Background: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma 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 multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%).
Results: Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met.
Conclusions: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy.
Limitations: Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded.
Future work: Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population.
Trial registration: This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99.
Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.
The improved survival for patients with cancer is in part down to chemotherapy drugs called anthracyclines. This medication can cause the unwanted side effect of heart muscle pump injury in a minority of patients. Cancer survivors have increased rates of heart problems, including heart muscle pump failure.
Research questions: The Cardiac CARE trial tested whether tablet medications called angiotensin receptor blockers and B-blockers, taken together (cardioprotection therapy), can prevent heart muscle injury related to chemotherapy. Doctors treat heart pump failure using these medications. We examined whether a blood test called high sensitivity cardiac troponin I can detect very slight heart muscle injury and predict future problems with heart pump failure.
What we did: In the trial, only patients with increased levels of the troponin blood test marker were treated with cardioprotection therapy. Breast and blood cancer patients receiving anthracycline treatment were approached to take part. After giving consent they had a detailed scan of their heart prior to starting and 6 months after completing anthracycline chemotherapy. Patients receiving anthracycline had blood taken routinely 2 or 3 days before each treatment. Cardiac troponin levels were measured in these blood samples, and patients with an increased level were allocated at random to treatment with cardioprotection therapy or to normal care.
Research findings: We found no evidence that cardioprotection therapy prevented decline in heart function in anthracycline-treated patients with elevated cardiac troponin levels. Patients with no increased troponin level had a similar decline in heart function. It was reassuring that the reduction in heart muscle function following anthracycline chemotherapy was small. We believe the results show that cardioprotection therapy is not effective and may not be required for most patients.
Copyright © 2024 Henriksen et al.