Response by Piccini et al to Letters Regarding Article, “Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation”
Authors: Jonathan P. Piccini, Anne S. Hellkamp, Jeffrey B. Washam, Richard C. Becker, Günter Breithardt, Scott D. Berkowitz, Jonathan L. Halperin, Graeme J. Hankey, Werner Hacke, Kenneth W. Mahaffey, Christopher C. Nessel, Daniel E. Singer, Keith A.A. Fox, Manesh R. Patel
Journal: Circulation (2016)

In Response:We appreciate the opportunity to reply to comments made by Imprialos and colleagues.As they point out, concomitant antiplatelet therapy is associated with a significantly increased risk of bleeding in patients with atrial fibrillation who are receiving oral anticoagulation.Our analysis of polypharmacy and subsequent outcomes in ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) included an adjustment for antiplatelet therapy (previous aspirin).Despite adjustment for prior aspirin therapy, we found that increasing medication burden was associated with a higher risk of bleeding but not stroke. 1Of 9059 patients who did not report previous chronic aspirin use, only 6.2% (565) reported postrandomization aspirin use.Finally, patients taking persistent nonsteroidal antiinflammatory agents and those on >100 mg aspirin daily were excluded from ROCKET AF.Bouatou et al raise concerns that the outcomes data from ROCKET AF are not sufficiently reassuring to permit clinicians to use rivaroxaban with combined inhibitors.Those authors correctly point out, as highlighted in our Methods section, that patients taking a strong CYP3A4 inhibitor or inducer were excluded from ROCKET AF.Thus, the findings from our analysis clearly do not apply to strong CYP3A4 inhibitors, and this information is included in our report.The authors also correctly point out that we analyzed combined inhibitors only at baseline.From our analysis, we concluded that there was no evidence of heterogeneity of treatment outcomes according to the use of combined mild to moderate CYP3A4 and permeability glycoprotein inhibitors unless patients were taking ≥2 combined inhibitors.However, as we noted in our article, 1 given the limitations of the sample size, larger studies in more heterogeneous populations are needed.We agree that the classification of mild to moderate CYP3A4 and permeability glycoprotein inhibitors is controversial; however, in our analysis and in the ROCKET AF trial, these medications were classified according to the official guidance from the US Food and Drug Administration. 2 The authors propose that a cumulative doseweighted model would be helpful.However, unlike the study they cite, 3 which analyzes the glucocorticoid dose equivalents for anti-inflammatory activity, there are no well-accepted standards of dose equivalence for combined CYP3A4 and permeability glycoprotein inhibition across medication types (eg, amiodarone versus diltiazem).Although we appreciate the theoretical concerns about the impact of mild to moderate CYP3A4 and permeability glycoprotein inhibitors and concerns about our inability to accommodate genetic factors or dose, we believe that the strength of our analysis is the use of outcomes data in treated patients rather than pharmacokinetic data to guide prescribing decisions.The absence of any evidence of worse outcomes in 1314 patients receiving rivaroxaban and