations age.
      • Chow C.M.
      • Donovan L.
      • Manuel D.
      • et al.
      Regional variation in self-reported heart disease prevalence in Canada.
      • Thadani U.
      Recurrent and refractory angina following revascularization procedures in patients with stable angina pectoris.
      • McGillion M.
      • Arthur H.
      • Andrell P.
      • Watt-Watson J.
      Self-management training in refractory angina.
      Effective care for the growing RFA population in Canada is critical. A number of patients have inadequate pain relief, revisit local hospital emergency departments, and undergo repeated investigations in coronary catheterization units.
      • McGillion M.
      • Watt-Watson J.
      • LeFort S.
      • Stevens B.
      Positive shifts in the perceived meaning of cardiac pain following a psychoeducation program for chronic stable angina.
      • Genius S.J.
      The proliferation of clinical practice guidelines: professional development or medicine-by-numbers?.
      • Manuel D.G.
      • Leung M.
      • Nguyen K.
      • et al.
      Burden of cardiovascular disease in Canada.
      • Stewart S.
      • Murphy N.
      • Walker A.
      • McGuire A.
      • McMurray J.J.V.
      The current cost of angina pectoris to the national health service in the UK.
      • McGillion M.
      • Croxford R.
      • Watt-Watson J.
      • et al.
      Cost of illness for chronic stable angina patients enrolled in a self-management education trial.
      The potential cost implications are considerable. In the UK, direct costs of persistent anginal pain including prescriptions, repeated emergency department and other admissions, outpatient referrals, and procedures account for 1.3% of the total National Health Service expenditure.
      • Stewart S.
      • Murphy N.
      • Walker A.
      • McGuire A.
      • McMurray J.J.V.
      The current cost of angina pectoris to the national health service in the UK.
      A more recent (2008) Ontario-based study conservatively estimated the annualized cost of angina-related disability from a societal perspective including direct, indirect, and system costs, at CAD$19,209 per patient.
      • McGillion M.
      • Croxford R.
      • Watt-Watson J.
      • et al.
      Cost of illness for chronic stable angina patients enrolled in a self-management education trial.
      These guidelines are predicated upon a 2009 Canadian Cardiovascular Society (CCS) Position Statement which identified that underlying the problem of RFA management is the lack of a formalized, coordinated, interprofessional strategy between the cardiovascular and pain science/clinical communities.
      • McGillion M.
      • L'Allier P.L.
      • Arthur H.M.
      • et al.
      Recommendations for advancing the care of Canadians living with refractory angina pectoris: a Canadian Cardiovascular Society position statement.
      The guidelines are therefore a joint initiative of the CCS and the Canadian Pain Society (CPS)
      • McGillion M.
      • L'Allier P.L.
      • Arthur H.M.
      • et al.
      Recommendations for advancing the care of Canadians living with refractory angina pectoris: a Canadian Cardiovascular Society position statement.
      and were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE)
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      • Jaeschke R.
      • Guyatt G.H.
      • Dellinger P.
      • et al.
      Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive.
      • Schünemann H.J.
      • Oxman A.D.
      • Brozek J.
      • et al.
      Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      system of evidence evaluation, in order to make practice recommendations about treatment options for RFA that are based on the best available evidence.

      Pathophysiology: Production and Persistence of Cardiac Pain

      Most events that trigger anginal pain do so by changing myocardial oxygen demand; these triggers may be physical, emotional, or metabolic.
      • Kones R.
      Recent advances in the management of chronic stable angina II Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization.
      The beneficial effects of most conventional anti-anginal treatments may be explained through their ability to correct determinants of myocardial oxygen supply and demand. However, by definition, RFA patients are resistant to all conventional treatments for ischemia.
      • McGillion M.
      • L'Allier P.L.
      • Arthur H.M.
      • et al.
      Recommendations for advancing the care of Canadians living with refractory angina pectoris: a Canadian Cardiovascular Society position statement.
      In RFA, there is an important link between mechanisms of chronic/recurrent myocardial ischemia and the neuropathophysiology of persistent pain.
      • McGillion M.
      • L'Allier P.L.
      • Arthur H.M.
      • et al.
      Recommendations for advancing the care of Canadians living with refractory angina pectoris: a Canadian Cardiovascular Society position statement.
      Cardiac sensory receptors triggered by myocardial ischemia lead to a sympathoexcitatory reflex.
      • Kones R.
      Recent advances in the management of chronic stable angina II Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization.
      The biochemical stimuli for RFA pain are multi-factorial and analogous to the pain hypersensitivity seen in other forms of chronic tissue injury. Concentrations of bradykinin, adenosine, lactate, and potassium from ischemic damage to the myocardium are released in the effluent of the coronary sinus,
      • Crea F.
      • Gaspardone A.
      New look to an old symptom: angina pectoris.
      • Zahner M.R.
      • Li D.P.
      • Chen S.R.
      • Pan H.L.
      Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats.
      • Ambrose J.
      Myocardial ischemia and infarction.
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Fox K.
      • Garcia M.A.
      • Ardissino D.
      • et al.
      Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology.
      activating capsaicin-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors, which serve as the primary transducer of the ischemic noxious stimulus.
      • Zahner M.R.
      • Li D.P.
      • Chen S.R.
      • Pan H.L.
      Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats.
      Neurochemicals, such as the neuropeptides substance P and calcitonin gene-related peptide, are also synthesized and released from the endings of cardiac afferents thereby augmenting adenosine-provoked pain.
      • Ambrose J.
      Myocardial ischemia and infarction.
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Foreman R.D.
      Mechanisms of cardiac pain.
      • Klein J.
      • Chao S.
      • Berman D.
      • Rozanski A.
      Is 'silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases.
      Cardiac primary afferents transmitting this noxious input ascend via multiple pathways including the spinothalamic tract and the spinoamygdaloid and spinohypothalamic pathways to neurons in cortical and subcortical areas of the brain that have somatic receptive fields in the chest, neck, and arms.
      • Klein J.
      • Chao S.
      • Berman D.
      • Rozanski A.
      Is 'silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases.
      Cognitive appraisal of the stimulus occurs in the parietal cortex and anterior cingulate cortex.
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Foreman R.D.
      Mechanisms of cardiac pain.
      The noxious stimulus is assessed in these structures as threatening, causing activation of the bilateral prefrontal cortex and limbic system, leading to apprehension of further pain and fear for the future.
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Foreman R.D.
      Mechanisms of cardiac pain.
      • Foreman R.D.
      • Qin C.
      Neuromodulation of cardiac pain and cerebral vasculature: neural mechanisms.
      For patient assessment and management, it is important to recognize that there is often no clear relationship between the severity of one's anginal pain and the degree of ischemia,
      • Klein J.
      • Chao S.
      • Berman D.
      • Rozanski A.
      Is 'silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases.
      as indicated by changes in objective diagnostic indicators such as stress electrocardiogram or serum levels of creatine kinase (CK) and CK-MB. As the 2002 European Society of Cardiology (ESC) Joint Study Group on RFA
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      and others
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Foreman R.D.
      Mechanisms of cardiac pain.
      • Foreman R.D.
      • Qin C.
      Neuromodulation of cardiac pain and cerebral vasculature: neural mechanisms.
      • Procacci P.
      • Zoppi M.
      • Maresca
      Heart, vascular and haemopathic pain.
      have argued, RFA, like other types of pain, is not simply the end-product of the linear transmission of a noxious stimulus. Increasing basic science and clinical evidence points in fact to the variability of cardiac pain, wherein pain may be experienced with minimal to no myocardial ischemia and, conversely, the majority of ischemic episodes are silent.
      • Sylven C.
      • Eriksson C.
      Thorax.
      • Foreman R.D.
      Mechanisms of cardiac pain.
      • Klein J.
      • Chao S.
      • Berman D.
      • Rozanski A.
      Is 'silent' myocardial ischemia really as severe as symptomatic ischemia? The analytical effect of patient selection biases.
      • Foreman R.D.
      • Qin C.
      Neuromodulation of cardiac pain and cerebral vasculature: neural mechanisms.
      • Procacci P.
      • Zoppi M.
      • Maresca
      Heart, vascular and haemopathic pain.
      Nociceptive processes arising in the periphery are modulated in the central nervous system by mechanisms that actively participate in the selection, abstraction, and synthesis of information from the total peripheral sensory input. The amount, quality, and nature of pain experienced are therefore dynamic and multidimensional products of sensory-discriminative, cognitive-evaluative, and affective-motivational components.
      • Melzack R.
      • Wall P.D.
      Pain mechanisms: a new theory.
      Recent discoveries related to the plasticity of the nervous system support neuronal modifiability as fundamental to, and chiefly responsible for, the experience of persistent pain.
      • Wolf C.J.
      • Salter M.
      Plasticity and pain.
      • Basbaum A.
      • Bushnell M.C.
      • Devor M.
      Pain: basic mechanisms.

      Definition of RFA

      Commensurate with the understanding that both ischemic and persistent pain mechanisms underlie the problem, the 2009 CCS position statement put forth the following definition of RFA, adapted from the 2002 ESC Joint Study Group definition:
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      Refractory angina is a persistent, painful condition characterized by the presence of angina caused by coronary insufficiency in the presence of coronary artery disease which cannot be controlled by a combination of medical therapy, angioplasty/percutaneous interventions, and coronary bypass surgery. While 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.

      Inclusion Criteria

      These guidelines included systematic reviews, single randomized controlled trials (RCTs), and quasi-experimental and pre-post studies. Observational/descriptive, retrospective, and case studies did not meet our criteria for systematic review. We reviewed 3 classes of interventions including invasive, noninvasive, and pharmacologic therapies. Our specific outcomes were patient-centred, including chest pain, nitrate use, HRQL, morbidity (myocardial infarction [MI], heart transplant, cerebrovascular events, other cardiac events, and associated hospitalizations), exercise tolerance, and mortality.

