Νεότερα αντιπηκτικά, νέες μελέτες, νέα φάρμακα και δεδομένα απο τον πραγματικό κόσμο

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1 Νεότερα αντιπηκτικά, νέες μελέτες, νέα φάρμακα και δεδομένα απο τον πραγματικό κόσμο Χαράλαμπος Βλαχόπουλος Επίκουρος Καθηγητής Καρδιολογίας 1 η Πανεπιστημιακή Κλινική, Ιπποκράτειο ΓΝΑ

2 Ελληνική πραγματικότητα Μελέτη RAFTING Farmakis et al. Hellenic J Cardiol 2013

3 Αποτελεσματικότητα Ασφάλεια Κόστος

4 Αγώνας δρόμου

5 Τόσο όμοια, τόσο διαφορετικά

6 Properties of novel agents for stroke prevention Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Dosing Fixed, twice daily Fixed, once daily Fixed, twice daily Half-life in hours Routine monitoring No No No Renal clearance 80% 33% 25% Involvement of CYP No Yes (CYP3A4) Yes (CYP3A4) CYP = cytochrome P450 Adapted from Eriksson B et al. Annu Rev Med 2011;62: Dec 2012

7 Novel agents for stroke prevention in patients with atrial fibrillation: summary data All agents at least as effective as warfarin, with lower rates of ICH Rivaroxaban is non-inferior to warfarin for the prevention of stroke/se with a similar rate of major bleeding Apixaban is superior to warfarin for the prevention of stroke/se with a lower rate of major bleeding Dabigatran etexilate 110 mg BID is non-inferior to warfarin for the prevention of stroke/se with a lower rate of major bleeding Dabigatran etexilate 150 mg BID is superior to warfarin for the prevention of stroke/se with a similar rate of major bleeding Only agent to significantly reduce ischaemic stroke vs warfarin Novel oral anticoagulants represent a significant improvement in stroke prevention in AF BID = twice daily; ICH = intracranial haemorrhage; SE = systemic embolism Dec 2012

8 Νέα δεδομένα Post-hoc αναλύσεις Δεδομένα από τον πραγματικό κόσμο

9 Μετά την κυκλοφορία των φαρμάκων στην αγορά The day after?

10 Dabigatran

11 Providencia et al, Heart 2014

12 Providencia et al, Heart 2014 κατάλυση την κατάλυση έναντι προστασία έναντι θρομβοεμβολικών και θρομβοεμβολικών κατά την Παρόμοια Παρόμοια προστασία επεισοδίων κατά επεισοδίων ΑΕΕ και ΑΕΕ

13 Providencia et al, Heart 2014

14 Providencia et al, Heart 2014 Παρόμοιος Παρόμοιος κίνδυνος κίνδυνος αιμορραγίας αιμορραγίας

15 Providencia et al, Heart 2014

16 Stroke/systemic embolism: RE-LY + RELY-ABLE RELY-ABLE patients only 5851 patients, mean FU 4.25 yr All dabigatran patients patients, mean FU 3 yr D150: 0.89 %/yr D110: 1.05 %/yr HR: % CI: D150: 1.25 %/yr D110: 1.54 %/yr HR: % CI: Cumulative risk Dabigatran 150 mg BID Dabigatran 110 mg BID No. at risk D110 D Years Years BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 16 Nov 2012

17 Stroke/systemic embolism: RE-LY + RELY-ABLE RELY-ABLE patients only 5851 patients, mean FU 4.25 yr All dabigatran patients patients, mean FU 3 yr D150: 0.89 %/yr D110: 1.05 %/yr HR: % CI: D150: 1.25 %/yr D110: 1.54 %/yr HR: % CI: Cumulative risk Dabigatran 150 mg BID Dabigatran 110 mg BID No. at risk D110 D Years BID = twice daily; D150 and D110 = dabigatran 150 and 110 mg BID, respectively; FU= follow -up; HR = hazard ratio Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details 1 2 Years In the secondary analysis of RE-LY and RELYABLE, dabigatran 150 mg BID was associated with a lower rate of stroke and systemic embolism than the 110 mg BID dose 17 Nov 2012

18 Αναφορές αιμορραγιών μετά την κυκλοφορία του φαρμάκου στην αγορά Βάση δεδομένων Mini-Sentinel του FDA: online φαρμακοεπαγρύπνιση. Οι αναφορές αιμορραγικών συμβαμάτων αμέσως μετά την κυκλοφορία του σκευάσματος ήταν δικαιολογημένες; Weber effect: Newly marketed products, by virtue of their novelty alone, may elicit adverse-event reports at high rates; reporting rates tend to decrease over time. Southworth et al, N Eng J Med 2013

19 Αναφορές αιμορραγιών μετά την κυκλοφορία του φαρμάκου στην αγορά Southworth et al, N Eng J Med 2013

20 Bleeding rates associated with dabigatran use during the period of interest did not appear to be higher than those associated with warfarin. Southworth et al, N Eng J Med 2013

