NEW ORLEANS — An anticoagulation strategy involving rivaroxaban conferred less bleeding risk than a strategy involving warfarin in patients with atrial fibrillation undergoing PCI with stenting, according to findings presented at the American Heart Association Scientific Sessions.
A strategy of either low-dose rivaroxaban (Xarelto, Janssen Pharmaceuticals) plus a P2Y12 inhibitor or very low-dose rivaroxaban plus dual antiplatelet therapy (DAPT) could replace the triple therapy of warfarin plus DAPT often prescribed to patients with AF who require a stent, which is known to increase bleeding risk, researchers reported.
“We now have a safer alternative to treat the patient who has both [AF] and a stent,” C. Michael Gibson, MD, MS, from the cardiovascular division of the department of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, told Cardiology Today. “If you treat with one of these two new regimens of rivaroxaban, you only need to treat 11 to 12 people to prevent one clinically significant bleed. You also only need to treat 10 to 15 patients to prevent one recurrent hospitalization, which is a huge benefit in terms of the cost drivers.”
C. Michael Gibson
Key data presented
The PIONEER AF-PCI investigators randomly assigned 2,124 patients with nonvalvular AF who underwent PCI with stenting to one of three postprocedural regimens:
- low-dose rivaroxaban (15 mg per day) plus a P2Y12 inhibitor but no aspirin for 12 months;
- ·very low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6 or 12 months; or
- standard triple therapy with a dose-adjusted vitamin K antagonist such as warfarin plus DAPT for 1, 6 or 12 months.
Antiplatelet therapy and DAPT duration were decided by each treating physician before randomization, Gibson said at a press conference.
The primary safety outcome was clinically significant bleeding, defined as TIMI major or minor bleeding or bleeding requiring medical attention at 12 months. Those results were simultaneously published in The New England Journal of Medicine.
In a post hoc analysis, the researchers analyzed the endpoint of all-cause mortality or recurrent hospitalization for a bleeding, CV or other adverse event at 12 months. Those results were simultaneously published in Circulation.
Compared with warfarin, both rivaroxaban groups had lower rates of clinically significant bleeding (low-dose rivaroxaban, 16.8%; very low-dose rivaroxaban, 18%; warfarin, 26.7%; HR for low-dose rivaroxaban vs. warfarin = 0.59; 95% CI, 0.47-0.76; number needed to treat = 11; HR for very low-dose rivaroxaban vs. warfarin = 0.63; 95% CI, 0.5-0.8; number needed to treat = 12), according to the researchers.
No significant difference emerged between the groups in the composite outcome of CV death, MI and stroke at 12 months (low-dose rivaroxaban, 6.5%; very low-dose rivaroxaban, 5.6%; warfarin, 6%), Gibson and colleagues found.
In the post hoc analysis, the risk for all-cause mortality or rehospitalization was 34.9% in the low-dose rivaroxaban group, 31.9% in the very low-dose rivaroxaban group and 41.9% in the warfarin group (HR for low-dose rivaroxaban vs. warfarin = 0.79; 95% CI, 0.66-0.94; number needed to treat = 15; HR for very low-dose rivaroxaban vs. warfarin = 0.75; 95% CI, 0.62-0.9; number needed to treat = 10).
Deaths or hospitalizations related to bleeding or CV events were significantly lower in the rivaroxaban groups than in the warfarin group (bleeding events: P for low-dose rivaroxaban vs. warfarin = .032; P for very low-dose rivaroxaban vs. warfarin = .012; CV events: P for low-dose rivaroxaban = .001; P for very low-dose rivaroxaban vs. warfarin = .011). However, deaths or hospitalizations from other causes were not lower with rivaroxaban, according to the findings.
Findings in context
During a discussant presentation, Philippe Gabriel Steg, MD, from the cardiology and physiology departments, Départment Hospitalo-Universitaire FIRE, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris Diderot University, Sorbonne Paris Cité, France, and Imperial College, Royal Brompton Hospital, London, said the results represent “a very robust finding.”
Philippe Gabriel Steg
According to Steg, “It is critical to remember that the doses of rivaroxaban that were used in this trial were reduced doses. … These haven’t really been formally tested [for prevention of stroke] with the exception of a Japanese trial of 15-mg rivaroxaban. … The dose of vitamin K antagonist was not reduced, and [that] might have been another option to explore.
“[Moreover], given that the doses [of rivaroxaban] were reduced and bleeding was lower, it isn’t really much of a surprise, but it begs the question of whether the safety of anticoagulation with lower doses of rivaroxaban is clearly established in terms of preventing stroke within the challenge of combination therapy. The trial did not establish, and did not test, noninferiority of rivaroxaban strategies compared with the standard of care for stroke prevention. … The recurrent hospitalization data are interesting, [but] we have to remember that post hoc analyses can only be viewed as hypothesis-generating,” Steg, a Cardiology Today’s Intervention Editorial Board member, said here.
In a related editorial published in Circulation, Cardiology Today’s Intervention Chief Medical Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, and professor of medicine, Harvard Medical School, noted that “from the PIONEER data to date, significant benefits can be realized from abandoning the strategy of full-dose triple therapy, with no apparent downside.”
Deepak L. Bhatt
While this study was not powered for efficacy and did not enroll many patients at high stroke risk, “it is important to realize that the gold standard of aspirin, clopidogrel and warfarin was never validated as such,” Bhatt wrote.
“We are delighted with the results,” Paul Burton, MD, PhD, FACC, vice president of medical affairs at Janssen Pharmaceuticals, told Cardiology Today. “We think it’s an area of unmet need and is clinically highly significant. [The data] continue to show the strong, robust profile of rivaroxaban in patients for whom there is a significant unmet medical need. … Anywhere where thrombosis has a clear role in the progression of disease, we think rivaroxaban might be an effective therapy for it, and we are actively studying that in the Explorer program.” – by Erik Swain
Gibson CM, et al. LBCT.02 – Pioneering the Future of HeART Interventions. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Bhatt DL. Circulation. 2016;doi:10.1161/CIRCULATIONAHA.116.025923.
Gibson CM, et al. Circulation. 2016;doi:10.1161/CIRCULATIONAHA.116.025783.
Gibson CM, et al. N Engl J Med. 2016;doi:10.1056/NEJMoa1611594.
Disclosures: The study was funded by Janssen Pharmaceuticals. Bhatt reports financial ties with multiple pharmaceutical, device and publishing companies. Burton is an employee of Janssen. Gibson reports financial ties with Amarin, Amgen, Angel Medical, Bayer, Boston Clinical Research Institute, CSL Behring, Eli Lilly, Gilead, Ikaria, Janssen Pharmaceuticals, Johnson & Johnson, Novo Nordisk, Ortho McNeil, Pfizer, Pharma Mar, Portola, Roche Diagnostics, Stealth Peptides, St. Jude Medical, The Medicines Company, UpToDate and WebMD; his spouse is an employee of and holds equity in Boston Clinical Research Institute. Steg reports financial ties with Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Medtronic, Merck, Novartis, Pfizer, Regeneron, Roche, Servier and The Medicines Company.