      Guidelines Development Process

      A detailed description of our development process including search methods, consensus-building procedure, appraisal of methodologic quality, and data synthesis (meta-analysis) is available as a slide kit on the CCS Web site (http://www.ccs.ca/consensus_conferences/cc_library_e.aspx).

      Grading of Evidence and Practice Recommendations

      The quality of the evidence that supports each practice recommendation was rated according to GRADE criteria
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      • Jaeschke R.
      • Guyatt G.H.
      • Dellinger P.
      • et al.
      Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive.
      • Schünemann H.J.
      • Oxman A.D.
      • Brozek J.
      • et al.
      Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.
      • Guyatt G.
      • Gutterman D.
      • Baumann M.H.
      • et al.
      Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force.
      as follows:
      • High: Further research is very unlikely to change our confidence in the estimate of effect.
      • Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
      • Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
      • Very Low: Any estimate of effect is very uncertain.
      Based on these evidence ratings, our practice recommendations made are either ‘Strong’ or ‘Weak’, according to the following operational definitions:
      • Strong: The desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not.
      • Weak: The trade-offs are less certain—either because of low-quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced.
      We also took into account key influencing factors, as outlined by Guyatt et al.,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • et al.
      Going from evidence to recommendations.
      including the quality of the available evidence, clinical insight into risks vs benefits of treatment options, patient values and preferences, and resource implications.

      Establishing a Diagnosis of RFA and Ongoing Evaluation of Symptoms

      Consistent with the definition of RFA employed in these guidelines, the presence of myocardial ischemia must first be established.
      • McGillion M.
      • L'Allier P.L.
      • Arthur H.M.
      • et al.
      Recommendations for advancing the care of Canadians living with refractory angina pectoris: a Canadian Cardiovascular Society position statement.
      A thorough evaluation of patients' cardiovascular status is required as well as a review of current pharmacotherapy to ensure maximally-tolerated and appropriate medical management; conventional revascularization procedures should also have been exhausted.
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Fox K.
      • Garcia M.A.
      • Ardissino D.
      • et al.
      Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology.
      • Fraker Jr, T.D.
      • Fihn S.D.
      • Gibbons R.J.
      • et al.
      2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina.
      • Gibbons R.J.
      • Abrams J.
      • Chatterjee K.
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina).
      In addition to standard CAD assessment, Table 1 lists originating sources of chest pain (as applicable) that should be ruled out to ensure a correct diagnosis of RFA.
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Kones R.
      Recent advances in the management of chronic stable angina I: approach to the patient, diagnosis, pathophysiology, risk stratification, and gender disparities.
      Table 1Sources of chest pain to be ruled out in diagnosing RFA
      • Aortic dissection
      • Aortic stenosis
      • Anemia
      • Cardiac syndrome X
      • Costochondritis
      • Dilated cardiomyopathy
      • Gallbladder disease
      • Hypertrophic cardiomyopathy
      • Intercostal neuralgia
      • Pancreatitis
      • Peptic ulcer
      • Pericarditis/pleuritis
      • Pneumonia
      • Pneumothorax
      • Pulmonary embolism
      • Pulmonary hypertension
      • Esophageal spasm
      • Reflux esophagitis
      • Thyrotoxicosis
      RFA, refractory angina.
      Once a baseline diagnosis of RFA is established, ongoing assessment of symptoms and functional ability is needed. This should include re-examination of CCS class,
      • Campeau L.
      The Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later.
      as well as comprehensive pain assessment including pain history, intensity, qualities, impact on mood, interference with everyday activities, and effectiveness of current treatments for symptom relief.
      Like all other types of pain, cardiac pain arising from RFA is a complex, subjective experience with sensory-discriminative, motivational-affective, and cognitive-evaluative components. Each of these dimensions, subserved by specialized systems in the brain (ie, spinal, limbic, reticular, neocortical), contribute to the overall patient experience of pain (and related individual response) and should therefore be addressed as part of routine assessment.
      • Melzack R.
      • Katz J.
      Pain assessment in adult patients.

      Invasive Therapies

      Transmyocardial laser revascularization

      Transmyocardial laser revascularization (TMLR) is a surgical treatment, developed in the 1980s,
      • Smith J.A.
      • Dunning J.J.
      • Parry A.J.
      • Large S.R.
      • Wallwork J.
      Transmyocardial laser revascularization.
      aimed at reducing anginal symptoms through the creation of transmural channels via a CO2, holmium yttrium-aluminum-garnet (Ho:YAG), or XeCL excimer lasers.
      • Allen K.B.
      • Dowling R.D.
      • Fudge T.L.
      • et al.
      Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina.
      • Burkhoff D.
      • Wesley M.N.
      • Resar J.R.
      • Lansing A.M.
      Factors correlating with risk of mortality after transmyocardial revascularization.
      • Aaberge L.
      • Nordstrand K.
      • Dragsund M.
      • et al.
      Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris Clinical results from the Norwegian randomized trial.
      • Frazier O.H.
      • March R.J.
      • Horvath K.A.
      Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease.
      • Schofield P.
      • Sharples L.
      • Caine N.
      • et al.
      Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial.
      • van der Sloot J.A.
      • Huikeshoven M.
      • Tukkie R.
      • et al.
      Transmyocardial revascularization using an XeCl excimer laser: results of a randomized trial.
      By way of thoracotomy or sternotomy, laser energy is directed to the epicardial surface of the left ventricle in order create a series of transmural channels in targeted regions of viable myocardium; a variety of protocols have been used that vary with respect to laser system, number of channels created, and levels of energy delivered.
      In a recent Cochrane Review, Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      reviewed the results of 7 RCTs published between 1999 and 2004 including 1137 patients in total; 559 were randomly allocated to the TMLR group. A CO2 laser was used in 3 studies,
      • Aaberge L.
      • Nordstrand K.
      • Dragsund M.
      • et al.
      Transmyocardial revascularization with CO2 laser in patients with refractory angina pectoris Clinical results from the Norwegian randomized trial.
      • Frazier O.H.
      • March R.J.
      • Horvath K.A.
      Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease.
      • Schofield P.
      • Sharples L.
      • Caine N.
      • et al.
      Transmyocardial laser revascularisation in patients with refractory angina: a randomised controlled trial.
      a Ho:YAG laser was used in another 3 studies,
      • Allen K.B.
      • Dowling R.D.
      • Fudge T.L.
      • et al.
      Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina.
      • Burkhoff D.
      • Schmidt S.
      • Schulman S.P.
      • et al.
      Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial ATLANTIC investigators. Angina treatments-lasers and normal therapies in comparison.
      • Jones J.W.
      • Schmidt S.E.
      • Richman B.W.
      • et al.
      Holmium: YAG laser transmyocardial revascularization relieves angina and improves functional status.
      and a single study used a XeCL excimer laser.
      • Oesterle S.N.
      Laser percutaneous myocardial revascularization.
      Operative procedures were similar across trials.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      This meta-analysis found that TMLR significantly reduced angina by at least 2 CCS classes for 43% of patients treated (n = 240) (odds ratio [OR] = 4.63; 95% confidence interval [CI], 3.43-6.25; P < 0.001) (Fig. 1), representing a clinically meaningful reduction in RFA symptoms.
      Figure thumbnail gr1
      Figure 1Comparison of transmyocardial laser revascularization vs medical treatment, outcome Canadian Cardiovascular Society (CCS) class. CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel; NYHA, New York Heart Association.
      Reproduced from Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      Copyright © 2009 Cochrane Collaboration, reproduced with permission.
      Impact of TMLR on HRQL was measured using the disease-specific Seattle Angina Questionnaire (SAQ).
      • Spertus J.A.
      • Winder J.A.
      • Dewhurst T.A.
      • et al.
      Development and evaluation of the Seattle angina questionnaire: a new functional status measure for coronary artery disease.
      A weighted mean difference of 13.10 (95% CI, 6.82-19.38; P < 0.001) for the SAQ-physical limitation subscale was found, suggesting significant improvement in physical limitation for the treatment group (Fig. 2). Despite this improvement in physical limitation, the meta-analysis found no significant improvement in exercise tolerance, however only two studies (n = 129) were amenable to statistical pooling (Fig. 3).
      Figure thumbnail gr2
      Figure 2Comparison of transmyocardial laser revascularization vs medical treatment, outcome Seattle Angina Questionnaire-physical limitation. CI, confidence interval; df, degree of freedom; IV, inverse variance; SD, standard deviation.
      Reproduced from Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      Copyright © 2009 Cochrane Collaboration, reproduced with permission.
      Figure thumbnail gr3
      Figure 3Comparison of transmyocardial laser revascularization vs medical treatment, outcome exercise tolerance. CI, confidence interval; df, degree of freedom; IV, inverse variance; SD, standard deviation.
      Reproduced from Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      Copyright © 2009 Cochrane Collaboration, reproduced with permission.
      Thirty-day mortality after TMLR was found to be 4% and 3.5% for treatment and control groups respectively, based on intention-to-treat (ITT) analyses.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      However, there was almost a 4-fold increase in early postoperative mortality for the treatment group when patients were analyzed as treated, taking into account patient crossovers (OR 3.76; 95% CI, 1.63-8.66) (Fig. 4).
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      therefore argued that the clinical benefits of TMLR do not outweigh the potential risks.
      Figure thumbnail gr4
      Figure 4Comparison of transmyocardial laser revascularization vs medical treatment, outcome early postoperative mortality (as treated). CI, confidence interval; df, degree of freedom; M-H, Mantel-Haenszel.
      Reproduced from Briones et al.
      • Briones E.
      • Lacalle J.R.
      • Marin I.
      Transmyocardial laser revascularization versus medical therapy for refractory angina.
      Copyright © 2009 Cochrane Collaboration, reproduced with permission.

