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The Definitive Thrombosis Update Pulmonary Embolism Harry R. Büller, MD, PhD Professor of Medicine Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands

The Definitive Thrombosis Update Pulmonary Embolism

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The Definitive Thrombosis Update Pulmonary Embolism . Harry R. Büller, MD, PhD Professor of Medicine Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands. Rivaroxaban. Specific, direct factor Xa inhibitor High, oral bioavailability Rapid onset of action - PowerPoint PPT Presentation

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Page 1: The Definitive Thrombosis Update Pulmonary Embolism

The Definitive Thrombosis UpdatePulmonary Embolism

Harry R. Büller, MD, PhDProfessor of Medicine

Department of Vascular Medicine Academic Medical Center

Amsterdam, The Netherlands

Page 2: The Definitive Thrombosis Update Pulmonary Embolism

Rivaroxaban• Specific, direct factor Xa inhibitor • High, oral bioavailability • Rapid onset of action• Half-life: 7 to 11 hours• Dual mode of elimination

– One-third of drug is excreted unchanged by the kidneys– Two-thirds of drug is metabolized by the liver: half excreted renally,

half excreted via the hepatobiliary route • Phase 2 dose-finding studies indicated that for VTE

treatment, a regimen consisting of rivaroxaban 15 mg, twice daily for 3 weeks followed by rivaroxaban 20 mg, once daily for the subsequent period appeared most optimal

Page 3: The Definitive Thrombosis Update Pulmonary Embolism

Confirmed PE without DVT

N = 4833

Rivaroxaban15 mg, 2x/d for 3 weeks

then 20 mg, 1x/d

Enoxaparin, 2x/d ≥ 5 days + VKA to target INR = 2.5 (range 2-3)

Primary outcome: symptomatic recurrent VTESecondary outcomes: clinically relevant bleeding (major bleeding + clinically relevant nonmajor bleeding); all deaths + other vascular events

EINSTEIN-PERandomized, Open-Label, Event-Driven, Noninferiority Study Up to 48 hours of

heparin/fondaparinux treatment permitted before study entry

• 30 days posttreatment period, predefined treatment period of 3, 6, or 12 months

• Noninferiority margin: 2.0• 88 primary efficacy outcomes needed

Page 4: The Definitive Thrombosis Update Pulmonary Embolism

Patient Groups

Rivaroxaban(n = 2420)

Enoxaparin/VKA(n = 2413)

ITT population 2419 2413

Safety population (as treated) 2412 2405

Per-protocol population 2224 2238

Withdrawal of consent 66 118

Lost to follow-up 8 10

Total patients = 4833

EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

Page 5: The Definitive Thrombosis Update Pulmonary Embolism

Patient CharacteristicsRivaroxaban

(n = 2419)Enoxaparin/VKA

(n = 2413)Males, % 54.1 51.7Age, mean (years) 57.9 57.5Body mass index, mean (kg/m2) 28.3 28.4Creatinine clearance, %

< 30 mL/min 0.2 <0.130-49 mL/min 8.6 7.950-79 mL/min 26.3 24.6≥ 80 mL/min 64.3 67.0

Active cancer, % 4.7 4.5Intended treatment duration, %

3 months 5.3 5.16 months 57.3 57.512 months 37.4 37.5

Anatomical extent baseline PE, %Limited (single lobe ≤ 25% of vasculature) 12.8 12.4Intermediate 57.5 59.0Extensive (multiple lobes > 25% of entire vasculature) 24.7 23.9

EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

ITT Population

Page 6: The Definitive Thrombosis Update Pulmonary Embolism

EINSTEIN-PE: Primary Efficacy Outcome Analysis Rivaroxaban

(n = 2419)Enoxaparin/VKA

(n = 2413)n % n %

First symptomatic recurrent VTE 50 2.1 44 1.8Recurrent DVT 18 0.7 17 0.7Recurrent DVT + PE 0 2 < 0.1Nonfatal PE 22 0.9 19 0.8Fatal PE/unexplained death wherePE cannot be ruled out 10 0.4 6 0.2

Rivaroxaban superior

Rivaroxaban noninferior

Rivaroxaban inferior

P = .0026 for noninferiority (1 sided)

P = .57 for superiority (2 sided)

1.00 0 2.00

0.75 1.12 1.68*

*Potential relative risk increase < 68.4%; absolute risk difference 0.24% (-0.5 to 1.02).

