Real World Evidence on the Use of NOACs

Transcription

1 Real World Evidence on the Use of NOACs Prof. Fausto J. Pinto, MD, PhD, FESC, FACC ESC President Head, Cardiology Dpt/University Hospital Sta Maria-HPV University of Lisbon, Portugal RIYHAD, 12 H FEBRUARY 2016

2 Professor Fausto J. Pinto, MD, PhD, FESC, FASE, FACC, FSCAI Disclosures: President , European Society of Cardiology (ESC) Consultancy, advisory boards, research support and modest lecture fees: Abbott, Astra Zeneca, Bayer, Bial, BMS, Benecke, Biotronik, Boehringher Ingelheim, Boston Scientific, Covidien, Daichi Sankyo, GE, Heartware, Irokio, Medtronic, Menarini, Merck Serono, MSD, Novartis, Pfizer, Philips-Volcano, Sanofi, Servier, St Jude Medical, Tabuk

3 Agenda Differences between real-life and clinical trial data Some selected AF real-life data of NOAC Adherence and persistence of NOAC Some selected data from AF registries XANTUS - The first phase IV study of rivaroxaban in real-life in AF

4 Real Life Data vs. Clinical Trial Data Real life data Clinical trial data Enrols Unselected eligible patients Selected patients Primarily investigates Sample size Key benefits Effectiveness Safety Management issues Based on many variables (centre size, funding) Patients closely represent everyday practice Efficacy Safety Determined by required statistical power Patients are selected and monitored carefully Key limitations Procedures and event definitions may vary between centres and individuals; differences may not be identifiable; potential reporting bias Will results translate into everyday practice? Study question/ Hypothesis Generation of new study questions and hypotheses Driven by study questions and hypotheses

5 Previous registry challenges: Selected centres not representative Lack of training, quality control and audit Selected patient populations included, e.g., hospitalised patients, patients seen in particular clinics, etc. Outcome measures inconsistent, ill-defined and usually not adjudicated Incomplete follow-up with many drop outs with no outcome data or vital status Retrospective versus prospective

6 Event rate (%/year) Event rate (%/year) Rivaroxaban Safety Profile in Real Life was Consistent with Findings from ROCKET AF ROCKET AF 1 Mean CHADS 2 score Rivaroxaban 3.6 US DoD PMSS 2 Mean CHADS 2 score 2.2 N= N=27, Major bleeding* 0 Major bleeding # Clinical endpoint % (n) ICH 0.8 (55) Fatal bleeding 0.4 (27) Major GI bleeding 3.2 (224) Clinical endpoint % (n) ICH 0.1 (36) Fatal bleeding <0.1 (14) Major GI bleeding 1.5 (423) Median duration of treatment exposure was 590 days Results are not intended for direct comparison *Major bleeding definitions according to ISTH; # major bleeding was defined by the Cunningham algorithm 3 1. Patel MR et al, N Engl J Med 2011;365: ; 2. Tamayo S et al, Clin Cardiol 2015;38:63-68; 3. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20: Rivaroxaban users were followed for 455 days

7 Event rate (%/year) Event rate (%/year) Rivaroxaban, Dabigatran and Warfarin: Findings on the Risk of Major Bleeding in Real Life Two retrospective analyses of U.S. Department of Defense records 1,2 Rivaroxaban PMSS 1 Dabigatran PMSS N=27, Clinical endpoint N=25,586 0 Clinical endpoint Rivaroxaban Rivaroxaban (%) ICH 0.1 Fatal bleeding <0.1 Major GI bleeding 1.5 Major GI bleeding Results are not intended for direct comparison Major bleeding was defined by the Cunningham algorithm 3 1. Tamayo S et al, Clin Cardiol 2015;38:63 68; 2. [accessed Aug 2015]; 3. Cunningham A et al, Pharmacoepidemiol Drug Saf 2011;20: Clinical endpoint Dabigatran Dabigatran (%/year) Warfarin Warfarin (%/year) ICH Fatal bleeding NR NR

8 Dabigatran: Favourable Benefit-Fisk Profile FDA study of > Medicare patients Dabigatran was associated with a lower risk of ischaemic stroke, intracranial haemorrhage and death than warfarin Incidence rate per 1000 person-years Dabigatran etexilate Warfarin Adjusted HR (95% CI) Ischaemic stroke ( ) Intracranial haemorrhage ( ) Major GI bleeding ( ) Acute MI ( ) Mortality ( ) Comparison of matched new-user cohorts treated with dabigatran etexilate 150 mg or 75 mg* or warfarin for non-valvular AF based on Medicare data *Primary findings are based on analysis of both doses (no stratification by dose) Graham DJ, et al. Circulation Oct 30. pii: CIRCULATIONAHA