      Quality of evidence according to GRADE

      The Cochrane Review was of high methodological quality, employing comprehensive search methods and risk of bias assessment as well as robust meta-analytic techniques. We rate the quality of the available evidence as high (Table 2).
      Table 2Quality of evidence according to GRADE
      HighModerateLowVery lowUnable to evaluate
      TMLR
      PMLR
      SCS
      EECP
      SMT
      TCS
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      HTEA
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      ETS
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      Allopurinol
      Shows promise; more RFA-specific evidence needed.
      Ranolazine
      Shows promise; more RFA-specific evidence needed.
      Trimetazidine
      Shows promise; more RFA-specific evidence needed.
      Nicorandil
      Shows promise; more RFA-specific evidence needed.
      Ivabradine
      Shows promise; more RFA-specific evidence needed.
      Intermittent thrombolysis
      Shows promise; more RFA-specific evidence needed.
      Shock wave therapy
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      Coronary sinus reducer
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      Myocardial cryotherapy
      Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      EECP, enhanced external counter-pulsation; ETS, endoscopic transthoracic sympathectomy; GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; HTEA, high thoracic epidual analgesia; PMLR, percutaneous laser revascularization; RFA, refractory angina; SCS, spinal cord stimulation; SMT, self-management training; TCS, temporary cardiac sympathectomy; TMLR, transmyocardial laser revascularization.
      low asterisk Existing evidence does not meet criteria for inclusion; limited to case reports and observational studies.
      Shows promise; more RFA-specific evidence needed.
      Despite some observed improvements in pain and physical limitations, TMLR is associated with significant early postoperative mortality risk and is not recommended (Strong Recommendation, High-Quality Evidence).
      Values and preferences. This recommendation places a high value on patient safety, recognizing that some patients still undergo TMLR, where available (ie, international centres).

      Percutaneous myocardial laser revascularization

      Percutaneous myocardial laser revascularization (PMLR) therapy emerged as a treatment option for RFA in the 1990's as an alternative to TMLR.
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      A major impetus for adopting PMLR was the elimination of the incumbent risks of sternotomy and/or left anterior thoracotomy required for the TMLR procedure.
      • Oesterle S.N.
      Laser percutaneous myocardial revascularization.
      • Oesterle S.N.
      • Sanborn T.A.
      • Ali N.
      • et al.
      Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial Potential class improvement from intramyocardial channels.
      • Salem M.
      • Rotevatn S.
      • Stavnes S.
      • et al.
      Usefulness and safety of percutaneous myocardial laser revascularization for refractory angina pectoris.
      PMLR entails the application of Ho:YAG laser energy to the endocardial surface of the left ventricle via a flexible catheter; laser firing is synchronized during systole to create a series of nontransmural channels in targeted regions with reversible ischemia.
      • Oesterle S.N.
      Laser percutaneous myocardial revascularization.
      • Oesterle S.N.
      • Sanborn T.A.
      • Ali N.
      • et al.
      Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial Potential class improvement from intramyocardial channels.
      Proposed mechanisms of action include direct perfusion,
      • Kohmoto T.
      • Fisher P.E.
      • Gu A.
      • et al.
      Physiology, histology, and 2-week morphology of acute transmyocardial channels made with a CO2 laser.
      • Gassler N.
      • Wintzer H.O.
      • Stubbe H.M.
      • Wullbrand A.
      • Helmchen U.
      Transmyocardial laser revascularization histological features in human nonresponder myocardium.
      • Mueller X.M.
      • Tevaearai H.H.
      • Genton C.Y.
      • Bettex D.
      • von Segesser L.K.
      Transmyocardial laser revascularisation in acutely ischaemic myocardium.
      microvascular angiogenesis,
      • Mirhoseini M.
      • Fisher J.C.
      • Cayton M.
      Myocardial revascularization by laser: a clinical report.
      • Mukherjee D.
      • Ellis S.G.
      New options for untreatable coronary artery disease: angiogenesis and laser revascularization.
      • Rimoldi O.
      • Burns S.M.
      • Rosen S.D.
      • et al.
      Measurement of myocardial blood flow with positron emission tomography before and after transmyocardial laser revascularization.
      • Burns S.M.
      • Brown S.
      • White C.A.
      • et al.
      Quantitative analysis of myocardial perfusion changes with transmyocardial laser revascularization.
      and cardiac afferent denervation, however evidence is contradictory.
      • Guzzetti S.
      • Colombo A.
      • Piccaluga E.
      • et al.
      Absence of clinical signs of cardiac denervation after percutaneous myocardial laser revascularization.
      • Al-Sheikh T.
      • Allen K.B.
      • Straka S.P.
      • et al.
      Cardiac sympathetic denervation after transmyocardial laser revascularization.
      • Myers J.
      • Oesterle S.N.
      • Jones J.
      • Burkhoff D.
      Do transmyocardial and percutaneous laser revascularization induce silent ischemia? An assessment by exercise testing.
      • Beek J.F.
      • van der Sloot J.A.
      • Huikeshoven M.
      • et al.
      Cardiac denervation after clinical transmyocardial laser revascularization: short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence.
      Symptom relief, improvements in exercise duration, HRQL, and safety have been reported in several RCTs.
      • Oesterle S.N.
      • Sanborn T.A.
      • Ali N.
      • et al.
      Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial Potential class improvement from intramyocardial channels.
      • Salem M.
      • Rotevatn S.
      • Stavnes S.
      • et al.
      Usefulness and safety of percutaneous myocardial laser revascularization for refractory angina pectoris.
      • Whitlow P.L.
      • DeMaio Jr, S.J.
      • Perin E.C.
      • et al.
      One-year results of percutaneous myocardial revascularization for refractory angina pectoris.
      • Gray T.J.
      • Burns S.M.
      • Clarke S.C.
      • et al.
      Percutaneous myocardial laser revascularization in patients with refractory angina pectoris.
      • Salem M.
      • Rotevatn S.
      • Nordrehaug J.E.
      Long-term results following percutaneous myocardial laser therapy.
      • McNab D.
      • Khan S.N.
      An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: the SPiRiT trial [reply].
      • Leon M.B.
      • Kornowski R.
      • Downey W.E.
      • et al.
      A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease.
      • Stone G.W.
      • Teirstein P.S.
      • Rubenstein R.
      • et al.
      A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions.
      In a recent systemic review,
      • Mirhoseini M.
      • Fisher J.C.
      • Cayton M.
      Myocardial revascularization by laser: a clinical report.
      we meta-analyzed the data from 5 of 7 available RCTs
      • Oesterle S.N.
      • Sanborn T.A.
      • Ali N.
      • et al.
      Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial Potential class improvement from intramyocardial channels.
      • Salem M.
      • Rotevatn S.
      • Stavnes S.
      • et al.
      Usefulness and safety of percutaneous myocardial laser revascularization for refractory angina pectoris.
      • Whitlow P.L.
      • DeMaio Jr, S.J.
      • Perin E.C.
      • et al.
      One-year results of percutaneous myocardial revascularization for refractory angina pectoris.
      • Gray T.J.
      • Burns S.M.
      • Clarke S.C.
      • et al.
      Percutaneous myocardial laser revascularization in patients with refractory angina pectoris.
      • Salem M.
      • Rotevatn S.
      • Nordrehaug J.E.
      Long-term results following percutaneous myocardial laser therapy.
      • McNab D.
      • Khan S.N.
      An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: the SPiRiT trial [reply].
      • Leon M.B.
      • Kornowski R.
      • Downey W.E.
      • et al.
      A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease.
      • Stone G.W.
      • Teirstein P.S.
      • Rubenstein R.
      • et al.
      A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions.
      of PMLR that were published between 2001 and 2006 including 1213 patients in total; 651 were randomly allocated to the PMLR group.
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      Our analyses
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      found that PMLR significantly reduced angina by at least 2 CCS classes (pooled OR 2.13; 95% CI, 1.22-3.73; P = 0.008) (Fig. 5), representing a clinically meaningful reduction in RFA symptoms. Impact of PMLR on HRQL was measured using the SAQ, and a small difference
      • Cohen J.
      Statistical Power Analysis for the Behavioral Sciences.
      • Juni P.
      • Altman D.G.
      • Egger M.
      Assessing the quality of controlled clinical trials.
      in the positive impact of PMLR plus maximal medical therapy (ie, treatment) vs maximal medical therapy alone (ie, control) was found (Figure 6, Figure 7, Figure 8, Figure 9, Figure 10).
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      The clinical significance of these findings is uncertain. Nonetheless, coupled with the improvements found in CCS class, they are encouraging considering the high levels of perceived psychological burden and related disability associated with unrelieved CCS class III-IV angina symptoms.
      Figure thumbnail gr5
      Figure 5Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Canadian Cardiovascular Society class. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr6
      Figure 6Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Seattle Angina Questionnaire-angina frequency. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr7
      Figure 7Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Seattle Angina Questionnaire-disease perception. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr8
      Figure 8Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Seattle Angina Questionnaire-physical limitation. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr9
      Figure 9Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Seattle Angina Questionnaire-angina severity. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr10
      Figure 10Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome Seattle Angina Questionnaire-treatment satisfaction. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      With respect to exercise performance, extractable data were combined from 3 trials,
      • Whitlow P.L.
      • DeMaio Jr, S.J.
      • Perin E.C.
      • et al.
      One-year results of percutaneous myocardial revascularization for refractory angina pectoris.
      • Salem M.
      • Rotevatn S.
      • Nordrehaug J.E.
      Long-term results following percutaneous myocardial laser therapy.
      • Ekre O.
      • Eliasson T.
      • Norrsell H.
      • Wahrborg P.
      • Mannheimer C.
      Long-term effects of spinal cord stimulation and coronary artery bypass grafting on quality of life and survival in the ESBY study.
      each with different approaches to measurement including the modified Bruce protocol,
      • Leon M.B.
      • Kornowski R.
      • Downey W.E.
      • et al.
      A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease.
      the Naughton protocol,
      • Whitlow P.L.
      • DeMaio Jr, S.J.
      • Perin E.C.
      • et al.
      One-year results of percutaneous myocardial revascularization for refractory angina pectoris.
      and treadmill or bicycle ergometry. We found that PMLR did not significantly improve exercise performance, perhaps due to inconsistent exercise protocols (Fig. 11).
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      We also found that PMLR had no significant impact on all-cause mortality (Fig. 12).
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      The available data seem to suggest that PMLR is as effective as TMLR and that it poses less risk, but this could not be concluded definitively. Lack of detailed reporting on mortality vs adverse events in some trials necessitated an examination of all-cause mortality. The validity of this end point as a proxy for the safety of PMLR is uncertain. The incidence and severity of periprocedural risks (eg, pericardial effusion and hematoma, tamponade, and left ventricular and coronary perforation) during PMLR (vs TMLR) should also be examined for a more comprehensive assessment of safety.
      Figure thumbnail gr11
      Figure 11Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome exercise performance. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.
      Figure thumbnail gr12
      Figure 12Comparison of percutaneous myocardial laser revascularization vs maximal medical therapy, outcome all-cause mortality. CI, confidence interval; df, degree of freedom; IV, inverse variance; LD, low dose; SD, standard deviation.
      Reprinted from McGillion et al.,
      • McGillion M.
      • Cook A.
      • Victor J.C.
      • et al.
      Effectiveness of percutaneous laser revascularization therapy for refractory angina.
      © 2010, with permission from Dove Medical Press Ltd.

