The STOP-MED CTRCD Trial (STOP-MED)

A Multi-Centre Non-Inferiority Randomized Controlled Trial of STOPping Cardiac MEDications in Patients With Normalized Cancer Therapy Related Cardiac Dysfunction: The STOP-MED CTRCD Trial

Cancer therapy-related cardiac dysfunction (CTRCD) is when the heart's ability to pump oxygenated blood to the body is compromised. It is a side effect of cancer therapy which can occur as commonly as in 1 in 5 patients. When this occurs, heart failure medications are started to protect the heart from progressing to heart failure. With early detection and treatment, heart function recovers to normal in >80% of patients. Unfortunately, heart failure medications are associated with an undesirable long-term pill burden, financial costs, and side-effects (e.g., dizziness and fatigue). As a result, cancer survivors frequently ask if they can safely stop their heart failure medications once their heart function has returned to normal. Currently there is no scientific evidence in this area of Cardio-Oncology.

To address this knowledge gap, the investigators have designed a randomized control trial to assess the safety of stopping heart failure medication in patients with CTRCD and recovered heart function. The investigators will enrol patients who have completed their cancer therapy and are on heart medications for their CTRCD, which has now normalized. The investigators will randomize patients with no other reasons to continue heart failure medications (e.g., kidney disease) to continuing or stopping their heart medications safely. All patients will undergo a cardiac MRI at baseline, 1 and 5 years with safety assessments at 6-8 weeks, 6 and 9 months and 3 and 5 years. The investigators will determine if stopping medications is non-inferior to continuing medications by counting the numbers of patients who develop heart dysfunction by 1 year in each group.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Cancer; Cardiotoxicity; Cardiac Toxicity; Antineoplastics Toxicity
• Intervention / Treatment: Other: Stopping Heart Failure Medication(s)

• Study Type: Interventional
• Enrollment (Estimated): 335
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Paaladinesh Thavendiranathan, MD; Phone Number: 416-340-5326; Email: dinesh.thavendiranathan@uhn.ca

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Not yet recruiting
      • Baker Heart and Diabetes Institute
      • Contact: Tom Marwick, MD
      • Principal Investigator: Tom Marwick, MD
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Not yet recruiting
      • Foothills Medical Centre
      • Contact: James White, MD
      • Principal Investigator: James White, MD
    • Edmonton, Alberta, Canada, T6G 1C9
      • Not yet recruiting
      • Edmonton Clinic Health Academy
      • Contact: Edith Pituskin, PhD
      • Principal Investigator: Edith Pituskin, PhD
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • Not yet recruiting
      • St. Boniface Hospital
      • Contact: Davinder Jassal, MD
      • Principal Investigator: Davinder Jassal, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Not yet recruiting
      • Hamilton General Hospital
      • Principal Investigator: Darryl Leong, MD
      • Contact: Darryl Leong, MD
    • Ottawa, Ontario, Canada, K1Y 4W7
      • Not yet recruiting
      • University of Ottawa Heart Institute
      • Contact: Ian Paterson, MD
      • Principal Investigator: Ian Paterson, MD
    • Toronto, Ontario, Canada, M5G2C4
      • Recruiting
      • University Health Network
      • Contact: Paaladinesh Thavendiranathan, MD; Phone Number: 416-340-5326; Email: dinesh.thavendiranathan@uhn.ca
      • Principal Investigator: Paaladinesh Thavendiranathan, MD
    • Toronto, Ontario, Canada, M5B 1W8
      • Not yet recruiting
      • St Michael's Hospital
      • Principal Investigator: Kim Connelly, MD
      • Contact: Kim Connelly, MD
• United Kingdom
  • London, United Kingdom
    • Not yet recruiting
    • University College London
    • Contact: Charlotte Manisty, MD
    • Principal Investigator: Charlotte Manisty, MD
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Not yet recruiting
      • Brigham and Women's Hospital
      • Principal Investigator: Anju Nohria, MD
      • Contact: Anju Nohria, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients (age ≥18 years) with cancer therapy completed more than 6 months prior (other than hormonal therapy) and no plan for further cancer treatments with potential risk for CTRCD.
• Prior cancer therapy with anthracyclines and/ or HER2-targeted therapy.
• Prior asymptomatic, moderate CTRCD, defined using the European Society of Cardiology criteria (≥10% drop in LVEF from baseline to 40% to 49.9% OR <10% drop to 40-49.9% with a reduction in GLS by >15% or new abnormal Troponin I/T or NT-proBNP), diagnosed within 1 year of completing potentially cardiotoxic cancer therapy.
• Current use of ≥1 HF medication started for CTRCD for at least 6 months with LVEF ≥55% by recently performed (≤6 months) echocardiogram, normal NT-proBNP, and no symptoms attributable to HF.
• Confirmation of LVEF ≥55% and normal volumes at baseline CMR (i.e., some patients recruited based on echocardiography, may be excluded if baseline CMR LVEF/volumes are not normal). This is included given that the primary outcome includes the use of CMR LVEF.

