Guida agli anticoagulanti orali diretti nel basso dosaggio: evitare l abuso e saper scegliere con appropriatezza

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1 Guida agli anticoagulanti orali diretti nel basso dosaggio: evitare l abuso e saper scegliere con appropriatezza Enrico Natale I UOC Cardiologia, Ospedale S.Camillo, Roma

2 Steinberg BA, et al: American Heart Journal (2017), doi: /j.ahj

3 43% Steinberg BA, et al: American Heart Journal (2017), doi: /j.ahj

4 71% Steinberg BA, et al: American Heart Journal (2017), doi: /j.ahj

5 Pattern di prescrizione dei NOAC per paese in relazione al dosaggio Apixaban Rivaroxaban Dabigatran Q Q Q PAESE 2.5mg 5mg 10mg 15mg 20mg 75mg 110mg 150mg USA 24% 76% 6% 21% 73% 16% 0% 84% GIAPPONE 58% 42% 55% 45% 0% 40% 60% 0% GERMANIA 41% 59% 4% 34% 61% 2% 61% 37% CANADA 38% 62% 6% 26% 68% 1% 52% 47% AUSTRALIA 39% 61% 2% 30% 68% 0% 63% 37% REGNO UNITO 42% 58% 6% 22% 71% 3% 51% 46% SPAGNA 37% 63% 5% 33% 63% 3% 60% 38% FRANCIA 46% 54% 0% 0% 0% 0% 0% 0% BELGIO 30% 70% 2% 42% 56% 0% 60% 40% ITALIA 35% 65% 2% 37% 61% 0% 63% 36% Vene N. et al. Plos One 2016 Data source: IMS MIDAS and CSD GERS(France) data

6 Vene N. et al. Plos One 2016 Le basse dosi dei NAO nei trial

7 Gonzalez-Quesada CJ and Giugliano RP: Am J Cardiovasc Drugs 2014;14:111-27

8 Gonzalez-Quesada CJ and Giugliano RP: Am J Cardiovasc Drugs 2014;14:111-27

9 Dosi assegnate per randomizzazione. Nessun aggiustamento al basale né al follow-up 20.6% 15 mg/die nei pazienti con VFG ml/min per 1.73 m 2 al basale 4.7% 2.5 mg b.i.d. se almeno due 2 dei seguenti: età > 80, peso < 60 Kg o creatininemia > 1.5 mg/dl al basale % +7% In ciascuno dei 2 bracci randomizzati: Dosi dimezzate se: VFG ml/min oppure peso <60 kg oppure verapamil, chinidina o dronedarone, sia al basale che durante il follow-up Vene N. et al. Plos One 2016

10 RE LY DABI 110 mg RE NEW IL PAZIENTE ANZIANO <75 aa aa >84 aa ICTUS o EMBOLIA SISTEMICA -7% -25% -48% <75 aa aa aa >84 aa EMORRAGIA INTRACRANICA -78% -49% -70% -87% Vene N. et al. Plos One 2016 Riadattata da Lauw MN, et al. Heart 2017;0:1 9. doi: /heartjnl

11 Events (%/year) ROCKET AF: Primary Efficacy Endpoint in Patients with Moderate Renal Impairment Primary efficacy endpoint: Stroke/SE HR 0.86 (95% CI ) HR 0.89 (95% CI ) Warfarin Rivaroxaban CrCl (ml/min) Consistent efficacy of rivaroxaban vs. warfarin in NVAF patients with moderate renal impairment Intention-to-treat population Fox KA et al. Eur Heart J. 2011;32(19):

12 Events (%/year) ROCKET AF: Consistent Safety Outcomes in NVAF Patients With Moderate Renal Impairment 1.5 HR 0.55 (95% CI ) 1.4 Warfarin Rivaroxaban 15 mg OD HR 0.81 (95% CI ) HR 0.39 (95% CI ) Critical organ bleeding ICH Fatal bleeding Safety on-treatment population Fox KA et al. Eur Heart J. 2011;32(19):

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15 Le basse dosi dei NAO nell insufficienza renale Vene N. et al. Plos One 2016

16 EHRA PRACTICAL GUIDE Approved European labels for NOACs and their dosing in CKD Heidbuchel H et al: Updated EHRA Practical Guide on the use of NOACs in patients with NVAF. Europace 2015 Vene N. et al. Plos One 2016

