Rivaroxaban for Stroke Prevention in Patients With Nonvalvular Atrial Fibrillation and Active Cancer

Rivaroxaban is broadly used for the primary prevention of stroke and systemic embolism in the general population with nonvalvular atrial fibrillation (AF). However, there is little published evidence on the safety and efficacy of rivaroxaban for AF in patients with active cancer. The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and AF. The use of rivaroxaban in patients with cancer at the Memorial Sloan Kettering Cancer Center is monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and AF, treated with rivaroxaban from January 1, 2014, to March 31, 2016, are included in this analysis. Clinical end points were defined a priori and assessed through text searches of medical records. A total of 163 evaluable patients were identified. After adjusting for competing risks, the estimated 1-year cumulative incidence of ischemic stroke was 1.4% (95% CI 0% to 3.4%) and major bleeding was 1.2% (95% CI 0% to 2.9%). The risk of clinically relevant nonmajor bleeding leading to discontinuation of anticoagulation at 1 year was 14.0% (95% CI 4.2% to 22.7%). The cumulative incidence of mortality was 22.6% (95% CI 12.2% to 31.7%) at 1 year, reflecting an active cancer population. One patient died after developing an acute ischemic cerebrovascular insult. In conclusion, the safety and efficacy of rivaroxaban treatment for nonvalvular AF in patients with active cancer is comparable to the results of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study in the general population. Rivaroxaban is broadly used for the primary prevention of stroke and systemic embolism in the general population with nonvalvular atrial fibrillation (AF). However, there is little published evidence on the safety and efficacy of rivaroxaban for AF in patients with active cancer. The aim of this study was to assess the safety and efficacy of rivaroxaban in patients with active cancer and AF. The use of rivaroxaban in patients with cancer at the Memorial Sloan Kettering Cancer Center is monitored in the setting of a Quality Assessment Initiative. Patients with active cancer and AF, treated with rivaroxaban from January 1, 2014, to March 31, 2016, are included in this analysis. Clinical end points were defined a priori and assessed through text searches of medical records. A total of 163 evaluable patients were identified. After adjusting for competing risks, the estimated 1-year cumulative incidence of ischemic stroke was 1.4% (95% CI 0% to 3.4%) and major bleeding was 1.2% (95% CI 0% to 2.9%). The risk of clinically relevant nonmajor bleeding leading to discontinuation of anticoagulation at 1 year was 14.0% (95% CI 4.2% to 22.7%). The cumulative incidence of mortality was 22.6% (95% CI 12.2% to 31.7%) at 1 year, reflecting an active cancer population. One patient died after developing an acute ischemic cerebrovascular insult. In conclusion, the safety and efficacy of rivaroxaban treatment for nonvalvular AF in patients with active cancer is comparable to the results of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study in the general population. The new direct oral anticoagulants (DOAC's) have been established as safe and effective alternatives to vitamin K antagonists (VKAs) in the general patient population and within treatment recommendation guidelines for patients with nonvalvular atrial fibrillation (AF).1Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar, 2Granger C.B. Alexander J.H. McMurray J.J. Lopes R.D. Hylek E.M. Hanna M. Al-Khalidi H.R. Ansell J. Atar D. Avezum A. Bahit M.C. Diaz R. Easton J.D. Ezekowitz J.A. Flaker G. Garcia D. Geraldes M. Gersh B.J. Golitsyn S. Goto S. Hermosillo A.G. Hohnloser S.H. Horowitz J. Mohan P. Jansky P. Lewis B.S. Lopez-Sendon J.L. Pais P. Parkhomenko A. Verheugt F.W. Zhu J. Wallentin L. Aristotle Committees and InvestigatorsApixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (6664) Google Scholar, 3Connolly S.J. Ezekowitz M.D. Yusuf S. Eikelboom J. Oldgren J. Parekh A. Pogue J. Reilly P.A. Themeles E. Varrone J. Wang S. Alings M. Xavier D. Zhu J. Diaz R. Lewis B.S. Darius H. Diener H.C. Joyner C.D. Wallentin L. RE-LY Steering Committee InvestigatorsDabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (8845) Google Scholar, 4Giugliano R.P. Ruff C.T. Braunwald E. Murphy S.A. Wiviott S.D. Halperin J.L. Waldo A.L. Ezekowitz M.D. Weitz J.I. Spinar J. Ruzyllo W. Ruda M. Koretsune Y. Betcher J. Shi M. Grip L.T. Patel S.P. Patel I. Hanyok J.J. Mercuri M. Antman E.M. ENGAGE AF-TIMI InvestigatorsEdoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3543) Google Scholar, 5January C.T. Wann L.S. Alpert J.S. Calkins H. Cigarroa J.E. Cleveland Jr., J.C. Conti J.B. Ellinor P.T. Ezekowitz M.D. Field M.E. Murray K.T. Sacco R.L. Stevenson W.G. Tchou P.J. Tracy C.M. Yancy C.W. American College of Cardiology/American Heart Association Task Force on Practice Guidelines2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.J Am Coll Cardiol. 