Είναι τα δεδομένα από τον πραγματικό κόσμο σε συμφωνία με τα αποτελέσματα των τυχαιοποιημένων κλινικών δοκιμών?

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1 Είναι τα δεδομένα από τον πραγματικό κόσμο σε συμφωνία με τα αποτελέσματα των τυχαιοποιημένων κλινικών δοκιμών? Δ. ΡΙΧΤΕΡ, MD, FESC, FAHA -Διευθυντής Καρδιολογικής Κλ. Ευρωκλινικής Αθηνών -Αντιπρόεδρος ΙΜΕΘΑ

2 Το ταξίδι ενός φαρμάκου

3 από τις μελέτες φάσης III

4 Μέσω αυτών των RCTs

5 τα NOACs έγιναν πράξη

6 NOACs Showed a Favourable Benefit Risk Profile Versus Warfarin in patients with NVAF NOACs are associated with: A significant reduction in haemorrhagic stroke (with a strong trend towards lower rates of ischaemic stroke); all-cause mortality; ICH A trend towards lower rates of MI An increase in the risk of gastrointestinal bleeding Favours NOAC Favours warfarin Ruff CT et al, Lancet 2014;383:

7 Evaluation of bleeding events from Real Word Evidence (RWE)

8 Randomized Clinical Trials with strict inclusion/exclusion criteria in selected centers for a fixed time-period

9 Είναι σημαντικό να γνωρίζουμε how a treatment works in everyday clinical practice?

10 γιατί υπάρχουν παραδείγματα Mibefradil (Posicor) Calcium channel blocker Rofecoxib (Vioxx) COX-2 inhibitor Rosiglitazone (Avandia) Thiazolidinedione Ximelagatran (Exanta) Direct thrombin inhibitor after initial approval by agencies like the FDA and/or EMA, all were either withdrawn from the market or substantially limited in their use

11 Τι χρειαζόμαστε; Real World Data (RWD) EMA: Healthcare-related data that is collected outside of RCTs FDA: Data collected from outside the traditional clinical trials

12 Γιατί θέλουμε RWD; να επιβεβαιώσουμε τα αποτελέσματα των μεγάλων κλινικών μελετών σε ένα μη επιλεγμένο πληθυσμό με ποικίλες συνοσηρότητες με διαφορετικό προφίλ κινδύνου

13 RCTs Versus RWE RCTs: controlled patient population Approval Post-approval use: more varied medical settings and more diverse patient populations Nallamothu BK et al, Circulation 2008;118: RWE clarifies whether results observed under RCTs are also observed in everyday clinical practice

14 Οι μελέτες phase IV πολλές φορές είναι απαίτηση των εγκριτικών αρχών

15 RWE / Post-marketing bleeding events Food and Drug Administration (FDA) adverse event reporting International claims data Global registry data Vascular Health and Risk Management 2017:

16 Food and Drug Administration (FDA) adverse event reporting Mortality and Oral Anticoagulants in the FDA Adverse Event Reporting System (FAERS) FAERS (FDA Adverse Event Reporting System) is a database that contains information on adverse events and medication error reports that are submitted to the FDA This study included 34,546 deaths out of 283,217 records in the FAERS database between 2 November 1997 and 31 December 2015 Serebruany V et al, Open Heart 2017;4:e000629

17 NOACs are emerging with a death benefit over warfarin Drug Deaths n (%) c 2 PRR* (95% CI) p-value* PRR (95% CI) All NOACs (N=128,267) 14,917 (11.63) ( ) 6.05e -17 Apixaban (N=17,789) 1693 (9.52) ( ) 1.43e -33 Dabigatran (N=46,250) 6989 (15.11) ( ) 3.61e -42 Edoxaban (N=755) 53 (7.02) ( ) 4.18e -06 Rivaroxaban (N=64,512) 6318 (9.79) ( ) 3.72e -80 Warfarin (N=153,911) 19,493 (12.67) NA NA NA NA *Compared with warfarin. χ 2 The bigger the number, the more likely the two groups are different based on that feature Serebruany V et al, Open Heart 2017;4:e Favours warfarin Favours NOAC

