Refractory angina is an increasingly prevalent clinical syndrome characterized by ongoing ischaemic symptoms despite optimal medical management in patients for whom traditional revascularization is not an option
Data indicate that up to 10–15% of patients undergoing cardiac catheterization fit the clinical description for refractory angina, and that prognosis is improving, with an annual mortality of only 3–4%
The primary focus is on improving quality of life for patients with refractory angina
Traditional treatment for myocardial ischaemia involves increasing coronary blood in-flow, increasing blood oxygen-carrying capacity, and decreasing oxygen consumption; new treatments involve modulating myocyte metabolism and redistributing coronary flow
Emerging therapies include novel interventional techniques (percutaneous coronary intervention for chronic total occlusions, and the coronary sinus occluder), angiogenesis with cell therapy, shockwave therapy, and neuromodulation
Implementation of interdisciplinary, specialized clinics with advanced clinical care, as well as investigational options (including psychological and self-management approaches), could be important advances for patients with refractory angina
A growing number of patients, particularly those with advanced, chronic coronary artery disease, experience symptoms of angina that are refractory to treatment with β-blockers, calcium-channel blockers, and long-acting nitrates, despite revascularization. The management of patients with refractory angina who are unsuitable for further revascularization is strikingly different across the world, and is contingent on local resources and available expertise. Mortality in this patient population has decreased, but enhancing quality of life remains a challenge. New treatment principles are emerging in current practice, such as metabolic modulation, therapeutic angiogenesis, and novel interventional techniques (coronary in-flow redistribution and approaches to chronic total occlusion). The contemporary management of refractory angina encourages individualized, patient-centred care in interdisciplinary, specialized clinics. Global initiatives are required to address complex clinical problem-solving for patients with refractory angina. In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
The Coronary Sinus Reducer; 5-year Dutch experience
Netherlands Heart Journal Open Access 07 December 2020
Baseline factors identified for the prediction of good responders in patients with end-stage diffuse coronary artery disease undergoing intracoronary CD34+ cell therapy
Stem Cell Research & Therapy Open Access 29 July 2020
Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133+ cells in ischemic refractory cardiomyopathy trial (RECARDIO)
Stem Cell Research & Therapy Open Access 14 September 2018
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Jolicoeur, E. M. et al. Clinical and research issues regarding chronic advanced coronary artery disease: part I: contemporary and emerging therapies. Am. Heart J. 155, 418–434 (2008).
Jolicoeur, E. M. et al. Clinical and research issues regarding chronic advanced coronary artery disease part II: trial design, outcomes, and regulatory issues. Am. Heart J. 155, 435–444 (2008).
Mannheimer, C. et al. The problem of chronic refractory angina; report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur. Heart J. 23, 355–370 (2002).
McGillion, M. et al. Management of patients with refractory angina: Canadian Cardiovascular Society/Canadian Pain Society joint guidelines. Can. J. Cardiol. 28 (2 Suppl.), S20–S41 (2012).
Jolicoeur, E. M. et al. Patients with coronary refractory artery disease unsuitable for revascularization: definition, general principles, and a classification. Can. J. Cardiol. 28 (Suppl.), S50–S59 (2012).
National Institute for Health and Care Excellence. Clinical Guideline 126. The management of stable angina [online], (2011).
Fihn, S. D. et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J. Am. Coll. Cardiol. 60, e44–e164 (2012).
Montalescot, G. et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur. Heart J. 34, 2949–3003 (2013).
Mukherjee, D., Bhatt, D. L., Roe, M. T., Patel, V. & Ellis, S. G. Direct myocardial revascularization and angiogenesis—how many patients might be eligible? Am. J. Cardiol. 84, 598–600 (1999).
Williams, B. et al. Patients with coronary artery disease not amenable to traditional revascularization: prevalence and 3-year mortality. Catheter. Cardiovasc. Interv. 75, 886–891 (2010).
Mukherjee, D. et al. Clinical outcome of a cohort of patients eligible for therapeutic angiogenesis or transmyocardial revascularization. Am. Heart J. 142, 72–74 (2001).