2014; 64: e1-e76Crossref PubMed Scopus (2791) Google Scholar, 6Kirchhof P. Benussi S. Kotecha D. Ahlsson A. Atar D. Casadei B. Castella M. Diener H.C. Heidbuchel H. Hendriks J. Hindricks G. Manolis A.S. Oldgren J. Popescu B.A. Schotten U. Van Putte B. Vardas P. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS: the Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESCEndorsed by the European Stroke Organisation (ESO).Eur Heart J. 2016; 37: 2916-2919Crossref Scopus (5134) Google Scholar The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) study demonstrated the noninferiority of rivaroxaban compared with VKAs for prevention of thromboembolism in patients with nonvalvular AF.1Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar Patients with a serious concomitant illness associated with life expectancy of <2 years were excluded from this study, thereby limiting the extrapolation of those results to patients with active cancer. A post hoc pooled analysis of EINSTEIN PE and EINSTEIN DVT suggested that rivaroxaban appears to have reasonable efficacy and safety profiles for subjects with cancer-associated venous thromboembolism, as did single-institution cohort studies.7Prins M.H. Lensing A.W. Brighton T.A. Lyons R.M. Rehm J. Trajanovic M. Davidson B.L. Beyer-Westendorf J. Pap A.F. Berkowitz S.D. Cohen A.T. Kovacs M.J. Wells P.S. Prandoni P. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials.Lancet Haematol. 2014; 1: e37-e46Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 8Bott-Kitslaar D.M. Saadiq R.A. McBane R.D. Loprinzi C.L. Ashrani A.A. Ransone T.R. Wolfgram A.A. Berentsen M.M. Wysokinski W.E. Efficacy and safety of rivaroxaban in patients with venous thromboembolism and active malignancy: a single-center registry.Am J Med. 2016; 129: 615-619Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 9Mantha S. Laube E. Miao Y. Sarasohn D.M. Parameswaran R. Stefanik S. Brar G. Samedy P. Wills J. Harnicar S. Soff G.A. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study.J Thromb Thrombolysis. 2017; 43: 166-171Crossref PubMed Scopus (81) Google Scholar The objective of this study was to assess the safety and efficacy of rivaroxaban in nonvalvular AF patients with active cancer. The use of rivaroxaban and associated clinical outcomes in patients with active cancer at the Memorial Sloan Kettering Cancer Center (MSKCC) is monitored through an ongoing Quality Assessment Initiative. After approval by the institutional review board, all rivaroxaban orders within the institution starting on January 1, 2014, were reviewed by the Hematology Service, and clinical data on these patients were entered into the quality assessment database. A Clinical Pathway Guideline (Appendix 1) for the use of rivaroxaban in patients with cancer at MSKCC was derived at the end of 2013 by the Hematology/Anticoagulation Management Service. The clinical pathway addresses issues specific to the cancer population, including potential absorption defects, excretory organ function, drug interactions, thrombocytopenia, and bleeding risk. The recommended dose of rivaroxaban for AF is 20 mg daily.1Patel M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar For patients aged 75 years or older, we recommended 15 mg daily. We did not recommend rivaroxaban to patients with a creatinine clearance <30 ml/min. Patients with active cancer and AF treated with rivaroxaban from January 1, 2014, to February 14, 2016, were identified and are the subject of this analysis. Active cancer was defined as evidence of neoplasm on imaging, elevated levels of cancer markers on laboratory testing, or ongoing active cancer therapy (chemotherapy, hormone therapy, or radiation therapy). We also included patients if they were within 1 month of completion of adjuvant cancer therapy or within 1 month of cancer surgery. Patients with squamous cell cancer of the skin as their only malignancy, valvular disease (mitral stenosis, artificial heart valve, or mitral valve repair), or insufficient documentation were excluded from this analysis.10Fauchier L. Philippart R. Clementy N. Bourguignon T. Angoulvant D. Ivanes F. Babuty D. Bernard A. How to define valvular atrial fibrillation?.Arch Cardiovasc Dis. 2015; 108: 530-539Crossref PubMed Scopus (74) Google Scholar Patients were included regardless of the primary indication for anticoagulation. To adjudicate the end points, clinical notes were analyzed using an automated text search. The terms used to perform the text search are shown in Appendix 2. All clinical notes containing at least 1 keyword were identified and further reviewed by a study investigator. Potential events identified by this first observer were further reviewed by a second physician investigator. All available non-MSKCC records were manually reviewed because they were not subject to the text search. Because the risk of bleeding on anticoagulation decreases with time and not accounting for this detail could result in bias, the analysis was performed accounting for the distinct acute and chronic phases of anticoagulation. The acute phase consisted of the first 