Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Treatment of refractory angina in patients not suitable for revascularization

This article has been updated

Key Points

  • Refractory angina is an increasingly prevalent clinical syndrome characterized by ongoing ischaemic symptoms despite optimal medical management in patients for whom traditional revascularization is not an option

  • Data indicate that up to 10–15% of patients undergoing cardiac catheterization fit the clinical description for refractory angina, and that prognosis is improving, with an annual mortality of only 3–4%

  • The primary focus is on improving quality of life for patients with refractory angina

  • Traditional treatment for myocardial ischaemia involves increasing coronary blood in-flow, increasing blood oxygen-carrying capacity, and decreasing oxygen consumption; new treatments involve modulating myocyte metabolism and redistributing coronary flow

  • Emerging therapies include novel interventional techniques (percutaneous coronary intervention for chronic total occlusions, and the coronary sinus occluder), angiogenesis with cell therapy, shockwave therapy, and neuromodulation

  • Implementation of interdisciplinary, specialized clinics with advanced clinical care, as well as investigational options (including psychological and self-management approaches), could be important advances for patients with refractory angina

Abstract

A growing number of patients, particularly those with advanced, chronic coronary artery disease, experience symptoms of angina that are refractory to treatment with β-blockers, calcium-channel blockers, and long-acting nitrates, despite revascularization. The management of patients with refractory angina who are unsuitable for further revascularization is strikingly different across the world, and is contingent on local resources and available expertise. Mortality in this patient population has decreased, but enhancing quality of life remains a challenge. New treatment principles are emerging in current practice, such as metabolic modulation, therapeutic angiogenesis, and novel interventional techniques (coronary in-flow redistribution and approaches to chronic total occlusion). The contemporary management of refractory angina encourages individualized, patient-centred care in interdisciplinary, specialized clinics. Global initiatives are required to address complex clinical problem-solving for patients with refractory angina. In this Review, we discuss the epidemiology of refractory angina, and provide an update on the pharmacological, noninvasive, and interventional options that are available to these patients or are under development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Therapeutic principles of myocardial ischaemia.
Figure 2: Treatment options for refractory angina.
Figure 3: Metabolic factors influencing angina.
Figure 4: Successful percutaneous coronary intervention for chronic total occlusion is associated with reduced angina frequency.
Figure 5: Effect of BMSCs on primary outcomes in patients with refractory angina.
Figure 6: The neurogenic components of angina.
Figure 7: Effect of SCS on exercise capacity.

Similar content being viewed by others

Change history

  • 14 January 2014

    In the version of this article initially published online, the drug citalopram shown in Figure 6d should have been escitalopram. The error has been corrected for the print, HTML, and PDF versions of the article.

References

  1. 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).

    Article  PubMed  Google Scholar 

  2. 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).

    Article  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  PubMed  Google Scholar 

  5. 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).

    Article  PubMed  Google Scholar 

  6. National Institute for Health and Care Excellence. Clinical Guideline 126. The management of stable angina [online], (2011).

  7. 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).

    Article  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Oesterle, S. N. et al. Percutaneous transmyocardial laser revascularisation for severe angina: the PACIFIC randomised trial. Lancet 356, 1705–1710 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Henry, T. D. et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 107, 1359–1365 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Henry, T. D. et al. Long-term survival in patients with refractory angina. Eur. Heart J. 34, 2683–2688 (2013).

    Article  PubMed  Google Scholar 

  21. Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336, 924–926 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Bangalore, S. et al. β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 308, 1340–1349 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Treese, N., Erbel, R. & Meyer, J. Acute hemodynamic effects of nicorandil in coronary artery disease. J. Cardiovasc. Pharmacol. 20 (Suppl. 3), S52–S56 (1992).

    Article  PubMed  Google Scholar 

  24. 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).

  25. 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).

    Article  PubMed  Google Scholar 

  26. 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).

    Article  Google Scholar 

  27. 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).

    Article  PubMed  Google Scholar 

  28. 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).

    Article  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. Munzel, T., Daiber, A. & Gori, T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 123, 2132–2144 (2011).

