This editorial refers to ‘Long-term survival in patients with refractory angina’, by T.D. Henry et al., on page 2683

Refractory angina pectoris is a debilitating disease characterized by angina resistant to conventional therapies for coronary artery disease including drug therapy, percutaneous coronary interventions, and/or coronary artery bypass grafting. Individuals with refractory angina may suffer severely impaired quality of life, with recurrent and sustained chest pain, poor general health status, psychological distress, impaired role functioning and productivity, and restricted ability to perform activities. The European Society of Cardiology (ESC) Joint Study group on the Treatment of Refractory Angina emphasized that refractory angina is a clinical diagnosis (i.e. based on a combinations of history, physical examination, and investigations) and states that refractory angina pectoris is a chronic 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, and coronary bypass surgery.1 The presence of reversible myocardial ischaemia should be clinically established to be the cause of the symptoms. Chronicity is defined as a duration of >3 months. The ESC Joint Study group further states that the diagnosis of refractory angina requires a cardiological and cardiothoracic surgical assessment that the patient has angina of ischaemic origin and that revascularization is not feasible. Despite these robust definitions, the diagnosis has a subjective component particularly with determining the suitability for either percutaneous or surgical revascularization based on availability of local expertise. Furthermore, the group of refractory angina patients who are deemed as having no option for revascularization is a heterogeneous entity with many different reasons for not being a suitable candidate for revascularization, i.e. diffuse coronary disease, poor target vessels, lack of conduits, advanced/multiple co-morbidities, etc. Few data exist on the true prevalence of refractory angina and outcomes of this difficult to treat population.

Henry et al. have now reported on The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) programme at the Minneapolis Heart Institute.2 This prospective clinical database of 1200 patients suggests that long-term mortality in patients with refractory angina is lower than previously reported. The authors further suggest that since survival is comparable with that of patients with stable chronic ischaemic heart disease, therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life. There have been only few previous studies on the natural history and predictors of mortality for patients with refractory angina, and none this size. One study from the Cleveland Clinic in 500 consecutive patients undergoing cardiac catheterization found that 59 (11.8%) patients had ischaemia but were ineligible for revascularization.3 One-year mortality in the Cleveland Clinic series was quite high at ∼17%.4 The Mediators of Social Support Study (MOSS), a longitudinal observational study of patients undergoing cardiac catheterization at Duke University between August 1992 and January 1996, similarly reported a high mortality (38% at 2.2-year mean follow-up) in 487 patients who did not undergo revascularization within 30 days.5 In contrast, 1-year mortality from the OPTIMIST study was ∼4%. The obvious question is whether mortality has declined significantly in the last 15 years since the Cleveland Clinic and the Duke study or are we looking at very different patient populations. While differences in study cohort baseline characteristics cannot be entirely ruled out, it is likely that improved secondary prevention drugs such as more potent antiplatelet/antithrombotic agents, high-potency statins, optimal use of guideline-based medical therapies, and more advanced revascularization techniques, including wider use of left internal mammary artery graft to the left anterior descending, have contributed to a decline in mortality in patients with refractory angina, as has happened in other subset of patients with coronary artery disease.6 Despite some limitations of this study by Henry et al.,2 including its observational nature and lack of a control group, this large study provides important clinical insights into changing epidemiology and outcomes of patients with refractory angina in the contemporary era.

As evident in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, medical therapy has made significant progress over the last decade and appears comparable with percutaneous coronary revascularization in reducing the risk of death, myocardial infarction, or other major cardiovascular events in stable coronary artery disease.7 Similarly, among diabetics, traditionally considered a high-risk group, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.8 Based on proven benefits of contemporary medical therapy, it is important that clinicians have a standardized approach for the management of patients with refractory angina which should incorporate lifestyle modification, use of guideline-based medical therapies including newer agents such as ranolazine when indicated, and novel therapies such as EECP (enhanced external counterpulsation), spinal cord stimulation, laser revascularization, etc. as appropriate. Figure 1 outlines a simplified evidence-based approach for the management of patients with refractory angina.9 If, as is evident in this study, survival of patients with refractory angina is quite comparable with that of patients with stable ischaemic heart disease on optimal medical therapy, it would make clinical sense to target other outcomes such as angina relief and quality of life. However, we should not forget the lessons learnt from the Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis (VIVA) trial which showed that placebo may have a significant ameliorating effect on a subjective outcome such as angina pectoris.10 An important finding of the VIVA trial was the prominent placebo effect noted at day 60 with a 48 s improvement in exercise treadmill test time, 56% of patients improving at least one angina class, and a nearly 14-point improvement in the Seattle Angina Questionnaire angina frequency domain. It is therefore critically important to test new therapies for refractory angina in a randomized double blind design. For now, we cannot overemphasize the importance of optimal medical therapies in patients with refractory angina pectoris. Patients with refractory angina represent a high-risk group, where secondary prevention is likely to be particularly beneficial and cost-effective. Overall, refractory angina management requires an effective optimization of medical therapies with the use of different drugs in maximally tolerated doses,11 with judicious use of therapies such as transcutaneous electric nerve stimulation, spinal cord stimulation, EECP, and laser revascularization in selected cases for symptom relief.12

Figure 1

Simplified approach to a patient presenting with refractory angina. BMI, body mass inex; HbA1c, glycated haemoglobin.

