I nuovi anticoagulanti orali ed il dilemma delle copatologie

I nuovi anticoagulanti orali ed il dilemma delle copatologie

Bruno Trimarco

Dipartimento di Scienze Biomediche Avanzate

Università degli Studi di Napoli “Federico II”

Pathophysiology of thrombosis in heart failure.

Adapted from Weitz J. J Thromb Haemost 2005

New Oral Anticoagulants

DIVISION OF CARDIOLOGY - UNIVERSITY OF NAPLES

-New Oral Anticoagulants--New Oral Anticoagulants-An OverviewAn Overview

-New Oral Anticoagulants--New Oral Anticoagulants-An OverviewAn Overview

Adapted from Piccini et al. Curr Opin Cardiol 2010

-New Oral Anticoagulants--New Oral Anticoagulants-

Stroke and Systemic emboliStroke and Systemic emboli


Stroke and Systemic emboliStroke and Systemic emboli


Intracranial HemorrhageIntracranial Hemorrhage


Intracranial HemorrhageIntracranial Hemorrhage

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizedDouble Blind / Double Dummy

(n ~ 14,000)

Monthly MonitoringAdherence to standard of care guidelines

Study Design

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Risk FactorsStroke, TIA or Systemic embolusOR• CHF • Hypertension • Age 75 • Diabetes

At least 2 or 3 required*

Pathophysiology of thrombosis in heart failure.

Lip G Y et al. Eur J Heart Fail 2012;14:681-695

Pathophysiology of thrombosis in heart failure

Anticoagulants in heart failure The beginning

Anticoagulants in heart failure in the New Millennium

Methods - Definitions

HF was defined as a history of HF or left ventricular ejection fraction (LVEF) <40%

Pre-specified secondary HF sub-group analyses LVEF ≥40% vs. <40% New York Heart Association (NHYA) class CHADS2 score

Implantable cardioverter defibrillator (ICD) or biventricular-ICD (BiV-ICD)

Methods - Outcomes

Efficacy endpoints (intention-to-treat population)

Primary: Stroke or systemic embolism Secondary

– All-cause death– Stroke, systemic embolism, or vascular death

Safety endpoints (safety population)

Primary : Major or non-major clinically relevant (NMCR) bleeding

Secondary– Intracranial hemorrhage (ICH)– Hemorrhagic stroke

*All outcomes reported as adjusted hazard ratios (HR) per 100 patient-years (pt-yrs)

Results – HF vs. No HF 9033 (63.7%) of patients were defined as having HF

Selected Baseline VariablesSelected Baseline VariablesPatients with HFPatients with HF

(n=9033)(n=9033)

Patients without HFPatients without HF

(n=5138)(n=5138)

Age 72 74

Female 39.1% 40.3%

Persistent AF 83.0% 77.6%

Previous embolic event 3.8% 4.0%

CHADS2 score 3.7 3.1

LVEF <40% 33.9% Excluded

Hypertension 93.0% 86.1%

Diabetes mellitus 42.4% 35.4%

Previous and concurrent medications

Concurrent ASA use 31.0% 25.2%

Beta-blocker 69.6% 56.4%

Digitalis 44.9% 27.2%

ACE inhibitor 60.9% 42.0%

Diuretics 70.9% 39.6%

OutcomesHF

No HF

HF vs. No HFHR (95% CI)

p value

Efficacy Outcomes Stroke or systemic embolization 1.99 2.32 0.94 (0.78, 1.13) 0.51

Stroke, systemic embolization, or vascular death

5.00 3.50 1.28 (1.11, 1.47) <0.01

Stroke 1.84 2.16 0.95 (0.78, 1.15) 0.57Systemic embolization 0.17 0.17 0.93 (0.48, 1.82) 0.84

All-cause death 5.26 3.37 1.34 (1.17, 1.55) <0.01Vascular death 3.53 1.75 1.65 (1.37, 1.98) <0.01

