Covid–19 thrombosis prophylaxis with rivaroxaban therapy

FOR EDUARDO RAMACCIOTTI
DECLARATION OF INTEREST

(*) Unrestricted research grant from Bayer S.A., which was not involved in design, conduct or interpretation of the study
EXECUTIVE/STEERING COMMITTEE
Eduardo Ramacciotti | Science Valley Research Institute
Leandro Barile Agati | Science Valley Research Institute
Daniela Calderaro| Heart Institute (InCor) and Clinics Hospital
Alfonso Tafur | Northshore University Health System
Alex C. Spyropoulos | Northwell Institutes for Medical Research
Renato D. Lopes | Brazilian Clinical Research Institute (BCRI)
Duke Clinical Research Institute (DCRI)
DATA SAFETY MONITORING BOARD
Rogério Krakauer (Santa Casa de São Paulo School of Medical Sciences)
Oswaldo De Lima (General Surgery, Leforte Hospital)
CLINICAL EVENTS CLASSIFICATION (CEC) COMMITTEE
Science Valley Research Institute
COORDINATING CENTER
Science Valley Research Institute
SPONSOR/ FUNDING
Bayer (*)
Science Valley Research Institute
COLLABORATION
Chang Chiann (University of São Paulo)
STATISTICAL ANALYSIS
TRIAL ORGANIZATION

BACKGROUND
The devastating Coronavirus disease (COVID-19) pandemic is associated with a high prothrombotic state 1
It is unclear if the coagulation abnormalities occur because of the direct effect of SARS-CoV-2 or indirectly by the cytokine storm and endothelial damage or by a combination of mechanisms 2
There is a clear indication of in-hospital pharmacological thromboprophylaxis for every patient with COVID-19 after bleeding risk assessment 3
There is no consensus on the role of extended thromboprophylaxis 4
Current antithrombotic statements are conflicting for the need (or not) for post-hospital discharge thromboprophylaxis in hospitalized COVID-19 patients 5
2
1
3
5
4
1. Klok et al. Thromb Res 2020;191:145-147; 2. Ackermann et al. N Engl J Med 2020;383(2):120-128; 3. Spyropoulos et al. J Thromb Haemost 2020;18(8):1859-1865; 4. Moores et al. Chest 2020;158(3):1143-1163; 5. Gerotziafas et al. Thromb Haemost 2020;120(12):1597-1628.

Spyropoulos A et al, N Engl J Med 2018
↓56% symptomatic VTE
No ↑Bleeds

Design: Prospective, randomized, open-label, controlled, multi-center trial
No anticoagulation
Rivaroxaban
(10 mg/day)
Day
35±4
R
Day 75
(phone call)
~320 COVID+
Medically Ill hospitalized
with IMPROVE ≥4
or
IMPROVE 2-3 with
Ddimer >500 ng/mL receiving LMWH or UFH
Discharge
Screening
Follow-up
Doppler US + pulmonary angioCT
at day 35+4
Primary endp: symptomatic VTE, VTE-related death, VTE detected by mandatory bilateral lower limbs venous duplex scan and pulmonary angioCT on day 35±4 post-hospital discharge and (myocardial infarction [MI], non-hemorrhagic stroke, major adverse limb events [MALE] and cardiovascular [CV] death + all cause death up to day 35±4 post-hospital discharge.
Power: 80%, Two sided alpha 0.05 (Control 15%, Treatment 5%; 67% RRR)
STUDY DESIGN
Rivaroxaban is not approved for patients admitted or discharged for an acute medical illness by EMEA

KEY INCLUSION AND EXCLUSION CRITERIA

CLINICAL OUTCOMES
PRIMARY OUTCOME
Composite of symptomatic VTE, VTE-related death, and VTE detected at bilateral lower limbs venous duplex scan and computed tomography pulmonary angiogram and symptomatic arterial thromboembolism, myocardial infarction (MI), non-hemorrhagic stroke, major adverse limb event (MALE), and cardiovascular (CV) death at day 35
Clinical outcomes were adjudicated by an independent committee in a blinded fashion
SECONDARY OUTCOMES
Symptomatic and fatal VTE
Symptomatic VTE + all cause mortality
Symptomatic VTE, MI, stroke and cardiovascular death
KEY SAFETY OUTCOME
Incidence of major bleeding according to ISTH criteria

SAMPLE SIZE CALCULATIONS
STATISTICAL ANALYSIS
2
1
3
5
4
Power of 80% and ⍺ =0.05
Anticipated occurrence of the primary efficacy endpoint of 15% of patients in the control group and 5% of patients in the treatment group (RRR = 67%)
If there is a true difference in favor of the proposed treatment of an absolute risk reduction of 10%
(15% vs. 5%), then 282 patients were required
With a drop-out rate of 10%, a total of 320 patients was necessary (160 per arm)
The primary analysis was performed using the intention-to-treat principle

STUDY FLOW-DIAGRAM
Analyzed (n= 159)
Intention-to-treat-analysis
AngioCT scans available = 114 (73%)
Doppler US available = 134 (85%)
Lost to follow-up (n=1)
(withdrawn informed consent)
Allocated to rivaroxaban (n=160)
-
-Received allocated intervention (n=158)
- Did not receive allocated intervention (n=2)
- 1 patient allocated to another study
- 1 patient prolonged hospitalization
Lost to follow-up (n=1)
(withdrawn informed consent)
Allocated to no anticoagulation (n= 160)
RANDOMIZED (N=320)
ALLOCATION
FOLLOW-UP
ANALYSIS
Analyzed (n= 159)
Intention-to-treat-analysis
AngioCT scans available = 90 (57%)
Doppler US available = 118 (75%)

BASELINE CHARACTERISTICS

PRIMARY EFFICACY/SAFETY OUTCOMES
*Composite of composite of symptomatic VTE, VTE-related death, asymptomatic VTE (Doppler and AngioCT scan) and symptomatic ATE, MI, non-hemorrhagic stroke, (MALE), and cardiovascular death at day 35.
RRR =67%
RR = 0.33 (0.13—0.90)
p=0.03 (superiority)
NNT = 16

SECONDARY EFFICACY OUTCOMES

SECONDARY EFFICACY OUTCOMES

SAFETY OUTCOMES

SUBGROUP ANALYSIS
1
Favors rivaroxaban
Favors control

CONCLUSION
In patients discharged after hospitalization due to COVID-19 with increased IMPROVE score, thromboprophylaxis with rivaroxaban 10 mg once-daily for 35 days improved clinical outcomes, without increasing bleeding compared with no out-of-hospital anticoagulation