Optimising Pacing for Contractility 2 (OPT-cont 2)

Mechanisms, Safety and Efficacy of Optimising Pacemaker Heart Rate for Contractility: Effects on Walk Time, Cardiac Remodelling and Quality of Life

The investigators have demonstrated that they can reliably identify an optimum heart rate range for contractility of the left ventricle in patients with chronic heart failure (CHF). They have also demonstrated in an acute cross-over and a small parallel group feasibility study that keeping the heart rate in this range (versus standard rate-response programming) in patients with CHF is associated with increased exercise time on a treadmill (around 60s or 10%). They now want to explore in a randomised, placebo-controlled 3-arm parallel group trial whether optimal programming versus standard rate-response programming versus no rate-response programming for 6 months leads to appreciable improvements in exercise time and quality of life, while having no adverse effects on left ventricular function and battery longevity and what the mechanisms of this might be.

400 patients with CHF and a pacemaker will undergo the non-invasive echocardiographic assessment to establish the force frequency relationship and the optimal heart rate for contractility. They will then perform a treadmill walk test, complete quality of life questionnaires and be offered the opportunity to participate in a series of mechanistic substudies. They will then be randomised to optimal rate-response settings, standard rate response settings or no rate-response settings and followed up at 6 months at which point the tests will be repeated.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure, Systolic; Pacemaker
• Intervention / Treatment: Device: Heart rate optimisation using force frequency data

Detailed Description

Detailed Description:

Design: This will be a randomised, double-blind 'placebo' controlled trial of optimised programming versus standard rate-response settings, aiming to determine whether the short term improvements translate into longer term benefits.

Study participants: 400 adult patients (>18years).

Study Procedures: Patients attending the heart failure clinic, the pacemaker clinic or previous research participants will be approached with a standard letter and information sheet and then a telephone call to make sure any remaining questions are answered.

Patients agreeing to participate will attend the clinical research facility (CRF) and will be asked to sign a consent form. Each patient will have a standard device check, check of their demographic data, and co-morbidities. The investigators will record a resting cardiac ultrasound, and measure the force frequency relationship (FFR) to determine critical heart rate (HR), and the optimal range of HR rise. All images will be stored for offline analysis. Participants will then be asked to do a symptom-limited walk test on the treadmill (until they cannot do any more). At this first visit, participants will also complete quality of life questionnaires and be invited to participate in substudies including cardiac magnetic resonance, blood tests, tests of autonomic dysfunction. All of these activities will take place in the Clinical Research Facility at Leeds General Infirmary.

Randomisation: Each patient will then be randomised to either optimised programming (n=200) as predicted by their force-frequency curve (n=200), standard settings (n=100) or no rate response programming (n=100). In the optimised group, programming will keep heart rates below the critical HR. Randomisation will be by a random number generator and programming will be undertaken by one of my colleagues to maintain blinding.

Follow-up: Each patient will be called at one month to check that they are tolerating any changes and will then be invited back at 6 months for a repeat resting echocardiogram, treadmill walk test and quality of life assessment.

Data: All data will be stored on a bespoke Excel spreadsheet on an LTHT server in a password-protected folder.

Primary Endpoint: The effects of heart rate programming that optimises heart rate for contractility on change in treadmill-based walk distance over six months in patients with heart failure and a pacemaker.

Secondary endpoints: 1) the safety of pacemaker programming optimised for heart rate in patients with heart failure and a pacemaker, 2) the effect of this programming on change of quality of life at 6 months 3) the effect of this programming on change in cardiac function at 6 months.

Mechanistic endpoints: 1) The effect of heart rate programming on measures of autonomic function, 2) Changes in cardiac function during exercise, 3) The effect of optimised heart rate programming on strain, wall stress and perfusion by cardiac magnetic resonance, 4) changes in biomarkers associated with heart failure

• Study Type: Interventional
• Enrollment (Anticipated): 400
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Klaus K Witte, MD; Phone Number: 01133926642; Email: k.k.witte@leeds.ac.uk

Study Locations

• United Kingdom
  • Leeds, United Kingdom
    • Recruiting
    • Leeds General Infirmary
    • Principal Investigator: Klaus K Witte, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Left ventricular systolic dysfunction (LVEF<50%),
• Cardiac pacemaker,
• Able to perform a peak exercise test,
• Willing and able to give informed consent.

Exclusion Criteria:

• Angina pectoris symptoms limiting exercise tolerance,
• Unstable heart failure symptoms (medical therapy changes in last three months), Poor image quality,
• Calcium channel blockers (CCBs).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard rate-response settings; Patients allocated to standard rate-response settings.
Active Comparator: Rate-response settings off; Patients allocated to deactivated rate-response settings.	Device: Heart rate optimisation using force frequency data; Programming heart rate rise according to the force frequency relationship
Experimental: Optimized rate-response settings; Patients allocated to optimised rate-response settings.	Device: Heart rate optimisation using force frequency data; Programming heart rate rise according to the force frequency relationship

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treadmill walk time	Time walked during a standard incremental treadmill test	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life 1	EQ5D-5L score	6 months
Quality of life 2	KCCQ score	6 months
Clinical composite score	Clinical outcomes combined (death, hospitalisation, NYHA symptom level, diuretic dose	6 months
Cardiac function during exercise measured by LVEF on echocardiogrpahy	As assessed on a cycle ergometer	6 months
Wall stress by cardiac MRI	Wall stress assessed by cardiac MRI	6 months
Autonomic dysfunction	Measures of Muscle Sympathetic Nerve Activity	6 months
Autonomic dysfunction	Heart rate variability	6 months

Collaborators and Investigators

• Sponsor: University of Leeds

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 16, 2019

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 25, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Systolic
• Other Study ID Numbers: 277578

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: after initial analysis
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No