Figure 1

Simplified approach to a patient presenting with refractory angina. BMI, body mass inex; HbA1c, glycated haemoglobin.

Conflict of interest: none declared.

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Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/eht165.

Comments

2 Comments
The Coronary Sinus Reducer Stent for the treatment of refractory angina pectoris
25 June 2013
Yoav Paz

To the Editor

We read with great interest the important review by Professor Debabrata Mukherjee (1). We agree with the conclusion of the author that it is critically important to test new therapies for refractory angina in a randomized double blind design.

So, we would ask for the opportunity to introduce to the readers an emerging innovation for the treatment of these patients who continue to suffer from disabling symptoms despite optimal medical therapy namely: the Neovasc coronary sinus reducer stent (CSRS) (2,3).

In the mid-1990s Dr. Amihay Shinfeld and Dr. Yoav Paz initiate a novel approach to support the ischemic myocardium, they called it the upside-down strategy because they catheterized the coronary sinus instead of a coronary artery and reduced its diameter instead of expanding a narrowed coronary artery. In a pig model the coronary sinus diameter was reduced to 3 mm with a balloon-expandable stent, hourglass shaped that was developed especially for this purpose. Eight - 12 weeks after this intervention they found epicardial and intramyocardial neovascularization which is still not clear whether these were dormant or new generated blood vessels. Few years later these two cardiac surgeons manufactured the first percutaneous intravenous CSRS and gave it the name Neovasc, later known as Neovasc Medical, Inc.

Dr Claude Beck has described in the 1940s two types of coronary sinus interventions (4-6). Beck I procedure, consisted of: 1) operative narrowing the coronary sinus 2) abrading both epicardium and inner pericardium (some kind of neurectomy that was in those days a therapy for angina pectoris) 3) spilling of powdered asbestos and 5% aqueous trichloracetic acid on the epicardium 4) placement of mediastinal fat over the treated epicardium. Beck II procedure consisted of a vascular graft between the descending aorta and the coronary sinus followed by operative constriction of the coronary sinus ostium a few weeks later. Both procedures needed thoracotomy and have almost nothing in common with the CSRS.

The CSRS has already been implanted in 15 patients with refractory angina (7). All patients underwent uneventful implantations, discharged from hospital 1-2 days afterward, most patients had improved Canadian Cardiovascular Society scores, improved their stress-induced ST-segment depression, reduced myocardial ischemia as was shown by either dobutamine echocardiography or thallium single-photon emission computed tomography. Three years of follow-up had ended up without mortality or myocardial infarctions while persistence of clinical improvements continue (8).

The coronary sinus reducer for treatment of refractory angina (COSIRA) study has already begun and will reassess the efficacy of the CSRS (9). This trial is a double-blinded, randomized, sham-controlled multicenter trial (conducted in Canada, Europe and the UK) for which patient enrollment has already been completed in May 2013. We hope that CSRS will contribute a new option for the treatment of these uncontrollable and disabling angina symptoms.

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2. Bernhard Meier. Current best practice in interventional cardiology. Blackwell publishing 2010 p. 60-64.

3. Ever D. Grech. ABC of interventional cardiology. Wiley-Blackwell 2011 Second edition p. 33.

4. Edmunds LH. Cardiac surgery in the adults. New York: McGraw-Hill; 1997. p. 482.

5. Beck C. The coronary operation. Am Heart J 1941;22:539.

6. Beck C, Stanton E, Batinchok W, Leiter E. Revascularization of heart by graft of systemic artery. JAMA 1948;137:436.

7. Banai S, Ben Muvhar S, Parikh KH, 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 2007;49:1783-1789.

8. Banai S, Schwartz M, Sievert H, et al. Long-term follow-up to evaluate the safety of the Neovasc reducer a device based therapy for chronic refractory angina. J Am Coll Cardiol 2010;55:A98.E927.

9. CRT Online - Cardiovascular research technologies. http://clinicaltrials.gov/ct2/show/NCT01205893 (20 June 2013).

Conflict of Interest:

None declared

Submitted on 25/06/2013 8:00 PM GMT
Novel therapies for refractory angina
25 June 2013
Debabrata Mukherjee

I appreciate the response by Dr Paz highlighting the role of coronary Sinus Reducer Stent, another potential novel therapy for the treatment of refractory angina pectoris. Preliminary data appears promising but as pointed out by me in my original article, it is important to test new therapies for refractory angina in a randomized double blind design. I am hopeful that the "Use of the Neovasc Coronary Sinus Reducer System for the Treatment of Refractory Angina Pectoris in Patients With Angina Class 3-4 Who Are Not Candidates for Revascularization trial- NCT01566175" and the "Coronary Sinus Reducer for Treatment of Refractory Angina - COSIRA" study will provide important insight into the role of coronary sinus reducer stents for the treatment of refractory angina pectoris.

Conflict of Interest:

None declared

Submitted on 25/06/2013 8:00 PM GMT