EFFICACIA E SICUREZZA METANALISI

(1)

(2)

Endpoint Risultato (NAO vs AVK) Riduzione del Rischio (NAO/AVK)

Mortalita totale 5,61% vs 6,02% RR 0,89;IC 95% 0,83-0,96

Mortalita CV 3,45% vs 3,65% RR 0,89; IC 95% 0,82-0,98 Ictus/Embolia sistemica 2,40% vs 3,13% RR 0,77; IC 95% 0,70-0,86 Ictus Ischemico 1,87% vs 2,02 RR 0,92; IC 95% 0,81-1,04* Sanguinamenti maggiori 4,90% vs 5,54% RR 0,86; IC 95% 0,72-1,02* Emorragia Intracranica 0,59% vs 1,30% RR 0,46; IC 95% 0,39-0,56 Infarto Miocardico 1,29% vs 1,29% RR 0,99; IC 95% 0,58-1,15**

EFFICACIA E SICUREZZA

METANALISI

*

Differenze non significative ma con trend favorevole ai NAO

(3)

I PAZIENTI DEI TRIALS SONO IDENTICI

A QUELLI DEL MONDO REALE ?

PROFILO DI RISCHIO

TRATTAMENTI CONCOMITANTI

ANALISI EVENTI

ADERENZA AL TRATTAMENTO

FOLLOW UP

(4)

In the USA, the licensed doses for Pradaxa® _{are: Pradaxa}® _{150 mg BID and Pradaxa}® _{75 mg BID for the prevention of stroke and}

systemic embolism in adult patients with nonvalvular AF

Graham DJ et al. Circulation 2015;131:157-64

Independent FDA study of Medicare

patients analysed

outcomes in >134 000 new users of dabigatran or warfarin

• >134 000 new users

(OAC treatment-naïve) of dabigatran

or warfarin

• All recently diagnosed with AF

• All aged ≥65 years

• 37 500 person-years of follow-up

• Adjustments were made for

confounding variables

• Observational cohort study

• US Medicare database

• Comparison of ischaemic stroke, ICH,

major GI bleeding, acute MI, and

mortality rates using insurance-claim

and administrative data

2010 2011 2012

Study period

(5)

In the USA, the licensed doses for Pradaxa®_{are: Pradaxa}®_{150 mg BID and Pradaxa}®_{75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF. Pradaxa}® _{110 mg BID is indicated for}

certain patients in Europe, and was shown to be as effective as warfarin in preventing stroke or systemic embolism. RE-LY® was a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) study *Primary findings for dabigatran are based on analysis of both 75 mg and 150 mg together without stratification by dose. Numbers above bars denote HRs vs warfarin. 1. Graham DJ et al. Circulation 2015;131:157-64; 2. Connolly SJ et al. N Engl J Med 2009;361:1139–51; 3. Connolly SJ et al. N Engl J Med 2010;363:1875–6; 4. Pradaxa®_{: EU SPC, 2014; 5. Connolly SJ et al. N Engl J Med 2014; 371:1464–5}

Independent FDA Medicare analysis

findings support favourable

benefit–risk profile of dabigatran shown in RE-LY

®

_*

HR: 0.86 P=0.006 HR: 1.28 P<0.001 HR: 0.80 P=0.02 HR: 0.92 P=0.29 HR: 0.34 P<0.001 HR: 0.97 P=0.50

Medicare

1 RR: 0.88 P=0.05 RR: 1.48 P=0.001 RR: 1.27 P=0.12 RR: 0.76 P=0.04 RR: 0.41 P<0.001 RR: 0.94 P=0.41

RE

-LY

®2 – 5 27

(6)

In the USA, the licensed doses for Pradaxa®_{are: Pradaxa}®_{150 mg BID and Pradaxa}®_{75 mg BID for the prevention of stroke and systemic embolism in adult patients with nonvalvular AF}

Comparison groups (each n=12 793) established using propensity score matching Villines TC et al. AHA 2014

Favourable benefit–risk profile of dabigatran supported

by real-world evidence:

US Department of Defense database

• >25 000 new users of

dabigatran or warfarin

available for matching

• All NVAF patients

• Aged 18–89 years at index

date

• Observational study (Oct

2010 to Jul 2012)

