Optimizing outcomes in Atrial Fibrillation Latest News and Clinical Applications of NOACs: What about Antidotes? McMaster Cardiology Update September 11, 2015
Agenda Real world data on the use of NOACs The emergence of specific reversal agents Ongoing trials
Which ONE of the following is incorrect? In relation to real world data on the use of NOACs: 1. Real world data allow us to reliably compare the efficacy of different NOACs 2. The real world data suggest that lower doses of NOACs are over-prescribed 3. Estimates of bleeding rates observed with NOACs in the real world are generally reassuring
Strengths and limitations of real world data Strengths Provides information on NOAC implementation in the community Provides estimates of post-marketing event rates Hypothesis-generating comparisons Limitations Greater potential for incomplete reporting of exposure/outcome data Does not allow reliable comparison of event rates with those in RCTs Less reliable than RCTs to compare 2 treatments
2014: Independent FDA Medicare Analysis Incidence rate per 100 person-years Event rate (% per year) Medicare 1 >134 000 patients 5 4 3 2 1 0 3.78 Mortality 3.26 3.42 2.65 Major GI bleeding RE-LY 2 4 >18 000 patients 5 4 3 2 1 0 4.13 3.64 1.07 1.56 0.64 1.69 1.57 1.39 Acute MI Warfarin D150 & D75 BID combined 1.13 Ischaemic stroke Warfarin D150 BID 0.96 0.81 1.14 0.86 0.76 Mortality GI bleeding MI Ischaemic stroke ICH 0.33 0.32 1. http://www.fda.gov/drugs/drugsafety/ucm396470.htm. Accessed on 14 May 2014; 2. Connolly SJ, et al. N Engl J Med 2009;361:1139-51; 3. Connolly SJ, et al. N Engl J Med 2010;363:1875-6; 4. Pradaxa Eu SmPC 2014 ICH
XANTUS: Study Design Prospective, single-arm, observational, non-interventional phase IV study Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention N=6,784 Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Primary outcomes: major bleeding (ISTH definition) all-cause mortality, any other adverse events Final visit: 1 year # Camm AJ et al, Vasc Health Risk Manag 2014;10:425 434. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466.
XANTUS: Patient disposition Major events, specifically major bleeding, stroke, SE, TIA and MI, adjudicated centrally by an independent CAC blinded to individual patient data Screened (N=10,934) Mean age 71.5 Mean CHADS 2 score 2.0 Primary analysis population: defined as all patients who had taken at least one dose of rivaroxaban Enrolled (N=6785) Safety population (N=6784) Rivaroxaban 20 mg od (n=5336) Rivaroxaban 15 mg od (n=1410) Another dose (n=35) # Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466.
XANTUS compared with ROCKET AF 4.0 3.5 3.0 ROCKET AF Xarelto 3.6 2.5 2.0 XANTUS Xarelto 1.9 2.1 2.5 2.0 1.7 1.7 1.9 2.0 1.5 1.5 1.0 0.5 0.8 0.7 0.4 0.9 1.0 0.5 0.5 0.0 Stroke/SE All strokes Death Major bleeding ICH GI bleeding 0.0 Stroke/SE All strokes Death Major bleeding ICH GI bleeding Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466.
XANTUS: Outcomes according to dose Incidence rate, %/year* 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 15 mg dose 3.7 20 mg dose 3.1 2.3 1.8 1.6 1.4 Thromboembolic events Major bleeding All-cause death Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466.
NOAC Prescribing Data for Canada and UK Canada prescription data (all indications; IMS data: 01/04/2014 31/03/2015) UK prescription data (all indications; IMS data: 01/06/2014 01/06/2015)
Agenda Real world data on the use of NOACs The emergence of specific reversal agents Ongoing trials
Which ONE of the following is incorrect? In relation to emergence of specific reversal agents for NOACs: 1. Rebound hypercoagulability following NOAC reversal explains the increase in risk of thromboembolic events 2. Specific reversal agents have not been shown to improve clinical outcomes 3. Specific reversal agents are likely to replace PCCs and rviia for NOAC reversal
When should we consider reversal of anticoagulation in a bleeding patient? Life-threatening (e.g., intracranial) Critical organ (e.g., pericardial, retroperitoneal) Ongoing (despite general measures to control bleeding)
Warfarin reversal Enable synthesis Replenish clotting factors Vitamin K Antagonism of Vitamin K VII IX X II Synthesis of Non Functional Coagulation Factors Warfarin
Fresh Frozen Plasma or PCC? Sarode R, et al. Circulation 2013; 128:1234-1243.
Association of timing and extent of INR reversal with hematoma enlargement Karamatsu JB, et al. JAMA 2015; 313: 824-36.
Prompt warfarin reversal may improve outcomes after ICH Hanger et al. Int Med J 2012
Resumption of VKA after ICH and survival Karamatsu JB, et al. JAMA 2015; 313: 824-36.
Reversal of NOACs Activate coagulation to overcome effects of the drug (PCCs, apccs) PCC 25-50 IU/kg FEIBA 25-50 IU/kg rfviia 90 ug/kg Remove drug Haemodialysis or haemofiltration Neutralize drug Specific reversal agents Lauw M, et al. Can J Cardiol 2014; 30: 381-4.
Neutralize the effects of the drug Specific reversal agents Structure Idarucizumab Humanized Fab fragment Andexanet alfa Human rxa variant Aripazine Synthetic small molecule Target Dabigatran FXa inhibitors Universal Binding Phase 2 results Phase 3 trial Non-competit. High affinity Rapid, complete reversal Competitive Rapid, complete Reversal Non-covalent Hydrogen bond Complete reversal Ongoing Ongoing Awaited Lauw M, et al. Can J Cardiol 2014
REVERSE-AD Study design Pollack CV, et al. Thromb Haemost 2015; 114: 198-205.
REVERSE-AD Primary outcome Bleeding patients Pollack CV, et al. N Engl J Med 2015 Jun 22 [Epub ahead of print].
REVERSE-AD Primary outcome Patients needing urgent procedures Pollack CV, et al. N Engl J Med 2015 Jun 22 [Epub ahead of print].
REVERSE-AD Secondary outcome Restoration of normal haemostasis Pollack CV, et al. N Engl J Med 2015 Jun 22 [Epub ahead of print].
Andexanet Alfa Rapid rivaroxaban reversal Anti-fXa Activity End of Bolus 400 End of Infusion Anti-fXa (ng/ml) 300 200 100 Placebo (Cohorts 1-3, n=9) 800 mg bolus + 960 mg infusion (n=6) 0 0.0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 Time after bolus (hr) Crowther, M.A., et al. 2013. Blood (abstract); 122: A3636
Agenda Real world data on the use of NOACs The emergence of specific reversal agents Ongoing trials
Ongoing trials in Cardiology Dabigatran Rivaroxaban Apixaban Stroke Secondary CV prevention PAD (REVASC) RESPECT ESUS DATAS I and II NAVIGATE ESUS COMPASS VOYAGER Post ACS GEMINI Post Stenting Triple therapy Heart Failure RE-DUAL PIONEER AF Factorial trial COMMANDER HF Subclinical AF ARTESIA
Summary Randomized trial data are increasingly being complemented by reassuring real world data Availability of highly effective and safe specific reversal agents seems imminent and may help to promote NOAC uptake Ongoing trials will help to resolve remaining uncertainties