Phase III studies of direct oral anticoagulants for treatment and - - PowerPoint PPT Presentation

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Phase III studies of direct oral anticoagulants for treatment and - - PowerPoint PPT Presentation

Dec 17, 2023 506 likes •713 views

Phase III studies of direct oral anticoagulants for treatment and prevention of VTE Dabigatran, apixaban, edoxaban and rivaroxaban Phase III VTE acute treatment studies Trial name Design Initial treatment Treatment Long-term Active with

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Phase III studies of direct oral anticoagulants for treatment and prevention of VTE

Dabigatran, apixaban, edoxaban and rivaroxaban

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Phase III VTE acute treatment studies

Trial name Design Initial treatment with heparin/ fondaparinux Treatment duration (months) Long-term treatment regimen Active comparator Rivaroxaban EINSTEIN DVT Open label No 3, 6 or 12

  • d

Enoxaparin/VKA EINSTEIN PE Open label No 3, 6 or 12

  • d

Enoxaparin/VKA Dabigatran RE-COVER Double blind Yes 6 bid UFH/LMWH/warfarin RE-COVER II Double blind Yes 6 bid UFH/LMWH/warfarin Apixaban AMPLIFY Double blind No 6 bid Enoxaparin/warfarin Edoxaban Hokusai-VTE Double blind Yes 3–12

  • d

UFH/LMWH/warfarin All studies had identical outcomes definitions and used the same independent adjudication committee

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Treatment of acute VTE: RE-COVER and RE-COVER II – study design

  • “Unselected” patient population
  • Dabigatran: thrombin inhibitor

Predefined treatment period of 6 months

UFH/LMWH Day 1 Day 6 VKA target INR 2.5 (range 2.0–3.0) Dabigatran 150 mg bid

R Symptomatic VTE RE-COVER Symptomatic VTE RE-COVER II

N=2568 N=2564

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  • Low bleeding risk population
  • Apixaban: Xa inhibitor

Treatment of acute VTE: AMPLIFY – study design

Agnelli G et al, N Engl J Med 2013

10 mg bid for 7 days, then 5 mg bid for 6 months

R

Enoxaparin 1 mg/kg bid warfarin (INR 2.0–3.0)

Treatment period of 6 months Symptomatic mainly unprovoked DVT

  • r PE

Standard therapy Apixaban

N=5395

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Treatment of acute VTE: Hokusai-VTE – study design

  • “Unselected” patient population
  • Edoxaban: Xa inhibitor

LMWH/UFH (at least 5 days) followed by edoxaban 60 mg* od LMWH/UFH (at least 5 days) and warfarin (INR 2.0–3.0)

Standard care Symptomatic DVT and/or PE R Maximum treatment period of 12 months Edoxaban

The Hokusai-VTE Investigators, N Engl J Med 2013

*30 mg od in patients with CrCl 30–50 ml/min, body weight ≤60 kg or receiving potent P-glycoprotein inhibitors N=8292

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Treatment of acute VTE: EINSTEIN DVT/PE – study design

Randomized, open-label, event-driven, non-inferiority studies of identical design with a priori specified combined analyses

 “Unselected” patient population  Rivaroxaban: Xa inhibitor 1. N Engl J Med 2010;363:2499 2. N Engl J Med 2012;366:1287–97 15 mg bid

DVT without PE1 N=3449 N=8282

Rivaroxaban Day 1 Day 21 Enoxaparin bid for at least 5 days + VKA, INR 2.0–3.0

PE with or without DVT N=4833

Predefined treatment period of 3, 6, or 12 months 20 mg od

30-day post-study treatment period

Rivaroxaban

R

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Treatment of acute VTE: RE-COVER 1 & 2 – efficacy and safety outcomes

Events Heparin/dabigatran Heparin/warfarin Pooled HR (95% CI) N=2553 n (%) N=2554 n (%) Recurrent VTE 60 (2.4) 55 (2.2) 1.09 (0.76-1.57)

p<0.001 (non-inferiority)

Major Bleeding 37 (1.4) 51 2.0 0.73 (0.48-1.11)

Schulman S et al, N Engl J Med 2009

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Treatment of acute VTE: AMPLIFY – efficacy and safety outcomes

Events Apixaban N=2691 Standard therapy N=2704 HR (95% CI) n (%) n (%) Recurrent VTE 59 (2.3) 71 (2.7) 0.84 (0.60–1.18) p<0.001 (non-inferiority) Major bleeding 15 (0.6) 49 (1.8) 0.31 (0.17–0.55) p<0.001

Agnelli et al, 2013

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Treatment of acute VTE: Hokusai-VTE – efficacy and safety outcomes

Events Heparin/edoxaban (N=4118) Heparin/warfarin (N=4122) HR (95% CI) n (%) n (%) Recurrent VTE At end of study period* 130 (3.2) 146 (3.5) p<0.001 (non-inferiority) 0.89 (0.70–1.13) On treatment 66 (1.6) 80 (1.9) 0.82 (0.60–1.14) Major bleeding 56 (1.4) 66 (1.6) 0.84 (0.59–1.21) p=0.35

