Abstracts From the Emerging Science Series, April 25, 2012
Outcomes of Discontinuing Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation: Analysis From the ROCKET AF Trial
Manesh Patel, Anne Hellkamp, Yuliya Lokhnygina, Duke Clinical Res Inst, Duke Univ Medical Ctr, Durham, NC; Guohua Pan, Johnson & Johnson Pharmaceutical Res & Development, Raritan, NJ; Daniel Singer, Massachusetts General Hosp and Harvard Medical Sch, Boston, MA; Werner Hacke, Ruprecht-Karls-Univ, Heidelberg, Germany; Gunter Breithardt, Hosp of the Univ of Munster, Munster, Germany; Jonathan L Halperin, Mount Sinai Medical Ctr, New York, NY; Graeme J Hankey, Royal Perth Hosp, Perth, Australia; Jonathan P Piccini, Richard C Becker, Duke Clinical Res Inst, Duke Univ Medical Ctr, Durham, NC; Christopher C Nessel, Johnson & Johnson Pharmaceutical Res & Development, Raritan, NJ; Scott D Berkowitz, Bayer HealthCare Pharmaceuticals, Montville, NJ; Keith A Fox, Univ of Edinburgh and Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; Robert M Califf, Duke Translational Med Inst, Duke Univ Medical Ctr, Durham, NC; Kenneth W Mahaffey, Duke Clinical Res Inst, Duke Univ Medical Ctr, Durham, NC
Background: Rivaroxaban is non-inferior to warfarin for prevention of stroke and non-CNS systemic embolism in moderate to high-risk AF patients. Concerns exist regarding an increased risk of stroke and thrombotic events early after discontinuation of rivaroxaban. Methods: In ROCKET AF (N=14,264), we evaluated patients who had a temporary discontinuation, early permanent study drug discontinuation, and all patients who completed the trial and transitioned to open-label therapy for stroke and non-CNS embolism and other thrombotic events including MI and death up to 30 days post-discontinuation. Results: Stroke and non-CNS embolism occurred at similar rates after temporary discontinuations (9 with rivaroxaban, 8 with warfarin [6.20 vs. 5.05 per 100 pt-years; HR 1.28; 95% CI 0.49-3.31; P=0.62]), and after early permanent discontinuation (42 with rivaroxaban, 36 with warfarin [25.60 vs. 23.28 per 100 pt-years; HR 1.10; 95% CI 0.71-1.72; P=0.66]). Significantly more strokes occurred in rivaroxaban (N=22) compared to warfarin-treated patients (N=6) after the blinded end of study transition to open-label warfarin (6.42 vs. 1.73 per 100 pt-years; HR 3.72; 95% CI, 1.51-9.16; P<0.0044) which lead to an increase for all patients discontinuing or transitioning to open-label warfarin (HR 1.50; 95% CI 1.05-2.15; P=0.003). All thrombotic events (stroke, embolism, MI, and death) were similar after all discontinuations and end of study transition (HR 1.08; 95% CI 0.89-1.32; P=0.44) (Table). Conclusion: In moderate to high-risk AF patients temporarily or permanently discontinuing anticoagulation, the risk or stroke or systemic embolism is high and similar when treated with rivaroxaban or warfarin. After end of study transition to warfarin, an increased risk of stroke and systemic embolism was observed for patients being treated with rivaroxaban compared with warfarin, underscoring the importance of anticoagulation coverage during the transition to a therapeutic INR.
M. Patel: Consultant/Advisory Board; Modest; Ortho McNeil Janssen, Bayer HealthCare, Genzyme. A. Hellkamp: None. Y. Lokhnygina: None. G. Pan: Employment; Significant; Johnson & Johnson Pharmaceutical Research & Development. D. Singer: Research Grant; Significant; Daiichi Sankyo. Speakers Bureau; Modest; Bristol-Myers Squibb, Pfizer. Consultant/Advisory Board; Modest; Johnson & Johnson, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck, Sanofi Aventis, Medtronic, St. Jude Medical. W. Hacke: Research Grant; Significant; Boehringer Ingelheim. Consultant/Advisory Board; Modest; Sygnis Pharma Germany, Boehringer Ingelheim, Photothera USA, Codman USA, Bayer. G. Breithardt: Research Grant; Significant; Sanofi Aventis, St. Jude Medical, Meda Pharma. Speakers Bureau; Modest; Sanofi Aventis, Boehringer Ingelheim, Bayer, Boston Scientific. Consultant/Advisory Board; Modest; Bayer, Sanofi Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, Boston Scientific, Otsuka Pharmaceutical. J.L. Halperin: Consultant/Advisory Board; Modest; Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Pfizer, Sanofi Aventis. G.J. Hankey: Speakers Bureau; Modest; Sanofi Aventis, Pfizer. Consultant/Advisory Board; Modest; Sanofi Aventis, Schering Plough, Boehringer Ingelheim. J.P. Piccini: Research Grant; Significant; Johnson & Johnson, Boston Scientific. Consultant/Advisory Board; Modest; Medtronic, Forest Laboratories, Sanofi Aventis, Johnson & Johnson. R.C. Becker: Research Grant; Significant; Johnson & Johnson, Bayer, Regado Biosciences, Bristol-Myers Squibb. Speakers Bureau; Modest; Merck, AstraZeneca. Consultant/Advisory Board; Modest; Boehringer Ingelheim. C.C. Nessel: Employment; Significant; Johnson & Johnson Pharmaceutical Research & Development. S.D. Berkowitz: Employment; Significant; Bayer HealthCare. K.A.A. Fox: Research Grant; Significant; Eli Lilly. Speakers Bureau; Modest; Eli Lilly, Sanofi Aventis, AstraZeneca. R.M. Califf: Research Grant; Significant; Novartis, Merck, Amilyn/Lilly. Ownership Interest; Significant; Nitrox. Consultant/Advisory Board; Modest; Kowa, Nile, Orexigen, Sanofi Aventis, Novartis, Xoma. K.W. Mahaffey: Research Grant; Significant; Abbott Vascular, Amgen, Amylin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CardioKinetix, Cierra, Cordis, Edwards LifeSciences, Eli Lilly, Genentech, GlaxoSmithKline, Guidant,, Innocoll Pharmaceuticals, Johnson & Johnson, KCI Medical, Luitpold Pharmaceutical, Medtronic, Merck, Momenta Pharmaceuticals, Novartis, Portola Pharmaceutical, Pozen, Regado Biotechnologies, Sanofi Aventis, Schering Plough, The Medicines Company. Consultant/Advisory Board; Modest; Adolor, Alexion, Amgen, Argolyn Bioscience, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Elsevier, Forest Labs, Genentech, GlaxoSmithKline, Guidant, Ikarja, Johnson & Johnson, Merck, Novartis, Pfizer, Proctor & Gamble, Sanofi Aventis, Schering Plough, Scios, WebMD.
Cerebrovascular Autoregulation Impairment Is Associated With Elevations in Plasma Glial Fibrillary Acidic Protein During Congenital Heart Surgery
Ronald B Easley, Baylor Coll of Med, Houston, TX; Jacky Jennings, Johns Hopkins Hosp, Baltimore, MD; Kathleen Kibler, Kenneth M. Brady, Brittany Serratos, Dean B. Andropoulos, Baylor Coll of Med, Houston, TX; Marissa Brunetti, Eugenie Heitmiller, Jennifer K. Lee, Michael Smith, Pratima Dulloor, Johns Hopkins Hosp, Baltimore, MD; Bradley S. Marino, James Spaeth, Cincinnati Children's Hosp Medical Ctr, Cincinnati, OH; Allen D. Everett, Johns Hopkins Hosp, Baltimore, MD
Background: Neurologic injury occurs in 30-70% of pediatric patients undergoing repair of congenital heart disease (CHD) and we have no means to acutely determine brain ischemia or injury. We developed a method of vascular reactivity monitoring using near-infrared spectroscopy called the hemoglobin volume index (HVx), which can detect the lower limit of pressure autoregulation (LLA). Time and absolute arterial blood pressure (ABP) below the LLA places the brain at risk for ischemia. To couple real-time physiologic brain monitoring with evidence of acute brain injury, we have developed a high sensitivity assay for the brain specific protein, glial fibrillary acidic protein (GFAP) as an indicator of end organ injury. We hypothesize that elevated HVx and time spent below the LLA during cardiopulmonary bypass (CPB) will identify ischemic periods detectable by serum GFAP elevation. Methods: A multi-center observational pilot study of children undergoing CPB was used to determine if HVx and GFAP monitoring could be performed during CPB. Intra-operative HVx was monitored and waste blood samples collected for GFAP measurement. HVx and GFAP data were analyzed by CPB phases. LLA was defined from HVx plotted across ABP for each subject. Results: LLA was identified in 85% (52/61) of subjects. Both the HVx and GFAP demonstrated significant perturbations during CPB, with peaks during re-warming (p<0.002, Figure). There was a trend towards increased GFAP with increased time below LLA (p=0.06). No clinical strokes were found. Conclusions: Dynamic HVx monitoring detected periods of impaired reactivity that were temporally related to elevations in GFAP. Further studies coupling HVx monitoring and neurobiomarkers with neurologic outcomes would set the stage for an interventional trial to optimize ABP management for brain protection during CPB.
R.B. Easley: Research Grant; Modest; American Heart Association. J. Jennings: None. K. Kibler: None. K.M. Brady: Consultant/Advisory Board; Modest; Somanetics, Inc. B. Serratos: None. D.B. Andropoulos: None. M. Brunetti: None. E. Heitmiller: None. J.K. Lee: None. M. Smith: None. P. Dulloor: None. B.S. Marino: None. J. Spaeth: None. A.D. Everett: None.
- © 2012 American Heart Association, Inc.