Mitral StenosisPhase 3RISE MSNCT03926156
RIvoraxaban in Mitral Stenosis
A Phase 3 study testing Rivaroxaban and Warfarin in people with Mitral Stenosis and Rheumatic Heart Disease, run by Rajaie Cardiovascular Medical and Research Center at 1 site in Iran.
Trial summary
In this randomized controlled clinical trial, patients with moderate to severe mitral valve stenosis (MS) and atrial fibrillation (AF) will be enrolled into the study.Participants will be divided into two groups based on the anticoagulation regimen type. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Mitral Stenosis, Rheumatic Heart Disease, Atrial Fibrillation
- What is being tested?
- Rivaroxaban and Warfarin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 1 siteIran
- Study dates
- 22 May 2019to 14 Aug 2021
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Men and women ≥ 18 year-old
- Diagnosed with moderate to severe mitral stenosis who have a history of AF of any duration documented by any electrical tracing within the prior 12 months and for which anticoagulation is indicated and planned for the duration of the study.
- Ability to take oral medication and be willing to adhere to the rivaroxaban regimen
Who cannot join
- Left atrial clot
- Severe renal dysfunction (creatinine clearance [CrCl] <15 mL/min), subjects with
- A condition associated with a high risk of bleeding
- Allergic to rivaroxabn/warfarin
Trial locations and contacts
1 site in 1 country.
About this study
Official title: RIvoraxaban Safety and Efficacy in Patients With Mitral Stenosis
In this randomized controlled clinical trial, patients with moderate to severe mitral valve stenosis (MS) and atrial fibrillation (AF) will be enrolled into the study.Participants will be divided into two groups based on the anticoagulation regimen type. The intervention group will receive rivaroxaban and the control group will be given warfarin. All patients will be observed closely during a period of one year. Through the follow up, embolic events and hemorrhagic complications will be recorded in both groups. In addition, patients in both group will undergo a baseline magnetic resonance imaging (MRI) and an MRI after one-year follow up, by which the silent embolic events will be compared in both groups.
Read the detailed description
Study rationale:
Since the introduction of warfarin as the main oral anticoagulation therapy in patients with MS and AF, no other drug has been replaced/suggested by any medical community for this group of patients. Warfarin is considered a drug with marginal therapeutic effect, with a need for constant monitoring, with lots of known drug interaction and finally a great probability of adverse complication. Novel oral anticoagulation agents have resolved several of these drawbacks and has been recommended as a viable option as a substitute of warfarin in various clinical scenario. Until now, no trial has evaluated the potentiality of using novel oral anticoagulations (NOACs) in patients with MS accompanied by AF. In this trial investigators are intended to elaborate the efficacy and safety of rivaroxaban in patients with MS complicated by AF
Background:
Since the introduction of NOAC, their indication has been expanded in various type of diseases. From protecting against ischemic stroke in AF patients to treatment of venous thromboembolism (VTE) events, NOAC were both safe and effective compared to warfarin. Importantly this new class of drug have omitted some of the major drawbacks of warfarin; their predictable therapeutic level has permitted to prescribed them as fixed dosage without constant laboratory tests. Also their shorter half-life has made critical situation in which reversal of anticoagulation agents were needed, more manageable.
There are solid evidences that AF is one of the major cause of cerebrovascular ischemic events, and anticoagulation therapy by decreasing thrombus formation reduces significantly these major adverse events. So there is no wonder that first studies on NOAC were performed on AF population. In the beginning AF caused by valvular heart diseases were judge to bear a much greater risk as cerebrovascular events are concerns, and consequently patients with valvular pathologies were eliminated from the earlier pivotal studies. However, through these years, there are lots of evidences showing the safety and efficacy of NOAC in valvular pathologies. Recently ENGAGE TIMI 48 Trial has showed the efficacy and safety of Edoxaban in patients with valvular heart diseases. By testing the theory in a large population, the ENGAGE TIMI 48 study emphasized on a greater risk of embolic events in patients with VHD and AF, but this increasing risk has no effect on the efficacy of edoxaban compared to warfarin. Interestingly the new agents had less major bleeding compared to warfarin.
