Post-marketing data for rivaroxaban and new understandings about NSAIDs and cardiovascular disease are presented.
Examining Prophlyactic Effectiveness
Rivaroxaban (Xarelto) is an oxazolidinone derivative and a selective inhibitor both free factor Xa and factor Xa bound in the prothrombinase complex with oral bioavailability and rapid onset of action.1
Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the coagulation cascade, inhibiting both thrombin formation and development of thrombi. Current FDA indications for rivaro-xaban include the reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation and prophylaxis of deep vein thrombosis.
In the recently completed XAMOS trial,2
an open label study, a total of 17,701 patients undergoing elective hip or knee replacement surgery were enrolled from 37 countries. Patients were treated with either rivaroxaban (81%) or standard treatment (low-molecular- weight heparin, fondaparinux, dabigatran, aspirin, unfractionated heparin, or warfarin). Physicians decided into which arm their patients would be placed. This obvious bias has not been analyzed and reported yet by the authors.
Overall results demonstrated that rivaroxaban was associated with fewer thrombotic events than standard care (odds ratio [OR] 0.89 vs 1.35, respectively; 95% confidence interval [CI], 0.65 [0.89-1.35]), but there was a trend toward increased bleeding for rivaroxaban (any bleeding, OR 4.67 vs 3.24; 95% CI, 1.46 [1.25-1.71]; major bleeding, OR 1.7 vs 1.44; 95% CI, 1.19 [0.93-1.51]). This study appears to be further proof of rivaroxaban’s effectiveness in real-world orthopedic prophylaxis.
Good News/Bad News for Rivaroxaban
In May 2012, the FDA posted a review3
stating that rivaroxaban reduces life-threatening blood clots in high-risk patients, but that it also increases the risk of internal bleeding. Johnson & Johnson is now asking the FDA to approve it as a preventive measure against lifethreatening blood clots in patients with acute coronary disease.
The fact that it significantly reduces the risk of heart attack, stroke, and death influenced an FDA reviewer to recommend approving the drug for the new indication despite an increased risk of major and fatal bleeding. The reviewer stated, “Overall the benefit- risk ratio for Xarelto appears to be favorable, predominantly because there is a reduction in cardiac death.”
Later in May 2012, however, a majority of an FDA panel of experts4
voted 6 to 4 (1 abstention) against approving the new use of the drug, stating that “too much information was missing from company studies to accurately gauge the drug’s benefit.” Apparently, approximately 15% of patients in the study dropped out before its completion and the company failed to follow up with the status of more than 1000 patients. The panel indicated these missing data may have influenced the study’s results. A final decision on the company’s request for the new indication is expected by June 29, 2012.
Mr. Brown is professor emeritus of clinical pharmacy and a clinical pharmacist at Purdue University College of Pharmacy, Nursing, and Health Sciences, Department of Pharmacy Practice, in West Lafayette, Indiana. This column’s information is based on current studies and references, but it may be changed without notice with newer studies or with different patient populations.
1. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2011.
2. Turpie AG, Jamal W, Schmidt A, et al.Xamos: A non-interventional study comparing oral rivaroxaban with conventional regimens for thromboprophylaxis after major surgery of the hip and knee. British Society of Hematology 2012 Scientific Meeting; April 16-18, 2012; Glasgow, Scotland.
3. Perrone M. FDA says Xarelto reduced deadly heart attacks. Associated Press, http://seattletimes.nwsource.com/html/health/2018254216_apusfdajjbloodthinner.html Accessed May 30, 2012.
4. FDA panel votes against new use for J&J’s Xarelto. Business Week website.www.businessweek.com/ap/2012-05/D9UULNEO0.htm Accessed May 30, 2012.
5. NSAIDs and Cardiovascular Risk Explained. ScienceDaily website. www.sciencedaily.com/releases/2012/05/120502143846.htm. Accessed May 8, 2012.