9 Lower Rates of Intracranial Bleeding with Novel OACs but Similar GI Bleeding Rate Compared with VKAs Data from the US Market Scan Commercial and Medicare Supplemental databases in the period Inclusion of patients initiating oral anticoagulants after NVAF diagnosis, and with at least 6 months of enrolment before first anticoagulant use Patients initiating dabigatran or rivaroxaban were matched with up to 5 warfarin users by age, sex and time in the database Warfarin (N=92,633) Dabigatran (N=32,918) Rivaroxaban (N=3301) Ischaemic stroke Intracranial bleeding GI Events HR (95% CI) Events HR (95% CI) Events HR (95% CI) (ref.) (ref.) (ref.) ( ) 1.2 ( ) ( ) 0.4 ( ) ( ) 0.9 ( ) Results are not intended for direct comparison. No head-to-head data comparing rivaroxaban to dabigatran are available Bengtson et al, Presented at AHA Abstract Consider number of patients included when looking at event rates

10 Risk of Stroke in CHA 2 DS 2 -VASc Score 1: Swedish Cohort Swedish nationwide health registries Retrospective data collection N = 140, 420 Quarantine / blanking period after the index AF diagnosis: 4 weeks Follow-up: 5 years Ischemic stroke: 0.6% Ischemic stroke, unspecified stroke, TIA, PE: 0.9% Riks-Stroke registry only: 0.3% Women: % Men % 0.9% Friberg L, et al. JACC 2015:65: Annual event rates, % + TIA + Pulmonary embolism + Unspecified stroke/se Ischemic stroke only CHA 2 D S 2VASc

11 Adherence and persistence of NOAC

12 Definition: Adherence and Persistence Start medication or observation Adherence The extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen Percentage of doses taken as prescribed Persistence Duration of time from initiation to discontinuation of therapy Days taking medication (without exceeding permissible gap) Stop medication or end observation Cramer JA et al. Value Health. 2008;11(1):44 47

13 Patient persistence (%) Patient persistence (%) In Real Life AF Patients Stayed Longer on Rivaroxaban Than on Warfarin Two retrospective U.S. database analyses Matched sample included 3654 rivaroxaban and 14,616 warfarin patients rivaroxaban patients were matched 1:1 with warfarin patients % 9000% 8000% 7000% 6000% 5000% 4000% 3000% 2000% 1000% 0% HR 0.66 (95% CI ) p< Rivaroxaban Warfarin Time to non-persistence (days) 10000% 9000% 8000% 7000% 6000% 5000% 4000% 3000% 2000% 1000% 0% HR 0.63 (95% CI ) p<0.001 Rivaroxaban Warfarin Time to non-persistence (days) Patients were significantly more persistent with Rivaroxaban than with Warfarin 1. Laliberté F et al, Curr Med Res Opin 2014;30: ; 2. Nelson WW et al, Curr Med Res Opin 2014;30:

14 Event-free survival for treatment discontinuation (%) Event-free survival for treatment discontinuation (%) Dresden NOAC Registry: Treatment Discontinuation Rates with Rivaroxaban and Dabigatran Two analyses of the prospective Dresden NOAC Registry 1200 AF patients treated with rivaroxaban AF patients treated with dabigatran % 9000% 8000% 7000% 6000% 5000% 4000% 3000% 2000% 1000% 0% 15/20 mg OD rivaroxaban Time (days) Median follow-up: 544 days The rate for Rivaroxaban discontinuation was 13.6%/year 10000% 9000% 8000% 7000% 6000% 5000% 4000% 3000% 2000% 1000% 0% mg BID dabigatran 110 mg BID dabigatran All patients Time (days) Median follow-up: 671 days The rate of Dabigatran discontinuation was 25.8%/year Results are not intended for direct comparison 1. Beyer-Westendorf J et al, Europace 2015;17: ; 2. Beyer-Westendorf J et al, Thromb Haemost 2015;113:

15 Patient persistence (%) Persistence with Rivaroxaban vs. Dabigatran or Apixaban in NVAF Patients Retrospective U.S. database analysis Rivaroxaban (n=4194) Dabigatran (n=5489) Apixaban (n=265) Rivaroxaban vs Dabigatran: p<0.001 Apixaban: p=ns Index NOAC only Rivaroxaban vs Dabigatran: p<0.001 Apixaban: p=0.037 Allowing switch to other NOAC Crivera C et al. Curr Med Res Opin 2015;doi: /

16 Patients with discontinuation (%) Real world discontinuation rates in the USA with apixaban vs warfarin Cumulative discontinuation rates on anticoagulation therapy initiation Time from anticoagulation initiation (days) *Adjusted for age, gender and baseline comorbidities; CI, confidence interval; HR, hazard ratio; NVAF, non-valvular atrial fibrillation Apixaban 270 Warfarin Apixaban vs warfarin: adjusted * HR, 0.61 (CI, ); p< Retrospective analysis of Truven Market scan & Medicare database to investigate treatment patterns in US patients with NVAF Study period: Jan 1, 2013 to Dec 31, ,870 eligible patients of whom: 42.34% on warfarin 8.73% on apixaban 13.27% on dabigatran 35.67% on rivaroxaban

17 Agenda Differences between real-life and clinical trial data Some selected AF real-life data of NOAC Adherence and persistence of NOAC Some selected data from AF registries XANTUS - The first phase IV study of rivaroxaban in real-life in AF

18 PREFER in AF The proportion of patients with permanent AF increases in each CHA 2 DS 2 VASc stratum while the proportion of patients with paroxysmal AF decreases Kirchhof P et al. Europace 2014; 16:6-14

19 PREFER in AF* - Use of antithrombotics by stroke risk Kirchhof P et al. Europace 2014; 16:6-14 *Austria, France, Germany, Italy, Spain, Switzerland UK

20 GARFIELD AF Study Design Observational study of adults with newly diagnosed non-valvular AF and 1 additional, investigator-defined stroke risk factor 1,2 Sites representative of AF care settings in each country No mandate for therapeutic intervention Consecutive patients recruited in five sequential cohorts: Target of 56,500 patients (51,500 prospective and 5000 retrospective) >1000 randomly selected sites in 35 countries Follow-up period of at least 2 years Bayer is supporting GARFIELD AF by an unrestricted educational grant 1. Kakkar AK et al, PLoS One 2013;8:e63479; 2. Apenteng PN et al, BMC Cardiovasc Disord 2013;13:31

21 Five Sequential Prospective Cohorts of Unselected Patients will Create a Unique Dataset A unique global registry Independent academic research initiative, supported by Bayer with an unrestricted educational grant ~56,500 patients with newly diagnosed AF in 35 countries Randomized selection of sites representative of national AF care settings Five sequential prospective cohorts; unselected eligible patients enrolled consecutively Long-term follow-up (minimum of 2 years); extensive monitoring (20% of CRFs) N 55,000 5,000 retrospective and 50,000 prospective/cohort as of 9June 2015: 42,597 patients recruited Cohort 1 December 2009 October 2013 June 2018 Cohort 2 October 2011 June 2015 June 2018 Recruitment Cohort 3 June 2013 August 2016 June 2018 Minimum follow-up Cohort 4 August 2014 June 2017 June 2018 Extended follow-up Cohort 5 August 2015 June ,580 patients recruited (as of 17 October 2015)

22 Proportion of patients on treatment (%) Evolution in Baseline Treatment for Patients Enrolled in Sequential Cohorts of GARFIELD AF 100 VKA±AP FXA/DTI±AP AP None Data on file Cohort 1 Cohort 2 Cohort 3 Cohort 4

23 The increase in use of AC was mainly in patients with CHA 2 DS 2 -VASc score 2

24 There was a greater proportion of AC use in patients aged >65 years which increased across the cohorts

25 Higher levels of AC use were observed in Norway, the Netherlands and Italy

26 NOAC use was highest in Belgium

27 In real life, anticoagulation control is suboptimal* regardless of the type of VKA and the method of analysis VKA therapy Mean FIR (%) Mean TTR (%) Warfarin Acenocoumarol Phenprocoumon Other *According to the UK National Institute for Health and Care Excellence (NICE), a TTR of <65% indicates poor anticoagulation control FIR = frequency in range TTR = time in therapeutic range Cohorts 1 3, N=28,624

28 Adjusted 1-year outcomes of patients with AF according to FIR and TTR Events occurring during the first year were analysed. Event rates are % per person-year. HRs were adjusted for CHA 2 DS 2 -VASc score Cohorts 1 3, N=28,624