But still in all these trials, moderate to severe MS and mechanical prosthetic valves were omitted from the studied population. The rationale behind this omission was the significant higher risk of thrombosis in the two mentioned subgroups. However, investigators have several hypotheses that patients with MS are different from patients undergoing mechanical prosthetic valve replacement:
- Although there is a higher risk of thromboembolic events in MS comparing to other valvular heart diseases, this has not resulted in increasing the magnitude of protection with warfarin; the recommended levels of international normalized ratio (INR) in MS population is 2-3 as other pathologies.
- Apart from patients with mechanical prosthesis implanted in mitral valve position, there is no other subgroup of patients whom higher INR and level of anticoagulation with warfarin proved to be more efficacious.
In conclusion, investigators think that the MS population might be a good target for NOAC and as other valvular heart disease, they could benefit from the advantages of these drugs.
- Conditions
- Mitral Stenosis, Rheumatic Heart Disease, Atrial Fibrillation, Anticoagulant Adverse Reaction
- Being tested
- Rivaroxaban, Warfarin
- Medical subject headings
- Mitral Valve Stenosis, Rheumatic Heart Disease, Atrial Fibrillation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RivaroxabanDrug
Rivaroxaban will be used as the anticoagulation drug for the intervention group. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no approved antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food
WarfarinDrug
Warfarin will be used as the anticoagulation drug for the control group. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree. A few days are required for full effect to occur and these effects can last for up to five days, and the final dose will be adjusted according to PT and related INR.
| Study group | Role | What they receive |
|---|---|---|
| Rivaroxaban | Experimental | Rivaroxaban will be used as the anticoagulation drug for the intervention group. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no approved antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food. Receives: Drug: Rivaroxaban |
| Warfarin | Active comparator | Warfarin will be used as the anticoagulation drug for the control group. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree. A few days are required for full effect to occur and these effects can last for up to five days, and the final dose will be adjusted according to PT and related INR. Receives: Drug: Warfarin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants with stroke
A stroke is defined as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that is not due to an identifiable nonvascular cause (i.e., brain tumor or trauma), and that either lasts at least 24 hours or results in death within 24 hours of onset.
Measured: 12 months
Number of participants with systemic embolic event
An SEE is defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system (CNS), coronary and pulmonary arterial circulation.
Measured: 12 months
Secondary outcomes (1)
Number of participants with bleeding complications
Bleeding complication will be assessed according to the International Society on Thrombosis and Haemostasis.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2019
- Study start22 May 2019
- Primary completion22 May 2021
- Study completion14 Aug 2021
Why it stopped: COVID-19 has impacted our study recruitment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Mitral StenosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rajaie Cardiovascular Medical and Research Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute for Medical Research and Development, Abidi Pharmaceuticals
- Responsible party
- Sponsor
- Investigators
- Majid Maleki, M.D., Study chair, Rajaie Cardiovascular Medical and Research Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03926156
- Sponsor's protocol ID
- 962426
- Acronym
- RISE MS
- Status last verified
- Aug 2021
- First submitted
- 22 Apr 2019
- Last updated
- 19 Aug 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Sadeghipour P, Pouraliakbar H, Parsaee M, Shojaeifard M, Farrashi M, JamalKhani S, Tashakori Beheshti A, Rostambeigi S, Ebrahimi Meimand S, Firouzi A, Peighambari MM, Alemzadeh-Ansari MJ, Haghjoo M, Noohi F, Maleki M, De Caterina R. RIvaroxaban in mitral stenosis (RISE MS): A pilot randomized clinical trial. Int J Cardiol. 2022 Jun 1;356:83-86. doi: 10.1016/j.ijcard.2022.03.037. Epub 2022 Mar 16.
PubMed 35306032
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- RIvoraxaban Safety and Efficacy in Patients With Mitral Stenosis
- ClinicalTrials.gov ID
- NCT03926156
- Acronym / sponsor ID
- RISE MS / 962426
- Conditions
- Mitral Stenosis, Rheumatic Heart Disease, Atrial Fibrillation, Anticoagulant Adverse Reaction
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: COVID-19 has impacted our study recruitment
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Rajaie Cardiovascular Medical and Research CenterUniversity, hospital or other
- Collaborators
- National Institute for Medical Research and Development, Abidi Pharmaceuticals
- Study start
- 22 May 2019 (actual)
- Primary completion
- 22 May 2021 (actual)
- Study completion
- 14 Aug 2021 (actual)
- First posted
- 24 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In this randomized controlled clinical trial, patients with moderate to severe mitral valve stenosis (MS) and atrial fibrillation (AF) will be enrolled into the study.Participants will be divided into two groups based on the anticoagulation regimen type. The intervention group will receive rivaroxaban and the control group will be given warfarin. All patients will be observed closely during a period of one year. Through the follow up, embolic events and hemorrhagic complications will be recorded in both groups. In addition, patients in both group will undergo a baseline magnetic resonance imaging (MRI) and an MRI after one-year follow up, by which the silent embolic events will be compared in both groups.
Detailed description
Study rationale:
Since the introduction of warfarin as the main oral anticoagulation therapy in patients with MS and AF, no other drug has been replaced/suggested by any medical community for this group of patients. Warfarin is considered a drug with marginal therapeutic effect, with a need for constant monitoring, with lots of known drug interaction and finally a great probability of adverse complication. Novel oral anticoagulation agents have resolved several of these drawbacks and has been recommended as a viable option as a substitute of warfarin in various clinical scenario. Until now, no trial has evaluated the potentiality of using novel oral anticoagulations (NOACs) in patients with MS accompanied by AF. In this trial investigators are intended to elaborate the efficacy and safety of rivaroxaban in patients with MS complicated by AF
Background:
Since the introduction of NOAC, their indication has been expanded in various type of diseases. From protecting against ischemic stroke in AF patients to treatment of venous thromboembolism (VTE) events, NOAC were both safe and effective compared to warfarin. Importantly this new class of drug have omitted some of the major drawbacks of warfarin; their predictable therapeutic level has permitted to prescribed them as fixed dosage without constant laboratory tests. Also their shorter half-life has made critical situation in which reversal of anticoagulation agents were needed, more manageable.
There are solid evidences that AF is one of the major cause of cerebrovascular ischemic events, and anticoagulation therapy by decreasing thrombus formation reduces significantly these major adverse events. So there is no wonder that first studies on NOAC were performed on AF population. In the beginning AF caused by valvular heart diseases were judge to bear a much greater risk as cerebrovascular events are concerns, and consequently patients with valvular pathologies were eliminated from the earlier pivotal studies. However, through these years, there are lots of evidences showing the safety and efficacy of NOAC in valvular pathologies. Recently ENGAGE TIMI 48 Trial has showed the efficacy and safety of Edoxaban in patients with valvular heart diseases. By testing the theory in a large population, the ENGAGE TIMI 48 study emphasized on a greater risk of embolic events in patients with VHD and AF, but this increasing risk has no effect on the efficacy of edoxaban compared to warfarin. Interestingly the new agents had less major bleeding compared to warfarin.
But still in all these trials, moderate to severe MS and mechanical prosthetic valves were omitted from the studied population. The rationale behind this omission was the significant higher risk of thrombosis in the two mentioned subgroups. However, investigators have several hypotheses that patients with MS are different from patients undergoing mechanical prosthetic valve replacement:
- Although there is a higher risk of thromboembolic events in MS comparing to other valvular heart diseases, this has not resulted in increasing the magnitude of protection with warfarin; the recommended levels of international normalized ratio (INR) in MS population is 2-3 as other pathologies.