    Article  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  PubMed  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Antzelevitch, C. et al. Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties. Circulation 110, 904–910 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Villano, A. et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. Am. J. Cardiol. 112, 8–13 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

  47. Bennett, N. M. et al. Ranolazine refractory angina registry trial: 1-year results [abstract 1074–362]. J. Am. Coll. Cardiol. 57, E1050 (2011).

    Article  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  Google Scholar 

  59. 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.

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. 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).

    Article  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. 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).

    Article  CAS  PubMed  Google Scholar 

  69. Rosano, G. M. et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation 99, 1666–1670 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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.

  73. 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).

    Article  PubMed  Google Scholar 

  74. Sinvhal, R. M., Gowda, R. M. & Khan, I. A. Enhanced external counterpulsation for refractory angina pectoris. Heart 89, 830–833 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  PubMed  Google Scholar 

  77. 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).

    Article  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Kiernan, T. J. et al. Effect of enhanced external counterpulsation on circulating CD34+ progenitor cell subsets. Int. J. Cardiol. 153, 202–206 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Campbell, A. R. et al. Enhanced external counterpulsation improves systolic blood pressure in patients with refractory angina. Am. Heart J. 156, 1217–1222 (2008).

    Article  PubMed  Google Scholar 

  81. 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).

    Article  CAS  PubMed  Google Scholar 

  82. 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).

    Article  PubMed  Google Scholar 

  83. Mariotto, S. et al. Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production. Nitric Oxide 12, 89–96 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Nishida, T. et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 110, 3055–3061 (2004).

    Article  PubMed  Google Scholar 

  85. Wang, Y. et al. A modified regimen of extracorporeal cardiac shock wave therapy for treatment of coronary artery disease. Cardiovasc. Ultrasound 10, 35 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

  87. 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).

    Article  PubMed  Google Scholar 

  88. 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).

    Article  PubMed  Google Scholar 

  89. 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).

    Article  PubMed  Google Scholar 

  90. Jolicoeur, E. M. et al. Percutaneous coronary interventions and cardiovascular outcomes for patients with chronic total occlusions. Catheter. Cardiovasc. Interv. 79, 603–612 (2012).

    Article  PubMed  Google Scholar 

  91. 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).

    Article  PubMed  Google Scholar 

  92. Tamburino, C. et al. Percutaneous recanalization of chronic total occlusions: wherein lies the body of proof? Am. Heart J. 165, 133–142 (2013).

    Article  PubMed  Google Scholar 

  93. 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).

    Article  PubMed  Google Scholar 

  94. 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).

    Article  PubMed  Google Scholar 

  95. 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).

    Article  PubMed  Google Scholar 

  96. Boden, W. E. et al. Optimal medical therapy with or without PCI for stable coronary disease. N. Engl. J. Med. 356, 1503–1516 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  PubMed  Google Scholar 

  99. 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).

    Article  PubMed  Google Scholar 

  100. 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).

    Article  PubMed  Google Scholar 

  101. Beck, C. S. et al. Revascularization of heart by graft of systemic artery into coronary sinus. JAMA 137, 436–442 (1948).

    Article  CAS  Google Scholar 

  102. Camici, P. G. & Crea, F. Coronary microvascular dysfunction. N. Engl. J. Med. 356, 830–840 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  Google Scholar 

  104. 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).

    Article  PubMed  Google Scholar 

  105. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  106. 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).

    CAS  PubMed  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Grines, C. L. et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105, 1291–1297 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Losordo, D. W. & Dimmeler, S. Therapeutic angiogenesis and vasculogenesis for ischemic disease: part II: cell-based therapies. Circulation 109, 2692–2697 (2004).

    Article  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kandala, J. et al. Meta-analysis of stem cell therapy in chronic ischemic cardiomyopathy. Am. J. Cardiol. 112, 217–225 (2013).

    Article  PubMed  Google Scholar 

  115. 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).

    Article  PubMed  Google Scholar 

  116. Wang, S., Cui, J., Peng, W. & Lu, M. Intracoronary autologous CD34+ stem cell therapy for intractable angina. Cardiology 117, 140–147 (2010).

