Coronary Sinus Stent May Aid Refractory Angina: Phase 2 Trial

Marlene Busko

February 05, 2015

BOSTON, MA — In a randomized trial of 104 patients with disabling angina, those who had the Reducer (Norvasc, Richmond, BC) implanted into their coronary sinus had significantly reduced symptoms and improved quality of life 6 months later, compared with patients who underwent a sham procedure[1].

The findings from the Coronary Sinus Reducer for Treatment of Refractory Angina (COSIRA) phase 2 trial by Dr Stefan Verheye (Antwerp Cardiovascular Center, Belgium) and colleagues are published in the February 5, 2015 issue of the New England Journal of Medicine.

Unlike traditional stents that are designed to open arteries, this balloon-expandable, hourglass-shaped stainless steel mesh device is designed to obstruct flow and increase coronary-sinus pressure to increase the perfusion by oxygenated blood to ischemic areas of the heart muscle.

The trial shows that this device provides "a safe and relatively simple and straightforward [option] for patients with angina that is refractory to medical therapy [who] had very poor quality of life [and] no treatment option until now," senior author Dr Shnuel Banai (Tel Aviv Medical Center, Israel), told heartwire in an email."

In an accompanying editorial[2], Dr Christopher B Granger (Duke Clinical Research Institute, Durham, NC) and Bernard J Gersh (Mayo Clinic, Rochester, MN) warn that initial promising findings with other strategies for angina failed to be substantiated in larger trials. But "if [angina improvements are] 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," they agree.

Potential Future Treatment for Refractive Angina?

As previously reported by heartwire , results from the first-in-human study of this device were published in 2007, and top-line results from COSIRA were announced in November 2013.

From 2010 to 2013, COSIRA enrolled 104 patients age 18 and older with refractory angina in 11 centers in Belgium, Canada, the Netherlands, the UK, Denmark, and Sweden.

Patients had Canadian Cardiovascular Society (CCS) class 3 or 4 angina and were unable to control symptoms with beta-blockers, calcium-channel blockers, nicorandil, ivabradine (Corlentor/Procoralan, Servier), and short- and long-acting nitrates. They also had reversible myocardial ischemia and a left ventricular ejection fraction greater than 25% and were deemed unsuitable candidates for coronary revascularization.

The participants had a mean age of 67.8 years, and 81% were men; 84% were CCS angina class 3. About three-quarters had previous CABG and/or PCI.

Patients were randomized to the device or sham-procedure groups, and the device was implanted via the right jugular vein into the coronary sinus. Cardiac wall motion was assessed at baseline and at 6 months using dobutamine echocardiography.

At 6 months, 18 of 52 patients in the treatment group and 8 of 52 patients in the control group had improved by at least two CCS classes, the primary efficacy outcome (35% vs 15%, P=0.02). The mean CCS class was reduced from 3.2 to 2.1 in the treatment group vs and from 3.1 to 2.6 in the control group (P=0.001).

In addition, 71% of the patients in the treatment group vs 42% in the control group improved by at least one CCS class (P=0.003). Quality of life, as measured by the Seattle Angina Questionnaire, improved by 17.6 points in the treated group and by 7.7 points in the control group (P=0.048).

Overall, 76 adverse events were reported in the treatment group and 93 in the control group. There were three MIs and one death (due to multiorgan failure) in the control group, and there was one periprocedural MI and no deaths in the treated group.

Asked about the placebo effect, Banai noted that "the patients in the COSIRA trial did not know whether or not they received the Reducer, [but] they tended to believe they got it, and therefore the placebo effect was significant, [which is] typical in . . . clinical trials," especially for devices.

MRI and positron-emission tomography might be attractive to use in a larger phase 3 study, the authors write.

Needs to Be Verified in a Larger, Conclusive Trial

"This high-quality trial had a well-defined population, a sham control, attempts to keep the patients and treating physicians unaware of the study assignment, and a complete follow-up," Granger and Gersh write.

However, the small sample size limits confidence about the effectiveness of the intervention. "It is important to note that this total number of 26 patients [18 in the treatment arm and eight in the sham arm] with this positive outcome is not sufficient for a reliable estimation of modest treatment effects."

Also, there is "uncertainty over the effectiveness of maintaining the double-blind nature of the trial, which is particularly important given the subjective nature of the outcome." For example, the blinded SYMPLICITY HTN-3 renal-denervation trial failed to replicate blood-pressure control that had been seen in earlier open-label trials and "provides a cautionary tale with regard to the hazards of the lack of effective blinding in the control group when cardiovascular procedures are evaluated."

The device obtained a CE mark in Europe in 2011, and the company plans to conduct a trial to obtain FDA approval.

Neovasc sponsored the COSIRA study. Banai is the medical director of Neovasc. Disclosures for the coauthors are listed on the journal website. Granger reports consulting for Gilead, Eli Lilly, Ross Medical, Salix Pharmaceuticals, and Hoffmann-La Roche; funding for research grants and consulting from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Sanofi, Takeda, the Medicines Company, AstraZeneca, Daiichi-Sankyo, Janssen Pharmaceuticals, and Bayer; and funding for research grants from Medtronic Foundation and Merck. Gersh has reported he has no relevant financial relationships.

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