• US DoD database

0.5 1.0 1.5 0.0 2.0 Stroke Ischaemic stroke Haemorrhagic stroke Major ICH MI Major bleeding Major GI bleeding Death 0.73 (0.55–0.97) 0.84 (0.62–1.13) 0.32 (0.14–0.73) 0.49 (0.30–0.79) 0.65 (0.45–0.95) 0.87 (0.74–1.02) 1.13 (0.94–1.37) 0.64 (0.55–0.74) HR (95% CI)

Favours dabigatran Favours warfarin

(7)

*Adjusted HR: age, components of CHA₂DS₂-VASc, HAS-BLED, months since August 2011, time since initiation of VKA therapy; W, warfarin

Larsen TB et al. Am J Med 2014;127:650–6.e5

Favourable benefit–risk profile of dabigatran supported by

real-world evidence:

independent Danish registry

• 11 315 first-time dabigatran users

(7063 VKA-naïve) vs 22 630

matched warfarin users

• VKA-naïve = ≥2 years since last

warfarin purchase

• All AF patients

• Observational cohort study (Aug

2011 to May 2013)

• Nationwide Danish registries

VKA-naïve stratum D110 vs W D150 vs W 0.72 (0.59–0.88) 0.93 (0.74–1.16) 0.52 (0.28–0.95) 0.50 (0.27–0.94) 0.30 (0.17–0.54)

Favours dabigatran Favours warfarin

0.68 (0.55–0.84) 0.67 (0.53–0.85) 0.70 (0.33–1.52) 1.45 (0.84–2.50) 0.33 (0.17–0.66) Any Major Fatal GI ICH Any Major Fatal GI ICH 0.10 0.50 1.00 2.00 5.00 HR* (95% CI) 29

(8)

Dabigatran adherence in atrial fibrillation

patients during the first year after diagnosis:

a nationwide cohort study

Gorst-Rasmussen A, J Thromb Haemost 2015

Nationwide Danish patient and prescription purchase registries

Final study population

2960 patients

(9)

Gorst-Rasmussen A, J Thromb Haemost 2015

Proportion of patients

with a 1-year PDC

> 80% was 76.8%

100% was 37.2%

More adherent patients:

• women

• pts. at high risk of stroke (CHA

₂

DS

₂

-VASc score ≥2)

• pts. with relatively higher morbidity (e.g. recent hospitalizations,

use of several cardiovascular medications)

(10)

Characterizing major bleeding in patients with

nonvalvular atrial fibrillation: a pharmacovigilance study

of 27.467 patients taking rivaroxaban

Tamayo et al., Clin Cardiol 2015

To provide longitudinal safety data by obtaining information associated with MB among

rivaroxaban users with NVAF Objective

5-year observational, post-marketing safety surveillance study using fully integrated electronic

medical records (EMRs) Design

Patient Characteristics

(11)

Characterizing major bleeding in patients with

nonvalvular atrial fibrillation: a pharmacovigilance study

of 27.467 patients taking rivaroxaban

5-year observational, post-marketing safety surveillance study using fully integrated electronic

Major Bleed Characteristics*

*MB classified using the Cunningham et al. defintion including: GI bleeding, hemorragic Strokes and other intracranial bleeds, genitourinarybleeding and bleeding at other sites.

(12)

Characterizing major bleeding in patients with

nonvalvular atrial fibrillation: a pharmacovigilance study

of 27.467 patients taking rivaroxaban

• Observational post-marketing study of

27.467 patients with NVAF followed for 455 days in real life

• Rate of MB 2.86% person/y

• Rate of MB in ROCKET AF trial: 3.6% person/y for rivaroxaban and 3.5 for warfarin*

• Patients who experienced MB were older and more likely to have comorbidity

• The most common bleeding site is GI

• Of the 478 patients who suffered a MB, 14 died (fatal bleeding rate 0.08% person/y)

• The MB rate was generally consistent with the registration trial results and fatal bleeds were rare.

