Journal Club

Emily Harvath, PharmD

Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial
Fibrillation. N Engl J Med. 2022 Sep 15;387(11):978-988. doi: 10.1056/NEJMoa2209051.
Background and Overview
Background - Current ACC/AHA Guidelines recommend use of NOACs over warfarin in fibrillation patients (except those
with mitral stenosis or mechanical valve) for those with CHA2DS2VASc ≥ 2 in men or ≥ 3 in women.1
- The REALIGN Trial looked at dabigatran in atrial fibrillation patients with mechanical mitral valve and found
higher risk of stroke and bleeding in the dabigatran group. Study included 252 patients, and stroke occurred in 9
patients and MI in 3 patients in the dabigatran group with no events in the warfarin group. Bleeding occurred in
45 dabigatran patients and 10 warfarin patients.2
- ACC/AHA atrial fibrillation guidelines state that dabigatran should not be used in patients with mechanical
mitral valve because they cause harm. They recommend warfarin as first line for patients with mechanical heart
valve.2
- ACC Guidelines state that chronic rheumatic heart disease (RHD) can be prevented with adequate early
identification and manamgement of rheumatic fever. First line management for acute rheumatic fever/rheumatic
heart disease is secondary prevention with continuous antibiotic prophylaxis to prevent recurrent infection with
Group A streptococcus.3
- Per ACC guidelines, for RHD with atrial fibrillation or flutter, anticoagulation with oral vitamin K antagonists
or direct oral anticoagulants is still recommended. However, the INVICTUS-VKA study is currently evaluating
noninferiority of rivaroxaban to warfarin.3
Funding The trial was designed, conducted, analyzed, and reported by the Population Health Research Institute.
This research was funded by an unrestricted grant from Bayer.
Objective To evaluate the efficacy and safety of rivaroxaban, as compared with vitamin K antagonist therapy, in patients
with rheumatic heart disease-associated atrial fibrillation in Africa, Asia, and Latin America
Methods
Study design - Randomized, noninferiority, event-driven trial conducted at 138 sites across 24 countries
- Patients were randomized in a 1:1 ratio to each treatment group
- Randomization was stratified according to site
- Open label with blinded assessment of outcomes
- Efficacy and safety outcomes were independently adjudicated
Inclusion & Inclusion: Exclusion:
Exclusion - Age ≥ 18 years - Presence of mechanical heart valve
- ECHO-proven rheumatic heart disease with atrial - Use of dual antiplatelet therapy
fibrillation or atrial flutter at any time - Treatment with strong CYP3A4 inhibitors and P-
- At least one of the following met: glycoprotein inhibitors
- CHA2DS2VASc ≥ 2 - eGFR < 15 mL/min
- Mitral stenosis w/ mitral valve area of ≤ 2 cm2 - Women of child-bearing age not on contraception
- Left atrial thrombus
Treatment Plan - Rivaroxaban group received 20mg daily if CrCl ≥ 50 mL/min
- 15mg daily if CrCl < 50 mL/min
- Vitamin K Antagonist (VKA) group received any locally approved VKA with an INR goal of 2-3
- INR was expected to be options no less than monthly
- Adherence to rivaroxaban was assessed by comparison of the number of pills administered with pill counts
made at each visit. No pill counts were done in patients assigned to VKA treatment.
Outcomes The original primary endpoint was a composite of stroke and systemic embolism. Overall rate of stroke was much
lower than expected and overall mortality was much higher than expected. Midway through the trial it was
deemed impractical to wait to achieve enough stroke events, and the trial steering committee opted to adopt the
below endpoints based on the ACTIVE W Trial
Primary Endpoint:
- Composite of stroke, systemic embolism, myocardial infarction, or death from any causes
Secondary Endpoints:
- Primary safety outcome of major bleeding
Statistical - Primary outcome was assessed in a time-to-event analysis
Analysis - A target number of 1079 primary outcome events would provide 80% power to detect a hazard ratio of 1.186 for
the primary outcome
- Two interim analyses of efficacy were planned, with a difference in favor of treatment greater than 4 standard
deviations at the first analysis or 3 standard deviations at the second analysis would warrant discontinuation of the
trial due to greater-than-expected efficacy. Trial was ultimate terminated early at the recommendation of the data
 and safety monitoring board because the primary question addressed by the trial had been satisfactorily answered.
- Intention-to-treat analysis was used
Results
Baseline - Of the 4,565 eligible patients who underwent randomization, 4,531 patients were included in the intent-to-treat
Characteristics analysis. Final vital status was known for 4,379 patients.
- The mean age of patients was 50.5 years, and 72.3% were women
- Moderate to severe mitral stenosis was present in 81.9% of patients
- Nearly half the patients had a CHA2DS2VASc < 2
- In the VKA Treatment group
- 79-85% of patients were treated with warfarin
- Almost all other patients were treated with Acenocoumarol
- Baseline INR was therapeutic in 33.2% of patients
Primary & Primary Endpoint:
Secondary - A primary outcome event occurred in 560 patients (24.6%) in the rivaroxaban group and 446 patients (19.8%) in
Endpoints the placebo group (HR 1.25; 95% CI 1.1 to 1.41; P value <0.001)
*More patients in the rivaroxaban group than VKA group experienced stroke (90 vs 65 patients)
*Endpoint was primarily driven by death (552/560 [98%] in rivaroxaban and 442/446 [99.1%] in VKA)
- Restricted mean survival time was 1,599 days in the rivaroxaban group and 1,675 days in the VKA group
