Beta Blockers for Heart Failure
(PRE-INFORMED Trial)
Recruiting in Palo Alto (17 mi)
PG
Overseen byParag Goyal, MD, MSc
Age: 65+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 4
Recruiting
Sponsor: Weill Medical College of Cornell University
Must be taking: Beta-blockers
Disqualifiers: Severe aortic stenosis, Angina, others
No Placebo Group
Prior Safety Data
Approved in 6 Jurisdictions
Trial Summary
What is the purpose of this trial?
Investigators will determine whether N-of-1 trials, as a pragmatic, participant-centered approach to medication optimization that can overcome key barriers of deprescribing, can lead to increased participant confidence regarding their preference to continue or discontinue beta-blockers in older adults with Heart Failure with Preserved Ejection Fraction (HFpEF).
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it focuses on whether to continue or stop beta-blockers. It seems you will need to be on a beta-blocker to participate.
What evidence supports the effectiveness of beta-blocker drugs for heart failure?
Is it safe to use beta blockers for heart failure?
Beta blockers like metoprolol, bisoprolol, and carvedilol are generally safe with a low risk of serious side effects when used properly, although they can sometimes cause issues like slow heart rate or breathing problems. Large studies have shown they improve survival and symptoms in heart failure patients.16789
What makes beta blockers unique for treating heart failure?
Beta blockers like carvedilol, metoprolol, bisoprolol, and nebivolol are unique because they improve survival and symptoms in heart failure by blocking certain receptors in the heart, which helps it pump more efficiently. Carvedilol also blocks additional receptors, offering broader benefits compared to some other beta blockers.110111213
Research Team
PG
Parag Goyal, MD, MSc
Principal Investigator
Weill Medical College of Cornell University
Eligibility Criteria
This trial is for adults aged 65 or older with Heart Failure with Preserved Ejection Fraction (HFpEF), who are currently taking beta-blockers and meet specific heart function criteria. People can't join if they have other heart conditions, recent severe cardiac events, certain arrhythmias, uncontrolled blood pressure, or any instability that could affect the study.Inclusion Criteria
I am 65 or older with heart failure but my heart still pumps well.
I am currently taking a beta-blocker medication.
Exclusion Criteria
I have had a heart attack or heart surgery in the last 3 years.
My heart condition is not caused by severe valve issues, constrictive pericarditis, high output failure, or infiltrative cardiomyopathy.
I have had episodes of very fast heartbeats.
See 7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants undergo a two-arm crossover withdrawal/reversal design with up to 6 periods, each lasting up to 6 weeks, involving titration of beta-blockers
12-36 weeks
Multiple visits as per participant's choice of 2-6 periods
Follow-up
Participants are monitored for safety and effectiveness after treatment, with qualitative interviews conducted to assess confidence and decision-making
up to 52 weeks
Treatment Details
Interventions
- Beta blocker (Beta Blocker)
Trial OverviewThe study aims to see if N-of-1 trials help patients decide whether to continue or stop using beta-blockers for HFpEF by increasing their confidence in the decision-making process.
Participant Groups
2Treatment groups
Active Control
Group I: Beta-Blocker ABAB SequenceActive Control1 Intervention
This arm will follow an ABAB sequence: ON beta-blockers (A) and OFF beta-blockers (B). Participants start with their home beta-blocker dose in Period 1 (A), and then switch to Period 2 (B), where the dose is slowly reduced until they are off their beta-blocker (or the lowest tolerable dose). Participants are then asked if they have enough information to clarify their preference about continuing or discontinuing their beta-blocker. Participants can choose to engage in 2-6 periods based on whether they need more information to make a preference. These extra phases follow the same ON-OFF pattern (ABABAB), meaning if the participant chooses to continue into Period 3 (A), the study team will restart the participant's beta-blocker, and slowly up-titrate until they reach their home dose, or their highest tolerable dose. This continues until the participant has enough information to clarify their preference about their beta-blocker, with a limit of 6 periods.
Group II: Beta-Blocker BABA SequenceActive Control1 Intervention
This arm will follow a BABA sequence: OFF beta-blockers (B) and ON beta-blockers (A). Participants start Period 1 (B) by slowly reducing the participant's beta-blocker home dose by 50% each week until they are off (or the lowest tolerable dose), then switch to Period 2 (A), where they restart their beta-blocker and slowly up-titrate until they reach their home dose (or the highest tolerable dose). Participants are then asked if they have enough information to clarify their preference about continuing or discontinuing their beta-blocker. Participants can choose to engage in 2-6 periods based on whether they need more information. The extra phases follow the same OFF-ON pattern (BABABA), meaning if they choose to continue into Period 3 (B), the participant will slowly reduce their beta-blocker until they are off (or the lowest tolerable dose). This continues until the participant has enough information to clarify their preference about their beta-blocker, with a max of 6 periods.
Beta blocker is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:
🇪🇺 Approved in European Union as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
🇺🇸 Approved in United States as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
🇨🇦 Approved in Canada as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
🇯🇵 Approved in Japan as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
🇨🇳 Approved in China as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
🇨🇭 Approved in Switzerland as Beta blockers for:
- Hypertension
- Heart failure
- Angina
- Arrhythmias
- Migraine
- Glaucoma
- Anxiety disorders
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Weill Cornell MedicineNew York, NY
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Who Is Running the Clinical Trial?
Weill Medical College of Cornell University
Lead Sponsor
Trials
1103
Patients Recruited
1,157,000+
National Institute on Aging (NIA)
Collaborator
Trials
1841
Patients Recruited
28,150,000+
References
Replacement of carvedilol for propranolol in patients with heart failure. [2019]Large clinical trials using the betablockers carvedilol, metoprolol, bisoprolol and nebivolol have demonstrated improvement of survival and symptoms in patients with heart failure. Despite the lack of scientific evidence, it is plausible that their beneficial effects are extensible to other betablockers.
Are all beta-blockers the same for chronic heart failure? [2019]beta-Adrenergic receptor blockade has been conclusively proven to increase survival and morbidity in patients with heart failure. Hospitalization rate decreases and patients feel better after receiving beta-blockers. Furthermore, this benefit is observed in a wide range of patients. The beta-blockers bisoprolol, metoprolol, and carvedilol have been extensively evaluated in heart failure patients. These drugs all show marked benefit. Bucindolol, an investigational beta-blocker, showed only mild improvement in survival in patients with heart failure. The beta-blockers differ regarding beta-selectivity, vasodilation properties, and perhaps other ancillary properties. At present, the importance and consequences of these differences are unknown.
Bisoprolol in the treatment of chronic heart failure: from pathophysiology to clinical pharmacology and trial results. [2021]Clinical trials have consistently shown the benefits of beta-blocker treatment in patients with chronic heart failure (HF). As a result, bisoprolol, carvedilol, and metoprolol succinate are now indicated for the treatment of all patients with chronic HF who do not have major contraindications. Bisoprolol is the first beta-blocker shown to improve survival in an outcome trial. In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), all-cause mortality and sudden death were reduced in patients treated with bisoprolol compared with those on placebo (11.8% vs 17.3%; p
Beta-blockade in heart failure: selective versus nonselective agents. [2018]Controlled clinical trials performed in more than 13 000 patients have, to date, consistently shown the beneficial effects of long term beta-adrenoceptor antagonist (beta-blocker) therapy in patients with chronic heart failure. It is not clear whether this represents a class effect or whether it is specific only to some agents. Beneficial effects on the prognosis of patients with mild to moderate heart failure have been shown with metoprolol, bisoprolol, and carvedilol. These beta-blockers, however, differ in their pharmacologic characteristics. Metoprolol and bisoprolol are selective for beta(1)-adrenergic receptors and are devoid of ancillary properties. Carvedilol, at a dosage of 50 mg/day, blocks all beta(1)-, beta(2)-, and alpha(1)-adrenergic receptors, and it has associated antiproliferative and antioxidant activities. These differences cause a varied acute hemodynamic response, with a reduction in cardiac output and a tendency toward a rise in pulmonary wedge pressure with selective agents and no change in cardiac output and a slight decrease in pulmonary pressures with carvedilol. Accordingly, when the therapy is started, the most frequent adverse effects are worsening heart failure with metoprolol and bisoprolol, and hypotension and dizziness with carvedilol. It remains controversial whether these differences also influence the long term effects of therapy. Carvedilol may provide a more comprehensive blockade of the cardiac adrenergic drive than selective beta-blockers because it does not upregulate beta(1)-adrenergic receptors, blocks all adrenergic receptors and decreases cardiac norepinephrine release. These properties may lead to a larger increase in left ventricular function and a lack of improvement in maximal exercise capacity with carvedilol, compared with selective beta-blockers. It is, however, unclear whether these differences also influence patient outcome. The long term effects of different beta-blockers on prognosis are currently being compared in the Carvedilol or Metoprolol European Trial (COMET) in which more than 3000 patients with chronic heart failure have been randomized in a 1 : 1 ratio to receive metoprolol or carvedilol.
