The study evaluated the efficacy and safety of rivaroxaban compared to vitamin K antagonists for stroke prevention in patients with rheumatic heart disease-associated atrial fibrillation (RHD-AF). Over 4565 patients from 24 countries were randomized to receive either rivaroxaban 20 mg daily or a vitamin K antagonist such as warfarin, with a mean follow up of 3.1 years. The primary outcome occurred in 560 patients (8.21% per year) in the rivaroxaban group and 446 patients (6.49% per year) in the vitamin K antagonist group, showing rivaroxaban to be less effective with a hazard ratio of 1.25. There were no significant

1. Anna Sandler, PharmD Candidate ‘2023
10.24.2022
1
BACKGROUND
Title  Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in Rheumatic Heart
Disease–Associated Atrial Fibrillation. N Engl J Med. 2022;387(11):978-988.
doi:10.1056/NEJMoa2209051
Background  Rheumatic heart disease (RHD) is a condition of permanent heart valve damage
that arises as a long-term sequela to an under-treated group A Streptococcus
(GAS) pharyngitis infection.
 RHD is the most critical form of acquired heart disease in children and young
adults living in resource-limited countries.1
 Approximately 40 million people worldwide are affected by RHD, and over
250,000 deaths are attributable to the disease each year.2,3
 Over time, valvular disease leads to stretching of the myocardium and slowing of
conduction velocity, creating a milieu for the development of atrial fibrillation
(AF).1
 Randomized trials that have established the efficacy and safety of direct oral
anticoagulants (DOACs) and vitamin K antagonists (VKAs) for stroke
prevention in patients with AF excluded those with RHD.
 Patients with RHD-associated AF (RHF-AF) tend to be younger and have more
advanced valvular disease than other patients with AF; as such, guidelines do not
recommend non-vitamin K antagonist oral anticoagulants for stroke prevention
in this group of patients.4–6
 The use of a DOAC in RHD-AF may lead to better health outcomes in areas
where frequent INR monitoring is not feasible due to limited health care
resources.
 Direct oral anticoagulant: Rivaroxaban (Xarelto®
)
 Indications: venous thromboembolism (VTE), peripheral artery disease,
coronary artery disease, Nonvalvular AF
 Mechanism of action (MOA): Factor Xa inhibitor Inhibition of
coagulation cascade
 Dosing in AF: 20 mg PO once daily with food
 Dose adjustments:
 CrCl 15-50 mL/min: 15 mg once daily
 CrCl < 15 mL/min: avoid use
 Avoid use in moderate to severe hepatic impairment
(Child-Pugh class B or C)
 Pharmacokinetics/Pharmacodynamics (PK/PD)
 Absorption: Rapid, 20 mg bioavailability (F) > 66% with
food, time to peak plasma 2-4 hours
 Distribution: Vd 50 L, ~92-95% protein bound (albumin)
 Metabolism: Hepatic CYP3A4/5 and CYP2J2
 Excretion: Urine (66%), feces (28%), Adult half-life (t1/2):
5-9 hours
 Contraindications (CIs)/Black box warning (BBW): Premature
discontinuation, spinal/epidural hematomas,
 Monitoring: Adverse effects (AEs): bleeding, increased LFTs
 Vitamin K antagonist: Warfarin (Coumadin®
, Jantoven®
)
 MOA: Inhibits vitamin K epoxide reductase  less activated vitamin K
decreased production of vitamin K-dependent clotting factors (II, VII, IX,
X)

2.  Dosing in AF: Most patients start at 5 mg PO once daily
 PK/PD:
 Absorption: rapid, complete
 Onset: Full effect generally seen 5-7 days after initiation
 Distribution: 99% protein-bound, Vd = 0.14 L/kg,
 Metabolism: (S) enantiomer: CYP2C9, CYP3A4;
(R) enantiomer: CYP 1A2, CYP3A4
 Excretion: Urine (92% mainly as metabolites), t1/2 20-
60 hours
 CIs/BBW: Major or fatal bleeding, monitoring and patient education
 Monitoring: Extensive INR checks, any changes in well-being, lifestyle,
social factors, medications, diet, liver and renal function,
?pharmacogenomics
Previous trials 2011: Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation
(ROCKET-AF trial)7
 Randomized double-blind non-inferiority trial comparing rivaroxaban to
warfarin for the prevention of stroke or systemic embolism in patients with
nonvalvular atrial fibrillation
 Rivaroxaban shown to be non-inferior in preventing the primary outcome;
hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.66-0.96; P <
0.001
 Limitations: Exclusions of patients with RHD and valvular AF
2017: Effects of Non-Vitamin K Antagonist Oral Anticoagulants Versus
Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: A
Systematic Review and Meta-Analysis8
 DOACs reduced stroke or systemic embolism (SE): HR 0.70; 95% CI
0.60-0.82 and intracranial hemorrhage: HR 0.47; 95% CI 0.24-0.92 in
patients with AF and NATIVE valvular heart disease
 Limitations: Retrospective pooled analysis, not specific to RHD-AF
Why this study?  DOACs may optimize RHD-AF outcomes in areas where frequent INR
monitoring is not feasible due to resource restraints, but there is a lack of safety
and efficacy data in this population
GENERAL STUDY OVERVIEW
Objectives  Evaluate the efficacy and safety of factor Xa inhibitor rivaroxaban as compared
with vitamin K antagonist therapy in patients with RHD-AF
Trial design  International, randomized, open-label, non-inferiority trial
Null Hypothesis  Rivaroxaban is not non-inferior to vitamin K antagonist therapy for the
prevention of total stroke, systemic embolism, myocardial infarction (MI), or
death
Funding Source  Funded by Bayer
METHODS
Inclusion criteria  ≥ 18 years old
 Confirmed RHD via echocardiography
 Documented AF or atrial flutter at any time
 At least one of the following: CHA2DS2VASc ≥ 2, mitral stenosis with mitral-
valve area ≤ 2 cm2
, echocardiographic evidence of left atrial spontaneous echo
contrast or left atrial thrombus
Exclusion criteria  Mechanical heart valve or likelihood of receiving one within 6 months
 Use of dual antiplatelet therapy
 Treatment with dual strong CYP3A4 and P-glycoprotein inhibitors
 Severe renal insufficiency (eGFR < 15 mL/min)
 Pregnancy or lack of effective contraception in women of child-bearing age