29 XANTUS: Study Objective and Design To collect real-life data on adverse events in patients with non-valvular AF treated with rivaroxaban to determine the safety profile of rivaroxaban across the broad range of patient risk profiles encountered in routine clinical practice Primary outcomes: major bleeding (ISTH definition), all-cause mortality, any other adverse events Population: Adult patients with non-valvular AF receiving rivaroxaban for stroke/ non-cns systemic embolism prevention, who had provided written informed consent Rivaroxaban; treatment duration and dose at physician s discretion Data collection at initial visit, hospital discharge (if applicable) and quarterly* 1 year Prospective, single-arm, observational, non-interventional phase IV study Statistical analyses were descriptive and exploratory in nature Final visit: 1 year # *Exact referral dates for follow-up visits not defined (every 3 months recommended); # for rivaroxaban discontinuation 1 year, observation period ends 30 days after last dose. Observational design means no interference with clinical practice was allowed Camm et al, Vasc Health Risk Manag 2014;10: ;

30 XANTUS: Participating Countries Patients were enrolled from June 2012 to December 2013 from 311 centres in Europe and Canada Participating countries included: Belgium, Canada, Czech Republic, Denmark, France, Germany, Hungary, Ireland, Israel, Moldova, The Netherlands, Norway, Poland, Portugal, Russia, Slovakia, Slovenia, Sweden, Ukraine, UK Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

31 XANTUS: Patient Disposition Major events, specifically major bleeding, stroke, SE, TIA and MI, adjudicated centrally by an Adjudication Committee blinded to individual patient data Primary analysis population: defined as all patients who had taken at least one dose of rivaroxaban Screened (N=10,934) Enrolled (N=6785) Safety population (N=6784) 4149 patients excluded* Patient decision (n=1222) Administrative reason (n=456) Availability of drug (n=18) Medical guidelines (n=399) Price of drug (n=473) Medical reasons (n=442) Internal hospital guidelines (n=30) Type of health insurance (n=183) Other (n=1454) 1 patient Did not take any rivaroxaban (n=1) Rivaroxaban 20 mg (n=5336) Rivaroxaban 15 mg (n=1410) Another dose (n=35) # *Reasons for not continuing in the study included, but were not limited to, patient decision, administrative or medical reasons. Some patients could have more than one reason for exclusion; # other dose includes any initial daily rivaroxaban dose besides 15/20 mg od (excluding missing information, n=3) Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

32 Baseline Demographics and Clinical Characteristics Age (years) Rivaroxaban (N=6784) Mean±SD 71.5±10.0 Age <65, n (%) 1478 (21.8) Age 65 75, n (%) 2782 (41.0) Age >75, n (%) 2524 (37.2) Gender (male), n (%) 4016 (59.2) Weight (kg), mean±sd 83.0±17.3 BMI (kg/m 2 ), mean±sd 28.3±5.0 CHADS 2 score, mean±sd 2.0±1.3 CHA 2 DS 2 -VASc score, mean±sd 3.4±1.7 AF, n (%) First diagnosed 1253 (18.5) Paroxysmal 2757 (40.6) Persistent 923 (13.6) Permanent 1835 (27.0) Missing 16 (0.2) Rivaroxaban (N=6784) VKA experienced 3089 (45.5) VKA naïve 3695 (54.5) Creatinine clearance, n (%) <15 ml/min 20 (0.3) 15 <30 ml/min 75 (1.1) 30 <50 ml/min 545 (8.0) ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4) Co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-cns SE/TIA 1291 (19.0) Congestive HF 1265 (18.6) Prior MI 688 (10.1) Hospitalization at baseline, n (%) 1226 (18.1) Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

33 Cumulative Rates (Kaplan Meier) for Treatment-Emergent Primary Outcomes Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

34 Event-Free Rate (Kaplan Meier) for Treatment-Emergent Primary Outcomes In total, 6522 (96.1%) patients did not experience any of the outcomes of treatment-emergent all-cause death, major bleeding or stroke/se Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

