RTD - Xarelto for Venous Thromboembolism (VTE) Patients.pptx

Ikhwan Handi R, MD, FIHA
Clinical and Emergencies Vascular
Disease : What’s Evidence Tell Us
(Focus on VTE and DOAC)

Disclaimer
These slides are for scientific and educational purposes only and are the
copyright of Bayer
The data contained within this slide deck do not support or recommend the use of
Xarelto® in any countries or indications in which it is not approved
In Indonesia, Xarelto® is registered for indications:
 Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or
knee replacement surgery
 To reduce the risk of stroke and systemic embolism in patients with non-valvular atrial
fibrillation
– With previous history of stroke or TIA
– With CHADS2 Score ≥ 2
 Treatment of deep vein thrombosis (DVT) in which duration of treatment should be based
on the underlying disease
 Treatment of patients with hemodynamically stable pulmonary embolism (PE) which is
must be confirmed by spiral CT imaging

Clinical Presentation
The Spectrum of Manifestations of PAD
• Asymptomatic
• Atypical symptoms
• Intermittent claudication
• Critical limb ischemia
– Rest Pain
– Ulceration
– Necrosis/Gangrene
• Acute limb ischemia

Ischemia in
Buttock, hip,
thigh
Thigh,
calf
Calf, ankle,
foot
Obstruction in
Aorta or
iliac artery
Femoral artery
or branches
Popliteal artery
or distal
Common Sites of Claudication

How to Perform and
Calculate the ABI
≥1.0 — Normal
0.81-0.90 — Mild Obstruction
0.41-0.80 — Moderate Obstruction
≤0.40 — Severe Obstruction
Right Arm
Pressure:
Left Arm
Pressure:
Pressure:
PT
DP
Right ABI
Higher Right Ankle Pressure mm Hg
Higher Arm Pressure mm Hg
= =
Left ABI
Higher Left Ankle Pressure mm Hg
Higher Arm Pressure mm Hg
Pressure:
PT
DP

Advanced Vascular Imaging
CT Angiography
• Maximum-intensity projection
(MIPs)
– Angiographic like
representation
• Volume rendering
– Preserves depth information
• Multi-planar reformat
• Curved planar reformat (CPR)
– Perpendicular to median arterial
centerline
MR Angiography
• Traditional: Time of flights
• Contrast-enhanced MRA
– Improves speed of exam, anatomic
coverage, and small- vessel resolution
• Time-resolved gadolinium enhanced
sequences
– Time-resolved imaging of contrast
kinetics (TRICKS)
– Provides angiographic like dynamic
contrast passage
• Moving-table technique or multi-array,
parallel-imaging
– Optimize large field-of-view imaging
Doppler
Ultrasound
Vascular

Rogers, J. H. et al. Circulation 2007;116:2072-2085
Overview of New Technologies

DVT
Thrombus
Embolus
VTE: Deep Vein Thrombosis and Pulmonary Embolism
Migration
PE

The Pathway Of A Pulmonary Embolus
 From the lower part of the body:
Inferior vena cava  right atrium
right ventricle  the pulmonary
artery.
 This might eventually obstruct
blood flow to the lung. Patients
with DVT are at risk of PE, a life-
threatening event

1. Girard P., et al. Chest. 1999;116:903–908. 2. Anderson F.A. Jr., Audet A-M. Available at: www.outcomes-umassmed.org/dvt/best_practice.
3. Hull R.D., et al. Chest. 1986;89:374S–383S. 4. Heart. What is Venous Thromboembolism (VTE)? Available at: https://www.heart.org/en/health-topics/venous-
thromboembolism/what-is-venous-thromboembolism-vte.
Patients With DVT Are at Risk of PE, Which Occurs When Emboli Travel Through the
Heart and Lodge in an Artery in the Lung
90% of PE
are the result
of DVT
82% of patients
with acute PE
have detectable
DVT at the time
PE is diagnosed

1. Cohen A.T., et al. Thromb Haemost. 2007;98:756–764. 2. Heit J.A., et al. Blood. 2005;106:Abstract 910. 3. ISTH Steering Committee for World Thrombosis Day. J Thromb
Haemost. 2014;12:1580–1590.
VTE is a Leading Cause of Death Worldwide
An estimated
300,000 VTE-
related deaths
occur in the US
each year
VTE is estimated to cause >370,000 deaths
in Europe every year
VTE is estimated to cause at least
3 million deaths a year worldwide

Virchow’s Triad Revisited
 Venous disorders
 Venous valvular damage
 Trauma or surgery
 Indwelling catheters
 Malignancy
 Pregnancy and peripartum period
 Oestrogen therapy
 Inflammatory bowel disease
 Sepsis
 Thrombophilia
 Left ventricular dysfunction
 Immobility or paralysis
 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;
Blann AD, Lip GYH. BMJ 2006;332:215–219; Geerts WH et al, Chest 2004;126:338S–400S;
Bennet PC et al, Thromb Haemost 2009;101:1032–1040
Circulatory stasis

Surgery
Trauma
Acute medical illness
Acute heart failure*
Acute respiratory failure
Central venous catheterization
History of VTE
Chronic heart failure
Advanced age
Varicose veins
Obesity
Immobility or paresis
Myeloproliferative disorders
Pregnancy/postpartum period
Inherited or acquired thrombophilia
Hormone therapies
Renal insufficiency
Several Factors Contribute to an Increased Risk of VTE
Cancer
Inflammatory
diseases
*New York Heart Association classification III and IV
Predisposing risk factors
(patient characteristics)
Exposing risk factors
(acute conditions or trauma, surgery)
Risk factors from: 1. Geerts WH et al, Chest 2004;126:338S–400S

