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Cardiology

Atorvastatin for Anthracycline-Associated Cardiac DysfunctionThe STOP-CA Randomized Clinical Trial

Educational Objective: To identify the key insights or developments described in this article.

1 Credit CME

JAMA

Published Online: August 8, 2023

Original Investigation

Article Information and Disclosures

Tomas G. Neilan, MD, MPH^1,2;

Thiago Quinaglia, MD, PhD¹;

Takeshi Onoue, MD³;

Syed S. Mahmood, MD, MPH¹;

Zsofia D. Drobni, MD⁴;

Hannah K. Gilman, BS¹;

Amanda Smith, MS³;

Julius C. Heemelaar, MD¹;

Priya Brahmbhatt, BS³;

Jor Sam Ho, MPH¹;

Supraja Sama, BS¹;

Jakub Svoboda, MD⁵;

Donna S. Neuberg, ScD⁶;

Jeremy S. Abramson, MD⁷;

Ephraim P. Hochberg, MD⁷;

Jefferey A. Barnes, MD, PhD⁷;

Philippe Armand, MD⁸;

Eric D. Jacobsen, MD⁸;

Caron A. Jacobson, MD⁸;

Austin I. Kim, MD⁸;

Jacob D. Soumerai, MD⁷;

Yuchi Han, MD³;

Robb S. Friedman, MD⁷;

Ann S. Lacasce, MD⁸;

Bonnie Ky, MD³;

Dan Landsburg, MD⁵;

Sunita Nasta, MD⁵;

Raymond Y. Kwong, MD⁹;

Michael Jerosch-Herold, PhD¹⁰;

Robert A. Redd, MS⁶;

Lanqi Hua, MS^2,11;

James L. Januzzi, MD^2,12;

Aarti Asnani, MD¹³;

Negareh Mousavi, MD¹⁴;

Marielle Scherrer-Crosbie, MD, PhD³

Author Affiliations

¹Cardiovascular Imaging Research Center, Division of Cardiology, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
²Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston
³Division of Cardiology, Hospital of the University of Pennsylvania, Philadelphia
⁴Heart and Vascular Center, Semmelweis University, Budapest, Hungary
⁵Division of Hematology/Oncology, Hospital of the University of Pennsylvania, Philadelphia
⁶Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts
⁷Division of Hematology-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston
⁸Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
⁹Cardiology Division, Brigham and Women’s Hospital, Boston, Massachusetts
¹⁰Department of Radiology, Brigham and Women’s Hospital, Boston, Massachusetts
¹¹Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston
¹²Heart Failure Trials, Baim Institute for Clinical Research, Boston, Massachusetts
¹³Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
¹⁴Division of Cardiology, McGill University Hospital, Montreal, Quebec, Canada

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Key Points

Question Does 1 year of treatment with atorvastatin, 40 mg/d, started prior to anthracycline-based chemotherapy among patients with lymphoma, reduce the chance of a significant decrease in left ventricular ejection fraction (LVEF) compared with placebo?

Findings In this randomized trial of 300 adult patients with lymphoma, the percentage of patients with a decrease in cardiac function (≥10% absolute decline in LVEF from prior to chemotherapy to a final value of <55% over the 12-month study period), among those randomized to atorvastatin was 9% compared with a rate of 22% among patients randomized to placebo. This difference met statistical significance.

Meaning Atorvastatin reduced cardiac functional impairment in patients with lymphoma treated with anthracyclines. This finding may support the use of atorvastatin in patients with lymphoma at risk of cardiac dysfunction due to anthracycline treatment.

Abstract

Importance Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use.

Objective To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction.

Design, Setting, and Participants Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022.

Interventions Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months.

Main Outcomes and Measures The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months.

Results Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups.

Conclusions and Relevance Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use.

Trial Registration ClinicalTrials.gov Identifier: NCT02943590

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Article Information

Corresponding Author: Tomas G. Neilan, MD, MPH, Cardio-oncology Program and Cardiovascular Imaging Research Center, Massachusetts General Hospital, 165 Cambridge St, Ste 400, Boston, MA 02114 (tneilan@mgh.harvard.edu).

Accepted for Publication: June 12, 2023.

Author Contributions: Drs Neilan and Scherrer-Crosbie had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Neilan, Mahmood, Gilman, Neuberg, Hochberg, Kwong, Redd, Asnani, Scherrer-Crosbie.

Acquisition, analysis, or interpretation of data: Neilan, Quinaglia, Onoue, Mahmood, Drobni, Smith, Heemelaar, Brahmbhatt, Ho, Sama, Svoboda, Neuberg, Abramson, Barnes, Armand, Jacobsen, Jacobson, Kim, Soumerai, Han, Friedman, Lacasce, Ky, Landsburg, Nasta, Kwong, Jerosch-Herold, Redd, Hua, Januzzi, Asnani, Mousavi, Scherrer-Crosbie.