      Quality of evidence according to GRADE

      The methodological quality of the 5 trials was found to range from moderate
      • Whitlow P.L.
      • DeMaio Jr, S.J.
      • Perin E.C.
      • et al.
      One-year results of percutaneous myocardial revascularization for refractory angina pectoris.
      • Stone G.W.
      • Teirstein P.S.
      • Rubenstein R.
      • et al.
      A prospective, multicenter, randomized trial of percutaneous transmyocardial laser revascularization in patients with nonrecanalizable chronic total occlusions.
      to high,
      • Oesterle S.N.
      • Sanborn T.A.
      • Ali N.
      • et al.
      Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial Potential class improvement from intramyocardial channels.
      • Salem M.
      • Rotevatn S.
      • Nordrehaug J.E.
      Long-term results following percutaneous myocardial laser therapy.
      • McNab D.
      • Khan S.N.
      An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: the SPiRiT trial [reply].
      • Leon M.B.
      • Kornowski R.
      • Downey W.E.
      • et al.
      A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease.
      with 5 trials blinding outcome assessors, 4 trials blinding participants, and 3 trials blinding PMLR operators and other clinicians involved. Although most trials were of good to excellent methodological quality, variations in laser dose across trials produced inconsistent results. We rate the quality of the available evidence as moderate (see Table 2).
      PMLR may be considered for reduction in the perceived severity of angina pain symptoms (Weak Recommendation, Moderate-Quality Evidence).
      PMLR may be considered for improvement in aspects of HRQL (Weak Recommendation, Moderate-Quality Evidence).
      PMLR is not associated with significant increase in all-cause mortality compared with medical management up to 1 year post intervention (Weak Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations recognize that some patients may choose to pursue PMLR, where available (ie, international centres) and balance improvement in symptoms and aspects of HRQL with procedural risk.

      Spinal cord stimulation

      Spinal cord stimulation (SCS) is a minimally invasive therapy that involves application of electrical current to the dorsal columns of the spinal cord with the goal of reducing angina.
      • Ekre O.
      • Eliasson T.
      • Norrsell H.
      • Wahrborg P.
      • Mannheimer C.
      Long-term effects of spinal cord stimulation and coronary artery bypass grafting on quality of life and survival in the ESBY study.
      • DeJongste M.J.L.
      Efficacy, safety and mechanisms of spinal cord stimulation used as an additional therapy for patients suffering from chronic refractory angina pectoris.
      • TenVaarwerk I.A.M.
      • Jessurun G.A.J.
      • DeJongste M.J.L.
      • et al.
      Clinical outcome of patients treated with spinal cord stimulation for therapeutically refractory angina pectoris.
      Electrodes are implanted into the epidural space at the level which induces bilateral paresthesia across the chest, typically between C7 and T4. The electrodes are attached to an implanted pulse generator; treatment may be intermittent or continuous as required using a patient-controlled programmer. Complications reported include lead dislodgement, electrode fracture, and subcutaneous infections. Periprocedural complications are rare as the electrodes are inserted percutaneously.
      • DeJongste M.J.L.
      Efficacy, safety and mechanisms of spinal cord stimulation used as an additional therapy for patients suffering from chronic refractory angina pectoris.
      • Eliasson T.
      • Augustinsson L.E.
      • Mannheimer C.
      Spinal cord stimulation in severe angina pectoris–presentation of current studies, indications and clinical experience.
      Treatment is not suitable for patients who have diseases of the spinal column or have cognitive impairment precluding safe use of an external programming device. SCS produces anti-ischemic effects in addition to analgesic effects.
      • Mannheimer C.
      • Camici P.
      • Chester M.R.
      • et al.
      The problem of chronic refractory angina report from the ESC joint study group on the treatment of refractory angina.
      • Svorkdal N.
      Treatment of inoperable coronary disease and refractory angina: spinal stimulators, epidurals, gene therapy, transmyocardial laser, and counterpulsation.
      Pain is modulated by selective stimulation of the inhibitory afferent fibres in the posterior horns of the spinal cord.
      • Eliasson T.
      • Augustinsson L.E.
      • Mannheimer C.
      Spinal cord stimulation in severe angina pectoris–presentation of current studies, indications and clinical experience.
      Treatment does not mask myocardial ischemia.
      • Eliasson T.
      • Augustinsson L.E.
      • Mannheimer C.
      Spinal cord stimulation in severe angina pectoris–presentation of current studies, indications and clinical experience.
      Taylor et al.
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      meta-analyzed the results of 7 RCTs published between 1998 and 2008 including 270 RFA patients in total; 162 were randomly allocated to the SCS group. Key outcomes included angina symptoms, HRQL, ischemic burden, exercise capacity, and adverse events.
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      SCS was compared with no SCS controls,
      • Di Pede F.
      • Zuin G.
      • Giada F.
      • et al.
      Long-term effects of spinal cord stimulation on myocardial ischemia and heart rate variability: results of a 48-hour ambulatory electrocardiographic monitoring.
      • Eddicks S.
      • Maier-Hauff K.
      • Schenk M.
      • et al.
      Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study.
      • Jessurun G.A.J.
      • Dejongste M.J.L.
      • Hautvast R.W.M.
      • et al.
      Clinical follow-up after cessation of chronic electrical neuromodulation in patients with severe coronary artery disease: A prospective randomized controlled study on putative involvement of sympathetic activity.
      • Hautvast R.W.
      • DeJongste M.J.
      • Staal M.J.
      • van Gilst W.H.
      • Lie K.I.
      Spinal cord stimulation in chronic intractable angina pectoris: a randomized, controlled efficacy study.
      • DeJongste M.J.
      • Hautvast R.W.
      • Hillege H.L.
      • Lie K.L.
      Efficacy of spinal cord stimulation as adjuvant therapy for intractable angina pectoris: a prospective, randomized clinical study Working Group on Neurocardiology.
      coronary artery bypass grafting,
      • Mannheimer C.
      • Eliasson T.
      • Augustinsson L.
      • et al.
      Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study.
      and PMLR.
      • McNab D.
      • Khan S.N.
      • Sharples L.D.
      • et al.
      An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: The SPiRiT trial.
      Follow-up periods ranged from 48 hours
      • Di Pede F.
      • Lanza G.A.
      • Zuin G.
      • et al.
      Immediate and long-term clinical outcome after spinal cord stimulation for refractory stable angina pectoris.
      to 5 years.
      • Norrsell H.
      • Pilhall M.
      • Eliasson T.
      • Mannheimer C.
      Effects of spinal cord stimulation and coronary artery bypass grafting on myocardial ischemia and heart rate variability: further results from the ESBY study.
      Taylor et al.
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      reported a pooled standardized mean difference (SMD) of 0.76 (95% CI, 0.07-1.46; P = 0.03) with respect to exercise capacity, indicating a significant improvement for those allocated to SCS (Fig. 13). HRQL, as measured by aggregate scores, was also significantly improved (SMD 0.83; 95% CI, 0.32-1.34; P = 0.001) (Fig. 14). Low complication rates including infection (1%) and lead displacement or fracture (7%) were reported across trials.
      Figure thumbnail gr13
      Figure 13Comparison of SCS vs controls, outcome exercise capacity, between-group difference. CABG, coronary artery bypass grafting; CI, confidence interval; df, degree of freedom; ESBY, Electrical Stimulation vs Coronary Artery Bypass Surgery in Severe Angina Pectoris study; IV, inverse variance; PMR, percutaneous myocardial laser revascularization; SCS, spinal cord stimulation; SD, standard deviation; SPiRiT, Spinal Cord Stimulation vs Percutaneous Myocardial Laser Revascularization in Patients With Refractory Angina Pectoris Trial.
      Reproduced from Taylor et al.
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      with permission granted under BioMed Central's general open access terms. © 2009 Taylor et al; licensee BioMed Central Ltd.
      Figure thumbnail gr14
      Figure 14Comparison of SCS vs controls, outcome health-related quality of life, between-group difference. Based on NHP Part 1 score for ESBY 1993;
      • Mannheimer C.
      • Eliasson T.
      • Augustinsson L.
      • et al.
      Electrical stimulation versus coronary artery bypass surgery in severe angina pectoris: the ESBY study.
      SF-36 physical health scale at 2 years for SPiRiT 2006;
      • McNab D.
      • Khan S.N.
      • Sharples L.D.
      • et al.
      An open label, single-centre, randomized trial of spinal cord stimulation vs. percutaneous myocardial laser revascularization in patients with refractory angina pectoris: The SPiRiT trial.
      ADL score for DeJongste 1994,
      • DeJongste M.J.
      • Hautvast R.W.
      • Hillege H.L.
      • Lie K.L.
      Efficacy of spinal cord stimulation as adjuvant therapy for intractable angina pectoris: a prospective, randomized clinical study Working Group on Neurocardiology.
      EQ-5D VAS score for Eddicks 2007;
      • Eddicks S.
      • Maier-Hauff K.
      • Schenk M.
      • et al.
      Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study.
      LASA score for Hautvast 1998.
      • Hautvast R.W.
      • DeJongste M.J.
      • Staal M.J.
      • van Gilst W.H.
      • Lie K.I.
      Spinal cord stimulation in chronic intractable angina pectoris: a randomized, controlled efficacy study.
      ADL, Activities of Daily Living; CABG, coronary artery bypass grafting; CI, confidence interval; df, degree of freedom; EQ-5D VAS, EuroQol 5 Dimensions Visual Analogue Scale; ESBY, Electrical Stimulation vs Coronary Artery Bypass Surgery in Severe Angina Pectoris study; IV, inverse variance; LASA, Linear Analogue Self-Assessment; NPH, Nottingham Health Profile; PMR, percutaneous myocardial laser revascularization; SCS, spinal cord stimulation; SD, standard deviation; SF-36, Medical Outcomes Study Short Form-36; SPiRiT, Spinal Cord Stimulation vs Percutaneous Myocardial Laser Revascularization in Patients With Refractory Angina Pectoris Trial.
      Reproduced from Taylor et al.
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      with permission granted under BioMed Central's general open access terms. © 2009 Taylor et al; licensee BioMed Central Ltd.