Myocardial infarction 1.15 0.71 1.20 (0.89, 1.63) 0.23

Results - HF vs. No HF

Safety Outcomes Major or NMCR bleeding 14.12 15.73 1.00 (0.92, 1.08) 0.99

Hemorrhagic stroke 0.29 0.45 0.73 (0.45, 1.20) 0.22Intracranial hemorrhage 0.53 0.77 0.84 (0.58, 1.22) 0.36

Results – HF Status and Treatment Assignment

Selected Variables

Heart Failure No Heart Failure

Rivaroxaban(N=4530)

Warfarin(N=4503)

Rivaroxaban(N=2551)

Warfarin(N=2587)

Age 72 72 74 74

Female 39.1% 39.1% 40.3% 40.3%

Persistent AF 83.6% 82.3% 77.0% 78.2%

Previous embolic event 3.7% 4.0% 4.1% 3.8%

CHADS2 score 3.7 3.7 3.2 3.1

LVEF <40% 33.3% 34.5% N/A N/A

NYHA Class III/IV 30.0% 29.9% N/A N/A

ICD or BiV-ICD 3.6% 3.7% 0.4% 0.3%

Hypertension 92.8% 93.3% 85.7% 86.4%

Diabetes mellitus 42.3% 42.5% 36.7% 34.2%

Previous and concurrent medications

Concurrent ASA use 30.3% 31.7% 25.8% 24.7%

Beta-blocker 68.7% 70.5% 56.8% 56.0%

Digitalis 44.7% 45.2% 27.4% 27.1%

ACE inhibitor 61.6% 60.1% 41.5% 42.5%

Diuretics 71.4% 70.4% 39.4% 39.9%

Results – HF Subgroups

HF Subgroup

Stroke or non-CNS embolism

Rivaroxaban WarfarinRivaroxaban vs. Warfarin

HR (95% CI)p-value

LVEF

≥40% 2.00 2.06 0.98 (0.74, 1.31) 0.38

<40% 1.34 1.87 0.72 (0.46, 1.12)

NYHA Class

I or II 1.90 2.02 0.94 (0.73, 1.22) 0.68

III or IV 1.88 2.10 0.90 (0.61, 1.32)

Device Therapy

No Device 1.96 2.08 0.94 (0.75, 1.18) 0.11

ICD or BiV-ICD 0.33 1.96 0.17 (0.02, 1.39)

CHADS2 Score

2 1.30 1.16 1.09 (0.44, 2.69) 0.48

≥3 1.96 2.18 0.90 (0.72, 1.12)

Results – Heart Failure Subgroups

Heart Failure Subgroup

Major or Non-Major Clinically Relevant Bleeding

Rivaroxaban WarfarinRivaroxaban vs. Warfarin

HR (95% CI) p-value

Ejection Fraction

≥ 40% 14.18 14.81 1.00 (0.88, 1.13) 0.051

< 40% 15.34 14.10 1.15 (0.96, 1.36)

NYHA Class

I or II 14.83 14.15 1.08 (0.97, 1.21) 0.19

III or IV 12.45 13.54 0.96 (0.80, 1.15)

Device therapy

No Device 13.08 13.72 0.99 (0.89, 1.09) 0.002

ICD or BiV-ICD 32.43 16.37 2.00 (1.31, 3.05)

CHADS2 score

2 15.96 10.02 1.54 (1.10, 2.16) 0.15

≥3 14.06 14.42 1.02 (0.92, 1.12)

Available now online from European Heart Journal

http://eurheartj.oxfordjournals.org/cgi/content/full/ehr342

ASA, acetylsalicylic acid; IQR, interquartile range; VKA, vitamin K antagonistSafety population (minus 9 pts in warfarin arm with no CrCl data)

Baseline demographics

Characteristic

CrCl 30–49 ml/min CrCl ≥50 ml/min

Rivaroxaban 15 mg od(N=1474)

Warfarin(N=1476)


Warfarin(N=5640)

