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The RE-LY Study: Randomized Evaluation of Long- term anticoagulant therapY Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation.

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Presentation on theme: "The RE-LY Study: Randomized Evaluation of Long- term anticoagulant therapY Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation."— Presentation transcript:

1 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

2 Atrial Fibrillation and Stroke AF responsible for 1/6 of all strokes Warfarin reduces stroke in AF by 64% – significant increase in intracranial and other hemorrhage – Difficult to use Only 50% of eligible patients receive warfarin An alternative treatment is needed

3 Dabigatran Dabigatran Etexilate, a pro-drug, is rapidly converted to dabigatran 6.5% bioavailability, 80% excreted by kidney Half-life of hours Phase 2 data identified 220 mg daily and 150 mg BID as viable doses

4 RE-LY: A Non-inferiority Trial Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in 44 countries R Warfarin (INR ) N=6000 Dabigatran Etexilate 110 mg b.i.d. N=6000 Dabigatran Etexilate 150 mg b.i.d. N=6000 PROBE=Prospective Randomized Open Trial with Blinded Adjudication of Events. 1 0 efficacy outcome = stroke or systemic embolism 1 0 safety outcome = major bleeding Non-inferiority margin 1.46 open Blinded

5 Trial Execution Performed December 2005-March 2009 Median Follow up 2.0 years Follow up 99.9% complete Mean TTR = 64% (patients on warfarin)

6 Baseline Characteristics Characteristic Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized Mean age (years) Male (%) CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) Prior stroke/TIA (%) Prior MI (%) CHF (%) Baseline ASA (%) Warfarin Naïve (%)

7 Permanent Discontinuation Years of Follow-up Stopping Rates Dabigatran110 Dabigatran150 Warfarin D110 D150 W # at RiskYear

8 Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Dabigatran 150 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 <0.001 Margin = 1.46 HR (95% CI)

9 Primary Outcome D 110mgD 150mgwarfarin D 110mg vs. Warfarin D 150mg vs. Warfarin Numberrate/yrNumberrate/yrNumberrate/yrRR 95% CI P*RR P* Stroke or systemic Embolism %/yr %/yr %/yr <0.001 Stroke %/yr %/yr %/yr <0.001 Systemic Embolism %/yr %/yr %/yr * These, and all subsequent, p values, are for superiority

10 Stroke Classification D 110mgD 150mgwarfarin D 110 mg vs. Warfarin D 150 mg vs. Warfarin Numberrate/yrNumberrate/yrNumberrate/yrRR 95% CI pRR p Ischemic/ Unspecified %/yr %/yr %/yr Hemorrhagic %/yr %/yr %/yr < <0.001

11 Stroke or Systemic Embolism Cumulative Hazard Rates Dabigatran110 Dabigatran 150 Warfarin No. at Risk W D110 D150 Years

12 All Intracranial Bleeding Years Cumulative Hazard Rates Dabigatran110 Dabigatran150 Warfarin # at RiskYear D110 D150 W

13 Hemorrhagic Stroke Years Cumulative Hazard Rates Dabigatran110 Dabigatran150 Warfarin # at RiskYear D110 D150 W

14 MI, Hospitalization and Death D 110mgD 150mgwarfarin D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrate Annual AnnualrateRR 95% CI pRR p Myocardial Infarction 0.7% 0.5 % Hospitalization19.4 %20.2%20.8 % Vascular Death 2.4 %2.3 %2.7 % Death3.8 %3.6 %4.1 %

15 Bleeding and Net Clinical Benefit D 110mg D 150mg warfarin D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrateAnnualrateRR 95% CI pRR p Major Bleeding2.7 %3.1 %3.4 % Life- Threatening major 1.2 %1.5 %1.8 % < Minor Bleeding13.2 %14.8 %16.4% < Total Bleeding (Major+Minor) < Net Clinical Benefit* 7.1 %6.9 %7.6 % * stroke, systemic embolism, myocardial infarction, pulmonary embolism, death and major bleed

16 Important Sites of Major Bleeding D 110mgD 150mgwarfarin D 110mg vs. Warfarin D 150mg vs. Warfarin AnnualrateAnnualrateAnnualrateRR 95% CI pRR p Gastro- intestinal (GI) 1.1 %1.5 %1.0 % <0.001 Intracranial (ICH) 0.2 %0.3 %0.7 % < <0.001 Major Bleed (non-GI, non-ICH) 1.5 % 1.8 %

17 Major Bleeding Years Cumulative Hazard Rates Dabigatran110 Dabigatran150 Warfarin # at RiskYear D110 D150 W

18 Dabigatran 150 mg vs. 110 mg Dabigatran 110mg Dabigatran 150mg D 150mg vs. D 110 mg Numberrate/yrNumberrate/yr Relative Risk 95% CI p Stroke and systemic embolism 1.5%1.1 % Ischemic/unspecified stroke 1.3 %0.9 % Hemorrhagic stroke0.1% Major Hemorrhage2.7 %3.1 % GI Major Hemorrhage1.1 %1.5 % Net Clinical Benefit7.1 %6.9 %

19 ALT or AST >3x ULN Years Cumulative Risk Dabigatran110 Dabigatran150 Warfarin # at Risk Year D110 D150 W

20 Adverse events occurring in >5% of any group Dabigatran 110 mg% Dabigatran 150 mg% Warfarin% Dyspepsia * Dyspnea Dizziness Peripheral edema Fatigue Cough Chest pain Arthralgia Back pain Nasopharyngitis Diarrhea Atrial fibrillation Urinary tract infection Upper respiratory tract infection Common Adverse Events *Occurred more commonly on dabigatran p<0.001

21 Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cranial and life- threatening hemorrhage Both doses are free of liver and other major toxicity, although they increase dyspepsia and GI bleeding

22 Conclusions Both Dabigatran doses offer advantages over warfarin Dabigatran 150 is more effective and dabigatran 110 has a better safety profile The availability of two effective doses, with different benefit risk profiles, creates the potential to tailor therapy to individual patient characteristics


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