Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline Pilot Study

NCT03186404 | Unknown Phase 2 DMC

• 1 other identifier: SPARE HF Pilot
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

Brief Summary

Anthracycline (AC) chemotherapy has substantially reduced the mortality rate from several common cancers globally. Unfortunately, AC treatment is associated with up to 19% risk of heart failure (HF). Current standard of care for preventing AC induced HF (AIHF) is cardiac surveillance followed by initiation of treatment once HF is diagnosed. With this approach 89% of patients fail to recover heart function and 46% will experience adverse cardiac events. Therefore there is a need for effective preventive therapy to reduce the risk of AIHF. Based on small human studies, animal studies, and our own pilot data, statins are an ideal class of drug for this purpose. We will conduct a pilot double blinded, placebo controlled, randomized controlled trial to assess whether pre-treatment with statins before AC can prevent heart dysfunction. Eligible patients with cardiovascular risk factors scheduled to receive AC will be recruited. They will be randomized to statin therapy or placebo and followed until the end of cancer treatment. Primary outcome is the difference in cardiac MRI-determined left ventricular ejection fraction between pre-AC and end of treatment.

Conditions

Cancer; Heart Failure; Cardiotoxicity

Outcome Measures

Primary Outcomes (1)

• Cardiac MRI measured LVEF within 4 weeks of anthracycline completion

  Cardiac MRI LVEF at the end of treatment will be measured before cancer treatment and within 4 weeks after completion of anthracycline-based treatment. The pre-treatment measurement will facilitate a baseline adjusted comparison between placebo and statin treated groups.

  Within 4 weeks of cancer therapy completion

Other Outcomes (7)

• Cardiac MRI measured LV end diastolic volume (LVEDV) and end systolic volume (LVESV) at the end of treatment

  Within 4 weeks of anthracycline completion

• The incidence of cardiotoxicity

  From start of anthracycline therapy to upto 4 weeks of anthracycline completion

• Interruption of study drug due to side effects or permanent cessation of study drug or cancer treatment due to cardiac dysfunction

  From start of anthracycline therapy to upto 4 weeks of anthracycline completion

Study Arms (2)

Placebos

PLACEBO COMPARATOR

Placebos

Drug: Placebo oral tablet

Statin

EXPERIMENTAL

Atorvastatin 40mg

Drug: Atorvastatin

Interventions

Atorvastatin DRUG

Atorvastatin 40mg OD

Also known as: Statin

Statin

Placebo oral tablet DRUG

Placebo

Also known as: Placebo

Placebos

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with one of the following malignancies requiring anthracycline based chemotherapy with a curative intent: breast cancer; aggressive lymphomas; leukemia (acute myelogenous leukemia, acute lymphoblastic leukemia, mixed phenotype acute leukemia) or; sarcoma
• Patients with high cardiovascular risk defined as:
• I. ≥60 years and at least one of the following:
• i. Compromised cardiac function based on baseline LVEF \<55% measured by echocardiography or MUGA or moderate left sided valvular heart disease (moderate mitral or aortic regurgitation or stenosis) ii. Planned cumulative doxorubicin dose equivalent 200mg/m² or more iii. Prior anthracycline therapy at any cumulative dose or prior chest/mediastinal radiation therapy iv. Any one of hypertension, smoking, obesity (BMI≥30), history of cardiomyopathy or heart failure but with recovered LVEF to ≥ 50%
• II. Age \<60 years with one of the following:
• i. and at least 2 of the risk factors listed above (I i-iv) ii. type 2 diabetes with age \<40 iii. type 1 diabetes duration \<15 years
• III. High anthracycline dose defined as ≥250mg/m² of doxorubicin, ≥600mg/m² epirubicin, or other isoequivalent dose
• Living within geographic area conducive to repeated clinical and imaging follow-up

You may not qualify if:

• Participating in another clinical research study where randomization would be unacceptable
• Previous history of statin intolerance
• Already on statin therapy or known statin indicated condition:
• I. atherosclerosis i. myocardial infarction ii. acute coronary syndrome iii. stable angina iv. documented coronary disease by angiography (\>10% stenosis) v. stroke vi. TIA vii. documented carotid disease viii. peripheral arterial disease ix. claudication and/or ABI \<0.9
• II. abdominal aortic aneurysm (\>3.0cm or previous aneurysm surgery)
• III. chronic kidney disease (\>3 months duration and ACR \>3.0mg/mmol or eGFR \<60mL/min/1.73m²)
• CK level \>3x upper limit of normal
• Evidence of hepatic dysfunction (ALT level \>2x upper limit of normal)
• On a drug that is a strong inhibitor of cytochrome P450 3A4 or may require such treatment during the treatment period (because atorvastatin is metabolized by this pathway)
• Significant valvular heart disease defined as severe stenotic or regurgitant lesions of any of the cardiac valves
• Life expectancy less than 12 months
• Contraindication to cardiac MRI (e.g. implanted pacemakers, ICDs, other implanted ferromagnetic objects unsafe for cardiac MRI or will result in significant artifact, eGFR \<30)
• Creatinine \>177umol/L
• Known history of uncontrolled hypothyroidism (TSH level \>1.5x upper limit of normal)

Sponsors & Collaborators

• University Health Network, Toronto: lead
• Mount Sinai Hospital, Canada: collaborator
• Unity Health Toronto: collaborator
• Sunnybrook Health Sciences Centre: collaborator
• Scarborough General Hospital: collaborator

Study Sites (1)

Toronto General Hospital

Toronto, Ontario, M5G 2N2, Canada

Location

Related Publications (1)

• Thavendiranathan P, Houbois C, Marwick TH, Kei T, Saha S, Runeckles K, Huang F, Shalmon T, Thorpe KE, Pezo RC, Prica A, Maze D, Abdel-Qadir H, Connelly KA, Chan J, Billia F, Power C, Hanneman K, Wintersperger BJ, Brezden-Masley C, Amir E. Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines. Eur Heart J Cardiovasc Pharmacother. 2023 Sep 20;9(6):515-525. doi: 10.1093/ehjcvp/pvad031.

  PMID: 37120736 DERIVED

MeSH Terms

Conditions

Neoplasms; Heart Failure; Cardiotoxicity

Interventions

Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses

Study Officials

• Paaladinesh Thavendiranathan

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

• Eitan Amir

  University Health Network, Toronto

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 9, 2017
• First Posted: June 14, 2017
• Study Start: May 10, 2018
• Primary Completion: December 21, 2021
• Study Completion: December 1, 2023
• Last Updated: February 8, 2022

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)