      Quality of evidence according to GRADE

      While the investigators
      • Taylor R.S.
      • De Vries J.
      • Buscher E.
      • DeJongste M.J.L.
      Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials.
      were comprehensive in their search methods, selection of studies, and statistical methods, limited reporting of methodological details across primary trials hampered risk of bias assessment. Some methodological problems included lack of clarity about allocation concealment and lack of blinding. The overall quality of the available evidence is moderate (Table 2).
      SCS may be considered for improving exercise capacity (Weak Recommendation, Moderate-Quality Evidence).
      SCS may be considered for improving HRQL (Weak Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations place a high value on the results of multiple RCTs and a meta-analysis reporting significant improvements in exercise capacity and HRQL outcomes.

      Additional invasive therapies

      Three additional invasive therapies, used in some practices, were examined including temporary cardiac sympathectomy,
      • Moore R.
      • Groves D.
      • Hammond C.
      • Leach A.
      • Chester M.R.
      Temporary sympathectomy in the treatment of chronic refractory angina.
      • Chester M.
      • Hammond C.
      • Leach A.
      Long-term benefits of stellate ganglion block in severe chronic refractory angina.
      • Hammond C.
      • Collins A.
      • Leach A.A.
      • Chester M.R.
      Spinal cord stimulation for the treatment of refractory angina.
      high thoracic epidural analgesia,
      • Blomberg S.G.
      • Svorkdal N.
      Thoracic epidural anaesthesia for treatment of refractory angina pectoris.
      • Blomberg S.G.
      Long-term home self-treatment with high thoracic epidural anesthesia in patients with severe coronary artery disease.
      • Richter A.
      • Cederholm I.
      • Jonasson L.
      • et al.
      Effect of thoracic epidural analgesia on refractory angina pectoris: long-term home self-treatment.
      • Gramling-Babb P.
      High thoracic epidural analgesia for relief of coronary ischemia syndrome without cardiac surgery.
      • Gramling-Babb P.M.
      • Zile M.R.
      • Reeves S.T.
      Preliminary report on high thoracic epidural analgesia: relationship between its therapeutic effects and myocardial blood flow as assessed by stress thallium distribution.
      and endoscopic transthoracic sympathectomy.
      • Drott C.
      Results of endoscopic thoracic sympathectomy (ETS) on hyperhydrosis, facial blushing, angina pectoris, vascular disorders and pain syndromes of the hand and arm.
      • Wettervik C.
      • Claes G.
      • Drott C.
      • et al.
      Endoscopic transthoracic sympathectomy for severe angina.
      • Stritsky M.
      • Dobias M.
      • Demes R.
      • et al.
      Endoscopic thoracic sympathectomy; its effect in the treatment of refractory angina.
      • Breivik H.
      • Cousins M.J.
      • Lofstrom J.B.
      Sympathetic neural blockade of upper and lower extremity.
      The evidence for these therapies is limited to descriptive studies and case reports and was therefore not evaluated; no practice recommendations can be made at this time (Table 2).

