1. Extended Treatment of VTE: Who is the Right Candidate?
Moderator
Jeffrey I. Weitz, MD, FRCP(C)
Professor of Medicine and Biochemistry McMaster University
Hamilton, Ontario, Canada

2. Jan Beyer-Westendorf, MD Peter Verhamme, MD, PhD
Panelists
Jan Beyer-Westendorf, MD
Assistant Professor
University Hospital Carl Gustav Carus der Technische Universität Dresden Dresden, Germany
Peter Verhamme, MD, PhD
Professor Department of Cardiovascular Sciences University of Leuven Leuven, Belgium

3. Program Goals Increased knowledge regarding VTE as a chronic disease
Demonstrate greater confidence in their ability to
Decide when and how to extend anticoagulant treatment, based on current data
VTE = venous thromboembolism

4. Phases of VTE Treatment Acute, Long-Term, and Extended Treatment
Secondary Prevention
Initial (acute): 0 to about 7 d
Initial (acute): 0 to about 7 d
Long-term (subacute):
about 7 d to about 3 mo
Extended: about 3 mo to indefinite
1 wk wk
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

5. Estimating Risk of VTE Recurrence Primary Factors
VTE Provoked by
Surgery
Nonsurgical Transient Risk Factor
Unprovoked VTE
VTE Associated with
Cancer
Primary Factors
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

6. VTE Provoked by Surgery Risk of Recurrence
After Stopping AC Treatment
AC = anticoagulant
PE = pulmonary embolism
Guidelines recommendation for proximal VTE or PE provoked by surgery:
Recommend AC treatment for 3 mo
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

7. Unprovoked VTE Risk of Recurrence
After Stopping AC Treatment
DVT = deep vein thrombosis
Guidelines recommendation for first unprovoked proximal DVT or PE:
Low/moderate bleeding risk: Suggest extended AC treatment
High bleeding risk: Recommend AC treatment for 3 mo
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

8. VTE Provoked by Nonsurgical Transient Risk Factors Risk of Recurrence
Immobility (ie, hospitalized patients, leg injury)
Pregnancy
Estrogen therapy
Flight of >8 h
After Stopping AC Treatment
Guidelines recommendation for proximal DVT or PE provoked by a nonsurgical transient risk factor:
Low/moderate bleeding risk: Suggest AC treatment for 3 mo
High bleeding risk: Recommend AC treatment for 3 mo
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

9. VTE Associated With Cancer Risk of Recurrence
Annualized recurrence: 15%
Risk varies depending on whether cancer:
Is metastatic
Being treated with chemotherapy
Rapidly progressing
Guidelines recommended for DVT or PE and active cancer:
Low/moderate bleeding risk: Recommend extended AC treatment
High bleeding risk: Suggest extended AC treatment
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

10. Benefit/Risk of Extended AC Treatment
Reduction of recurrent VTE
Risk:
Increase in bleeding
Patient Preference
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

11. Estimating Risk of VTE Recurrence Other Factors
Type of Index Event:
PE vs DVT
D-dimer
tested one month after AC treatment withdrawal
Gender
PE:
Higher risk of recurrence
More likely to recur as PE
Positive vs negative d-dimer:
Positive double the risk of recurrence
Men vs women:
Men ~75% higher risk of recurrence +
Predictive value appears to be additive
No Guidelines Recommendation on extended AC treatment based on D-dimer and gender
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

12. Estimating Risk of VTE Recurrence Other Factors (cont)
# of VTE Events:
1st Unprovoked vs Subsequent
Location:
Distal vs Proximal
2nd or subsequent:
50% higher risk of recurrence vs 1st
Guidelines recommendation:
Low bleeding risk: recommend extended AC treatment
Moderate bleeding risk: suggest extended AC treatment
High bleeding risk: extended AC treatment not recommended
Isolated distal:
50% lower risk of recurrence vs proximal
Guidelines recommendation:
AC treatment for 3 mo
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

13. VTE Treatment VKA or NOAC
Extended:
~3 months to indefinite
Parenteral: Heparin,
LMWH, fondaparinux
Long term:
~7 days to ~ 3 months
Initial:
0 to ~7 days
Secondary Prevention
VKA = vitamin K antagonist
LMWH = low molecular weight heparin
NOAC = non-vitamin K antagonist oral anticoagulants
INR = international normalized ratio
VKA: initiated concurrently with parenteral anticoagulant; parenteral anticoagulant is continued until the INR≥2.0 for 24 hours
NOAC: initiated after parenteral anticoagulant (dabigatran and edoxaban) or initiated in place of parenteral anticoagulant (rivaroxaban and apixaban) and continued thereafter
a. Kearon C, et al. Chest. 2012;141(suppl):e419S-e496S; b. Kearon C, et al. Chest. 2016;149:

