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. 2024 Aug 27;6(5):684-696.
doi: 10.1016/j.jaccao.2024.07.010. eCollection 2024 Oct.

Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma: The PROACT Clinical Trial

David Austin  1   2 , Rebecca H Maier  1   2 , Nasima Akhter  3 , Mohammad Sayari  4 , Emmanuel Ogundimu  4 , Jamie M Maddox  5 , Sharareh Vahabi  6 , Alison C Humphreys  7 , Janine Graham  7   8 , Helen Oxenham  9 , Sophie Haney  7   10 , Nicola Cresti  11 , Mark Verrill  11 , Wendy Osborne  11 , Kathryn L Wright  11   12 , Rebecca Goranova  13 , James R Bailey  14 , Nagesh Kalakonda  15 , Mac Macheta  16 , Mari F Kilner  17 , Moya E Young  18 , Nick J Morley  19 , Pratap Neelakantan  20 , Georgia Gilbert  1 , Byju K Thomas  1 , Richard J Graham  1 , Takeshi Fujisawa  21 , Nicholas L Mills  21 , Victoria Hildreth  22 , Jonathan Prichard  22 , Adetayo S Kasim  23 , Helen C Hancock  22 , Chris Plummer  24   25
Affiliations

Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma: The PROACT Clinical Trial

David Austin et al. JACC CardioOncol. .

Abstract

Background: Cardiotoxicity is a concern for cancer survivors undergoing anthracycline chemotherapy. Enalapril has been explored for its potential to mitigate cardiotoxicity in cancer patients. The dose-dependent cardiotoxicity effects of anthracyclines can be detected early through the biomarker cardiac troponin.

Objectives: The PROACT (Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma) clinical trial assessed the effectiveness of enalapril in preventing cardiotoxicity, manifesting as myocardial injury and cardiac function impairment, in patients undergoing high-dose anthracycline-based chemotherapy for breast cancer or non-Hodgkin lymphoma.

Methods: This prospective, multicenter, open-label, randomized controlled trial employed a superiority design with observer-blinded endpoints. A total of 111 participants, scheduled for 6 cycles of chemotherapy with a planned dose of ≥300 mg/m2 doxorubicin equivalents, were randomized to receive either enalapril (titrated up to 20 mg daily) or standard care without enalapril.

Results: Myocardial injury, indicated by cardiac troponin T (≥14 ng/L), during and 1 month after chemotherapy, was observed in 42 (77.8%) of 54 patients in the enalapril group vs 45 (83.3%) of 54 patients in the standard care group (OR: 0.65; 95% CI: 0.23-1.78). Injury detected by cardiac troponin I (>26.2 ng/L) occurred in 25 (47.2%) of 53 patients on enalapril compared with 24 (45.3%) of 53 in standard care (OR: 1.10; 95% CI: 0.50-2.38). A relative decline of more than 15% from baseline in left ventricular global longitudinal strain was observed in 10 (21.3%) of 47 patients on enalapril and 9 (21.9%) of 41 in standard care (OR: 0.95; 95% CI: 0.33-2.74). An absolute decline of >10% to <50% in left ventricular ejection fraction was seen in 2 (4.1%) of 49 patients on enalapril vs none in patients in standard care.

Conclusions: Adding enalapril to standard care during chemotherapy did not prevent cardiotoxicity in patients receiving high-dose anthracycline-based chemotherapy. (PROACT: Can we prevent Chemotherapy-related Heart Damage in Patients With Breast Cancer and Lymphoma?; NCT03265574).

Keywords: anthracycline; biomarkers; breast cancer; echocardiography; lymphoma; prevention.

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Conflict of interest statement

This work was supported by the National Institute for Health and Care Research (PB-PG-0815-20061). Dr Gilbert was supported by a grant from JGW Patterson Foundation. Dr Mills was supported by a Chair Award (CH/F/21/90010), Programme Grant (RG/20/10/34966), and Research Excellence Award (RE/24/130012) from the British Heart Foundation. Dr Austin has received speaker fees from Philips Volcano, AstraZeneca, and Pfizer; and research grants awarded to Newcastle University from TA Sciences, Kancera, and AstraZeneca. Dr Maier has received research grants awarded to Newcastle University from TA Sciences, Kancera, and AstraZeneca. Dr Maddox has received funding to attend meetings from Novartis and AbbVie. Dr Mills has received research grants awarded to the University of Edinburgh from Abbott Diagnostics, Siemens Healthineers, and Roche Diagnostics, outside the submitted work; and honoraria from Abbott Diagnostics, Siemens Healthineers, Roche Diagnostics, LumiraDx, and Psyros Diagnostics. Dr Kasim was an employee of Durham University during his involvement in the PROACT trial, and is now an employee of GlaxoSmithKline. Dr Plummer has received speaker fees or travel expenses from Amgen, BeiGene, Calgene, Incyte, Ipsen, Novartis, and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Participant Flow Throughout the PROACT Trial This figure presents a CONSORT diagram outlining the flow of participants throughout the PROACT (Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma) trial. (Top) All patients initially considered for inclusion; (center) the progression to randomization. (Right) Reasons for exclusion both before and after obtaining informed consent. (Bottom) The patients who were included in the analyses for primary and secondary endpoint analyses. ACEI = angiotensin-converting enzyme inhibitor; cTnT = cardiac troponin T; GLS = global longitudinal strain; LV = left ventricular; LVEF = left ventricular ejection fraction; NHL = non-Hodgkin lymphoma; RAAS = renin-angiotensin-aldosterone system inhibitor.
Figure 2
Figure 2
Median and Cumulative Incidence of Myocardial Injury by Chemotherapy Cycle This figure summarizes the changes in cTn across chemotherapy cycles, with samples were taken at baseline (before cycle 1), <72 hours before each subsequent cycle, and 1 month after the last dose of anthracycline. Solid lines represent median (Q1-Q3) troponin levels, and dashed lines show the cumulative percentage of patients developing myocardial injury (elevated cardiac troponin) at each timepoint. (A) Cardiac troponin T (cTnT) levels and (B) cardiac troponin I (cTnI) levels, both illustrating the increasing risk of myocardial injury with progressive anthracycline doses. Notably, there is no attenuation of this risk with enalapril treatment. Furthermore, the cumulative rates of myocardial injury differ between the cTnT and cTnI assays, markedly underscoring the variable sensitivity of these biomarkers.
Figure 3
Figure 3
Changes by Group in Key Echocardiographic Parameters Over Time These line plots depict individual participant changes from baseline to 1 month after chemotherapy. (A) GLS changes, in which ascending lines indicate worsening LV function. (B) LVEF changes, in which descending lines indicate deterioration. For both panels, baseline values are arranged in ascending order for the enalapril group and descending for standard care. Boxplots show the first and third quartiles, with the median represented by a central solid line. Whiskers extend to the furthest points within 1.5 times the interquartile range from the quartiles. There were no significant differences in the absolute percentage changes in (A) GLS and (B) LVEF between the enalapril and standard care groups. Abbreviations as in Figure 1.
Central Illustration
Central Illustration
Does Enalapril Prevent Cardiotoxicity When Given Before and During High-Dose Anthracycline Chemotherapy? The PROACT (Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma) trial did not find evidence supporting the use of enalapril to prevent cardiotoxicity in patients receiving high-dose anthracycline chemotherapy for breast cancer or non-Hodgkin lymphoma. cTnI = cardiac troponin I; cTnT = cardiac troponin T; GLS = left ventricular global longitudinal strain; LVEF = left ventricular ejection fraction; RCT = randomized controlled trial.
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