Journal Club During Health Care Systems Rotation

1. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
BACKGROUND
Title Van Mieghem NM, Unverdorben M, Hengstenberg C, et al. Edoxaban versus
Vitamin K Antagonist for Atrial Fibrillation after TAVR. N Engl J Med.
2021;385(23):2150-2160. doi:10.1056/NEJMoa2111016
Background  Transcatheter aortic valve replacement (TAVR) is the mainstay
treatment for severe symptomatic aortic stenosis in those who are
unable to undergo open heart surgery.1
 Approximately one-third of patients develop complications following
TAVR; cerebrovascular events (e.g., stroke) secondary to pre-existing
or new onset atrial fibrillation (AF) can occur from 24 hours to 30
days after the procedure.2
 AF post-TAVR has been associated with a higher rate of
stroke/systemic embolism (SEE), and mortality.3–5
 Although oral anti-platelet therapy (OAP) is the antithrombotic
treatment post-TAVR, patients with a concurrent indication for oral
anticoagulation (OAC) such as AF with a CHA2DS2-VASc score of ≥
2 in males or ≥ 3 in females are indicated for either a direct oral
anticoagulant (DOAC) or vitamin K antagonist (VKA).6,7
 Available anticoagulation pharmacotherapy post TAVR:
o Warfarin (Coumadin®
, Jantoven®
); VKA9
 Mechanism of Action: Prevents the synthesis of
vitamin-K dependent clotting factors (II, VII, IX, and
X) via inhibition of vitamin-K epoxide reductase.
 Dosing: 5 mg PO daily (most patients).
 Pharmacokinetics (PK): Rapidly and completely
absorbed, 99% protein-bound, full therapeutic effect
generally seen between 5-7 days after initiation.
Metabolized primarily by CYP2C9; minor routes
include metabolism by CYP2C19 and CYP3A4.
 Black box warning: Bleeding, international
normalized ratio (INR) monitoring.
 Adverse drug reactions (ADRs): vasculitis, purple-
toe-syndrome.
o Edoxaban (Savaysa®
); DOAC10
 Mechanism of Action: Selectively inhibits factor Xa,
blocking thrombin-induced platelet aggregation.
 Dosing (non-valvular AF): CrCl 50-95 mL/min: 60
mg once daily; CrCl 15-50 mL: 30 mg PO daily;
CrCl < 15 mL/minute: Use not recommended.
 PK: CYP3A4-mediated conjugation and oxidation,
producing an active metabolite (M-4); time to peak: 1-
2 hours, elimination half-life 10-14 hours, renally
excreted (50% of total clearance).
 Black box warning: reduced efficacy in nonvalvular
AF patients with creatinine clearance > 95 mL/min.
 ADRs: Major hemorrhage (1-13%), minor
hemorrhage (7-13%), epistaxis (5%).

2. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Previous trials TAVR Patients Requiring Anticoagulation: Direct Oral Anticoagulant or
Vitamin K Antagonist?11
 Observational, multicenter trial that compared outcomes with
DOACs versus VKAs in patients post-TAVR from the FRANCE-
TAVI and FRANCE-2 registries using propensity score matching.
 Mortality and major bleeding including hemorrhagic stroke were
higher in patients on VKAs compared with those on DOACs.
Mortality hazard ratio (HR) 1.37; 95% confidence interval (CI)
1.12-1.67; P <0.005; major bleeding HR 1.64; 95% CI 1.17-2.29;
P <0.005.
 Limitations:
o Non-randomized trial and unmeasured confounds.
o Not specific to AF patients.
Edoxaban versus Warfarin in Patients with Atrial Fibrillation (ENGAGE
AF-TIMI 48 trial)12
 Randomized, double-blind, double dummy trial that compared
edoxaban to warfarin in patients with AF requiring OAC.
 Patients were randomized 1:1:1 to the following arms:
o Warfarin
o Edoxaban 60 mg
o Edoxaban 30 mg
 High-dose edoxaban was noninferior and superior with respect to
preventing stroke or SEE (HR 0.79; 97.5% CI 0.63-0.99; P < 0.001
for noninferiority; P=0.02 for superiority), and there were lower
rates of major bleeding with edoxaban.
 Limitations:
o Treatments were not studied in a TAVR population.
Why this study? The role of DOACs versus VKAs in patients with AF following a TAVR has
not been well established.
GENERAL STUDY OVERVIEW
Objectives The goal of The Edoxaban versus Standard of Care and Their Effects on
Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve
Implantation-Atrial Fibrillation (ENVISAGE-TAVI) trial was to compare the
efficacy and safety of edoxaban with those of VKAs in patients with
prevalent or incident atrial fibrillation after TAVR.
Trial design ENVISAGE-TAVI was a multicenter, prospective, randomized, open-label
non-inferiority trial.
Null Hypothesis Edoxaban is NOT comparable, or just as good as VKAs, for anticoagulating
patients with AF after TAVR.
Funding Source Daiichi Sankyo
METHODS
Inclusion criteria  Age ≥ 18 years old
 Indication for OAC: Prevalent or incident atrial fibrillation with a
duration of more than 30 seconds after successful TAVR for severe aortic
stenosis.

3. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Exclusion criteria  High-risk bleeding conditions: active peptic ulcer, malignancy at high
risk of bleeding, unresolved brain or spinal injury, recent spinal or
ophthalmic surgery, intracranial hemorrhage.
 Major surgery within 30 days prior to randomization
 Mechanical heart valves
 Elective percutaneous coronary intervention (PCI) within 7 days prior
to randomization
 Concomitant aspirin use (100 mg/day)
 Requirement of dual antiplatelet therapy (DAPT) for > 3 months
after randomization
 Overt stroke within 90 days before TAVR
 Active malignancy
 CrCl < 15 mL/min or dialysis
 Pregnancy or breastfeeding
 Platelet count < 50 X109
/L or Hemoglobin < 8 g/dL
Interventions + Control  Randomization was stratified based on presence or absence of a
coronary stent for which the patient would OAP for, as well as whether
the patient met the criteria for edoxaban dose adjustment:
 CrCl:15-50 mL/min
 ≤ 60 kg
 Use of P-glycoprotein inhibitors
 Patients were randomized 1:1 to receive:
 Edoxaban 60 mg PO daily
 Edoxaban dose adjustment: 30 mg PO once daily
 VKA based on local practice
 Warfarin, phenprocoumon, acenocoumarol,
fluindione
 DAPT was permitted for up to 3 months after TAVR, while single
therapy could be continued indefinitely.
 Patients were followed at 3 months post-randomization and 6 months
thereafter.

4. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Primary + Secondary
Endpoints
Primary Endpoint:  Net Adverse Clinical Events (NACE)
incidence: composite of death from any cause,
myocardial infarction (MI), ischemic stroke,
systemic thromboembolic event (SEE), valve
thrombosis, or major bleeding
o Major bleeding defined according to
International Society on
Thrombosis and Haemostasis
(ISTH) as a decrease in Hgb by ≥2
g/dL, requirement of ≥ 2 units whole
blood or PRBCs, intracranial,
intraspinal, pericardial bleeding, or a
fatal outcome

5. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Primary and Secondary
Endpoints
Statistical Test:  Primary analysis was performed in the
intention-to-treat (ITT) population
 Cumulative event-free survival was
estimated with Kaplan-Meier curves; a Cox
proportional-hazards regression was used
to analyze time from randomization to the
first outcome occurrence and generate HRs
with 95% CIs.
o Factors: Treatment arm,
randomization strata
(absence/presence of antiplatelet
medication and whether edoxaban was
dose-adjusted).
o The proportionality assumption was
tested with log-minus-log survival
curves, and the assumption was
upheld.
 A four-step hierarchical testing strategy
was used for the primary endpoints
o Testing conducted sequentially for
primary outcome noninferiority
major bleeding noninferiority-
major bleeding superiority primary
outcome superiority.
 Noninferiority would be established if the
upper bounds of the 95% CI did not exceed
1.38.
Secondary
Endpoint(s):
 Composite of all cause death, MI, ischemic
stroke, valve thrombosis, major bleeding and
SEE
 Cardiovascular (CV) death
 Ischemic stroke
 Hemorrhagic Stroke
 Fatal stroke
 SEE
 MI
Statistical Test: The secondary endpoint was analyzed in the ITT
population the same way as the primary endpoint;
however, the comparisons focused on superiority, and
a hierarchical analysis was NOT conduced.
Safety Endpoint(s) Endpoint:  All safety endpoints were conducted in the

6. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
ITT population.
 Primary
o Major bleeding defined according to
ISTH.
 Secondary
o Bleeding defined as TIMI major or
minor,
BARC 3 or 5, Gusto moderate
or severe
o Fatal bleeding
o Intracranial hemorrhage
o CV death
o All-cause death
Statistical Test: Descriptive statistics summarized the safety
outcomes.
Additional Statistical
Analyses
 The researchers estimated 320 events in 1400 patients would be
needed to be demonstrate noninferiority of edoxaban to VKAs with a
power of 80% and a two-sided significance level of 0.05.
o α= 0.05
o β = 0.2
RESULTS
Total Enrollment  A total of 1426 patients were randomized between April 2017-
January 2020 (ITT population), and 713 patients were assigned per
arm.
 173 centers in 14 countries: North America, Asia, Europe
 Throughout the trial period, 215 patients (30.2%) and 289 patients
(40.5%) of patients discontinued edoxaban and the VKA
respectively.
o Adverse event/suspected clinical event: 112 (15.7%) in the
edoxaban group, 97 (13.6%) in the VKA group.
o Discontinued by the patient: 63 (8.8%) in the edoxaban group,
126 (17.7%) in the VKA group.
 Median days of follow-up: edoxaban-554, VKA-530.
Baseline characteristics  ITT groups well matched
 Mean age: 82 years old
 Female: Edoxaban 49%, VKA 46%
 White: ~83%
 Asian: ~13%
 Creatinine clearance: ~58 +/- 24 mL/min
 Incident (new onset) AF: ~1%
 Mean CHA2DS2-VASc score in both groups: 4.5; Median (IQR) 4 (4-
5)
 Mean surgical 30-day mortality risk score1
4.9%
 Concomitant use of OAP: edoxaban 46%, VKA 50.4%
 Indication for edoxaban dose adjustment: ~46%
 History of coronary artery disease: ~42%
* Society of Thoracic Surgeons (STS) short-term risk score, < 4% is considered low risk, 4-8% intermediate risk,
and > 8% high risk

7. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Efficacy Primary:
 NACE:
o Edoxaban-170 patients (17.3/100 person-years); VKA-157
patients (16.5/100 person-years); HR 1.05; 95% CI 0.85-
1.31; P=0.001 for non-inferiority.
Secondary:
 Superiority was not demonstrated in any of the outcomes
o Death from any cause
o Death from CV causes
o Ischemic stroke
o Intracranial hemorrhage
Safety/Adverse Events Primary
 Major bleeding:
o Edoxaban-98 patients (9.7/100 person-years); VKA-68
patients (7.0/100 person-years); HR 1.40; 95% CI 1.03-1.91;
P=0.93 for non-inferiority.
o Number needed to harm (NNH)=~24 people
Secondary:
 GI bleeding
o Edoxaban- 56 (5.4 per 100 person-years) vs. 27 (2.7 per 100
person-years); HR 2.03, 95% CI, 1.28-3.22
 Subgroup analysis: Major bleeding and GI bleeding in patients
OAP
o Major bleeding significantly greater (HR >1) in patients OAP
assigned edoxaban.
o Major GI bleeding significantly greater (HR >1) in patients on
edoxaban IRRESPECTIVE of whether patients were on OAP.
AUTHORS’ CONCLUSIONS
Based on the 95% CI, edoxaban was noninferior to VKAs with respect to NACE. Edoxaban was
associated with more major bleeding rates, which was mainly due to increased GI bleeding rates.
Incidences of intracranial hemorrhage or fatal bleeding were low and similar in the two arms.
CRITIQUE/DISCUSSION
Patient Population Strengths:  Baseline characteristics were evenly distributed.
 High number of patients were enrolled and randomized.
Limitations
:
 Since 99% of patients enrolled had prevalent atrial
fibrillation before TAVR, the results are mainly
applicable to this population group. External validity is
limited to be able to draw conclusions in patients who
develop new-onset atrial fibrillation after TAVR.
 Approximately half the patients in each arm were
concomitantly taking antiplatelets, and higher major
bleeding rates with edoxaban were found to be
associated in patients OAP in the subgroup analysis.
Any beneficial outcomes with edoxaban may thus be
limited to a specific set of patients.

8. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Intervention Strengths:  Randomization with stratification
Limitations
:
 The open-label design without the use of sham INR
values to preserve blinding in the edoxaban arm
introduces potential bias.
Endpoints Strengths:  The endpoints are clinically meaningful in the context
of AF.
 Independent, blinded adjudication of the endpoints.
Limitations
:
 The grouping of a safety endpoint (major bleeding) in
the composite outcomes (e.g., NACE incidence)
weakens the internal validity of the trial.
 Lack of long-term follow-up and outcomes.
Statistics Strengths:  Hierarchical testing of the primary endpoint.
 The upper boundary threshold of the 95% CI is
consistent with other trials comparing DOACs to
warfarin in AF.7,12,13
Limitations  The researchers did not conduct the noninferiority
analysis in a per-protocol population.
CONCLUSION AND RECOMMENDATIONS
Presenter’s Discussion
and Conclusion
ENVISAGE-TAVI provides evidence in favor of selecting either edoxaban
or a VKA in older, moderate surgical risk patients with AF after TAVR. This
study is consistent with prior findings in ENGAGE AF-TIMI 48 that
provided evidence in support of using edoxaban in AF. However, this trial is
unique in that it analyzed edoxaban versus a VKA in patients with AF after
TAVR. The safety findings deviated from ENGAGE AF-TIMI as the
edoxaban arm exhibited higher rates of fatal and GI bleeding, which may
further be increased in patients on OAP. Higher rates of bleeding with a
DOAC is not a new phenomenon; ROCKET-AF13
revealed greater rates of
GI bleeding with rivaroxaban when compared to warfarin. Increased rates of
bleeding with concurrent use of OAP and anticoagulants are also consistent
with previous findings.14

9. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
Application to Patient
Care
On the basis of this trial, I would recommend either a DOAC or a VKA in
patients with AF after TAVR who are not taking concomitant OAP. Patients
at high risk of bleeding (e.g., coronary stent patients on OAP, prior history of
GI bleeds), would be more appropriate for a VKA. These recommendations
may not be applicable to younger patients or those with a high surgical
mortality risk.
References:
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Replacement Programs: Clinical Outcomes and Developments. J Am Heart Assoc.
2020;9(8):e015921. doi:10.1161/JAHA.120.015921
2. Fassa AA, Himbert D, Vahanian A. Mechanisms and management of TAVR-related
complications. Nat Rev Cardiol. 2013;10(12):685-695. doi:10.1038/nrcardio.2013.156
3. Biviano AB, Nazif T, Dizon J, et al. Atrial Fibrillation Is Associated With Increased
Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the
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2016;9(1):e002766. doi:10.1161/CIRCINTERVENTIONS.115.002766
4. Amat-Santos IJ, Rodés-Cabau J, Urena M, et al. Incidence, predictive factors, and prognostic
value of new-onset atrial fibrillation following transcatheter aortic valve implantation. J Am
Coll Cardiol. 2012;59(2):178-188. doi:10.1016/j.jacc.2011.09.061
5. Ryan T, Grindal A, Jinah R, et al. New-Onset Atrial Fibrillation After Transcatheter Aortic
Valve Replacement: A Systematic Review and Meta-Analysis. JACC Cardiovasc Interv.
2022;15(6):603-613. doi:10.1016/j.jcin.2022.01.018
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of Patients With Valvular Heart Disease: A Report of the American College of
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Atrial Fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039

10. JOURNAL CLUB Anna Sandler, PharmD Candidate, ‘2023
8. Guedeney P, Mehran R, Collet JP, Claessen BE, ten Berg J, Dangas GD. Antithrombotic
Therapy After Transcatheter Aortic Valve Replacement. Circ Cardiovasc Interv.
2019;12(1):e007411. doi:10.1161/CIRCINTERVENTIONS.118.007411
9. Product Information: Jantoven (warfarin sodium) tablets, for oral use. Published online 2011.
10. Product Information: Savaysa (edoxaban) tablets for oral use. Published online 2015.
11. Didier R, Lhermusier T, Auffret V, et al. TAVR Patients Requiring Anticoagulation: Direct
Oral Anticoagulant or Vitamin K Antagonist? JACC Cardiovasc Interv. 2021;14(15):1704-
1713. doi:10.1016/j.jcin.2021.05.025
12. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with
Atrial Fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907
13. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial
Fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
14. Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without Clopidogrel after
Transcatheter Aortic-Valve Implantation. N Engl J Med. 2020;382(18):1696-1707.
doi:10.1056/NEJMoa1915152