Ειδικοί πληθυσμοί και νεότερα δεδομένα από τον πραγματικό κόσμο (RWD) για την Απιξαμπάνη

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1 Ειδικοί πληθυσμοί και νεότερα δεδομένα από τον πραγματικό κόσμο (RWD) για την Απιξαμπάνη ΔΗΜΗΤΡΙΟΣ ΛΥΣΙΤΣΑΣ, MD, PhD, MRCP Επεμβατικός Ηλεκτροφυσιολόγος Κλινική Άγιος Λουκάς θεσσαλονίκη

2 Δήλωση συμφερόντων Lecture and training fees from Novartis, Galenica, Pfizer, Boehringer, St Jude, Boston, Medtronic, Biosense Webster

3 Δεδομένα για την κολπική μαρμαρυγή

4 Κουμαρινικά και καρδιολόγοι μια μακροχρόνια σχέση

5 AHJ 2013;165:93-101

6 Συμμόρφωση στα φάρμακα μετά από ΑΕΕ

7 Αντιπηκτική αγωγή Η τέχνη της ισορροπίας Αποτελεσματικότητα και ασφάλεια είναι το ίδιο σημαντικά

8 Το εγκεφαλικό είναι του...θεού και η αιμορραγία του...γιατρού

9 Ο γαλαξίας των αντιπηκτικών

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11 ESC 2016: Initiation of stroke prevention therapy in atrial fibrillation Mechanical heart valves or moderate or severe mitral stenosis Yes No Estimate stroke risk based on number of CHA 2 DS 2 -VASc risk factors 0 a 1 2 b No antiplatelet or anticoagulant treatment (IIIB) OAC should be considered (IIaB) Oral anticoagulation indicated Assess for contraindications Correct reversible bleeding risk factors LAA occluding devices may be considered in patients with clear contraindications for OAC (IIbC) NOAC (IA) VKA (IA) c * a Includes women without other stroke risk factors b IIaB for women with only one additional stroke risk factor c IB for patients with mechanical heart valves or mitral stenosis *Solid arrow indicates preference 1. Kirchhof P et al. Eur Heart J 2016; Europace Aug 27. pii: euw295. [Epub ahead of print].

12 Stroke/SE Bleeding Cameron et al, BMJ 2014

13 Τι μας λένε οι μετα-αναλύσεις Σε γενικές γραμμές η αποτελεσματικότητα φαίνεται ικανοποιητική για τα νέα αντιπηκτικά Σχετίζονται με σημαντική μείωση των σοβαρών αιμορραγιών και κυρίως των θανατηφόρων Τα NOACs δείχνουν να βελτιώνουν την αναλογία αποτελεσματικότητας/ασφάλειας

14 Cardiology International 2011

15 Κλινικές μελέτες vs κλινική πράξη RCTs Real world

16 BMS and Pfizer Internal Use Only. Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND, Noseworthy PA Content is based on independent data and data generation has not been supported by BMS and/or Pfizer Yao et al. J Am Heart Assoc. 2016;5:e Yao X, et al. J Am Heart Assoc 2016;6:e003725

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18 US retrospective real-world database research (OptumLabs): Stroke/SE outcomes for NOAC vs VKA PAIRWISE PROPENSITY-MATCHED MEDICATION COMPARISON STROKE/SE* ISCHAEMIC HAEMORRHAGIC STROKE/SE* ISCHAEMIC HAEMORRHAGIC STROKE/SE* ISCHAEMIC HAEMORRHAGIC APIXABAN VS WARFARIN n=7695 n= DABIGATRAN VS WARFARIN n= RIVAROXABAN VS WARFARIN n= n= n= FAVOURS NOAC HR (95% CI) ( ) 0.83 ( ) 0.35 ( ) 0.98 ( ) 1.06 ( ) 0.56 ( ) 0.93 ( ) 1.01 ( ) 0.61 ( ) FAVOURS WARFARIN P VALUE *Included ischaemic stroke, haemorrhagic stroke, and systemic embolism (SE) Adapted from Yao X, et al. J Am Heart Assoc 2016;6:e003725