Beta-blockers in heart failure: are pharmacological differences clinically important? [2018]Beta-blockers are not an homogeneous group of agents. Only three beta-blockers, carvedilol, bisoprolol and metoprolol succinate, have had favorable effects on prognosis in controlled clinical trials in the patients with chronic heart failure. However, pharmacological differences exist between them. Metoprolol and bisoprolol are selective for beta(1)-adrenergic receptors while carvedilol blocks also beta(2)-, and alpha(1)- adrenergic receptors, and has associated antioxidant, anti-endothelin and antiproliferative properties. In COMET carvedilol was associated with a significant reduction in mortality compared to metoprolol tartrate further showing that different beta-blockers may have different effects on the outcome. These differences may be related to the ancillary properties of carvedilol or to its broader antiadrenergic profile. However, also more effective and prolonged blockade of beta1 adrenergic receptors may occur with carvedilol compared to metoprolol.
Role of Metoprolol Succinate in the Treatment of Heart Failure and Atrial Fibrillation: A Systematic Review. [2021]Beta-blockers are one of the most important classes of cardiovascular agents and have been considered a cornerstone therapy in heart diseases, such as heart failure (HF) and atrial fibrillation (AF). Among different beta-blockers, metoprolol is a selective beta1-adrenergic antagonist, which has been extensively used since the 1970s.
[Endothelial dysfunction: role of vasodilating betablockers in hypertension and chronic heart failure]. [2010]The beneficial effects of beta blocking drugs in hypertension and heart failure are well known. However, this class of drugs is pharmacologically heterogeneous. In contrast to the non vasodilator betablockers like propranolol, atenolol or metoprolol which, in hypertension do not decrease intima media thinckness both in arterioles and large arteries, do not decrease arterial rigidity and can induce diabetes mellitus, the betablockers with vasodilating properties are beneficial on these parameters. Moreover, in heart failure, they more markedly decrease left ventricular workload than betablockers without any vascular relaxing effect and the results of SENIOR with nebivolol could suggest the beneficial role of NO on left ventricular dysfunction. Finally, the third generation betablockers, represented by celiprolol, carvedilol and nebivolol, have antioxidant properties which are probably implicated in their endothelial protective effects and in their absence of deleterious metabolic effects, effects which are probably of interest in term of protection of target organs during chronic treatment of hypertensive patients.
[Differential therapy with beta blockers. What is their value, what are the risks?]. [2017]The selective beta blockers metoprolol, bisoprolol and atenolol, but also the non-selective beta blocker carvedilol, are drugs with individually specific properties that are widely prescribed for a wide range of indications. Modern beta blockers are safe drugs with a low profile of side effects, which, applied with proper consideration being given to contraindications, rarely produce serious side effects such as bradyarrhythmia, bronchial obstruction, or aggravation of heart failure. Their prognostic benefit, for example, in the treatment of post-myocardial infarction patients, or in cardiac insufficiency, has been demonstrated in large randomized clinical trials.
The large-scale placebo-controlled beta-blocker studies in systolic heart failure revisited: results from CIBIS-II, COPERNICUS and SENIORS-SHF compared with stratified subsets from MERIT-HF. [2022]The four pivotal beta-blocker trials in heart failure (HF) had different inclusion criteria, making comparison difficult without patient stratifying. The aim of this study was to compare, in similar patients, the effects of bisoprolol, metoprolol controlled release/extended release (CR/XL), carvedilol and nebivolol on (i) total mortality, (ii) all-cause mortality or hospitalization due to cardiovascular causes (time to first event), (iii) all-cause mortality or hospitalization because of HF and (iv) tolerability, defined as discontinuation of randomized treatment.
Using beta-blockers to treat heart failure. [2016]Bisoprolol, carvedilol, metoprolol, and nebivolol are beta-blocker drugs used to improve survival in patients with systolic heart failure. This article reviews these drugs and how practitioners can initiate and titrate them for maximum patient benefit.
Effects of nebivolol versus carvedilol on left ventricular function in patients with chronic heart failure and reduced left ventricular systolic function. [2018]Beta-adrenoceptor antagonist (beta-blocker) therapy results in a significant improvement in left ventricular (LV) systolic function and prognosis in patients with chronic heart failure. Both carvedilol and nebivolol produce hemodynamic and clinical benefits in chronic heart failure, but it is unknown whether their peculiar pharmacologic properties produce different effects on LV function.
Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET. [2018]Beta-blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the beta1-blocker metoprolol tartrate and the beta1-, beta2-, and alpha1-blocker carvedilol.
Multiparametric comparison of CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. [2022]Several β-blockers, with different pharmacological characteristics, are available for heart failure (HF) treatment. We compared Carvedilol (β1-β2-α-blocker), Bisoprolol (β1-blocker), and Nebivolol (β1-blocker, NO-releasing activity).