FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE...

FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI

E CONSEGUENTI IMPLICAZIONI GESTIONALI

HEARTLINE HSM Genoa Cardiology Meeting

Genova, 22 Ottobre 2011

FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI

E CONSEGUENTI IMPLICAZIONI GESTIONALI

HEARTLINE HSM Genoa Cardiology Meeting

Genova, 22 Ottobre 2011

Giuseppe Di PasqualeUnità Operativa Cardiologia Ospedale Maggiore, Bologna

Disclosures

• Member of Advisory Board of Dabigatran, Rivaroxaban, Apixaban, Dronedarone

• Consulting fees / honoraria- Boehringer Ingelheim- Bayer AG- Sanofi Aventis - BMS

Antithrombotic Therapy for AFibStroke Risk Reduction

Antiplatelet drugsvs. Placebo

Warfarin vs.Placebo/Control

100%100% 50%50% 00 - 50%- 50%

6 Trialsn = 2,900

8 Trialsn = 4,876

TreatmentBetter

TreatmentWorse

Hart RG et al. Ann Intern Med 2007; 146: 857

-64%

-19%

Limiti della terapia con antagonisti della Vitamina K

Risposta non prevedibile

Monitoraggio routinario dei fattori della coagulazione

Lente insorgenza/termine

d’azione

Resistenza al Warfarin

La terapia con antagonisti

della vitamina K presenta

diversi limiti che ne

rendono difficoltoso l’impiego

nella pratica clinica

Numerose interazioni con altri farmaci

Numerose interazioni alimentari

Frequenti aggiustamenti della

doseFinestra di

trattamento stretta (INR range 2-3)

1. Ansell J, et al. Chest 2008;133;160S-198S; 2. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187.

Limiti della Terapia Anticoagulante Orale

Un significativo numero di pazienti con FA a rischio di stroke non riceve la TAO


Conseguenze nella FA

Steering Committee

Giuseppe Di Pasquale (Chairman ANMCO), Giovanni Mathieu (Chairman FADOI), Francesco Chiarella, Fabrizio Colombo, Michele Gulizia,

Gualberto Gussoni, Carlo Nozzoli, Domenico Panuccio, Salvatore Pirelli, Marino Scherillo, Giorgio Vescovo, Massimo Zoni Berisso

Setting of the Study

360 Participating Centers7148 enrolled patients

164Cardiology

DepartmentsCardiology wardCardiology ward and Cath LabCardiology ward with Cath Lab and CCH

196Internal Medicine Dept.

Hospital without cardiologyHospital with cardiology wardHospital with cardiology ward and Cath Lab (with or without CCH)

From each Center:Duration of the enrollment 4 weeks

Antithrombotic Treatments innon valvular AF (4.845 pts)

OACNone Other ATT

Limiti della Terapia Anticoagulante Orale


L’intensità della scoagulazione è spesso al di fuori del range terapeutico (INR 2.0 – 3.0)


L’intensità della scoagulazione è spesso al di fuori del range terapeutico (INR 2.0 – 3.0)

Conseguenze nella FA

Anticoagulation Control in Real Life in Italy

% of INR Determinations by Range in VKA Treated Patients% of INR Determinations by Range in VKA Treated Patients

Range INRVKA

Experiencedmean median (p25 - p75)

% INR < 2 No 33.4% 28.8% (15.4% - 47.9%)

% INR < 2 Yes 25.3% 20.0% (7.7% - 36.4%)

% INR 2.0-3.0 No 47.9% 50.0% (33.3% - 66.7%)

% INR 2.0-3.0 Yes 56.3% 58.3% (42.5% - 73.1%)

% INR > 3 No 16.9% 13.3% (0.0% - 25.0%)

% INR > 3 Yes 17.9% 14.3% (4.0% - 26.7%)

The Promise of New Anticoagulants

•Coagulationcascade

• Drug

•Initiation

•Propagation

•Thrombin activity

•TF/VIIa

•VIIa•IXa

•IX•X

•Xa

•Va

•II

•IIa

•Fibrinogen •Fibrin

Tissue factor Tissue factor pathway inhibitors:pathway inhibitors:NAPc2NAPc2

Indirect: fondaparinux, Indirect: fondaparinux, idraparinuxidraparinux

Direct Oral: rivaroxaban, Direct Oral: rivaroxaban, apixaban, edoxabanapixaban, edoxaban

Direct Parenteral: Direct Parenteral: bivalirudinbivalirudinDirect Oral: ximelagatran, Direct Oral: ximelagatran, dabigatran, AZD0837dabigatran, AZD0837

New Anticoagulants

N Engl J Med 2009;361(12):1139-51N Engl J Med 2009;361(12):1139-51

N Engl J Med August 10, 2011N Engl J Med August 10, 2011

Atrial Fibrillation Phase 3 Study Timelines

Apixaban

ROCKET AFPublished

August 2011

ROCKET AFPublished

August 2011

Rivaroxaban

RE-LYPublished 2009

RE-LYPublished 2009

Dabigatran

2009 2010 2011 2012

AVERROESPublished

February 2011

AVERROESPublished

February 2011

ARISTOTLEPublished

August 2011

ARISTOTLEPublished

August 2011

ENGAGE AF TIMI 48Study ongoingExpected 2012


Edoxaban

The RE-LY Study:Randomized Evaluation of

Long-term anticoagulant therapY

Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke

Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

RE-LY® – study design

Atrial fibrillation with ≥ 1 risk factorAbsence of contraindications

R

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran etexilate 110 mg bid

N=6000

Dabigatran etexilate 150 mg bid

N=6000

Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin

Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up

Ezekowitz MD, et al. Am Heart J 2009;157:805-10.