19 US retrospective real-world database research (OptumLabs): Bleeding outcomes for NOAC vs VKA PAIRWISE PROPENSITY-MATCHED MEDICATION COMPARISON MAJOR BLEEDING* INTRACRANIAL GASTROINTESTINAL MAJOR BLEEDING* INTRACRANIAL GASTROINTESTINAL MAJOR BLEEDING* INTRACRANIAL GASTROINTESTINAL APIXABAN VS WARFARIN n=7695 n= DABIGATRAN VS WARFARIN n= n= n= RIVAROXABAN VS WARFARIN n= HR (95% CI) 0.45 ( ) 0.24 ( ) 0.51 ( ) 0.79 ( ) 0.36 ( ) 1.03 ( ) 1.04 ( ) 0.51 ( ) 1.21 ( ) P VALUE <0.001 <0.001 <0.001 <0.01 < < FAVOURS NOAC FAVOURS WARFARIN *Included ischaemic stroke, haemorrhagic stroke, and systemic embolism (SE) Adapted from Yao X, et al. J Am Heart Assoc 2016;6:e003725

20 Danish retrospective real-world research: Stroke/SE and mortality outcomes for NOAC vs VKA ISCHAEMIC STROKE or SE* ISCHAEMIC STROKE DEATH HR (95% CI) HR (95% CI) HR (95% CI) APIXABAN 1.08 ( ) 1.11 ( ) DABIGATRAN 1.17 ( ) 1.24 ( ) RIVAROXABAN 0.83 ( ) 0.86 ( ) 0.65 ( ) 0.63 ( ) 0.92 ( ) FAVOURS NOAC FAVOURS WARFARIN FAVOURS NOAC FAVOURS WARFARIN FAVOURS NOAC FAVOURS WARFARIN *Ischaemic stroke or systemic embolism (SE) only (haemorrhagic stroke was not included); Larsen TB, et al. BMJ 2016;353:i3189

21 Danish retrospective real-world research: Bleeding outcomes for NOAC vs VKA ANY BLEEDING * HR (95% CI) HR (95% CI) COHORT WITH ATRIAL FIBRILLATION (MAIN ANALYSIS) MAJOR BLEEDING INTRACRANIAL BLEEDING HR (95% CI) APIXABAN 0.63 ( ) 0.61 ( ) 0.72 ( ) DABIGATRAN 0.61 ( ) 0.58 ( ) 0.40 ( ) RIVAROXABAN 0.99 ( ) 1.06 ( ) 0.56 ( ) FAVOURS FAVOURS FAVOURS FAVOURS FAVOURS NOAC WARFARIN NOAC WARFARIN NOAC FAVOURS WARFARIN *Included major (IC and extracranial bleeding), IC (including traumatic IC bleeding) and GI bleeding; Included IC (including traumatic bleeding) and extracranial bleeding (defined as bleeding with anaemia, haemothorax, haematuria, epistaxis, and bleeding in the eye); Included traumatic IC bleeding; Adapted from Larsen TB, et al. BMJ 2016;353:i3189

22 Is the safety profile of NOACs vs warfarin observed in RCTs consistently reported in the real-world setting? RECENT RETROSPECTIVE REAL-WORLD DATABASE RESEARCH ON OACS IN NVAF: STUDY DESIGNS STUDY PERIOD LIP GYH et al 1 HOHNLOSER SH, et al 2 LIN I, et al 3 1/1/12 31/12/14 (includes 1-year baseline) 1/1/13 31/3/15 1/1/13 31/3/15 FOLLOW-UP Up to 24 months Up to 27 months Up to 180 days ENDPOINT & DEFINITION Major bleeding: First bleeding requiring hospitalisation with a bleeding diagnosis code as the first listed ICD-9-CM code Major bleeding: Bleeding consists of emergency admission to hospital and pre-specified ICD-10-GM hospital discharge diagnosis Any bleeding: bleeding in an inpatient or outpatient setting with a ICD-9-CM code indicative of major or clinically relevant non-major bleeding METHODS 1:1 PSM was used to balance patient baseline characteristics Cox proportional hazards model adjusted for patient baseline characteristics Cox proportional hazards model adjusted for patient baseline characteristics 1. Lip GYH, et al. Thromb Haemost 2016; Hohnloser SH, et al. Presented at: ESC Congress; August 27 31, 2016; Rome, Italy; 3. Lin I, et al. at ESC Congress; August 27 31, 2016; Rome, Italy. PSM: propensity score matching.

