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ESC-HFA 2015Antithrombotics in heart failure: the controversy continues

Antithrombotic Drug(s) of choice in atrial fibrillation.(in pts with HF)

Faiez ZannadHypertension and Heart Failure Unit,Inserm Clinical Investigation Center

Institut Lorrain du Coeur et des VaisseauxCHU and Univeristé de Lorraine, France

DGOS

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Disclosures• Relative to this presentation: Chair steering committee

COMMANDER HF (J&J)• Otherwise:

• steering committee fees : Bayer, Boston Scientific, Janssen, Novartis, Pfizer, Resmed, and Takeda

• Consultant/scientific advisory board fees : Air Liquide, Amgen, CVRx, Relypsa, Servier, St Jude, Stealth peptide, ZS Pharma; Quantuum Genomics.

• co-founder of CRS.• Institution receives research grant from Roche Diagnostics.

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OutcomesHF 

No HF 

HF vs. No HFHR (95% CI)  p

CV Outcomes        Stroke or systemic embolization 1.99 2.32 0.94 (0.78, 1.13) 0.51Stroke, 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) 0.84All-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) <0.01Myocardial infarction 1.15 0.71 1.20 (0.89, 1.63) 0.23

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

Rocket AF. Higher rate of thrombotic events in HF (LVEF<40%)

Sean van Diepen et al. Circ Heart Fail. 2013;6:740-747

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Stroke or SE Vascular Death

With sHF Without sHF0

0.5

1

1.5

2

2.5

Rate

 (% p

er y

ear)

1.75

1.35

HR=1.30 (1.08-1.57) P=0.005

With sHF Without sHF0

1

2

3

4

5

6

Rate

 (% p

er y

ear)

4.69

1.67

HR=2.82 (2.47-3.21) P<0.001

N=4904 N=4904N=13209 N=13209

RELYSymptomatic HF is associated with higher

rates of stroke/SE and vascular death.

Adapted from Ferreira J et al , AHA 2011

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Warfarin, The gold standard

• Guidelines (ACC/AHA and ESC): • class I recommendation in all patients with heart failure and

atrial fibrillation in the absence of contraindications.

• Evidence: • High-level evidence (A)• Meta-analysis of 29 clinical trials spanning 18 years: • warfarin reduces stroke risk in patients with Afib by

approximately 64%. (1)

(1) Hart RG et al. Ann Intern Med. 2007;146:857–867

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Warfarin, not simple to use

• Limitations:– Narrow therapeutic window, – Variable amount of time spent in treatment range– Numerous drug-drug interactions– Variable dose requirements, – Unpredictable anticoagulant response– Need for frequent monitoring– Need for a stable diet– Slow onset of action– Bleeding risk most pronounced in older

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Warfarin, underused

79.2% of warfarin-eligible patients were discharged without a prescription, despite being at high risk for stroke.

Not receiving warfarin was independently associated with a

higher risk of death 1 year after discharge

Hess PL et al. Clinical Cardiology 2012

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Overall, NOACS, more efficacious than Warfarin

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Overall, NOACS, safer than Warfarin(Except for GI bleeding)

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DE 110 vs. Warfarin DE 150 vs. Warfarin

Rate (% per year)

DE 110 DE WWith sHFWithout sHF

1.90 1.44 1.921.41 1.00 1.64

Stroke or SE

P(Inter)

1.000.50 1.50

0.51

HR & 95% CI

0.50 1.50

0.39

1.00

P(Inter)HR & 95% CI

W better

Major BleedingDE 110 vs. Warfarin DE 150 vs. Warfarin

Rate (% per year)

DE 110 DE W

With sHFWithout sHF

3.26 3.10 3.902.73 3.39 3.45

P(Inter)

1.000.50 1.50

DE better

0.20

HR & 95% CI

0.50 1.50

0.74

1.00

P(Inter)HR & 95% CI

DE better W better

RE-LY , Overall benefits of dabigatran relative to warfarin unchanged in Pts with HF

Adapted from Ferreira J et al , AHA 2011

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Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily15 mg for CrCl 30-49

Atrial Fibrillation

RandomizedDouble blind /

Double Dummy(n = 14,264)

Monthly MonitoringAdherence to standard-of-care guidelines

ROCKET - AF

* 10% enrolled without stroke, TIA, systemic embolus and only 2 factors, as per per protocol

Risk Factors• CHF • Hypertension • Age  75 • Diabetes OR• Stroke, TIA or    Systemic embolus 

At least 3 required*

Sean van Diepen et al. Circ Heart Fail. 2013;6:740-747

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Heart Failure Subgroup ITT (n)

Stroke or non-CNS embolism

Rivaroxaban WarfarinRivaroxaban vs. 

WarfarinHR (95% CI)

p-valuefor interaction

Ejection Fraction  ≥40% 4914 2.00 2.06 0.98 (0.74, 1.31) 0.38

                             <40% 2521 1.34 1.87  0.72 (0.46, 1.12)  

NYHA Class           I or II 6217 1.90  2.02  0.94 (0.73, 1.22) 0.68

                           III or IV 2676 1.88  2.10  0.90 (0.61, 1.32)  

No Device 7937 1.96  2.08 0.94 (0.75, 1.18) 0.11

ICD or BiV-ICD 297 0.33 0.17 (0.02, 1.39)  

 CHADS2            Score 2 610 1.30  1.16 1.09 (0.44, 2.69) 0.48

                                   ≥3 8467 1.96  2.18 0.90 (0.72, 1.12)  

ROCKET – AF Rivaroxaban and warfarin , both equally effective among pre-specified HF subgroups

Sean van Diepen et al. Circ Heart Fail. 2013;6:740-747

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Heart Failure Subgroup

Safetyn

Major or Non-Major Clinically Relevant Bleeding

Rivaroxaban WarfarinRivaroxaban vs. 

WarfarinHR (95% CI) 

p-valuefor interaction

E F              ≥ 40% 4893 14.18 14.81 1.00 (0.88, 1.13) 0.051< 40% 2497 15.34 14.10  1.15 (0.96, 1.36)  

NYHA Class  I or II 6205 14.83 14.15 1.08 (0.97, 1.21) 0.19III or IV 2645 12.45 13.54 0.96 (0.80, 1.15)  

No Device 7899 13.08 13.72 0.99 (0.89, 1.09) 0.002ICD or BiV-ICD 298 32.43 16.37 2.00 (1.31, 3.05)  CHADS2 score     2 610 15.96 10.02 1.54 (1.10, 2.16) 0.15

≥3 8423 14.06 14.42 1.02 (0.92, 1.12)  

ROCKET – AF Rivaroxaban and warfarin , both equally safe among pre-specified HF subgroups

Sean van Diepen et al. Circ Heart Fail. 2013;6:740-747

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Edoxaban, HF subgroup analysis No interaction

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Edoxaban, HF subgroup analysis No interaction

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New oral anticoagulant drugs (direct thrombin inhibitors and factor Xa inhibitors) 

• contraindicated in severe renal impairment (creatinine clearance < 30 mL/min).

• Clearly a concern in many patients with HF• If used, serial monitoring of renal function is

required. • There is no known way to reverse the

anticoagulant action of these new drugs.

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New Oral anticoagulants