      Noninvasive Therapies

      Enhanced external counter-pulsation

      Enhanced external counter-pulsation (EECP) is a noninvasive therapy that employs the application of compressive cuffs to the calves, lower thighs, and upper thighs. The cuffs are synchronized to inflate in a distal to proximal sequence during early diastole and to simultaneously deflate at the onset of systole.
      • Loh P.H.
      • Cleland J.G.
      • Louis A.A.
      • et al.
      Enhanced external counterpulsation in the treatment of chronic refractory angina: A long-term follow-up outcome from the international enhanced external counterpulsation patient registry.
      • Soran O.
      Treatment options for refractory angina pectoris: enhanced external counterpulsation therapy.
      The hemodynamic effect of the treatment augments diastolic pressure, presumably resulting in increased coronary perfusion during cuff inflation.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
      The rapid cuff deflation immediately before systole decreases systemic vascular resistance and cardiac workload. A typical treatment course consists of 1- to 2-hour sessions over several weeks, for a total of 35 hours of treatment.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
      Proposed mechanisms of action have included increased coronary perfusion resulting in increased collateralization, angiogenesis, and improved endothelial function as a result of treatment-induced shear stress.
      • Michaels A.D.
      • Accad M.P.
      • Thomas A.
      • Grossman W.
      Left ventricular systolic unloading and augmentation of intracoronary pressure and doppler flow during enhanced external counterpulsation.
      • Masuda D.
      • Nohara R.
      • Hirai T.
      • et al.
      Enhanced external counter-pulsation improved myocardial perfusion and coronary flow reserve in patients with chronic stable angina; evaluation by(13)N-ammonia positron emission tomography.
      • Werner D.
      • Schneider M.
      • Weise M.
      • Nonnast-Daniel B.
      • Daniel W.G.
      Pneumatic external counterpulsation: a new noninvasive method to improve organ perfusion.
      • Barsheshet A.
      • Hod H.
      • Shechter M.
      • et al.
      The effects of external counter pulsation therapy on circulating endothelial progenitor cells in patients with angina pectoris.
      • Bonetti P.O.
      • Barsness G.W.
      • Keelan P.C.
      • et al.
      Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease.
      • Shechter M.
      • Matetzky S.
      • Feinberg M.S.
      • et al.
      External counterpulsation therapy improves endothelial function in patients with refractory angina pectoris.
      A more recent study supports that EECP has beneficial effects on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents.
      • Braith R.W.
      • Conti C.R.
      • Nichols W.W.
      • et al.
      Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina A randomized sham-controlled study.
      EECP is contraindicated for persons with arrhythmias that interfere with the device triggering mechanism, bleeding diathesis, active thrombophlebitis, peripheral vascular disease, aortic aneurysm, or aortic stenosis, uncontrolled hypertension (ie, 180/110), severe lower extremity arterial-occlusive disease, uncontrolled congestive heart failure, and pregnancy.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
      A Cochrane Review by Amin et al.
      • Amin F.
      • Al Hajeri A.
      • Civelek B.
      • Fedorowicz Z.
      • Manzer B.M.
      Enhanced external counterpulsation for chronic angina pectoris.
      identified 1 RCT of EECP including 139 patients in total (the Multicenter Study of Enhanced External Counterpulsation [MUST-EECP] trial).
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation.
      Seventy-two patients were randomized to EECP; controls (n = 72) received ‘sham’ EECP, consisting of inactive counter-pulsation treatments. Key outcomes included self-reported HRQL, angina frequency, nitrate use, and exercise treadmill test (exercise duration and time to ≥ 1-mm ST-segment depression) 1 week post-treatment. Eighty-six percent of participants were male with baseline symptom severity ranging from CCS class I-III.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation.
      An additional 7 pre-post observational studies,
      • Loh P.H.
      • Cleland J.G.
      • Louis A.A.
      • et al.
      Enhanced external counterpulsation in the treatment of chronic refractory angina: A long-term follow-up outcome from the international enhanced external counterpulsation patient registry.
      • Kumar A.
      • Aronow W.S.
      • Vadnerkar A.
      • et al.
      Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35 days of treatment and at 1-year follow up in 47 patients with chronic refractory angina pectoris.
      • Michaels A.D.
      • Raisinghani A.
      • Soran O.
      • et al.
      The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: A multicenter radionuclide study.
      • Springer S.
      • Fife A.
      • Lawson W.
      • et al.
      Psychosocial effects of enhanced external counterpulsation in the angina patient: a second study.
      • Tartaglia J.
      • Stenerson Jr, J.
      • Charney R.
      • et al.
      Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation.
      • Werner D.
      • Kropp J.
      • Schellong S.
      • et al.
      Practicability and limitations of enhanced external counterpulsation as an additional treatment for angina.
      • Pettersson T.
      • Bondesson S.
      • Cojocaru D.
      • et al.
      One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.
      • Loh P.H.
      • Louis A.A.
      • Windram J.
      • et al.
      The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina.
      • Werner D.
      • Kropp J.
      • Schellong S.
      • et al.
      Practicability and limitations of enhanced external counterpulsation as an additional treatment for angina.
      • Loh P.H.
      • Louis A.A.
      • Windram J.
      • et al.
      The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina.
      • Barlow J.H.
      • Shaw K.L.
      • Harrison K.
      Consulting the 'experts': children's and parents' perceptions of psycho-educational interventions in the context of juvenile chronic arthritis.
      • McGillion M.H.
      • Watt-Watson J.
      • Stevens B.
      • et al.
      Randomized controlled trial of a psychoeducation program for the self-management of chronic cardiac pain.
      including 313 patients in total, were reviewed. Although an EECP registry exists, the International EECP Patient Registry (IEPR), it did not meet our inclusion criteria for scientific rigour.
      The MUST-EECP trial
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation.
      found that active EECP (compared with sham treatment) significantly improved 3 of 9 parameters of self-reported HRQL. However, response rates were poor (54%) and skewed toward the sham EECP group. ITT analysis found no significant differences between groups with respect to change in angina counts, frequency of nitroglycerine usage, or exercise duration.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
      There was a statistically significant 38-second difference between groups in the change in time to exercise-induced ischemia, favouring the active EECP group.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes.
      • Amin F.
      • Al Hajeri A.
      • Civelek B.
      • Fedorowicz Z.
      • Manzer B.M.
      Enhanced external counterpulsation for chronic angina pectoris.
      Minor adverse events (eg, skin abrasions, and leg and back pain) related to EECP were reported by 55% of the treatment group, compared with 20% in the sham group.
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation.
      We meta-analyzed the additional 7 pre-post observational studies,
      • Loh P.H.
      • Cleland J.G.
      • Louis A.A.
      • et al.
      Enhanced external counterpulsation in the treatment of chronic refractory angina: A long-term follow-up outcome from the international enhanced external counterpulsation patient registry.
      • Kumar A.
      • Aronow W.S.
      • Vadnerkar A.
      • et al.
      Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35 days of treatment and at 1-year follow up in 47 patients with chronic refractory angina pectoris.
      • Michaels A.D.
      • Raisinghani A.
      • Soran O.
      • et al.
      The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: A multicenter radionuclide study.
      • Springer S.
      • Fife A.
      • Lawson W.
      • et al.
      Psychosocial effects of enhanced external counterpulsation in the angina patient: a second study.
      • Tartaglia J.
      • Stenerson Jr, J.
      • Charney R.
      • et al.
      Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation.
      • Werner D.
      • Kropp J.
      • Schellong S.
      • et al.
      Practicability and limitations of enhanced external counterpulsation as an additional treatment for angina.
      • Pettersson T.
      • Bondesson S.
      • Cojocaru D.
      • et al.
      One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.
      where statistical pooling was possible, by outcome. Sample sizes ranged from 25 to 61. Across studies, follow-up periods varied from immediate post-treatment
      • Michaels A.D.
      • Raisinghani A.
      • Soran O.
      • et al.
      The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: A multicenter radionuclide study.
      • Springer S.
      • Fife A.
      • Lawson W.
      • et al.
      Psychosocial effects of enhanced external counterpulsation in the angina patient: a second study.
      • Tartaglia J.
      • Stenerson Jr, J.
      • Charney R.
      • et al.
      Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation.
      to 1 year,
      • Kumar A.
      • Aronow W.S.
      • Vadnerkar A.
      • et al.
      Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35 days of treatment and at 1-year follow up in 47 patients with chronic refractory angina pectoris.
      • Pettersson T.
      • Bondesson S.
      • Cojocaru D.
      • et al.
      One year follow-up of patients with refractory angina pectoris treated with enhanced external counterpulsation.
      • Loh P.H.
      • Louis A.A.
      • Windram J.
      • et al.
      The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina.
      • Werner D.
      • Kropp J.
      • Schellong S.
      • et al.
      Practicability and limitations of enhanced external counterpulsation as an additional treatment for angina.
      CCS class varied from class I to IV. The pooled proportion of patients experiencing a CCS class change of 1 or more (2 studies, n = 86)
      • Tartaglia J.
      • Stenerson Jr, J.
      • Charney R.
      • et al.
      Exercise capability and myocardial perfusion in chronic angina patients treated with enhanced external counterpulsation.
      • Loh P.H.
      • Louis A.A.
      • Windram J.
      • et al.
      The immediate and long-term outcome of enhanced external counterpulsation in treatment of chronic stable refractory angina.
      was found to be 45.5% (95% CI, 31.9-61.6) at 12-month follow-up. A small, significant improvement in anginal stability, as measured by the SAQ (2 studies, n = 87),
      • Kumar A.
      • Aronow W.S.
      • Vadnerkar A.
      • et al.
      Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35 days of treatment and at 1-year follow up in 47 patients with chronic refractory angina pectoris.
      • Springer S.
      • Fife A.
      • Lawson W.
      • et al.
      Psychosocial effects of enhanced external counterpulsation in the angina patient: a second study.
      was also found (SMD −0.34; 95% CI, −0.65 to −0.02; P = 0.04) (Fig. 15).
      Figure thumbnail gr15
      Figure 15Enhanced external counter-pulsation: comparison of pre- vs post-treatment, outcome Seattle Angina Questionnaire-anginal stability. CI, confidence interval; df, degree of freedom; IV, inverse variance; SE, standard error.

      Quality of evidence according to GRADE

      The MUST-EECP trial
      • Arora R.R.
      • Chou T.M.
      • Jain D.
      • et al.
      Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation.
      is of poor methodological quality, with problems that include incomplete reporting, significant loss to follow-up, unclear blinding of outcome assessment, and lack of ITT analysis principles.
      • Amin F.
      • Al Hajeri A.
      • Civelek B.
      • Fedorowicz Z.
      • Manzer B.M.
      Enhanced external counterpulsation for chronic angina pectoris.
      Similar methodological problems were noted among the pre-post studies we reviewed. We rate the overall quality of the evidence as low (Table 2).
      EECP may be considered for improvements in aspects of HRQL (Weak Recommendation, Low-Quality Evidence).
      EECP may be considered for improvement in severity of angina symptoms (Weak Recommendation, Low-Quality Evidence).
      Values and preferences. These recommendations place a high value on the decision of individual patients to pursue symptom relief and improvements in HRQL outcomes.

      Cognitive-behavioural self-management interventions

      Cognitive-behavioural self-management interventions are multi-modal treatment packages that employ learning materials and cognitive-behavioural strategies to achieve changes in knowledge and behaviour for effective disease self-management.
      • Barlow J.H.
      • Shaw K.L.
      • Harrison K.
      Consulting the 'experts': children's and parents' perceptions of psycho-educational interventions in the context of juvenile chronic arthritis.
      They target day-to-day problems that patients encounter such as angina pain, fatigue, decreased mobility and endurance, anxiety, and stress.
      • Barlow J.H.
      • Shaw K.L.
      • Harrison K.
      Consulting the 'experts': children's and parents' perceptions of psycho-educational interventions in the context of juvenile chronic arthritis.
      Patients are taught several symptom self-management techniques including safe exercise habits, energy conservation, pacing and sleep quality enhancement, and communication and decision-making skills. A sound underpinning in social, cognitive and/or behavioural theories is critical to the success of self-management programs.
      • Barlow J.H.
      • Shaw K.L.
      • Harrison K.
      Consulting the 'experts': children's and parents' perceptions of psycho-educational interventions in the context of juvenile chronic arthritis.
      • McGillion M.H.
      • Watt-Watson J.
      • Stevens B.
      • et al.
      Randomized controlled trial of a psychoeducation program for the self-management of chronic cardiac pain.
      • Barlow J.H.
      • Sturt J.
      • Hearnshaw H.
      Self-management interventions for people with chronic conditions in primary care: examples from arthritis, asthma and diabetes.
      • Holman H.
      • Lorig K.
      Patient self-management: a key to effectiveness and efficiency in care of chronic disease.
      • Bodenheimer T.
      • Lorig K.
      • Holman H.
      • Grumbach K.
      Patient self-management of chronic disease in primary care.
      • McGillion M.H.
      • Watt-Watson J.H.
      • Kim J.
      • Graham A.
      Learning by heart: a focused group study to determine the self-management learning needs of chronic stable angina patients.
      • Holman H.
      • Lorig K.
      Patients as partners in managing chronic disease Partnership is a prerequisite for effective and efficient health care.
      • LeFort S.M.
      • Gray-Donald K.
      • Rowat K.M.
      • Jeans M.E.
      Randomized controlled trial of a community-based psychoeducation program for the self-management of chronic pain.
      A meta-analysis by McGillion et al.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      pooled the results of 7 RCTs of self-management programs for chronic angina—including RFA—involving 949 patients in total. Outcomes examined included angina frequency and duration, sublingual (SL) nitroglycerine use, HRQL, and aspects of psychological well-being including anxiety and depression.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      Six trials
      • McGillion M.H.
      • Watt-Watson J.
      • Stevens B.
      • et al.
      Randomized controlled trial of a psychoeducation program for the self-management of chronic cardiac pain.
      • Bundy C.
      • Carroll D.
      • Wallace L.
      • Nagle R.
      Psychological treatment of chronic stable angina pectoris.
      • Gallacher J.E.J.
      • Hopkinson C.A.
      • Bennett M.L.
      • Burr M.L.
      • Elwood P.C.
      Effect of stress management on angina.
      • Lewin R.J.
      • Furze G.
      • Robinson J.
      • et al.
      A randomised controlled trial of a self-management plan for patients with newly diagnosed angina.
      • Payne T.J.
      • Johnson C.A.
      • Penzien D.B.
      • et al.
      Chest pain self-management training for patients with coronary artery disease.
      • Lewin B.
      • Cay E.
      • Todd I.
      • et al.
      The angina management programme: a rehabilitation treatment.
      tested small-group self-management interventions (6-15 patients); intervention duration, format, and process varied. The authors found that self-management training resulted in approximately 3 fewer angina episodes per week (delta [Δ] = −2.85; 95% CI, −4.04 to −1.66) (Fig. 16).
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      This was accompanied by a decrease in weekly SL nitrate usage (Δ = −3.69; 95% CI, −5.50 to −1.89) (Fig. 17).
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      Significant HRQL improvements, as measured by the SAQ, were also found (Figure 18, Figure 19).
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      No pooled estimate of the effect on psychological well-being was generated due to heterogeneity of measures.
      Figure thumbnail gr16
      Figure 16Comparison of self-management training with controls, outcome frequency of angina episodes per week. CI, confidence interval.
      Modified and reproduced from McGillion et al.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      with permission from Bentham Science Publishers Ltd. © 2008 Bentham Science Publishers Ltd.
      Figure thumbnail gr17
      Figure 17Comparison of self-management training with controls, outcome sublingual nitrate usages per week. CI, confidence interval.
      Modified and reproduced from McGillion et al.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      with permission from Bentham Science Publishers Ltd. © 2008 Bentham Science Publishers Ltd.
      Figure thumbnail gr18
      Figure 18Comparison of self-management training with controls, outcome Seattle Angina Questionnaire-physical limitation. CI, confidence interval.
      Modified and reproduced from McGillion et al.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      with permission from Bentham Science Publishers Ltd. © 2008 Bentham Science Publishers Ltd.
      Figure thumbnail gr19
      Figure 19Comparison of self-management training with controls, outcome Seattle Angina Questionnaire-disease perception. CI, confidence interval.
      Modified and reproduced from McGillion et al.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      with permission from Bentham Science Publishers Ltd. © 2008 Bentham Science Publishers Ltd.

