Stopping Heart Medications for Cancer Survivors

(STOP-MED Trial)

Recruiting at 10 trial locations

Overseen By Paaladinesh Thavendiranathan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University Health Network, Toronto

Must be taking: Heart failure medications

Must not be taking: Loop diuretics

Disqualifiers: Chronic kidney disease, Vascular disease, Arrhythmias, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 1 year

335 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether cancer survivors who previously experienced heart problems due to cancer treatment can safely stop taking heart medications once their heart function normalizes. The study compares two groups: one continues their heart medication, while the other stops it under medical supervision. It suits those who have undergone cancer treatments like anthracyclines or HER2-targeted therapy, have since recovered heart function, and are currently on heart medications such as Carvedilol (also known as Coreg). Participants will undergo various heart health assessments over several years to ensure safety. As a Phase 4 trial, this study involves treatments already FDA-approved and proven effective, aiming to understand how they benefit more patients.

Will I have to stop taking my current medications?

The trial is designed to assess the safety of stopping heart failure medications in cancer survivors whose heart function has returned to normal. Participants will be randomly assigned to either continue or stop their heart medications, so you may be asked to stop taking them if you join the trial.

What is the safety track record for stopping heart failure medications in cancer survivors?

Research is examining whether cancer survivors with recovered heart function can safely discontinue certain heart medications. These medications, such as ACE inhibitors, ARBs, and beta-blockers, typically protect the heart. However, they have not shown significant benefits in preventing heart damage specifically from cancer treatments. This suggests these drugs might not be as crucial for heart health in this context as previously thought.

When patients stopped taking renin-angiotensin system inhibitors, nearly half experienced some heart strain, only slightly more than those who continued the medication. This indicates that discontinuing these medications might not significantly increase heart problems for those with recovered heart function.

Currently, the trial is in a phase with substantial safety data available. It aims to determine if stopping these medications is safe for individuals whose heart health has returned to normal after cancer treatment. Participants will receive close monitoring to detect any heart issues early. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores the impact of stopping heart failure medications in cancer survivors, a group for whom long-term medication use might not be necessary. Unlike the standard of care where heart failure medications like beta-blockers and ACE inhibitors are continued indefinitely, this approach systematically reduces and stops these medications under supervision. By potentially reducing medication burden, this method could improve quality of life for cancer survivors who no longer need these drugs. The trial aims to find out if stopping these medications is safe and if it could be a viable option for those who are in remission from cancer and no longer exhibit heart failure symptoms.

What evidence suggests that stopping heart failure medications could be safe for cancer survivors with recovered heart function?

Research suggests that cancer survivors with normal heart function might safely stop taking heart failure medications. In this trial, participants in the "Stop Group" will discontinue their heart failure medications, such as beta-blockers and ACE inhibitors, under the study team's supervision. Studies have shown that these drugs, which help relax blood vessels, may not significantly reduce long-term heart problems for these patients. Additionally, these medications can cause side effects and lead to ongoing costs and inconvenience. Although limited evidence exists specifically about stopping these medications, current data suggest it might be possible without increasing heart risks. This trial aims to determine if stopping these medications is as safe as continuing them, as will be done in the "Standard of Care Group." ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for cancer survivors who've had heart issues (CTRCD) due to cancer therapy but now have normal heart function. They should have completed their cancer treatment and be on heart medications with no other reason, like kidney disease, to keep taking them.

Inclusion Criteria

I finished cancer treatment over 6 months ago and have no plans for more treatments that could affect my heart.

I have previously received treatment with anthracyclines or drugs targeting HER2.

My heart's pumping ability is normal as confirmed by a CMR test.

Exclusion Criteria

I need to continue heart failure medications due to ongoing symptoms or other conditions like CKD.

I have had a major heart event or heart surgery in the past.

My heart's pumping ability is severely reduced.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo a cardiac MRI and baseline safety assessments

1 week

1 visit (in-person)

Treatment

Participants are randomized to either stop or continue heart failure medications with dose adjustments as necessary

1 year

Regular visits for safety assessments at 6-8 weeks, 6 and 9 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including cardiac MRI at 1 and 5 years

5 years

Visits at 1 year, 3 years, and 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Stopping Heart Failure Medication(s)

Trial Overview The study tests if it's safe for these patients to stop taking their heart failure meds compared to those who continue. It involves regular check-ups and cardiac MRIs over five years to see if there's any difference in the return of heart problems between the two groups.

