Rivaroxaban vs. Warfarin in Patients With Mechanical Heart Valves
Phase: PHASE3
Conditions: Valvular Heart Disease Patients
Sponsor: Rawalpindi Institute of Cardiology

COVER PAGE 
 
Title of Study: 
 
A Prospective Comparative Study of Rivaroxaban versus Warfarin in Patients 
with Mechanical Heart Valves 
 
NCT Number: 
 
NCT ID not yet assigned 
 
Date of Document: 
 
20th June, 2025 
 
 
 
 
 
 
 
 
 
 
 
STUDY SYNOPSIS 
Title 
A Prospective Comparative Study of Rivaroxaban versus Warfarin in Patients with 
Mechanical Heart Valves 
 
1. General Information 
Study Title 
Rivaroxaban versus Warfarin in Patients with Mechanical Heart Valves 
 
Principal Investigator 
Dr. Musfireh Siddiqeh 
Professor of Cardiac Surgery 

Executive Director 
Rawalpindi Institute of Cardiology 
Rawalpindi, Pakistan 
Contact: 051-9281374 
 
Study Site 
Department of Cardiac Surgery and Cardiology 
Rawalpindi Institute of Cardiology 
Rawalpindi, Pakistan 
 
Study Duration 
From regulatory approval until completion of one year of follow-up for the last enrolled 
participant. 
Approval granted on 12th Nov 2025 From DRAP Pakistan 
2. Background and Rationale 
Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical 
heart valves However, achieving the ideal balance between effective anticoagulation and 
minimal bleeding risks demands regular coagulation monitoring, potential dietary constraints, 
and vigilant drug interaction monitoring. Moreover, warfarin requires frequent INR 
monitoring, which may be difficult for patients in remote areas or those with limited access to 
healthcare facilities. Furthermore, warfarin therapy can be associated with bleeding and 
thromboembolic complications despite careful monitoring. As alternatives to warfarin, oral 
direct-acting factor Xa inhibitors have gained approval for venous thromboembolism 
prophylaxis, treatment, and the reduction of stroke and systemic embolization 

Rawalpindi Institute of Cardiology stands as a specialized cardiac training center where 
countless young and courageous patients undergo life-saving mechanical valve replacement 
surgeries. Yet their journey does not end in the operating room. After surgery, they must rely 
on lifelong anticoagulation, most commonly warfarin, which demands strict adherence and 
frequent INR monitoring. In Pakistan, a resource-limited country where INR facilities are 
scarce and often inaccessible, especially for patients traveling from remote and far-flung 
areas, this simple requirement becomes an overwhelming burden. Many rely on local general 
practitioners, unable to obtain regular INR testing, and as a result, they return to us in the 
emergency department with devastating complications such as stuck valves, leaving families 
shattered and clinicians forced to intervene urgently with treatments like streptokinase. These 
preventable tragedies form the emotional and clinical foundation of our trial. We seek a safer, 
more practical alternative, rivaroxaban, which does not require frequent INR monitoring and 
has fewer drug interactions. 
In a pilot study of four to five patients who either could not tolerate warfarin or could not 
access INR testing due to geographic and socioeconomic barriers, rivaroxaban allowed them 
to be followed for a full year without returning with such complications. Their stability and 
improved quality of life strengthened our resolve. It is this lived reality, of patients lost in the 
gaps of our healthcare system, that drives the significance of our study and fuels the need to 
explore rivaroxaban as a viable alternative to warfarin. Within this clinical trial, only patients 
who have experienced bleeding complications secondary to warfarin therapy, or who have 
presented to the emergency department with warfarin-related complications, are being 
enrolled. Such patients are transitioned to alternative anticoagulation therapy, including 
rivaroxaban, as clinically indicated. Additionally, patients with limited access to regular INR 
monitoring due to geographic or logistical constraints are included in the study. 
Rivaroxaban, a direct oral anticoagulant (DOAC), has been suggested as a potential 
alternative, as it does not require routine INR monitoring and may offer more convenient 
management. However, the safety and efficacy of rivaroxaban compared to warfarin in 
patients with mechanical heart valves remains inadequately explored, especially in terms of 
bleeding and thromboembolic complications. This study aims to compare these outcomes in 
patients switched from warfarin to rivaroxaban due to complications or inaccessibility to INR 
monitoring . we intend to prove use of rivoroxaban in metallic heart valves although it has 
already proven benefit in patients with DVT , pulmonary embolism. Our aim is to use tablet 
rivoroxaban in place of warfarin in patients with metallic heart valves with strict monitoring 
initially. If rivoroxaban can be used with same efficacy as warfarin we will make it a standard 
practice in our institute this will greatly help patients especially those who lack facility of 
frequent INR monitoring by blood samples and those who are unable to maintain optimal 
INR due to food and drug interactions. 
 