21 Κόστος; Σε ασθενείς με ΚΜ και προηγούμενο ισχαιμικό ή παροδικό ισχαιμικό ΑΕΕ: Kamel et al, Stroke 2012

22 1. Ετήσιο κόστος παρακολούθησης INR ανά ασθενή = 301 ευρώ 2. Το κόστος των συμβάντων βασίστηκε στα ΚΕΝ 3. Δεν υπολογίστηκε το μισθολογικό κόστος που ανέρχεται σε 40 70% του κόστους της υγειονομικής περίθαλψης Andrikopoulos G., Fragoulakis V., Maniadakis N. Hellenic J Cardiol Jul Aug;54(4):289 Aug;54(4):

23 Dabigatran in AF: The Denmark experience 2013 Jun 4;61(22): ,315 first-time Dabigatran users with atrial fibrillation,with an average follow-up time of 13 months VKA-naïve warfarin initiators had the highest overall bleeding rate No evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users, irrespective of prior VKA experience

24 Dabigatran in AF: The Denmark experience

25 Time to discontinuation by treatment group and risk of stroke A ,745 matched pairs of patients B 1.00 Stroke risk = high; treatment = dabigatran Stroke risk = high; treatment = warfarin Stroke risk = low; treatment = dabigatran Stroke risk = low; treatment = warfarin Persistence probability Persistence probability Time to discontinuation (days) Time to discontinuation (days) A) 30-day medication gap B) 60-day medication gap In both treatment groups, patients with low-to-moderate stroke risk (CHADS 2 score <2) were less persistent than patients with higher risk Kaplan Meier survival curves for unmatched patients by treatment groups and risk of stroke Zalesak M et al. Circ Cardiovasc Qual Outcomes 2013;6: Disclaimer: Dabigatran etexilate is approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details

26 Persistence rates by treatment group after patient matching

27 Higher Persistence in Newly Diagnosed Nonvalvular Atrial Fibrillation Patients Treated With Dabigatran Versus Warfarin Zalesak M et al. Circulation: Cardiovascular Quality and Outcomes 2013;6: Oral anticoagulation therapy can achieve significant stroke-risk reduction when taken in accordance with recommended guidelines 1,745 matched pairs of patients with newly diagnosed nonvalvular A-fib on oral anticoagulation with either warfarin or dabigatran between October 28, 2010, and June 30, Treatment discontinuation rates for warfarin are high, largely due to its complex dosing regimen and INR monitoring requirements Goal: To compare real-world persistence rates in newly diagnosed patients with NVAF who begin dabigatran or warfarin, and the factors associated with discontinuation of treatment

28 Persistence rates by treatment group after patient matching Patients prescribed dabigatran had higher persistence rates than patients prescribed warfarin at all time periods, analyzed with both a 30-day and a 60-day medication gap

29 Therapy persistence: author conclusions Newly diagnosed NVAF patients starting dabigatran showed consistently higher persistence than those treated with warfarin After 6, 9, and 12 months of therapy Analyzed using both a 30-day and a 60-day permissible treatment gap Patients who were younger, with lower stroke risk, or with increased bleeding risk were more likely to discontinue treatment In addition to superior stroke-risk reduction, dabigatran may contribute to improved patient outcomes through increasing persistence with therapy

30 Dabigatran in AF: Denmark experience J Am Coll Cardiol Jun 4;61(22):

31 Ασθενείς με βαλβιδοπάθεια Compared to patients without VHD, patients with VHD had a comparable risk of stroke and systemic embolism, but were at higher risk of death and of major bleeding. However, the relative benefits of dabigatran compared to warfarin regarding stroke, systemic embolism major bleeding and life-threatening or intracranial bleeds were similar in both groups (P-values for interaction not significant). Poster ACC.14

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33 Original Article Accepted October Dabigatran Versus Warfarin in Patients With Atrial Fibrillation An Analysis of Patients Undergoing Cardioversion Rangadham Nagarakanti, MD; Michael D. Ezekowitz, MBChB, DPhil, FRCP, FACC; Jonas Oldgren, MD, PhD; Sean Yang, MSc; Michael Chernick, PhD; Timothy H. Aikens, BA; Greg Flaker, MD; Josep Brugada, MD; Gabriel Kamenský, MD, PhD, FESC; Amit Parekh, MD; Paul A. Reilly, PhD; Salim Yusuf, FRCPC, DPhil; Stuart J. Connolly, MD

34 Dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. A total of 1983 cardioversions were performed in 1270 pts 647, 672 and 664 in the D110, D150 and warfarin groups respectively. For D110, D150, and warfarin, transesophageal echocardiography was performed before 25.5%, 24.1%, and 13.3% of cardioversions, of which 1.8%, 1.2%, and 1.1% were positive for left atrial thrombi. Continuous treatment with study drug for 3 weeks before cardioversion was lower in D110 (76.4%) and D150 (79.2%) compared with warfarin (85.5%; P<0.01 for both). Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6% (D110 versus warfarin, P=0.71; D150 versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (D110 versus warfarin, P=0.06; D150 versus warfarin, P=0.99).

