Clinical trial NCT06964464: Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
Official title: Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Heart Failure With Reduced Ejection Fraction (HFrEF)
Sudden Cardiac Death
Ventricular Arrhythmia
Implantable Cardioverter Defibrillator (ICD)
Beta-blocker Therapy
Cardiomyopathy
Keywords: arrhythmia
heart failure
ICD
implantable cardioverter defibrillator
ICD shock
carvedilol
metoprolol succinate
beta-blocker
Lead sponsor: University of Rochester
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
First posted: 2025-05-09
Enrollment: 2000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This prospective, multicenter, open-label, randomized comparative effectiveness trial, titled CARVTOP-ICD, evaluates the impact of carvedilol versus metoprolol succinate in patients with heart failure with reduced ejection fraction (HFrEF) and an implantable cardioverter defibrillator (ICD). The study will enroll 2,000 participants across 100 U.S. sites and includes an 18-month feasibility phase with 100 participants from 15 sites. Eligible participants must be currently treated with metoprolol succinate and willing to switch to carvedilol, with randomization in a 1:1 ratio. Participants will be followed for up to 3 years, with regular assessments including ICD interrogations, medication adherence, healthcare utilization, and quality of life surveys. The primary endpoint is the first occurrence of any ICD therapy (appropriate or inappropriate), cardiovascular (CV) hospitalization, or CV death. Secondary endpoints include ICD shock burden, healthcare utilization, and patient-reported quality of life. The trial aims to provide high-quality comparative data to address clinical equipoise surrounding the two commonly used beta-blockers in HFrEF management.

Detailed description: The Comparative Effectiveness of Carvedilol versus Metoprolol Succinate in Heart Failure Patients with an Implantable Cardioverter Defibrillator (CARVTOP-ICD) study is a prospective, multicenter, open-label, two-arm, randomized clinical trial designed to assess the comparative effectiveness of carvedilol versus metoprolol succinate in patients with heart failure with reduced ejection fraction (HFrEF) and an implantable cardioverter defibrillator (ICD). The study will enroll a total of 2,000 participants from 100 sites across the United States, with an initial feasibility phase enrolling 100 participants from 15 sites over 18 months.

The feasibility phase will assess study infrastructure, recruitment, consent processes, medication switching protocols, safety, adherence, and retention. A patient-centered approach, including engagement of caregivers and stakeholders, underpins this phase. Strategies to improve patient and provider participation, address barriers to beta-blocker switching, and ensure diversity in enrollment will be employed. Lessons learned will guide the full-scale study.

Eligible participants must have an ICD implanted for primary prevention of sudden cardiac death due to HFrEF (either ischemic or non-ischemic etiology), be currently treated with metoprolol succinate, and be willing to switch to carvedilol. Participants will be randomized 1:1 to either remain on metoprolol succinate or switch to an equivalent dose of carvedilol, with titration to maximally tolerated doses per protocol. Key exclusion criteria include treatment with any beta-blocker other than metoprolol succinate, systolic blood pressure \<100 mmHg, known intolerance to carvedilol, or inability to comply with the study protocol.

The primary endpoint is the first occurrence of any ICD therapy (appropriate or inappropriate), cardiovascular hospitalization, or cardiovascular death. Secondary endpoints include the burden of ICD shocks, healthcare utilization (including emergency visits and hospitalizations), and quality of life (QoL) measured by the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12), Florida Shock Anxiety Scale (FSAS), and Patient Health Questionnaire-2 (PHQ-2). Tertiary endpoints include specific analyses of ventricular tachyarrhythmias and atrial arrhythmias leading to inappropriate ICD therapies.

Participants will be followed for an average of 3 years. Assessments will be conducted at baseline, weeks 2 and 4, and quarterly thereafter. Study data will include standard of care tests such as cardiac imaging, ICD interrogations, laboratory measures (BNP/NT-proBNP, creatinine, BUN, potassium, sodium), NYHA classification, CV medication data, adverse events, protocol deviations, and patient-reported outcomes.

The study will also assess subgroup responses by sex, age, race/ethnicity, heart failure etiology (ischemic vs non-ischemic), ICD type (ICD vs CRT-D), and degree of LVEF impairment.

This PCORI-funded trial will generate robust, real-world evidence to guide clinical decision-making on beta-blocker choice in HFrEF patients with ICDs, addressing a significant gap in evidence and helping inform personalized treatment strategies to improve clinical and arrhythmic outcomes.

More information can be found at www.carvtop.org

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* ICD implanted for primary prevention for HFrEF (either ICM or NICM) with remote monitoring capability
* Current treatment with metoprolol succinate and willing to switch to carvedilol
* LVEF \<50% during the past 12 months prior to consent

Exclusion Criteria:

* Unwilling or unable to follow the protocol
* Treatment with any other ßB than metoprolol succinate or no ßB treatment
* Known prior intolerance or contraindication to carvedilol
* Systolic blood pressure \<100 mmHg
* Enrollment in another clinical trial
* Inability or unwilling to consent

Primary outcomes:
measure: Composite Endpoint: First Occurrence of ICD Therapy, Cardiovascular Hospitalization, or Cardiovascular Death
timeFrame: Up to 3 years
Secondary outcomes:
measure: Healthcare Utilization
timeFrame: Average of 3 years
measure: ICD Shock Burden
timeFrame: Average of 3 years
measure: Quality of Life - Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12)
timeFrame: Baseline, Year 1, Year 2, Year 3
measure: Quality of Life - Florida Shock Anxiety Scale (FSAS)
timeFrame: Baseline, Year 1, Year 2, Year 3
measure: Quality of Life - Patient Health Questionnaire-2 (PHQ-2)
timeFrame: Baseline, Year 1, Year 2, Year 3
Other outcomes:
Locations:
Study officials:
References:
citation: Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001 May 31;344(22):1651-8. doi: 10.1056/NEJM200105313442201.
citation: Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55. doi: 10.1056/NEJM199605233342101.
citation: Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lubsen J, Lutiger B, Metra M, Remme WJ, Torp-Pedersen C, Scherhag A, Skene A; Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5;362(9377):7-13. doi: 10.1016/S0140-6736(03)13800-7.
citation: Diamond A, Goldenberg I, Younis A, Goldenberg I, Sampath R, Kutyifa V, Chen AY, McNitt S, Polonsky B, Steinberg JS, Zareba W, Aktas MK. Effect of Carvedilol vs Metoprolol on Atrial and Ventricular Arrhythmias Among Implantable Cardioverter-Defibrillator Recipients. JACC Clin Electrophysiol. 2023 Oct;9(10):2122-2131. doi: 10.1016/j.jacep.2023.06.009. Epub 2023 Aug 30.
citation: Ruwald MH, Abu-Zeitone A, Jons C, Ruwald AC, McNitt S, Kutyifa V, Zareba W, Moss AJ. Impact of carvedilol and metoprolol on inappropriate implantable cardioverter-defibrillator therapy: the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy). J Am Coll Cardiol. 2013 Oct 8;62(15):1343-50. doi: 10.1016/j.jacc.2013.03.087. Epub 2013 Jun 13.
citation: Ruwald MH, Ruwald AC, Jons C, Alexis J, McNitt S, Zareba W, Moss AJ. Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy). J Am Coll Cardiol. 2013 Apr 9;61(14):1518-26. doi: 10.1016/j.jacc.2013.01.020.
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