Χάρης Κοσσυβάκης Επιμελητής A Καρδιολογικό Τμήμα Γ.Ν.Α. «Γ. ΓΕΝΝΗΜΑΤΑΣ»

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1 Η ισορροπία ασφάλειας και αποτελεσματικότητας: Η συνέπεια στα αποτελέσματα των τυχαιοποιημένων κλινικών μελετών και των δεδομένων κλινικής πρακτικής της Απιξαμπάνης Χάρης Κοσσυβάκης Επιμελητής A Καρδιολογικό Τμήμα Γ.Ν.Α. «Γ. ΓΕΝΝΗΜΑΤΑΣ»

2 «Δηλώνω ότι έχω λάβει τιμητική αμοιβή από την Pfizer Hellas» «Οι απόψεις που εκφράζονται σε αυτή την παρουσίαση ανήκουν στον ομιλητή και δεν εκφράζουν απαραίτητα τις απόψεις της εταιρείας. Για όλα τα φαρμακευτικά προϊόντα που αναφέρονται παρακαλείσθε να συμβουλεύεσθε τις εγκεκριμένες Περιλήψεις Χαρακτηριστικών των Προϊόντων».

3 RCTs vs real world data

4 Randomised clinical trials (RCTs) vs real-world data (RWD) RCT RCTs are randomised clinical trials conducted to test the safety and efficacy of healthcare products or services under carefully controlled conditions RWD RWD study is observational in nature and generally uses data from actual practice settings to perform analyses on comparative effectiveness, comparative costs, quality of life and signal detection, among others RCT compared with RWD? May include a broader and more heterogeneous patient population Generate data within the routine healthcare system Can address research questions that require larger patient numbers and long follow-up periods Can address research questions that cannot be studied by experiments for ethical or feasibility reasons RWD complements and augments RCT data 1. Garrison et al. Value Health. 2007;10: ; 2. Annemans et al. ISPOR Connections Available at: 4

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6 maximizing the use of real world evidence Journal of Multidisciplinary Healthcare 2018:

7 ARISTOTLE: Study design and objectives 1 Event Driven* Apixaban 5.0 mg oral BD Patient Population 2 Aged 18 years Patients with NVAF and 1 risk factors for stroke Randomised, double-blind, double-dummy (2.5 mg oral BD in select patients [4.7%]) Warfarin (adjusted to an INR of2 3) The primary objective of the trial was to determine if apixaban was non-inferior to warfarin for the prevention ofstroke and systemic embolism. If non-inferiority was met, the following endpoints were tested for superiority 1,3 Stroke or systemic embolism (primary efficacy endpoint) ISTH major bleeding (primary safety endpoint) Death due to any cause (key secondary endpoint) *448 primary study events were needed. 2 of the following: age 80 years, weight 60 kg, serum creatinine level 1.5 mg/dl 1. Granger et al. N Engl J Med 2011;365: Lopes et al. Am Heart J 2010;159: Apixaban SmPC

8 Event rate (% / year) Apixaban is the only oral anticoagulant to demonstrate superiority vs. warfarin in all of the following 3 outcomes Superior stroke/systemic embolism prevention 21% RRR p=0.01 Superior profile in reducing major bleeding 31% RRR p<0.001 Superior reduction in all-cause mortality 11% RRR p= % 265/ % 212/ % 462/ % 327/ % 669/ % 603/9120 Primary efficacy endpoint Primary safety endpoint Key secondary endpoint Median duration of follow-up 1.8 years Figure created from data in Grangeret al. N Engl J Med 2011;365: Apixaban Warfarin (target INR )

9 Primary efficacy results for apixaban were consistent across major subgroups in ARISTOTLE Characteristics No. of patients Apixaban Warfarin Hazard Ratio (95% CI) No. of events (%/yr) All patients 18, (1.27) 265 (1.60) P value for interaction Prior warfarin/vka 0.39 Yes 10, (1.1) 138 (1.5) No 7, (1.5) 127 (1.8) Age 0.12 < 65 yrs 5, (1.0) 44 (0.9) 65 to < 75 yrs 7, (1.3) 112 (1.7) 75 yrs 5, (1.6) 109 (2.2) Sex 0.60 Male 11, (1.2) 160 (1.5) Female 6, (1.4) 105 (1.8) Weight kg 1, (2.0) 52 (3.2) > 60 kg 16, (1.2) 212 (1.4) Type of AF 0.70 Permanent/Persistent 15, (1.4) 235 (1.7) Paroxysmal 2, (0.8) 30 (1.1) Prior stroke or TIA 0.71 Yes 3, (2.5) 98 (3.2) No 14, (1.0) 167 (1.2) Diabetes mellitus 0.71 Yes 4, (1.4) 75 (1.9) No 13, (1.2) 190 (1.5) Primary efficacy endpoint: stroke or systemic embolism Apixaban better Warfarin better Adapted from Granger et al. N Engl J Med2011;365:

10 Primary efficacy results for apixaban were consistent across major subgroups in ARISTOTLE (cont) Characteristics No. of patients Apixaban Warfarin Hazard Ratio (95% CI) No. of events (%/yr) All patients 18, (1.27) 265 (1.60) P value for interaction Heart failure 0.50 Yes 5, (1.4) 79 (1.6) No 12, (1.2) 186 (1.6) CHADS 2 score , (0.7) 51 (0.9) 2 6, (1.2) 82 (1.4) 3 5, (1.9) 132 (2.8) Level of renal impairment 0.72 Severe or Moderate 3, (2.1) 69 (2.7) Mild 7, (1.2) 116 (1.7) No impairment 7, (1.0) 79 (1.1) Apixaban dose mg BID or placebo (1.7) 22 (3.3) 5 mg BID or placebo 17, (1.3) 243 (1.5) Geographic region 0.44 North America 4, (1.0) 56 (1.3) Latin America 3, (1.4) 52 (1.8) Europe 7, (1.1) 77 (1.1) Asian Pacific 2, (2.0) 80 (3.1) ASA use at randomisation 0.44 Yes 5, (1.3) 94 (1.9) No 12, (1.2) 171 (1.5) Primary efficacy endpoint: stroke or systemic embolism Apixaban better Warfarin better Adapted from Granger et al. N Engl J Med2011;365:

11 Relative to warfarin, apixaban was associated with a 33% lower major bleeding risk, Relative to rivaroxaban, apixaban was associated with a 48% lower risk of major bleeding risk. Apixaban was associated with a lower risk of major gastrointestinal bleeding than dabigatran. J Manag Care Spec Pharm. 2017;23(9):968-78

12 Among Japanese patients with NVAF, treatment with apixaban 5/2.5mg BID was associated with a significantly lower risk of major bleeding as well as any bleeding when compared to warfarin. Treatment with dabigatran 150/110mg BID or rivaroxaban 15/10mg QD was associated with a significantly lower risk of major bleeding, but not with a lower risk of any bleeding, compared to warfarin CURRENT MEDICAL RESEARCH AND OPINION, 2017 VOL. 33, NO. 11,

13 24 studies /retrospective analyses of administrative claims databases and patient registries half were based in the United States Apixaban showed a significantly lower risk of MB versus warfarin in all eight included studies. CURRENT MEDICAL RESEARCH AND OPINION, 2017 VOL. 33, NO. 9,

14 Apixaban vs Dabigatran Seven studies compared apixaban with dabigatran. Six studies reported that apixaban was associated with a numerically lower risk of MB compared to dabigatran no statistical significance in five of the studies. CURRENT MEDICAL RESEARCH AND OPINION, 2017 VOL. 33, NO. 9,

15 Apixaban vs Rivaroxaban All studies reported that apixaban was associated with a significantly lower risk of MB compared to rivaroxaban (HR: ; range of 95% CIs: ). Non-industry-sponsored studies reported a larger treatment effect for this comparison compared to industry-sponsored studies. CURRENT MEDICAL RESEARCH AND OPINION, 2017 VOL. 33, NO. 9,