(difference -76 days; 95% CI -121 to -31 days; P<0.001 for superiority)
- In the VKA group, INR was therapeutic in:
- 56.1% of patients at 6 months
- 59% of patients at 1 year
- 64.1% of patients at 4 years
- Mean adherence to rivaroxaban therapy was 83.7%±16.5%
Secondary Endpoints:
- Rates of major bleeding did not differ significantly between the two groups
*40 patients in rivaroxaban group vs 56 patients in VKA group (HR 0.76; 95% CI 0.51 to 1.15; P = 0.18)
Adverse Events - Rate of fatal bleeding was lower with rivaroxaban than with VKA (4 vs 15 patients)
- Rate of hemorrhagic stroke was equivalent between the two treatment groups (7 patients in each group)
- Discontinuation of therapy was higher in the rivaroxaban group
*96.4% of patients still receiving trial medication in the VKA group at 4 years
*79% of patients still receiving trial medication in the rivaroxaban group at 4 years
*Primary reasons for discontinuation: valve surgery (subsequently switched to VKA), patient decision
Author’s Among patients with rheumatic heart disease-associated atrial fibrillation, vitamin K antagonist therapy led to a
Conclusion lower rate of a composite of cardiovascular events or death than rivaroxaban therapy, without a higher rate of
bleeding.
 Critique
Journal and Authors:
- The New England Journal of Medicine is a peer reviewed journal with an impact factor of 91.25. 4 This impact factor is the highest
of all general medical journals.
Study Subjects:
- Asian and African patients were well represented in this study at ~40% and 25%, respectively. This increases generalizability.
- The majority of patients in the VKA group were treated with warfarin, thus increasing generalizability to the United States.
- Patients in this study were younger and more likely to be female than in previous studies of anticoagulation in atrial fibrillation not
associated with rheumatic heart disease. This profile aligns well with studied trends of atrial fibrillation in rheumatic heard disease. 5
- Baseline characteristics were evenly distributed between the two treatment groups, thus increasing internal validity.
Study Design:
- Multicenter trial design in multiple countries improves external validity.
- Open-label design decreases internal validity, but blinded outcome analysis helps to mitigate the issue
- Stratification of patients according to site increases internal validity.
- Requiring monthly INR checks at minimum increases internal validity and generalizability.
Outcome Measures:
- Changing outcome measures partially through the trial decreases internal validity
- The composite of stroke, systemic embolism, myocardial infarction, or death from any causes is appropriate for determining
noninferiority of rivaroxaban to VKA. Would have preferred that they use the same endpoint as ACTIVE W Trial with vascular
death as the marker rather than death from any cause.
Statistical Analysis:
- Intention-to-treat analysis was used, which is a conservative form of data analysis and therefore increases internal validity.
- The lack of a reported alpha level makes it difficult to interpret the reliability of the study’s efforts to minimize type I error.
- The power of 80% was appropriate to minimize type II error.
- Blinded analysis of outcomes increases internal validity
Results:
- By using a primary composite outcome, this study was not powered to evaluate any of the individual aspects of the composite
endpoint alone
- The results of this study support previous conclusions that onset of warfarin benefits is delayed over time.
- Debatable clinical relevance of 76 days of life over the course of a slow developing and life-long disease when considering the
relative pros and cons to selecting rivaroxaban vs VKA
- Percentage of achieving goal INR is similar to what would be expected in clinical practice, increasing generalizability of the study.
Noteworthy that the mortality benefit was seen even though only 64.1% of patients achieved INR goals at 4 years
- Adherence to rivaroxaban was very high at 83.7%, which increases internal validity
Overall Conclusion and Clinical Application:
- Rivaroxaban in rheumatic heart disease patients with atrial fibrillation results in higher mortality rates than VKA treatment without
a significant difference in major bleeding rates. NOACs such as Rivaroxaban should continue to be avoided for use in valvular atrial
fibrillation patients as well as rheumatic heart disease patients.

References:
1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014
AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the
American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines
and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019
Jul 9;140(2):e125-e151. doi: 10.1161/CIR.0000000000000665.
2. Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin
in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14. doi:
10.1056/NEJMoa1300615.
3. Kumar RK, Antunes MJ, Beaton A et al; American Heart Association Council on Lifelong Congenital
Heart Disease and Heart Health in the Young; Council on Cardiovascular and Stroke Nursing; and Council
on Clinical Cardiology. Contemporary Diagnosis and Management of Rheumatic Heart Disease:
Implications for Closing the Gap: A Scientific Statement From the American Heart Association.
Circulation. 2020 Nov 17;142(20):e337-e357. doi: 10.1161/CIR.0000000000000921.
4. InCites Journal Citation Reports. Clarivate Analytics. New England Journal of Medicine. Accessed on
September 10, 2021.
5. Sharma SK, Verma SH. A Clinical Evaluation of Atrial Fibrillation in Rheumatic Heart Disease. J Assoc
Physicians India. 2015 Jun;63(6):22-5. PMID: 26710395.