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

Trial Summary

What is the purpose of this 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.

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 data supports the effectiveness of the drug carvedilol for cancer survivors stopping heart medications?

Carvedilol has been shown to protect the heart from damage caused by certain cancer treatments and improve heart function in patients with heart failure. It reduces mortality and hospitalizations in heart failure patients, suggesting it may help cancer survivors who need to stop heart medications. ^{1 2 3 4 5}

Is it safe to stop heart medications like carvedilol for cancer survivors?

Carvedilol is generally well tolerated in patients with heart failure, but there is no specific evidence on the safety of stopping heart medications like carvedilol in cancer survivors who have recovered from treatment-related heart issues. A study is being conducted to evaluate if stopping these medications is safe for low-risk patients. ^{2 3 4 5 6}

How does stopping carvedilol differ from other heart failure treatments for cancer survivors?

Stopping carvedilol, a beta-blocker, is unique because it has been shown to protect against heart damage caused by certain cancer drugs like anthracyclines, which can lead to heart failure. This approach is different from other treatments that may not specifically address the heart damage caused by cancer therapies. ^{1 5 7 8 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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 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.

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+

Findings from Research

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]

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 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]

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]

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]

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 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 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]

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]

References

1. India pubmed.ncbi.nlm.nih.gov

Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway. [2019]

2. England pubmed.ncbi.nlm.nih.gov

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

3. New Zealand pubmed.ncbi.nlm.nih.gov

Carvedilol: a review of its use in chronic heart failure. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical Pharmacology of Carvedilol. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Protective effect of carvedilol in cardiomyopathy caused by anthracyclines in patients suffering from breast cancer and lymphoma. [2019]

6. Australia pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Cessation Of Pharmacotherapy In Recovered Chemotherapy-induced cardioToxicity (COP-RCT): A Pilot Study. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Association of Neurohormonal Antagonists on Incident Cardiotoxicity in Patients With Breast Cancer. [2023]

8. Japan pubmed.ncbi.nlm.nih.gov

Five cases of anthracycline-induced cardiomyopathy effectively treated with carvedilol. [2019]

9. India pubmed.ncbi.nlm.nih.gov

Preventive role of carvedilol in adriamycin-induced cardiomyopathy. [2018]