Burton, Paul

Introduction: Higher body mass index (BMI) is an independent risk factor for incident atrial fibrillation (AF). However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear. Methods: The study cohort included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry from June 2010 through August 2011. Participants with BMI > 18.5 kg/m2 were stratified into normal (18.5 - 25 kg/m2), overweight (25 - 30 kg/m2), Class I obese (30 - 35 kg/m2), Class II obese (35 - 40 kg/m2), and Class III obese (>40 kg/m2) categories. Unadjusted and adjusted Cox frailty models were constructed to assess the categorical and continuous association of BMI with AF progression, mortality, and incidence of thromboembolic events. Results: We evaluated 9,606 patients with AF (mean age: 74 + 11 years; 42% women) from 174 US ORBIT participating practices. Patients in the higher BMI categories were younger and had a higher prevalence of comorbidities such as diabetes, hypertension, and obstructive sleep apnea. AF symptom burden was greatest among patients in extreme BMI categories. Proportional use of anticoagulation, antiarrhythmic drugs, and invasive rhythm control strategies was significantly greater among patients in higher BMI categories. Rates for mortality and stroke/non-CNS embolism decreased in a near linear fashion across successively higher BMI categories (P<0.001; Table). After multivariable adjustment, higher BMI categories were associated with lower risk for mortality (p = 0.0002), with the lowest risk observed among overweight patients [Hazard Ratio (HR) (95% CI): 0.65 (0.54 - 0.79) ref. group: normal weight]. For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 6% lower [HR (95% CI): 0.94 (0.89 - 0.98)]. In contrast, the association between BMI and risk for stroke/non-CNS embolism was significant on unadjusted analysis (P <0.001) but attenuated after adjustment for risk factors (P = 0.78; Table). No significant association was observed between BMI and AF progression rates in either unadjusted (P = 0.35) or adjusted analyses (P = 0.17). Conclusion: Among patients with AF, higher BMI was associated with a greater use of anticoagulation, rhythm control strategies, and lower mortality risk.

Introduction: Warfarin and non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran are effective for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). However, few analyses have compared persistence rates of warfarin vs. dabigatran-treated patients. Methods: The ORBIT-AF registry enrolled patients with AF from 173 clinical practices across the US. One-year persistence of warfarin vs. dabigatran was defined as treatment at baseline visit and at 1-year follow-up. Multivariable logistic regression analysis was used to identify characteristics associated with warfarin or NOAC persistent use. Results: At baseline, 6.4% (N=459/7,150) were treated with dabigatran and 93.6% (N=6,691/7,150) with warfarin. Patients treated with warfarin at baseline were older (74 vs. 71, p<.0001), had more NYHA class III/IV heart failure (7 vs. 5, p=.0007), lower creatinine clearance (77 vs. 88, p<.0001), higher CHA2DS2-VASc risk scores, and more prior CVA/TIA events (16 vs. 11, p=.003). Patients treated with dabigatran had more severe symptoms (EHRA class III: 20 vs. 14, p<.0001), higher rates of treatment with a rhythm control strategy (42.7 vs. 28.2, p<.0001), more attempts at cardioversion (38.3 vs. 32.1, p<.006), and catheter ablation of AF (9.8 vs. 5.2, p<.0001). At 12 months, adjusted persistence rates for warfarin were higher than dabigatran [82% (80-84) vs. 67% (61-73) p<.0001]. Factors independently associated with one year persistence were: African American race (OR 1.53, 95% C.I. 1.07-2.19, p=0.02), Hispanic race (OR 1.66, 95% C.I. 1.06-2.60), paroxysmal AF (vs. new onset) (OR 1.68, 95% C.I. 1.21-2.33, p=.002), LVH (OR 1.40, 95% C.I. 1.08-1.81, p=.01), persistent AF (vs. new onset) (OR 1.91, 95% C.I. 1.35-2.69, p=.0002), and CHA2DS2-VASc risk scores ≥ 2 (OR 1.94, 95% C.I. 1.18-3.19, p=.009). Conclusion: Persistence rates for warfarin were higher at one year than those on dabigatran. In addition, factors associated with persistence of warfarin include: African American and Hispanic race, type of AF including permanent and persistent, LVH, and CHA2DS2-VASc risk scores ≥ 2.

Abstract Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.