Relationship between Center Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results from the ROCKET AF Trial

Transcription

1 Relationship between Center Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results from the ROCKET AF Trial Jonathan P. Piccini, Frank Harrell, Yulia Lokhnygina, Manesh R. Patel, James Pan, Len Oppenheimer, Daniel Singer, Kenneth W. Mahaffey, Keith A. A. Fox, Robert M. Califf on behalf of the ROCKET AF Investigators Presented by Günter Breithardt, Münster, Germany, on behalf of the ROCKET AF Investigators

2 Financial Disclosures Dr. Breithardt has received consulting fees from Bayer HealthCare, Sanofi Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, Boston Scientific, and Otsuka Pharmaceutical; grant support from Sanofi Aventis, St. Jude, and Meda Pharma; and lecture fees from Sanofi Aventis, Boehringer Ingelheim, Bayer HealthCare, and Boston Scientific. ROCKET AF was sponsored by Janssen Research & Development, J&J, Raritan, NJ, USA and Bayer HealthCare AG, Leverkusen, Germany.

3 Study Design Atrial fibrillation Risk factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA, or systemic embolism Rivaroxaban 20 mg daily 15 mg for CrCl ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target: 2.5 ( 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%

4 TTR is a quality measure on how well INR as a biomarker is controlled Warfarin AF Thrombus Time in Therapeutic Range Prevention of stroke and Embolus In ROCKET AF, rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism in patients with moderate to high risk nonvalvular AF Time in therapeutic range is an important quality measure for warfarin use. We analyzed center time in therapeutic range (cttr) and treatment effect in ROCKET AF. Fleming TR. Annals Int Med 1997; 126 (8):667 Patel MR. N Engl J Med. 2011; 365:

5 Objective & Methods In order to understand the impact of the quality of warfarin therapy, we analyzed center time in therapeutic range (cttr) and treatment effect in ROCKET AF. TTR was calculated using the Rosendaal method, without exclusion of INR values performed during warfarin initiation Warfarin interruptions >7 days were excluded. The primary efficacy endpoint (stroke or non-cns embolism) was examined by quartiles of cttr and by cttr as a continuous function.

6 Time in Therapeutic Range (TTR) Warfarin INR range Median (25 th, 75 th ) < ( ) 1.5 to < ( ) 1.8 to < ( ) 2.0 to ( ) >3.0 to ( ) >3.2 to ( ) > ( ) Based on Rosendaal method with all INR values included Based on Safety Population

7 Baseline Characteristics by cttr in Warfarin Treated Subjects Center TTR <50.7% % % % Randomized No Prior VKA 59.3% 43.8% 31.1% 16.6% Median Age (years) Male 56.3% 58.6% 61.1% 65.1% Median Weight (kg) CHADS2 Score Mean CHADS2 Score % 89.4% 87.5% 81.6% Age >75 (years) 32.4% 39.9% 47.4% 54.3% Prior Stroke 35.3% 33.7% 36.2% 32.1% Heart Failure 71.4% 69.4% 61.1% 48.8% Diabetes Mellitus 37.0% 39.0% 41.6% 41.7% Hypertension 90.6% 91.8% 91.0% 88.9% Prior Myocardial Infarction 16.7% 15.7% 16.9% 19.6%

8 ROCKET-AF: Treatment Effect not Diminished in Best Quartile of cttr in Pre-Specified Analysis Rivaroxaban Warfarin Center TTR N= 7061 n Event Rate (100 ptyr) N= 7082 n Event Rate (100 ptyr) Hazard Ratio and 95%CI Rivaroxaban Favors Warfarin % % % %