23 Bleeding rates of NOACs vs VKA in recent retrospective real-world database research BLEEDING RATES FOR NOAC VS VKA ACROSS REAL-WORLD DATABASE STUDIES NOAC VS VKA US 1* APIXABAN RIVAROXABAN DABIGATRAN GERMANY 2 APIXABAN RIVAROXABAN DABIGATRAN US 3 APIXABAN RIVAROXABAN DABIGATRAN HR (95% CI) FAVOURS 0.0 NOAC < 1.0 > FAVOURS 2.0VKA HR (95% CI) 0.53 ( ) 0.98 ( ) 0.69 ( ) 0.68 ( ) 1.10 ( ) 0.76 ( ) 0.88 ( ) 0.99 ( ) 0.70 ( ) 1. Lip GYH, et al. Thromb Haemost 2016; Hohnloser SH, et al. Presented at: ESC Congress; August 27 31, 2016; Rome, Italy; 3. Lin I, et al. at ESC Congress; August 27 31, 2016; Rome, Italy.

24 Non-Vitamin K Oral Anticoagulants Are Non-Inferior for Stroke Prevention but Cause Fewer Major Bleedings Than Well-Managed Warfarin With Time in Therapeutic Range 70% or Higher in Sweden AHA Nov 2016

25 Τι μας δείχνει η καθημερινή κλινική πράξη Βελτίωση αναλογίας αποτελεσματικότητας\ασφάλειας

26 Special AF Population older age significant renal disease Diabetic CAD due to their special risk profile that includes increased risks of both thromboembolic and bleeding events High risk of bleeding (HAS-BLED score 3)

27 Patients with AF in the real world have a high proportion of comorbidities Euro Heart Survey 1 * AFNET 2 * REALISE- AF 3 EORP 4 PREFER- AF 5 Patients (n) Mean age (years) CKD or renal failure (%) 4.2*** 9.2*** 3.9*** 13.2** 12.9** Heart failure (%) Hypertension (%) CAD (%) Prior stroke / TIA (%) 4.2 / / / / / NR Period of data collection *First detected AF cohort; ** CKD; *** Renal failure. NR, not reported 1. Nieuwlaat R et al. Eur Heart J 2005;26: ; 2. Nabauer M et al. Europace 2009;11: ; 3. Steg P et al. Heart 2012;98: ; 4. Lip G et al. Europace 2014;16: ; 5. Kirchhof P et al. Europace 2014;16:6-14.

28 Non-Vitamin K Oral Anticoagulants Are Non-Inferior for Stroke Prevention but Cause Fewer Major Bleedings Than Well-Managed Warfarin With Time in Therapeutic Range 70% or Higher in Sweden AHA Nov 2016

29 Elderly Patients with AF

30 Elderly Patients in RCTs In real world data ~45% of pts with AF are 75 years Stroke rates of up to 36.2% at age of years Go et al. JAMA 2001 and NOACs Trials

31 Oral anticoagulation in the elderly: Current Status REPOSI: Prospective observational study in Italian elderly patients ( ) Patients at high thromboembolic risk OAC + AP OAC AP None Internal medical and geriatric wards ,7 O v e r t r e a t e d ( 6. 8 % ) Mean age: 82 (76 86) CKD: ~29% ~99 % of patients had a CHA 2 DS 2 -VASc score >2 (high risk) Internal medical and geriatric wards Under-treatment associated with: all-cause deaths (OR 2.30, 95% CI 1.32, 4.02, p=0.003) ,8 E S C g u i d e l i n e - t r e a t e d ( % ) U n d e r t r e a t e d ( % ) CV deaths (OR 2.88, 95% CI 1.13, 7.39, p=0.027) ,5 AF, atrial fibrillation; AP, antiplatelet; OAC, oral anticoagulant; SE, systemic embolism 1. Yiin GSC, et al. Circulation. 2014; 130: ; 2. Proietti M, et al. Clin Res Cardiol 2016 May 31. [Epub ahead of print].

