THE ROLE OF RIVAROXABAN

ON VTE

Dr. dr. Tutik Harjianti, Sp. PD-KHOM, FINASIM

Medical Hemato-oncology Division

Internal Medicine Hasanuddin University Makassar
12 Sept 2021
 INTRODUCTION
DISEASE BURDEN OF VTE

2 to 7 per 1,000 population age > 70 yrs

1 to 3 episodes per 1,000 population
 547,596 hospitalizations with VTE in US 2007- 2009
 Estimated 900,000 cases per year in US
 100,000 to 300,000 VTE-related deaths in US each year
 684,000 DVT, 434,000 PE, and 543,000 VTE-related
deaths in European Union 2004 (pop 454.4 million)
 VTE a leading cause of hospital - associated
premature death and disability (DALY) world wide
Heit J, Cohen A, Anderson F. Estimated annual number of incident and recurrent, fatal and non-fatal venous thromboembolism (VTE) events in
the US. Blood 2005;106:267a; Yusuf H et al. MMWR 2012; 61: 22: 401 – 404 ;ISTH Steering Committee for World Thrombosis Day.
Thrombosis: a major contributor to global disease burden. J Thromb Haemost 2014; 12: doi: 10.111/jth.12698
 Venous Thromboembolism (VTE)

Pulmonary embolism (PE)

40% of non-fatal cases

Severity depends on size and

cardiopulmonary reserve

Sub-segmental PE has important

risk of recurrence

30% to 70% have residual DVT

Deep-vein thrombosis (DVT)

60% of non-fatal cases

Proximal DVT prognostic marker

for recurrence and mortality
Image from VF Tapson. NEJM 2008; 358: 1037
VTE: OFTEN UNDETECTED
UNTIL TOO LATE
Over 70% of fatal PE are
detected post mortem1,3

Approximately 80%
of DVTs
are clinically silent2,3
1. Stein PD, et al. Chest 1995;108:978–81.
2. Lethen H, et al. Am J Cardiol 1997;80:1066–9.
3. Sandler DA, et al. J R Soc Med 1989;82:203–5.
MAJORITY OF HOSPITALIZED PATIENTS ARE AT
RISK OF VTE

VTE risk varied according to medical

diagnosis, from 31.2% of patients with

gastrointestinal/hepatobiliary diseases to

100% of patients with acute heart failure,

active noninfectious respiratory disease, or
pulmonary infection.

Global rate, 41.5%

Bergmann JF,et al. Thrombosis and Haemostasis

103.4/2010
 Lessons from a recent nationwide multicenter
study in china (dissolve-2)

Result summary (n=13,609)

• High VTE risk in surgical and medical
inpatients was 53.4% and 36,6%,

Any prophylaxis
respectively.

Appropriate prophylaxis
• Among medical patients, overall rate of

Any prophylaxis
prophylaxis was 10.3% and appropriate

Appropriate
prophylaxis
prophylaxis was 6.0%.
*using PADUA and CAPRINI score

“A large proportion of hospitalized patients reported VTE risk and low rate of
CHEST-recommended prophylaxis. The data highlight the insufficient
management of VTE risk”
Zhai Z, et al.CHEST.2019;155(1):114-22.
 VIRCHOW’S TRIAD
• Acute phase postop • Surgery
• Cancer • Trauma
• Thrombophilia • Indwelling catheter
• Estrogen therapy • Atherosclerosis
• Pregnancy and
• Heart valve
postpartum period
• Inflammatory bowel
disease or
disease replacement

Venous stasis
• Immobility or paralysis
• Heart failure
• Venous insufficiency or varicose veins
• Venous obstruction from tumour, obesity or pregnancy

Virchow R, ed. Gesammelte Abhandlungun zur Wissenschaftichen Medicin. Von Meidinger Sohn, Frankfurt, 1856.
 TREATMENT FOR VTE
GOALS OF TREATMENT FOR VTE

 Prevent death from pulmonary embolism

 Prevent symptomatic recurrent VTE 25% risk of

symptomatic recurrent VTE during 3 time if inadequate
therapy
 Prevent and/or reduce morbidity from
post-thrombotic syndrome (PTS) 25% at 2 yr

 Minimizethe risk of bleeding and

other side effects
 EVIDENCE-BASED GUIDELINES FOR TREATMENT
OF VTE
 American College of Chest Physicians (ACCP) 9th ed 2012
Kearon et al CHEST 2012; 141: (2) Suppl: e419s-e494s
 Treatment of Venous Thromboembolism
Wells P et al JAMA 2014; 311: 717-728
 European Society of Cardiology
2014 ESC Guideline on the diagnosis and management of
acute pulmonary embolism
European Heart Journal 2014; doi 10.1093/eurheart/ehu283
 New guidelines from the Thrombosis and Haemostasis Society of Australia and
New Zealand (2019) for the diagnosis and management of venous
thromboembolism