    Article  PubMed  Google Scholar 

  117. Losordo, D. W. et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ. Res. 109, 428–436 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  Google Scholar 

  119. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Copland, I. B. et al. Coupling erythropoietin secretion to mesenchymal stromal cells enhances their regenerative properties. Cardiovasc. Res. 79, 405–415 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Tachibana, M. et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell 153, 1228–1238 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. Prager, J. P. What does the mechanism of spinal cord stimulation tell us about complex regional pain syndrome? Pain Med. 11, 1278–1283 (2010).

    Article  PubMed  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. 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).

    Article  CAS  Google Scholar 

  126. 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).

    Article  PubMed  Google Scholar 

  127. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 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).

    Article  PubMed  Google Scholar 

  129. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 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).

    Article  PubMed  Google Scholar 

  131. 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).

    Article  PubMed  Google Scholar 

  132. 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).

    Article  PubMed  Google Scholar 

  133. 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).

    Article  PubMed  Google Scholar 

  134. Claes, G. F. et al. Angina pectoris treated by thoracoscopic sympathecotomy. Cardiovasc. Surg. 4, 830–831 (1996).

    Article  CAS  PubMed  Google Scholar 

  135. 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).

    Article  CAS  PubMed  Google Scholar 

  136. 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).

    Article  PubMed  Google Scholar 

  137. 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).

    Article  CAS  PubMed  Google Scholar 

  138. Asbury, E. A. et al. Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study. Cardiology 122, 170–177 (2012).

    Article  PubMed  Google Scholar 

  139. 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).

    Article  PubMed  Google Scholar 

  140. Strike, P. C. & Steptoe, A. Systematic review of mental stress-induced myocardial ischaemia. Eur. Heart J. 24, 690–703 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. Jiang, W. et al. Effect of escitalopram on mental stress-induced myocardial ischemia: results of the REMIT trial. JAMA 309, 2139–2149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Glassman, A. H. et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA 288, 701–709 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 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).

    Article  PubMed  Google Scholar 

  147. 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).

    Article  CAS  PubMed  Google Scholar 

  148. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 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).

    Article  CAS  PubMed  Google Scholar 

  150. 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).

    Article  CAS  PubMed  Google Scholar 

  151. 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).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    Article  PubMed  Google Scholar 

  153. 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).

    Article  CAS  PubMed  Google Scholar 

  154. 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).

    Article  PubMed  Google Scholar 

  155. 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).

    Article  CAS  PubMed  Google Scholar 

  156. DiFrancesco, D. The role of the funny current in pacemaker activity. Circ. Res. 106, 434–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  157. Heusch, G. et al. α-Adrenergic coronary vasoconstriction and myocardial ischemia in humans. Circulation 101, 689–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. McCloskey, D. J. et al. Selective serotonin reuptake inhibitors: measurement of effect on platelet function. Transl Res. 151, 168–172 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Cannon, R. O. III et al. Imipramine in patients with chest pain despite normal coronary angiograms. N. Engl. J. Med. 330, 1411–1417 (1994).

    Article  PubMed  Google Scholar 

  161. 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).

    Article  CAS  PubMed  Google Scholar 

  162. Lamb, D. J. & Leake, D. S. The effect of EDTA on the oxidation of low density lipoprotein. Atherosclerosis 94, 35–42 (1992).

    Article  CAS  PubMed  Google Scholar 

  163. Bukoski, R. D., Ishibashi, K. & Bian, K. Vascular actions of the calcium-regulating hormones. Semin. Nephrol. 15, 536–549 (1995).

    CAS  PubMed  Google Scholar 

  164. 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).

    Article  CAS  PubMed  Google Scholar 

  165. 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).

    Article  CAS  PubMed  Google Scholar 

  166. Leschke, M. Rheology and coronary heart disease [German]. Dtsch. Med. Wochenschr. 133 (Suppl. 8), S270–S273 (2008).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All the authors contributed substantially to researching data for the article, discussing its content, writing the manuscript, and reviewing/editing it before submission.

Corresponding author

Correspondence to Timothy D. Henry.

Ethics declarations

Competing interests

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.

PowerPoint slides

Rights and permissions

Reprints 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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2013.200

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing