L approccio per paziente nella gestione dei NAO: analisi per età e funzionalità renale. Niccolò Marchionni

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1 L approccio per paziente nella gestione dei NAO: analisi per età e funzionalità renale Niccolò Marchionni Cattedra di Geriatria, Università di Firenze Azienda Ospedaliero-Universitaria Careggi, Firenze Società Italiana di Cardiologia Geriatrica Chaiperson, Geriatric Expert Group, European Medicines Agency, London

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3 Stroke or systemic embolic events RR NOA N=42411, Age: 71.6 y Warfarin N=29272, Age: 71.5 y RR (95% CI) P RR=0.81 ( ), P< Ruff CT, 2014

4 Major bleeding RR (95%CI) Secondary efficacy and safety outcomes 0.71 RR (95% CI) 0.80 P Efficacy Safety < < Ruff CT, 2014

5 Anziano & NAO: una relazione particolare

6 FA e NAO: perchél anziano èun paziente particolare? Key points Elevata prevalenza di FA rischio cardioembolico (CHA 2 DS 2 -VASC) Comorbilità( CKD) rischio emorragico con TAO (HAS-BLED)

7 ARE GERIATRIC SYNDROMES ASSOCIATED WITH RELUCTANCE TO INITIATE ORAL ANTICOAGULATION THERAPY IN ELDERLY ADULTS WITH NONVALVULAR ATRIAL FIBRILLATION? Multivariate Predictors of the Absence of Oral Anticoagulation Therapy (N=137; Age: 82 years; Permanent AF: 70%; Not anticoagulated: 51%; High risk CHA 2 DS 2 VASc: 99%; HAS-BLED: 39%) OR 95%CI p Age / / NS Female / / NS Lives alone / / NS Education Years / / NS Depressive Symptoms <0.05 Cognitive impairment CHA 2 DS 2 VASc score / / NS HAS-BLED score <0.05 Depressive Symptoms: Geriatric Depression Scale >5; Cognitive impairment: Mini-Mental State Examination 23 Sánchez-Barba B, 2013

8 Anziano & NAO: sub-analisi e meta-analisi RCTs

9 Heidbuchel H, 2013 Assorbimento e metabolismo dei NAO Dabigatran Apixaban Edoxaban Rivaroxaban Biodisponibilità 3-7% 50% 62% 66% 100% pasti Profarmaco Si No No No Eliminazione renale 80% 27% 50% 35% CYP3A4 No Minore Minima Si Interazione con cibo Raccomandato ai pasti No No % + 39% No No / Si Anti-H2/PPI % No No No Emivita Y E

10 RE-LY: With comparable efficacy for Stroke/SE and safety for ICH, rates of major bleeding and extracranial bleeding were higher in subjects 75 years compared to younger subjects Rates of stroke, major bleeding, ICH and extracranial bleeding with Dabigatran 110 and 150 mg BD vs. warfarin in patients aged < 75 (n=10,865) and 75 (n=7258) years Dabigatran 110 BD Dabigatran 150 BD Warfarin Stroke/SE Age < Dabigatran 110 vs. warfarin Interaction Pvalue Dabigatran 150 vs. warfarin Interaction Pvalue Age Major Bleeding <0.001 <0.001 Age < Age ICH Age < Age Extracranial Bleeding < Age < Age Dabigatran Better Warfarin Better Dabigatran Better Warfarin Better 1. Adapted from Eikelboom JW et al. Circulation 2011;123:

11 RE-LY Extracranial Major Bleeding Rate, by Age-Group 10 8 Dabigatran 150 Dabigatran 110 Warfarin Dabigatran 110 vs. Warfarin p=0.006 Dabigatran 150 vs. Warfarin p=0.002 Event rate (%/year) < Age (years) Eikelboom JW, 2011

12 Dose-Normalized Plasma Through Concentrations of Dabigatran by Demographic Characteristics in the RE-LY Trial (1) N = 8449 Mean Concentration (ng/ml/mg) Gender Age (years) Weight (Kg) Reilly PA, 2014

13 Dose-Normalized Plasma Through Concentrations of Dabigatran by Demographic Characteristics in the RE-LY Trial (2) N = 8449 Mean Concentration (ng/ml/mg) CrCl (ml/min) CHA 2 DS 2 -VASc HAS-BLED Reilly PA, 2014

14 Cumulative proportion of patients experiencing primary end points over 24 months by age-group group Stroke/Systemic Embolism (%) W R Age >75 years (N=6229) Age: 79 y, y CHA 2 DS 2 : 3.69 Age <75 years (N=8035) Age: 66 y, y CHA 2 DS 2 : 3.30 Rivaroxaban vs. Warfarin Age >75 years HR: 0.80, ( ) Age <75 years HR: 0.95, ( ) P for interaction = %/year 2.29%/year 2.10%/year 2.00%/year Months since Randomization Halperin JL, 2014

15 The effect of apixaban vs. warfarin according to age (1) Stroke / Systemic embolism All-cause mortality P interaction = 0.11 P interaction = 0.43 Events (% / year) <65 N=5471; N=7052; 75 N=5678 Age-groups (years) Halvorsen S, 2014

16 The effect of apixaban vs. warfarin according to age (2) All bleeding Intracranial bleeding P interaction = 0.94 P interaction = 0.20 Events (% / year) <65 N=5471; N=7052; 75 N=5678 Age-groups (years) Halvorsen S, 2014

17 Warfarin rate (%/y) ISTH major bleeding Intracranial hemorrhage Absolute risk reduction Both P interaction vs. Warfarin=NS Both P interaction vs. Warfarin=NS <65 years N= years N=7134 >74 years N=8474 Toda Kato E, 2014