35 Treatment-Emergent Bleeding Events Rivaroxaban (N=6784) Incidence proportion, n (%) Incidence rate, %/year (95% CI)* Major bleeding 128 (1.9) 2.1 ( ) Fatal 12 (0.2) 0.2 ( ) Critical organ bleeding 43 (0.6) 0.7 ( ) Intracranial haemorrhage 26 (0.4) 0.4 ( ) Mucosal bleeding # 60 (0.9) 1.0 ( ) Gastrointestinal 52 (0.8) 0.9 ( ) Haemoglobin decrease 2 g/dl 52 (0.8) 0.9 ( ) Transfusion of 2 units of packed RBCs or whole blood 53 (0.8) 0.9 ( ) Non-major bleeding events 878 (12.9) 15.4 ( ) *Events per 100 patient-years. # Numbers are for major mucosal and gastrointestinal bleeding events. Representing major bleeding. Patients could experience multiple bleeding events in different categories Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

36 Adjudicated Causes of Death Number of patients (N=118*), n (%) Cardiovascular 49 (41.5) Cardiac decompensation, heart failure 24 (20.3) Sudden or unwitnessed death 14 (11.9) MI 6 (5.1) Non-haemorrhagic stroke 4 (3.4) Dysrhythmia 1 (0.8) Cancer 23 (19.5) Other 16 (13.6) Bleeding 12 (10.2) Extracranial haemorrhage 5 (4.2) Intracranial bleeding 7 (5.9) Infectious disease 10 (8.5) Unexplained 9 (7.6) *Multiple reasons were recorded for the cause of treatment-emergent adjudicated death of some patients Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

37 Treatment Persistence and Patient Satisfaction Persistence with rivaroxaban in XANTUS was 80% at 1 year Over 75% of patients were very satisfied/satisfied with their treatment Rivaroxaban N=6784 n (%) Very satisfied 2247 (33.1) Satisfied 2849 (42.0) Neutral 877 (12.9) Unsatisfied 340 (5.0) Very unsatisfied 116 (1.7) Missing 355 (5.2) Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

38 Incidence rate Events per 100 patient-years Outcomes According to Dosing (20/15 mg od) Major bleeding, all-cause death, and thromboembolic events occurred at higher incidence rates for the 15 mg od versus the 20 mg od dose mg dose 20 mg dose Stroke/SE/TIA/MI Major bleeding Mortality 28/ / / / / /5336 Dosing decisions may have been based on other clinical considerations besides impaired renal function Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

39 Incidence rate Event per 100 patient-years Comparison of Main Outcomes: XANTUS versus ROCKET AF ROCKET AF XANTUS CHADS 2 Prior stroke* ROCKET AF % XANTUS % Stroke/SE Major bleeding Death All strokes ICH GI bleeding *Includes prior stroke, SE or TIA Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

40 Strengths and Limitations of XANTUS Strengths Large sample size Prospective design Independent endpoint adjudication Limitations Single-arm, open-label study Selection bias: Patients agreeing to participate in the study self-selected for risk of stroke or bleeding, and conscientious participation Investigators may have selected patients based around intact cognitive function Limited influence on data completeness in observational setting Outcomes not adjusted for baseline risk factors Camm AJ.et al Eur Heart J 2015; doi: /eurheartj/ehv466

41 Summary XANTUS is the first large prospective study that describes the use of rivaroxaban in a broad patient population with non-valvular AF Patients in XANTUS were at lower overall risk than those in the rivaroxaban phase III ROCKET AF clinical trial The rates of major bleeding and stroke with rivaroxaban were low in routine clinical practice

42 General Conclusions Real life evidence of novel OACs is important to delineate effectiveness and safety in patients with AF 1,2 Rivaroxaban in real life was associated with low rates of cardiovascular events, which supports outcomes reported in ROCKET AF 1,2 Major bleeding rates (including fatal bleeding and ICH) were generally consistent with those reported in ROCKET AF and can normally be conservatively managed 1 3 Rivaroxaban once daily in real life is associated with higher patient persistence compared with warfarin. 4 7 The net clinical benefit with rivaroxaban in a real life population was demonstrated to be greater than that with warfarin treatment 8 1. Patel MR et al, N Engl J Med 2011;365: ; 2. Tamayo S et al, Clin Cardiol 2015;38:63 68; 3. Beyer-Westendorf et al, Blood 2014;124; ; 4. Laliberté F et al, Curr Med Res Opin 2014;30: ; 5. Nelson WW et al, Curr Med Res Opin 2014;30: ; 6. Beyer-Westendorf J et al, Europace 2015;17: ; 7. Beyer-Westendorf J et al, Thromb Haemost 2015;113: ; 8. Banerjee A et al, Thromb Haemost 2012;107: