Statins to Prevent the Cardiotoxicity of Anthracyclines - STOP-CA

Aug 08, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC; Amit Saha, MD
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
National Heart, Lung, and Blood Institute
Date Published:
08/08/2023
Date Updated:
08/08/2023
Original Posted Date:
08/08/2023
References

Contribution To Literature:

The STOP-CA trial showed that in patients with lymphoma receiving anthracycline-based chemotherapy, atorvastatin 40 mg/day reduces the incidence of cardiac systolic dysfunction compared with placebo.

Description:

The goal of this trial was to assess whether concomitant treatment with atorvastatin may prevent the reduction in left ventricular ejection fraction (LVEF) that may be seen in patients with lymphoma receiving anthracycline-based chemotherapy.

Study Design

  • Randomized
  • Placebo-controlled
  • Double-blind
  • Multicenter

Patients with a new diagnosis of lymphoma who did not have an existing indication for statin therapy were randomized to start atorvastatin 40 mg daily (n = 150) or placebo (n = 150) prior to initiation of anthracycline-based chemotherapy. Baseline and follow-up LVEF were assessed primarily by cardiac magnetic resonance imaging (MRI) or, if unfeasible due to constraints during the COVID-19 pandemic, transthoracic echocardiogram.

  • Total number of enrollees: 300
  • Duration of follow-up: 12 months
  • Mean patient age: 50 years
  • Percentage female: 47%
  • Percentage non-White: 11%

Inclusion criteria:

  • Age ≥18 years
  • New diagnosis of Hodgkin or non-Hodgkin lymphoma without prior treatment
  • Scheduled to receive anthracycline-based chemotherapy regimen

Exclusion criteria:

  • Already on statin therapy or meet an existing indication for statin therapy
  • Pregnancy or breastfeeding
  • Estimated glomerular filtration rate <45 mL/min/1.73 m2
  • Unexplained, persistent elevation in serum aminotransferases >3 times the upper limit of normal
  • Contraindication to MRI
  • Baseline LVEF <50%

Other salient features/characteristics:

  • Mean baseline LVEF: 63%
  • Non-Hodgkin lymphoma: 73%
  • Mean doxorubicin-equivalent cumulative anthracycline dose: 264 mg/m2
  • Radiation therapy to cardiac silhouette: 1.3%
  • Study drug adherence: 91%

Principal Findings:

The primary outcome, LVEF decline ≥10% to a final LVEF <55% at 12 months, for atorvastatin vs. placebo, was: 9% vs. 22% (p = 0.002).

Secondary outcomes for atorvastatin vs. placebo:

  • LVEF decline ≥5% to a final LVEF <55% at 12 months: 13% vs. 29% (p = 0.001)
  • Mean change in LVEF at 12 months: -4.1% vs. -5.4% (p = 0.03)
  • Incident heart failure at 24 months: 3% vs. 6% (p = 0.26)

Prespecified subgroup analyses of mean change in LVEF at 12 months, for atorvastatin vs. placebo:

  • Female: -3.1% vs. -5.4% (p = 0.02)
  • Age ≥52 years: -4.4% vs. -6.6% (p = 0.03)
  • Cumulative doxorubicin-equivalent dose ≥250 mg/m2: -4.3% vs. -6.2% (p = 0.01)
  • Body mass index ≥30 kg/m2: -3.0% vs. -5.6% (p = 0.02)

Safety outcomes at 12 months, for atorvastatin vs. placebo:

  • Myalgia: 19% vs. 21% (p = 0.35)
  • Elevated aminotransferases: 18% vs. 16%
  • Renal failure: 1.3% vs. 2.7%

Interpretation:

The STOP-CA trial demonstrates that atorvastatin is associated with a decreased incidence of clinically significant reduction in LVEF in patients with lymphoma receiving anthracycline-based chemotherapy. Study drug adherence was high with an adverse event profile comparable between atorvastatin and placebo, suggesting treatment was well tolerated.

These findings are important for lymphoma patients who may receive anthracycline-based chemotherapy given the high proportion (29%) of patients in the placebo arm achieving the primary outcome, which is consistent with prior observational data. Statins, which reduce anthracycline-associated oxidative stress and cardiomyocyte death in vitro, have become a potential therapy of interest. This is the first large, randomized trial to identify a cardioprotective effect with statins in anthracycline-based chemotherapy. The PREVENT trial previously found no association between atorvastatin 40 mg and LVEF at 24 months. Among this trial’s population, however, the primary malignancy was mostly breast (85%), and the cumulative mean age and anthracycline dose were lower at 49 years and 240 mg/m2, respectively.

The present study’s subgroup analyses, though exploratory, suggest that certain patients with lymphoma, namely those who are older, female, or obese, may derive greater cardioprotective benefit from atorvastatin. Additionally, dose-dependent cardiotoxicity may support the greater treatment effect of atorvastatin in patients requiring higher cumulative doses of anthracyclines. Lymphoma patients, particularly those at greater risk of cardiotoxicity, may therefore warrant consideration of prophylactic treatment with atorvastatin.

References:

Neilan TG, Quinaglia T, Onoue T, et al. Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial. JAMA 2023;330:528-36.

Clinical Topics: Cardio-Oncology, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging

Keywords: Anthracyclines, Atorvastatin, Cardiotoxicity, Doxorubicin, Echocardiography, Heart Failure, Hodgkin Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lymphoma, Non-Hodgkin, Magnetic Resonance Imaging, Myalgia, Obesity, Secondary Prevention, Stroke Volume, Ventricular Function, Left


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