Adverse effects of anthracyclines: does atorvastatin STOP-CArdiotoxicity?

Comment on ‘Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial’, recently published in the JAMA, https://doi.org/10.1001/jama.2023.11887. The Statins to Prevent the Cardiotoxicity of Anthracyclines (STOP-CA) is a multi-centre, double-blind, randomized, placebo-controlled trial funded by the US National Heart, Lung, and Blood Institute, aiming to determine whether atorvastatin prevents the development of cardiac dysfunction over 12 months, among patients with lymphoma receiving anthracycline-based chemotherapy.1 Asymptomatic subjects aged ≥18 years [mean age ± standard deviation (SD), 50 ± 17 years; 47% females; 89% White] with a new diagnosis of lymphoma (73%, non-Hodgkin lymphoma) and scheduled to receive an anthracycline were randomized 1:1 to receive atorvastatin 40 mg/day orally (n = 150) or placebo (n = 150), starting prior to the first anthracycline infusion and continued for 12 months. Statin use or an indication for statin use, based on current guidelines, represented exclusion criteria. No study participant was treated with dexrazoxane or liposomal doxorubicin. The primary endpoint was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) ≥10% from prior to chemotherapy to a final value <55% over the 12-month study period. A secondary outcome was the proportion of participants with an absolute decline in LVEF ≥5% to a final value <55% at 12-month follow-up. Left ventricular ejection fraction was measured using cardiac magnetic resonance imaging (MRI). A minority of patients had LVEF assessment performed by a protocol echocardiography due to logistical issues during the COVID-19 pandemic. Both the MRI and echocardiographic measures of LVEF were performed on anonymized images in a core laboratory. From January 2017 to September 2021, a total of 300 participants were enrolled at 9 academic medical centres in the USA and Canada. This sample size provided the study with >90% power to detect an absolute 15% difference in the proportion of participants reaching the primary endpoint at a two-sided significance level of 0.05, assuming a 20% incidence in the placebo group. All participants were treated with anthracyclines with an average doxorubicin-equivalent cumulative dose of 264 (SD, 60) mg/m2; 55% of them were treated with a cumulative anthracycline dose of 300 mg/m2. Only a minority of participants were treated with radiation therapy, with no differences between the study groups. In total, 286 participants (95%) completed the trial with high study drug adherence. The baseline mean LVEF was 63% (SD, 4.6%) in the whole study population. The incidence of the primary endpoint at 12 months was 9% in the atorvastatin group (13 events) and 22% in the placebo group (33 events; P = .002), with three-fold greater odds of experiencing a ≥10% decline in LVEF to a final value of <55% after anthracycline treatment for the placebo group compared with the atorvastatin group (odds ratio 2.9; 95% confidence interval, 1.4–6.4). The number needed to treat with atorvastatin to avoid one such event was about eight patients. By restricting analysis to the 77% of participants with MRI measurements, the beneficial effect of atorvastatin on the primary outcome was unchanged. Among participants who met the primary study endpoint, the mean reduction in LVEF was 14% (SD, 4.0%). In comparison, among participants who did not meet the primary study endpoint, the mean reduction in LVEF was 3% (SD, 4.7%). The incidence of the secondary outcome was 13% in the atorvastatin group and 29% in the placebo group (P = .001). In an exploratory analysis, the rates of incident heart failure (HF) at 24-month follow-up were compared. At the time of this analysis, 93% of the study population had either died or reached 24 months of follow-up. Among these, there were 13 HF events (4%), with 11 of 13 participants who also met the primary study endpoint. There were nine HF events (6%) in the placebo group and four (3%) in the atorvastatin group (P = .26). There was no difference in overall survival and in serious adverse events between the two groups. Anthracyclines represent the cornerstone of several chemotherapy protocols with curative purposes in childhood leukaemia, lymphoma, breast cancer, and other solid tumours. The cardiotoxic potential of this class of drugs still represents a major concern, with an increased risk of heart failure (HF, starting with the first cycle of chemotherapy (acute-onset cardiotoxicity) and continuing beyond 5 years of follow-up (late-onset chronic