3. Review of Preclinical and Clinical Evidence 
Warfarin 

Warfarin inhibits vitamin K epoxide reductase, leading to reduced synthesis of vitamin K- 
dependent clotting factors II, VII, IX, and X, as well as proteins C and S. Its broad 
anticoagulant effect has proven efficacy in mechanical heart valves but requires close 
monitoring and dose adjustment. 
 
Rivaroxaban 
Rivaroxaban is a direct factor Xa inhibitor that blocks thrombin generation and fibrin 
formation. It has predictable pharmacokinetics, rapid onset of action, and does not require 
routine coagulation monitoring. 
 
Relevant Studies 
 
Pilot Mechanical Valve Study (NCT02128841): No thromboembolic or bleeding 
events over six months in low-risk patients receiving rivaroxaban. 
 
RIWA Trial: A randomized phase II/III pilot study comparing rivaroxaban and 
warfarin in mechanical heart valve patients; results pending. 
 
Preclinical Porcine Model: Demonstrated reduced valve thrombosis and platelet 
deposition with rivaroxaban. 
 
EINSTEIN-DVT and EINSTEIN-PE Trials: Established safety and efficacy of 
rivaroxaban in venous thromboembolism. 
 
These data support further investigation of rivaroxaban in mechanical heart valve patients 
under controlled conditions. 
 
4. Study Objectives 
Primary Objective 
To compare the incidence of thromboembolic and bleeding events over a 12-month period in 
patients with mechanical heart valves treated with rivaroxaban versus dose-adjusted warfarin. 
 
Secondary Objectives 
 
To assess the safety profile of rivaroxaban in this population. 
 
To evaluate treatment adherence and feasibility, particularly in patients with limited 
access to INR monitoring. 
 
To assess prosthetic valve function using serial echocardiographic measurements. 
 
5. Trial Design 
This is a single-center, prospective comparative study. 
 
Study Groups 
1. Rivaroxaban Group: 
Patients switched from warfarin to rivaroxaban due to warfarin-related complications 
or inability to maintain regular INR monitoring. 

2. Warfarin Group: 
Patients continuing dose-adjusted warfarin therapy with regular INR monitoring. 
 
Sample Size 
A total of 60 patients with mechanical heart valves: 
 
 
30 patients in the rivaroxaban group 
 
30 patients in the warfarin group 
 
Study Duration 
Each participant will be followed for 12 months. 
 
6. Selection and Withdrawal of Subjects 
Inclusion Criteria 
 
Age ≥18 years 
 
Mechanical aortic or mitral valve replacement 
 
History of thromboembolic or bleeding complications on warfarin, or limited access 
to INR monitoring 
 
Ability to provide informed consent 
 
Exclusion Criteria 
 
Contraindication to rivaroxaban 
 
Hemorrhagic stroke or ischemic stroke within the past 3 months 
 
Severe renal impairment (creatinine clearance <30 mL/min) 
 
Known bleeding disorders or high bleeding risk 
 
Withdrawal Criteria 
 
Occurrence of a serious adverse event requiring discontinuation 
 
Non-compliance with treatment or follow-up 
 
Withdrawal of consent 
 
7. Treatment of Subjects 
Rivaroxaban Group 
 
Rivaroxaban 20 mg once daily with aspirin 75 mg once daily 
 
Patients weighing >80 kg may receive rivaroxaban 15 mg twice daily 
 
Warfarin Group 
 
Dose-adjusted warfarin therapy 
 
Target INR range: 2.5–3.5 

 
Regular INR monitoring per standard guidelines 
 
8. Assessment of Efficacy 
Efficacy will be assessed by the incidence of: 
 
 
Thromboembolic events (stroke, TIA, valve thrombosis, DVT, PE) 
 
Major and minor bleeding events 
 
Major bleeding is defined as bleeding requiring medical intervention or hospitalization. 
Minor bleeding includes less severe bleeding not requiring intervention. 
 
9. Assessment of Safety 
Safety assessments include: 
 
 
Monitoring of adverse events 
 
Laboratory evaluations (renal function, liver enzymes, hematologic parameters) 
 
Serial echocardiographic evaluation of valve gradients and function 
All serious adverse events will be documented and reviewed. 
A Data Safety Monitoring Board (DSMB) will oversee patient safety and trial integrity. 
 
