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
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
EINSTEIN-PE
Randomized, Open-Label, Event-Driven, Noninferiority
Study
Up to 48 hours of
Confirmed PE
without DVT
N = 4833
Rivaroxaban
15 mg, 2x/d for 3 weeks
then 20 mg, 1x/d
heparin/fondaparinux
treatment permitted
before study entry
Enoxaparin, 2x/d ≥ 5
days + VKA to target
INR = 2.5 (range 2-3)
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
Patient Groups
Total patients = 4833
Rivaroxaban Enoxaparin/VKA
(n = 2420)
(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;366:1287-1297.
Patient Characteristics
ITT Population
Males, %
Age, mean (years)
Body mass index, mean (kg/m2)
Creatinine clearance, %
< 30 mL/min
30-49 mL/min
50-79 mL/min
≥ 80 mL/min
Active cancer, %
Intended treatment duration, %
3 months
6 months
12 months
Anatomical extent baseline PE, %
Limited (single lobe ≤ 25% of vasculature)
Intermediate
Extensive (multiple lobes > 25% of entire
vasculature)
Rivaroxaban
(n = 2419)
54.1
57.9
28.3
Enoxaparin/VKA
(n = 2413)
51.7
57.5
28.4
0.2
8.6
26.3
64.3
4.7
<0.1
7.9
24.6
67.0
4.5
5.3
57.3
37.4
5.1
57.5
37.5
12.8
57.5
12.4
59.0
24.7
23.9
EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.
EINSTEIN-PE: Primary Efficacy Outcome
Analysis
Rivaroxaban
Enoxaparin/VKA
First symptomatic recurrent VTE
Recurrent DVT
Recurrent DVT + PE
Nonfatal PE
Fatal PE/unexplained death where
PE cannot be ruled out
(n = 2419)
n
%
50
2.1
18
0.7
0
22
0.9
(n = 2413)
n
%
44
1.8
17
0.7
2
< 0.1
19
0.8
10
6
0.4
0.2
HR
1.12
0.75
0
1.68*
1.00
Rivaroxaban
superior
Rivaroxaban
noninferior
2.00
Rivaroxaban
inferior
P = .57 for superiority
P = .0026 for noninferiority
(2 sided)
(1 sided)
*Potential relative risk increase < 68.4%; absolute risk difference 0.24% (-0.5 to 1.02).
Büller HR. ACC 2012.
EINSTEIN-PE: Primary Efficacy Outcome:
Time to First Event
ITT Population
Cumulative Event Rate, %
3.0
Rivaroxaban
n = 2419
2.5
2.0
Enoxaparin/VKA
n = 2413
1.5
1.0
HR: 1.12; P < .0026 (noninferiority)
0.5
0.0
TTR: 62.7%
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to Event, days
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:
1287-1297.
EINSTEIN-PE: Principal Safety Outcome: Major
or Nonmajor Clinically Relevant Bleeding
Cumulative Event Rate, %
Safety Population
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Enoxaparin/VKA
n = 2405
Rivaroxaban
n = 2412
Rivaroxaban
Enoxaparin/VKA
10.3%
0
30
60
90
120
150
0.90 (0.76-1.07)
11.4%
180
210
240
HR (95% CI)
P = .23
270
300
330
360
Time to Event, days
No. of Patients at Risk
Rivaroxaban
2412 2183 2133 2024
1953 1913
1211
696
671
632
600
588 313
Enoxaparin/VKA
2405 2184
1923 1887
1092
687
660
620
589
574 251
2115 1990
From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:
1287-1297.
EINSTEIN-PE: Major Bleeding
Safety Population
Cumulative Event Rate, %
3.0
Rivaroxaban
Enoxaparin/VKA
1.1%
2.2%
HR (95% CI)
0.49 (0.31-0.79)
P =.0032
2.5
Enoxaparin/VKA
n = 2405
2.0
1.5
1.0
Rivaroxaban
n = 2412
0.5
0.0
0
30
60
90
120
150
180
210
240
270
300
330
360
Time to Event, days
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
From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:
1287-1297.
EINSTEIN-PE: Key Secondary Outcomes
Enoxaparin/
Rivaroxaban
VKA
Outcome
%
%
HR
(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
< 0.1
< 0.1
0.1
< 0.1
0.2
0.2
Off-treatment (+ 30 days)
•
Cerebrovascular events
•
ACS
ALT > 3 × ULN + bilirubin > 2 × ULN
*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 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