Keith A. A. Fox on behalf of the ROCKET AF Investigators

Transcription

1 Prevention of Stroke and non-cns Embolism with Compared with in Patients with Non-valvular Atrial Fibrillation and Moderate Renal Impairment Keith A. A. Fox on behalf of the ROCKET AF Investigators

2 Disclosures Supported by grants from Johnson & Johnson Pharmaceutical Research & Development L.L.C. and Bayer HealthCare Pharmaceuticals An international executive committee designed the trial and was responsible for oversight of study conduct. The committee retained independent ability to analyse and present the data and to take responsibility for the accuracy and completeness of data analyses

3 Background Direct, specific, competitive Factor Xa inhibitor Half-life: 5 9 hours in young, healthy individuals hours in the elderly Clearance: 1/3 direct renal excretion 2/3 metabolism, mainly via CYP 450 enzymes, of which half is excreted renally half is excreted via the biliary-faecal route Oral, once-daily dosing without need for coagulation monitoring Studied in >25,000 patients in post-operative THR or TKR, DVT, PE, medically ill, and ACS patients X Fibrinogen TF/VIIa VIIIa Xa II Va IIa IXa IX Fibrin Adapted from Weitz et al, 2005; 2008

4 Study Design Atrial Fibrillation Risk Factors Stroke, TIA or Systemic embolus OR CHF Hypertension Age 75 Diabetes At least 2 or 3 required* 20 mg daily 15 mg for Cr Cl ml/min Randomized Double Blind / Double Dummy (n ~ 14,000) INR target ( inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

5 Statistical Methods Sample Size event rate ~2.3 Type 1 error 0.05 (2-sided) 405 events; >95% power ~14,000 patients Superiority Non-inferiority Inferiority Better Better Primary Efficacy Evaluation: Stroke or non-cns Embolism (non-inferiority: per-protocol, on treatment) Primary Safety Evaluation: Major or non-major Clinically Relevant Bleeding

6 Enrollment 45 countries, 1178 sites, 14,264 patients Canada: 750 United States: 1,932 Mexico: 168 Panama: 0 Venezuela: 20 Colombia: 268 Peru: 84 Brazil: 483 Chile: 287 Argentina: 569 Poland: 528 Finland: 16 Lithuania: 245 Sweden: 28 Hungary: 237 Norway: 49 Romania: 783 Czech Rep: 598 Bulgaria: 678 Denmark: 123 Russia: 1,292 Ukraine: 1,011 U.K.: 159 Netherlands: 161 Belgium: 96 Korea: 204 France: 71 China: 496 Spain: 250 Taiwan: 159 Germany: 530 India: 269 Hong Kong: 73 Switzerland: 7 Thailand: 87 Philippines: 368 Austria: 32 Malaysia: 51 Italy: 139 Singapore: 44 Greece: 29 Turkey: 101 Israel: 189 Australia: 242 South Africa: 247 New Zealand: 116

7 Study Conduct Randomized, n Lost to Follow-up, n Premature Discontinuation, n (%) Withdrew Consent, n Median (25 th, 75 th ) Exposure (days) Median (25 th, 75 th ) Follow-up (days) (23.7) (396, 805) 706 (522, 884) (22.2) (404, 810) 708 (518, 886)

8 Cumulative event rate (%) Primary Efficacy Endpoint Stroke and non-cns Embolism 6 5 Event Rate HR (95% CI): 0.79 (0.66, 0.96) 1 P-value Non-Inferiority: < No. at risk: Event rates are % per year Based on Protocol Compliant on Treatment Population Days since Randomization 840

9 Baseline demographics Characteristic CrCl ml/min 15 mg od (N=1474) (N=1476) 20 mg od (N=5637) CrCl 50 ml/min (N=5640) Age, median (IQR), yrs 79 (75 82) 79 (75 83) 71 (63 76) 71 (63 76) Female (%) BMI, median (IQR), kg/m ( ) 25.2 ( ) 29.2 ( ) 28.9 ( ) SBP, median (IQR), mm Hg 130 ( ) 130 ( ) 130 ( ) 130 ( ) Paroxysmal AF (%) Prior ASA use (%) Prior VKA use (%) ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonist Safety population (minus 9 pts in warfarin arm with no CrCl data)

10 Baseline demographics (continued) CrCl ml/min CrCl 50 ml/min Characteristic 15 mg od (N=1474) (N=1476) 20 mg od (N=5637) (N=5640) CHADS 2 score (mean ± SD) Prior stroke/tia or systemic embolism (%) 3.68 ± ± ± ± Congestive heart failure (%) Hypertension (%) Diabetes mellitus (%) Prior myocardial infarction (%) SD, standard deviation; TIA, transient ischaemic attack Safety population (minus 9 pts in warfarin arm with no CrCl data)