35 Rivaroxaban

36 Safety and efficacy of rivaroxaban and dabigatran in octa- and nonagenerians with atrial fibrillation: A community based experience pts treated for afib with warfarin, rivaroxaban or dabigatran from Jan to Jan were retrospectively reviewed End-points of stroke/tia and bleeding were analyzed in the overall population and an older/elderly (>80yrs) subpopulation Results compared to RE-LY and ROCKET-AF

37 Safety and efficacy of rivaroxaban and dabigatran in octa- and nonagenerians with atrial fibrillation: A community based experience

38 Real world comparative effectiveness and safety of Rivaroxaban and Warfarin in NonValvular Atrial Fibrillation patients 3,654 rivaroxaban and 14,616 warfarin patients. EFFECTIVE AND SAFE IN AFIB

39 Real world comparative effectiveness and safety of Rivaroxaban and Warfarin in NonValvular Atrial Fibrillation patients HIGHER PERSISTENCE

40 Economic evaluation of rivaroxaban in stroke prevention for patients with atrial fibrillation in Greece Goal: To undertake an economic evaluation of rivaroxaban relative to the standard of care for stroke prevention in patients with non-valvular atrial fibrillation (AF) in Greece. Economic evaluation was undertaken to compare, from a payer perspective, rivaroxaban relative to acenocoumarol for the prevention of stroke in patients with AF in Greece. it was assumed that the clinical outcomes obtained from the ROCKET AF trial were applicable to the Greek health care setting.

41 Economic evaluation of rivaroxaban in stroke prevention for patients with atrial fibrillation in Greece

42 Economic evaluation of rivaroxaban in stroke prevention for patients with atrial fibrillation in Greece Based on SOT data from the ROCKET AF trial, the analysis predicted a discounted QALY of 6.50 and 6.28 in rivaroxaban- and VKA-treated patients. The total lifetime cost was lower in the rivaroxaban arm ( 7,868) compared to the VKA arm ( 8,107), resulting in a cost saving of 239. Rivaroxaban was associated with additional drug acquisition cost ( 4,033), however this was totally offset by reduced monitoring (- 3,929) and event management (- 341) costs. Therefore, rivaroxaban seems to be a dominant alternative over VKA, as the former is related with lower cost and greater health benefit. Kourlaba G. et al.

43 Apixaban

44 Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical Outcomes The ARISTOTLE trial enrolled 18,201 patients from 1034 clinical sites in 39 countries. Major hemorrhage occurred in 789 patients (4.3%) overall; 327 in the apixaban group (2.13% per year) compared with 462 in the warfarin group (3.09% per year) (hazard ratio [HR] 0.69, 95% confidence interval [CI] ; P<0.001). Patients who sustained a major bleed were older (74 vs. 70 years), more commonly had a history of myocardial infarction, prior hemorrhage impaired renal function Hylek E, et al. JACC 14

45 Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical Outcomes 18,201 patients from 1034 clinical sites in 39 countries. Hylek E, et al. JACC 14

46 Major Bleeding in Patients with Atrial Fibrillation Receiving Apixaban or Warfarin in the ARISTOTLE Trial: Predictors, Characteristics, and Clinical Outcomes Hylek E, et al. JACC 14

47 Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial 18,201 patients with AF were randomized to apixaban or warfarin A total of 6639 (36.5%) patients had prior CAD. The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause Bahit MC, et al. 2013

48 Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial Bahit MC, et al. 2013

49 Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial Halvorsen et al. JACC 2013

50 Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial Superiority of apixaban vs warfarin was shown to be consistent in patients with AF regardless of age Even greater absolute benefit with increasing age Attractive alternative for elderly patients with AF Halvorsen et al. JACC 2013

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52 Global Registry on Long-Term Oral Antithrombotic Treatment in AF Patients Collection of data on dabigatran etexilate in countries/regions and globally Increase knowledge on AF patients, treatment patterns, and outcome events in a real-world setting Involvement of up to 2200 physicians worldwide: GPs, cardiologists, neurologists, internists, geriatricians etc. hospital based or private practice up to 56,000 patients 2,200 sites up to 50 countries 52

53 Global Registry on Long-Term Oral Antithrombotic Treatment in AF Patients

54 Η ΜΕΛΕΤΗ GLORIA-AF ΣΤΗΝ ΕΛΛΑΔΑ

55 Κολπική Μαρμαρυγή και οι κίνδυνοι που ελλοχεύουν

56 Νεότερα αντιπηκτικά στον πραγματικό κόσμο Περισσότερα δεδομένα για υποομάδες Δεδομένα από τον πραγματικό κόσμο Ισχύουν τα δεδομένα των μεγάλων μελετών σχέση κόστους οφέλους