Editor's Note: Commentary based on Verheye S, Jolicœur EM, Behan MW, et al. Efficacy of a Device to Narrow the Coronary Sinus in Refractory Angina. N Engl J Med 2015;372:519-527.

Background

Despite improvements in medical and surgical treatments of coronary artery disease, there remains a relatively large number of patients with refractory angina. Percutaneous reduction of the coronary sinus is an emerging treatment for myocardial ischemia that increases coronary sinus pressure to reduce myocardial ischemia by redistribution of blood from non-ischemic to ischemic myocardium. In this study, the safety and efficacy of the Coronary Sinus Reducer was evaluated in patients with refractory angina on optimal medical therapy who were not candidates for revascularization.

Methods

This was a randomized, double-blind, sham-controlled clinical trial conducted at 11 centers and included 104 patients who had Canadian Cardiovascular Society (CCS) class III or IV angina and evidence of reversible myocardial ischemia despite medical therapy for at least 30 days before screening. Patients were randomized to device implantation (treatment group) or to a sham procedure (control group). The primary end point was improvement by at least two CCS angina classes at six months.

Results

Mean age of the participants was 67.8 years, 81% were men, 84% with CCS angina class 3, and about three-quarters had previous CABG and/or PCI. Successful device implantation was accomplished in 96% of the participants. Improvement by at least two CCS angina classes was noted in 35% of the treatment group compared to 15% of the control group (p = .02). There was an improvement of at least one CCS angina class in the treatment group (71% vs. 42%, p =.003). A similar improvement was observed in Quality of Life Index (17.6/100 vs. 7.6/100, p =.03). There were no statistically significant differences for other endpoints including angina stability and frequency, exercise duration, change in the time to ST-segment depression of 1 mm, or change in the wall-motion index according to dobutamine stress echocardiography. A peri-procedural myocardial infarction occurred in one patient in the treatment group. CT angiography six months after device implantation was performed in 72% (36/50) confirming no device migration or occlusion.

Conclusion

The authors concluded that the coronary sinus reducing device led to a reduction in symptoms and improved quality of life in patients with disabling angina pectoris.

Commentary/Perspective

The number of patients with severe CAD is increasing because of improved survival rates and an aging population. Despite continued development and improvement of myocardial revascularization, a substantial proportion of those patients does not achieve complete revascularization and continues to experience refractory angina in spite of optimal medical therapy.¹ Despite low mortality, refractory angina is a debilitating condition.² This has stimulated interest in alternative strategies including myocardial angiogenesis, novel pharmacological agents (i.e., trimetazidine, nicorandil, allopurinol, bosentan, or ivabradine), enhanced external counter pulsation (EECP), spinal cord stimulation, and transmyocardial revascularization.³ Among those, EECP is the best-studied therapy, but it is not widely used. The coronary sinus reducing device is the most recent novel development in this field.⁴

The coronary sinus reducing device is mounted on a balloon catheter and inserted into the coronary sinus percutaneously via a venous route.⁴ Balloon expansion leads to the permanent implantation of an hourglass-shaped metal mesh that leads, over time, to partial obstruction of the coronary sinus. The original idea behind the development of this device was to increase stenotic coronary artery perfusion pressure by limiting its outflow. However, it seems the benefit comes from neovascularization and recruitment of coronary collateral flow with redistribution from the less-ischemic epicardium to the ischemic endocardium.⁵ Its feasibility and safety was first reported in 2007 in a Phase I trial on 15 patients.⁶ The key finding from the current Phase II trial is that the device is simple, safe, and potentially improves symptoms and quality of life in these "no-option" patients with refractory angina.

The major strength of the study is use of a sham control group and complete follow-up. The major limitation is a small sample size with symptom improvement in only 18 patients in the treatment group. The primary efficacy was reliance on a change in CCS class, which is a very soft non-specific endpoint, and it was underpowered for secondary endpoints to show an objective index of improvement. Furthermore, because of the relative short-term follow-up, safety and efficacy beyond six months is unknown. In addition, strict inclusion criteria may make the results less generalizable to the broader population of patients with refractory angina. Finally, skepticism can arise surrounding the optimal medical treatment because none of the patients was on ranolazine, and only 23% in treatment group were on three anti-anginal agents.

However, despite these limitations, this Phase II trial showed that the coronary sinus reducer is feasible, safe, and potentially efficacious. A new, larger, European trial involving 400 patients and a Phase II, FDA-approved feasibility trial in the United States will further evaluate the safety and efficacy of this device.⁷ If successfully proven to be helpful in a larger population, this could be a breakthrough in management of these "no-option" patients with chronic refractory angina.

References

1. Jolicoeur EM1, Granger CB, Henry TD, Holmes DJ, Pepine CJ, Mark D, Chaitman BR, Gersh BJ, Ohman EM; Working Group Members.; Working Group Members. Clinical and research issues regarding chronic advanced coronary artery disease part I: contemporary and emerging strategies. Am Heart J 2008;155:418-434
2. Henry TD, Satran D, Hodges JS, Johnson RK, Poulose AK, Campbell AR, Garberich RF, Bart BA, Olson RE, Boisjolie CR, Harvey KL, Arndt TL, Traverse JH. Long-term survival in patients with refractory angina. Eur Heart J 2013;34(34):2683-8.
3. Henry TD, Satran D, Jolicoeur EM. Treatment of refractory angina in patients not suitable for revascularization. Nat Rev Cardiol 2014;11:78-95
4. Verheye S, Jolicoeur EM, Behan MW, et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med 2015;372:519-527
5. 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 2001;280:H1361-H1367
6. 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
7. Neale T. Narrowing Coronary Sinus May Provide Relief From Refractory Angina. http://www.tctmd.com/show.aspx?id=127912 (accessed April 18, 2015).

Keywords: Acetanilides, Allopurinol, Angina Pectoris, Angiography, Benzazepines, Control Groups, Coronary Artery Disease, Coronary Sinus, Double-Blind Method, Echocardiography, Stress, Endocardium, Follow-Up Studies, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Myocardium, Nicorandil, Pericardium, Piperazines, Quality of Life, Sample Size, Spinal Cord Stimulation, Sulfonamides, Survival Rate, Trimetazidine

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