10. Ethical Considerations 
 
The study will comply with the Declaration of Helsinki and GCP guidelines 
 
Approval will be obtained from the Institutional Review Board/Ethics Committee 
 
Regulatory approval from DRAP and NBC will be secured 
 
Written informed consent will be obtained from all participants 
 
Patient confidentiality will be maintained 
 
11. Data Handling and Record Keeping 
 
Data will be collected using pre-designed case report forms 
 
Stored in a secure electronic database 
 
Records will be retained for at least five years 
 
Access limited to authorized personnel 
 
12. Financing and Insurance 
 
Medications and investigations will be provided by the hospital 
 
Echocardiography and follow-up visits covered by institutional resources 
 
Management of complications will be provided by the hospital 
 
13. Publication Policy 

 
Results will be published in peer-reviewed journals 
 
Findings will be presented at scientific meetings 
 
Authorship will follow standard ethical guidelines 
 
14. Detailed Plan of Action Flow Diagram 
 
RIVAROXABAN (XCEPT GROUP) 
WARFARIN GROUP 
Eligibility confirmed 
• Mechanical valve 
• Warfarin-related complication OR poor 
INR access 
Baseline: 
• Clinical exam 
• Labs (Hb, platelets, creatinine, LFTs) 
• Baseline Echocardiography 
Eligibility confirmed 
• Mechanical valve 
• Suitable for warfarin 
Baseline: 
• Clinical exam 
• Labs (Hb, platelets, creatinine, LFTs) 
• Baseline Echocardiography 
Initiation of XCEPT Protocol 
• Rivaroxaban 20 mg OD + Aspirin 75 mg 
• >80 kg: 15 mg BD 
• No routine INR monitoring 
Warfarin Initiation / Continuation 
• Dose-adjusted warfarin 
• Target INR 2.5–3.5 
• Regular INR monitoring 
Early Safety Phase (Day 0–15) 
• Bleeding assessment 
• Thromboembolic symptoms 
• Renal & hepatic function if indicated 
Early Safety Phase (Day 0–15) 
• INR monitoring & dose adjustment 
• Bleeding / thromboembolism assessment 
Echocardiography Schedule 
• Baseline 
• Day 15 
• Monthly up to 12 months 
(Valve gradients, leaflet motion, 
thrombus, LVEF) 
Echocardiography Schedule 
• Baseline 
• Monthly up to 12 months 
(Valve gradients, leaflet motion, 
thrombus, LVEF) 
Adverse Event Pathway 
• Major bleed / thrombosis → 
Hospitalization (length of hospital/ICU 
stay/frequency of hospital visits) 
• Warfarin dose modification 
• Drug adjustment or discontinuation 
• DSMB review 
Adverse Event Pathway 
• Major bleed / thrombosis → 
Hospitalization (length of hospital/ICU 
stay/frequency of hospital visits) 
• Warfarin dose modification 
• DSMB review 
Final Outcome Assessment at 12 Months 
• Thromboembolic events 
• Major & minor bleeding 
• Prosthetic valve function 
 
Hospitalization (frequency and length of stay) 
• Mortality & treatment adherence 

15. Statistical Analysis Plan 
This study will be conducted as an experimental comparative study with a total sample size 
of 60 patients, with 30 patients allocated to each treatment group. Statistical analysis will be 
performed using IBM SPSS Statistics. A p-value < 0.05 will be considered statistically 
significant, and all tests will be two-tailed. 
 
 
 
Variables 
 
Continuous Variables 
 
Age, body mass index, baseline international normalized ratio (INR), hemoglobin level, 
platelet count, serum creatinine, peak and mean transvalvular gradients, left ventricular 
ejection fraction (LVEF), and pulmonary artery systolic pressure (PASP) will be analyzed as 
continuous variables. 
 
Categorical Variables 
 
Gender, type of mechanical valve, study group (rivaroxaban or warfarin), comorbidities, 
previous thromboembolic events, previous bleeding events, presence of thrombus or pannus, 
valve leaflet motion, degree of regurgitation, bleeding events, thromboembolic events, 
hospitalization, and mortality at 12 months will be analyzed as categorical variables. 
 
Descriptive Statistics 
 
Continuous variables will be summarized as mean ± standard deviation for normally 
distributed data and as median with interquartile range for non-normally distributed data. 
Categorical variables will be expressed as frequencies and percentages. 
 
Normality Testing 
 
Given the small sample size, non-parametric tests will be predominantly used for the 
analysis of continuous variables. Normality will be formally assessed using the Shapiro– 
Wilk test for key continuous variables, including: 
 
 
Age 
 
Body mass index 
 
Baseline INR 
 
Mean transvalvular gradient 
 
Left ventricular ejection fraction (LVEF) 
 
Based on the results of the normality testing, appropriate parametric or non-parametric 
statistical tests will be applied. 
 
Comparison Between Groups 
Continuous Variables 

 
The independent samples t-test will be used for normally distributed variables. 
 
The Mann–Whitney U test will be used for non-normally distributed variables. 
 
Categorical Variables 
 
 
The chi-square test will be applied 
Analysis of Outcomes 
Thromboembolic events and bleeding events will be compared between the two groups 
using Fisher’s exact test. Echocardiographic parameters over follow-up will be 
analyzed using the Friedman test, with repeated measures ANOVA being used only when 
normality assumptions are satisfied.