18 Independent FDA study of Medicare patients mirrors the favourable benefit risk profile of dabigatran established in RE-LY RE-LY 1 4 N> Warfarin D150 BID INCIDENCE PER 100 PERSON-YEARS RCT EVENT RATE (% PER YEAR) HR: 0.76 P=0.04 RR: 0.41 P<0.001 RR: 0.94 P=0.41 RR: 1.48 P=0.001 RR: 1.27 P=0.12 RR: 0.88 P=0.051 ISCHAEMIC STROKE ICH MAJOR BLEEDING GI BLEEDING MI MORTALITY MEDICARE *5 N> Warfarin D150 & D75 BID combined Real-world data HR: 0.80 P=0.02 HR: 0.34 P<0.001 HR: 0.97 P=0.50 HR: 1.28 P<0.001 HR: 0.92 P=0.29 HR: 0.86 P=0.006 In the USA, the licensed doses for Pradaxa are: 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF *Primary findings for dabigatran are based on analysis of both 75 mg &150 mg together without stratification by dose 1. Connolly SJ et al. N Engl J Med 2009;361: Connolly SJ et al. N Engl J Med 2010;363: Pradaxa : EU SPC, January Connolly SJ et al. N Engl J Med 2014;371: Graham DJ et al. Circulation 2015;131: July 2015

19 International claims data Claims data are collected by payers to track and assure reimbursement for healthcare services provided Some claims databases are: Medicare database 1 Department of Defense databases 2 National healthcare databases (e.g. Danish Nationwide Databases) 3 5 Truven MarketScan 6 Optum Insight 7 Regardless of database type, rarely was this data originally collected for research purposes! 1. Medicare. [accessed Dec 2016]; 2. Tamayo S et al, Clin Cardiol 2015;38:63 68; 3. Lynge E et al, Scand J Public Health 2011;39:30 33; 4. Kildemoes HW et al, Scand J Public Health 2011;39:38 41; 5. Pedersen CB et al, Scand J Public Health 2011;39:22 25; 6. Hansen L, The MarketScan Databases for Life Sciences Researchers. White Paper May 2016; 7. Optum Labs-Partners, Data and Design. [accessed Dec 2016]

20 Major bleeding per 100 person-yrs Lip et al. Thromb Haemost 2016;116: Major bleeding during follow-up (all doses pooled for each NOAC) Incidence and HRs (95% CI) in propensity-score-matched cohorts HR 1.41 ( ) HR 1.82 ( ) HR 1.05 ( ) Apixaban (n=4407) Dabigatran (n=4407) Apixaban (n=7399) Rivaroxaban (n=7399) Dabigatran (n=4657) Rivaroxaban (n=4657) When analysing all NOAC doses, dabigatran was associated with a similar rate of major bleeding vs apixaban Bold HR values indicate statistical significance. Follow-up <6 months. Major bleeding defined as bleeding requiring hospitalization. Limitations: moderate sample size; not all relevant variables may have been used for adjustment 20

21 Bleeding comparisons between DOACs and warfarin from international claims data Vascular Health and Risk Management 2017:

22 22 Weighted event rate (1 year follow-up)* Weighted event rate (1 year follow-up)* Larsen et al. BMJ 2016;353:i3189 Major bleeding Adjusted HR (95% CI) vs warfarin All-cause mortality Adjusted HR (95% CI) vs warfarin HR: 1.06 ( ) HR: 0.61 ( ) HR: 0.58 ( ) 10 8 HR: 0.92 ( ) HR: 0.65 ( ) HR: 0.63 ( ) D Apixaban A Rivaroxaban R W Dabigatran n=12701 n=6349 n=7192 Warfarin n= D Apixaban A Rivaroxaban R W Dabigatran n=12701 n=6349 n=7192 Warfarin n=35436 Dabigatran and apixaban were associated with a statistically significantly lower risk of any bleeding, major bleeding, and death compared with rivaroxaban or warfarin Only standard doses of NOACs were compared in this study. Average follow-up: 1.9 years. *Inverse probability of treatment weighted and expressed as population average treatment rates per 100 years. Bold HR values indicate statistical significance. Limitations: intent-to-treat analysis; limited variables for adjustment; patients included prior to availability of apixaban and rivaroxaban

