Cardioprotective Therapy Initiation in Chemotherapy Patients
By Michael H. Crawford, MD, Editor
Synopsis: An international study of patients undergoing cancer chemotherapy or left chest radiation therapy showed that those who showed isolated reductions in echocardiography left ventricular global longitudinal strain but not ejection fraction during follow-up who were randomized to neurohormonal therapy vs. usual care showed better preservation of 12-month cardiac magnetic resonance-determined ejection fraction.
Source: Marwick TH, Dewar E, Nolan M, et al. Strain surveillance during chemotherapy to improve cardiovascular outcomes: The SUCCOUR-MRI trial. Eur Heart J. 2024;45(41):4414-4424.
Currently, left ventricular ejection fraction (LVEF) by echocardiography is commonly used to detect cancer therapy-related cardiac dysfunction (CTRCD), but echo EF is not highly reproducible (±10%). Reductions in echocardiographic LV global longitudinal strain (GLS) also have been used and it is more reproducible than EF, but there is a lack of consensus as to whether a change in GLS without a meaningful change in EF is enough to enact cardioprotective therapy.
The Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcomes (SUCCOUR-MRI) study was designed to test the hypothesis that the initiation of cardioprotective therapy in cancer chemotherapy patients with isolated relative changes in LV GLS > 12% would limit decrements in cardiac magnetic resonance (CMR)-determined LVEF and the development of CTRCD at 12 months.
SUCCOUR-MRI was a multicenter, prospective, randomized, open-blinded endpoint trial of patients with normal echocardiographic LVEF at baseline at risk of CTRCD because of anthracycline, trastuzumab, or tyrosine kinase inhibitor chemotherapy or left-sided chest radiotherapy and at increased risk of heart failure (age > 65 years, diabetes, hypertension) undergoing echo surveillance of LV function. Patients were recruited from 14 centers in Australia or Canada. Excluded were patients with a life expectancy < 12 months, preexisting heart disease, or contraindications to neurohormonal inhibition therapy or existing therapy with beta-blockers and renin-angiotensin system blockers.
Echocardiograms were performed at three-month intervals. Echo EF was measured preferentially with three-dimensional echo when feasible and peak systolic GLS was obtained from three LV apical views using semiautomated speckle tracking. CMR was performed at baseline and was repeated at one year in the subclinical dysfunction group and at the diagnosis of CTRCD in the overt dysfunction group (LVEF < 50%).
CMR was not involved in decision-making and was analyzed in a core laboratory in Canada. The primary endpoint was a change in 12-month MRI EF. Secondary endpoints were incidence of heart failure (HF) and MRI EF-defined CTRCD. From 2018 to 2023, 333 patients (average age 59 years, 79% women) were recruited and 25 failed to complete the trial for a variety of reasons.
The 308 remaining patients were divided into three groups: no change in EF or GLS making the threshold for CTRCD (191 patients), GLS meeting criteria for CTRCD but not EF (105 patients), and both measures meeting CTRCD criteria (12 patients). Those who exhibited subclinical LV dysfunction manifested by only a GLS reduction of ≥ 12% were randomized to neurohormonal blockade or usual care, the majority (62%) at three months. In 43% of subjects, side effects limited the dose of cardioprotection drugs to 50% to 75% of target doses. Dizziness caused by low blood pressure was the most common side effect.
CMR EF at 12 months was higher in the cardioprotection group vs. the usual care group (59% vs. 55%, P < 0.001). After adjustment for baseline EF, the mean difference between these two groups was -3.6% (95% confidence interval, -1.8 to -5.5%; P < 0.001). With cardioprotection, only one of 49 patients developed 12-month CMR EF-defined CTRCD compared to six of 56 patients in the usual care group (P = 0.075). GLS improved three months after randomization in the cardioprotection group with little change in the usual care group.
The authors concluded that in patients with isolated GLS reduction after chemotherapy or left chest radiation therapy for cancer, cardioprotection therapy demonstrated better preservation of CMR LVEF at 12 months compared to usual care.
Commentary
GLS by echocardiography has been available for about 20 years and is included in the guidelines for the detection of subclinical cardiac dysfunction. In those with absolute LVEF decreases ≥ 10%, cardioprotective therapy is a class I indication, and in those with < 10% decrease in EF or a change within normal limits with a relative GLS decrease of > 15%, cardioprotective therapy is a class IIa recommendation. These recommendations are based on observational data. Hence, the SUCCOUR-MRI study is of interest.
A major strength of this study is the use of magnetic resonance imaging (MRI) to determine LVEF, since its variability is less than echo (≤ 4%). This is important since the initial SUCCOUR study, which evaluated GLS vs. LVEF by echo to indicate who would benefit from cardioprotective therapy, showed no difference in LVEF at one and three years between the two strategies.1
It was observed that the changes in echo EF were within the reproducibility of the measurement. Thus, the investigators concluded that the lack of precision in echo EF measurements probably explained the negative results and the use of the more precise MRI EF in SUCCOUR-MRI clarified the benefits of using GLS to determine cardioprotection use. However, MRI may not be practical for routine clinical use because of its expense and limited availability.
Another strength of SUCCOUR-MRI is that a single-blinded observer evaluated the echocardiograms, and a random sample of studies were evaluated in a core laboratory to assure quality. Also, SUCCOUR-MRI enrolled cancer patients with a higher risk of cardiovascular disease.
There were limitations to SUCCOUR-MRI. COVID reduced the number of patients the investigators hoped to enroll by 25%. There were no biomarker data, although previous studies have shown that biomarkers are sensitive for cardiac injury but not very specific. Also, cardioprotection therapy was only neurohormones and did not include sacubitril/valsartan, statins, or sodium-glucose cotransporter-2 inhibitors. However, data for these alternative agents is sparse.
In summary, about one-third of patients undergoing cancer therapy at risk for cardiovascular disease developed isolated reductions in GLS > 12% and, when such patients were given cardioprotective therapy, they were more likely to maintain a normal LVEF at one year than those not so treated.
Michael H. Crawford, MD, is Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.
REFERENCE
1. Negishi T, Thavendiranathan P, Negishi K, Marwick TH; SUCCOUR investigators. Rationale and design of the strain surveillance of chemotherapy for improving cardiovascular outcomes: The SUCCOUR trial. JACC Cardiovasc Imaging. 2018;11(8):1098-1105.
An international study of patients undergoing cancer chemotherapy or left chest radiation therapy showed that those who showed isolated reductions in echocardiography left ventricular global longitudinal strain but not ejection fraction during follow-up who were randomized to neurohormonal therapy vs. usual care showed better preservation of 12-month cardiac magnetic resonance-determined ejection fraction.
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