Allen, K. B. et al. Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. N. Engl. J. Med. 341, 1029–1036 (1999).
Burkhoff, D. et al. Transmyocardial laser revascularisation compared with continued medical therapy for treatment of refractory angina pectoris: a prospective randomised trial. Lancet 354, 885–890 (1999).
Frazier, O. H., March, R. J. & Horvath, K. A. Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. N. Engl. J. Med. 341, 1021–1028 (1999).
Oesterle, S. N. et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Lancet 356, 1705–1710 (2000).
Henry, T. D. et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 107, 1359–1365 (2003).
Simons, M. et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105, 788–793 (2002).
Henry, T. D. et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J. Am. Coll. Cardiol. 50, 1038–1046 (2007).
Kastrup, J. et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris. A randomized double-blind placebo-controlled study: the Euroinject One trial. J. Am. Coll. Cardiol. 45, 982–988 (2005).
Henry, T. D. et al. Long-term survival in patients with refractory angina. Eur. Heart J. 34, 2683–2688 (2013).
Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336, 924–926 (2008).
Bangalore, S. et al. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 308, 1340–1349 (2012).
Treese, N., Erbel, R. & Meyer, J. Acute hemodynamic effects of nicorandil in coronary artery disease. J. Cardiovasc. Pharmacol. 20 (Suppl. 3), S52–S56 (1992).
The IONA Study Group. Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial. Lancet 359, 1269–1275 (2002).
Döring, 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. J. Cardiovasc. Pharmacol. 20 (Suppl. 30), S74–S81 (1992).
Di, S. S. et al. A double-blind comparison of nicorandil and metoprolol in stable effort angina pectoris. Cardiovasc. Drugs Ther. 7, 119–123 (1993).
Ulvenstam, 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. J. Cardiovasc. Pharmacol. 20 (Suppl. 3), S67–S73 (1992).
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. Eur. Heart J. 14 (Suppl. B), 30–34 (1993).
Zhu, W. L. 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. Circ. J. 71, 826–833 (2007).
Sekiya, M. et al. Effects of the long-term administration of nicorandil on vascular endothelial function and the progression of arteriosclerosis. J. Cardiovasc. Pharmacol. 46, 63–67 (2005).
Munzel, T., Daiber, A. & Gori, T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 123, 2132–2144 (2011).
Tardif, J. C., Ford, I., Tendera, M., Bourassa, M. G. & Fox, K. for the INITIATIVE investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur. Heart J. 26, 2529–2536 (2005).
Heusch, G. et al. Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction. Eur. Heart J. 29, 2265–2275 (2008).
Tardif, J. C., Ponikowski, P. & Kahan, T. for the ASSOCIATE study investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur. Heart J. 30, 540–548 (2009).
Fox, K., Ford, I., Steg, P. G., Tendera, M. & Ferrari, R. for the BEAUTIFUL investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372, 807–816 (2008).
Fox, K. et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur. Heart J. 30, 2337–2345 (2009).
Fox, K. et al. Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur. Heart J. 34, 2263–2270 (2013).
Antzelevitch, C. et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110, 904–910 (2004).
Belardinelli, L., Shryock, J. C. & Fraser, H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart 92 (Suppl. 4), iv6–iv14 (2006).
Stone, P. H. et al. The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. J. Am. Coll. Cardiol. 56, 934–942 (2010).
Chaitman, B. R. et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J. Am. Coll. Cardiol. 43, 1375–1382 (2004).
Chaitman, B. R. et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 291, 309–316 (2004).
Stone, P. H., Gratsiansky, N. A., Blokhin, A., Huang, I. Z. & Meng, L. for the ERICA investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J. Am. Coll. Cardiol. 48, 566–575 (2006).
Villano, A. et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am. J. Cardiol. 112, 8–13 (2013).
Mehta, P. K. et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC Cardiovasc. Imaging 4, 514–522 (2011).
Kosiborod M. et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina). J. Am. Coll. Cardiol. 61, 2038–2045 (2013).
Bennett, N. M. et al. Ranolazine refractory angina registry trial: 1-year results [abstract 1074–362]. J. Am. Coll. Cardiol. 57, E1050 (2011).
