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

Peter A Henriksen*, Peter S Hall, Iain R MacPherson, Shruti Joshi, Trisha Singh, Morag Maclean, Steff C Lewis, Aryelly Rodriguez, Alex Fletcher, Russell J. Everett, Harriet Stavert, Angus Broom, Lois Eddie, Lorraine Primrose, Heather McVicars, Pam McKay, Annabel Borley , Clare Rowntree, Simon Lord, Graham CollinsJohn Radford, Amy Guppy , Michelle C Williams, Alan Japp, John R. Payne, David E Newby, Nicholas L Mills, Olga Oikonomidou, Ninian Lang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction 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 left ventricular ejection fraction and tested for equivalence of ±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 left ventricular ejection fractions 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 respectively. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between cardioprotection and standard care groups was -0.37% (95% confidence interval, -3.59 to 2.85%; P=0.82). In low-risk non-randomized patients, baseline and 6-month left ventricular ejection fractions were 69.35.7% and 66.46.3% respectively: estimated mean difference, 2.87% (95% confidence interval, 1.63 to 4.10%; P=0.92, not equivalent)
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 left ventricular ejection fraction questioning the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy needs to be better defined in patients receiving high-dose anthracycline.

Original languageEnglish
JournalCirculation
Publication statusPublished - 25 Sept 2023

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