90 days from initiation of any anticoagulant, whereas the chronic phase was defined as occurring after the first 90 days of anticoagulation. Some patients had initially been treated with another therapeutic anticoagulant (VKA, low-molecular-weight heparin, or unfractionated heparin), before transitioning to rivaroxaban. Only events that occurred while the patients were on rivaroxaban are included in the analysis. We conducted a time-to-event analysis. The following primary end points were defined a priori: stroke, systemic embolism, major bleeding, death, and clinically relevant nonmajor bleeding (CRNMB) leading to discontinuation of the drug for at least 7 days. Major bleeding was as defined by the International Society on Thrombosis and Haemostasis.11Schulman S. Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and HaemostasisDefinition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.J Thromb Haemost. 2005; 3: 692-694Crossref PubMed Scopus (3121) Google Scholar For patients transitioning to hospice care, the date of transfer to hospice was considered the date of death due to the lack of clinical documentation after such a transfer. We used a different definition of CRNMB than in ROCKET-AF. We only counted a CRNMB episode if it led to discontinuation of rivaroxaban for at least 7 days, whereas ROCKET-AF included as CRNMB instances of a patient contacting the study physician. March 31, 2016, was the last day of observation for this analysis. All patients who had not reached one of the aforementioned end points were censored on that date. Patients were censored if they discontinued rivaroxaban for any reason other than reaching a predefined end point or transferred their care to another institution without further follow-up at MSKCC. Patients were also censored if they no longer had active cancer and were no longer receiving cancer directed therapy or if they were more than 3 months after their latest cancer surgery. The cohort was considered left truncated and right censored, as several subjects had been exposed to anticoagulation before starting treatment with rivaroxaban. Survival analysis was performed by means of a counting process, whereas individual patients were observed only from the day they started rivaroxaban onward, having entered the cohort on the day they started anticoagulation with any agent. We performed competing risks analysis for stroke, major bleeding, death, and CRNMB leading to discontinuation of rivaroxaban for at least 7 days. The cumulative incidence was computed for each individual end point, treating the other 3 end points as competing risks. In addition, standard univariate analysis was performed, and pertinent covariates were entered in a Cox proportional hazards survival model. A total of 163 patients with active cancer and AF treated with rivaroxaban were identified between January 1, 2014, and February 14, 2016. Baseline information is summarized in Table 1. The mean CHA2DS2-VASc was 3.2, and the mean CHADS2 score was 1.7.12Lip G.Y. Nieuwlaat R. Pisters R. Lane D.A. Crijns H.J. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.Chest. 2010; 137: 263-272Abstract Full Text Full Text PDF PubMed Scopus (4806) Google Scholar Six patients had a CHA2DS2-VASc score of 0. Three of these patients were on anticoagulation primarily for pulmonary embolism or a deep venous were on anticoagulation for and 1 had been on anticoagulation with a before transitioning to of in years of was not to and was to clearance was estimated using the no evidence of Cancer was not to and The was clearance was estimated using the M.H. of creatinine clearance from PubMed Scopus Google Scholar in a new no evidence of The mean score was F. S. P. J.A. M. G.Y. The score for major bleeding than CHADS2 or CHA2DS2-VASc in patients with atrial Am Coll Cardiol. 2013; PubMed Scopus Google Scholar Because the is not pertinent to the use of the from the score was not the points for this cohort for the score were of patients were in the chronic phase of anticoagulation. patients were within the 90 days of anticoagulation In the date was not available was to within the last 90 days. In those the observation date was by 90 days, and they were included in the chronic cohort after 90 days. patients reached a clinical end point the observation points were stroke major bleeding CRNMB leading to discontinuation and death All the subjects with stroke or major bleeding had and for these systemic events were identified. The mean observation was days 1 to patients were to their day of anticoagulation without reaching an end for competing risks and a 1-year the estimated cumulative incidence for major bleeding was 1.2% (95% CI 0% to CRNMB leading to discontinuation of (95% CI 4.2% to stroke, 1.4% (95% CI 0% to and death, 22.6% (95% CI 12.2% to Table and were no of systemic embolism or One patient died of a with an acute ischemic cerebrovascular incidence of competing risks for patients in the and phases of incidence for the chronic phase are to reaching day 90 of anticoagulation without an The chronic