Statins for the Primary Prevention of Heart Failure in Patients Receiving Anthracycline Pilot Study (SPARE-HF)

Randomized Double Blind Placebo Controlled Trial of Statins for the Primary pREvention of Heart Failure in Patients With Cancer Receiving Anthracycline Based Chemotherapy

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure; Cancer; Cardiotoxicity
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Atorvastatin

Detailed Description

STUDY DESIGN: This is a double blind, placebo controlled randomized controlled trial (RCT). We will also use stratification to ensure that the proportion of patients with different malignancies is balanced between the study arms.

PATIENT RECRUITMENT: Patients will be recruited from respective oncology clinics at Princess Margaret Hospital, Mount Sinai Hospital, St. Michael's Hospital, Sunnybrook Health Sciences Centre and Scarborough General Hospital.

INTERVENTION: Patients will receive treatment with 40mg/day of atorvastatin or placebo started 2-10 days prior to the initiation of AC and continued for up to one month after completion of the AC portion of cancer treatment.

CARDIAC MRI (CMR): Studies will be performed on a 3.0T scanner (Siemens) and will include complete function and tissue characterization. CMR studies will be performed pre-therapy, after completion of AC, and 2 years after completion of AC. After de-identification and randomization, a research assistant blinded to all clinical data will perform all CMR analysis using commercially available software.

ECHOCARDIOGRAPHY: Routine echocardiography studies will be performed at baseline, post-anthracycline completion, and at 6 months, 1 year, and 2 years follow up.

SERUM BIOMARKERS: Blood work will be obtained on the day of baseline imaging, immediately after each cycle of anthracycline, on the day of post treatment imaging, and at the 6 months, 1 year and 2 year follow up. At each time point, optional samples of bio-banking may be collected. Blood sample collection will be done locally at the participant's respective site and transferred to University Health Network (UHN) biobank for future analysis or analysis of markers that are not available at all sites (e.g. high sensitivity troponin I and BNP).

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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

2. 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%

   OR

   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

   OR

   III. High anthracycline dose defined as ≥250mg/m² of doxorubicin, ≥600mg/m² epirubicin, or other isoequivalent dose

3. Living within geographic area conducive to repeated clinical and imaging follow-up

Exclusion Criteria:

1. Participating in another clinical research study where randomization would be unacceptable
2. Previous history of statin intolerance

3. 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)

4. CK level >3x upper limit of normal
5. Evidence of hepatic dysfunction (ALT level >2x upper limit of normal)
6. 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)
7. Significant valvular heart disease defined as severe stenotic or regurgitant lesions of any of the cardiac valves
8. Life expectancy less than 12 months
9. 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)
10. Creatinine >177umol/L
11. Known history of uncontrolled hypothyroidism (TSH level >1.5x upper limit of normal)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebos	Drug: Placebo oral tablet; Placebo; Other Names: Placebo
Experimental: Statin; Atorvastatin 40mg	Drug: Atorvastatin; Atorvastatin 40mg OD; Other Names: Statin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac MRI measured LV end diastolic volume (LVEDV) and end systolic volume (LVESV) at the end of treatment	these measures will be obtained at the same time as the LVEF measures with pre-treatment measurements facilitating a baseline adjusted comparison between placebo and statin treated groups	Within 4 weeks of anthracycline completion
The incidence of cardiotoxicity	defined by LVEF fall >10% from pre-cancer treatment assessment to <53%	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	as defined by reduction in drug dose or delay of cancer treatment by more than 1 week or permanent cessation	From start of anthracycline therapy to upto 4 weeks of anthracycline completion
Troponin I	Maximal increase in troponin I	Maximal increase in Troponin I between pre-anthracycline therapy to within 4 weeks of anthracycline completion
BNP	Maximal increase in BNP	From start of anthracycline therapy to within 4 weeks of cancer therapy completion
Myocardial strain	Maximal change in myocardial strain	From start of anthracycline therapy to within 4 weeks of cancer therapy completion
MRI tissue characterization parameters	Maximal change in myocardial tissue characterization parameters as measured by cardiac MRI from pre-anthracycline treatment to within 4 weeks of anthracycline completion	Within 4 weeks of anthracycline completion

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Collaborators: Sunnybrook Health Sciences Centre; Unity Health Toronto; Mount Sinai Hospital, Canada; Scarborough General Hospital
• Investigators: Principal Investigator: Paaladinesh Thavendiranathan, University Health Network, Toronto; Principal Investigator: Eitan Amir, University Health Network, Toronto

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2018
• Primary Completion (Actual): December 21, 2021
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: June 9, 2017
• First Submitted That Met QC Criteria: June 12, 2017
• First Posted (Actual): June 14, 2017

Study Record Updates

• Last Update Posted (Actual): February 8, 2022
• Last Update Submitted That Met QC Criteria: February 4, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• 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; Heart Failure; Cardiotoxicity; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: SPARE HF Pilot

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
• product manufactured in and exported from the U.S.: No