14. VTE Extension Trials with NOACs Efficacy and Safety Outcomes
AMPLIFY-EXT[a]
Apixaban
2.5 mg, n=840
5 mg, n=813
Placebo
n=829
P Value
Recurrent VTE or
VTE-related death, %
1.7
8.8
<.001
Major bleeding, %
0.2
0.1
0.5 --
RE-SONATE[b]
Dabigatran
n=681
n=662
Recurrent or fatal VTE, %
0.4
5.6
0.3
1.0
EINSTEIN-EXT[c]
Rivaroxaban
n=602
n=594
Recurrent VTE, %
1.3
7.1
0.7
.11
Note to AE: this slide has been fact checked previously
a. Agnelli G, et al. N Engl J Med. 2013;368: ; b. Schulman S, et al. N Engl J Med. 2013;368: ; c. EINSTEIN Investigators, et al. N Engl J Med. 2010;363:

15. EINSTEIN CHOICE Study Design
Patients with confirmed symptomatic DVT or PE who have completed anticoagulation treatment for to 12 mo
Rivaroxaban, 10 mg/d
Treatment for 12 mo
Rivaroxaban, 20 mg/d R
Aspirin, 100 mg/d
N=3365
230 sites in 31 countries
R = randomized
Weitz JI, Bauersachs R, Beyer-Westendorf J, et al; EINSTEIN CHOICE Investigators. Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost. 2015;114:
A total of 3365 patients were included in the intention-to-treat analyses (median
treatment duration, 351 days).
Primary endpoint: fatal or nonfatal symptomatic recurrent VTE
Primary safety outcome: major bleeding
Weitz J, et al. Thromb Haemost. 2015;114:

16. EINSTEIN CHOICE Patient Population
Patients were excluded if they had:
Symptomatic VTE recurrence during a 6 to 12 mo treatment period
Indication for extended AC therapy (recurrent VTE, severe thrombophilia, or antiphospholipid syndrome)
Target Population:
Patients for whom treating physician was uncertain about the need for continued AC therapy
Weitz J, et al. Thromb Haemost. 2015;114:

17. INSPIRE Aspirin for Prevention of Recurrent VTE
CONTENT NO LONGER AVAILABLE
CI = confidence interval
CV = cardiovascular
HR = hazard ratio
MI = myocardial infarction
Figure 3 from
Simes J, Becattini C, Agnelli G, et al; INSPIRE Study Investigators (International Collaboration of Aspirin Trials for Recurrent Venous Thromboembolism). Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130:
Major vascular events: composite of recurrent VTE, MI, stroke, or CV death
Net clinical benefit: recurrent VTE, MI, stroke, all-cause mortality, and major bleeding
Simes J, et al. Circulation. 2014;130:

18. EINSTEIN CHOICE Primary Outcome Recurrent VTE
A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients
(4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban
vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons).
HR (95% CI) P
Rivaroxaban 20 mg vs aspirin
0.34 (0.20, 0.59)
<.001
Rivaroxaban 10 mg vs aspirin
0.26 (0.14, 0.47)
Rivaroxaban 20 mg vs 10 mg
1.34 (0.65, 2.75)
0.42
Weitz J, et al. N Engl J Med. 2017;376:

19. EINSTEIN CHOICE Bleeding Outcomes
P = NS for all comparisons
CRNM = clinically relevant nonmajor bleeding
NS = nonsignificant
ISTH = International Society on Thrombosis and Haemostasis
Content Slide Layout: TEXT
Weitz JI, et al. N Engl J Med. 2017;376:

20. EINSTEIN CHOICE Clinical Implications
10-mg dose:
For most patients
For patients with bleeding concerns
20-mg dose:
For high-risk patients
Recurrent VTE
Severe thrombophilia
Antiphospholipid syndrome
Cancer

21. Summary VTE is a chronic disease and a major health concern
Many patients remain at high risk for recurrence
NOACs provide a simplified treatment option for these patients
Acute phase: high-dose treatment up front with apixaban for 1 week or rivaroxaban for 3 weeks
Long-term phase: Continue with NOAC dose
Extended phase (for eligible patients): option of lower-dose rivaroxaban
Data from trials such as EINSTEIN CHOICE demonstrate that extended treatment with NOACs is safe and effective

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LLA
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