      Quality of evidence according to GRADE

      Most trials had small samples and adequacy of random allocation concealment and blinding was varied.
      • McGillion M.
      • Arthur H.
      • Victor J.C.
      • Watt-Watson J.
      • Cosman T.
      Effectiveness of psychoeducational interventions for improving symptoms, health-related quality of life, and psychological well being in patients with stable angina.
      We rate the overall methodological quality of the evidence as moderate (Table 2).
      Self-management training may be considered for reduction in angina pain symptoms and related use of SL nitrates (Weak Recommendation, Moderate-Quality Evidence).
      Self-management training may be considered for improvements in HRQL (Weak Recommendation, Moderate-Quality Evidence).
      Values and preferences. These recommendations place a high value on addressing cognitive and behavioural responses to improve symptoms and HRQL outcomes.

      Pharmacologic Therapies

      Level of access in Canada to pharmacologic therapies reviewed varies (eg, widely available, approved for use in clinical trials, not available). Readers are referred to the Health Canada Drug Product Database (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdon/index-eng.php) for drug availability status and related information.

      Metabolic agents

      Allopurinol

      Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the transformation of hypoxanthine into xantine and uric acid. Allopurinol has generated growing interest due to a series of retrospective clinical observations which have suggested that it could improve the mechano-energetic uncoupling of the failing myocardium.
      • Mellin V.
      • Isabelle M.
      • Oudot A.
      • et al.
      Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure.
      How allopurinol reduces myocardial ischemia is not entirely clear. At least 2 mechanisms of action have been proposed. Xanthine oxidase is a main source of the reactive oxygen species responsible for the oxidative stress occurring in the ischemic myocardium. By inhibiting xanthine oxidase, allopurinol reduces the oxygen wastage caused by the oxidative stress and may therefore increase the molecular oxygen available to transform fatty acids and pyruvate into energy in the ischemic myocytes. The global antioxidant effect of allopurinol could improve the endothelial dysfunction known to compromise the vasoreactivity of coronary arteries.
      • Farquharson C.A.J.
      • Butler R.
      • Hill A.
      • Belch J.J.F.
      • Struthers A.D.
      Allopurinol improves endothelial dysfunction in chronic heart failure.
      While encouraging, the anti-ischemic effect of allopurinol awaits validation in larger, independent trials. Likewise, whether allopurinol will be efficient for optimally medicated patients with advanced CAD and RFA remains to be seen.
      A recent trial by Noman et al. suggested that allopurinol could relieve myocardial ischemia and improve time to ST-segment depression in patients with chronic stable angina (n = 65).
      • Noman A.
      • Ang D.S.
      • Ogston S.
      • Lang C.C.
      • Struthers A.D.
      Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
      Most of the patients were treated with at least a β-blocker (87%) and 1 additional anti-anginal medication, such as oral nitrate (48%), calcium channel blockers (22%), or nicorandil (22%).
      • Noman A.
      • Ang D.S.
      • Ogston S.
      • Lang C.C.
      • Struthers A.D.
      Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
      Interestingly, patients treated with allopurinol showed an improved double-product at the peak of the stress test, suggesting indeed that allopurinol reduced myocardial ischemia independently of the usual chronotropic and vasodilatory mechanisms seen with more traditional anti-anginal medications. As noted by the authors, allopurinol had an anti-ischemic effect size similar to other anti-anginal agents, such as amlodipine (+ 36 seconds), nitrates (+60 seconds) or β-blockers (+50 seconds).
      • Noman A.
      • Ang D.S.
      • Ogston S.
      • Lang C.C.
      • Struthers A.D.
      Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial.
      No adverse effects were reported. Results of this RCT are promising but their applicability to those with true RFA is unclear. Additional work is also needed to corroborate the observed anti-ischemic effects of allopurinol.

      Quality of evidence according to GRADE

      The anti-ischemic effects of allopurinol require validation and the applicability of the current evidence to RFA patients is uncertain. Pilot trials to date are also small. Therefore (in the context of RFA), we rate the overall quality of the evidence as very low (Table 2).
      More robust RCTs are needed before allopurinol can be recommended as an anti-anginal agent for RFA patients (Strong Recommendation, Very Low-Quality Evidence).
      Values and preferences. This recommendation recognizes the potential benefits of allopurinol and the need for high-quality, RFA-specific evidence to support future practice recommendations.

      Ranolazine

      Ranolazine is the first molecule approved by the United States Food and Drug Administration in 2 decades for the treatment of stable angina, but not RFA specifically. Ranolazine is believed to exert an anti-anginal effect by partially inhibiting the late sodium current (lNa+). During myocardial ischemia, defective trans-cellular sodium currents would lead to sodium overload if it was not for the Na+/Ca++ exchanger that maintains ionic homeostasis. The sodium expelled outside the cell via the exchanger leads in return to a calcium overload. The abnormal calcium concentration impairs the myocardial contraction-relaxation coupling, leading to relaxation abnormalities and reduced endocardial perfusion.
      In the Combination Assessment of Ranolazine in Stable Angina (CARISA) trial, the combination of ranolazine with either atenolol, diltiazem, or amlodipine significantly improved the time to 1 mm ST-segment depression and the total exercise time during stress testing.
      • Chaitman B.R.
      Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions.
      • Chaitman B.R.
      • Pepine C.J.
      • Parker J.O.
      • et al.
      Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial.
      The CARISA trial was followed by the Efficacy of Ranolazine in Chronic Angina (ERICA) trial to determine whether ranolazine improves angina in stable coronary patients with persisting symptoms despite maximum therapy with 1 of the agents listed above.
      • Stone P.H.
      • Gratsiansky N.A.
      • Blokhin A.
      • et al.
      Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.
      Though the participants in CARISA were not strictly defined as RFA patients, their characteristics in terms of unrelenting angina despite best available treatment suggest that they closely resemble the definition of RFA proposed in these guidelines. In ERICA, patients had to remain symptomatic (more than 3 anginal attacks per week) despite optimal dose of amlodipine (10 mg daily). Over a course of 6 weeks, the addition of ranolazine 1000 mg twice daily to amlodipine was superior to the matching placebo at reducing the weekly frequency of angina episodes (2.88 ± 0.19 episodes vs 3.31± 0.22 episodes, respectively; P = 0.03) and of nitroglycerin caps administration (2.03 ± 0.20 caps vs 2.68 ± 0.22, respectively; P = 0.01).
      • Stone P.H.
      • Gratsiansky N.A.
      • Blokhin A.
      • et al.
      Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial.
      Ranolazine appears to be safe and generally well tolerated;
      • Scirica B.M.
      • Morrow D.A.
      • Hod H.
      • et al.
      Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial.
      fewer than 10% of the patients discontinued ranolazine because of adverse events.
      • Koren M.J.
      • Crager M.R.
      • Sweeney M.
      Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: The ranolazine open label experience (ROLE).
      Clinically, ranolazine can improve myocardial ischemia without affecting heart rate or blood pressure. Its unique mode of action makes it a potentially useful agent for the care of patients with persistent symptoms despite optimal doses of β-blockers, calcium agonists, or nitrates, especially when patients are limited by bradycardia and orthostatic hypotension. However, the use of ranolazine in a population of optimally medicated patients with advanced CAD has not been sufficiently studied; the applicability of findings to RFA patients is therefore unknown.

      Quality of evidence according to GRADE

      The current evidence demonstrates that ranolazine appears to be an effective anti-anginal agent in patients with stable CAD. However, the ERICA trial was limited to short-term follow up (ie, 6 weeks) and the use of amlodipine alone in combination with ranolazine. More trials are needed to further examine the effectiveness of ranolazine in combination with clinically relevant, maximally-tolerated combination medical therapy for patients with advanced CAD and a confirmed diagnosis of RFA. We therefore rate the overall quality of the evidence as moderate (Table 2).
      Robust RCTs focused on patients with RFA are needed before ranolazine can be recommended definitively as an anti-anginal agent (Strong Recommendation, Moderate-Quality Evidence).
      Ranolazine may hold promise for reduction in angina symptoms, particularly for those patients who cannot tolerate upward titration of conventional anti-anginal agents due to depressive effects on heart rate and blood pressure (Weak Recommendation, Moderate-Quality Evidence).
      Values and preferences. The recommendations place a high value on the need for high-quality, RFA-specific evidence to support future practice recommendations, as well as the potential benefit of ranolazine to reduce angina symptoms, particularly among those who cannot tolerate upward titration of conventional anti-anginal agents.