 2019 PERDICI Consensus Perhimpunan Dokter Intensive Care Indonesia

 GUIDANCE FOR THE TREATMENT OF DVT AND PE :
Treatment options in different phase of VTE

IV : intravenous; SQ : subcutaneous; LMWH : low molecular weight heparin; ASA : acetyl salicylic acid
DOAC : direct oral anticoagulant Streiff MB, et al.J Thromb Thrombolysis.2016;41:32-67
Nostrok)
RIVAROXABAN
NEW ANTICOAGULANTS
ORAL PARENTERAL
TF/VIIa TFPI (tifacogin)
TTP889
X IX

APC (drotrecogin alfa)

IXa
VIIIa sTM (ART-123)
Rivaroxaban
Apixaban Va
LY517717 AT Fondaparinux
YM150 Xa Idraparinux
DU-176b
PRT-054021
II DX-9065a
Otamixaban
Ximelagatran
Dabigatran IIa

Fibrinogen Fibrin

Adapted from Weitz & Bates, J Thromb Haemost 2005

 DIRECT FACTOR XA INHIBITION

Tissue

×
XIIa factor
XIa VIIa
IXa
Xa Rivaroxaban
Apixaban
DU-176b
YM150
LY517717
Factor II PRT-054021
(prothrombin)

Fibrinogen Fibrin clot

RIVAROXABAN
HUMAN FACTOR XA/RIVAROXABAN COMPLEX
O
Cl
O S
O N N H
N
O
Rivaroxaban O

S4

S1

▪ Rivaroxaban is an oral, direct Factor Xa inhibitor, with high selectivity for

Factor Xa (Ki 0.4±0.02 nM)
▪ IC50 for Factor VIIa, Factor XIa, thrombin, activated protein C, plasmin,
urokinase, trypsin: >20,000 nM
Roehrig et al., J Med Chem 2005; Perzborn et al., J Thromb Haemost 2005
New guidelines from the Thrombosis and Haemostasis Society
of Australia and New Zealand for the diagnosis and
management of venous thromboembolism
New guidelines from the Thrombosis and Haemostasis Society of
Australia and New Zealand for the diagnosis and management of
venous thromboembolism
VTE TREATMENT STUDIES DIRECT ORAL ANTICOAGULANTS
Hokusai-VTE AMPLIFY EINSTEIN-DVT RE-COVER I
EINSTEIN-PE RE-COVER II

Drug Edoxaban Apixaban Rivaroxaban Dabigatran

Study design Double-blind Double-blind Open label Double-blind

Heparin lead-in At least 5 days None None At least 5 days

Dose 60 mg qd 10 mg bid x 7 days 15 mg bid x 3 wk 150 mg bid

30 mg qd then 5 mg bid then 20 mg qd
(CrCl, bw, P-gp)

Non-inferiority 1.5 1.8 2.0 2.75

margin
Sample size 8,292 5,400 EINSTEIN-DVT RE-COVER I
3,449 2,564
EINSTEIN-PE RE-COVER II
4,832 2,568

Treatment Flexible 6 months Pre-specified 6 months

duration 3 to 12 months 3, 6, or 12 months
Adapted from Raskob et al. J Thromb Haemost 2013; 11: 1287 - 1294
Rivaroxaban menawarkan
pendekatan obat tunggal
yang sederhana.untuk terapi
jangka pendek dan
berkelanjutan dengan
meningkatkan faktor
manfaat daripada faktor
resiko
CLINICAL TRIALS OF RIVAROXABAN FOR VTE
Open-label, non-inferiority
3, 6, or 12 months
Rivaroxaban Rivaroxaban
N=3,449
15 mg bid 20 mg od
R Day 21 Double-blind, superiority
Enoxaparin bid for at least 5 days, plus 6 or 12 months
VKA target INR 2.5 (INR range 2–3) Rivaroxaban 20 mg od
N=1,197

Open-label, non-inferiority R
3, 6, or 12 months Placebo
Rivaroxaban Rivaroxaban
N~4,500
15 mg bid 20 mg od Outside of the EINSTEIN programme
R Day 21 Patients with confirmed symptomatic DVT
Enoxaparin bid for at least 5 days, plus or PE completing 6 or 12 months of VKA

VKA target INR 2.5 (INR range 2–3)

N Engl J Med 2010;363:2499-510

N Engl J Med 2012; 366:1287 -1297

24
 EINSTEIN DVT TRIAL RECURRENT VTE
4.0
Cumulative event rate (%)

Enoxaparin/VKA (N=1,718)
3.0
Rivaroxaban (N=1,731)

2.0
Rivaroxaban Enox / VKA HR
(n / N) (n / N) (95% CI)
1.0 TTR = 57.7% No. of 36 / 1,731 51 / 1,718 0.68
events 2.1% 3.0% (0.44–1.04)