Exclusion Criteria:

• Indication for continuation of HF medications i.e., ongoing HF symptoms, chronic kidney disease (CKD), vascular disease, atrial or ventricular arrythmias, other (note: participants with hypertension will be switched to other guideline-based antihypertensive therapy).
• Contraindications for CMR (e.g., MRI non-compatible implanted pacemakers).
• Patients with severe CTRCD defined as having a nadir LVEF <40% due to the known poor prognosis in these patients.
• Continued use of loop diuretic therapy for heart failure purposes i.e., furosemide.
• Life expectancy <1 year or metastatic disease.
• Prior history of major cardiovascular event (defined as myocardial infarction, cerebral vascular event, admission for HF) or therapeutic cardiovascular procedure (e.g., percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG)).
• Issues that prevent communication, understanding or presentation for study-related visits and inability to provide informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard of Care Group; This group with continue with their heart failure medication(s) for at least 1 year.
Experimental: Stop Group; This group will stop their heart failure medication(s) under the supervision of the study team. The investigators expect most participants in the STOP group to only be on beta-blockers and/or angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). The ACEi or ARB will be stopped first. The ACEi or ARB will be reduced by 50% every 7 days and stopped 7 days after 25% of maximal recommended dose for HF is reached. At this point (or at baseline if only on BB), the BB dose will be reduced by 50% every 7 days then stopped once 25% of the maximal dose is reached.	Other: Stopping Heart Failure Medication(s); This group will stop their heart failure medication(s) under the supervision of the study team.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cancer Therapy Related Cardiac Dysfunction Relapse	To compare the proportion of those that develop by 1 year of follow-up one or both of the following (i) left ventricular ejection fraction <50% by cardiac magnetic resonance (CMR) (ii) new heart failure signs (at least two physical findings or one physical finding and one laboratory finding) AND symptoms (at least one) with the initiation of qualifying heart failure therapy.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in cardiac magnetic resonance parameters	Differences between the two groups in the following measures.; Changes in CMR LVEF as a continuous parameter.; Proportion of participants with increased CMR indexed LV volumes by ≥10% to higher-than-normal limits.; Proportion of participants with decline in CMR LVEF to <50% with a >10% absolute fall compared to pre-HF medication withdrawal.; CMR peak systolic global longitudinal strain (GLS) worsening by >15%.	1 year
Left ventricular diastolic function	Proportion of participants with new diastolic dysfunction or worsening diastolic function ≥1 grade by echocardiography between the two study groups.	1 year
Cost effectiveness analysis	We will compare the cost per quality adjusted life years between the two study groups.	1 year
Non-adherence of heart failure medication(s)	Proportion of participants with non-adherence of heart failure medication(s) by 1 year between the two study groups. Non-adherence is defined in the STOP group as the proportion of participants in whom successful cessation of all medications used to treat CTRCD was not possible or re-addition of the same medications used in that participant for HF was necessary for non-HF indications (e.g., palpitations). In the standard of care (SOC) group non-adherence is defined as the proportion of participants who stopped all HF medications used to treat CTRCD.	1 year
N-terminal pro B-type Natriuretic Peptide (NT-pro BNP)	Doubling of NT-pro BNP compared to pre-HF therapy cessation between the two study groups.	1 year
Changes in quality of life score	Difference in patient questionnaires scores between the two groups using the following patient questionnaires: Kansas City Cardiomyopathy Questionnaire; Short Form (SF) Survey -36; EQ-5D-5L	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longer term changes in cardiac magnetic resonance parameters	Differences between the two groups in the following measures.; Changes in CMR LVEF as a continuous parameter.; Proportion of participants with increased CMR indexed LV volumes by ≥10% to higher-than-normal limits.; Proportion of participants with decline in CMR LVEF to <50% with a >10% absolute fall compared to pre-HF medication withdrawal.; CMR peak systolic global longitudinal strain (GLS) worsening by >15%.	5 years
Longer term changes in left ventricular diastolic function	Proportion of participants with new diastolic dysfunction or worsening diastolic function ≥1 grade by echocardiography between the two study groups.	3 and 5 years
Changes in quality of life score	Difference in patient questionnaires scores between the two groups using the following patient questionnaires: Kansas City Cardiomyopathy Questionnaire; SF-36; EQ-5D-5L	3 and
Impact of gender	Differences in the GENESIS-PRAXY score between groups	1 year
Novel biomarkers and genomic factors	Incidence of novel biomarkers and genomic factors that may determine the risk of developing the primary endpoint between the two groups.	1 year
Clinical heart failure	Difference in proportion of participants with clinical HF between the two groups.	1 year

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: University College London Hospitals; Brigham and Women's Hospital; University of Alberta; Unity Health Toronto; Hamilton Health Sciences Corporation; St. Boniface Hospital; Alberta Health Services, Calgary; Baker Heart and Diabetes Institute; University of Ottawa Heart Institute, Canada

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2024
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2031

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 27, 2023

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: cancer therapy related cardiac dysfunction
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Cardiotoxicity; Physiological Effects of Drugs; Protective Agents; Cariostatic Agents; Tin Fluorides
• Other Study ID Numbers: STOPMED-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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