21v2 November 2010

TIME TO FIRST STROKE OR SSE

Warfarin

Years

RRR35%

Cu

mu

lati

ve h

azar

d r

ates

0

0.01

0.02

0.03

0.05

0.04

0.0

0.5 1.0 1.5 2.0 2.5

RR 0.90(95% CI: 0.74–1.10)P<0.001 (NI)P=0.30 (Sup)

RR 0.65(95% CI: 0.52–0.81)P<0.001 (NI)P<0.001 (Sup)

RR = relative risk; RRR = relative risk reduction; SSE = systemic embolism.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

Dabigatran 150 mg BID Dabigatran 110 mg BID

3.0

22v2 November 2010

MAJOR BLEEDING RATES

342 / 6,015399 / 6,076 421 / 6,022

Rat

e p

er y

ear

(%)

0

1.0

2.0

3.0

4.0

5.0

3.32

D110 mg BIDD150 mg BID Warfarin

RR 0.80 (95% CI: 0.70–0.93)P=0.003 (superiority)

2.873.57

RR 0.93 (95% CI: 0.81–1.07) P=0.32 (superiority)

D = dabigatran; RR = relative risk; RRR = relative risk reduction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Connolly SJ, et al. N Engl J Med 2009;361:1139-1151.

RRR20%

Events/n:

23v2 November 2010

MAJOR BLEEDING AND COMPONENTS

CharacteristicDabigatran

150 mg

Dabigatran

110 mgWarfarin

P value

D150 vs. W

P value

D110vs. W

Number of patients 6,076 6,015 6,022

Major bleeding rate (% per year)

3.32 2.87 3.57 0.32 0.003

Life threatening

Non-life threatening

Gastro-intestinal

1.49

2.06

1.56

1.24

1.83

1.15

1.85

1.92

1.07

0.03

0.39

0.001

<0.001

0.65

0.52

D = dabigatran; W = warfarin. Data represent %/year.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Connolly SJ, et al. N Engl J Med 2010;363:1875-1876.

RR 0.26 (95% CI: 0.14–0.49)

p<0.001 (sup)

Hemorrhagic stroke



RR 0.31 (95% CI: 0.17–0.56)

p<0.001 (sup)

Nu

mb

er o

f ev

ents

6,015 6,076 6,022

1412

45

0

10

20

30

40

50

D110 mg BID D150 mg BID Warfarin

0.10%

0.38%RRR69%

RRR74%

0.12%

Mortalità per qualsiasi causa

Mortalità vascolare

RE-LY Subgroup Analyses

RE-LY Subgroup Analysis:Prior TIA or Stroke

Lancet Neurology 2010; 9: 1157-63

Prior stroke/TIA: time to primary outcome

Years of follow-up

0.0

0.0

20.0

40.0

60.0

8

0 0.5 1.0 1.5 2.0 2.5

Dabigatran 150 mg

Dabigatran 110 mg

Warfarin

# at Risk Year 0.5 1.0 1.5 2.0 2.5D110D150W

1195 1160 1132 908 573 2891233 1201 1164 938 617 3211195 1160 1126 895 565 262

Cu

mu

lati

ve H

azard

Rate

s

Intra-cranial bleeding rates in patients with prior stroke or TIA

6

13

30

0

10

20

30

D110 mg bid D150 mg bid Warfarin

RRR 80%

Nu

mb

er

of

even

ts

RRR 59%

1195 1233 1195

RR 0.20 (95% CI: 0.08–0.47)

p<0.001RR 0.41 (95% CI: 0.21–0.79)

P=0.007

RE-LY Subgroup Analysis:Age & Renal Function

Circulation 2011;123:2363-72Circulation 2011;123:2363-72

34v2 November 2010

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: STROKE AND NON-CNS EMBOLISM

BID = twice daily; CNS = central nervous system; D = dabigatran; P values for interaction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Healey JS, et al. ACC 2010; abstr 1078-120.

Annual rate (%)

D 110 mg BID

D 150 mg BID

Warfarin

Age (yrs)

<65 1.48 0.69 1.35

65–74 1.26 0.98 1.43

≥75 1.87 1.43 2.1

Creatinine clearance (mL/min)

30–50 2.26 1.33 2.65

51–80 1.65 1.24 1.76

>80 0.92 0.72 1

P=0.072

D 150 mg BID vs. warfarin

P=0.76


P=0.036P=0.58

0.5 1.0 1.5Dabigatran better

Warfarinbetter

0 2.00.5 1.0 1.5Dabigatran better

Warfarinbetter

0 2.0

35v2 November 2010

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: MAJOR BLEEDING

BID = twice daily; D = dabigatran; P values for interaction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Healey JS, et al. ACC 2010; abstr 1078-120.