DVT– symptoms and signs are unreliable
Probability test – Wells Score
D – Dimers level
Compression Ultrasonography
Venography
 Redness
 Pain
 Oedema/swelling
 Symptoms may be vague or absent
 Increased circumference
 Pain by palpation along the deep vein truncs
ACCP 9th Edition, Chest 2012;141;7S-47S DOI 10.1378/chest.1412S3
Modality

Factor Points
Active cancer (treatment within last six months or palliative) 1
Calf swelling ≥3 cm compared to asymptomatic calf (measured 10 cm below tibial tuberosity) 1
Collateral superficial veins (non-varicose) 1
Pitting edema (confined to symptomatic leg) 1
Swelling of entire leg 1
Localized tenderness along distribution of deep venous system 1
Paralysis, paresis, or recent cast immobilisation of lower extremities 1
Recently bedridden ≥3 days, or major surgery requiring regional or general anesthetic in the
previous 12 weeks
1
Previously documented deep-vein thrombosis 1
Alternative diagnosis at least as likely as DVT -2
Wells score DVT
Interpretation: For dichotomised evaluation (likely Vs unlikely)
score of 2 or higher - DVT is “likely”
score of less than 2 - DVT is “unlikely” (2)
(1) Tovey C, Wyatt S. Diagnosis, investigation, and management of deep vein thrombosis. BMJ. 2003;326(7400):1180-4
(2) Scottish Intercollegiate Guidelines Network (SIGN) 2010. Prevention and Management of Venous Thromboembolism

Variable Points
Clinical Signs or Symptoms of Deep Vein Thrombosis (DVT) 3.0
Alternative diagnosis less likely than Pulmonary Embolism 3.0
Heart rate >100 beats/min 1.5
Immobilization or surgery in the previous 4 weeks 1.5
Previous VTE 1.5
Hemoptysis 1.0
Active Cancer 1.0
Simplified Wells score PE
A total score of 4.0 or lower indicates that pulmonary embolism is unlikely, and a score higher than 4.0
indicates that pulmonary embolism is likely.
P Prandoni, et al. N Engl J Med 2016; 375:1524-1531

Diagnosis of Thrombosis
 Clinical examination (non-specific)
 Physical findings may include a palpable cord over the calf, ipsilateral edema, warmth,
and/or superficial venous dilatation
 Contrast venography
 Non-invasive testing
Compression ultrasonography
 Recommended in moderate to high pre-test probability
D-dimer
 Useful in low pre-test probability to exclude diagnosis of VTE
 Sensitivity and negative predictive value are high (~99%)
Magnetic resonance venography
Computed tomography
Echocardiography, ventilation-perfusion (V/Q) scanning, and pulmonary angiography
Grant and Leung. UpToDate. Accessed online 10/20

ACCP 2016 Guidelines Supports Use of DOACs for
Treatment of DVT/PE
ACCP recommendation Grade of
recommendation
Initial anticoagulation
Acute DVT or haemodynamically
stable PE and no cancer
DOAC preferred to LMWH/VKA 2B
LMWH/VKA preferred to LMWH alone 2C
PE with hypotension Thrombolytic therapy (systemic rather than catheter-directed unless
bleeding risk is high)
2B (2C)
DVT or PE with cancer LMWH suggested over DOAC or VKA 2C
Duration of anticoagulant therapy
Proximal DVT or PE 3 months recommended over shorter duration 1B
First proximal DVT or PE provoked
by surgery or other transient risk
factor
3 months 1B
(2B if low/moderate
bleeding risk; 1B if
high)
Unprovoked DVT or PE Extended therapy if bleeding risk is low/moderate 2B
3 months if bleeding risk is high 1B
DVT or PE associated with
active cancer
Extended therapy recommended over 3 months’ therapy 1B
(2B if high bleeding
risk)
Kearon C et al, Chest 2016;149:315–352

IMPROVE bleeding risk assessment
Risk Factors Point
Moderate renal failure (CrCl 30-50 ml/min) 1
Male Sex 1
Age 40-84 years old 1.5
Active Cancer 2
Rheumatic disease 2
Central Venous Catheters 2
Admission in Intensive Care (ICU) 2.5
Severe Renal Failure (CrCl <30ml/min) 2.5
Liver Insufficiency (INR >1.5) 2.5
Age ≥85 years old 3.5
Thrombocytopenia 4
Recent (3 months) bleeding 4
Active gastrointestinal ulcer 4.5
High Bleeding Risk when total score ≥7
Decousus H, et al. Chest. 2011;139:69-79

ASH 2020 VTE Guidelines Supports Use of DOACs for
Treatment of DVT/PE
ASH 2020 VTE Guidelines Recommendation Level of
recommendation
For patients with DVT and/or PE, suggests using direct oral anticoagulants
(DOACs) over vitamin K antagonists (VKAs)

In most patients with proximal DVT, suggests anticoagulation therapy alone over
thrombolytic therapy in addition to anticoagulation

For primary treatment of patients with DVT and/or PE, whether provoked by a
transient risk factor (recommendation 12) or by a chronic risk factor
(recommendation 13) or unprovoked (recommendation 14), suggests using a
shorter course of anticoagulation for primary treatment (3-6 months) over a
longer course of anticoagulation for primary treatment (6-12 months)

For patients with DVT and/or PE who have completed primary treatment and will
continue to receive secondary prevention, suggests using anticoagulation over
aspirin

Ortel et al. 2020. ASH VTE Guidelines: Treatment of DVT and PE. DOI10.1182/bloodadvances.2020001830.

