Heart FailurePhase 2/3SIMPLIFY-HFNCT07489547
Medication Withdrawal in Stable HF With Improved LVEF
A Phase 2/3 study testing Discontinuation of MRAs and Continue MRAs in people with Heart Failure, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
Trial summary
The goal of this clinical trial is to evaluate the safety and feasibility of withdrawing mineralocorticoid antagonists (MRA) in patients with stable heart failure with improved left ventricular ejection fraction (HFimpEF). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- Discontinuation of MRAs and Continue MRAs
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 90 participants
- Where
- 1 siteBrazil
- Study dates
- 1 Mar 2025to 31 Dec 2026
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of heart failure (HF) and use of MRAs and an ACE inhibitor/ARB/ARNI for at least 12 months
- Left ventricular ejection fraction (LVEF) ≥40%, improved from a prior value ≤35%, with a sustained absolute increase >10%
- Left ventricular end-diastolic diameter within normal limits according to predefined criteria (≤59 mm for men and ≤53 mm for women)
- NYHA functional class I or II
- BNP levels <100 pg/mL, or NT-proBNP levels within age-adjusted thresholds: ≥450 pg/mL for individuals <50 years, ≥900 pg/mL for those 50-75 years, and ≥1800 pg/mL for individuals >75 years
- In cases of atrial fibrillation, NT-proBNP thresholds should be doubled
Show all 10Show fewer
- Clinical stability defined as no hospitalizations or need for increased diuretic therapy due to congestion within the previous 12 months
- Optimized heart failure medications with no modifications for at least 3 months
- Maximum allowed dose of furosemide of 80 mg/day
- Acceptable etiologies: HF following cardiac resynchronization therapy (CRT); non-ischemic HF after myocarditis; non-ischemic HF due to tachycardiomyopathy; non-ischemic HF due to alcoholic cardiomyopathy; non-ischemic HF due to cardiotoxicity; non-ischemic HF due to peripartum cardiomyopathy; non-ischemic HF after correction or intervention for valvular disease; ischemic HF after revascularization
Who cannot join
- Acute coronary syndrome within the past 12 months
- Arrhythmia requiring therapy within the past 12 months
- Syncope or appropriate device therapy (if ICD present) within the past 12 months
- Uncorrected moderate to severe valvular disease
- Severe unrevascularized coronary artery disease, defined as >50% stenosis of the left main coronary artery (LMCA) or >70% stenosis of the left anterior descending artery (LAD), circumflex artery (LCx), or right coronary artery (RCA)
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Brazil1 site, 1 recruiting
- Recruiting
Hospital de Clínicas de Porto Alegre
Porto Alegre, Rio Grande do Sul
Lucas C Petersen, 555196950660, lpetersen@hcpa.edu.br
About this study
Official title: Simplification of Treatment by Withdrawal of Medications in Stable Heart Failure With Improved Left Ventricular Ejection Fraction
The goal of this clinical trial is to evaluate the safety and feasibility of withdrawing mineralocorticoid antagonists (MRA) in patients with stable heart failure with improved left ventricular ejection fraction (HFimpEF). The main questions it aims to answer are:
Does withdrawal of MRAs lead to a reduction in left ventricular ejection fraction greater than 10%, resulting in a final LVEF below 40%? Does withdrawal of MRAs cause a relative increase in NT-proBNP levels greater than 50% above age-adjusted thresholds? Researchers will compare MRAs withdrawal (placebo) with continuation of therapy to determine whether medication withdrawal can be performed safely without worsening heart failure status.
Read more
Participants will:
Attend scheduled clinical visits over a 24-week follow-up period; Undergo echocardiographic evaluation of left ventricular ejection fraction before study visits; Provide blood samples for NT-proBNP measurement at each visit; Provide one blood sample for genetic analysis of polymorphisms related to the renin-angiotensin-aldosterone system; Receive either continued MRA therapy or placebo as part of a double-blind randomized design; Be monitored for clinical stability, symptoms of heart failure, and potential adverse events during follow-up.
Read the detailed description
Heart failure (HF) is a major global health problem associated with high rates of hospitalization, mortality, and healthcare costs. Contemporary guideline-directed medical therapy has substantially improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Standard pharmacological management includes four major therapeutic pillars: beta-blockers, inhibitors of the renin-angiotensin system (ACE inhibitors, ARBs, or ARNI), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. These therapies improve survival and reduce hospitalizations.