17 Since dabigatran is cleared primarily by the kidneys, patients with impaired renal function could potentially benefit from a lower dose. Patients with severe renal impairment were excluded from RE-LY, but we examined patients (n = 3.343) with moderate renal impairment (creatinine clearance >30 to 50 ml per minute), whose dabigatran concentrations were two to three times as high as those in patients with normal renal function. In this population, the rate of stroke or systemic embolism with 150 mg of dabigatran (1.3 per 100 patient-years) was approximately half that with 110 mg (2.4 per 100 patient-years), and the rate of bleeding was no greater (5.3 vs. 5.7 major bleeding episodes per 100 patient-years). Thus, even in a population exposed to relatively high concentrations of dabigatran, the 150-mg dose had a superior benefit risk profile. N Engl J Med ;19

18 Patients with moderate renal impairment treated with DABIGATRAN: Results from RE-LY Stroke and systemic embolism Study drug (%/yr) Warfarin (%/yr) HR P inter Dabigatran 150 mg Dabigatran 110 mg Major bleeding Study drug (%/yr) Warfarin (%/yr) Favours NOAC Favours warfarin HR Dabigatran 150 mg Dabigatran 110 mg Favours NOAC Favours warfarin Hijazi Z et al. Circulation 2014;129:961

19 Comparison between apixaban 5 mg bid (n = 8665) and warfarin (n = 8657) in pts with 1 dose-reduction criterion and no dose-reduction criterion Rates of Major Bleeding and the Effect of Apixaban Compared With Warfarin P for interaction =.71 Alexander JH, et al. JAMA Cardiol 2016, Published online July 27, doi: /jamacardio

20 Comparison between apixaban 5 mg bid (n = 8665) and warfarin (n = 8657) in pts with 1 dose-reduction criterion and no dose-reduction criterion Alexander JH, et al. JAMA Cardiol 2016, Published online July 27, doi: /jamacardio

21 Comparison between apixaban 5 mg bid (n = 8665) and warfarin (n = 8657) in pts with 1 dose-reduction criterion and no dose-reduction criterion Dose- Reduction Criteria and Probability of Major Bleeding During 1 Year of Treatment Alexander JH, et al. JAMA Cardiol 2016, Published online July 27, doi: /jamacardio

22 Le basse dosi dei NAO nelle interazioni farmacologiche Vene N. et al. Plos One 2016

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25 Le basse dosi dei NAO nelle schede tecniche europee Vene N. et al. Plos One 2016

26 Dose Adjustments in NVAF Pts with 1 Risk Factors for Stroke/Systemic Embolism Dabigatran SmPC Vene N. et al. Plos One 2016

27 Dose Adjustments in NVAF Pts with 1 Risk Factors for Stroke/Systemic Embolism Rivaroxaban SmPC Vene N. et al. Plos One 2016

28 Dose Adjustments in NVAF Pts with 1 Risk Factors for Stroke/Systemic Embolism Apixaban SmPC Vene N. et al. Plos One 2016

29 Dose Adjustments in NVAF Pts with 1 Risk Factors for Stroke/Systemic Embolism Edoxaban SmPC Vene N. et al. Plos One 2016

30 Vene N. et al. Plos One 2016 Le dosi inappropriate nel mondo reale

31 High vs low dose of NOACs The Italian experience The 2016/2017 IMS data Vene N. et al. Plos One 2016

32 The FANTASIIA Registry Spanish acronym for Atrial fibrillation: Influence of anticoagulation level and type on stroke and bleeding event incidence a prospective, observational, national, multicentre study that included an adult population of Spanish patients with AF on anticoagulant treatment Frequency of appropriate dose; infradose (standard dose recommended but prescribed reduced dose); and overdose (reduced dose recommended but prescribed standard dose) of DOACs in the study population. 530 patients Vene N. et al. Plos One 2016 Ortiz MR, et al. Europace (2017) 0, 1 7.

33 The ORBIT-AF II Registry NOAC dosing by drug Vene N. et al. Plos One 2016 Steinberg BA et al. J Am Coll Cardiol 2016;68(24):

34 In XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation), a Phase IV observational study of patients with AF prescribed rivaroxaban, more than one-third of patients with CrCl <50 ml/min received the standard dose, whereas 15% of patients with CrCl >50 ml/min received the reduced dose. Camm AJ, et al. European Heart Journal doi: /eurheartj/ehv466

35 Vene N. et al. Plos One 2016 L impatto sugli outcome

36 The ORBIT-AF II Registry Off-Label Dosing of NOACs: Prevalence and Outcomes by Dosing N=5,738 Vene N. et al. Plos One 2016 Steinberg BA et al. J Am Coll Cardiol 2016;68(24):

37 Prevalence and Impact of Inappropriate NOAC Dosing in Pts With AF and Renal Dysfunction Outcomes Associated With Underdosing a large U.S. administrative database: 14,865 patients Yao X, et al. J Am Coll Cardiol 2017;69:

38 Prevalence and Impact of Inappropriate NOAC Dosing in Patients With Atrial Fibrillation and Renal Dysfunction Outcomes Associated With Overdosing a large U.S. administrative database: 14,865 patients Yao X, et al. J Am Coll Cardiol 2017;69:

39 Effectiveness and safety of reduced dose NOACs and warfarin in pts with AF: propensity weighted nationwide cohort study 3 nationwide registries in Denmark (55,644 pts). Ischaemic stroke or systemic embolism Any bleeding Cumulative risk of events depicted by weighted failure curves in pts with AF according to initiated treatment Nielsen PB, et al. BMJ 2017;356:j510 Vene N. et al. Plos One 2016 Years since treatment initiation

40 Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in NVAF pts: Comparative effectiveness and safety evaluated using a propensityscorematched approach 5 mg Pooled data from 4 American claims database sources 2.5 mg Vene N. et al. Plos One 2016 Li X, et al. PLoS ONE 13(1): e

41 Key points L uso degli ACO, e dei NAO in particolare, è in progressivo aumento, ma l uso di dosi inappropriate per i NAO (soprattutto basse dosi) è inaccettabilmente eccessivo. Il sottodosaggio dei NAO può esporre il paziente ad un rischio aumentato di ictus/embolie sistemiche, senza un apprezzabile vantaggio sulle emorragie. Il sovradosaggio dei NAO non offre benefici sul rischio di ictus/embolie sistemiche, mentre aumenta le emorragie. E necessario sviluppare e condividere strumenti decisionali per migliorare la appropriatezza prescrittiva dei NAO.

42 Guida alle basse dosi degli anticoagulanti orali diretti Dabigatran 110 mg BID età > 80 anni, uso concomitante di verapamil; aumentato rischio sanguinamento (HAS-BLED > 3) Rivaroxaban 15 mg OD CrCl ml/min Apixaban 2.5 mg BID 2 dei seguenti: età 80 anni, peso 60 kg, creatinina sierica 1.5 mg/dl oppure CrCl ml/min Edoxaban 30 mg OD CrCl ml/min, peso 60 kg, o uso concomitante di verapamil, chinidina, dronedarone (P-gp inibitori) Vene N. et al. Plos One 2016

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44 Vene N. et al. Plos One 2016

45 Prevalence and Impact of Inappropriate NOAC Dosing in Patients With Atrial Fibrillation and Renal Dysfunction a large U.S. administrative database: 14,865 patients Percentage of Patients Underdosed % patients who did not have a renal indication for dose reduction but received reduced dose NOAC 13.3% of 13,392 pts Yao X, et al. J Am Coll Cardiol 2017;69:

46 Prevalence and Impact of Inappropriate NOAC Dosing in Patients With Atrial Fibrillation and Renal Dysfunction a large U.S. administrative database: 14,865 patients Percentage of Patients Overdosed % patients who had a renal indication for dose reduction but received standard dose NOAC 43.0% of 1,473 pts Yao X, et al. J Am Coll Cardiol 2017;69:

47 Incidence rate, %/year* XANTUS: Outcomes According to Dosing (20/15 mg od) Major bleeding, all-cause death and thromboembolic events (stroke/se/tia/mi) occurred at higher incidence rates for the 15 mg od versus the 20 mg od dose mg dose mg dose Thromboembolic events Major bleeding All-cause death Dosing decisions may have been based on other clinical considerations besides impaired renal function *Events per 100 patient-years Camm AJ et al, Eur Heart J 2015; doi: /eurheartj/ehv466;

48 X-fold increase in use of low-dose vs phase III trial Low-Dose Usage in Real World vs Clinical Trials Use of low-dose rivaroxaban consistent with expectations from phase III Rivaroxaban 15 mg od Apixaban 2.5 mg bid 0 Low-dose usage (%) Phase III ROCKET AF 1 Real-world data* 2 Phase III ARISTOTLE 3 Real-world data* *Mean and range: data from US, Germany, Canada and UK 1. Fox KA et al, Eur Heart J 2011;32: ; 2.IMS MIDAS. Q4 2014; 3. Granger GB et al, N Engl J Med 2011;365:

49 Distribution of dabigatran dosing overall and in high-risk subgroups ORBIT-AF Steinberg BA, et al. J Am Heart Assoc. 2013;2:e doi: /jaha