HR

Büller HR. ACC 2012.

Page 7: The Definitive Thrombosis Update Pulmonary Embolism

EINSTEIN-PE: Primary Efficacy Outcome: Time to First Event

ITT Population3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

No. of Patients at Risk

Rivaroxaban 2419 2350 2321 2303 2180 2167 2063 837 794 785 757 725 672

Enoxaparin/VKA 2413 2316 2295 2274 2155 2146 2050 835 787 772 746 722 675

Time to Event, days

Rivaroxabann = 2419

Enoxaparin/VKAn = 2413

HR: 1.12; P < .0026 (noninferiority)

TTR: 62.7%Cum

ulati

ve E

vent

Rat

e, %

From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

Page 8: The Definitive Thrombosis Update Pulmonary Embolism

EINSTEIN-PE: Principal Safety Outcome: Major or Nonmajor Clinically Relevant Bleeding

Rivaroxaban Enoxaparin/VKA HR (95% CI)

10.3% 11.4%0.90 (0.76-1.07)

P = .23

0 30 60 90 120 150 180 210 240 270 300 330 360

1514

10

131211

9876543210

No. of Patients at Risk

Rivaroxaban 2412 2183 2133 2024 1953 1913 1211 696 671 632 600 588 313

Enoxaparin/VKA 2405 2184 2115 1990 1923 1887 1092 687 660 620 589 574 251

Time to Event, days

Rivaroxabann = 2412

Enoxaparin/VKAn = 2405

Cum

ulati

ve E

vent

Rat

e, %

From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

Safety Population

Page 9: The Definitive Thrombosis Update Pulmonary Embolism

3.0

2.5

2.0

1.5

1.0

0.0

0.5

0 30 60 90 120 150 180 210 240 270 300 330 360

Cum

ulati

ve E

vent

Rat

e, %

Time to Event, days

Rivaroxabann = 2412

Enoxaparin/VKAn = 2405

No. of Patients at Risk

Rivaroxaban 2412 2281 2248 2156 2091 2063 1317 761 735 700 669 659 350

Enoxaparin/VKA 2405 2270 2224 2116 2063 2036 1176 746 719 680 658 642 278

EINSTEIN-PE: Major Bleeding

Rivaroxaban Enoxaparin/VKA HR (95% CI)

1.1% 2.2%0.49 (0.31-0.79)

P =.0032

From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

Safety Population

Page 10: The Definitive Thrombosis Update Pulmonary Embolism

EINSTEIN-PE: Key Secondary Outcomes

Outcome

Rivaroxaban

Enoxaparin/

VKAHR

(95% CI)% %Net clinical benefit* 3.4 4.0 0.85 (0.63-1.14)

Total mortality 2.4 2.1 1.13 (0.77-1.65)

On-treatment

• Cerebrovascular events 0.5 0.5

• ACS 0.6 0.9

Off-treatment (+ 30 days)

• Cerebrovascular events < 0.1 < 0.1

• ACS 0.1 < 0.1

ALT > 3 × ULN + bilirubin > 2 × ULN 0.2 0.2

*Primary efficacy outcome plus major bleeding.

EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

Page 11: The Definitive Thrombosis Update Pulmonary Embolism

EINSTEIN-PE: Conclusions

In patients with acute symptomatic PE with or without DVT, rivaroxaban showed

• Noninferiority to LMWH/VKA for efficacy: HR = 1.12 (95% CI, 0.75-1.69); P = .0026 for noninferiority margin of 2.0

• Similar findings for principal safety outcome: HR = 0.90 (95% CI, 0.76-1.07); P = .23

• Superiority for major bleeding: HR = 0.49 (95% CI, 0.31-0.79); P = .0032

• Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function, or cancer

• No evidence for liver toxicity

Page 12: The Definitive Thrombosis Update Pulmonary Embolism

The Definitive Thrombosis Update

Venous ThromboembolismProfessor the Lord Ajay K. Kakkar, MD, PhD

Prevention of Atrial Fibrillation-Related StrokeKeith A. A. Fox, MB, ChB

Secondary Prevention Following Acute Coronary Syndrome

Freek W. A. Verheugt, MD

Pulmonary EmbolismHarry R. Büller, MD, PhD