23 Vascular Health and Risk Management 2017: Global registry data

24 GARFIELD -AF Of the 60.8% of patients given anticoagulant therapy, half were started on warfarin and 10.8% were started on a DOAC. A total of 27.4% of patients were started on antiplatelet therapy only and 11.8% were not started on anticoagulant or antiplatelet therapy. The rate of first major bleeding was 0.70 per 100 person-years (95% CI ) and rates were significantly higher within the first 4 months and significantly decreased beyond this (P=0.001), possibly due to better control of anticoagulation, especially in patients taking warfarin. GI bleeding was the most common site of bleeding and occurred in 1.47% of the total population. Intracranial bleeding occurred in 0.22% of the total population. Vascular Health and Risk Management 2017:

25 XANTUS pooled To collect real world data on adverse events in patients with NVAF treated with rivaroxaban Primary outcomes: major bleeding (ISTH definition), all-cause mortality, any other adverse events N=16,187 Population: Adult patients with NVAF receiving rivaroxaban for stroke/non-cns SE prevention N=11,121 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 # Kirchhof P et al, presented at the ESC 2017, abstr 86691

26 On-treatment event rate (events/100 patient-years) On-treatment event rate (events/100 patient-years) Efficacy Outcomes: XANTUS vs. ROCKET-AF CHADS 2 Prior stroke CHADS 2 Prior stroke XANTUS % ROCKET AF % Stroke/SE Death 0 Stroke/SE Death Kirchhof P et al, presented at the ESC 2017, abstr 86691

27 On-treatment event rate (events/100 patient-years) Safety Outcomes: XANTUS vs. ROCKET-AF CHADS 2 Prior stroke CHADS 2 Prior stroke XANTUS % ROCKET AF % Major bleeding ICH GI bleeding 0 Major bleeding ICH GI bleeding είναι καλύτερα τα αποτελέσματα της XANTUS; Kirchhof P et al, presented at the ESC 2017, abstr 86691

28 Πριν πανηγυρίσουμε

29 ας αναζητήσουμε την αλήθεια after adjustment for CHADS 2 and age similar rates of major bleeding and stroke were observed, with higher rate of all-cause death in XANTUS vs ROCKET AF Camm AJ et al. ACC 2017 poster

30 Επιλέγουμε data Coleman C et al, Curr Med Res Opin. 2016;32:

31 REVISIT-US Rivaroxaban Warfarin HR (95% CI) Rate Rate rivaroxaban vs. warfarin (%/year) (%/year) HR (95% CI) rivaroxaban vs. warfarin ICH ( )* Ischemic stroke ( ) Combined ( )* Favors rivaroxaban Favors warfarin Apixaban Warfarin HR (95% CI) apixaban vs. warfarin Rate (%/year) Rate (%/year) HR (95% CI) apixaban vs. warfarin ICH ( )* Ischemic stroke ( ) Combined ( ) it was not possible to determine TTR Favors Favors apixaban warfarin Coleman C et al, Curr Med Res Opin. 2016;32:

32 Second Medicare analysis a new-user cohort study of patients receiving dabigatran 150 mg or rivaroxaban 20 mg the mean duration of on-treatment follow-up was less than 4 mo Graham D et al, JAMA Intern Med. 2016;176:

33 Συνταγογραφούμε σωστά; Use of low-dose rivaroxaban consistent with expectations from phase III trials

34 Inappropriate reduced dose of a NOAC no renal indication for dose reduction may increase the risk of Stroke/SE Yao et al, J Am Coll Cardiol 2017;69:

35 πάλι προβληματιζόμαστε Weight was not available in the claims data the authors used the CKD-EPI equation to calculate egfr instead of the Cockroft-Gault equation that underdosed apixaban was associated with higher rates of stroke was based on 7 events Median follow-up <4 months

36 Αν δεν υπάρχει we will ALWAYS have residual confounding

37 In observational studies a large variation (from 38% to 95%) in the reported adherence, depending on the methodology of adherence assessment and data source Raparelli et al, Thromb Haemost 2017; 117:

38 Οι παγίδες των RWD Coleman et al, Curr Med Res Opin. 2017;33:

39 Οι παγίδες των RWD Coleman et al, Curr Med Res Opin. 2017;33:

40 Οι παγίδες των RWD Coleman et al, Curr Med Res Opin. 2017;33:

41 Οι παγίδες των RWD Coleman et al, Curr Med Res Opin. 2017;33:

42 Skepticism about RWD