16 Newly initiated on apixaban or warfarin meeting selection criteria N=18,591 Apixaban n=4,332 Warfarin n=14,259 Following propensity-score matching, stratified by exposure status 4,083 apixaban and 4,083 warfarin users were identified *PY=Patient-years Characteristics of included patients (matched cohorts) Parameter Apixaban (n=4,083) 2,125 PYs* Warfarin (n=4,083) 1,951 PYs* Age in years, mean (SD) (11.32) (11.25) Male, % CHADS 2 score, 180 day; mean (SD) CHA 2 DS 2 -VASc score, 180 day; mean (SD) HAS-BLED Score, 180 day; mean (SD) 1.93 (1.07) 1.92 (1.07) 3.47 (1.38) 3.47 (1.35) 1.65 (0.69) 1.66 (0.72) Reduced dose, % 15.5 NA

17 Apixaban was associated with a significant* 62% reduction in ICH vs. warfarin 13% non-significant increase in ischemic stroke vs. warfarin Non-significant 37% reduction in the combined endpoint of ICH and ischemic stroke vs. warfarin Apixaban Warfarin HR (95% CI) Rate (%/year) Rate (%/year) apixaban vs. warfarin HR (95% CI) apixaban vs. warfarin ICH ( ) Ischemic stroke ( ) Combined ( ) *p< Favors Favors apixaban warfarin

18 similar effectiveness of apixaban in stroke or TE prevention in the settings of real-world studies stroke Apixaban was safer than warfarin in the risks of major bleeding major bleeding Am J Cardiol 2017;120:

19 similar effectiveness for stroke or TE prevention and major bleeding when compared with dabigatran Am J Cardiol 2017;120:

20 similar effectiveness for stroke or TE prevention when compared with rivaroxaban A lower risk of major bleeding was seen in real-world studies when apixaban was compared with rivaroxaban Am J Cardiol 2017;120:

21 Three Danish nationwide databases, August 2011 to October patients No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin. BMJ 2016;353:i3189

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23 Apixaban vs VKAs for efficacy outcomes 3 studies that included patients Similar risk of ischemic stroke compared with VKAs (HR, 0.95; 95% CI, one study of patients Similar risk of ischemic stroke/systemic embolism compared with VKAs (HR, 1.07; 95% CI, ) Stroke. 2017;48:

24 Apixaban vs VKAs for intracranial hemorrhage 4 pooled studies that included patients apixaban was associated with lower risk for intracranial hemorrhage (HR, 0.45; 95% CI, ) Similar with Aristotle results Stroke. 2017;48:

25 Apixaban vs VKAs for major hemorrhage. 4 studies that included patients apixaban was associated with lower risk for major hemorrhage in (HR, 0.55; 95% CI, ) 31% reduction in ARISTOTLE trial Stroke. 2017;48:

26 Apixaban vs VKAs for gastrointestinal hemorrhage 2 studies that included patients lower risk for gastrointestinal hemorrhage in (HR, 0.63; 95% CI, ) In RE-LY, the dabigatran 150 mg arm had a 48% increased risk of gastrointestinal hemorrhage that was not present with the 110 mg dose 5 In the ROCKET-AF, this risk for rivaroxaban was increased by 46% as compared with warfarin In ARISTOTLE a non signification risk reduction of 11% was found with apixaban

27 Apixaban vs VKAs for mortality apixaban had lower mortality compared with VKAs in the ARISTOTLES trial apixaban was associated with a significant 11% reduction of mortality Stroke. 2017;48:

28 Retrospective study four large US claims databases (MarketScan, PharMetrics, Optum, and Humana) of NVAF patients newly initiating apixaban or warfarin from January 1, 2013 to September 30, Thromb Haemost 2017; 117:

29 Cumulative incidence of stroke/ systemic embolism and major bleeding Compared to warfarin, apixaban was associated with a 33 % lower risk of stroke/se (hazard ratio [HR]: 0.67, 95 % confidence interval [CI]: , p<0.001) within one year of treatment initiation Compared to warfarin, apixaban use was associated with a 40 % lower risk of major bleeding (HR: 0.60, 95 % CI: , p<0.001 within one year of treatment initiation) Thromb Haemost 2017; 117:

30 Hazard ratio of stroke/se and major bleeding for propensity score matched apixaban and warfarin patient Thromb Haemost 2017; 117:

31 stroke/se Subgroup analyses Major bleeding Consistently lower risks of stroke/se and major bleeding associated with apixaban as compared to warfarin treatment Thromb Haemost 2017; 117:

32 a total of patients treated with apixaban 16 studies PubMed and Scopus databases Stroke. 2018;49:98-106

33 Apixaban vs Warfarin for stroke no significant difference was found between apixaban and warfarin, both in the regular and reduced dose subgroups. Stroke. 2018;49:98-106

34 Apixaban vs Warfarin for hemorrhagic stroke hemorrhagic stroke risk was significantly reduced in apixaban treated patients (36% relative risk reduction [RRR]; P=0.0003), especially for the regular dose group Stroke. 2018;49:98-106

35 Apixaban vs Warfarin for major bleeding Compared with warfarin, major bleeding risk was significantly lower for patients treated with apixaban (OR, 0.62; 95% CI, ), with consistency for regular and low dose subgroups Stroke. 2018;49:98-106

36 Apixaban vs Warfarin for ICH Stroke. 2018;49: Risk reduction with apixaban was even greater when considering ICH (46% RRR; P< ) or GIB (OR, 0.63; 95% CI, ; P< ) compared with warfarin

37 Apixaban vs Dabigatran for stroke/ any thromboembolic event nonsignificant differences between apixaban and dabigatran in risk of any thromboembolic event (P=0.30) No difference was seen for stroke risk Stroke. 2018;49:98-106

38 Apixaban vs Dabigatran for major bleeding Major bleeding risk was significantly lower in apixaban patients compared with dabigatran ones (35% RRR; P< ) even though only 1 study was included in the reduced dose subgroup Stroke. 2018;49:98-106

39 Stroke. 2018;49: patients prescribed apixaban had a significantly lower risk for GIB (57% RRR; P< ) and any bleeding (31% RRR; P< )

40 Apixaban vs Dabigatran for intracranial hemorrhage/all cause death no difference was found for ICH and all-cause death between apixaban and dabigatran Stroke. 2018;49:98-106

41 Apixaban vs Rivaroxaban for major bleeding and ICH The risk of major bleeding was significantly lower in patients treated with apixaban compared with rivaroxaban (46% RRR; P< ), consistent with doses subgroups There was a significant risk reduction in ICH (OR, 0.46; 95% CI, ) Stroke. 2018;49:98-106

42 There was a significant risk reduction in GIB for apixaban compared with rivaroxaban (64% RRR; P< ), as well as for any bleeding (OR, 0.56; 95% CI, Stroke. 2018;49:98-106

43 Stroke. 2018;49:98-106

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48 Deitelzweig et al, ACC 2018

49 Deitelzweig et al, ACC 2018

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51 rates of permanent drug discontinuation dabigatran 110 mg 20.7% dabigatran 150 mg 21.2% rivaroxaban 25.3% apixaban 17.9% edoxaban 30 mg 33.0% edoxaban 60 mg 34.4% Mayo Clin Proc. 2014;89(7):

52 adherence to anticoagulation continues to be a challenge J Am Heart Assoc. 2016;5:e003074

53 LIMITATIONS observational clinical data cannot establish a cause effect relationship between medication prescription and outcomes but only an association between the studied variables and should not be regarded as direct comparisons between NOACs. The size of study cohort, follow-up duration, NOAC prescribing patterns(eg,standard doses only), Type of analysis(eg,claims-based retrospective analysis), end point definition(s), method used to adjust for baseline differences (eg, propensity score matching)

54 CONCLUSIONS Real world data consistently confirm apixaban as a safe and effective option treatment in patients with nonvalvular atrial fibrillation Complementary, real world data supports the main conclusions of Aristotle trial compared with warfarin, the use of apixaban in real-life is associated with an overall similar effectiveness in reducing stroke/systemic embolism, and superiority regarding major bleeding, all cause mortality In absence of direct head-to-head comparator RCT for the NOACs, real world data indicate apixaban, as a safer option for patients needing anticoagulation in comparison with other NOACs.

55 apixaban could possibly represent an apropriate alternative for OAC therapy, balancing effectiveness and safety