Morrow, D. A. et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA 297, 1775–1783 (2007).
Mellin, V. 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. Eur. Heart J. 26, 1544–1550 (2005).
Rajendra, N. S. et al. Mechanistic insights into the therapeutic use of high-dose allopurinol in angina pectoris. J. Am. Coll. Cardiol. 58, 820–828, (2011).
George, J., Carr, E., Davies, J., Belch, J. J. & Struthers, A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 114, 2508–2516 (2006).
Farquharson, C. A., Butler, R., Hill, A., Belch, J. J. & Struthers. A. D. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 106, 221–226 (2002).
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. Lancet 375, 2161–2167 (2010).
MacInnes, A. et al. The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 93, e26–e32 (2003).
Kantor, P. F., Lucien, A., Kozak, R. & Lopaschuk, G. D. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 86, 580–588 (2000).
Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).
Szwed, H. et al. Combination treatment in stable effort angina using trimetazidine and metoprolol: results of a randomized, double-blind, multicentre study (TRIMPOL II). Eur. Heart J. 22, 2267–2274 (2001).
Ribeiro, L. W., Ribeiro, J. P., Stein, R., Leitão, C. & Polanczyk, C. A. Trimetazidine added to combined hemodynamic antianginal therapy in patients with type 2 diabetes: a randomized crossover trial. Am. Heart J. 154, 78.e1–e7 (2007).
Ciapponi, A., Pizarro, R., Harrison, J. Trimetazidine for stable angina. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD003614. http://dx.doi.org/10.1002/14651858.CD003614.pub2.
Kennedy, J. A., Kiosoglous, A. J., Murphy, G. A., Pelle, M. A. & Horowitz, J. D. Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J. Cardiovasc. Pharmacol. 36, 794–801 (2000).
Cole, P. L. et al. Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 81, 1260–1270 (1990).
Phan, T. T. et al. Multi-centre experience on the use of perhexiline in chronic heart failure and refractory angina: old drug, new hope. Eur. J. Heart Fail. 11, 881–886 (2009).
Lee, L. et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 112, 3280–3288 (2005).
Egashira, K., Hirooka, Y., Kuga, T., Mohri, M. & Takeshita, A. Effects of L-arginine supplementation on endothelium-dependent coronary vasodilation in patients with angina pectoris and normal coronary arteriograms. Circulation 94, 130–134 (1996).
Lerman, A., Burnett, J. C. Jr, Higano, S. T., McKinley, L. J. & Holmes, D. R. Jr. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 97, 2123–2128 (1998).
Ceremuzyński, L., Chamiec, T. & Herbaczyńska-Cedro, K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am. J. Cardiol. 80, 331–333 (1997).
Leschke, M. et al. Long-term intermittent urokinase therapy in patients with end-stage coronary artery disease and refractory angina pectoris: a randomized dose–response trial. J. Am. Coll. Cardiol. 27, 575–584 (1996).
English, K. M., Steeds, R. P., Jones, T. H., Diver, M. J. & Channer, K. S. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation 102, 1906–1911 (2000).
Rosano, G. M. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99, 1666–1670 (1999).
Mathur, A. et al. Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men. Eur. J. Endocrinol. 161, 443–449 (2009).
Lamas, G. A. et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA 309, 1241–1250 (2013).
Sidhu, M. S., Saour, B. M. & Boden, W. E. A TACTful reappraisal of chelation therapy in cardiovascular disease. Nat. Rev. Cardiol. http://dx.doi.org/10.1038/nrcardio.2013.176.
Michaels, A. D. et al. Primer: practical approach to the selection of patients for and application of EECP. Nat. Clin. Pract. Cardiovasc. Med. 3, 623–632 (2006).
Sinvhal, R. M., Gowda, R. M. & Khan, I. A. Enhanced external counterpulsation for refractory angina pectoris. Heart 89, 830–833 (2003).
Braith, R. W. et al. Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study. Circulation 122, 1612–1620 (2010).
Bonetti, P. O. et al. Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. J. Am. Coll. Cardiol. 41, 1761–1768 (2003).
Michaels, A. D. et al. The effects of enhanced external counterpulsation on myocardial perfusion in patients with stable angina: a multicenter radionuclide study. Am. Heart J. 150, 1066–1073 (2005).
Akhtar, M., Wu, G. F., Du, Z. M., Zheng, Z. S. & Michaels, A. D. Effect of external counterpulsation on plasma nitric oxide and endothelin-1 levels. Am. J. Cardiol. 98, 28–30 (2006).
Kiernan, T. J. et al. Effect of enhanced external counterpulsation on circulating CD34+ progenitor cell subsets. Int. J. Cardiol. 153, 202–206 (2011).
Campbell, A. R. et al. Enhanced external counterpulsation improves systolic blood pressure in patients with refractory angina. Am. Heart J. 156, 1217–1222 (2008).
Arora, R. R. et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J. Am. Coll. Cardiol. 33, 1833–1840 (1999).
Aicher, A. et al. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation 114, 2823–2830 (2006).
Mariotto, S. et al. Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production. Nitric Oxide 12, 89–96 (2005).
Nishida, T. et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 110, 3055–3061 (2004).
Wang, Y. et al. A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease. Cardiovasc. Ultrasound 10, 35 (2012).
Assmus, B. et al. Effect of shock wave-facilitated intracoronary cell therapy on LVEF in patients with chronic heart failure: the CELLWAVE randomized clinical trial. JAMA 309, 1622–1631 (2013).
Rathore, S. et al. Retrograde percutaneous recanalization of chronic total occlusion of the coronary arteries: procedural outcomes and predictors of success in contemporary practice. Circ. Cardiovasc. Interv. 2, 124–132 (2009).
Khan, M. F., Wendel, C. S., Thai, H. M. & Movahed, M. R. Effects of percutaneous revascularization of chronic total occlusions on clinical outcomes: a meta-analysis comparing successful versus failed percutaneous intervention for chronic total occlusion. Catheter. Cardiovasc. Interv. 82, 95–107 (2013).
Grantham, J. A., Jones, P. G., Cannon, L. & Spertus, J. A. Quantifying the early health status benefits of successful chronic total occlusion recanalization: results from the FlowCardia's Approach to Chronic Total Occlusion Recanalization (FACTOR) trial. Circ. Cardiovasc. Qual. Outcomes. 3, 284–290 (2010).
Jolicoeur, E. M. et al. Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions. Catheter. Cardiovasc. Interv. 79, 603–612 (2012).
Olivari, Z. et al. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J. Am. Coll. Cardiol. 41, 1672–1678 (2003).
Tamburino, C. et al. Percutaneous recanalization of chronic total occlusions: wherein lies the body of proof? Am. Heart J. 165, 133–142 (2013).
Joyal, D., Afilalo, J. & Rinfret, S. Effectiveness of recanalization of chronic total occlusions: a systematic review and meta-analysis. Am. Heart J. 160, 179–187 (2010).
Borgia, F. F. et al. Improved cardiac survival, freedom from mace and angina-related quality of life after successful percutaneous recanalization of coronary artery chronic total occlusions. Int. J. Cardiol. 161, 31–38 (2012).
Jaffe, R., Charron, T., Puley, G., Dick, A. & Strauss, B. H. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention. Circulation 117, 3152–3156 (2008).
Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007).
Weintraub, W. S. et al. Effect of PCI on quality of life in patients with stable coronary disease. N. Engl. J. Med. 359, 677–687 (2008).
Pancholy, S. B. et al. Meta-analysis of effect on mortality of percutaneous recanalization of coronary chronic total occlusions using a stent-based strategy. Am. J. Cardiol. 111, 521–525 (2013).
Levine, G. N. et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J. Am. Coll. Cardiol. 58, e44–e122 (2011).
Patel, M. R. et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization: a report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. J. Am. Coll. Cardiol. 53, 530–553 (2009).
Beck, C. S. et al. Revascularization of heart by graft of systemic artery into coronary sinus. JAMA 137, 436–442 (1948).
Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356, 830–840 (2007).
Ido, A., Hasebe, N., Matsuhashi, H. & Kikuchi, K. Coronary sinus occlusion enhances coronary collateral flow and reduces subendocardial ischemia. Am. J. Physiol. Heart Circ. Physiol. 280, H1361–H1367 (2001).
Banai, S. et al. Coronary sinus reducer stent for the treatment of chronic refractory angina pectoris: a prospective, open-label, multicenter, safety feasibility first-in-man study. J. Am. Coll. Cardiol. 49, 1783–1789 (2007).
Jolicoeur, E. M. et al. A phase II, sham-controlled, double-blinded study testing the safety and efficacy of the coronary sinus reducer in patients with refractory angina: study protocol for a randomized controlled trial. Trials 14, 46 (2013).
Henry, T. D. & Abraham, J. A. Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr. Interv. Cardiol. Rep. 2, 228–241 (2000).
Giordano, F. J. et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat. Med. 2, 534–539 (1996).
Kocher, A. A. et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat. Med. 7, 430–436 (2001).
Grines, C. L. et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105, 1291–1297 (2002).
Grines, C. L. et al. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J. Am. Coll. Cardiol. 42, 1339–1347 (2003).
Stewart, D. J. et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol. Ther. 17, 1109–1115 (2009).
Losordo, D. W. & Dimmeler, S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation 109, 2692–2697 (2004).
Fisher, S. A., Dorée, C., Brunskill, S. J., Mathur, A. & Martin-Rendon, E. Bone marrow stem cell treatment for ischemic heart disease in patients with no option of revascularization: a systematic review and meta-analysis. PLoS ONE 8, e64669 (2013).
Kandala, J. et al. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Am. J. Cardiol. 112, 217–225 (2013).
Li, N. et al. Stem cell therapy is a promising tool for refractory angina: a meta-analysis of randomized controlled trials. Can. J. Cardiol. 29, 908–914 (2013).
Wang, S., Cui, J., Peng, W. & Lu, M. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology 117, 140–147 (2010).
Losordo, D. W. et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ. Res. 109, 428–436 (2011).
Povsic, T. J. et al. A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study. Am. Heart J. 165, 854–861 (2013).
Tuma, J. F. et al. Safety and feasibility of percutaneous retrograde coronary sinus delivery of autologous bone marrow mononuclear cell transplantation in patients with chronic refractory angina. J. Transl. Med. 9, 183 (2011).
Copland, I. B. et al. Coupling erythropoietin secretion to mesenchymal stromal cells enhances their regenerative properties. Cardiovasc. Res. 79, 405–415 (2008).
Tachibana, M. et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238 (2013).
De Decker, K. F., Beese, U. F., Staal, M. J. & DeJongste, M. J. Electrical neuromodulation for patients with cardiac diseases. Neth. Heart J. 21, 91–94 (2013).
Prager, J. P. What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome? Pain Med. 11, 1278–1283 (2010).
Hautvast, R. W. et al. Effect of spinal cord stimulation on myocardial blood flow assessed by positron emission tomography in patients with refractory angina pectoris. Am. J. Cardiol. 77, 462–467 (1996).
DeJongste, M. J. et al. Effects of spinal cord stimulation on myocardial ischaemia during daily life in patients with severe coronary artery disease. A prospective ambulatory electrocardiographic study. Br. Heart J. 71, 413–418 (1994).
Kingma, J. G. Jr et al. Neuromodulation therapy does not influence blood flow distribution or left-ventricular dynamics during acute myocardial ischemia. Auton. Neurosci. 91, 47–54 (2001).
Taylor, R. S., De Vries, J., Buchser, E. & DeJongste, M. J. Spinal cord stimulation in the treatment of refractory angina: systematic review and meta-analysis of randomised controlled trials. BMC Cardiovasc. Disord. 9, 13 (2009).
Andréll, P. et al. Long-term effects of spinal cord stimulation on angina symptoms and quality of life in patients with refractory angina pectoris—results from the European Angina Registry Link study (EARL). Heart 96, 1132–1136 (2010).
Eddicks, S. et al. Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study. Heart 93, 585–590 (2007).
Lanza, G. A. et al. Spinal cord stimulation for the treatment of refractory angina pectoris: a multicenter randomzied single-blind study (the SCS-ITA trial). Pain 152, 45–52 (2011).
Zipes, D. P. et al. Spinal cord stimulation therapy for patients with refractory angina who are not candidates for revascularization. Neuromodulation 15, 550–558 (2012).
Börjesson, M. et al. Spinal cord stimulation in severe angina pectoris—a systematic review based on the Swedish Council on Technology assessment in health care report on long-standing pain. Pain 140, 501–508 (2008).
Buiten, M. S. et al. Subcutaneous electrical nerve stimulation: a feasible and new method for the treatment of patients with refractory angina. Neuromodulation 14, 258–265 (2011).
Claes, G. F. et al. Angina pectoris treated by thoracoscopic sympathecotomy. Cardiovasc. Surg. 4, 830–831 (1996).
Gramling-Babb, P., Miller, M. J., Reeves, S. T., Roy, R. C. & Zile, M. R. Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: initial clinical experience. Am. Heart J. 133, 648–655 (1997).
Leon, M. B. et al. A blinded, randomized, placebo-controlled trial of percutaneous laser myocardial revascularization to improve angina symptoms in patients with severe coronary disease. J. Am. Coll. Cardiol. 46, 1812–1819 (2005).
Moore, R. K. et al. Health related quality of life of patients with refractory angina before and one year after enrolment onto a refractory angina program. Eur. J. Pain 9, 305–310 (2005).
Asbury, E. A. et al. Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study. Cardiology 122, 170–177 (2012).
Moore, R. K. et al. A brief cognitive-behavioral intervention reduces hospital admissions in refractory angina patients. J. Pain Symptom Manage. 33, 310–316 (2007).
Strike, P. C. & Steptoe, A. Systematic review of mental stress-induced myocardial ischaemia. Eur. Heart J. 24, 690–703 (2003).
Jiang, W. et al. Prevalence and clinical characteristics of mental stress-induced myocardial ischemia in patients with coronary heart disease. J. Am. Coll. Cardiol. 61, 714–722 (2013).
Rozanski, A. et al. Mental stress and the induction of silent myocardial ischemia in patients with coronary artery disease. N. Engl. J. Med. 318, 1005–1012 (1988).
Jiang, W. et al. Effect of escitalopram on mental stress-induced myocardial ischemia: results of the REMIT trial. JAMA 309, 2139–2149 (2013).
Glassman, A. H. et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288, 701–709 (2002).
O'Connor, C. M. et al. Safety and efficacy of sertraline for depression in patients with heart failure: results of the SADHART-CHF (Sertraline Against Depression and Heart Disease in Chronic Heart Failure) trial. J. Am. Coll. Cardiol. 56, 692–699 (2010).
Khan, A. & Schwartz, K. Suicide risk and symptom reduction in patients assigned to placebo in duloxetine and escitalopram clinical trials: analysis of the FDA summary basis of approval reports. Ann. Clin. Psychiatry 19, 31–36 (2007).
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. Health Educ. Res. 14, 597–610 (1999).
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. Curr. Cardiol. Rev. 4, 1–11 (2008).
Masmoudi, K., Masson, H., Gras, V. & Andrejak, M. Extrapyramidal adverse drug reactions associated with trimetazidine: a series of 21 cases. Fundam. Clin. Pharmacol. 26, 198–203 (2012).
Shimokawa, H. et al. Anti-anginal effect of fasudil, a Rho-kinase inhibitor, in patients with stable effort angina: a multicenter study. J. Cardiovasc. Pharmacol. 40, 751–761 (2002).
Mohri, M., Shimokawa, H., Hirakawa, Y., Masumoto, A. & Takeshita, A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. J. Am. Coll. Cardiol. 41, 15–19 (2003).
Messin, R. et al. Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris. Int. J. Cardiol. 98, 79–89 (2005).
Messin, R., Cerreer-Bruhwyler, F., Dubois, C., Famaey, J. P. & Geczy, J. Efficacy and safety of once- and twice-daily formulations of molsidomine in patients with stable angina pectoris: double-blind and open-label studies. Adv. Ther. 23, 107–130 (2006).