      Trimetazidine

      Trimetazidine is an anti-ischemic metabolic agent that stimulates myocardial glucose consumption through inhibition of fatty acid metabolism.
      • Harpey C.
      • Clauser P.
      • Labrid C.
      • Fryria J.
      • Poirier J.
      Trimetazidine, a cellular anti-ischemic agent.
      • Kantor P.F.
      • Lucien A.
      • Kozak R.
      • Lopaschuk G.D.
      The antianginal drug trimeetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long chain 3-ketoactly coenzyme A thiolase.
      • Lazar E.J.
      • Frishman W.H.
      Profile of an ideal antianginal agent.
      Trimetazidine inhibits reduction of intracellular adenosine triphosphate levels via conservation of cellular metabolism in ischemic regions. Such inhibition facilitates performance of ionic pumps, flow of transmembranous sodium-potassium, and ongoing cellular homeostasis. Recommended dosing of trimetazidine includes 20 mg 3 times daily; a 30 mg modified-release formulation is also available in some countries for twice-daily dosing. Contraindications include pregnancy, breastfeeding, and history of allergy. No known drug interactions have been reported.
      In a Cochrane Review, Ciapponi et al.
      • Ciapponi A.
      • Pizarro R.
      • Harrison J.
      Trimetazadine for stable angina.
      meta-analyzed the results of 23 RCTs published between 1967 and 2003 including 1378 patients in total. Trimetazidine was either administered as monotherapy (11 studies), compared with placebo (8 studies), or compared with another anti-anginal drug (3 studies). In an additional 13 studies, trimetazidine was examined as combination therapy vs placebo (11 studies), isosorbide mononitrate (1 study), and isosorbide dinitrate (1 study). Methodological quality of the studies ranged from good to poor.
      • Ciapponi A.
      • Pizarro R.
      • Harrison J.
      Trimetazadine for stable angina.
      The trial with the highest noted overall methodological quality (ie, allocation concealment, double blinding, losses to follow-up, and blinding of outcome assessment)
      • Szwed H.
      • Sadowski Z.
      • Elikowski W.
      • et al.
      Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II) TRIMetazidine in POLand.
      did not analyze outcomes according to ITT principles.
      With respect to symptoms, trimetazidine as compared with placebo significantly reduced the frequency of weekly angina episodes by approximately 1 episode per week (SMD −1.44; 95% CI, −2.10 to 00.79; P < 0.0001). SL nitrate consumption was similarly reduced (SMD −1.47; 95% CI, −2.20 to −0.73; P < 0.0001), yet significant statistical heterogeneity was detected for this outcome (I2 47.5%; P = 0.05). Time to 1-mm ST-segment depression was also significantly increased (SMD 0.32; 95% CI, 0.15-0.48; P = 0.0002). Despite some positive findings, the review found a lack of clear data on mortality, cardiovascular events, and quality of life outcomes.
      • Ciapponi A.
      • Pizarro R.
      • Harrison J.
      Trimetazadine for stable angina.
      The available data to date suggest that trimetazidine may be effective in the treatment of RFA symptoms either alone, or as combination therapy with other anti-anginal agents. Before this can be concluded definitively, robust clinical trials of trimetazidine, specific to RFA patients, and with long-term follow up are needed to clearly establish its therapeutic effectiveness. Careful attention should be paid to evaluation of mortality risk and adverse events, as well as the impact of trimetazidine on functional status, using well-established measures of HRQL.

      Quality of evidence according to GRADE

      Given the lack of clear data on anti-anginal efficacy of trimetazidine, mortality risk and adverse events, we rate the overall quality of the evidence as very low (Table 2).
      Robust, adequately powered RCTs with long-term follow up are needed to more definitively examine the anti-anginal effects, mortality risk, and adverse events associated with trimetazadine before it can be recommended for the treatment of RFA (Strong Recommendation, Very Low-Quality Evidence).
      Values and preferences. This recommendation places a high value on patient safety and the need for high-quality, RFA-specific evidence to support future practice recommendations.

      Nicorandil

      Nicorandil is a nicotinamide ester with a dual mode of action. A first nitrate-like moiety reduces angina by dilating the systemic veins and the coronary arteries. A second moiety protects ischemic myocytes by opening the mitochondrial adenosine triphosphate-sensitive potassium channels. This later property is thought to mimic the ischemic preconditioning phenomenon. The potassium channel opening is also thought to dilate the peripheral and coronary resistance arterioles which further increases the coronary blood flow.
      • Treese N.
      • Erbel R.
      • Meyer J.
      Acute hemodynamic effects of nicorandil in coronary artery disease.
      The anti-anginal properties of nicorandil have been known for more than 30 years.
      A series of small RCTs suggested that nicorandil can exert an anti-ischemic effect comparable to conventional doses of β-blockers, oral nitrates, and calcium antagonists in patients with stable effort angina pectoris.
      • Treese N.
      • Erbel R.
      • Meyer J.
      Acute hemodynamic effects of nicorandil in coronary artery disease.
      • Doring G.
      Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients.
      • Meeter K.
      • Kelder J.C.
      • Tijssen J.G.P.
      • et al.
      Efficacy of nicorandil versus propranolol in mild stable angina pectoris of effort: A long-term, double-blind, randomized study.
      • Hughes L.O.
      • Rose E.L.
      • Lahiri A.
      • Raftery E.B.
      Comparison of nicorandil and atenolol in stable angina pectoris.
      • Di Somma S.
      • Liguori V.
      • Petitto M.
      • et al.
      A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris.
      • Ulvenstam G.
      • Diderholm E.
      • Frithz G.
      • et al.
      Antianginal and anti-ischemic efficacy of nicorandil compared with nifedipine in patients with angina pectoris and coronary heart disease: a double-blind, randomized, multicenter study.
      • Guermonprez J.L.
      • Blin P.
      • Peterlongo F.
      A double-blind comparison of the long-term efficacy of a potassium channel opener and a calcium antagonist in stable angina pectoris.
      • Zhu W.L.
      • Shan Y.D.
      • Guo J.X.
      • et al.
      Double-blind, multicenter, active-controlled, randomized clinical trial to assess the safety and efficacy of orally administered nicorandil in patients with stable angina pectoris in china.
      Because of the large individual variations in the rates of anginal attack and exercise duration on treadmill stress test, these studies were underpowered to detect any significant differences between nicorandil and other anti-anginal agents. Thus, nicorandil has been positioned as a cardioprotective agent.
      In the Impact of Nicorandil in Angina (IONA) trial, nicorandil 10 mg twice daily was formally tested against placebo for the reduction of cardiovascular events in patients with recently diagnosed angina with established CAD.
      IONA Study Group
      Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial [erratum in 2002;360:806].
      Nicorandil 20 mg twice daily was superior to placebo at reducing the combined occurrence of cardiovascular death, nonfatal MI, or unplanned hospital admission for cardiac chest pain (hazard ratio [HR] 0.83; 95% CI, 0.72-0.97). While nicorandil reduced the rate of acute coronary syndromes (7.6% vs 6.1%; HR 0.79; 95% CI, 0.64-0.98), it did not significantly improve mortality (5.2% vs 4.2%; HR 0.79; 95% CI, 0.61-1.02; P = 0.07).
      IONA Study Group
      Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial [erratum in 2002;360:806].
      In the United Kingdom, nicorandil was later found to be cost-effective, as the additional cost of nicorandil was offset by the reduced use of hospital services.
      • Walker A.
      • McMurray J.
      • Stewart S.
      • et al.
      Economic evaluation of the impact of nicorandil in angina (IONA) trial.
      To date, most of the clinical experience with this agent relies on patients with newly diagnosed angina.

      Quality of evidence according to GRADE

      Given the lack of applicability of current data to RFA specifically, we rate the overall quality of the evidence as very low (Table 2).
      Robust RCTs are needed to examine the effectiveness of nicorandil for RFA patients before specific recommendations can be made (Strong recommendation, Very Low-Quality Evidence).
      Values and preferences. This recommendation recognizes the potential benefits of nicorandil and the need for high-quality, RFA-specific evidence to support future practice recommendations.

      Heart rate modulating agent

      Ivabradine

      Ivabradine is a heart rate lowering agent that inhibits the If pacemaker current in the sinoatrial node.
      • Fox K.
      Ivabradine - a selective and specific If inhibitor: efficacy and safety in stable angina.
      Ivabradine produces its anti-ischemic effect as a result of heart rate reduction
      • Fox K.
      Selective and specific I(f) inhibition: new perspectives for the treatment of stable angina.
      with no effect on blood pressure, intra-atrial, atrioventricular, or intraventricular conduction times, or myocardial contractility or ventricular repolarisation.
      • Camm A.J.
      • Lau C.P.
      Electrophysiological effect of a single intravenous administration of ivabradine (S16257) in adult patients with normal electrophysiology.
      • Vilaine J.P.
      • Bidourd J.P.
      • Lesage L.
      • Reure H.
      • Peglion J.L.
      Anti-ischemic effects of ivabradine, a selective heart rate reducing agent, in excercise induced myocardial ischemia in pigs.
      • Joannides R.
      • Moore N.
      • Iacob M.
      • et al.
      Comparative effects of ivabradine, a selective heart rate-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise.
      • Manz M.
      • Reuter M.
      • Lauck G.
      • Omran H.
      • Jung W.
      A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction.
      Heart rate reduction results in improved myocardial perfusion as a result of increased diastolic filling time and reduced myocardial oxygen demand.
      • Borer J.S.
      • Fox K.
      • Jaillon P.
      • Lerebours G.
      Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.
      Early trials of ivabradine
      • Fox K.
      Ivabradine - a selective and specific If inhibitor: efficacy and safety in stable angina.