Annual rate (%)

D 110 mg BID

D 150 mg BID

Warfarin

Age (yrs)

<65 0.76 0.79 2.32

65–74 2.12 2.45 3.08

≥75 4.21 4.81 4.09


30–50 5.07 4.85 5.17

51–80 2.62 3.04 3.44

>80 1.36 1.88 2.18

P=0.0001


P=0.0003


P=0.091P=0.1


Warfarinbetter


Warfarinbetter

0 2.0

36v2 November 2010

AGE AND RENAL FUNCTION SUBGROUP ANALYSIS: HAEMORRHAGIC STROKE

BID = twice daily; D = dabigatran; P values for interaction.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Healey JS, et al. ACC 2010; abstr 1078-120.

Annual rate (%)

D 110 mg BID

D 150 mg BID

Warfarin

Age (yrs)

<65 0.05 0.05 0.38

65–74 0.08 0.08 0.31

≥75 0.2 0.15 0.47


30–50 0.26 0.12 0.58

51–80 0.12 0.09 0.47

>80 0.03 0.08 0.13

P=0.75


P=0.51


P=0.4P=0.67


Warfarinbetter


Warfarinbetter

0 2.0

EMA approves PRADAXA with the flexibility of two dosing regimens

Overall the 150 mg bid dose is recommended; the 110 mg bid dose is indicated for elderly patients aged 80

years at higher risk of bleeding and for those taking verapamil

4 August 2011

ANTITHROMBOTIC PROPHYLAXIS IN AF

New oral direct thrombin inhibitors(other than ximelagatran)

Oral Factor Xa inhibitors

New oral direct thrombin inhibitors(other than ximelagatran)

Oral Factor Xa inhibitors

NEW PERSPECTIVES

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation

Rivaroxaban Bayer Phase III

Apixaban BMS / Pfizer Phase III

Edoxaban Daiichi Sankyo Phase III

Betrixaban Portola / Merck Phase II

Darexaban Astellas Pharma Phase II

LY 517717 Lilly Planned

TAK – 442 Takeda Planned

42

Warfarin target INR 2–3

Rivaroxaban 20 mg once daily#

Non-valvular AF

History of stroke, TIA or non-CNS SE

OR

≥2* of the following:

CHF Hypertension Age ≥75 years Diabetes

N=14,264

*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven.

ROCKET AF – study design

Randomized, double-blind, double-dummy, event-driven

Patel MR et al, 2011 Patel MR et al, 2011

En

d o

f s

tud

y

30-d

ay f

oll

ow

-up

R

~14 – 40 months‡~14 – 40 months‡

44

ROCKET AF – primary efficacy endpoint on and off treatment

Rivaroxaban n/N

(% per year)

Warfarin n/N

(% per year)Hazard ratio

(95% CI)

p-value

Non-inf. Sup.

Per protocol,

on treatment

188/6,958(1.7)

241/7,004(2.2)

0.79 (0.66,0.96) <0.001

Safety, on treatment

189/7,061(1.7)

243 /7,082 (2.2)

0.79 (0.65,0.95) 0.02

Favours rivaroxaban

Primary efficacy endpoint: stroke or systemic embolismITT on- and off-treatment: post hoc analyses

Favours warfarin

10.5 2

ITT 269/7,081 (2.1)

306/7,090(2.4)

0.88 (0.75,1.03) <0.001 0.12

ITT, on treatment

188(1.7)

240(2.2)

0.79 (0.66,0.96) 0.02

ITT, off treatment

81 (4.7) 66 (4.3) 1.10 (0.79,1.52) 0.58

Hazard ratio and 95% CIs

Patel MR et al, 2011.Patel MR et al, 2011.

45

Parameter

Rivaroxaban (N=7,111)

Warfarin (N=7,125)

Hazard ratio (95% CI)n (% per year) n (% per year)

Principal safety endpoint

1,475 (14.9) 1,449 (14.5) 1.03 (0.96,1.11)

Major bleeding 395 (3.6) 386 (3.4) 1.04 (0.90,1.20)

Haemoglobin drop (≥2 g/dl)

305 (2.8) 254 (2.3) 1.22 (1.03,1.44)*

Transfusion 183 (1.6) 149 (1.3) 1.25 (1.01,1.55)*

Critical organ bleeding

91 (0.8) 133 (1.2) 0.69 (0.53,0.91)*

Intracranial haemorrhage

55 (0.5) 84 (0.7) 0.67 (0.47,0.93)*

Fatal bleeding 27 (0.2) 55 (0.5) 0.50 (0.31,0.79)*

Non-major clinically relevant bleeding

1,185 (11.8) 1,151 (11.4) 1.04 (0.96,1.13)

Safety population – on-treatment analysis; *Statistically significant

ROCKET AF – bleeding analysis

Major bleeding from gastrointestinal site (upper, lower and rectal): rivaroxaban=224 events (3.2%); warfarin=154 events (2.2%); p<0.001*


0.2 0.5 1 2 5Favours

rivaroxabanFavours

warfarinPatel MR et al, 2011.Patel MR et al, 2011.