32 Apixaban in Elderly Adults The benefits of apixaban are consistent in pts with AF regardless of age S. Halvorsen et al. European Heart Journal 2014

33 Low-dose Apixaban vs Warfarin At least 2 of 3 Age 80 yrs, Cr 1.5 mg/dl, Wt 60 kg Granger CB et al. N Engl J Med 2011

34 Among older patients, falling is common (about 30% fall at least once a year), and subdural hematomas are uncommon persons taking warfarin must fall about 295 times in 1 year for warfarin to not be the optimal therapy. In ARISTOTLE, among patients with history of falls, there was an 80% lower rate of ICH with apixaban vs warfarin Arch Intern Med 1999;159: Rao M et al. ESC 2016

35 PATIENTS WITH RENAL IMPAIRMENT

36 X-fold increase in AUC vs. normal renal function Different Renal Clearance Mild 6 5 Moderate Severe Rivaroxaban Apixaban Dabigatran NOTE: Graphs based on data in respective SmPCs. No head to head comparison. Data for edoxaban are currently not available. 1. Rivaroxaban SmPC; 2. Apixaban SmPC; 3. Dabigatran SmPC; 4. Stangier J et al. Clin Pharmacokinet. 2010;49(4):

37 % of Patients Antithrombotic Therapy in AF: Renal Impairment Distribution of patients with AF according to renal function Leiden Anticoagulation Clinic (n=5,039; ) 1 AURICULA Registry, Malmö (n=2,603; ) % 34.2% 80 Using Different egfr Cut-off Values % % % 0.8% > % 4.3% <60 <45 <30 egfr, ml/min/1.73 m 2 (MDRD formula) egfr, ml/min/1.73 m 2 (MDRD formula) Kooiman et al. J Thromb Haemost 2011, Jönsson et al. Thromb Res 2011

38 Chronic kidney disease increases the risk of stroke, bleeding and all-cause death in AF patients Danish registry ( ) REFERENCE: NVAF PATIENTS WITH NO RENAL DESEASE (n= ) HR (95% Cl)* STROKE / SE Non-end-stage CKD 1.49 (1.38; 1.59) CKD requiring renal replacement therapy 1.83 (1.57; 2.14) MAJOR BLEEDING Non-end-stage CKD 2.24 (2.10; 2.38) CKD requiring renal replacement therapy 2.70 (2.38; 3.07) DEATH FROM ANY CAUSE Non-end-stage CKD 2.37 (2.30; 2.44) CKD requiring renal replacement therapy 3.35 (3.13; 3.58) Olesen et al. N Engl J Med 2012;367:625-35

39 Incidence of renal impairment in NOAC trials RE-LY (Dabigatran) ARISTOTLE (Apixaban) ROCKET-AF (Rivaroxaban) ENGAGE-AF (Edoxaban) Renal clearance 85% ~27% ~33% 50% CrCl (ml/min) NUMBER OF PATIENTS IN TRIAL >80 n = 5844 (33%) n = 7518 (41%) >50-80 n = 8553 (48%) n = 7587 (42%) n = (79%); CrCl 50 ml/min (80.5%)ⱡ (>50 ml/min) 50 n = 3554 (20%) n = 3017 (17%) n = 2950 (21%) 2740 (19.5%)ⱡ Exclusion criteria <30 ml/min <25 ml/min <30 ml/min <30 ml/min

40 pharmacokinetic curves for renally cleared drugs in patients with normal and impaired kidney function

41 Stroke/SE and major bleeding event rates for subgroups of patients with stage III CKD Stroke/SE Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 15 mg qd Apixaban 2.5/5.0 mg bid 0.77 ( ) 0.55 ( ) 0.86 ( ) 0.79 ( ) Major bleeding Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 15 mg qd Apixaban 2.5/5.0 mg bid 0.99 ( ) 1.03 ( ) 0.95 ( ) 0.50 ( ) New oral anticoagulant better Warfarin better New oral anticoagulant better Warfarin better Phase III trial data suggest NOACs may be preferable to warfarin in patients with moderate renal impairment Hart et al. Canadian Journal of Cardiology 2013