50 Dose Adjustments in NVAF Patients with 1 Risk Factors for Stroke/Systemic Embolism Rivaroxaban 1 Apixaban 2 Estimate CrCl Estimate CrCl <15 ml/min Not recommended ml/min* 15 mg od 50 ml/min 20 mg od <15 ml/min ml/min 30 ml/min Check age Check weight Check serum creatinine 80 years 60 kg 133 µmol/i If 2 features If 1 features Not recommended 2.5 mg bid 2.5 mg bid 5 mg bid Dabigatran 3 Edoxaban 4 Estimate CrCl Estimate CrCl <30 ml/min ml/min >50 ml/min <15 ml/min ml/min >50 ml/min Age >80 years Age 75 years or High risk of bleeding Age <75 years Age years Age >80 years 60 mg od Contraindicated Low thromboembolic risk and high bleeding risk Not recommended 30 mg od 60 kg Potent P-gp inhibitors 110 mg bid 110 mg bid 150 mg bid 150 mg bid 110 mg bid 150 mg bid 110 mg bid 30 mg od 30 mg od 1. Rivaroxaban SmPC; 2. Apixaban SmPC; 3. Dabigatran SmPC; 4. Edoxaban SmPC Approval Number: L.IT.MA

51 Effectiveness and safety of reduced dose NOACs and warfarin in pts with AF: propensity weighted nationwide cohort study 3 nationwide registries in Denmark (55,644 pts). Ischaemic stroke or systemic embolism Any bleeding Cumulative risk of events depicted by weighted failure curves in pts with AF according to initiated treatment All cause mortality Vene N. et al. Plos One 2016 Years since treatment initiation Nielsen PB, et al. BMJ 2017;356:j510

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53 Dabigatran: migliore profilo di sicurezza ed efficacia vs warfarin quando usato secondo labeling EU* Sanguinamento maggiore -15%RRR HR: 0.85 ICH -72%RRR HR: 0.28 Sanguinamento a rischio di vita -28%RRR HR: 0.72 Qualsiasi sanguinamento -14%RRR HR: 0.86 Ictus/SE HR: %RRR Mortalità vascolare HR: %RRR Dabigatran migliore Warfarin migliore L UTILIZZO SECONDO RCP EUROPEA CONFERMA LA SICUREZZA E L EFFICACIA DI PRADAXA Lip et al. Thromb Haemost 2014

54 RE LY DABI 150 mg RE NEW IL PAZIENTE ANZIANO <75 aa aa aa >84 aa ICTUS o EMBOLIA SISTEMICA -37% -35% -33% -30% <75 aa aa aa >84 aa EMORRAGIA INTRACRANICA -57% -77% -45% -39% Riadattata da Lauw MN, et al. Heart 2017;0:1 9. doi: /heartjnl

55 EU label post-hoc analisi Tutta la popolazione RE-LY D150 D110 W Post hoc analisi dei pazienti secondo le caratteristiche di base Dose raccomandata* D110 D150 D110 D150 Dose ricevuta D150 D150 D110 D110 Post hoc pool analisi Dose simulata di Dabigatran verso Warfarin in accordo a RCP Europea Iper-trattamento Drec Sotto-trattamento W Dose raccomandata *D110 recommended for 80 years OR HAS-BLED 3 OR verapamil;d150 recommended for <80 years AND HAS-BLED <3 Lip GY et al. Thromb Haemost 2014;111:933 42

56 Criteria for considering a patient as requiring a reduced dose of direct anticoagulant EHRA practical guide on the use of DOAC in patients with AF, EUROPACE 2015 Vene N. et al. Plos One 2016

57 A pooled analysis of the global XANTUS programme over 96% of pts not experiencing any of these outcomes Kirchhof P, et al: ESC 2017

58 A pooled analysis of the global XANTUS programme Outcomes as a function of CHA2DS2-VASc scores Kirchhof P, et al: ESC 2017

59 Comparison of Main Outcomes: XANTUS versus ROCKET AF CHADS 2 Prior stroke # ROCKET AF % XANTUS % ROCKET AF Rivaroxaban XANTUS Rivaroxaban Stroke/SE All strokes Death Major bleeding ICH GI bleeding 0.0 Stroke/SE All strokes Death Major bleeding ICH GI bleeding # Includes prior stroke, SE or TIA; *Events per 100 patient-years Adapted from 1. Camm AJ et al. Eur Heart J 2016;37: Patel MR et al, N Engl J Med 2011;365: Results are not intended for direct comparison

60 Key points I dati sui NAO nel mondo reale, rispetto ai dati dei trial, mostrano efficacia e sicurezza non inferiore o superiore rispetto agli AVK. Il profilo beneficio rischio è costantemente favorevole. La persistenza in terapia dei NAO è generalmente superiore agli AVK. Dai dati del mondo reale non è possibile stabilire la superiorità per efficacia o sicurezza di un NAO rispetto ad un altro. I sanguinamenti sono attribuibili più al profilo di rischio del paziente che al NAO utilizzato. L uso degli ACO, e dei NAO in particolare, è in progressivo aumento, ma l uso di dosi inappropriate per i NAO (soprattutto basse dosi) è inaccettabilmente eccessivo.