N Engl J Med 2011;364(9): 806-17 N Engl J Med 2011;364(9): 806-17

AVERROES

APIXABAN Phase 3 Clinical Trial vs Aspirin to Prevent Stroke or Embolism in AF Pts

Apixaban 2.5 mg bid or 5 mg bid

Aspirin 81-324 mg qd

Primary outcome measures: • Time to composite outcome of stroke or systemic embolism• Time to major bleeding

Patient characteristics

• Aged 50 years

• Atrial fibrillation

1 additional risk factor for stroke

• Not suitable for vitamin K antagonist

≈ 1.6 years

Ran

dom

izat

ionN=5600


AVERROES - Primary Efficacy OutcomeAVERROES - Primary Efficacy Outcome


AVERROES - Primary Safety OutcomeAVERROES - Primary Safety Outcome


Warfarin Warfarin (target INR 2-3)(target INR 2-3)

Apixaban 5 mg oral twice dailyApixaban 5 mg oral twice daily(2.5 mg BID in selected patients)(2.5 mg BID in selected patients)

Primary outcome: stroke or systemic embolismPrimary outcome: stroke or systemic embolism

Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

RandomizeRandomizedouble blind, double blind,

double dummydouble dummy(n = 18,201)(n = 18,201)

Inclusion risk factorsInclusion risk factorsAge ≥ 75 years Age ≥ 75 years Prior stroke, TIA, or SEPrior stroke, TIA, or SEHF or LVEF ≤ 40%HF or LVEF ≤ 40%Diabetes mellitusDiabetes mellitusHypertensionHypertension

Inclusion risk factorsInclusion risk factorsAge ≥ 75 years Age ≥ 75 years Prior stroke, TIA, or SEPrior stroke, TIA, or SEHF or LVEF ≤ 40%HF or LVEF ≤ 40%Diabetes mellitusDiabetes mellitusHypertensionHypertension

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

Major exclusion criteriaMechanical prosthetic valveSevere renal insufficiencyNeed for aspirin plus thienopyridine

Major exclusion criteriaMechanical prosthetic valveSevere renal insufficiencyNeed for aspirin plus thienopyridine

N Engl J Med 2011N Engl J Med 2011

Atrial Fibrillation with at Least One Additional Risk Factor for StrokeAtrial Fibrillation with at Least One Additional Risk Factor for Stroke

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per yearHR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011

No. at RiskApixaban 9120 8726 8440 6051 3464 1754Warfarin 9081 8620 8301 5972 3405 1768

P (non-inferiority)<0.001

21% RRR

Primary OutcomeStroke (ischemic or hemorrhagic) or systemic embolismPrimary OutcomeStroke (ischemic or hemorrhagic) or systemic embolism


Outcome

Apixaban(N=9120)

Warfarin(N=9081)

HR (95% CI)P

ValueEvent Rate(%/yr)

Event Rate(%/yr)

Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011

Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012

Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42

Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001

Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70

All-cause death* 3.52 3.94 0.89 (0.80,0.998) 0.047

Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019

Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37


Efficacy OutcomesEfficacy Outcomes

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per yearHR 0.69 (95% CI, 0.60–0.80); P<0.001

No. at RiskApixaban 9088 8103 7564 5365 3048 1515Warfarin 9052 7910 7335 5196 2956 1491

31% RRR


Major BleedingISTH definitionMajor BleedingISTH definition

Outcome

Apixaban(N=9088)

Warfarin(N=9052)

HR (95% CI) P ValueEvent Rate

(%/yr)Event Rate

(%/yr)

Primary safety outcome: ISTH major bleeding*

2.13 3.09 0.69 (0.60, 0.80) <0.001

Intracranial 0.33 0.80 0.42 (0.30, 0.58) <0.001

Gastrointestinal 0.76 0.86 0.89 (0.70, 1.15) 0.37

Major or clinically relevant non-major bleeding

4.07 6.01 0.68 (0.61, 0.75) <0.001

GUSTO severe bleeding 0.52 1.13 0.46 (0.35, 0.60) <0.001

TIMI major bleeding 0.96 1.69 0.57 (0.46, 0.70) <0.001

Any bleeding 18.1 25.8 0.71 (0.68, 0.75) <0.001


Bleeding OutcomesBleeding Outcomes

ENGAGE-AF-TIMI 48(Study for Evaluation of DU-176b vs Warfarin in Subjects with AF)

Low Exposure StrategyDU-176b 30 mg QD(n=5500)

Active ControlWarfarin(n=5500)

High Exposure StrategyDU-176b 60 mg QD(n=5500)

1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)2º EP = Stroke or SEE or All-Cause MortalitySafety EP’s = Major Bleeding, Hepatic Function

AF on ECG < 12 mosIntended oral A/CCHADS2 Score > 2

R

Randomization Strata:1. CHADS2 2-3 vs 4-62. Drug clearance

Median Duration of Followup 24 months

n~16,500

Atrial Fibrillation Phase 3 Study Timelines

Apixaban

ROCKET AFPublished

August 2011

ROCKET AFPublished

August 2011

Rivaroxaban

RE-LYPublished 2009

RE-LYPublished 2009

Dabigatran

2009 2010 2011 2012

AVERROESPublished

February 2011

AVERROESPublished

February 2011

ARISTOTLEPublished

August 2011

ARISTOTLEPublished

August 2011



Edoxaban

E’ possibile un confronto tra dabigatran, rivaroxaban e apixaban ?

