Statins and Left Ventricular Ejection Fraction Following Doxorubicin Treatment

Hundley, W. Gregory; D’Agostino, Ralph B.; Crotts, Teresa; Craver, Karen; Hackney, Mary Helen; Jordan, Jennifer H.; Ky, Bonnie; Wagner, Lynne I.; Herrington, David M.; Yeboah, Joseph; Reding, Kerryn W.; Ladd, Amy C.; Rapp, Stéphen R.; Russo, Sandra A.; O’Connell, Nathaniel S.; Weaver, Kathryn E.; Dressler, Emily V.; Ge, Yaorong; Melin, Susan A.; Gudena, Vinay; Lesser, Glenn J.

doi:10.1056/evidoa2200097

Cited by 51 publications

(44 citation statements)

References 22 publications

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“…20,21 The hypothesis was supported both by basic science experiments and by observational studies 7 ; however, a recent randomized trial of atorvastatin, 40 mg/d, administered over 24 months failed to show a difference in the absolute decline in LVEF after anthracycline treatment. 9 Specifically, the mean LVEF values were 61.7% before treatment and 57.4% at 24 months in the placebo group and 62.6% before treatment and 57.7% at 24 months in the atorvastatin group, with a 24-month decline in LVEF of 3.3% in the placebo group and 3.2% among those randomized to atorvastatin. Several important differences between studies exist that merit consideration.…”

Section: Discussionmentioning

confidence: 89%

“…In contrast, some studies have selected the absolute difference in the decline in LVEF as the primary end point. 9,20,21 In STOP-CA, when the entire cohort was compared, there was only a minor difference of 1.3% in LVEF at 12 months between groups, suggesting that for a proportion of the anthracycline population, atorvastatin may have little benefit; however, atorvastatin has a sub-stantial benefit among patients at higher risk of anthracyclineassociated cardiac systolic dysfunction. However, despite the differences between study design, availability of baseline and follow-up data, study drug adherence, the study population, and the end point chosen, broadly conflicting data exist on whether statins protect against anthracycline-associated cardiac dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…8 However, in a recent randomized trial among women with primarily breast cancer, atorvastatin did not prevent an absolute decline in LVEF with anthracyclines. 9 Herein, we present the results of the STOP-CA (Statins to Prevent the Cardiotoxicity of Anthracyclines) trial, a multicenter, double-blind, randomized, placebocontrolled trial of 40 mg/d of atorvastatin administered to patients receiving anthracyclines for lymphoma, with pretreatment and 12-month posttreatment measurement of LVEF.…”

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confidence: 99%

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Atorvastatin for Anthracycline-Associated Cardiac Dysfunction

Neilan

Quinaglia

Onoue

et al. 2023

JAMA

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ImportanceAnthracyclines 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.ObjectiveTo test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction.Design, Setting, and ParticipantsDouble-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.InterventionsParticipants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months.Main Outcomes and MeasuresThe 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 &lt;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 &lt;55% over 12 months.ResultsOf 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT02943590

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Atorvastatin for Anthracycline-Associated Cardiac Dysfunction

Neilan

Quinaglia

Onoue

et al. 2023

JAMA

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“…The decline in LVEF at 6 months was smaller than previous studies using echocardiographic monitoring (20,21) but comparable to recent multicenter studies enrolling similar patient populations using cardiac magnetic resonance. (14,22) We observed small deteriorations in both global and longitudinal strain across all groups. There was no difference in these early markers of ventricular dysfunction between randomized groups and the cardiotoxicity threshold of > 15% relative fall in strain was uncommon at 6 months.…”

Section: Discussionmentioning

confidence: 76%

A multicenter prospective randomized controlled trial of high sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta-blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE trial

Henriksen

Hall

Macpherson

et al. 2023

Preprint

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Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicenter prospective randomized open label blinded endpoint trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard of care plus cardioprotection (combination carvedilol and candesartan therapy) or standard of care alone. The primary outcome was adjusted change in left ventricular ejection fraction (LVEF) at 6 months. In low-risk non-randomized patients with cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in LVEF (±2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had LVEFs of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy. After adjusting for age, pre-treatment LVEF and planned anthracycline dose, the estimated mean difference in 6-month LVEF between cardioprotection and standard care groups was -0.4% (95% CI, -3.59 to 2.85%; P=0.82). In low-risk non-randomized patients, baseline and 6-month LVEFs were 69.3±5.7% and 66.4±6.3% respectively: estimated mean difference, 2.9% (95% CI, 1.45 to 4.28%; P<0.001). Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk non-randomized patients had similar declines in LVEF casting doubt over the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in LVEF suggest that the value and clinical impact of early cardioprotection therapy needs to be better defined in patients receiving high dose anthracycline regimes.

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“…In a prospective randomized trial, Hundley et al 3 investigated whether statins provided cardio-protection in 279 patients with either breast cancer or lymphoma; the answer was no. Atorvastatin 40 mg per day, initiated 2 days before the start of doxorubicin-based therapy and continued for 2 years thereafter, did not reduce the decline in LVEF overall or in subgroups.…”

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confidence: 99%