Increased Pacemaker Lower Rate in ATTR Cardiac Amyloidosis

Official title

Increased Pacemaker Lower Rate in ATTR Cardiac Amyloidosis: a Randomized, Crossover Clinical Trial (PACE-ATTR)

Overview

In cardiac amyloidosis, the heart muscle becomes thick and stiff, making it difficult to pump enough blood with each beat. The heart also often cannot increase its stroke volume, making patients with cardiac amyloidosis more dependent on having an adequate heart rate. Many develop conduction problems and need a pacemaker. In a related condition, heart failure with preserved ejection fraction, setting a higher pacemaker rate improved patients' quality of life. It is not known if the same benefits apply to amyloidosis. This study will test whether raising the pacemaker rate improves well-being and daily function in affected patients.

Detailed description

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of restrictive cardiomyopathy, characterized by reduced ventricular compliance, low stroke volume, and marked dependence on heart rate for maintenance of cardiac output. Conduction disease is common in ATTR-CM, and a substantial proportion of patients require permanent pacemaker implantation.

Although disease-modifying therapy can slow disease progression, evidence guiding optimization of pacemaker therapy in ATTR-CM is lacking. In heart failure with preserved ejection fraction, a condition also characterized by reduced ventricular compliance, increased pacemaker lower rate settings have been shown to improve functional capacity and quality of life. However, patients with cardiac amyloidosis were excluded from these studies. Consequently, current practice in ATTR-CM relies largely on extrapolation and expert opinion.

In this randomized multicenter 2×2 crossover trial, we aim to determine whether a higher pacemaker lower rate (80 bpm) improves health-related quality of life (QoL) and functional capacity in patients with ATTR-CM compared with the standard setting of 60 bpm.

Interventions

• Device Increasing the pacemaker lower rate
  Increasing the pacemaker lower rate from 60 to 80 bpm
• Device Standard setting
  Lower rate setting of 60 bpm

Primary outcome measures

• Minnesota Living with Heart Failure Questionnaire (MLHFQ) [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]

Secondary outcome measures (8)

• Distance walked during the 6-Minute Walk Test (6MWT) [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]
• Levels of N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]
• New York Heart Association (NYHA) Functional Class [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]
• National Amyloidosis Centre (NAC) Stage [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]
• Number of participants with hospitalization or urgent outpatient visit for atrial fibrillation [Time frame: During each treatment period (approximately 3 months per period)]
• Atrial fibrillation burden assessed by implanted pacemaker [Time frame: During each treatment period (approximately 3 months per period)]
• Physical activity level assessed by implanted pacemaker [Time frame: During each treatment period (approximately 3 months per period)]
• Levels of High-Sensitivity Cardiac Troponin (hs-cTn) [Time frame: End of each treatment period (Visit 2 at approximately 3 months and Visit 4 at approximately 7 months)]

Eligibility criteria

Inclusion criteria

• ATTR-CM defined as one of the following:
• a.Positive cardiac biopsy for ATTR amyloidosis
• b.Positive extra-cardiac biopsy for ATTR amyloidosis AND cardiac involvement demonstrated by CMR or echocardiography
• c.Grade 2-3 uptake on DPD-scintigraphy AND negative serum free light chain and negative urine and serum immunofixation AND cardiac involvement demonstrated by CMR or echocardiography
• Ongoing treatment with a transthyretin stabilizer or silencer OR considered not to be a candidate for these therapies with no planned initiation during the study period.
• NYHA functional class II-III
• Pre-existing pacemaker and either:
• a.Atrial pacing with minimal RV pacing (<2%), or
• b.His bundle or left bundle branch area pacing, or
• c.Biventricular pacing, or
• d.Ongoing RV pacing with a high degree of RV pace (>80%)
• NT-proBNP >600 ng/L
• Age ≥18 years
• Ability and willingness to provide written informed consent
• Pacing >80% with a programmed lower rate of 60 (AAI/CSP/CRT/RV-pace)

Exclusion criteria

• Inability to perform the 6-minute walk test.
• Planned coronary revascularization, ablation of atrial flutter/fibrillation, or any severe (obstructive or regurgitant) valvular heart disease expected to require intervention during the trial in the investigator's opinion.
• MI, unstable angina, coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), ablation of atrial flutter/fibrillation, cardioversion, valve repair/replacement, hospitalization for decompensated heart failure or cardiac resynchronisation therapy within 12 weeks prior to enrollment.
• Planned upgrade to CRT or conduction system pacing in patients with RV pacing.
• More than moderate valvular stenosis or regurgitation
• Inability of the patient, in the opinion of the investigator, to understand and/or comply with procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
• Presence of any other disease than heart failure with a life expectancy of < 1year in the investigators opinion
• Enrollment in other interventional device or drug trials during the study period, with the exception of open label extension studies
• Listed for cardiac transplantation
• Initiation of SGLT2-inhibitor or mineralocorticoid receptor antagonist within 4 weeks prior to enrollment
• Initiation or change in loop diuretic therapy within 4 weeks prior to enrollment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

Sweden · 7 centers

• Sahlgrenska University Hospital — Gothenburg
• Linköping University Hospital — Linköping
• Skane University Hospital — Lund
• Skellefteå Hospital — Skellefteå
• Karolinska University Hospital — Stockholm
• Norrland University Hospital — Umeå
• Academic University Hospital — Uppsala

Denmark · 2 centers

• Aarhus University Hospital — Aarhus
• Rigshospitalet — Copenhagen

Identifiers

NCT: NCT07413081 · 2025-07764-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