Narrowing Coronary Sinus May Provide Relief From Refractory Angina
A device that narrows the coronary sinus can reduce angina symptoms and improve quality of life in patients with refractory angina who are not candidates for revascularization, according to phase II trial results published in the February 5, 2015, issue of the New England Journal of Medicine.
“If confirmed in subsequent trials, coronary sinus–reducing therapy may be a welcome and needed addition to the options to improve the quality of life of patients with refractory angina,” Christopher B. Granger, MD, of the Duke Clinical Research Institute (Durham, NC), and Bernard J. Gersh, MBChB, DPhil, of the Mayo Clinic (Rochester, MN), write in an accompanying editorial.
In the COSIRA trial, researchers led by Shmuel Banai, MD, of Tel Aviv Medical Center (Tel Aviv, Israel), evaluated Reducer (Neovasc; Richmond, Canada), a balloon-expandable, hourglass-shaped device consisting of stainless steel mesh. After the device is implanted into the coronary sinus, the center maintains a diameter of 3 mm while the ends are expanded to 8 to 12 mm. The mesh becomes covered in tissue over the next 4 to 6 weeks, creating a narrowing of the sinus that increases pressure and redistributes blood from nonischemic to ischemic myocardium.
The trial, conducted at 11 centers, included 104 patients (mean age 67.8 years; 81% male) who had evidence of reversible myocardial ischemia, Canadian Cardiovascular Society (CCS) class III or IV angina despite medical therapy for at least 30 days before screening, and an LVEF greater than 25%. None were candidates for revascularization, although 70% to 80% had undergone prior PCI, CABG, or both. Patients were randomized to device implantation or a sham procedure.
All patients had a 6-Fr diagnostic catheter introduced into the right atrium to measure right atrial pressure. The catheter was then introduced into the coronary sinus to obtain an angiogram and determine the implantation site.
In the intervention group, a preshaped 9-Fr guiding catheter was introduced into the coronary sinus to implant the device and angiography was used to assess the quality of the implantation. The Reducer device was successfully placed in all but 2 patients (96%), in whom failure resulted from the presence of a venous valve in the sinus that could not be crossed with the device.
Device Improves Symptoms, Quality of Life
The proportion of patients who improved by at least 2 CCS angina classes from baseline to 6 months (primary endpoint) was greater in the device group (35% vs 15%; P = .02), as was the percentage who improved by at least 1 class (71% vs 42%; P = .003). Mean CCS class dropped from 3.2 to 2.1 in the device group and from 3.1 to 2.6 in the control group.
Quality of life, as assessed with the Seattle Angina Questionnaire, improved by 17.6 points in the device arm compared with 7.6 points in the control arm (P = .048).
There were no differences between groups 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.
In all, 64% of patients in the device arm and 69% in the control arm had at least 1 adverse event (P = .68). By 6 months, there was 1 periprocedural MI and no deaths in the device group, while 3 MIs and 1 death occurred in the control group.
Few Options for Refractory Angina
With aging populations and the ability to improve life expectancy among patients with ischemic heart disease, refractory angina is a growing problem around the world that has limited treatments, Drs. Granger and Gersh note in the editorial.
“The mortality among patients with refractory angina is surprisingly low,” they write, “but the effect of persistent, recurrent, and frequent symptoms on quality of life is substantial and emphasizes the need for alternative therapeutic options.”
Before laying out a detailed critique of the COSIRA results, they highlight previous interventions designed to ease refractory angina that had shown promising initial results but failed to demonstrate benefits in larger randomized trials. “Although there is some experimental evidence to suggest that obstructing the coronary sinus may protect against myocardial ischemia, this approach has not been established as a clinically useful strategy,” they argue.
They suggest that 1 of the major shortcomings of COSIRA is its small size, as the 26 patients who achieved a 2-class improvement in angina (18 with the device, 8 in the control arm) “is not sufficient for a reliable estimation of modest treatment effects, which underscores the limitation of small trials like this one to provide definitive information.”
Another major limitation, Drs. Granger and Gersh write, is the uncertainty about whether the double-blind design of the trial was effective given the “subjective” nature of outcomes. “Even when the control group has been effectively kept unaware of the study assignment, patients may believe that they have received the active treatment, which may explain why 15% of the patients in the control group had substantial improvement in their angina,” they write.
Yet another limitation may be the strict inclusion criteria, which “are justified but that may make the results less generalizable to the broader population of patients with refractory angina,” they write.
Large Potential Impact
In a telephone interview with TCTMD, Dr. Banai said about 20% of patients who undergo successful PCI or CABG still suffer from angina after revascularization. “The Reducer is a very simple, straightforward, and effective treatment for these kinds of patients” who would not necessarily be candidates for additional intervention, he said.
The device is not expected to improve prognosis by reducing mortality or MI risks, he added. “The only reason for this device is to improve the very poor quality of life of these patients, who don’t have any other options for treatment,” he said, noting that even the 1-class improvement seen in about three-quarters of the intervention patients is substantial.
“When you have a patient [who] is limited just walking to the bathroom—which is CCS class III—and now he can walk 20 minutes outside the house. It’s only a 1-class improvement but it is very significant,” he said.
Dr. Banai added that in follow-up of up to 5 years in some patients the effect of the device persisted. Evaluation of Reducer will continue in a new 400-patient, single-arm trial in Europe and in a phase II, FDA-approved feasibility trial expected to start in the United States later this year.
Those additional data will be important to address some of the weaknesses of COSIRA, including the small sample size and reliance on change in CCS class, which “is a pretty blunt endpoint [that is] not that sophisticated or specific,” for the primary endpoint, according to Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY).
Nevertheless, the study importantly demonstrates the benefit of a device-based therapy for angina vs a sham control, he told TCTMD in a telephone interview. It also shows that increasing pressure in the coronary sinus and improving perfusion pressure can relieve symptoms.
“If this is borne out in larger studies, patients will be helped by this,” he said.
1. 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.
2. Granger CB, Gersh BJ. Potential relief for refractory angina [editorial]. N Engl J Med 2015;372:566-567.
- The COSIRA trial was funded by Neovasc.
- Dr. Banai reports receiving personal fees for serving as medical director of Neovasc.
- Dr. Granger reports relationships with multiple pharmaceutical and device companies.
- Dr. Kirtane reports institutional research grants from Abbott Vascular, Abiomed, Boston Scientific, Eli Lilly, Medtronic, St. Jude Medical, and Vascular Dynamics.
- Dr. Gersh reports no relevant conflicts of interest.