42 J Am Coll Cardiol 2016;67:

43 ARISTOTLE: OUTOMES according to RENAL FUNCTION (Cockcroft-Gault) egfr APIXABAN 5 mg BID* WARFARIN % / yr (no. of events) HAZARD RATIO (95% Cl) P VALUE FOR INTERACTION STROKE / SE 0.71 >80 ml/min a 0.99% (70) 1.12% (79) >50-80 ml/min b 1.24% (87) 1.69% (116) 50 ml/min c 2.11% (54) 2.67% (69) MAJOR BLEEDING 0.03 >80 ml/min a 1.46% (96) 1.84% (119) >50-80 ml/min b 2.45% (157) 3.21% (199) 50 ml/min c 3.21% (73) 6.44% (142) Apixaban better Warfarin better a n=7518 (41%); b n=7587 (42%); c n=3017 (17%). Results were consistent regardless of methods for GFR estimation. Patients with severe renal insufficiency [serum creatinine >2.5 mg/dl (221 μmol/l) or calculated creatinine clearance <25 ml/min] were excluded from the trial. CI, confidence interval *Refer to SmPC for specific dose reduction criteria; Adapted from Hohnloser et al. Eur Heart J 2012;33:

44 ARISTOTLE: OUTCOMES IN ELDERLY PATIENTS ( 75 YEARS) BY RENAL FUNCTION COCKROFT- GAULT (egfr) N 75 APIXABAN 5 mg BID* WARFARIN %/yr (no. of events) HAZARD RATIO (95% Cl) P VALUE FOR INTERACTION STROKE / SE 0.50 >80 ml/min (8) 2.16 (11) >50-80 ml/min (39) 1.70 (45) >30-50 ml/min (28) 2.69 (44) 30 ml/min (3) 5.57 (9) MAJOR BLEEDING 0.16 >80 ml/min (11) 3.39 (15) >50-80 ml/min (85) 4.45 (104) >30-50 ml/min (47) 6.27 (87) 30 ml/min (7) 13.4 (17) Apixaban better Warfarin better Halvorsen S, et al. European Heart J 2014;35:

45 Major Bleeding by Creatinine 5 mg Twice Daily Dose Only Creatinine (mg/dl) at randomization Hohnloser SH et al Eur Heart J. 2012

46 How to use NOACs in AF patients with renal impairment Renal impairment (creatinine clearance) Apixaban (5 mg BD) Mild No dose (50 80 ml/min or adjustment ml/min) 1 4 * Moderate No dose (30 49 ml/min or adjustment ml/min) 1,2,4 * Severe Reduce (15 29 ml/min or dose to 2.5 <30 ml/min) 1,2,4 End-stage renal disease 1 4 (<15 ml/min) mg BD Not recommended SmPC recommendation Rivaroxaba 2 (20 mg OD) No dose adjustmen t Reduce dose to 15 mg OD Reduce dose to 15 mg OD Not recommended Edoxaban 3 (60 mg OD) No dose adjustmen t Reduce dose to 30 mg OD Reduce dose to 30 mg OD Not recommended Dabigatran (150 mg BD) No dose adjustmen t 150 mg BD; reduce to 110 mg BD if high risk of bleeding Contraindicated Contraindicated * Unless the patient fulfils the criteria for a dose reduction to apixaban 2.5 mg BD, i.e. at least two of the following characteristics: age 80 years; weight 60 kg; serum creatinine 1.5 mg/dl (133 µmol/l). In patientswith severe renal impairment, rivaroxaban should be used with caution. 1. Apixaban SmPC; 2. Rivaroxaban SmPC; 3. Edoxaban SmPC; 4. Dabigatran SmPC.

