Antineoplastics Toxicity, Cancer, Cardiac Toxicity, Cardiotoxicity, Heart Failure
Conditions
Keywords
cancer therapy related cardiac dysfunction
Brief summary
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 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.
Interventions
OTHERStopping Heart Failure Medication(s)
This group will stop their heart failure medication(s) under the supervision of the study team.
Sponsors
Dinesh Thavendiranathan
Unity Health Toronto
Hamilton Health Sciences Corporation
St. Boniface Hospital
Ottawa Heart Institute Research Corporation
University College London Hospitals
Brigham and Women's Hospital
Baker Heart and Diabetes Institute
University of California, Los Angeles
Alberta Health services
Hospital Universitario La Paz
Liverpool Heart and Chest Hospital NHS Foundation Trust
Guy's and St Thomas' NHS Foundation Trust
Maria Sklodowska-Curie National Research Institute of Oncology
Memorial Sloan Kettering Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 to severe CTRCD, defined using the ESC/ICOS criteria (MODERATE: ≥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 or SEVERE: new LVEF reduction to \<40% from normal baseline LVEF), 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 ≥50% by recently performed (≤6 months) echocardiogram, normal sex and age adjusted NT-proBNP or BNP ≤97.5th Centile, and no symptoms attributable to HF. * Reference ranges for NT-proBNP and BNP by age and sex: \<30 years: Female: NT-proBNP ≤196 pg/ml, BNP ≤55 pg/ml Male: NT-proBNP ≤104 pg/ml, BNP ≤29 pg/ml 30-39 years: Female: NT-proBNP ≤209 pg/ml, BNP ≤59 pg/ml Male: NT-proBNP ≤102 pg/ml, BNP ≤29 pg/ml 40-49 years: Female: NT-proBNP ≤233 pg/ml, BNP ≤65 pg/ml Male: NT-proBNP ≤137 pg/ml, BNP ≤38 pg/ml 50-59 years: Female: NT-proBNP ≤299 pg/ml, BNP ≤84 pg/ml Male: NT-proBNP ≤195 pg/ml, BNP ≤55 pg/ml 60-69 years: Female: NT-proBNP ≤399 pg/ml, BNP ≤112 pg/ml Male: NT-proBNP ≤333 pg/ml, BNP ≤93 pg/ml 70-79 years: Female: NT-proBNP ≤743 pg/ml, BNP ≤208 pg/ml Male: NT-proBNP ≤763 pg/ml, BNP ≤214 pg/ml ≥80 years: Female: NT-proBNP ≤2,704 pg/ml, BNP ≤757 pg/ml Male: NT-proBNP ≤6,792 pg/ml, BNP ≤1,902 pg/ml * Confirmation of LVEF ≥50% 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. * Normal Ventricular end-diastolic volumes by CMR as defined by the Society of Cardiac Magnetic Resonance 2025 update.
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 pre-CTRCD will continue their antihypertensive as only medication started for CTRCD will be ceased). * Contraindications for CMR (e.g., MRI non-compatible implanted pacemakers). * Patients with cardiac devices i.e. defibrillator, CRT, pacemaker, etc. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cancer Therapy Related Cardiac Dysfunction Relapse | 1 year | 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% and an absolute decline of \>5% from baseline 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dichotomized Primary Outcome | 1 year | The primary outcome stratified by baseline LVEF of 50-55% vs \>55% . |
| Moderate to severe CTRCD by 1 year | 1 year | The development of moderate to severe asymptomatic CTRCD as per the 2022 ESC guidelines by 1 year follow-up. |
| Changes in cardiac magnetic resonance parameters | 1 year | Differences between the two groups in the following measures. 1. Changes in CMR LVEF as a continuous parameter. 2. Proportion of participants with increased CMR indexed LV volumes by ≥10% to higher-than-normal limits. 3. Proportion of participants with decline in CMR LVEF to \<50% with a \>10% absolute fall compared to pre-HF medication withdrawal. 4. CMR peak systolic global longitudinal strain (GLS) worsening by \>15%. |
| Left ventricular diastolic function | 1 year | Proportion of participants with new diastolic dysfunction or worsening diastolic function ≥1 grade by echocardiography between the two study groups. |
| Non-adherence of heart failure medication(s) | 1 year | 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. |
| N-terminal pro B-type Natriuretic Peptide (NT-pro BNP) | 1 year | Doubling of NT-pro BNP compared to pre-HF therapy cessation between the two study groups. |
| Changes in quality of life score | 1 year | Difference in patient questionnaires scores between the two groups using the following patient questionnaires: 1. Kansas City Cardiomyopathy Questionnaire 2. Short Form (SF) Survey -36 3. EQ-5D-5L |
| Cost effectiveness analysis | 1 year | We will compare the cost per quality adjusted life years between the two study groups. |
| Proportion of participants developing the primary outcome by whether they developed moderate versus severe CTRCD at original diagnosis | 1 year | The proportion of those that develop the primary outcome stratified by CTRCD LVEF \<40% or ≥40% |
| Incidence of novel biomarkers and genomic factors that may determine the risk of developing the primary endpoint | 1 year | Incidence of cardiac, inflammatory, endothelial and other novel biomarkers and genomic factors that may determine the risk of developing the primary endpoint. |
| Proportion of participants developing the primary outcome stratified by natriuretic peptides thresholds. | 1 year | Proportion of participants developing the primary outcome stratified by natriuretic peptides thresholds. |
Countries
Australia, Canada, Poland, Spain, United Kingdom, United States
Contacts
CONTACTPaaladinesh Thavendiranathan, MD
CONTACTSadia Khan
Outcome results
None listed