Age, median (IQR), yrs 79 (75–82) 79 (75–83) 71 (63–76) 71 (63–76)

Female (%) 55.0 55.9 35.6 35.4

BMI, median (IQR),kg/m2 25.1 (22.7–28.0) 25.2 (22.8–27.9) 29.2 (26.1–33.0) 28.9 (26.0–32.7)

SBP, median (IQR),mm Hg 130 (120–140) 130 (120–140) 130 (120–140) 130 (120–140)

Paroxysmal AF (%) 16.6 14.6 17.7 18.7

Prior ASA use (%) 35.9 37.4 36.4 36.5

Prior VKA use (%) 62.7 61.3 62.2 62.9

Baseline demographics (continued)

Characteristic



Warfarin(N=1476)


Warfarin(N=5640)

CHADS2 score(mean ± SD) 3.68 ± 1.00 3.67 ± 1.01 3.42 ± 0.91 3.41 ± 0.92

Prior stroke/TIA orsystemic embolism (%) 50.1 49.1 56.2 56.0

Congestive heart failure (%) 66.0 65.3 61.8 61.5

Hypertension (%) 91.7 92.1 89.9 90.4

Diabetes mellitus (%) 31.8 33.3 42.6 41.1

Prior myocardialinfarction (%) 18.7 20.5 16.0 17.3

SD, standard deviation; TIA, transient ischaemic attackSafety population (minus 9 pts in warfarin arm with no CrCl data)

ROCKET AF: stroke or non-CNS embolism among patients with CrCl 30–49 ml/min

0

1

2

3

4

5

6

7

8

0 120 240 360 480 600 720 840

Cu

mu

lati

ve e

ven

t ra

te (

%)

Warfarin

Rivaroxaban

HR (95% CI): 0.84 (0.57, 1.23)

Days since randomizationNo. at risk:Rivaroxaban 1,434 1,226 1,103 1,027 806 621 442 275Warfarin 1,439 1,261 1,140 1,052 832 656 455 272

Event rates are % per year; Based on Protocol Compliant on Treatment Population

Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394

ROCKET AF: Primary efficacy endpoint: stroke or non-CNS embolism patients with CrCl 30–49 ml/min vs. ROCKET AF overall

1 Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394; 2 Patel MR et al. N Engl J Med 2011;365:883–8911 Fox KA et al. Eur Heart J 2011; 32 (19): 2387-2394; 2 Patel MR et al. N Engl J Med 2011;365:883–891

Days since randomization

0 120 240 480 600 7200

1

2

3

4

5

6

840360

Cu

mu

lati

ve e

ven

t ra

te (

%)

* among patients with CrCl 30-49 ml/min:HR 0.84 (95% CI: 0.57-1.23)

** HR 0.79 (95% CI: 0.66-0.96) p<0.001 (non-inferiority)

Warfarin, overall**,2Warfarin, overall**,2

Warfarin, renally impaired*,1Warfarin, renally impaired*,1

Rivaroxaban overall**,2Rivaroxaban overall**,2

Rivaroxaban renally impaired*,1Rivaroxaban renally impaired*,1

Per-protocol population on-treatment

Safety outcomes

Clinical endpoint(% per year)

Rivaroxaban(N=7111)

Warfarin(N=7116)

HR (95% CI)Rivaroxabanvs warfarin

P(interaction)

Principal safety outcome*

14.2417.82

13.6718.28

1.04 (0.96–1.13)0.98 (0.84–1.14)

0.45

Major bleeding3.394.49

3.174.70

1.07 (0.91–1.26)0.95 (0.72–1.26)

0.48

Hct or Hb drop2.543.76

2.033.28

1.25 (1.03–1.52)1.14 (0.83–1.58)

0.65

Transfusion1.492.34

1.162.00

1.28 (0.99–1.65)1.17 (0.77–1.76)

0.71

Critical organ0.830.76

1.131.39

0.74 (0.55–0.99)0.55 (0.30–1.00)