3. Anna Sandler, PharmD Candidate ‘2023
10.24.2022
3
Interventions + Control  Patients randomized with stratification according to site
 Patients randomly assigned 1:1 to receive rivaroxaban 20 mg daily or locally
available VKA
 Rivaroxaban 15 mg daily if CrCl < 50 mL/min
 No less than monthly INR monitoring for VKA group, INR goal 2.0-3.0, goal
time in range: ≥ 55%
 Follow-up: 1 month after randomization and every 6 months thereafter
 Patients switched to VKA if undergoing valve-replacement (cross-over)
Primary + Secondary
Endpoints
Primary Endpoint:  Composite: stroke, systemic embolism,
myocardial infarction (MI), or death from
vascular (cardiac or noncardiac) or unknown
causes
Statistical Test:  Kaplan-Meier curves analyzed with proportional-
hazards model adjusted for site
 Restricted mean survival time (RMST) analysis If
strong evidence of nonproportionality (difference
in RMST)
 Generated HRs and 95% CIs with an upper
boundary for noninferiority of 1.1869
 Superiority testing if noninferiority
demonstrated
Secondary
Endpoint(s):
 Composite: stroke (Ischemic, hemorrhagic,
unknown causes) or systemic embolism
 MI
 Death from vascular causes and nonvascular
causes
Statistical Test:  Same as for the primary outcome
Safety Endpoint(s) Endpoint:  Major bleeding as defined by the International
Society of Thrombosis and Hemostasis
Statistical Test:  Same as for the efficacy outcomes
 Descriptive statistics
Additional Statistical
Analyses
 Efficacy analyses performed in the intention-to-treat (ITT) group AND in the
on-treatment group (patients receiving ≥ 1 dose of treatment + events
occurring UP TO 5 days post discontinuation of trial drug)
 Safety outcomes analyzed in the on-treatment group
 Power analysis: 1078 total primary outcomes to have 80% power after
adjustment for lower stroke rate
 Two interim analyses planned to evaluate possibility of greater-than-expected
efficacy
RESULTS
Timeline and Total
Enrollment
 Aug 2016-Sep 2019
 Total of 4565 patients enrolled from 138 trial sites across 24 countries (Africa
Asia, Latin America)
 Feb 4, 2022: Data Safety & Monitoring Board recommended termination as
primary question had been satisfactorily answered

4.  Mean duration of follow-up: 3.1 +/- 1.2 years
Baseline characteristics  Rivaroxaban: n = 2292; VKA: n = 2273
 ITT population: n = 4531; rivaroxaban: n = 2275; VKA: n = 2256
 Groups well balanced
 Mean age (yr): ~ 50 +/- 15
 Female (%): ~ 72
 Black African (%): ~ 25
 South Asian (%): ~18
 Arab (%): ~17
 Chinese (%): ~ 5
 Latin American (%): ~ 8
 CrCl (ml/min, +/- SD): ~ 80 +/- 30
 Congestive HF (%): 39
 Hypertension (HTN) (%): ~24
 Coronary artery disease (CAD) (%): ~1
 Stroke (%): ~11
 TIA (%): ~3
 Mitral-valve repair (%): ~ 3
 CHA2DS2VASc ≥ 2 (%): ~ 57
 CHA2DS2VASc score (+/- SD): ~ 2.0 +/- 1.4
 CHA2DS2VASc ≥ 2 score as only criterion (%): ~15
 Moderate-to-severe mitral stenosis (%): ~ 82
 Present mitral-valve regurgitation (%): ~ 85
 Diuretic (%): ~85
 Beta-blocker (%): ~71-73
 VKA (%): ~52-53
 Digoxin (%): ~43-41
 ACE inhibitor or ARB (%): ~29-28
VKA monitoring  Most patients received warfarin, other VKA: acenocoumarol
 Therapeutic INR (2.0-3.0) (% patients)
o Before enrollment: 33
o 6 months: 56
o 1 year: 59
o 2 years: 65
o 3 years: 65
Compliance  Higher discontinuation rates in rivaroxaban group (4-year retention: 79.0% and
96.4% in rivaroxaban and VKA groups respectively)
 Most common reasons: valve surgery-crossover, patient decision, non-serious
AE, hospitalization,
Primary outcome:
(ITT: Riva n= 2275; VKA
n= 2256)
 Rivaroxaban: 560 (8.21%/yr),VKA: 446 (6.49%/yr); HR 1.25; 95% CI 1.10-
1.41
 Number needed to harm (NNH) ~21
 Difference in RMST: -76; 95% CI -121 to -31; (P < 0.001 for superiority)
 Similar trends in the on-treatment analysis
Secondary outcomes
(ITT: Riva n= 2275; VKA
n= 2256)
 Stroke or systemic embolism- Rivaroxaban: 94 (1.38%/yr), VKA 75 (1.09%/yr);
HR 1.24 (95% CI 0.92-1.68)
 Ischemic stroke-Rivaroxaban 74 (1.08%/yr), VKA 48 (0.70%/yr); HR 1.53
(95% CI 1.06-2.20); NNH ~89
 Death due to vascular causes-Rivaroxaban: 439 (6.33%/yr), VKA 337
(4.84%/yr); HR 1.29 (95% CI 1.12-1.49); NNH ~23
 Non-significant differences in hemorrhagic stroke, death due to nonvascular
causes or hospitalizations

