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

2. 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

3. EINSTEIN-PE Randomized, Open-Label, Event-Driven, Noninferiority Study
Confirmed PE
without DVT
N = 4833
Up to 48 hours of heparin/fondaparinux treatment permitted before study entry
Enoxaparin, 2x/d ≥ 5 days + VKA to target INR = 2.5 (range 2-3)
Rivaroxaban
15 mg, 2x/d for 3 weeks then 20 mg, 1x/d
Primary outcome: symptomatic recurrent VTE
Secondary outcomes: clinically relevant bleeding (major bleeding + clinically relevant nonmajor bleeding); all deaths + other vascular events
30 days posttreatment period, predefined treatment period of 3, 6, or 12 months
Noninferiority margin: 2.0
88 primary efficacy outcomes needed

4. EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.
Patient Groups
Rivaroxaban clinical development
Total patients = 4833
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
EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 4

5. Patient Characteristics
Rivaroxaban clinical development
ITT Population
Rivaroxaban (n = 2419)
Enoxaparin/VKA (n = 2413)
Males, %
54.1
51.7
Age, mean (years)
57.9
57.5
Body mass index, mean (kg/m2)
28.3
28.4
Creatinine clearance, %
< 30 mL/min
0.2
<0.1
30-49 mL/min
8.6
7.9
50-79 mL/min
26.3
24.6
≥ 80 mL/min
64.3
67.0
Active cancer, %
4.7
4.5
Intended treatment duration, %
3 months
5.3
5.1
6 months
57.3
12 months
37.4
37.5
Anatomical extent baseline PE, %
Limited (single lobe ≤ 25% of vasculature)
12.8
12.4
Intermediate
59.0
Extensive (multiple lobes > 25% of entire vasculature)
24.7
23.9
EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 5

6. EINSTEIN-PE: Primary Efficacy Outcome Analysis
Rivaroxaban clinical development
EINSTEIN-PE: Primary Efficacy Outcome Analysis
Rivaroxaban
(n = 2419)
Enoxaparin/VKA
(n = 2413) n %
First symptomatic recurrent VTE 50
2.1 44
1.8
Recurrent DVT 18
0.7 17
Recurrent DVT + PE 2
< 0.1
Nonfatal PE 22
0.9 19
0.8
Fatal PE/unexplained death where PE cannot be ruled out 10
0.4 6
0.2 HR
0.75
1.12
1.68*
1.00
2.00
Rivaroxaban superior
Rivaroxaban noninferior
Rivaroxaban inferior
P = .57 for superiority
(2 sided)
P = for noninferiority (1 sided)
*Potential relative risk increase < 68.4%; absolute risk difference 0.24% (-0.5 to 1.02).
Büller HR. ACC 2012. 6

7. EINSTEIN-PE: Primary Efficacy Outcome: Time to First Event
Rivaroxaban clinical development
EINSTEIN-PE: Primary Efficacy Outcome: Time to First Event
ITT Population
3.0
2.5
2.0
1.5
1.0
0.0
0.5
Rivaroxaban
n = 2419
Enoxaparin/VKA
n = 2413
Cumulative Event Rate, %
HR: 1.12; P < (noninferiority)
TTR: 62.7%
Time to Event, days 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
From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 7

8. Cumulative Event Rate, %
Rivaroxaban clinical development
EINSTEIN-PE: Principal Safety Outcome: Major or Nonmajor Clinically Relevant Bleeding
Safety Population 15 14 10 13 12 11 9 8 7 6 5 4 3 2 1
Enoxaparin/VKA
n = 2405
Rivaroxaban
n = 2412
Cumulative Event Rate, %
Rivaroxaban
Enoxaparin/VKA
HR (95% CI)
10.3%
11.4%
0.90 ( )
P = .23
Time to Event, days 30 60 90
120
150
180
210
240
270
300
330
360
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
From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 8

9. EINSTEIN-PE: Major Bleeding
Rivaroxaban clinical development
Safety Population
Rivaroxaban
Enoxaparin/VKA
HR (95% CI)
1.1%
2.2%
0.49 ( )
P =.0032
3.0
2.5
2.0
1.5
1.0
0.0
0.5
Enoxaparin/VKA
n = 2405
Cumulative Event Rate, %
Rivaroxaban
n = 2412
Time to Event, days 30 60 90
120
150
180
210
240
270
300
330
360
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
2036
1176
746
719
680
658
642
278
From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 9

10. EINSTEIN-PE: Key Secondary Outcomes
Rivaroxaban clinical development
Outcome
Rivaroxaban
Enoxaparin/
VKA
HR (95% CI) %
Net clinical benefit*
3.4
4.0
0.85 ( )
Total mortality
2.4
2.1
1.13 ( )
On-treatment
Cerebrovascular events
0.5
ACS
0.6
0.9
Off-treatment (+ 30 days)
< 0.1
0.1
ALT > 3 × ULN + bilirubin > 2 × ULN
0.2
*Primary efficacy outcome plus major bleeding.
EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366: 10

11. 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, ); P = for noninferiority margin of 2.0
Similar findings for principal safety outcome: HR = 0.90 (95% CI, ); P = .23
Superiority for major bleeding: HR = 0.49 (95% CI, ); P = .0032
Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function, or cancer
No evidence for liver toxicity 11

12. The Definitive Thrombosis Update
Venous Thromboembolism
Professor the Lord Ajay K. Kakkar, MD, PhD
Prevention of Atrial Fibrillation-Related Stroke
Keith A. A. Fox, MB, ChB
Secondary Prevention Following Acute Coronary Syndrome
Freek W. A. Verheugt, MD
Pulmonary Embolism
Harry R. Büller, MD, PhD