Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial

Transcription

1 Events after discontinuation of randomized treatment at the end of the ARISTOTLE trial Christopher Granger, John Alexander, Michael Hanna, Jerry Wang, Puneet Mohan, Jack Lawrence, Elaine Hylek, Jack Ansell, Lars Wallentin for the ARISTOTLE investigators. Sponsored by Bristol-Myers Squibb and Pfizer

2 Disclosures for Christopher Granger Research contracts: AstraZeneca, Novartis, GSK, Merck, Sanofi- Aventis, BMS, Pfizer, The Medicines Company, Astellas, Medtronic, and Boehringer Ingelheim Consulting/Honoraria: AstraZeneca, GSK, BMS, Pfizer, Lilly, Novartis, Roche, Boehringer Ingelheim, The Medicines Company, and Sanofi- Aventis For full listing see

3 Background During the ARISTOTLE trial apixaban reduced stroke or systemic embolism, mortality, and major bleeding compared with warfarin in patients with atrial fibrillation. Events occurring after discontinuing study drug at the end of the trial could be influenced by stopping the blinded treatment (ie, withdrawal of anticoagulation) and/or initiation of subsequent anticoagulation (with warfarin/vka).

4 Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Age 75 years Prior stroke, TIA or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Exclusion Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism

5 Main Trial Results Stroke or systemic embolism ISTH major bleeding 21% RRR 31% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, ); P=0.011 Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, ); P<0.001 Median TTR 66%

6 Discontinuation of blinded study drug at trial completion Common efficacy cut-off date of January 30, 2011 At or after that date, blinded study drug was stopped and openlabel vitamin K antagonist (VKA) was recommended. For patients completing the trial on blinded study drug a 2 day bridging period with apixaban or apixaban-placebo was recommended (while beginning open-label VKA). Patients were followed for an additional 30 days.

7 Objectives To assess and understand the occurrence of clinical events according to treatment assignment in the early period after blinded study drug discontinuation.

8 Methods We assessed the occurrence of clinical events at the time of study drug discontinuation at trial completion Stroke or systemic embolism Major (ISTH) bleeding We also evaluated Events occurring after premature permanent study drug discontinuation before the end of the trial (another assessment of impact of discontinuation), and Events occurring during initiation of treatment in the warfarinnaïve population (another assessment of pattern of events during initiation of warfarin).

9 Statistical Analysis Efficacy analyses included all randomized patients (18201 subjects). The analyses of bleeding events included all patients who received at least one dose of study drug (18140 subjects).

10 Results 6791 apixaban and 6569 warfarin patients completed study drug at end of trial. For patients who completed double-blind treatment, 85% converted to open-label VKA. Warfarin VKA Apixaban VKA

11 Stroke or Systemic Embolism Patients Who Completed Treatment Apixaban Warfarin Days After Last Dose n/n % / yr n/n % / yr / / / / / / / / / /

12 Major Bleeding Patients Who Completed Treatment Apixaban Warfarin Days After Last Dose n/n % / yr n/n % / yr / / / / / / / / / /

13 Stroke or Systemic Embolism At Start of Trial At End of Trial Day 1 30 following randomization (warfarin group) Day 1 30 after completing double-blind study drug (pts who completed treatment ) (% / yr) (% / yr) warfarin experienced warfarin 1.42 warfarin open-label warfarin treatment 0.99 warfarin naive warfarin 5.41 apixaban open-label warfarin treatment 4.02

14 Percent with Stroke or Systemic Embolism Stroke or Systemic Embolism to Day 30 Warfarin Naïve at Baseline 0,5 0,4 Warfarin Naïve >> Apixaban (3/3912) Warfarin Naïve >> Warfarin (17/3888) 0,3 0,2 0,1 0, Time (Days) # of Patients Naïve Apix Naïve War

15 Stroke or Systemic Embolism Patients Who Completed Treatment and Received VKA Apixaban Warfarin Days After Last Dose n/n % / yr n/n % / yr / / / / / / / / / /

16 Stroke or Systemic Embolism Patients Who Permanently Discontinued Treatment Early Apixaban Warfarin Days After Last Dose n/n % / yr n/n % / yr / / / / / / / / / /

17 Conclusion There was an excess in thromboembolic and bleeding events in the apixaban arm upon discontinuation at end of the trial. Excess events in apixaban arm were likely due to an increased risk associated with the new initiation of a VKA: Excess events mainly more than one week after stopping Occurred both in stroke and in major bleeding Similar pattern to excess events in warfarin-naive patients with warfarin initiation It is uncertain whether two or more days of apixaban bridging improves outcome during VKA transition

18 Extras

19 Delay to Therapeutic INR in Patients Completing the Study on Rivaroxaban Warfarin 81.3 Rivaroxaban 48.8 Safety/Days 3 to 30 after the last dose Patel MR, AHA ESS, Apr 25, 2012

20 Post-Therapy Primary Efficacy Endpoint Events Safety/Days 3 to 30 after the Last Dose n/n Rivaroxaban Warfarin Rivaroxaban vs. Warfarin Event Rate Event Rate (per 100 pt-yrs) n/n (per 100 pt-yrs) HR (95% CI) p-value All Participants 64/ / (1.02,2.23) Completed Study Medication 22/ / (1.51,9.16) Early Study Medication Discontinuation 42/ / (0.71,1.72) Temporary interruptions 3 9/ / days during study 1.27 (0.49,3.31) From last dose plus 3 days to 3 days after resumption n=number of interruptions ROCKET AF trial Patel MR, AHA ESS, Apr 25, 2012 CC-20