Horinaka, S. et al. Effects of nicorandil on cardiovascular events in patients with coronary artery disease in the Japanese Coronary Artery Disease (JCAD) study. Circ. J. 74, 503–509 (2010).
Toquero, L., Briggs, C. D., Bassuini, M. M. & Rochester, J. R. Anal ulceration associated with nicorandil: case series and review of the literature. Colorectal. Dis. 8, 717–720 (2006).
DiFrancesco, D. The role of the funny current in pacemaker activity. Circ. Res. 106, 434–446 (2010).
Heusch, G. et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101, 689–694 (2000).
Kamarck, T. W. et al. Citalopram improves metabolic risk factors among high hostile adults: results of a placebo-controlled intervention. Psychoneuroendocrinology 36, 1070–1079 (2011).
McCloskey, D. J. et al. Selective serotonin reuptake inhibitors: measurement of effect on platelet function. Transl Res. 151, 168–172 (2008).
Cannon, R. O. III et al. Imipramine in patients with chest pain despite normal coronary angiograms. N. Engl. J. Med. 330, 1411–1417 (1994).
Cox, I. D., Hann, C. M. & Kaski, J. C. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur. Heart J. 19, 250–254 (1998).
Lamb, D. J. & Leake, D. S. The effect of EDTA on the oxidation of low density lipoprotein. Atherosclerosis 94, 35–42 (1992).
Bukoski, R. D., Ishibashi, K. & Bian, K. Vascular actions of the calcium-regulating hormones. Semin. Nephrol. 15, 536–549 (1995).
Peters, A. J. et al. Long-term urokinase therapy and isovolemic hemodilution: a clinical and hemodynamic comparison in patients with refractory angina pectoris. Int. J. Angiol. 8, 44–49 (1999).
Schoebel, F. C., Leschke, M., Jax, T. W., Stein, D. & Strauer, B. E. Chronic-intermittent urokinase therapy in patients with end-stage coronary artery disease and refractory angina pectoris—a pilot study. Clin. Cardiol. 19, 115–120 (1996).
Leschke, M. Rheology and coronary heart disease [German]. Dtsch. Med. Wochenschr. 133 (Suppl. 8), S270–S273 (2008).
T. D. Henry declares associations with the following companies: Abbott Vascular, Baxter, Gilead, and Neovasc. T. D. Henry is supported by grants from the NIH Cardiovascular Cell Therapy Research Network. The Minneapolis Heart Institute is supported by research grants from Baxter, Gilead, Cytori, and the NIH. E. M. Jolicoeur declares associations with the following companies: Baxter, Gilead, Neovasc, and Servier. E. M. Jolicoeur is supported by research grants from les Fonds la Recherche du Québec en santé, the Canadian Institutes for Health Research, and la Fondation de l'Institut de Cardiologie de Montréal. D. Satran declares no competing interests.
Rights and permissions
About this article
Cite this article
Henry, T., Satran, D. & Jolicoeur, E. Treatment of refractory angina in patients not suitable for revascularization. Nat Rev Cardiol 11, 78–95 (2014). https://doi.org/10.1038/nrcardio.2013.200
This article is cited by
Is Cardiac Shock Wave Therapy an Option for the Treatment of Myocardial Ischemia in Patients with Refractory Angina?
Journal of Nuclear Cardiology (2022)
Coronary Sinus Reducer for the Treatment of Chronic Refractory Angina: Will This Challenge the Treatment of Coronary Chronic Total Occlusions?
Current Cardiology Reports (2021)
The Coronary Sinus Reducer; 5-year Dutch experience
Netherlands Heart Journal (2021)
Baseline factors identified for the prediction of good responders in patients with end-stage diffuse coronary artery disease undergoing intracoronary CD34+ cell therapy
Stem Cell Research & Therapy (2020)
Individual shear rate therapy (ISRT)—further development of external counterpulsation for decreasing blood pressure in patients with symptomatic coronary artery disease (CAD)
Hypertension Research (2020)