How Is the Trial Designed?

Group I: Stop Group Experimental Treatment 1 Intervention

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 (BB) 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. Participants on 75% of the maximal dose will be reduced to 50% of the maximal dose before reducing by 50% every 7 days. Other HF medications will be stopped as follows: MRA: reduce by 50% every 7 days then stop once 50% of maximal dose is reached; SGLT2i: stopped without titration, ARNi: reduce by 50% every 7 days then stop once 25% of the maximal dose.

Group II: Standard of Care Group Active Control 1 Intervention

This group with continue with their heart failure medication(s) for at least 1 year.

Stopping Heart Failure Medication(s) is already approved in United States, European Union for the following indications:

Approved in United States as Coreg for:

• Heart failure
• High blood pressure
• Left ventricular dysfunction following myocardial infarction

Approved in European Union as Carvedilol for:

• Heart failure
• Hypertension
• Left ventricular dysfunction following myocardial infarction

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Unity Health Toronto

Collaborator

Trials

572

Recruited

470,000+

Hamilton Health Sciences Corporation

Collaborator

Trials

380

Recruited

345,000+

St. Boniface Hospital

Collaborator

Trials

55

Recruited

15,000+

University of Alberta

Collaborator

Trials

957

Recruited

437,000+

University of Ottawa Heart Institute, Canada

Collaborator

Trials

2

Recruited

1,700+

University College London Hospitals

Collaborator

Trials

204

Recruited

1,221,000+

Alberta Health Services, Calgary

Collaborator

Trials

15

Recruited

2,600+

Brigham and Women's Hospital

Collaborator

Trials

1,694

Recruited

14,790,000+

Baker Heart and Diabetes Institute

Collaborator

Trials

38

Recruited

10,900+

Published Research Related to This Trial

Carvedilol significantly improves left ventricular ejection fraction (LVEF) and reduces mortality in patients with chronic heart failure (CHF), as shown in multiple studies including the US Carvedilol Heart Failure Trials Program with 1094 participants.

Compared to metoprolol, carvedilol demonstrated lower mortality rates in patients with CHF, indicating it may be the preferred beta-blocker for treatment, while also being well tolerated with fewer adverse events compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol: a review of its use in chronic heart failure. Keating, GM., Jarvis, B.[2022]

In a study of 459 breast cancer patients, factors such as older age, recent smoking, and receiving both trastuzumab and anthracycline therapies were linked to a higher risk of developing cardiotoxicity after chemotherapy.

The use of neurohormonal antagonists like ACE inhibitors, ARBs, or β-blockers did not show any significant protective effect against cardiotoxicity in these patients, indicating that these medications may not prevent heart damage associated with cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer. Umadat, G., Ray, J., Cornell, L., et al.[2023]

In a study of 54 cancer patients undergoing Adriamycin treatment, the use of carvedilol was associated with the preservation of left ventricular function, as indicated by stable ejection fraction and diameter measurements over six months.

Patients receiving carvedilol showed no significant decline in heart function, while those in the control group experienced a significant drop in ejection fraction and increased heart size, suggesting carvedilol's protective effect against Adriamycin-induced cardiomyopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventive role of carvedilol in adriamycin-induced cardiomyopathy. Jhorawat, R., Kumari, S., Varma, SC., et al.[2018]

Carvedilol, a non-selective beta-blocker, has shown significant benefits in reducing mortality and morbidity in patients with mild-to-moderate heart failure, as evidenced by large-scale studies like the US Carvedilol Heart Failure Program.

Preliminary results from the COPERNICUS study indicate that carvedilol may also improve outcomes in patients with advanced heart failure, suggesting its unique properties could offer advantages over other beta-blockers, although further studies are needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol in the treatment of chronic heart failure. Moe, G.[2019]

Carvedilol (CAR) significantly reduces the migration and invasion of breast cancer cells, indicating its potential as an anti-metastatic agent.

