By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Verheye S et al. Efficacy of a device to narrow the coronary sinus in refractory angina. N Engl J Med 2015;372:519-527.
Despite advances in medical therapy and in coronary revascularization techniques, the population of patients with chronic, stable, but debilitating angina continues to grow. The mortality of such patients is surprisingly low, such that patients with this disorder often suffer limiting symptoms for many years. Clearly more options for treatment are needed, but what?
The area of surgical manipulation of the cardiac venous anatomy, rather than the coronary arterial supply, has a fascinating history dating back as far as the 1940s. More recent advocates have theorized that increasing the pressure in the coronary sinus may lead to redistribution of collateral blood flow from non-ischemic into ischemic territories of the myocardium. An implantable, stainless-steel, balloon-expandable stent designed to create a narrowing within the coronary sinus (The Coronary Sinus Reducer, Neovasc Medical, Inc) and, thus, increase coronary venous pressure was initially presented in a phase 1 first-in-human study published in JACC in 2007. That trial, which was a nonrandomized, open-label study in 15 patients, reported a high degree of safety as well as a clinical benefit maintained at 3 years of follow up. A phase 2 study of the device was recently published in the New England Journal of Medicine.
In this study, 104 patients with Canadian Cardiovascular Society (CCS) class III or IV angina who were on maximal medical therapy and deemed not to be candidates for further revascularization were randomized to receive the Reducer device or a sham procedure. Medical therapy included beta-blockers, calcium channel blockers, and short- and long-acting nitrates, as well as two medications not currently available in the United States — nicorandil and ivabradine. In each case, evidence of reversible ischemia was required for enrollment. Patients with recent revascularization or acute coronary syndrome were excluded, as were patients with severely reduced ejection fraction (EF) (<25%) and those with permanent pacemaker or defibrillator leads in the right heart.
All patients underwent a right heart catheterization and coronary sinus angiogram. Those with appropriate anatomy for the device were eligible for randomization (the percentage of patients who were anatomically ineligible for the procedure is not reported). Although the implanting physicians obviously were aware of the randomization, the patients as well as downstream investigators performing follow-up assessments were kept blinded. Among the 52 patients assigned to the treatment group, 50 had successful implantation of the device.
At the 6-month follow up, 35% of patients in the treatment group showed an improvement of at least two Canadian Cardiovascular Society (CCS) classes (the pre-specified primary endpoint), vs 15% in the control group (P = 0.02). In the treatment group, 71% had an improvement of at least one CCS class, as compared with 42% in the control group (P = 0.003). Quality of life, as assessed by the Seattle Angina Questionnaire, was also significantly improved in the device group.
The procedure did not show significant improvements in other endpoints when compared with controls, including angina stability and frequency, exercise duration, change in the time to ST-segment depression, or change in the wall-motion index on dobutamine stress echocardiography.
The authors concluded that the device showed an improvement in angina and quality of life in patients with refractory angina, but larger studies would be needed to assess objective measures of ischemia.
Over the years, many competing therapies have been investigated for refractory angina, including trans-myocardial laser revascularization, gene therapy, cell therapy, and so on — all have shown initial promise, but solid randomized trial data are lacking for most. A significant number of patients remain undertreated, and the need for further therapeutic options is clear.
This was a well-done trial, which included a sham procedure control, which is increasingly recognized as an essential element in trials assessing the effect of procedures on a subjective endpoint such as angina. Given this recognition, however, an assessment of the effectiveness of blinding would have been an appropriate addition (such assessments have been featured in other recent trials, such as SYMPLICITY HTN-3).
Although the reported benefits seem promising, the study size is simply too small to make definitive conclusions. A larger phase 3 study will be needed to corroborate these findings and, potentially, to predict which patients are most likely to benefit.
Even if the reported benefits are true, do the reported effects — only 71% of patients showing at least one CCS class improvement — justify an expensive invasive procedure? Only further investigation will tell.