Somiglianze e differenze tra gli studi

PK/PD of 5 Novel Oral Agents

Ruff CR and Giugliano RP. Hot Topics in Cardiology 2010;4:7-14Ericksson BI et al. Clin Pharmacokinet 2009; 48: 1-22

Ruff CR et al. Am Heart J 2010; 160:635-41

Dabigatran Apixaban Rivaroxaban Edoxaban

(DU-176b)

Betrixaban

(PRT054021)

Target IIa IIa (thrombin)(thrombin)

XaXa XaXa XaXa XaXa

Hrs to Cmax 22 1-31-3 2-42-4 1-21-2 NRNR

CYP Metabolism NoneNone 15%15% 32%32% NRNR NoneNone

Half-Life 12-14h12-14h 8-15h8-15h 9-13h9-13h 8-10h8-10h 19-20h19-20h

Renal Elimination 80%80% 40%40% 33%33% 35%35% <5%<5%

CYP = cytochrome P450; NR = not reported

Phase III AF Trials

Re-LY ROCKET-AF

ARISTO

TLE

ENGAGE AF-TIMI 48

Drug DabigatranDabigatran RivaroxabanRivaroxaban ApixabanApixaban EdoxabanEdoxaban

Dose (mg)

Freq

150, 110150, 110

BIDBID

20 20 (15*)(15*)

QDQD

5 5 (2.5*)(2.5*)

BIDBID

60*, 30*60*, 30*

QDQD

N 18,11318,113 14,26614,266 18,20618,206 >21,000>21,000

Design PROBEPROBE 2x blind2x blind 2x blind2x blind 2x blind2x blind

AF criteria AF x 1AF x 1

< 6 mths< 6 mths

AF x 2AF x 2

((>>1 in <30d)1 in <30d)

AF or AFl x 2AF or AFl x 2

<12 mths<12 mths

AF x 1 AF x 1

< 12 mths< 12 mths

% VKA naive 50%50% 38%38% 43%43% 40% goal40% goal

*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEE

PROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

RELY Dabigatran 110 mg

Dabigatran 150 mg

Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.12.132.632.634.734.732.732.7

2.22.232.232.235.235.232.632.6

2.12.130.930.937.037.032.132.1

C. Michael Gibson, M.S., M.D.C. Michael Gibson, M.S., M.D.

ROCKET AF Rivaroxaban Warfarin

CHADS2 Mean 2 (%) 3 (%) 4 (%) 5 (%) 6 (%)

3.53.5131343432929131322

3.53.5131344442828121222

ARISTOTLE Rivaroxaban Warfarin

CHADS2 Mean 0-1 (%) 2 (%) 3+ (%)

2.12.13434

35.835.830.230.2

2.12.13434

35.835.830.230.2

Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

3+3+87%87%

Comparison of Trial MetricsComparison of Trial Metrics

RE-LY ROCKET AF ARISTOTLE

Time in Therapeutic Range (TTR)

64%64%67% warfarin-67% warfarin-experiencedexperienced

61% warfarin-naïve61% warfarin-naïve

Mean 55%Mean 55%Median 58%Median 58%

Mean 62%Mean 62%Median 66%Median 66%

C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

Stroke

199 (1.19) 250 (1.51)

184 (1.65) 221 (1.96)

NOAC Warfarin

0.5 1.0

Favors NOAC Favors warfarin

HR 95% CI

0.65-0.950.79

0.70-1.030.85

171 (1.44) 186 (1.58)Dabi 110(ITT)

0.74-1.120.91

1.50.0

Riva (safety AT)

Apixaban(ITT)

122 (1.01) 186 (1.58)Dabi 150(ITT)

0.51-0.810.64

No. of events (%/yr)

2.0

Not head to head comparison – For illustrative purposes only – adapted from references 1-41. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

ITT: Intention to Treat – AT: as treated

Ischemic or Unspecified Stroke

162 (0.97) 175 (1.05)

149 (1.34) 161 (1.42)

NOAC Warfarin

0.5 1.0


HR 95% CI

0.74-1.13

0.92

0.75-1.17

0.94

159 (1.34) 143 (1.21)Dabi 110(ITT)

0.88-1.39

1.11

1.50.0

Riva*(safety AT)

Apixaban**(ITT)

111 (0.92) 143 (1.21)Dabi 150(ITT)

0.59-0.97

0.76


2.0

*Only ischemic strokes are counted here. The no. of strokes with unknown type were 7 and 11 in the rivaroxaban and warfarin groups, respectively.** Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with ischemic strokes, hemorrhagic transformation occurred in 12 patients with apixaban and 20 patients with warfarin.