Drafting of the manuscript: Neilan, Onoue, Gilman, Heemelaar, Ho, Redd, Hua, Januzzi, Scherrer-Crosbie.

Critical review of the manuscript for important intellectual content: Sama, Barnes, Kim.

Statistical analysis: Ho, Neuberg, Redd.

Obtained funding: Neilan, Scherrer-Crosbie.

Administrative, technical, or material support: Quinaglia, Onoue, Mahmood, Drobni, Gilman, Smith, Heemelaar, Brahmbhatt, Ho, Sama, Svoboda, Abramson, Hochberg, Jacobsen, Jacobson, Kim, Friedman, Lacasce, Ky, Nasta, Kwong, Asnani, Mousavi.

Supervision: Neilan, Gilman, Hochberg, Han, Kwong, Januzzi.

Conflict of Interest Disclosures: Dr Neilan reported receipt of personal fees for consulting from Bristol Myers Squibb; receipt of personal fees from Genentech, Roche, Sanofi, C4 Therapeutics, CardiolRx, and CRC Oncology; and receipt of grants from Bristol Myers Squibb and AstraZeneca. Dr Mahmood reported receipt of personal fees from AltaThera and Nektar Therapeutics. Dr Abramson reported receipt of personal fees from Celgene, Incyte, Takeda, Janssen, Genentech, Eli Lilly, Kite Pharma, AbbVie, AstraZeneca, Epizyme, Genmab, Century Therapeutics, Regeneron, MorphoSys, BeiGene, Mustang Bio, Ono Pharma, Kymera, Bluebird Bio, C4 Therapeutics, Caribou Biosciences, Interius, Cellectar, and Bristol Myers Squibb and receipt of grants from Bristol Myers Squibb, Seattle Genetics, Mustang Bio, Cellectis, and Merck. Dr Armand reported consulting for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, AstraZeneca, Genentech/Roche, Xencor, and Foresight; receipt of research funding/grants from Merck, Bristol Myers Squibb, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM, AstraZeneca, and Kite; and receipt of honoraria from Merck. Dr Jacobsen reported receipt of personal fees from Merck, Celgene, Beigene, Daiichi, Novartis, Pharmacyclics, Janssen, AstraZeneca, and Bayer and receipt of grants from Merck. Dr Jacobson reported receipt of personal fees from Kite/Gilead, Novartis, Bristol Myers Squibb/Celgene, Instil Bio, Abintus Bio, Caribou Bio, ImmPACT Bio, Daiichi-Sankyo, AstraZeneca, Morphosys, ADC Therapeutics, AbbVie, Miltenyi, and Synthekine. Dr Soumerai reported receipt of personal fees for consulting from AstraZeneca, AbbVie, Beigene, Biogen, Roche/Genentech, Verastem, and TG Therapeutics and receipt of research support paid to his institution from Bristol Myers Squibb, Seattle Genetics, Adaptive Biotechnologies, BostonGene, GlaxoSmithKline, Moderna, and Takeda. Dr Han reported receipt of personal fees for consulting from Vertex Inc. Dr Ky reported consulting for Bristol Myers Squibb, AstraZeneca, Roche, and Pfizer; receipt of grants from Pfizer, the National Institutes of Health, and the American Heart Association; and serving as editor for the American College of Cardiology. Dr Januzzi reported being a trustee of the American College of Cardiology, a board member of Imbria Pharmaceuticals, and a director at Jana Care; receipt of grants from Abbott Diagnostics, Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Roche Diagnostics; receipt of personal fees for consulting from Abbott, Beckman, Bristol Myers Squibb, Cytokinetics, Janssen, Novartis Pharmaceuticals, Prevencio, Roche Diagnostics and Siemens; and participation in clinical end-point committees/data and safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Intercept, Pfizer, Siemens, and Takeda. No other disclosures were reported.

Funding/Support: This study was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI) (R01HL130539) to Drs Neilan and Scherrer-Crosbie. Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg and from Christina and Paul Kazilionis, the Michael and Kathryn Park Endowed Chair in Cardiology, and a Hassenfeld Scholar Award and has additional grant funding from the National Institutes of Health/NHLBI (R01HL137562, K24HL150238). Dr Drobni was supported by the ÚNKP-22-4-II-SE New National Excellence Program of the Ministry for Innovation and Technology from the National Research, Development, and Innovation Fund, Hungary. Dr Scherrer-Crosbie was supported by the NHLBI (R01131613) and has additional grant funding from the American Society of Echocardiography.

Role of the Funder/Sponsor: The study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Meeting Presentation: The findings of this study were presented as a late-breaking clinical trial at the Scientific Sessions of the American College of Cardiology, Saturday, March 3, 2023; New Orleans, Louisiana.

Additional Contributions: We gratefully acknowledge the CIRC research team for providing feedback on the study design and interpretation. CIRC is a combined effort from the Division of Cardiology and the Department of Radiology at Massachusetts General Hospital.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
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