0.39

Fatal bleeding0.230.28

0.430.74

0.55 (0.32–0.93)0.39 (0.15–0.99)

0.53

Intracranial haemorrhage

0.440.71

0.710.88

0.62 (0.42–0.92)0.81 (0.41–1.60)

0.51

Based on safety population on treatment*Composite of major plus non-major clinically relevant bleeding. †Rivaroxaban 20 mg od. ‡Rivaroxaban 15 mg od

0.01 0.1 1 10

CrCl ≥50 ml/min†

CrCl 30–49 ml/min‡

Bleeding sites

Major bleeding(% per year)


Rivaroxaban15 mg

(N = 1474)

Warfarin(N=1476)

Rivaroxaban20 mg

(N=5637)

Warfarin(N=5640)

GI (upper, lower, and rectal)† 2.88 1.77 1.79 1.12

Intracranial haemorrhage‡ 0.71 0.88 0.44 0.71

Macroscopic haematuria 0.05 0.18 0.28 0.19

Bleeding associated with non-cardiac surgery 0.24 0.42 0.15 0.19

Intra-articular 0.00 0.23 0.18 0.17

Epistaxis 0.19 0.09 0.10 0.13

† p=0.02 (riva vs. warf in CrCl 30–49 ml/min); p=0.0002 (riva vs. warf in CrCl ≥50 ml/min)‡ p=0.02 (riva vs. warf in CrCl ≥50 ml/min)

28

ROCKET AF – PREVENZIONE SECONDARIA

http://www.thelancet.com/journals/laneur/issue/current

Secondary prevention cohortkey demographics

Rivaroxaban Warfarin

With prior stroke* (N=3,754)

Without prior stroke* (N=3,377)

With prior stroke* (N=3,714)

Without prior stroke* (N=3,419)

Age (years)# 69.7±9.46 72.9±9.15 69.7±9.33 72.8±9.20

TTR Median (IQR) 57.1 (42.6–70.1) 58.6 (43.6–71.0)

CHADS2 score# 3.93±0.91 2.97±0.66 3.93±0.93 2.96±0.67

Prior medications

ASA 37.5% 34.9% 37.7% 35.7%

Vitamin K antagonists 59.2% 65.8% 59.4% 65.9%

Clinical risk factors

Hypertension 84.8% 96.3% 85.1% 97.0%

Congestive heart failure 50.7% 75.9% 50.6% 74.9%

Diabetes 24.6% 57.9% 23.8% 56.5%

Myocardial infarction 14.3% 19.1% 16.0% 20.2%

*‘Prior stroke’ includes TIA, ischaemic stroke, stroke of unknown type, and haemorrhagic stroke. #Mean±SD. IQR, interquartile range; TTR, time in therapeutic INR range *‘Prior stroke’ includes TIA, ischaemic stroke, stroke of unknown type, and haemorrhagic stroke. #Mean±SD. IQR, interquartile range; TTR, time in therapeutic INR range

Results: Primary efficacy endpoint

Per protocol population, on-treatment

Kaplan–Meier survival curve showing time to the primary endpoint (stroke or systemic embolism)

Months from randomizationMonths from randomization

Cu

mu

lati

ve e

ven

t ra

te –

str

oke

or

syst

emic

em

bo

lism

(%

)C

um

ula

tive

eve

nt

rate

– s

tro

ke o

r sy

stem

ic e

mb

olis

m (

%)

00

11

22

33

00

44

55

66

77

No prior stroke/TIA, warfarinNo prior stroke/TIA, warfarin

3030

Prior stroke/TIA, warfarinPrior stroke/TIA, warfarin

66 1212 1818 2424

No prior stroke/TIA, rivaroxabanNo prior stroke/TIA, rivaroxaban

Prior stroke/TIA, rivaroxabanPrior stroke/TIA, rivaroxaban

Rivaroxaban

Events/100 pt-yrs

Warfarin

Events/100 pt-yrsInteraction p-

value

Stroke or systemic embolism

1.09

2.26

1.69

2.600.15

Any stroke1.06

2.21

1.53

2.370.16

Haemorrhagic stroke0.17

0.35

0.41

0.470.22

Ischaemic or unknown stroke

0.89

1.86

1.11

1.920.41

Disabling or fatal stroke0.45

1.15

0.88

1.310.07

Non-CNS systemic embolism

0.04

0.05

0.16

0.230.99

Any cause death2.00

1.74

2.35

2.070.94

Vascular death1.61

1.44

1.70

1.710.60

Results: Efficacy analysis

Per protocol population, on-treatmentNo prior stroke or TIAPrior stroke or TIA

Rivaroxaban

Events/100 pt-yrs

Warfarin

Events/100 pt-yrsInteraction p-

value

Major and non-major clinically relevant bleeding†

16.6913.31

15.1913.87

0.0800

Major bleeding4.103.13

3.693.22

0.3598

Haemoglobin/ Haematocrit drop3.422.16

2.532.00

0.1924

Transfusion2.281.06

1.531.12

0.0488

Gastrointestinal major bleeding0.690.21

0.390.17

0.4600

Critical organbleeding

0.611.01

1.191.17

0.0625

ICH 0.390.59

0.680.80

0.4656

Fatal bleeding 0.220.26

0.480.49

0.7419

Non-major clinically relevant bleeding

12.9310.78

11.7810.98

0.1995

Results: Principal safety outcome

Safety population, on-treatment†Principal safety outcome

No prior stroke or TIAPrior stroke or TIA

ROCKET AF – subanalysis elderly patients - Rationale To determine the efficacy and safety of rivaroxaban To determine the efficacy and safety of rivaroxaban

compared with warfarin among elderly patients (compared with warfarin among elderly patients (>>75 years 75 years old) with AF old) with AF compared with patients <75 years

6,229 patients were ≥75 years6,229 patients were ≥75 years Mean CHADSMean CHADS22 3.7 vs 3.3 3.7 vs 3.3

Female 46% vs. 35%Female 46% vs. 35%

Prior stroke/TIA 42% vs 65%Prior stroke/TIA 42% vs 65%

Halperin JL et al. presented at AHA 2012

Rivaroxaban better

Warfarin better

<75

≥75

Stroke/SE(n=14.171)

Rivaroxaban better

Warfarin better

Major Bleeding(n=14.236)

ROCKET AF - subanalysis elderly patients - Results

HR 0.95 (0.76-1.19)

HR 0.80 (0.63-1.02)p*=0.31

HR 0.96 (0.78-1.19)

HR 1.11 (0.92-1.34)p*=0.34

* p-value for interaction


ROCKET AF - subanalysis elderly patients - Results

%/year

Age ≥ 75 years Age < 75 years

p-value*

RN=3082

WN=3082 HR (95% CI)

RN=3999

WN=4088 HR (95% CI)

Stroke/SE1 2.29 2.85 0.80 (0.63-1.02) 2.00 2.10 0.95 (0.76-1.19) 0.31

Fatal/disabling stroke1

1.14 1.50 0.76 (0.55-1.06) 0.90 1.09 0.83 (0.60-1.15) 0.72

Mortality2 2.08 2.49 0.84 (0.64-1.07) 1.71 2.01 0.85 (0.66-1.09) 0.93

Major bleeding3

4.86 4.40 1.11 (0.92-1.34) 2.69 2.79 0.964 (0.78-1.19)

0.34

ICH3 0.66 0.83 0.80 (0.499-1.282)

0.37 0.68 0.54 (0.33-0.89) 0.27

CRNMB3 15.61 13.54 1.15 (1.03-1.23) 9.22 9.87 0.94 (0.83-1.05) 0.01


R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage; CRNMB=clinically relevant non-major bleeding1ITT population, 2 safety population excluding a GCP violating site, 3safety population

I nuovi anticoagulanti orali ed il dilemma delle copatologie

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