The Hokusai-VTE Investigators, N Engl J Med 2013

*12 months after the start of treatment regardless of treatment duration

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Treatment of acute VTE: EINSTEIN DVT/PE – efficacy and safety outcomes

Events Rivaroxaban (N=4150) Standard therapy (N=4131) HR (95% CI) n (%) n (%) Recurrent VTE 86 (2.1) 95 (2.3) 0.89 (0.66–1.19) p<0.001 (non-inferiority) Major bleeding 405 (1.0) 72 (1.7) 0.54 (0.37–0.79) p<0.002

Agnelli et al, 2013

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Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n % n % Major bleeding* 40 1.0 72 1.7 0.54 (0.37–0.79) p=0.002 Fatal Retroperitoneal Intracranial Gastrointestinal/thorax In a critical site Retroperitoneal Intracranial Pericardial Other Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units Gastrointestinal

EINSTEIN DVT/PE: types of major bleeding

*Some patients had >1 event

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Outcome Rivaroxaban (N=4130) Enoxaparin/VKA (N=4116) HR (95% CI) p-value n % n % Major bleeding* 40 1.0 72 1.7 0.54 (0.37–0.79) p=0.002 Fatal 3 <0.1 8 0.2 Retroperitoneal 1 <0.1 Intracranial 2 <0.1 4 <0.1 Gastrointestinal/thorax 1 <0.1 3 <0.1 In a critical site 10 0.2 29 0.7 Retroperitoneal 1 <0.1 8 0.2 Intracranial 3 <0.1 10 0.2 Pericardial 2 <0.1 Other 6 0.1 7 0.2 Fall in hemoglobin ≥2 g/dl and/or transfusions ≥2 units 27 0.7 37 0.9 Gastrointestinal 15 0.4 26 0.6

EINSTEIN DVT/PE: types of major bleeding

*Some patients had >1 event

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Einstein DVT/PE: Clinical presentation of major bleeding

Major bleeding Rivaroxaban n=45 VKA n=79 Category 1 Controllable 18 (40.0%) 17 (21.5%) Category 2 Not serious but requires measures to control 19 (42.2%) 34 (43.0%) Category 3 Serious 7 (15.6%) 26 (32.9%) Category 4 Fatal 1 (2.2%) 2 (2.5%)

Category 3+4 rivaroxaban vs VKA: odds ratio 0.39, 95% CI: 0.16-0.96; p=0.04)

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Einstein DVT/PE: Prohemostatic measures

Rivaroxaban n=45 Enox/VKA n=79 Vitamin K 1 30 FFP 4 11 Prothrombin complex 2 9 rFVIIa 1

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Outcome Rivaroxaban Enoxaparin/VKA HR (95% CI) n/N % n/N % Recurrent VTE Fragile 21/791 2.7 30/782 3.8 0.68 (0.39–1.18) Non-fragile 65/3359 1.9 65/3349 1.9 0.98 (0.70–1.38) Major bleeding Fragile 10/788 1.3 35/779 4.5 0.27 (0.13–0.54) Non-fragile 30/3342 0.9 37/3337 1.1 0.80 (0.49–1.29)

EINSTEIN DVT/PE:

  • utcomes in fragile patients*

*Age >75 years, CrCl <50 ml/min, or body weight ≤50 kg

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Rivaroxaban Enoxaparin/VKA n/N % n/N % Limited

≤25% of a single lobe, popliteal vein only

11/814 1.4 19/826 2.3 Intermediate 47/1941 2.4 50/1942 2.6 Extensive

multiple lobes and >25% of entire pulmonary vasculature; involving common femoral/ iliac vein

28/1218 2.3 25/1190 2.1

EINSTEIN DVT/PE: Clot size and recurrent VTE

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EINSTEIN PE: Repeat CT scan at 3 weeks in 264 patients

Rivaroxaban N=135 Enoxaparin/VKA N=129 Complete resolution 59 (44%) 57 (44%) Partial resolution 61 (45%) 58 (45%) No change 15 (11%) 12 (9%) Deteriorated

Van Es, et al. JTH, 11: 679–85

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EINSTEIN DVT/PE: Outcomes in cancer patients

Active cancer* Rivaroxaban Enoxaparin/VKA HR (95% CI) Recurrent VTE, n (%) 16/354 (4.5) 20/301 (6.6) 0.67 (0.35–1.30) Major bleeding, n (%) 8/353 (2.3) 15/298 (5.0) 0.42 (0.18–0.99) Mortality, n (%) 58/354 (16.4) 53/301 (17.6) 0.93 (0.64–1.35)

*At baseline or diagnosed during the study

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Overall summary: acute treatment studies

  • All DOACs non-inferior to standard therapy

– important reductions in major bleeding with apixaban and rivaroxaban single drug treatment – No reduction in major bleeding for dabigatran and edoxaban dual drug treatment

  • Major bleeding is less severe with DOACs

– less fatal bleeds – less critical organ bleeds (intracranial, retroperitoneal) – presentation and course of major bleeding less severe with DOACs

  • Results are consistent for subgroups