11 Cumulative event rate (%) Stroke or non-cns embolism among those with CrCl ml/min Event Rate 15 mg (INR 2-3) HR (95% CI): 0.84 (0.57, 1.23) Days since Randomization No. at risk: Event rates are % per year Based on Protocol Compliant on Treatment Population

12 Efficacy endpoints on treatment Clinical endpoint (% per year) (N=7111) (N=7116) CrCl 50 ml/min CrCl ml/min HR (95% CI) vs warfarin P (interaction) Primary efficacy endpoint* ( ) 0.84 ( ) 0.76 PE + vascular death ( ) 0.96 ( ) 0.38 PE + MI, vascular death ( ) 0.85 ( ) 0.98 Stroke Ischaemic ( ) 1.11 ( ) 0.41 Haemorrhagic ( ) 0.56 ( ) 0.88 Undetermined ( ) 0.51 ( ) Based on per-protocol population on treatment *Stroke and systemic embolism 20 mg od. 15 mg od

13 Safety outcomes Clinical endpoint (% per year) (N=7111) (N=7116) CrCl 50 ml/min CrCl ml/min HR (95% CI) vs warfarin P (interaction) Principal safety outcome* ( ) 0.98 ( ) 0.45 Major bleeding ( ) 0.95 ( ) 0.48 Hct or Hb drop ( ) 1.14 ( ) 0.65 Transfusion ( ) 1.17 ( ) 0.71 Critical organ ( ) 0.55 ( ) 0.39 Fatal bleeding ( ) 0.39 ( ) 0.53 Intracranial haemorrhage ( ) 0.81 ( ) Based on safety population on treatment *Composite of major plus non-major clinically relevant bleeding. 20 mg od. 15 mg od

14 Bleeding sites Major bleeding (% per year) CrCl ml/min 15 mg (N = 1474) (N=1476) CrCl 50 ml/min 20 mg (N=5637) (N=5640) GI (upper, lower, and rectal) Intracranial haemorrhage Macroscopic haematuria Bleeding associated with non-cardiac surgery Intra-articular Epistaxis p=0.02 (riva vs. warf in CrCl ml/min); p= (riva vs. warf in CrCl 50 ml/min) p=0.02 (riva vs. warf in CrCl 50 ml/min)

15 Adverse Event (%) Adverse Events* according to Renal Function & Randomised Treatment CrCl ml/min Riva 15 mg (N=1474) (N=1476) * Treatment-emergent adverse events with frequency 5% based on rivaroxaban group, plus haematuria Based on safety population on treatment CrCl 50 ml/min Riva 20 mg (N=5637) (N=5640) Total patients Epistaxis Peripheral oedema Dizziness Cardiac failure Bronchitis Diarrhoea Dyspnea Cough Nasopharyngitis Arthralgia Haematuria

16 Conclusions Those with renal dysfunction are at higher risk for stroke and higher risk of bleeding events compared with those without renal dysfunction The outcomes among patients with moderate renal dysfunction were similar for rivaroxaban and warfarin In summary, the reduced dose of rivaroxaban in this patient subgroup yielded efficacy and safety results consistent with the overall trial, with similar rates of bleeding and adverse events and fewer fatal bleeds, compared with warfarin

17 Study Organization Sponsors J & J and Bayer Christopher Nessel, Kimberly Schwabe, Scott Berkowitz, John Paolini Steering Committee Diego Ardissino, Alvaro Avezum, Phil Aylward, Barbara Biedermann, Christoph Bode, Antonio Carolei, Ramon Corbalan, Laszlo Csiba, Anthony Dalby, Rafael Diaz, Hans Diener, Geoffrey Donnan, Shaun Goodman, Bas Hamer, Hein Heidbuchel, Dai-Yi Hu, Kurt Huber, Gorm Jensen, Matyas Keltai, Basil Lewis, Jose Lopez-Sandon, Jean Louis Mas, Ayrton Massaro, Gordon MacInnes, Bo Norrving, Martin Penicka, Dorairaj Prabhakaran, Risto Roine, Tan Ru San, Per Anton Sirnes, Veronika Skvortsova, Gabriel Steg, Harvey White, Lawrence Wong Executive Steering Committee Co-Chairs Keith A. A. Fox Robert M. Califf Duke Clinical Research Institute Jonathan Piccini, Karen Hannan, Jyotsna Garg, Lisa Eskenazi, Angela Kaiser, Patricia Stone Canadian Heart Research Center Shaun Goodman Maggie Godin-Edgecomb IDMC Joe Alpert, Chair Allen Skene, Co-chair Gudrun Boysen John Eikelboom Peter Rothwell CEC Manesh Patel Joni O'Briant Lauren Price

18 Available now online from European Heart Journal