Recommendations for duration of oral anticoagulation Class of
recommendation
Level of
evidence
Therapeutic anticoagulation for ≥3 months is recommended for all patients with PE I A
For patients with first PE/VTE secondary to a major transient/reversible risk factor,
discontinuation of therapeutic oral anticoagulation is recommended after 3 months
I B
Oral anticoagulant treatment of indefinite duration is recommended for patients
presenting with recurrent VTE not related to a major transient or reversible
risk factor
I B
Oral anticoagulant treatment with a VKA for an indefinite period is recommended
for patients with antiphospholipid antibody syndrome
I B
Extended oral anticoagulation of indefinite duration should be considered for
patients with a first episode of PE and no identifiable risk factor
IIa A
Recommendations for early discharge and home treatment Class of
recommendation
Level of
evidence
Carefully selected patients with low-risk PE should be considered for early
discharge and continuation of treatment at home, if proper outpatient care and
anticoagulant treatment can be provided
IIa A
Konstantinides SV et al, Eur Heart J 2019; doi:10.1093/eurheartj/ehz405
2019 ESC PE Guidelines: Treatment Recommendations

2019 ESC PE Guidelines: Acute Treatment of Patients with
Low–Intermediate Risk PE Without Cancer
Konstantinides et al, 2014
Konstantinides SV et al, Eur Heart J 2019: doi:10.1093/eurheartj/ehz405
Recommendations for acute phase treatment Class of
recommendation
Level of
evidence
Initiation of anticoagulation is recommended without delay in patients
with high or intermediate clinical probability of PE, while diagnostic
workup is in progress.
I C
When oral anticoagulation is started in a patient with PE who is
eligible for a DOAC (apixaban, dabigatran, edoxaban or
rivaroxaban), a DOAC is recommended in preference to a VKA
I A
Recommendations for the regimen and duration of
anticoagulation after PE in patients without cancer
Class of
recommendation
Level of
evidence
Therapeutic anticoagulation for ≥3 months is recommended for all
patients with PE
I A
DOACs are not recommended in patients with severe renal
impairment, during pregnancy and lactation, and in patients with
antiphospholipid antibody syndrome
III C

Treatment Approaches for VTE
Acute Intermediate Chronic
Bridging
Dabigatran 150 mg bid
Edoxaban 60 mg od
Parenteral Agent Switching to DOAC
Xarelto®
15 mg bid, 20 mg od
Apixaban
10 mg bid, 5 mg bid
Single-drug approach
Initial UFH, LMWH,
fondaparinux
≥5 days Early maintenance
VKA (INR 2.0–3.0)
≥3 months Long-term secondary prevention
VKA (INR 2.0–3.0)
≥3 months, years or indefinite with periodic assessment
Treatment schemes with DOACs
Goldhaber SZ, Bounameaux H. Lancet 2012;379:1835–1846
Conventional treatment

Traditional Anticoagulants: Drawbacks
 UFH1
 Parenteral administration
 Monitoring and dose adjustment required
 Risk of HIT
 LMWH1
 Parenteral administration
 Weight-adjusted dosing
 Oral VKAs2
 Narrow therapeutic window
 Interaction with food and drugs
 Frequent monitoring and
dose adjustment required
1. Hirsh J et al, Chest 2008;133;141S–159S; 2. Ansell J et al, Chest 2008;133;160S–198S

Problems with VKAs
Narrow therapeutic window
 Difficult to keep within therapeutic range
Frequent INR monitoring/ dose -
adjustment
Multiple drug–drug and food–drug
interactions
Slow onset/offset of action
Increased risk of bleeding
Warfarin thrombosis
Warfarin bleeding
Dose
Thrombosis
Bleeding
Narrow
therapeutic
window
1. Ansell J et al, Chest 2004;126:204S–233S

Xabans DTI
Xarelto® Apixaban Edoxaban Dabigatran
Target Factor Xa Factor Xa Factor Xa Thrombin
Prodrug No No No Yes
Oral bioavailability 80–100%* 50% 62% 6.5%
Renal clearance of
absorbed active drug
33% 27% ~55-60% >80%
Tmax (h) 2–4 1–3 1–2 2–6#
Half-life (h) 5–13 8–13 10–14 12–14
Dosing BID then OD BID OD BID
Initial Parenteral
anticoagulation
None None
5-10 days of
heparin/LMWH
5-10 days of
heparin/LMWH
DOACs (Xabans and DTIs) Have Fundamentally Different Pharmacological
Characteristics1–10
1. Eriksson BI et al. Annu Rev Med. 2011;62:41-57; 2. Frost et al. J Thromb Haemost. 2007;5(Suppl 2):P-M-664;
3. Kubitza D et al. Clin Pharmacol Ther. 2005;78(4):412-421; 4. Ogata K et al. J Clin Pharmacol. 2010;50(7):743-753;
5. Stangier J et al. J Clin Pharmacol 2005;45(5):555-563; 6. Dabigatran SmPC; 7. Apixaban SmPC; 8. Xarelto®® SmPC; 9. Edoxaban SmPC; 10. Heidbuchel et al. Europace 2013;15(5):625-651
*15–20 mg to be taken with food; #Postoperative period;

Phase III Studies of Xarelto® in VTE Patients:
EINSTEIN Programme

Randomized, open-label, event-driven, non-inferiority study
Patients with confirmed acute symptomatic DVT without symptomatic PE
88 primary efficacy outcomes needed
EINSTEIN DVT: Study Design
1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510
Treatment period: 3, 6 or 12 months
15 mg bid
Confirmed
symptomatic DVT
without
symptomatic PE
N=3449
Xarelto®
Day 1
Day 21
Enoxaparin (1.0 mg/kg) bid for at least 5 days,
plus VKA target INR 2.5 (INR range 2.0–3.0)
20 mg od
Xarelto®
R
30-day
observation
after
treatment
cessation

EINSTEIN DVT: Primary Efficacy Outcome Analysis
Xarelto®
(n=1731)
Enoxaparin/VKA
(n=1718)
n (%) n (%)
First symptomatic recurrent VTE 36 (2.1) 51 (3.0)
Recurrent DVT 14 (0.8) 28 (1.6)
Recurrent DVT + PE 1 (<0.1) 0 (0.0)
Non-fatal PE 20 (1.2) 18 (1.0)
Fatal PE/unexplained death where
PE cannot be ruled out
4 (0.2) 6 (0.3)
ITT population
p<0.001 for non-inferiority
(one-sided)
1.00
0
0.44 1.04
0.68
Hazard ratio
Xarelto®
superior
Xarelto®
non-inferior
Xarelto® inferior
p=0.08 for superiority
(two-sided)
2.00

EINSTEIN DVT: Primary Efficacy Outcome –
Time to First Event
Cumulative
event
rate
(%)
0 30 60 90 120 150 180 210 240 270 300 330 360
Xarelto® (n=1731)
Enoxaparin/VKA (n=1718)
Time to event (days)
HR=0.68; p<0.001 (non-inferiority)
RR=32%
0
1.0
2.0
3.0
4.0
Xarelto® showed significantly 32% reduction in recurrent DVT
32%
RRR

EINSTEIN DVT: Principal Safety Outcome (Composite of
Major or Non-major Clinically Relevant Bleeding)
Cumulative
event
rate
(%)
0 30 60 90 120 150 180 210 240 270 300 330 360
0
2
4
6
8
10
12
14
Xarelto® (n=1718)
Xarelto® showed similar findings in principal safety outcome
HR=0.97; 95% CI 0.76–1.22; p=0.77

EINSTEIN DVT: Principal Safety Outcome Analysis
Xarelto®
(n=1718)
Enoxaparin/VKA
(n=1711)
HR (95% CI)
n (%) n (%) p-value
First major or non-major clinically relevant
bleeding
139 (8.1) 138 (8.1)
0.97 (0.76–1.22)
p=0.77
Major bleeding 14 (0.8) 20 (1.2)
0.65 (0.33–1.30)
p=0.21
Contributing to death 1 (<0.1) 5 (0.3)
In a critical site 3 (0.2) 3 (0.2)
Associated with fall in haemoglobin
2 g/dl and/or transfusion of 2 units
10 (0.6) 12 (0.7)
Non-major clinically relevant bleeding 126 (7.3) 119 (7.0)
Safety population

EINSTEIN DVT: Conclusions
In patients who had acute symptomatic proximal DVT without symptomatic PE, Xarelto® showed:
 Non-inferiority to LMWH/VKA for efficacy (HR=0.68; 95% CI 0.44–1.04; p<0.001)
 Similar findings for principal safety outcome between the two groups (HR=0.97; 95% CI 0.76–1.22;
p=0.77)
 Consistent efficacy and safety results irrespective of age, body weight, gender, creatinine clearance and
cancer
 No evidence of liver toxicity
Oral Xarelto®, 15 mg bid for 21 days followed by Xarelto® 20 mg od, could provide clinicians and
patients with a simple, single-drug approach for the acute treatment of DVT that potentially
improves the benefit–risk profile of anticoagulation

Randomized, open-label, event-driven, non-inferiority study
Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry
88 primary efficacy outcomes needed
Non-inferiority margin: 2.0
EINSTEIN PE: Study Design
1. The EINSTEIN–PE Investigators. N Engl J Med 2012; 366:1287–1297
Predefined treatment period of 3, 6 or 12 months
15 mg bid
Xarelto®
Day 1 Day 21
Enoxaparin (1 mg/kg) bid for at least 5 days,
plus VKA target INR 2.5 (INR range 2.0–3.0)
20 mg od
N=4832
Xarelto®
R
Objectively
confirmed PE ±
DVT
30-day
observation
period after
treatment
cessation

EINSTEIN PE: Primary Efficacy Outcome Analysis
Xarelto® (n=2419)
Enoxaparin/VKA
(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
PE cannot be ruled out
10 (0.4) 6 (0.2)
Symptomatic recurrent VTE
Xarelto®
superior
Xarelto®
non-inferior
Xarelto®
inferior
p=0.0026 for non-inferiority
(one-sided)
p=0.57 for superiority
(two-sided)
1.00
0 2.00
0.75 1.12 1.68
ITT population

EINSTEIN PE: Primary Efficacy Outcome –
Time to First Event
Symptomatic recurrent VTE
3.0
2.5
2.0
1.5
1.0
0.0
0.5
0 30 60 90 120 150 180 210 240 270 300 330 360
Cumulative
event
rate
(%)
Xarelto® (n=2419)
HR=1.12; p=0.0026 (non-inferiority)
ITT Population

EINSTEIN PE: Principal Safety Outcome
Major or non-major clinically relevant bleeding
Safety population
0 30 60 90 120 150 180 210 240 270 300 330 360
14
10
12
8
6
4
2
0
Cumulative
event
rate
(%)
Xarelto® (n=2412)
HR=0.90;
95% CI 0.76–1.07; p=0.23
RRR
10%

EINSTEIN PE: Major Bleeding
Safety population
3.0
2.5
2.0
1.5
1.0
0.0
0.5
0 30 60 90 120 150 180 210 240 270 300 330 360
Xarelto® (n=2412)
Cumulative
event
rate
(%)
HR=0.49; 95% CI 0.31–0.79; p=0.003
RRR
51%

EINSTEIN PE: The Only Novel OAC Study to Confirm Early Clot Regression
Following Acute PE
Baseline PE
Following 21 days
of Xarelto® or
enoxaparin/VKA
Complete clot
resolution
(n=142)
Partial clot
resolution
(n=162)
No change
(n=43)
12%
Worsening
0%
88%
Pre-defined safety analysis of the EINSTEIN PE study involving 347 patients with scan-confirmed PE who received a follow up CT or Q scan after
21 days of anticoagulant therapy; *3 patients with symptomatic worsening and confirmed recurrent PE were excluded from this analysis
1. van Es J et al, J Thromb Haemost 2013;11:679–685
41% 47%

EINSTEIN PE: Conclusions
In patients with acute symptomatic PE  DVT, Xarelto® showed:
 Non-inferiority to LMWH/VKA for efficacy (HR=1.12; 95% CI 0.75–1.68; pnon-inferiority =0.003 [margin: 2.0])
 Similar findings for principal safety outcome (HR=0.90; 95% CI 0.76–1.07; p=0.23)
 Superiority for major bleeding (HR=0.49; 95% CI 0.31–0.79; p=0.003)
 Demonstrable improvements in clot burden
Xarelto®, 15 mg bid for 21 days followed by 20 mg od, could provide clinicians and patients with
a simple, single-drug approach for the acute and continued treatment of PE that potentially
improves the benefit–risk profile of anticoagulation

Risk of VTE Recurrence is Highest in the First
3–4 Weeks After the Index DVT/PE Event
Meta-analysis of 15 trials; n=27,237; trials of extended treatment and cancer patients excluded
1. Limone BL et al, Thromb Res 2013;132:420–426
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
1 2 3 4 5 6 7 8 9 10 11 12
Venous
thromboembolic
events
per
person-year
Time period after index event (weekly intervals)
VTE recurrence remains a
persistent threat

Simplified Guidelines Assist Decision-making When Considering Extended
Treatment For Patients
Risk of recurrence
Major transient
[provoked]
For example
major surgery
or trauma
Minor transient
[provoked]
For example
pregnancy or
long-haul flight
[Unprovoked]
No identifiable
risk factor
Persistent
[provoked]
For example
active cancer
Low risk <3%* High risk >8%*
Consider extended anticoagulation
Intermediate risk 3–8%*
Konstantinides SV et al. Eur Heart J 2019;41:543–603.
*Estimated annual risk for long-term recurrence.

EINSTEIN EXT: Study Background
Treatment for index venous thromboembolic event
6–12 months’ anticoagulation
Continue
anticoagulation
Equipoise
Should anticoagulation
be stopped
or continue?
Stop treatment
Routine coagulation
monitoring, with dose
adjustment and
attendant risk of
bleeding
EINSTEIN EXT

EINSTEIN EXT: Study Design
Randomized, double-blind, placebo-controlled, event-driven (n=30), superiority study
Xarelto® 20 mg od
Placebo
N=1197
30-day
observation
period
Confirmed
symptomatic DVT or
PE completing
6–12 months of
Xarelto® or VKA in
EINSTEIN VTE
programme
R
Treatment period of 6 or 12 months
Day 1
Confirmed
symptomatic DVT or
PE completing
6–12 months
of VKA
~53%
~47%

Enduring Protection Against Recurrent VTE
When Treatment is Continued
Xarelto®
n/N (%)
Placebo
n/N (%)
8/602
(1.3)
42/594
(7.1)
11
10
5
2
1
Cumulative
event
rate
(%)
3
4
9
13
6
7
8
12
0
0 30 60 90 120 150 180 210 240 270 300 330 360
Xarelto® (n=602)
Placebo (n=594)
HR: 0.18
(95% CI 0.09–0.39)
p<0.001
82%
RRR
8.2% ARR
Recurrent VTE measured in the ITT population; all analyses were based on the first event

EINSTEIN EXT: Major Bleeding
Xarelto®
(n=598)
Placebo
(n=590)
n (%) n (%)
Major bleeding 4 (0.7)* 0 (0)
Bleeding contributing to death 0 (0) 0 (0)
Bleeding in a critical site 0 (0) 0 (0)
Associated with fall in haemoglobin
2 g/dl and/or transfusion of 2 units
4 (0.7) 0 (0)
Gastrointestinal bleeding 3 (0.5) 0 (0)
Menorrhagia 1 (0.2) 0 (0)
Safety population; *p=0.11

EINSTEIN EXT: Conclusions
In patients who had completed 6–12 months of anticoagulation, Xarelto® showed:
 An 82% RRR in the recurrence of VTE (HR=0.18; p<0.001)
 Absolute risk reduction 5.8%; hence 15 patients need to be treated to prevent one recurrent venous
thromboembolic event
 Low incidence of major bleeding (0.7%; p=0.11; NNH approximately 139)
 Modest increase in non-major clinically relevant bleeding (5.4% vs 1.2%)
 No signal for liver toxicity
Xarelto® 20 mg od could provide clinicians and patients with a simple and effective option for
continued anticoagulant treatment

Balancing the Risk of Recurrent VTE Versus Bleeding Is Critical
for Deciding to Extend Treatment
DOACs significantly reduced the risk of recurrent VTE by >80% with major bleeding risk
comparable to placebo in extended treatment of VTE2
Attempts to reduce bleeding risk include lower dose anticoagulant therapy or ASA2,3
1. Haxaire C et al, PLoS One 2015;10:e0142070; 2. Weitz JI et al, Thromb Hemost 2015;114:645–650; 3. Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518
Recurrences without
anticoagulation
Bleeding while
receiving
anticoagulation
Patient’s
preference1

EINSTEIN CHOICE Evaluated Xarelto® Versus ASA for
Extended Treatment of VTE
30-day
follow-up
Xarelto® 10 mg od
n=1136
Day 1
ASA 100 mg od
n=1139
12-month planned treatment duration†
Population:
Patients with confirmed
symptomatic PE/DVT
who completed
6–12 months’
anticoagulation*
R
N=3396
Objectives: Compare the efficacy and safety of once daily Xarelto® (20 or 10 mg) with aspirin (100
mg) in VTE patients who completed 6 to 12 months of treatment and with equipoise regarding the
need for extended anticoagulation
Xarelto® 20 mg od
n=1121
*Completed 6–12 months anticoagulation at randomization with no interruption of anticoagulation >1 week
† Patients randomized after the requisite number of primary efficacy outcomes was reached were treated for ≥6 months
Multicentre, randomized, double-blind, active-comparator, event-driven, superiority study
Weitz JI et al, Thromb Hemost 2015;114:645–650; Weitz JI et al, N Engl J Med
2017:doi:10.1056/NEJMoa1700518

Both Xarelto® Doses Provided Superior Reduction in Recurrent VTE Rates
Compared with ASA
Intention-to-treat analysis
ASA 100 mg od
Xarelto® 20 mg od
Xarelto® 10 mg od
Days
0
1
2
3
4
5
Cumulative
incidence
(%)
1 30 60 90 120 150 180 210 240 270 300 330 367
Xarelto® 20 mg od vs ASA
17/1107 (1.5%) vs 50/1131 (4.4%)
HR=0.34 (95% CI 0.20–0.59),
p<0.001
13/1127 (1.2%) vs 50/1131 (4.4%)
HR=0.26 (95% CI 0.14–0.47), p<0.001
74%
RRR
66%
RRR
Weitz JI et al, N Engl J Med 2017:doi:10.1056/NEJMoa1700518

Other Efficacy Endpoints Reduced with Both Xarelto® Doses
Versus ASA
5.0 4.9 5.0
5.6
1.6
1.3 1.4
1.9
1.7
2.1
1.8
2.0
0
1
2
3
4
5
6
Recurrent VTE, MI,
ischaemic stroke or SE
Recurrent VTE,
all-cause mortality
Recurrent VTE,
venous thrombosis
in other locations
Recurrent VTE, MI,
ischaemic stroke, SE or
venous thrombosis
in other locations
Incidence
(%)
ASA 100 mg od (n=1131) Xarelto 10 mg od (n=1127) Xarelto 20 mg od (n=1107)
* * * * * * * *
Intention-to-treat analysis. *p<0.001 versus ASA 100 mg od

Rates of Major Bleeding Were ≤0.5% and
Similar to ASA
Safety analysis. No events after Day 360 up to Day 480
0
1
2
4
5
3
Days
ASA 100 mg od
Xarelto® 20 mg od
Xarelto® 10 mg od
1 30 60 90 120 150 180 210 240 270 300 330 360
Cumulative
incidence
(%)
6/1107 (0.5%) vs 3/1131 (0.3%)
HR=2.01 (95% CI 0.50–8.04), p=0.32
5/1127 (0.4%) vs 3/1131 (0.3%)
HR=1.64 (95% CI 0.39–6.84), p=0.50

Bleeding Outcome Analyses
0.3
2.0
1.8
1.1
0.4
2.4
2.0
1.1
0.5
3.3
2.7
1.5
0
1
2
3
4
Major bleeding Major or CRNM bleeding CRNM bleeding Non-major bleeding associated with
study drug interruption for more
than 14 days
Incidence
(%)
ASA 100 mg od (n=1131) Xarelto 10 mg od (n=1127) Xarelto 20 mg od (n=1107)
Similar rates of bleeding were observed in the Xarelto® and ASA treatment groups
Safety analysis. All treatment comparisons p>0.05

Summary and Conclusions
In patients with symptomatic VTE who completed 6 to 12 months of treatment
and with equipoise regarding the need for extended anticoagulation
 Both Xarelto® regimens (20 or 10 mg once daily) are superior to aspirin for the primary and
other efficacy outcomes and are associated with similar rates of bleeding
 Compared with aspirin, numbers needed to treat with Xarelto® 20 or 10 mg for one year to
prevent one VTE without an increase in bleeding are 33 and 30, respectively
 Consistent results in subgroups of patients
Xarelto® 10 mg once daily provides an additional option for extended VTE
treatment
 Patients requiring full-dose anticoagulant therapy were excluded and may need extended
treatment with the 20 mg once daily Xarelto® regimen
*Number needed to treat (NNT) compared with aspirin for primary efficacy outcome up to 1 year

Real-World Evidence of Xarelto® in VTE

The controlled trial versus the “Real World”
Allows for minimization of bias through
randomization1
Protocol-driven treatment1
Adjudicated outcome assessment2
Blinding of providers/patients to
intervention3
Diverse and unselected populations4
Routine clinical practice4
Comparator(s) of interest may be different
from what was studied in the RCT4
RCT: Can the drug work?
1. Kennedy-Martin T et al, Trials 2015:14:493–509; 2. Ndounga Diakou LA et al, Cochrane Database Syst Rev 2016:3:MR000043;
3. Odgaard-Jensen J et al, Cochrane Database Syst Rev 2011:4:MR000012; 4. ISPOR. Market access and reimbursement: the increasing role of real-world evidence. Available at:
https://www.ispor.org/research_pdfs/48/pdffiles/PHP280.pdf [accessed 14 August 2017]
RWE: Does the drug work?

Objective: collect real-life data in patients with acute DVT and/or PE treated with Xarelto® or standard anticoagulation
from regions not included in the original XALIA study
XALIA-LEA Study Design
Investigators to collect data at initial
visit, 1 month and then quarterly*
Final
assessment
Xarelto® for ≥3 months
Standard anticoagulation, e.g.
initial treatment with LMWH/fondaparinux,
followed by VKA or parenteral anticoagulation for ≥3 months
Patients with
diagnosis of
acute DVT
and/or PE and
with an
indication for
anticoagulant
therapy for
≥3 months
Type, dose
and duration
of drug used
at discretion
of attending
physician
(1 month
after end of
treatment)
Primary
outcomes
Major bleeding
events,
symptomatic
recurrent VTE
and all-cause
mortality
ClinicalTrials.gov NCT02210819; *Data were collected at the initial visit and during routine follow-up visits or via mail, telephone, or email
Turpie A. G.G. et al., 26th Biennial International Society on Thrombosis and Haemostasis (ISTH) 2017, 8–13 July 2017, Berlin, Germany

XALIA-LEA Participating Countries

XALIA-LEA Enrolment by Region
Region, n (%) Xarelto®
(N=1285)
Standard
anticoagulation
(N=402)
Early switchers
(N=285)
Asia-Pacific 720 (56.0) 167 (41.5) 157 (55.1)
Eastern Europe, Middle
East and Africa
473 (36.8) 196 (48.8) 121 (42.5)
Latin America 92 (7.2) 39 (9.7) 7 (2.5)

XALIA-LEA Enrolment by Country
Country, n (%) Xarelto®
(N=1285)
Standard anticoagulation
(N=402)
Early switchers
(N=285)
Algeria 32 (2.5) 7 (1.7) 0 (0.0)
Egypt 145 (11.3) 58 (14.4) 20 (7.0)
Indonesia 46 (3.6) 7 (1.7) 1 (0.4)
Jordan 13 (1.0) 4 (1.0) 2 (0.7)
Kazakhstan 47 (3.7) 2 (0.5) 48 (16.8)
Kenya 12 (0.9) 13 (3.2) 10 (3.5)
Lebanon 34 (2.6) 5 (1.2) 4 (1.4)
Malaysia 15 (1.2) 14 (3.5) 6 (2.1)
Mexico 92 (7.2) 39 (9.7) 7 (2.5)
Philippines 13 (1.0) 4 (1.0) 1 (0.4)
Russia 103 (8.0) 36 (9.0) 25 (8.8)
Saudi Arabia 48 (3.7) 62 (15.4) 9 (3.2)
Singapore 12 (0.9) 20 (5.0) 6 (2.1)
South Korea 607 (47.2) 110 (27.4) 118 (41.4)
Taiwan 27 (2.1) 12 (3.0) 25 (8.8)
Ukraine 39 (3.0) 9 (2.2) 3 (1.1)

XALIA-LEA Primary Outcomes (Adjusted for Covariates)
2.9 2.6
4.2
8.2 8.8
15.8
0
5
10
15
20
25
Major bleeding Recurrent VTE All-cause mortality
Annualized
event
rate
(%/year)
Xarelto Standard anticoagulation (N=402)
HR=0.36
95% CI 0.18–0.71
p=0.003
HR=0.32
95% CI 0.16–0.64
p=0.001
HR=0.37
95% CI 0.21–0.63
p<0.003
Covariates were selected using a stepwise selection procedure with a threshold of p=0.10
RRR
64%
RRR
68%
RRR
63%
Xarelto® consistently showed significantly reduced risk of major bleeding, recurrent VTE and all-
cause mortality in real world studies

Conclusions
XALIA-LEA provides data on VTE treatment in regions not studied in XALIA
Results for the three primary outcomes demonstrated that Xarelto® is safe and effective in a
broad range of patients, supporting the observations from XALIA and the phase III EINSTEIN
studies1–3
Baseline characteristics between treatment groups were more similar in XALIA-LEA than in
XALIA (including age and cancer rates)
 Increased familiarity with Xarelto® in clinical practice since the XALIA study may have
influenced prescription patterns
Major bleeding rates and all-cause mortality were considerably higher in XALIA-LEA compared
with XALIA (for the respective Xarelto® and standard anticoagulation groups)
 This was possibly due to the higher proportion of patients with PE and known cancer at
baseline enrolled in XALIA-LEA
1. ClinicalTrials.gov NCT02210819; 2. Ageno W et al, Lancet Haematol 2016;3:e12–e21; 3. Prins MH et al, Lancet Haematol 2014;1:e37–e46

VTE Patients can be treated with the right dose to resolve his
clot and prevent it returning
15 mg BID
20 mg OD
10 mg OD
20 mg OD
Initial treatment Continued treatment Extended treatment*
21 days 6 months Extended treatment
*When extended treatment is indicated, the recommended dose is 10 mg OD. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities,
or who have developed recurrent DVT or PE on extended prevention with Xarelto® 10 mg OD, a dose of Xarelto® 20 mg OD should be considered.
Xarelto® treatment dosing regimen1
If extended oral anticoagulation is decided after PE in a patient without cancer, a
reduced dose of Xarelto® (10 mg OD) should be considered after 6 months of
therapeutic anticoagulation2
1. Xarelto® Product Information Indonesia 2019; 2. Konstantinides SV et al. Eur Heart J 2019;41:543–603.

Balancing Act with Anticoagulation Therapy:
Risk Versus Benefit
Bleeding is a risk associated with ALL
anticoagulants
Benefits of anticoagulation should be
balanced against risk of bleeding
Safety and efficacy of novel OACs, such as
Xarelto®, are well established in large
phase III programmes across several
thromboembolic disorders Bleeding
risk
Anticoagulation
benefits

76
STATIN
ANTI PLATELETS ACE-i / ARB
and / or
CCB
DIURETIK
NITRAT Beta-
Blocker
ANTI COAGULANT

Xarelto® Regimen for Your VTE Patients
Renal function
(CrCl, ml/min)
Dose
adjustment
Not necessary Not necessary# Not necessary;
use with caution#
Use not
recommended
50–80 30–49 15–29 <15
*Not recommended in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy; #a reduction in the dose from 20 mg once daily to
15 mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE
Treatment of
DVT and PE*
From day 22
transition to
15 mg twice daily
with food
20 mg once daily
with food
1. Xarelto® Product Information as approved by BPOM-RI (2019).

The Many Advantages to The Oral Single-Drug,
Once-Daily Treatment Approach with Xarelto®
1. Prins MH et al, Thromb J 2013 Sep 20;11:21; 2. van Es J et al, J Thromb Haemost 2013;11:679–685;
3. Agnelli G et al, Circulation 2007;116:180–187; 4. The EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510; 5. IMS Health MIDAS, 2014
Fast, effective
protection from
early recurrence in
the first 21 days2,3
Halves the risk
of major
bleeding1
Oral single-drug
treatment for
ongoing
protection4 with
no routine
coagulation
monitoring
Simple to start
and
easy to maintain
Efficacy
Safety Simplicity Experience

Xarelto® Is Easy to Use
*15 mg and 20 mg tablets must be taken with food
1. Xarelto® SmPC, 2014; 2. Kubitza D et al, Clin Pharmacol Drug Dev 2013;2:270–277; 3. Coumadin PI; 4. Enoxaparin SmPC; 5. Scottish Medicines Consortium, 2013; 6. NICE.
Xarelto®® in the treatment of DVT and prevention of recurrent VTE events 2011;
7. van Bellen B et al, Curr Med Res Opin 2014;30:829–837
Oral administration1
No dietary restrictions*1
No injections1,4/fewer
nurse visits/shorter
hospital stays compared
with LMWH/VKAs5–7
Fewer drug–drug
interactions compared
with VKAs1,3
Simple dosing1
Single-drug approach
with fast onset of
action1,2
No need for routine
coagulation monitoring1

Xarelto®: The First Oral, Direct Factor Xa Inhibitor
Direct, specific, competitive Factor Xa inhibitor
Inhibits free and fibrin-bound Factor Xa activity and
prothrombinase activity
Inhibits thrombin generation
No direct effect on thrombin-induced platelet aggregation
Bioavailability 80–100%
1. Roehrig S et al, J Med Chem 2005;48:5900–5908; 2. Perzborn E et al, J Thromb Haemost 2005;3:514–521;
3. Perzborn E et al, Nat Rev Drug Discov 2011;10:61–75 ; 4. Kreutz R, Curr Clin Pharmacol 2014;9:75–83

80–100%
bioavailability*
66% metabolic
degradation
33%
hepatobiliary
elimination of
inactive drug
33% renal
elimination of
inactive drug
33% renally
excreted as
unchanged active
substance in urine
Xarelto® Metabolism and Elimination
*Rivaroxaban dose >10 mg taken with food

Converting From VKA to Xarelto®
 VKA therapy should be stopped
 INR measurement has to continue
 Xarelto® should be initiated when INR is ≤ 2.5
(DVT, PE treatment)
 The full process of converting is
described in the Product Information
Guidance Evidence
Converting from VKA to Xarelto®
VKA Xarelto®*
INR testing
(duration according to
individual decrease of VKA
plasma levels)
Days
DVT, PE and prevention of recurrent DVT and PE:
Initiate Xarelto® once INR ≤ 2.5
Stop VKA
*See dosing recommendations for required daily dose
Xarelto® Product Information as approved by BPOM-RI (2019).

Ikhwan Handi R, MD, FIHA
Xarelto® for Venous Thromboembolism (VTE) Patients

RTD - Xarelto for Venous Thromboembolism (VTE) Patients.pptx

Recommended

Recommended

More Related Content

Similar to RTD - Xarelto for Venous Thromboembolism (VTE) Patients.pptx

Similar to RTD - Xarelto for Venous Thromboembolism (VTE) Patients.pptx (20)

Recently uploaded

Recently uploaded (20)

RTD - Xarelto for Venous Thromboembolism (VTE) Patients.pptx