Oral rivaroxaban for the treatment of symptomatic venous thromboembolism (a pooled analysis of the EINSTEIN DVT

Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies... Rivaroxaban Can Rivaroxaban be given in a fix

Oral Rivaroxaban for the Treatment of

Symptomatic Venous Thromboembolism:

A Pooled Analysis of the EINSTEIN DVT

and EINSTEIN PE Studies

Venous thromboembolism

 recurrent thrombotic complications in 20-30%

 VKA has a slow onset of action; heparin is needed for the first week of treatment

 VKA has an unpredictable anticoagulant effect, requiring

Rivaroxaban

 Specific, direct factor Xa inhibitor

 High oral bioavailability

 Rapid onset of action

 Half-life: 7–11 hours

 Only 1/3 renally cleared

 Small change in exposure with varying bodyweight

 Wide therapeutic window

 Absorption limited if > 50 mg

Rivaroxaban

Can Rivaroxaban be given in a fixed dose without the requirement for monitoring and replace heparin and VKA

treatment in DVT/PE patients?

EINSTEIN DVT and EINSTEIN PE studies

Randomized, open-label, event-driven, non-inferiority studies of

identical design with a priori specified combined analyses

 Primary efficacy outcome: recurrent VTE

 Safety outcome: major bleeding

1 N Engl J Med 2010;363:2499 2 N Engl J Med 2012;366:1287–97

EINSTEIN DVT/PE:

primary efficacy outcome

Number of patients at risk

0.5

3.0 2.5 2.0 1.5 1.0

0.0

Rivaroxaban N=4150

Enoxaparin/VKA N=4131

Enoxaparin/VKA n/N (%)

HR (95% CI)

86/4150 (2.1)

95/4131 (2.3)

0.89 (0.66–1.19)

0.0

Rivaroxaban N=4130

Enoxaparin/VKA N=4116

Enoxaparin/VKA n/N (%)

HR (95% CI)

p-value

40/4130 (1.0)

72/4116 (1.7)

0.54 (0.37–0.79)

p=0.002

Outcome

Rivaroxaban (N=4130)

Enoxaparin/VKA (N=4116) HR (95% CI)

types of major bleeding

*Some patients had >1 event

Einstein DVT/PE:

Clinical presentation of major bleeding

Einstein DVT/PE - Major bleeding and use of prohemostatic measures

Rivaroxaban

n=45

Enox/VKA n=79

Outcome Rivaroxaban Enoxaparin/VKA HR (95% CI)

outcomes in fragile patients*

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

ptrend=0.01

multiple lobes and >25% of

entire pulmonary vasculature;

involving common femoral/

EINSTEIN PE:

Repeat CT scan at 3 weeks in 264 patients

Rivaroxaban N=135

Enoxaparin/VKA N=129

Venous thromboembolism and cancer

Long-term LMWH is recommended

LMWH is often not used based on medical,

economic and quality of life considerations

In EINSTEIN DVT/PE patients with cancer were not excluded

Classification of DVT/PE patients with cancer

 Patients with cancer were classified as:

months or recurrent or metastatic cancer)

cancer)

EINSTEIN DVT/PE:

Analysis populations

Active cancer

at baseline (n=462)

Active cancer during study (n=193)

History of cancer (n=469)

No known cancer (n=7157)

8281 patients randomized

EINSTEIN DVT/PE:

Outcomes

No known cancer Rivaroxaban Enoxaparin/VKA HR (95% CI)

Recurrent VTE, n (%) 65/3563 (1.8) 70/3594 (1.9) 0.93 (0.66–1.30)

Major bleeding, n (%) 31/3546 (0.9) 53/3582 (1.5) 0.58 (0.37–0.91)

Mortality, n (%) 33/3563 (0.9) 42/3594(1.2) 0.77 (0.49–1.22)

EINSTEIN DVT/PE:

Outcomes

History of cancer Rivaroxaban Enoxaparin/VKA HR (95% CI)

Recurrent VTE, n (%) 5/233 (2.1) 5/236 (2.1) 0.98 (0.28–3.43)

Major bleeding, n (%) 1/231 (0.4) 4/236 (1.7) 0.23 (0.03–2.06)

EINSTEIN DVT/PE in cancer:

Major bleeding and kidney function

ptrend=0.92

ptrend=0.01

EINSTEIN DVT/PE:

conclusions

 In patients with acute symptomatic DVT and/or

PE, rivaroxaban showed:

age, body weight, gender, renal function, severity of DVT/PE, and treatment of first/recurrent VTE