The mechanism of action involves the inhibition of Src activation through different signaling pathways: the cAMP/PKA-Src pathway in MDA-MB-231 cells and the PKCδ-Src pathway in MCF-7 cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. Dezong, G., Zhongbing, M., Qinye, F., et al.[2019]

In a clinical trial involving 66 patients with breast cancer and lymphoma, carvedilol was evaluated for its protective effects against cardiomyopathy caused by anthracycline chemotherapy.

The study found that a daily dose of 12.5mg of carvedilol provided protection against diastolic dysfunction, while a higher dose of 25mg offered protection against both systolic and diastolic dysfunction, suggesting its potential as a cardioprotective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma. Salehi, R., Zamani, B., Esfehani, A., et al.[2019]

Carvedilol is an effective treatment for heart failure, showing significant benefits such as reduced hospitalization and mortality rates, as well as improvements in left ventricular function.

The drug's multiple actions, including nonselective beta-blockade and antioxidant properties, contribute to its therapeutic efficacy in managing heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacology of Carvedilol. Carlson, W., Oberg, K.[2019]

The COP-RCT study aims to determine if stopping cardioprotective therapy (CPT) is safe for low-risk cancer survivors who have recovered from cancer therapeutics-related cardiac dysfunction (CTRCD), with a focus on changes in left ventricular ejection fraction (LVEF) over 6 months.

This multicentre trial will provide crucial evidence on the feasibility of CPT cessation, potentially reducing long-term medication burden and side effects for millions of cancer survivors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Cessation Of Pharmacotherapy In Recovered Chemotherapy-induced cardioToxicity (COP-RCT): A Pilot Study. Yu, C., Negishi, T., Pathan, F., et al.[2023]

In a report of 5 cases, severe chronic heart failure caused by anthracycline-induced cardiomyopathy (ACM) was effectively treated with the beta-blocker carvedilol.

Patients showed persistent improvement in left ventricular function and cardiac symptoms, indicating that carvedilol could be a promising treatment option for ACM, similar to its use in other chronic heart failure cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five cases of anthracycline-induced cardiomyopathy effectively treated with carvedilol. Mukai, Y., Yoshida, T., Nakaike, R., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7418354/

Cardiovascular Outcomes in Relation to Antihypertensive ... Whereas there was no difference in risk of cardiac events comparing ACEi/ARB with BB use among cancer‐free women (HR = 0.99 [0.88–1.12]), among cancer survivors ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12066945/

Cardioprotective drugs and heart failure/cardiomyopathy ... We found no evidence that general practitioner prescribed beta-blocker, ARB, or ACEi use was associated with a reduced incidence of HF/CM in this population.

3. ahajournals.org ahajournals.org/doi/10.1161/CIRCOUTCOMES.117.004356?doi=10.1161/CIRCOUTCOMES.117.004356

Clinical Events After Discontinuation of β‐Blockers in ... β-blockers have been among the first medications shown to improve outcomes after acute myocardial infarction (AMI).

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525730414001946

Incidental Receipt of Cardiac Medications and Survival ... The aim of this study was to estimate survival outcomes in patients receiving incidental cardiac medications during treatment for lung cancer, and to compare ...

5. academic.oup.com academic.oup.com/ehjcvp/advance-article/doi/10.1093/ehjcvp/pvaf051/8241184

Long-term effectiveness of ACE inhibitors or angiotensin ... In summary, we estimated that ACEi/ARBs had little or no effect on the 5-year risk of death, myocardial infarction, and heart failure among low- ...

6. withpower.com withpower.com/trial/phase-4-antineoplastics-toxicity-2024-bd84d

Stopping Heart Medications for Cancer Survivors The use of neurohormonal antagonists like ACE inhibitors, ARBs, or β-blockers did not show any significant protective effect against cardiotoxicity in these ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05880160

Study Details | NCT05880160 | Safety of Withdrawal ... The investigators will carefully stop their heart drugs whilst monitoring them closely with special heart scans and blood tests to detect problems early. The ...

8. academic.oup.com academic.oup.com/eurheartj/article/45/13/1146/7339818

Discontinuation vs. continuation of renin–angiotensin system ... Forty-eight per cent of patients sustained myocardial injury after stopping RAS inhibitors, compared with 41% of patients who continued therapy.