5. Anna Sandler, PharmD Candidate ‘2023
10.24.2022
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Safety/Adverse Events
(On-treatment: Riva n=
2265; VKA n= 2251)
 Non-significant differences in major bleeding, intracranial hemorrhage, or
life-threatening bleeding between groups
 Fatal bleeding- Rivaroxaban 4 (0.07%/yr), VKA 15 (0.22%/yr); HR 0.29 (0.10-
0.88); Number needed to treat ~ 204
AUTHORS’ CONCLUSIONS
The data revealed that compared with rivaroxaban, VKA therapy led to a lower rate of ischemic stroke among
patients with RHD-AF and lower mortality due to vascular causes without increasing the rate of major bleeding.
The results of the present trial were unexpected. Observed differences in stroke or mortality were not expected. The
trial may have been underpowered to observe the expected stroke rates, suggesting the difference may be due to
chance. The rate of stroke or systemic embolism did not differ between the treatment groups while the difference in
mortality was large and thus unlikely to be due to chance. Potential explanations for fewer strokes and deaths in the
VKA group include more frequent physician visits and higher adherence to the VKA given need for frequent
monitoring. Ultimately the results of the trial support the current guidelines in their recommendation of VKA
therapy for the prevention of stroke in patients with RHD-AF.
CRITIQUE/DISCUSSION
Population Strengths  Multicenter and International
 Inclusion of patients with valvular AF (mitral stenosis)6,10
 High n
Limitations  Low representation of higher CHA2DS2VASc scores
 Low representation of other disease states: CAD, CrCl, HTN
Intervention Strengths:  Randomization with stratification according to site
 Longer duration of follow-up
Limitations  Cross-over from rivaroxaban  VKA
 Unclear how patients were transitioned from baseline non-study
VKA  rivaroxaban
 Open-label
 Patients likely not bridged to therapeutic INR if assigned to
VKA
 Less frequent initial INR monitoring
Endpoints Strengths:  Independently and blindly adjudicated by expert committee
 Clinically meaningful and consistent with previous trials
Limitations:  Inclusion of hemorrhagic stroke in composite outcome,
potentially favoring rivaroxaban > VKA7
Statistics Strengths:  Conducted a competing-risk analysis of the primary outcome
 Analyzed results in the on-treatment group to account for
potential cross-over effects from rivaroxaban VKA
Limitations:  Results were not analyzed in the per protocol group
 Researchers did not correct for multiplicity when testing
secondary or other outcomes
CONCLUSION AND RECOMMENDATIONS

6. Presenter’s Discussion and
Conclusion
The results of the current trial were unexpected based on previous studies, favoring
the current guideline recommendations to use VKAs over DOACs in RHD-AF.
INVICTUS was a larger multi-center trial that adequately represented a RHD-AF
population. This trial also followed patients for a longer period of time compared to
other trials. 7,11
The trial had strengths to provide sound results such as stratification
by site, testing in an on-treatment group, and conducting a competing risk analysis.
Notable limitations included absence of a double-dummy design with sham INRs to
preserve blinding and lack of specific details with respect to transitioning from
baseline VKA to rivaroxaban. It is worth noting that patients with comorbidities
such as HTN and CAD were not heavily represented, and the average renal function
was on the higher end.
It would be interesting to study DOACs inn patients with RHD-AF who only have
an elevated CHA2DS2VASc score without moderate-severe valvular stenosis or
regurgitation.
Application to Patient Care On the basis of this trial and current guidelines, I would use VKA therapy over
DOACs for stroke prevention in patients with RHD – AF.

7. Anna Sandler, PharmD Candidate ‘2023
10.24.2022
7
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