phase was defined as days and the Stroke (95% bleeding (95% (95% (95% clinically relevant nonmajor bleeding leading to discontinuation of rivaroxaban for at least 7 incidence for the chronic phase are to reaching day 90 of anticoagulation without an The chronic phase was defined as days and the days. in a new CRNMB clinically relevant nonmajor bleeding leading to discontinuation of rivaroxaban for at least 7 days. A total of patients were censored before reaching days. for included of clinical transfer of care to another institution to follow-up and rivaroxaban discontinuation for patients to including 3 due to patients for medical The medical leading to discontinuation of rivaroxaban included the of or thrombocytopenia, potential drug between rivaroxaban and a in or after cancer for other medical and no further of anticoagulation. One patient discontinued rivaroxaban and to a different anticoagulant after of an deep venous patients reached the end of observation date 31, before days of anticoagulation. The mean observation time for these patients was days to A total of were performed the observation In rivaroxaban was for at least 3 patients and rivaroxaban had not been Rivaroxaban was not to in one for major or ischemic stroke occurred the or within after the patients were not on rivaroxaban after their due to medical of were The mean of was days, from 1 to days. In of these the dose of rivaroxaban was not of the had only a that In the drug was One episode of was associated with a CRNMB leading to discontinuation of rivaroxaban. clearance was observed in patients of M.H. of creatinine clearance from PubMed Scopus Google Scholar Rivaroxaban was and in 3 discontinued in 1 and not in major bleeding or stroke occurred these of events not included in the primary analysis. CRNMB did not to a discontinuation of rivaroxaban for 7 days or longer and venous thromboembolic events analysis did not any between and a between cancer and death was observed as A Cox including and cancer this to the of major bleeding as as stroke, no further analysis was events not included in the primary analysis. CRNMB did not to a discontinuation of rivaroxaban for 7 days or longer and venous thromboembolic events Cancer is associated with a as as risk of risks are not by stratification or D. J. G. into atrial fibrillation in Am Coll Cardiol. 2014; PubMed Scopus (223) Google Scholar cancer cohort had CHA2DS2-VASc to the ROCKET-AF In the ROCKET-AF study of the patients had a CHA2DS2-VASc score or to compared to for the MSKCC is no established for anticoagulation management of AF, specific to patients with active cancer. a reasonable anticoagulant in cancer to or drug than and and than have a than for more to of or for G.A. A new of oral direct Thromb PubMed Scopus Google Scholar from this Quality Assessment data on the safety and efficacy of rivaroxaban in cancer patients with AF. The safety and efficacy in this study were to those in the general population in the ROCKET-AF M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar was to and than was observed in the study a population treated with for venous thromboembolic C. M. J.A. S. Kovacs M.J. M. of versus Oral for the Prevention of in Patients with Cancer versus a for the prevention of venous thromboembolism in patients with Engl J Med. PubMed Scopus Google Scholar The cumulative incidence of stroke adjusting for competing risks was 1.4% at 1 year in this cancer to the year for stroke and systemic embolism in the rivaroxaban in the safety population of M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar The months of major bleeding in cohort was with the in the rivaroxaban in M.R. Mahaffey K.W. Garg J. Pan G. Singer D.E. Hacke W. Breithardt G. Halperin J.L. Hankey G.J. Piccini J.P. Becker R.C. Nessel C.C. Paolini J.F. Berkowitz S.D. Fox K.A. Califf R.M. ROCKET AF InvestigatorsRivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7155) Google Scholar The major bleeding was patient years in the cancer of the for of Atrial Fibrillation C. P. J. Piccini J. G. Ansell J. Gersh B. A. Hylek E. I. Mahaffey E. P. Management and of patients with atrial fibrillation and the Am Coll Cardiol. 2016; Google Scholar The cancer of the pooled patients with a and cohort compared to as is a and ROCKET-AF was a prospective clinical of could for a observed risk of major bleeding, including not accounting for anticoagulation and the of a more of patients by treating with these in we not evidence of safety or efficacy with use of rivaroxaban for treatment of AF in patients with active cancer. are other to cohort analysis. Rivaroxaban is in the and institutional guidelines recommend use of rivaroxaban in patients with active or due to an risk of bleeding in those could to and to a patient population cohort also not all patients with active cancer and AF at as anticoagulation care at the of their or in could the of However, the of patients or all of their care within the institution and records documentation from medical this potential of The have no of to with Appendix 1 with Appendix