18 Patients aged more than 75 years: Stroke or systemic embolism Rivaroxaban ROCKET-AF Subtotal Apixaban ARISTOTLE AVERROES Subtotal Odds Ratio MH 95%CI New oral anticoagulants vs. conventional therapy for participants aged >75 years NOAC N: Control N: 9177 Dabigatran RE-LY Subtotal NNT: number needed to treat Total NOAC: 3.3 vs. C: 4.7% OR=0.65 NNT=71 95%CI= NOAC Control Favors Sardar P, 2014

19 Patients aged more than 75 years: Major or clinically relevant bleeding Rivaroxaban EINSTEIN PE EINSTEIN EINSTEIN-Extension ROCKET-AF Subtotal Odds Ratio MH 95%CI New oral anticoagulants vs. conventional therapy for participants aged >75 years Apixaban ARISTOTLE AVERROES Subtotal NOAC N: Control N: Dabigatran RE-LY Subtotal Total NOAC: 6.4 vs. C: 6.3% OR= %CI= NOAC Control Favors Sardar P, 2014

20 Dati real life

21 Thromb Hemost 2012

22 March 13, Drug-safety investigation, focused on the occurrence of bleeding, promoted by Food and Drug Administration (FDA) over the period October 19, 2010 to December 31, Mini-Sentinel

23 13 Maggio 2014

24 Incidence rate per 1,000 person-years Pradaxa (dabigatran) Warfarin Adjusted hazard ratio (95% CI) Ischemic stroke ( ) Intracranial hemorrhage ( ) Major GI bleeding ( ) Acute MI ( ) Mortality ( ) Possibile causa dell aumento dei sanguinamenti gastrici potrebbe essere il fatto che in USA l uso del 110 mg non è registrato e la popolazione di pazienti studiata è più anziana rispetto al MiniSentinel.

25 30 ottobre 2014 New-user cohorts of PSM elderly patients enrolled in Medicare (Oct Dec. 2012) n= 134,314 58% 59%

26 30 ottobre 2014 New-user cohorts of PSM elderly patients enrolled in Medicare (Oct Dec. 2012) n= 134,314

27 2 large US health insurance databases From Oct 2010 to Dec % stroke rate reduction 25% reduction in the rate of major hemorrhage

28 Department of Defense Military Health System database. From October 1, 2009 to July 31, 2013

29 ~ 134,000 pt ~ 38,000 pt ~ 25,000 pt Almost 200,000 pt

30 CKD & NAO: sub-analisi RCTs

31 HRs for patients with stage III CKD from randomized trials comparing NOACs with warfarin for stroke and systemic embolism Cr Cl ml/min 2.2% per year 1.5% per year 2.8% per year ml/min Cr Cl Cockcroft-Gault equation RE-LY N=3505; ROCKET-AF N=2950; ARISTOTLE N=3017 New oral anticoagulant better HR (95%CI) Warfarin better Hart RG, 2013

32 HRs for patients with stage III CKD from randomized trials comparing NOAs with warfarin for major bleeding Cr Cl ml/min ml/min 3,2% per year 6,4% per year Hemorrhagic stroke HR=0.06 ( ) New oral anticoagulant better HR (95%CI) Warfarin better Hart RG, 2013

33 Possible considerations for selecting between NOA based on patient characteristics Savalieva I, 2014

34 NOACs in patients with renal impairment: EU labels Patient population Mild renal impairment (CrCl ml/min) Moderate renal impairment (CrCl ml/min) Dosing recommendations according to EU label Dabigatran 150 mg BID Rivaroxaban 20 mg OD Apixaban 5 mg BID Dabigatran 150 mg BID (110 mg BID should be considered in patients at high bleeding risk) Rivaroxaban 15 mg OD Apixaban 5 mg BID Severe renal impairment (CrCl ml/min) Dabigatran contraindicated Rivaroxaban 15 mg OD Apixaban 2.5 mg BID Rivaroxaban and apixaban not recommended in patients with CrCl <15 ml/min BID = twice daily; EU = European Union; OD = once daily Pradaxa : EU SmPC, 2012; Xarelto: EU SmPC, 2012; Eliquis: EU SmPC, 2012 Feb 2013

35 NOACs in patients with renal impairment: ESC guidelines

36 2012 ESC guidelines update Recommendation Class Level Baseline and subsequent regular assessment of renal function (by CrCl) is recommended in patients following initiation of any NOAC, and should be done annually but more frequently in those with moderate renal impairment, where CrCl should be assessed 2 3 times per year IIa A NOACs (dabigatran, rivaroxaban, and apixaban) are not recommended in patients with severe renal impairment (CrCl <30 ml/min) III A ALL NOACs are not recommended in patients with severe renal impairment (CrCl <30 ml/min) CrCl = creatinine clearance; ESC = European Society of Cardiology; NOAC = novel oral anticoagulant; NVAF = nonvalvular atrial fibrillation Camm AJ et al. Eur Heart J 2012;33: Feb 2013

37 2012 ESC guidelines update: patients with moderate renal impairment (CrCl ml/min) Recommendation Class Level When dabigatran is prescribed, a dose of 150 mg BID should be considered for most patients in preference to 110 mg BID, with the latter dose recommended in: elderly patients, age 80 years concomitant use of interacting drugs (e.g. verapamil) high bleeding risk (HAS-BLED score 3) moderate renal impairment (CrCl ml/min) Where rivaroxabanis being considered, a dose of 20 mg o.d. should be considered for most patients in preference to 15 mg OD, with the latter dose recommended in: high bleeding risk (HAS-BLED score 3) moderate renal impairment (CrCl ml/min) IIa IIa B C BID = twice daily; CrCl = creatinine clearance; ESC = European Society of Cardiology; OD = once daily Camm AJ et al. Eur Heart J 2012;33: Feb 2013