A subset of patients with HFrEF experiences significant improvement in cardiac function after treatment and is now classified as having heart failure with improved ejection fraction (HFimpEF). These patients typically demonstrate recovery of left ventricular ejection fraction from previously reduced values to ≥40%. However, recovery of ejection fraction does not necessarily represent complete reversal of the underlying disease process, and structural or molecular abnormalities may persist. Current clinical guidelines generally recommend continuation of guideline-directed medical therapy even after improvement in ejection fraction due to concerns about relapse.
Despite the benefits of these therapies, patients with heart failure frequently require multiple medications to manage both their cardiac condition and associated comorbidities. Polypharmacy can increase the risk of adverse drug reactions, medication non-adherence, drug interactions, and treatment complexity. Simplification of pharmacological regimens may therefore represent an important strategy to improve adherence and reduce treatment burden in selected patients.
Previous studies investigating withdrawal of heart failure therapies have shown mixed results. In some populations, withdrawal of key disease-modifying medications resulted in relapse of cardiac dysfunction or worsening clinical status. However, there is limited evidence regarding selective withdrawal of specific medication classes in carefully selected patients who have achieved clinical stability and significant improvement in cardiac function.
Mineralocorticoid receptor antagonists, such as spironolactone, play an important role in the treatment of HFrEF by blocking the effects of aldosterone, thereby reducing myocardial fibrosis, neurohormonal activation, and ventricular remodeling. Although their benefits in patients with reduced ejection fraction are well established, the necessity of maintaining this therapy indefinitely in patients with stable HFimpEF remains uncertain.
The SIMPLIFY-HF study is designed to evaluate the safety and feasibility of discontinuing MRAs in clinically stable patients with HFimpEF. This study will be a multicenter, randomized, double-blind clinical trial comparing withdrawal of MRAs (with placebo substitution) versus continuation of therapy. Eligible participants will have a history of heart failure with previously reduced ejection fraction that improved to ≥40%, stable clinical status, optimized background therapy, and no recent hospitalizations or signs of decompensation.
Participants will be followed for 24 weeks with scheduled clinical visits, echocardiographic evaluation of left ventricular function, and measurement of NT-proBNP levels as a biomarker of cardiac stress. Safety monitoring will be performed throughout the study to detect any signs of worsening heart failure, including deterioration in functional status, reduction in ejection fraction, or significant increases in natriuretic peptide levels.
The results of this study may provide important evidence regarding whether selected patients with stable HFimpEF can safely undergo simplification of pharmacological therapy through withdrawal of MRAs, potentially reducing treatment burden while maintaining clinical stability.
- Conditions
- Heart Failure
- Being tested
- Discontinuation of MRAs, Continue MRAs
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Discontinuation of MRAsDrug
Participants assigned to the intervention group will undergo discontinuation of MRAs as part of a treatment simplification strategy in patients with stable heart failure with improved left ventricular ejection fraction. All other guideline-directed medical therapies will be maintained according to the treating physician's judgment. Participants will be clinically monitored during follow-up to assess stability, potential recurrence of heart failure symptoms, and other clinical outcomes after withdrawal of MRAs.
Continue MRAsDrug
Participants assigned to the control group will continue MRAs as part of their guideline-directed medical therapy for heart failure with improved left ventricular ejection fraction. All other heart failure medications will be maintained according to standard clinical practice and the treating physician's judgment. Participants will be clinically monitored during follow-up to assess clinical stability, heart failure symptoms, and other relevant outcomes.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | A placebo is an inactive substance that has no therapeutic effect. Receives: Drug: Discontinuation of MRAs |
| Continue MRAs | Active comparator | Not described Receives: Drug: Continue MRAs |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Left Ventricular Ejection Fraction
Decrease from baseline in left ventricular ejection fraction (LVEF) of greater than 10%, resulting in a final LVEF below 40%.
Measured: 6 months
Change in NT-proBNP Levels
Increase from baseline in NT-proBNP levels of greater than 50%, with age-specific cut-off values: 450 pg/mL for participants younger than 50 years, 900 pg/mL for those between 50 and 75 years, and 1800 pg/mL for participants older than 75 years.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2026
- Study start1 Mar 2025
- Primary completionDec 2026 (estimated)
- Study completion31 Dec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Hospital de Clinicas de Porto AlegreThe sponsor's other registered studies.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 90 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hospital de Clinicas de Porto Alegre
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Luis E. Rohde, Full Professor, Principal investigator, Hospital de Clinicas de Porto Alegre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07489547
- Sponsor's protocol ID
- 2024-0387
- Acronym
- SIMPLIFY-HF
- Status last verified
- Mar 2026
- First submitted
- 18 Mar 2026
- Last updated
- 30 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Simplification of Treatment by Withdrawal of Medications in Stable Heart Failure With Improved Left Ventricular Ejection Fraction
- ClinicalTrials.gov ID
- NCT07489547
- Acronym / sponsor ID
- SIMPLIFY-HF / 2024-0387
- Conditions
- Heart Failure
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 90 participants (estimated)
- Lead sponsor
- Hospital de Clinicas de Porto AlegreUniversity, hospital or other
- Study start
- 1 Mar 2025 (actual)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- 31 Dec 2026 (estimated)
- First posted
- 24 Mar 2026 (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.
The goal of this clinical trial is to evaluate the safety and feasibility of withdrawing mineralocorticoid antagonists (MRA) in patients with stable heart failure with improved left ventricular ejection fraction (HFimpEF). The main questions it aims to answer are:
Does withdrawal of MRAs lead to a reduction in left ventricular ejection fraction greater than 10%, resulting in a final LVEF below 40%? Does withdrawal of MRAs cause a relative increase in NT-proBNP levels greater than 50% above age-adjusted thresholds? Researchers will compare MRAs withdrawal (placebo) with continuation of therapy to determine whether medication withdrawal can be performed safely without worsening heart failure status.
Participants will:
Attend scheduled clinical visits over a 24-week follow-up period; Undergo echocardiographic evaluation of left ventricular ejection fraction before study visits; Provide blood samples for NT-proBNP measurement at each visit; Provide one blood sample for genetic analysis of polymorphisms related to the renin-angiotensin-aldosterone system; Receive either continued MRA therapy or placebo as part of a double-blind randomized design; Be monitored for clinical stability, symptoms of heart failure, and potential adverse events during follow-up.
Detailed description
Heart failure (HF) is a major global health problem associated with high rates of hospitalization, mortality, and healthcare costs. Contemporary guideline-directed medical therapy has substantially improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Standard pharmacological management includes four major therapeutic pillars: beta-blockers, inhibitors of the renin-angiotensin system (ACE inhibitors, ARBs, or ARNI), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. These therapies improve survival and reduce hospitalizations.
A subset of patients with HFrEF experiences significant improvement in cardiac function after treatment and is now classified as having heart failure with improved ejection fraction (HFimpEF). These patients typically demonstrate recovery of left ventricular ejection fraction from previously reduced values to ≥40%. However, recovery of ejection fraction does not necessarily represent complete reversal of the underlying disease process, and structural or molecular abnormalities may persist. Current clinical guidelines generally recommend continuation of guideline-directed medical therapy even after improvement in ejection fraction due to concerns about relapse.
Despite the benefits of these therapies, patients with heart failure frequently require multiple medications to manage both their cardiac condition and associated comorbidities. Polypharmacy can increase the risk of adverse drug reactions, medication non-adherence, drug interactions, and treatment complexity. Simplification of pharmacological regimens may therefore represent an important strategy to improve adherence and reduce treatment burden in selected patients.
Previous studies investigating withdrawal of heart failure therapies have shown mixed results. In some populations, withdrawal of key disease-modifying medications resulted in relapse of cardiac dysfunction or worsening clinical status. However, there is limited evidence regarding selective withdrawal of specific medication classes in carefully selected patients who have achieved clinical stability and significant improvement in cardiac function.
Mineralocorticoid receptor antagonists, such as spironolactone, play an important role in the treatment of HFrEF by blocking the effects of aldosterone, thereby reducing myocardial fibrosis, neurohormonal activation, and ventricular remodeling. Although their benefits in patients with reduced ejection fraction are well established, the necessity of maintaining this therapy indefinitely in patients with stable HFimpEF remains uncertain.
The SIMPLIFY-HF study is designed to evaluate the safety and feasibility of discontinuing MRAs in clinically stable patients with HFimpEF. This study will be a multicenter, randomized, double-blind clinical trial comparing withdrawal of MRAs (with placebo substitution) versus continuation of therapy. Eligible participants will have a history of heart failure with previously reduced ejection fraction that improved to ≥40%, stable clinical status, optimized background therapy, and no recent hospitalizations or signs of decompensation.
Participants will be followed for 24 weeks with scheduled clinical visits, echocardiographic evaluation of left ventricular function, and measurement of NT-proBNP levels as a biomarker of cardiac stress. Safety monitoring will be performed throughout the study to detect any signs of worsening heart failure, including deterioration in functional status, reduction in ejection fraction, or significant increases in natriuretic peptide levels.
The results of this study may provide important evidence regarding whether selected patients with stable HFimpEF can safely undergo simplification of pharmacological therapy through withdrawal of MRAs, potentially reducing treatment burden while maintaining clinical stability.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo | Placebo comparator | Drug: Discontinuation of MRAsA placebo is an inactive substance that has no therapeutic effect. |
| Continue MRAs | Active comparator | Drug: Continue MRAs |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Diagnosis of heart failure (HF) and use of MRAs and an ACE inhibitor/ARB/ARNI for at least 12 months
- Left ventricular ejection fraction (LVEF) ≥40%, improved from a prior value ≤35%, with a sustained absolute increase >10%
- Left ventricular end-diastolic diameter within normal limits according to predefined criteria (≤59 mm for men and ≤53 mm for women)
- NYHA functional class I or II
- BNP levels <100 pg/mL, or NT-proBNP levels within age-adjusted thresholds: ≥450 pg/mL for individuals <50 years, ≥900 pg/mL for those 50-75 years, and ≥1800 pg/mL for individuals >75 years
Key exclusion criteria (5 listed)
- Acute coronary syndrome within the past 12 months
- Arrhythmia requiring therapy within the past 12 months
- Syncope or appropriate device therapy (if ICD present) within the past 12 months
- Uncorrected moderate to severe valvular disease
- Severe unrevascularized coronary artery disease, defined as >50% stenosis of the left main coronary artery (LMCA) or >70% stenosis of the left anterior descending artery (LAD), circumflex artery (LCx), or right coronary artery (RCA)
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 |
|---|---|---|
| Discontinuation of MRAsParticipants assigned to the intervention group will undergo discontinuation of MRAs as part of a treatment simplification strategy in patients with stable heart failure with improved left ventricular ejection fraction. All other guideline-directed medical therapies will be maintained according to the treating physician's judgment. Participants will be clinically monitored during follow-up to assess stability, potential recurrence of heart failure symptoms, and other clinical outcomes after withdrawal of MRAs. | Drug | Placebo |
| Continue MRAsParticipants assigned to the control group will continue MRAs as part of their guideline-directed medical therapy for heart failure with improved left ventricular ejection fraction. All other heart failure medications will be maintained according to standard clinical practice and the treating physician's judgment. Participants will be clinically monitored during follow-up to assess clinical stability, heart failure symptoms, and other relevant outcomes. | Drug | Continue MRAs |
Primary outcome
Change in Left Ventricular Ejection Fraction
Time frame: 6 months
Decrease from baseline in left ventricular ejection fraction (LVEF) of greater than 10%, resulting in a final LVEF below 40%.
Change in NT-proBNP Levels
Time frame: 6 months
Increase from baseline in NT-proBNP levels of greater than 50%, with age-specific cut-off values: 450 pg/mL for participants younger than 50 years, 900 pg/mL for those between 50 and 75 years, and 1800 pg/mL for participants older than 75 years.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Mar 2026.
- Individual participant dataSharing planned: No
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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.
Luis E. Rohde, Full Professor principal investigator
Hospital de Clinicas de Porto Alegre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Discontinuation of MRAs and Continue MRAs in people with Heart Failure, run by Hospital de Clinicas de Porto Alegre at 1 site in Brazil.
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 10 inclusion and 5 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: looking for participants now, as of the sponsor's last update on 30 Mar 2026. 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 Brazil. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Lucas C Petersen, Dr (555196950660, lpetersen@hcpa.edu.br), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Left Ventricular Ejection Fraction (time frame: 6 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?
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 30 Mar 2026.