Conclusions

(13)

(14)

(15)

13%TOTALE PZ/ANNO

14,1% NUOVI TRATTATI PZ/ANNO

12,7% VKA>RIVAROX. PZ/ANNO

(16)

Medication persistence and discontinuation of

rivaroxaban versus warfarin among patients with

non-valvular atrial fibrillation

Nelson et al., CMRO 2014

To compare the rates of medication persistence and discontinuation among rivaroxaban and warfarin patients using real-world data from a large, nationally representative claims database

in the US

Objective

A large nationally representative US claims database of patients with NVAF treated from July

2010 through March 2013 Design

Medication persistence: absence of refill gap of > 60 days

Discontinuation: no additional refill for at least 90 days and until the end of follow up

(17)

Medication persistence and discontinuation of

rivaroxaban versus warfarin among patients with

non-valvular atrial fibrillation

• Patients receiving rivaroxaban for NVAF had 37% lower hazard of non-persistence, and were 46% less likely to discontinue therapy compared to those receiving warfarin

Conclusion

(18)

Medication persistence and discontinuation of

rivaroxaban versus warfarin among patients with

non-valvular atrial fibrillation

(19)

Medication persistence and discontinuation of

rivaroxaban versus warfarin among patients with

non-valvular atrial fibrillation

(20)

XANTUS: Patient Flow

Screened

(N=10,934)

1 patient

Did not take any rivaroxaban (n=1)

Enrolled

(N=6785)

Safety population

(N=6784)

Another dose

(n=35)

#

Rivaroxaban 20 mg od

(n=5336)

Rivaroxaban 15 mg od

(n=1410)

4149 patients excluded* Patient decision (n=1222) Administrative reason (n=456) Availability of drug (n=18) Medical guidelines (n=399) Price of drug (n=473) Medical reasons (n=442)

Internal hospital guidelines (n=30)

Type of health insurance (n=183)

Other (n=1454)

*Reasons for not continuing in the study included, but were not limited to, patient decision, administrative or medical reasons. Some patients could have more than one reason for exclusion; #_{other dose includes any initial daily rivaroxaban}

dose besides 15/20 mg od (excluding missing information, n=3) 1. Camm AJ et al,Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

Primary analysis population: defined as all patients who had taken at least one dose of

rivaroxaban

Major events, specifically major bleeding, stroke, SE, TIA and MI, adjudicated centrally by an independent CAC blinded to individual patient data

(21)

XANTUS: Baseline Demographics –

Distribution of Stroke Risk Factors

CHA

₂

DS

₂

-VASc score*

CHADS

₂

score

*3 patients had missing CHA₂DS₂-VASc scores

1. Camm AJ et al,Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

(22)

XANTUS: Treatment Persistence and Patient

Satisfaction



_{Persistence with rivaroxaban in XANTUS was 80% at 1 year}



Over 75% of patients were ‘very satisfied/satisfied’ with their treatment

(23)

(24)

(25)

(26)

(27)

CON LA RISERVA DI RIVALUTARE I DATI ASSICURATIVI

CONTRARIAMENTE A QUANTO DI SOLITO ACCADE

I RISULTATI DEI REGISTRI

CONFERMANO E AMPLIFICANO I RISULTATI

DEI TRIALS IN TERMINI DI VANTAGGIO PER

LA SICUREZZA E EFFICACIA

DEI NAO VS AVK

(28)

(29)

SICUREZZA E EFFICACIA DEL DABIGATRAN

NEL MONDO REALE

FDA > 130000 US MEDICARE

> 25.000 PTS US DEPARTMENT DEFENSE

38000 PTS US HEALTH INSURANCE

(30)

Shore S, Am Heart J 2014

5.376 patients with NVAF

at least 30 days of follow-up and filling

dabigatran prescription of at least 30 days

duration at VA pharmacy between October

2010 and September 2012

72.2%

(n. 3.882) patients

were adherent to dabigatran

(PDC ≥ 80%)

(31)

XANTUS: Management of Major Bleeding



Major bleeding occurred in 1.9% of patients (n=128)

1



Major bleeding was mostly treated using conservative methods

1



0.8% of patients (n=53) received transfusions of ≥2 units of packed RBCs or whole blood



