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
Authors: Henriksen Peter A. , Hall Peter , MacPherson Iain R. , Joshi Shruti S , Singh Trisha , Maclean Morag , Lewis Steff , Rodriguez Aryelly , Fletcher Alex , Everett Russell J , Stavert Harriet , Broom Angus , Eddie Lois , Primrose Lorraine , McVicars Heather , McKay Pam , Borley Annabel , Rowntree Clare , Lord Simon , Collins Graham , Radford John , Guppy Amy , Williams Michelle C , Japp Alan , Payne John R. , Newby David E. , Mills Nick L. , Oikonomidou Olga , Lang Ninian N. 
Published: February 2023

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 (±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 regimes.

REGISTRATION

EudraCT 2017-000896-99, ISRCTN24439460

Clinical Perspective

What is new?

In this randomized controlled trial of patients at high risk of anthracycline cardiotoxicity, combined candesartan and carvedilol therapy did not protect against decline in 6-month left ventricular ejection fraction after completion of chemotherapy.

Overall decline in 6-month left ventricular ejection fraction occurred irrespective of changes in cardiac troponin concentration during chemotherapy.

What are the clinical implications?

The Cardiac CARE trial findings do not support recent guideline recommendations advocating the use of cardiac troponin monitoring and early preventive neurohormonal blockade in patients at risk of anthracycline cardiotoxicity.

Future studies should focus on factors determining transition to subsequent development of heart failure from initial mild and asymptomatic changes in cardiac function following anthracycline chemotherapy.