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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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The Definitive Thrombosis UpdatePulmonary Embolism
Harry R. Büller, MD, PhDProfessor 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• 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
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
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.
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
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.
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.
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
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
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.
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
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