Not head to head comparison – For illustrative purpose only – adapted from references 1-41. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

ITT: Intention to Treat – AT: as treated.

Hemorrhagic Stroke

40 (0.24) 78 (0.47)

29 (0.26) 50 (0.44)

NOAC Warfarin

0.5 1.0


HR 95% CI

0.35-0.750.51

0.37-0.930.59

14 (0.12) 45 (0.38)Dabi 110(ITT)

0.17-0.560.31

1.50.0

Riva(safety AT)

Apixaban(ITT)

12 (0.10) 45 (0.38)Dabi 150(ITT)

0.14-0.490.26


2.0


ITT: Intention to Treat – AT: as treated.

Major Bleeding

327 (2.13) 462 (3.09)

395 (3.6) 386 (3.4)

NOAC Warfarin

0.5 1.0


HR 95% CI

0.60-0.80

0.69

0.90-1.20

1.04

342 (2.87) 421 (3.57)Dabi 110 0.70-0.93

0.80

1.50.0

Riva

Apixaban

399 (3.32) 421 (3.57)Dabi 150 0.81-1.07

0.93


2.0


Death From Any Cause

603 (3.52) 669 (3.94)

208 (1.87) 250 (2.21)

NOAC Warfarin

0.5 1.0


HR 95% CI

0.80-0.990.89

0.70-1.02

0.85

446 (3.75) 487 (4.13)Dabi 110(ITT)

0.80-1.03

0.91

1.50.0

Rivaroxaban (safety AT)Apixaban(ITT)

438 (3.64) 487 (4.13)Dabi 150(ITT)

0.77-1.00

0.88


2.0

582 (4.5) 632 (4.9) 0.82-1.03

0.92Rivaroxaban (ITT)

Not head to head comparison – For illustrative purpose only – adapted from references 1-4

1. Connolly et al. NEJM 2009; 361: 1139-51. 2. Connolly et al. NEJM 2010; 363: 1875-6. 3. Patel et al. NEJM 2011; 365: 883-91. 4. Granger et al. NEJM 2011; 365: 981-92.

Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici?G Ital Cardiol 2010; 11 (4): 263-268

William Turner, The Fighting Temeraire (National Gallery, Londra)

G Ital Cardiol 2011; 12(9): 556-65

Nuovi Anticoagulanti Orali non VKA Antagonisti

Vantaggi

• Dose – risposta prevedibile : dose fissa giornaliera • Non necessità di monitoraggio dell’anticoagulazione• Elevata efficacia e sicurezza• Significativa riduzione del rischio emorragico• Inizio e termine d’azione rapidi: non necessità di bridge con eparina• Minime interazioni farmacologiche• Assenza di interazioni alimentari

Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

Nuovi Anticoagulanti Oralianti non VKA Antagonisti

Svantaggi

• Aggiustamento empirico del dosaggio• Necessità di nuovi test laboratoristici da eseguire in caso di eventi

emorragici o trombotici• Difficoltà di valutare l’aderenza del paziente alla terapia• Mancanza di antidoto in caso di sovradosaggio o emorragie• Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti

con bassa aderenza terapeutica• Possibile ridotta consapevolezza della terapia da parte del paziente • Costo elevato

Di Pasquale G, Riva L, G Ital Cardiol 2011; 12: 556-65

Nuove Strategie Antitrombotiche per la Profilassi Tromboembolica della Fibrillazione Atriale

Problemi Aperti

• Per quali pazienti (A chi ?)


Problemi Aperti


• Con quale sorveglianza (Come ?)


Problemi Aperti



• Con quale responsabilità di presa in carico (Da chi ?)


Problemi Aperti



Futuri Scenari Clinici

• Pazienti con FA di nuovo riscontro con indicazioni all’anticoagulazione (naive)




• Pazienti con FA già in TAO in presenza di specifiche problematiche





• Pazienti con FA già in TAO in assenza di specifiche problematiche






• Pazienti con FA attualmente non in TAO




NAO come terapia di scelta, soprattutto nei pazienti con difficoltà logistiche per la gestione della TAO




▪ qualità TAO non soddisfacente (TTR < 55-50%) ▪ dosi giornaliere molto basse di VKA

▪ difficoltà logistiche (assistenza domiciliare) ▪ pregressa emorragia cerebrale ▪ farmaci associati interferenti necessari ▪ non disponibilità ai controlli periodici

proponibile lo switch dalla TAO ai NAO




non ragionevole uno switch immediato ai NAO

da non trascurare però le preferenze del paziente

adeguatamente informato



• Pazienti con FA non in TAO

▪ pazienti esclusi dalla TAO a causa di elevato rischio emorragico

dubbi candidati per i NAO

(dabigatran bassa dose in pazienti selezionati ?)

▪ pazienti esclusi dalla TAO per problemi logistici

possibili candidati ai NAO, previo accertamento

della compliance


Problemi Aperti



Dalla Sorveglianza Laboratoristicaalla Sorveglianza Clinica

• Colloquio ad inizio terapia (medico, infermiere)

• Controlli clinici periodici (ogni 3-4 mesi ?) per verificare tolleranza, compliance, eventi emorragici (visite brevi)

• Controlli periodici funzionalità renale (cadenza individualizzata)

• Trasferimento di risorse infermieristiche e mediche dall’Ambulatorio TAO alla Sorveglianza clinica


Problemi Aperti



• Con quale responsabilità di presa in carico (Da chi ?)