47 DIABETIC PATIENTS

48 European Heart Journal Cardiovascular Pharmacotherapy 2015

49 European Heart Journal Cardiovascular Pharmacotherapy 2015

50 PATIENTS WITH CAD

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53 Apixaban versus warfarin according to coronary artery disease status International Journal of Cardiology 2016; 225:

54 AUGUSTUS

55 Thromboembolic events Major bleedings J Interv Card Electrophysiol 2016;46:

56 Selection of OAC in special AF Populations Potpara et al. PROGRESS IN CARDIOVASCULAR DISEASES 2015

57 EHJ 2017

58 Συμμόρφωση ασθενών

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60 Yao et al JAHA 2016

61 Yao et al JAHA 2016

62 Tομείς ερευνητικού ενδιαφέροντος στην καρδιολογία και τη φλεβική θρομβοεμβολή (ΦΘΕ) του Alliance BMS/Pfizer Διαδερμική τοποθέτηση αορτικής βαλβίδας Υποκλινική MBKM Καρδιομετατροπή Συμμόρφωση Μη καλυπτόμενες ανάγκες αντιπηκτικής θεραπείας Κατάλυση ΜΒΚΜ + οξύ στεφανιαίο σύνδρομο/ διαδερμική στεφανιαία επέμβαση Θεραπευτική στρατηγική για την ΠΕ Καρκινοπαθείς Ασθενείς υψηλού κινδύνου με ΦΘΕ ΦΘΕ: φλεβική θρομβοεμβολή. ΟΣΣ: οξύ στεφανιαίο σύνδρομο, ΜΒΚΜ: μη βαλβιδική κολπική μαρμαρυγή. PCΙ: διαδερμική στεφανιαία παρέμβαση, ΠΕ: πνευμονική εμβολή

63 ΠΟΛΥΚΕΝΤΡΙΚΕΣ ΜΕΛΕΤΕΣ ΣΕ ΚΛΙΝΙΚΕΣ ΜΕΛΕΤΕΣ EMANATE (Cardioversion) AXAFA* (Ablation) AXSES (Device implantation) ATLANTIS* (TAVI) ARTESIA* (Silent AF) AUGUSTUS (KM με ΟΣΣ και/ή Ιγενή αγγειοπλαστική) ΕΞΕΛΙΞΗ ΕΡΩΤΗΜΑΤΑ ΠΟΥ ΘΑ ΑΠΑΝΤΗΘΟΥΝ Είναι το apixaban ασφαλές και αποτελεσματικό στην πρώιμη καρδιοανάταξη? Είναι η κατάλυση της κολπικής μαρμαρυγής ασφαλής, όταν πραγματοποιείται υπό apixaban? Είναι ασφαλές να εμφυτεύσουμε βηματοδότη σε ασθενείς με κολπική μαρμαρυγή υπό apixaban? Είναι το apixaban αποτελεσματικό στο να προφυλάξει από καρδιοαγγειακά συμβάματα ασθενείς μετά από επιτυχή διακαθετηριακή εμφύτευση αορτικής βαλβίδας σε αορτική στένωση? Πρέπει η υποκλινική κολπικη μαρμαρυγή που ανιχνεύεται στις καρδιαγγειακές συσκευές να θεραπεύεται με apixaban? Ποια είναι η ιδανική αντιαιμοπεταλιακή θεραπεία σε συνδυασμό με apixaban μετά από οξύ στεφανιαίο σύνδρομο/αγγειοπλαστική? ANNEXA-A (Portola Ph 3) Υπάρχει αντίδοτο που αναστρέφει τη δράση των αναστολέων Xa? AEGEAN (Adherence) Πώς μπορούμε να αυξήσουμε τη συμμόρφωση στη λήψη apixaban σε πραγματικές συνθήκες? Note: Alliance-supported Multinational Collaborative Trials [Investigator Sponsored Research (ISR) ΟΣΣ, acute coronary syndrome; AF, atrial fibrillation; Ιγενής αγγειοπλαστική, percutaneous coronary intervention

64 Apixaban Γεγονότα από τον αληθινό κόσμο 1. Βελτιώνει το απόλυτο ώφελος για τον ασθενή μας (net benefit) 2. Θα πρέπει να είμαστε ρεαλιστές ως προς το TTR των κουμαρινικών 3. Πιθανόν το καταλληλότερο NOAC για ασθενείς με ειδικά χαρακτηριστικά