Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines

Paaladinesh Thavendiranathan; Christian Houbois; Thomas H Marwick; Tiffanie Kei; Sudipta Saha; Kyle Runeckles; Flora Huang; Tamar Shalmon; Kevin E Thorpe; Rossanna C Pezo; Anca Prica; Dawn Maze; Husam Abdel-Qadir; Kim A Connelly; Joyce Chan; Filio Billia; Coleen Power; Kate Hanneman; Bernd J Wintersperger; Christine Brezden-Masley; Eitan Amir

doi:10.1093/ehjcvp/pvad031

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.

Authors

Paaladinesh Thavendiranathan¹, Christian Houbois^{2

3}, Thomas H Marwick⁴, Tiffanie Kei¹, Sudipta Saha⁵, Kyle Runeckles⁵, Flora Huang¹, Tamar Shalmon¹, Kevin E Thorpe⁶, Rossanna C Pezo⁷, Anca Prica⁸, Dawn Maze⁸, Husam Abdel-Qadir^{1

9}, Kim A Connelly¹⁰, Joyce Chan¹¹, Filio Billia¹¹, Coleen Power¹, Kate Hanneman^{12

3}, Bernd J Wintersperger^{12

3}, Christine Brezden-Masley¹³, Eitan Amir¹⁴

Affiliations

¹ Department of Medicine, Division of Cardiology, Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
² Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
³ Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
⁴ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Victoria, Australia.
⁵ Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁶ Dalla Lana School of Public Health, University of Toronto and Applied Health Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
⁷ Department of Medicine, Division of Medical Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
⁸ Department of Medicine, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
⁹ Women's College Hospital (WCH), Toronto, ON, Canada.
¹⁰ Keenan Research Centre, Li Ka Shing Knowledge Institute, Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
¹¹ Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
¹² Joint Department of Medical Imaging, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
¹³ Department of Medicine, Division of Medical Oncology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Medicine, Division of Medical Oncology, Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Abstract

Background and aims: Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction (LVEF) in anthracycline-treated patients at increased risk for CTRCD.

Methods: In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by >10% to <53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP).

Results: We randomized 112 patients (56.9 ± 13.6 years, 87 female, and 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (P = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (P = 0.20) or end-systolic volume (P = 0.12), CMR myocardial edema and/or fibrosis (P = 0.06-0.47), or peak hsTnI (P ≥ 0.99) and BNP (P = 0.23). CTRCD incidence was similar (4% versus 4%, P ≥ 0.99). There was no difference in adverse events.

Conclusions: In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate early LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes.

Trial registration: NCT03186404.

Keywords: Anthracycline; Cardiotoxicity; Magnetic resonance imaging; Primary prevention; Statins.

Publication types

Randomized Controlled Trial
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Anthracyclines / adverse effects
Antibiotics, Antineoplastic / adverse effects
Atorvastatin / adverse effects
Biomarkers
Breast Neoplasms* / chemically induced
Breast Neoplasms* / drug therapy
Cardiotoxicity / drug therapy
Female
Heart Diseases* / diagnosis
Heart Diseases* / diagnostic imaging
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects
Stroke Volume
Ventricular Function, Left

Substances

Anthracyclines
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Atorvastatin
Antibiotics, Antineoplastic
Biomarkers

Associated data

ClinicalTrials.gov/NCT03186404

Grants and funding

147 814/CIHR/Canada