Download Rivaroxaban or Aspirin for Extended Treatment of Venous

Rivaroxaban or Aspirin for Extended
Treatment of Venous Thromboembolism
Jonathan Kaplan, MD
Internal Medicine and Psychiatry PGY3
Emory University
May 2017
Objectives
 Present a common and relevant clinical scenario
 Briefly review risk factors for DVT/PE
 Discuss the EINSTEIN Project that compares rivaroxaban to




placebo for secondary prevention of DVT/PE
Discuss a meta-analysis comparing DVT/PE prevention and
bleed risk for various anticoagulant and antiplatelet drugs
Discuss the EINSTEIN CHOICE study comparing
rivaroxaban and aspirin
Practice relevant calculations to critically appraise the article
Make a clinical decision for our patient
Clinical Scenario
 You are called for an admission for a patient with a RLE DVT and
a sub-segmental PE on CT PE Protocol
 Patient is a 60 y.o. obese woman with a hx of HTN, IDDM,
HFrEF 40%, and R hip replacement 6 weeks ago. She is a long
haul truck driver driving distances 10+ hours. Her last drive was
prior to her hip surgery but she plans to return to work.
 On exam, VS - BP 130/84, P 115, RR 18, O2 sat 96% on room
air, afebrile. She has unlabored, clear lungs, cardiac RRR w/
tachycardia. Bedside TTE shows no flattening of the interventricular septum. EKG has S1Q3T3 pattern.
 Her PESI score is 90 (60 years old, HFrEF, pulse 115; placing her
in an intermediate risk category)
Clinical Scenario Continued
 In the morning the intern asks you how long she needs to
continue treatment and you reply 3-6 months.You go home
to sleep knowing at some point, some physician will have to
decide if they should continue treatment and with what agent
 At discharge, the diligent intern makes a follow up
appointment at Grady in the anticoagulation clinic and
decides that for continuity of care, this patient will also be
scheduled in your clinic
 The patient arrives 6 months later and wonders about the
next steps for treatment…So do you.
Risk factors for VTE
Major transient risk factors:
 Hospitalization
 Plaster cast immobilization
 Surgery
 Trauma
Minor transient risk factors:
 Oral contraceptives or hormone
therapy
 Pregnancy
 Presence of major risk factor 1 to 3
months before VTE
 Prolonged travel (≥ 2 hours)*
Potential acquired or persistent risk
factors:
 Collagen vascular diseases
 Heart failure
 Malignancy
 Medications
 Myeloproliferative disorders
 Nephrotic syndrome
 Recurrent pregnancy loss
• Risk of recurrent DVT/PE for patients without reversible risk factors is as
high as 10% in the first year
•The risk of DVT/PE is higher for patients with non-surgical provoked
events than surgical provoked events
EINSTEIN Project
 Three studies: DVT, PE, and continued treatment study (EXT trial)
 EINSTEIN EXT Trial
 Enrolled patients who completed 6 - 12 months of treatment with either
VKA or rivaroxaban for DVT or PE and randomly assigned them to
continue treatment with rivaroxaban 20mg daily or placebo, goal to treat
for an additional 6 -12 months
 Recurrent DVT occurred in 1.3% of treatment group compared to 7.1%
of placebo group
 Major bleeding occurred in 0.7% of treatment group and 0% of placebo
group, non major bleeding occurred in 5.4% of treatment group and
1.2% in placebo group
 Authors determine that the benefit in preventing recurrent events is
worth the risk of bleeding as there were no fatal bleeding events
Systematic Review and Meta-Analysis,
2013
 At the time of this study, CHEST recommendations were
treatment of VTE and PE for three months if the event was
provoked and reversible
 Unclear recommendations regarding long term treatment for
unprovoked events but suggestion that treatment should continue
if risk for bleeding is low
 Selected 12 randomized controlled trials of anticoagulant drugs
(rivaroxaban, apixiban, dabigatran, ximelagatran), vitamin K
antagonists, placebo, or observation
 11,999 participants included in efficacy analysis. 12,167 included
in safety analysis.
Systematic Review and Meta-Analysis,
2013
 Results
 Vitamin K antagonists at goal INR 2-3 demonstrated the highest risk
difference and aspirin demonstrated to lowest risk difference when
compared to placebo and observation, but aspirin still outperformed placebo
 Vitamin K antagonists were associated with the greatest risk of major
bleeding
 Other anticoagulants outperformed placebo and there was a suggestion that
they outperformed aspirin
 Limitations
 Oral anticoagulants had shorter length of study and risks/benefits could not
be extrapolated beyond one year
 Efficacy of aspirin vs oral anticoagulants remained unclear
 Data for rivaroxaban was from one study (EINSTEIN EXT) and the number
of bleeding events was very low overall and difficult to compare to other
agents
Rivaroxaban or Aspirin for Extended Treatment
of Venous Thromboembolism, The Einstein
Choice Trial
vs.
Methods
 Randomized, double-blind, non placebo controlled
 Three groups: rivaroxaban 20mg, rivaroxaban 10mg, and
aspirin 100mg
 Primary Efficacy Outcome: Recurrent fatal or non fatal DVT
or PE
 Primary Safety Outcome: Major bleeding defined as decrease
in Hb 2+g/dL, transfusion of 2+units RBC, bleeding from a
critical site, or bleeding causing death
Secondary Efficacy and Safety
Outcomes
 Secondary Efficacy Outcomes:
 Myocardial infarction, ischemic stroke, systemic embolism, VTE
at an location other than deep veins of lower limbs, and death
 Secondary Safety Outcomes:
 Clinically relevant non major bleeding: overt bleeding not
meeting criteria for major bleeding but needing medical
attention, or required 14 day interruption of the study drug or
discontinuation of the study drug, impairment in ADLs
Inclusion/Exclusion criteria
 Inclusion criteria:




18 years and older
Confirmed DVT/PE
Treatment for 6-12 months with VKA or DOAC
Treatment uninterrupted for more than 7 days prior to
randomization
 Exclusion Criteria:
 Contraindication to continued anticoagulant therapy
 Required extended anticoagulant therapy at therapeutic doses or
required antiplatelet therapy
 Creatinine clearance less than 30mL/min
 Hepatic Disease with a coagulopathy
Randomization and Monitoring
 Randomized in a 1:1:1 ratio into three groups rivaroxaban
20mg daily, rivaroxaban 10mg daily, aspirin 100mg daily
 Assessment at 30, 90, 180, 270, and 360 days and at 30 days
after stopping the study medication
 Participants who stopped a study drug early were followed
until the end of the intended treatment period
Results
Rivaroxaban 20mg
Rivaroxaban 10mg
Aspirin 100mg
Primary Efficacy
Outcome: Recurrent
fatal or non fatal
DVT/PE
17/1107 (1.5%)
13/1127 (1.2%)
50/1131 (4.4%)
Primary Safety
Outcome: Major
Bleeding
6/1107 (0.5%)
5/1127 (0.4%)
3/1131 (0.3%)
Secondary Safety
Outcome: Any other
clinically relevant
bleed
30/1107 (2.7%)
22/1127 (2.0%)
20/1131 (1.8%)
Recurrent VTE
VTE
Absolute Risk
(Number of
Events in
Group divided
by total group)
Rivaroxaban 17/1107 (1.5%)
20 mg
Rivaroxaban 13/1127 (1.2%)
10mg
Aspirin
100mg
50/1131 (4.4%)
Absolute
Risk
Reduction
(AR in
group - AR
in
comparative
group)
4.4%-1.5% =
2.9%
4.4%-1.2% =
3.2%
Relative
Risk (AR in
group / AR
in
comparative
group)
Relative
Risk
Reduction
(AR in
aspirin – AR
in
rivaroxaban
) divided by
AR in
aspirin
Number
needed to
treat (1
divided by
the ARR)
0.015/0.044= (0.0440.34= 34%
0.015)/0.044
= 0.66 = 66%
1/0.029 =
34.5
0.012/0.044 = (0.0440.27= 27%
0.015)/0.04
4= 0.73 =
73%
1/0.032 = 31.3
Major Bleeding
Major
Bleed
Absolute
Risk
(Number of
Events in
Group
divided by
total group)
Absolute
Risk
Increase
(AR in
group - AR
in
comparativ
e group)
Relative
Risk (AR in
group / AR
in
comparative
group)
Relative Risk
Increase (ARI
divided by AR
in comparable
group)
Number
needed to
harm (1
divided by
the ARI)
Rivaroxaban
20 mg
6/1107 =
(0.5%)
0.5%-0.3% = 0.5%/0.3% = (0.5%0.2%
1.66
0.3%)/0.3% =
0.66 = 66%
1/0.002 =
500
Rivaroxaban
10mg
5/1127 =
(0.4%)
0.4%-0.3% = 0.4%/0.3% = (0.4%0.1%
1.33
0.3%)/0.3% =
0.33 = 33%
1/0.001 =
1000
Aspirin
100mg
3/1131 =
(0.3%)
Validity
 Applicability:
 Well designed study with broad inclusion, performed across 244 sites in 31
countries
 Clinically relevant timing of intervention and outcomes
 Frequency of follow up mimics what could be expected in standard practice
 3365 took study medication, 537 (16%) did not complete the study due to
adverse events, non adherence to the study regimen (80% of drug taken),
safety and efficacy outcomes
 Limitations:
 Not placebo controlled
 Sponsored by Bayer, sponsor responsible for collecting, maintaining, and
analyzing data; academic authors had access to data at all times and verified
the data and analysis
 Excluded patients who required extended treatment with therapeutic doses,
limiting applicability of rivaroxaban 10mg daily in this population
 Study not powered to determine a difference between rivaroxaban groups
 Treatment period was only 12 months, what happens after that?
 Study extended recruitment because an early review of blinded data revealed
fewer than expected DVT/PE
Conclusion
 Rivaroxaban, at either dose, had better outcomes in the
primary efficacy measure at the cost of a clinically
insignificant and statistically insignificant risk for major
bleeding
 What do we do for our patient?
References
 Galioto NJ, Danley DL, Van Maanen RJ. Recurrent venous thromboembolism. Am Fam
Physician. 2011 Feb 1;83(3):293-300. Review. PubMed PMID: 21302870.
 Weitz JI, Lensing AWA, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H,
Brighton TA, Cohen AT, Davidson BL, Decousus H, Freitas MCS, Holberg G, Kakkar AK,
Haskell L, van Bellen B, Pap AF, Berkowitz SD, Verhamme P, Wells PS, Prandoni P;
EINSTEIN CHOICE Investigators.. Rivaroxaban or Aspirin for Extended Treatment of
Venous Thromboembolism. N Engl J Med. 2017 Mar 30;376(13):1211-1222. doi:
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Gandara E, Wells G, Carrier M. Efficacy and safety outcomes of oral anticoagulants and
antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic
review and network meta-analysis. BMJ. 2013 Aug 30;347:f5133. doi:
10.1136/bmj.f5133. Review. PubMed PMID: 23996149; PubMed Central PMCID:
PMC3758108.
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