- Apart from patients with mechanical prosthesis implanted in mitral valve position, there is no other subgroup of patients whom higher INR and level of anticoagulation with warfarin proved to be more efficacious.
In conclusion, investigators think that the MS population might be a good target for NOAC and as other valvular heart disease, they could benefit from the advantages of these drugs.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Rivaroxaban | Experimental | Drug: RivaroxabanRivaroxaban will be used as the anticoagulation drug for the intervention group. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no approved antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food. |
| Warfarin | Active comparator | Drug: WarfarinWarfarin will be used as the anticoagulation drug for the control group. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree. A few days are required for full effect to occur and these effects can last for up to five days, and the final dose will be adjusted according to PT and related INR. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Provision of signed and dated informed consent form
- Stated willingness to comply with all study procedures and availability for the duration of the study
- Men and women ≥ 18 year-old
- Diagnosed with moderate to severe mitral stenosis who have a history of AF of any duration documented by any electrical tracing within the prior 12 months and for which anticoagulation is indicated and planned for the duration of the study.
- Ability to take oral medication and be willing to adhere to the rivaroxaban regimen
Key exclusion criteria (4 listed)
- Left atrial clot
- Severe renal dysfunction (creatinine clearance [CrCl] <15 mL/min), subjects with
- A condition associated with a high risk of bleeding
- Allergic to rivaroxabn/warfarin
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RivaroxabanRivaroxaban will be used as the anticoagulation drug for the intervention group. Rivaroxaban is an anticoagulant and the first orally active direct factor Xa inhibitor. Unlike warfarin, routine lab monitoring of INR is not necessary. However there is no approved antidote available in the event of a major bleed. Only the 10 mg tablet can be taken without regard to food. The 15 mg and 20 mg tablet should be taken with food | Drug | Rivaroxaban |
| WarfarinWarfarin will be used as the anticoagulation drug for the control group. Warfarin decreases blood clotting by blocking an enzyme called vitamin K epoxide reductase that reactivates vitamin K1. Without sufficient active vitamin K1, clotting factors II, VII, IX, and X have decreased clotting ability. The anticlotting protein C and protein S are also inhibited but to a lesser degree. A few days are required for full effect to occur and these effects can last for up to five days, and the final dose will be adjusted according to PT and related INR. | Drug | Warfarin |
Primary outcome
Number of participants with stroke
Time frame: 12 months
A stroke is defined as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that is not due to an identifiable nonvascular cause (i.e., brain tumor or trauma), and that either lasts at least 24 hours or results in death within 24 hours of onset.
Number of participants with systemic embolic event
Time frame: 12 months
An SEE is defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system (CNS), coronary and pulmonary arterial circulation.
1 secondary outcome
Number of participants with bleeding complications
Time frame: 12 months
Results and safety
The study was stopped early (reason given: COVID-19 has impacted our study recruitment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2021.
- Derived from this study: PubMed 35306032Sadeghipour P, Pouraliakbar H, Parsaee M, Shojaeifard M, Farrashi M, JamalKhani S, Tashakori Beheshti A, Rostambeigi S, Ebrahimi Meimand S, Firouzi A, Peighambari MM, Alemzadeh-Ansari MJ, Haghjoo M, Noohi F, Maleki M, De Caterina R. RIvaroxaban in mitral stenosis (RISE MS): A pilot randomized clinical trial. Int J Cardiol. 2022 Jun 1;356:83-86. doi: 10.1016/j.ijcard.2022.03.037. Epub 2022 Mar 16.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Majid Maleki, M.D. study chair
Rajaie Cardiovascular Medical and Research Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Rivaroxaban and Warfarin in people with Mitral Stenosis and Rheumatic Heart Disease, run by Rajaie Cardiovascular Medical and Research Center at 1 site in Iran.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 19 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Iran. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: COVID-19 has impacted our study recruitment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of participants with stroke (time frame: 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03926156, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2021.