Presa in carico del paziente con FA anticoagulato con i nuovi anticoagulanti orali

Possibili Attori

• Centri TAO FCSA (solo 20% dei pazienti anticoagulati)

• Cardiologie Ospedaliere

(Servizio Ambulatoriale ± Ambulatorio TAO)

• Cardiologie Territoriali

• Medicine Interne / Geriatrie

(Servizio Ambulatoriale ± Ambulatorio TAO)

• Medico di Medicina Generale (NCP, MMG associati)

Attività essenziali per il trattamento con VKA o NAO

AVK NAO

Visita prescrizione SI SI

Giusta indicazione e dose SI SI

Informazione /educazione pz. SI SI

Controlli laboratorio SI NO

Aggiustamento dose SI NO

Controllo compliance NO SI

Guida per condizioni rischio SI SI

Controllo clinico periodico NO SI

95

Rivaroxaban

Selective, direct Factor Xa inhibitor1

High oral bioavailability2

Rapid onset of action3

Half-life:2–4 5–9 hours in young healthyindividuals 11–13 hours in the elderly

Dual mode of elimination:5

1/3 of active drug excreted unchanged by the kidneys

2/3 of drug metabolized by the liver; half of which is excreted renally, half excreted via the hepatobiliary route

1. Perzborn E et al, 2005; 2. Kubitza D et al, 2005; 3. Kubitza D et al, 2005; 4. Kubitza D et al, 2008; 5. Weinz C et al, 2009.

Rivaroxaban

Xa

IIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

TF/VIIa

Adapted from Weitz JI et al, 2005; 2008.

Rivaroxaban Once-daily oral direct factor Xa inhibition

Compared with vitamin K antagonism for prevention

of stroke and Embolism Trial in Atrial Fibrillation

97

Warfarin target INR 2–3

Rivaroxaban 20 mg once daily#

Non-valvular AF

History of stroke, TIA or non-CNS SE

OR

≥2* of the following:

CHF Hypertension Age ≥75 years Diabetes

N=14,264

*Enrolment of patients with <3 risk factors or without prior stroke/TIA or non-CNS SE was limited to 10%.#Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily. ‡Duration of therapy varied for each patient as study was event-driven.

ROCKET AF – study design

Randomized, double-blind, double-dummy, event-driven

Patel MR et al, 2011 Patel MR et al, 2011

En

d o

f s

tud

y

30-d

ay f

oll

ow

-up

R

~14 – 40 months‡~14 – 40 months‡

98

Number of subjects at riskRivaroxaban 6,958 6,211 5,786 5,468 4,406 3,407 2,472 1,496Warfarin 7,004 6,327 5,911 5,542 4,461 3,478 2,539 1,538

ROCKET AF – primary efficacy endpoint

Per-protocol population – as treated

Warfarin

Rivaroxaban

Days since randomization

HR=0.79 (0.66, 0.96)p<0.001 (non-inferiority)

0 120 240 480 600 7200

1

2

3

4

5

6

840360

Cu

mu

lati

ve e

ven

t ra

te (

%)

Stroke or systemic embolismStroke or systemic embolism


99

ROCKET AF – major bleeding by site

Site*Rivaroxaban

(N=7,111)Warfarin(N=7,125)

Major bleeding, n (%) 395 (5.6) 386 (5.4)

Gastrointestinal (upper, lower, rectal)# 224 (3.2) 154 (2.2)

Intracranial‡ 55 (0.8) 84 (1.2)

Intraparenchymal‡ 37 (0.5) 56 (0.8)

Non-traumatic‡ 33 (0.5) 54 (1.8)

Traumatic 4 (0.1) 2 (0.03)

Intraventricular 2 (0.03) 4 (0.1)

Subdural haematoma 12 (0.2) 22 (0.3)

Subarachnoid 4 (0.1) 1 (0.01)

Epidural haematoma 0 1 (0.01)

Macroscopic haematuria 26 (0.4) 21 (0.3)

Bleeding associated with non-cardiac surgery 19 (0.3) 26 (0.4)

Intraocular/retinal 17 (0.2) 24 (0.3)

Intraarticular 16 (0.2) 21 (0.3)

Epistaxis 13 (0.2) 14 (0.2)

*Site based on blinded adjudication.#Combined gastrointestinal bleed rate p<0.001; ‡p<0.05*Site based on blinded adjudication.#Combined gastrointestinal bleed rate p<0.001; ‡p<0.05Patel MR et al, 2011.Patel MR et al, 2011.