0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time to event (days)

0.44 0.68 1.04 N Engl J Med 2010;363:2499-510

0 1.00 2.00
Hazard ratio
Rivaroxaban Rivaroxaban Rivaroxaban
superior non-inferior inferior
25
p=0.076 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided)
25
EINSTEIN DVT TRIAL BLEEDING
OUTCOMES
Rivaroxaban Enox/VKA
(N=1,718) (N=1,711) HR (95% CI)
n (%) n (%) p-value
First major or clinically relevant 139 (8.1) 138 (8.1) 0.97 (0.76–1.22)
non-major bleeding p=0.77
Major bleeding 14 (0.8) 20 (1.2)
Contributing to death 1 (<0.1) 5 (0.3)
In a critical site 3 (0.2) 3 (0.2)
Associated with fall in Hb 2 g/dL
10 (0.6) 12 (0.7)
and/or transfusion of ≥2 units
Clinically relevant non-major 126 (7.3) 119 (7.0)
bleeding

Safety population N Engl J Med 2010; 363: 2499-510

26

26
 EINSTEIN PE TRIAL RECURRENT VTE

Rivaroxaban Enoxaparin/VKA
(N=2419) (N=2413)
n (%) n (%)
First symptomatic recurrent VTE 50 (2.1) 44 (1.8)
Recurrent DVT 18 (0.7) 17 (0.7)
Recurrent DVT + PE 0 2 (<0.1)
Non-fatal PE 22 (0.9) 19 (0.8)
Fatal PE/unexplained death where
10 (0.4) 6 (0.2)
PE cannot be ruled out
HR
0.75 1.12 1.68

0 1.00 2.00
Rivaroxaban Rivaroxaban Rivaroxaban
superior non-inferior inferior
p=0.57 for superiority P=0.0026 for non-inferiority
(two-sided) (one-sided)
Absolute risk difference 0.24% , 95% CI - 0.5 to 1.02 N Engl J Med 2012; 366:1287 -1297
 EINSTEIN PE TRIAL BLEEDING
OUTCOMES
Rivaroxaban Enox/VKA
(N=2,412) (N= 2,405) HR (95% CI)
n (%) n (%) p-value
First major or clinically relevant 249 (10.3) 274 (11.4) 0.90 (0.76–1.07)
non-major bleeding p=0.23
Major bleeding 26 (1.1) 52 (2.2) P=0.003
Contributing to death 2 (<0.1) 3 (0.1)
In a critical site 7 (0.3) 26 (1.1)
Associated with fall in Hb 2 g/dL
17 (0.7) 26 (1.1)
and/or transfusion of ≥2 units
Clinically relevant non-major 223 (9.2) 222 (9.2)
bleeding

Safety population N Engl J Med 2012; 366: 1287-1297

28

28
A once daily 10 mg oral
dose of Rivaroxaban was
significantly more effective
for extended
thrombophrophylaxis than
once daily 40 mg sc dose
of enoxaparin. With similar
safety profiles.
Pada pasien AF
Rivaroxaban 20 mg setara
dengan Warfarin dengan
efek samping yang lebih
minimal
Relative Risk Reduction (RRR) 21%.
kejadian ES lebih rendah dibanding Warfarin
 APPROVED CLINICAL INDICATION

J Am Heart Assoc 2020;9: e017559

Rivaroxaban 10 mg per hari selama 31-
39 hari direkomendasikan oleh FDA
untuk pencegahan VTE setelah pasien
rawat di rumah sakit.
ISTH UPDATE GUIDELINE

Spyropoulos AC, et al. Scientific and

Standardization Committee Communication:
Clinical Guidance on the Diagnosis, Prevention
and Treatment of Venous Thromboembolism in
Hospitalized Patients with COVID-19.
https://onlinelibrary.wiley.com/doi/epdf/10.111
1/jth.14929

Disclaimer: Enoxaparin is indicated for prophylactic treatment of DVT in patients who are bedridden due to an acute medical condition such as heart failure (NYHA class III or
IV), acute respiratory failure, episode of acute infection or acute rheumatic disorder associated with at least one other risk of VTE factor. Enoxaparin is not indicated
specifically to treat Covid-19 patients. Registration condition differs internationally, therefore Enoxaparin might have different indication approval outside Indonesia
 Conclusions
• VTE a leading cause of hospital - associated
premature death and disability (DALY) world
wide

• Minimize the risk of bleeding and other side

effects is the goals of tretment for VTE

• New oral anticoagulants improve safety for

primary prevention and enhance secondary
prevention of recurrent VTE

• Rivaroxaban offers a convenient, effective and

generally well tolerated single drug treatment
option for patients with VTE
Terima Kasih