cardiotoxicity).2 Current guidelines recommend accurate risk stratification for cardiovascular toxicity in all patients with cancer (Class Ib), and the Heart Failure Association-International Cardio-Oncology Society risk assessment tool allows classifying patients into low, moderate, high, and very high risk, based on several recognized risk factors.3 While low-risk patients may benefit from aggressive management of common cardiovascular risk factors, for high- and very high-risk subject guidelines3 recommend the use of strategies aimed at directly reducing the anthracycline-related cardiomyocyte injury, including dexrazoxane treatment and the use of pegylated or liposomal anthracyclines. Moreover, although large randomized trials are lacking, the use of medications with established roles in the treatment and prevention of HF, such as renin–angiotensin–aldosterone system blockers, beta-blockers, and mineralocorticoid receptor antagonists, may be beneficial in this high-risk group.4,5 Given their proven effects in reducing inflammation, reactive oxygen species, and lipid peroxidation,6,7 important mechanisms of anthracycline-induced cardiotoxicity,4,5 the role of statins in the primary prevention of cardiotoxicity has been investigated in relatively small recent studies.8–10 The PREVENT trial compared patients treated with 40 mg atorvastatin with placebo and found no differences in mean left ventricular ejection fraction (LVEF) decline 24 months after anthracycline chemotherapy in patients with mostly breast cancer or lymphoma.10 The different results of the STOP-CA trial may be related, at least in part, to the use of a categorical rather than continuous variable as the primary endpoint and to the enrolment of a higher risk group. Indeed, patients in the PREVENT trial received a cumulative, median anthracycline dose of 240 mg/m2, while the median anthracycline dose in the STOP-CA was 300 mg/m2, which is typical for treating patients with lymphoma, but higher than that used for patients with breast cancer. Despite these apparently conflicting results, statin therapy is suggested to be considered among preventive strategies in high-risk patients, particularly those receiving doxorubicin ≥300 mg/m2 (or equivalent).4 As stated by the authors, the main limitation of the trial is the use of LVEF as a surrogate for the development of HF, since the study was not powered to detect changes in the relatively low incidence of HF. This is particularly relevant when considering the absence of data on biomarker levels or functional class changes. Use of surrogate endpoints, as well as limited sample size and duration of treatment, are not unusual in the Oncology field and should be viewed within the context of limited therapeutic options and patients’ expectations. Second, the STOP-CA trial did not enrol a racially or ethnically diverse population, an important limitation. Third, not all study participants had a magnetic resonance imaging of the heart at baseline and at follow-up. Furthermore, this trial was a single-dose study given over a 12-month period, and it is not known if there is any dose or duration-of-treatment effect. Finally, the mechanism(s) underlying a cardio-protective effect of atorvastatin remains unanswered by the present study.4,5 In conclusion, this study provides evidence supporting the use of atorvastatin among patients with lymphoma being treated with high-dose anthracyclines. These findings, in the absence of a clinical correlate, are probably not sufficient to change guideline indications for the use of statins; thus, further studies with larger populations and longer follow-up will be needed to clarify which subgroups of patients may benefit most from this strategy and to examine whether statin therapy prevents symptomatic HF. It should also be mentioned that promising data come from studies exploring the role of sacubitril/valsartan and sodium-glucose cotransporter-2 inhibitors in this setting.11,12 When considering the importance of anthracycline therapy and its detrimental effects on ventricular function, every step towards mitigating its cardiotoxic potential through effective preventive strategies is crucial to achieve better survival, limited chemotherapy discontinuation, and better prognosis for cancer patients. D.P. received speaker’s fees from Daiichi-Sankyo, outside the submitted work. C.P. received consultant and speaker fees from AbbVie, Amgen, Bayer, Eli Lilly, and Tremeau and grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.

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