100

ROCKET AF – all-cause mortality

Safety population – on-treatment analysis


0.2 0.5 1 2 5Favours

rivaroxabanFavours

warfarin

Endpoints


Warfarin (N=7,082)

Hazard ratio (95% CI)

n(% per year)

n(% per year)

All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70,1.02)

Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10)

Non-vascular death 21 (0.2) 34 (0.3) 0.63 (0.36, 1.08)

Unknown cause 17 (0.2) 23 (0.2) 0.75 (0.40, 1.41)


102

ROCKET AF – secondary endpoints

Safety population – on-treatment analysis. *Statistically significant

Endpoints


Warfarin (N=7,082)

Hazard ratio (95% CI)n (% per year) n (% per year)

Composite of stroke, non CNS SE, vascular death

346 (3.1) 410 (3.6) 0.86 (0.74, 0.99)*

Composite of stroke, non-CNS SE, vascular death and MI

433 (3.9) 519 (4.6) 0.85 (0.74, 0.96)*

Components of major secondary endpoints

All-cause stroke 184 (1.7) 221 (2.0) 0.85 (0.70, 1.03)

Non-CNS SE 5 (0.04) 22 (0.2) 0.23 (0.09, 0.61)*

MI 101 (0.9) 126 (1.1) 0.81 (0.63, 1.06)

Vascular death 170 (1.5) 193 (1.7) 0.89 (0.73, 1.10)

All-cause mortality 208 (1.9) 250 (2.2) 0.85 (0.70, 1.02)


103

*p-value for interactionSafety population – on-treatment analysis

ROCKET AF – primary efficacy endpointsubgroup analysis

Rivaroxaban Warfarin

p-value*n/N (%) n/N (%)

Overall 189/7,061 2.7 243/7,082 3.4

Sex 0.92

Male 103/4,270 2.4 136/4,283 3.2

Female 86/2,791 3.1 107/2,799 3.8

Age (years) 0.11

<75 107/3,988 2.7 119/4,005 3.0

≥75 82/3,073 2.7 124/3,077 4.0

Weight (kg) 0.78

≤70 63/2,004 3.1 78/2,008 3.9

70–≤90 92/3,022 3.0 129/3,133 4.1

>90 34/2,033 1.7 36/1,940 1.9

CrCl (ml/min) 0.72

<50 50/1,485 3.4 60/1,456 4.1

50–80 91/3,290 2.8 128/3,396 3.8

>80 47/2,278 2.1 54/2,221 2.4


0.1 0.2 0.5 1 2 5 10Favours

rivaroxabanFavours warfarin


104

cTTRRivaroxaban (% per year)

Warfarin(% per year)

Hazard ratio (95% CI)

0.0–50.6% 1.8 2.5 0.70 (0.48, 1.03)

50.7–58.5% 1.9 2.2 0.89 (0.62, 1.29)

58.6–65.7% 1.9 2.1 0.89 (0.62, 1.28)

65.7–100.0% 1.3 1.8 0.74 (0.49, 1.12)

cTTR, centre-based time in therapeutic rangeBased on Rosendaal method with all INR values included*p-value for interaction=0.74Safety population (N=7,061 [rivaroxaban], N=7,082 [warfarin])


Favours warfarin10.5 2

Favours rivaroxaban

Bet

ter I

NR

con

trol

ROCKET AF – primary efficacy endpoint centre-based INR control*


105

ROCKET AF – conclusions

Based on the prespecified primary efficacy outcome: A once-daily fixed dose regimen of rivaroxaban was non-inferior to warfarin for

prevention of stroke or non-CNS systemic embolism Rivaroxaban was superior to warfarin while patients were taking study drug Less MIs and vascular death with rivaroxaban (not statistically significant)

Safety: Similar overall incidence of bleeding and adverse events Increase in gastrointestinal bleeds with rivaroxaban fewer intracranial haemorrhages with rivaroxaban less fatal bleeding with rivaroxaban Less overall mortality (not statistically significant)

Implication: Rivaroxaban, once approved in the indication, is a once-daily, proven alternative to

warfarin with superior efficacy ‘on treatment’, similar overall bleeding and fewer intracranial haemorrhages

Additional safety outcomes: Liver enzyme elevations

D110 D150 Warfarin

No. of patients N=6,015 N=6,076 N=6,022

ALT or AST >3xULN

121 111 126

% 2.0 1.8 2.1

ALT or AST >3xULN and bilirubin >2xULN

11 14 22

% 0.2 0.2 0.4



Camm J.: Oral presentation at ESC on Aug 30th 2009. Dabigatran etexilate is in clinical development and not licensed for

clinical use in stroke prevention for patients with atrial fibrillation

Meta-analysis of ischaemic stroke or systemic embolism

W vs placebo

W vs W low dose

W vs ASA

W vs ASA + clopidogrel

W vs ximelagatran

W vs dabigatran 150

0 0.3 0.6 0.9 1.2 1.5 1.8 2.0

Favours warfarin Favours other treatment

Category

RE-LY in perspective

Lo studio RE-LY: è iniziato il crepuscolo dei dicumarolici?G Ital Cardiol 2010; 11 (4): 263-268

William Turner, The Fighting Temeraire (National Gallery, Londra)

Eerenberg ES et al. Circulation. 2011; 124:1573-79

FIBRILLAZIONE ATRIALE : NUOVI SCENARI TERAPEUTICI E CONSEGUENTI IMPLICAZIONI GESTIONALI HEARTLINE...

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