9 Subjects Evaluable for Safety (Excluding Site ), Last Dose Plus 2 Days Hazards for Stroke or Non-CNS Embolism (R vs W) for cttr (FDA Method) >Threshold RANDOMIZATION TO FIRST PRIMARY EFFICACY ENDPOINT Estimated Hazard Ratio of Rivaroxaban vs. Warfarin plus 95% CI ALL REGIONS Mean TTRE (%) for Combined Centers with Warfarin Center TTRE > Threshold > 0 > 5 > 10 > 15 > 20 > 25 > 30 > 35 > 40 > 45 > 50 > 55 > 60 > 65 > 70 > 75 > 80 A verage Center W arfarin TTRE (% ) Threshold Total Number of Subjects/Total Number of Events: Note: Only centers with calculable average Warfarin center TTRE from safety evaluable subjects (excluding site ) were used. Done in safety/on-treatment population. TTR: The % of days with imputed INR in 2-3 between the first and last dose dates but excluding temporary interruptions

10 Estimated Hazard Ratio of Rivaroxaban vs. Warfarin plus 95% CI Mean TTRE (%) for Combined Centers with Warfarin Center TTRE > Threshold Primary Efficacy Endpoint Plus MI and Vascular Death HR for Ctr Avg Warfarin TTRE >Threshold. Safety/On-Treatment 90 ALL REGIONS > 0 > 5 > 10 > 15 > 20 > 25 > 30 > 35 > 40 > 45 > 50 > 55 > 60 > 65 > 70 > 75 > 80 Average Center Warfarin TTRE (%) Threshold Total Number of Subjects/Total Number of Events: Note: Only centers with calculable average Warfarin center TTRE from safety evaluable subjects (excluding site ) were used. ROCKET AF Trial

11 Subjects Evaluable for Safety (Excluding Site ), Last Dose Plus 2 Days RANDOMIZATION TO FIRST MAJ OR SECONDARY EFFICACY ENDPOINT 2 ICH for Center Average Warfarin TTR > Threshold Safety/On-Treatment Estimated Hazard Ratio of Rivaroxaban vs. Warfarin plus 95% CI ALL REGIONS > 0 > 5 > 10 > 15 > 20 > 25 > 30 > 35 > 40 > 45 > 50 > 55 > 60 > 65 > 70 > 75 > 80 A verage Center W arfarin TTR (% ) Threshold Total Number of Subjects/Total Number of Events: Note: Only centers with calculable average Warfarin center TTR from safety evaluable subjects (excluding site ) were used. ROCKET AF trial

12 Across Regions with Various Levels of INR Control, Treatment Efficacy is Preserved Primary Efficacy Endpoint NA NI=1.38 WE LA AP EE NI Margin

13 Conclusions The treatment effect with rivaroxaban on the primary endpoint across cttr quartiles, was consistent (p for interaction = 0.74). Estimated hazard ratios for rivaroxaban vs. warfarin favored rivaroxaban over a wide range of cttrs. Across prespecified regions, North America had the highest mean cttr (64%) and a trend to a more pronounced treatment effect (HR 0.58, 95% CI ) but the p-interaction for region by treatment effect was 0.618).

14 Clinical Implications While TTR is an important quality measure for VKA, the treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cttr.

15 Thank you very much for your attention

16 Supplemental Slides

17 Primary Efficacy Endpoint by Center TTR ROCKET AF - RE-LY - ARISTOTLE Treatment Group n/j (rate) Warfarin n/j (rate) RE-LY (Dabigatran 150 mg) 0.20 <57.1% 32/1509 (1.1) 54/1504 (1.92) % 32/1526 (1.04) 62/1514 (2.06) % 31/1484 (1.04) 45/1487 (1.51) >72.6% 38/1514 (1.27) 40/1509 (1.34) p -value (interaction) ROCKET AF % 45/1735 (1.77) 62/1689 (2.53) % 53/1746 (1.94) 63/1807 (2.18) % 54/1734 (1.90) 62/1758 (2.14) % 37/1676 (1.33) 55/1826 (1.80) Rivaroxaban Hazard Ratio (95% CI) Favors Warfarin ARISTOTLE 0.29 < /2266 (1.75) 88/2252 (2.28) /2251(1.30) 68/2278(1.61) /2256 (1.21) 65/2266 (1.55) > /2266 (0.83) 44/2251(1.02) Wallentin et al ESC Rate = number of events per 100 patient-years; n = subjects with events; J = number of subjects in each subgroup