Throughout the study use of non-specific reversal agents – such as prothrombin

complex concentrate (PCC) - was low

1



Use of PCC documented in two patients



Use of tranexamic acid documented in three patients



Use of etamsylate documented in one patient



These findings are in line with outcomes from ROCKET AF

2

and the Dresden

NOAC Registry

3

1. Camm AJ et al,Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466; 2. Piccini JP et al, Eur Heart J 2014; 35(28):1873-80; 3. Beyer-Westendorf J et al, Blood 2014; 124(6):955-62

(32)

XANTUS: Module Summary



XANTUS is the first large, international prospective study to describe

rivaroxaban use in a broad patient population with NVAF



Patients were at lower overall risk than in the phase III ROCKET AF trial



Over 96% patients receiving rivaroxaban did not experience any of the outcomes of

stroke/SE, treatment-emergent major bleeding or all-cause death



In XANTUS, rivaroxaban demonstrated low rates of stroke/SE and major

bleeding, including intracranial and GI bleeding



Incidences of these outcomes generally increased with higher stroke risk scores



Major bleeding was mostly treated conservatively; reversal agents were rarely used



Treatment persistence and patient satisfaction were high



80% of patients remained on rivaroxaban



75% reported they were satisfied with their treatment at 1 year

1. Camm AJ et al,Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

(33)

(34)

In merito alle segnalazioni di danno epatico indotto da farmaco (DILI:

Drug-Induced Liver Injury):

• per dabigatran: nessuna associazione ″farmaco-evento avverso″

statisticamente significativa (le segnalazioni di DILI sono state il 1.7% di tutte le

segnalazioni)

• per rivaroxaban si osserva una sproporzione nelle segnalazioni statisticamente

significativa (le segnalazioni di DILI sono state il 3,7% di tutte le segnalazioni)

• per apixaban le segnalazioni post-marketing sono ancora insufficienti per

trarre conclusioni definitive

Liver injury with novel oral anticoagulants: assessing post-marketing

reports in the US Food and Drug Administration Adverse Event

Reporting System

(35)

Comparison of Main Outcomes:

XANTUS versus ROCKET AF

CHADS₂ Prior stroke#

ROCKET AF1 _3.5 _55%

XANTUS2 _2.0 _19%

#_{Includes prior stroke, SE or TIA; *Events per 100 patient-years}

1. Patel MR et al, N Engl J Med 2011;365:883–891; 2. Camm AJ et al, Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

GI

MB

(36)

Characterizing major bleeding in patients with

nonvalvular atrial fibrillation: a pharmacovigilance study

of 27.467 patients taking rivaroxaban

5-year observational, post-marketing safety surveillance study using fully integrated electronic

(37)

. Camm AJ et al,Eur Heart J 2015; doi: 10.1093/eurheartj/ehv466

XANTUS: Baseline Demographics –

Clinical Characteristics

Rivaroxaban (N=6784) Age (years) Mean ± SD 71.5±10.0 Age <65, n (%) 1478 (21.8) Age ≥65–≤75, n (%) 2782 (41.0) Age >75, n (%) 2524 (37.2) Gender (male): n (%) 4016 (59.2) Weight (kg): mean ± SD 83.0±17.3 BMI (kg/m2_{): mean ± SD} _28.3±5.0 BMI >30 kg/m2_{, n (%)} _{1701 (25.1)} AF, n (%) First diagnosed 1253 (18.5) Paroxysmal 2757 (40.6) Persistent 923 (13.6) Permanent 1835 (27.0) Rivaroxaban (N=6784) Creatinine clearance, n (%) <15 ml/min 20 (0.3) ≥15–<30 ml/min 75 (1.1) ≥30–<50 ml/min 545 (8.0) ≥50–≤80 ml/min 2354 (34.7) >80 ml/min 1458 (21.5) Missing 2332 (34.4) Existing co-morbidities, n (%) Hypertension 5065 (74.7) Diabetes mellitus 1333 (19.6) Prior stroke/non-CNS SE/TIA 1291 (19.0)

Congestive HF 1265 (18.6)

Prior MI 688 (10.1)

(38)

Characterizing major bleeding in patients with

nonvalvular atrial fibrillation: a pharmacovigilance study

of 27.467 patients taking rivaroxaban

(39)