The SUCCOUR trial was an international, multicenter, randomized controlled study developed to assess the value of medical intervention in response to changes in GLS by echocardiography performed for monitoring of anthracycline cardiotoxicity in patients with risk factors for HF.¹

This trial was grounded on data suggesting that changes in GLS in patients undergoing cardiotoxic chemotherapy predicts incident left ventricular (LV) systolic dysfunction.¹ The primary study endpoint was a decrease in left ventricular ejection fraction (LVEF) between a GLS surveillance group and LVEF surveillance group in 1-3 years. For the study design, they estimated a 10% ± 5% LVEF reduction in the LVEF surveillance group and a 5% ± 5% reduction in the GLS surveillance group, with 80% power to identify a difference for a p < 0.05 per intention-to-treat approach. The projected enrollment was 320 subjects, with the goal to recruit 160 subjects per surveillance group. Cardioprotective therapy was started when threshold for treatment was met per study definition of cancer-therapy-related cardiac dysfunction. For the LVEF surveillance group, this was defined by a symptomatic drop of >5% of LVEF or >10% asymptomatic drop in LVEF compared to baseline to less than 55%. In the GLS surveillance group, this was defined by a relative reduction of GLS by 12% in any of the follow-up studies. Cardioprotective medications used for treatment were angiotensin-converting enzyme inhibitors (if not tolerated, an angiotensin-receptor blocker) and beta-blockers as tolerated per patient.¹

The results of the trial including 1-year follow-up were published by Thavendiranathan et al. in the Journal of the American College of Cardiology.² Total enrollment was 331 subjects, but 2 patients died and 22 withdrew consent during follow-up, leaving 307 total patients in the study. There were 154 subjects in the GLS surveillance arm versus 153 in LVEF surveillance arm. Of patients in the LVEF surveillance group, 13.7% met criteria for cancer-therapy-related cardiac dysfunction versus 5.8% in GLS group, so the incidence of predefined events was less in the GLS surveillance arm. This was an unexpected finding because if it was assumed that GLS is a more sensitive marker for cancer-therapy-related cardiac dysfunction than LVEF, it was expected to see more events in the GLS arm. Conversely, they had more events in the LVEF arm.

Part of the definition of cancer-therapy-related cardiac dysfunction for LVEF group includes "a symptomatic drop of >5% of LVEF," but those changes could have possibly included error from interobserver variability of LVEF measurements. The primary endpoint was not met because the difference of LVEF between groups at 1-year follow-up was not statistically significant (GLS group 57% ± 6% vs. LVEF group 55% ± 7%; p = 0.05). Interestingly, they noted in subgroup analysis that patients receiving cardioprotective medications in the LVEF surveillance group had larger reductions in LVEF at follow-up than in GLS surveillance group (9.1% ± 10.9% vs. 2.9 ± 7.4; p = 0.03). More patients in the GLS surveillance group received cardioprotective treatment than the LVEF surveillance group (25% vs. 10%, respectively), which may account for this difference. A similar effect size has been seen in multiple randomized controlled trials on prophylactic use of cardioprotective medications in the setting of cardiotoxic treatment, with a mean pooled decline of 5.4% (95% confidence interval, 3.5-7.3%).³

The authors and co-investigators should be commended for this rigorous trial and the effort that they underwent in collecting and analyzing these complex data with limited support and resources. The results highlight the need for more information to determine if GLS as an imaging marker can identify patients who would benefit from cardioprotective treatment to prevent cancer-therapy-related cardiac dysfunction. Abnormalities in myocardial mechanics identified by strain do not always indicate LV dysfunction given its preload dependency.^4,5 For example, in patients with cancer, a sequential decrease of LV end-diastolic volume detected by cardiac magnetic resonance imaging can identify patients with strain and LVEF abnormalities secondary to hypovolemia.⁵ This could be more common (16% in one study)⁵ than the incidence of contemporary anthracycline toxicity, which in a large prospective study was 9%,⁶ because many patients with cancer develop poor appetite and nausea (hence poor oral intake) during chemotherapy.

The long-term consequences of changes in GLS are not known. Perhaps future GLS studies should focus into harder endpoints⁷ other than modest changes in cardiac mechanics or ventricular volumes. This would require large sample sizes in order to adequately power the study for less common but more clinically significant events. Despite its inaccuracies and limitations, LVEF continues to be the simplest and most practical approach to quantify LV systolic function during cardiotoxicity monitoring.

References

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;11:1098-105.
2. Thavendiranathan P, Negishi T, Somerset E, et al. Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy. J Am Coll Cardiol 2021;77:392-401.
3. Jeyaprakash P, Sangha S, Ellenberger K, Sivapathan S, Pathan F, Negishi K. Cardiotoxic Effect of Modern Anthracycline Dosing on Left Ventricular Ejection Fraction: A Systematic Review and Meta-Analysis of Placebo Arms From Randomized Controlled Trials. J Am Heart Assoc 2021;10:e018802.
4. Choi JO, Shin DH, Cho SW, et al. Effect of preload on left ventricular longitudinal strain by 2D speckle tracking. Echocardiography 2008;25:873-9.
5. Jordan JH, Sukpraphrute B, Meléndez GC, Jolly MP, D'Agostino RB Jr, Hundley WG. Early Myocardial Strain Changes During Potentially Cardiotoxic Chemotherapy May Occur as a Result of Reductions in Left Ventricular End-Diastolic Volume: The Need to Interpret Left Ventricular Strain With Volumes. Circulation 2017;135:2575-7.
6. Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
7. Lopez-Mattei JC, Palaskas N, Iliescu C. Skip Soft Definitions and Focus on Hard Endpoints∗. JACC CardioOnc 2019;1:218-20.

Clinical Topics: Cardio-Oncology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging

Keywords: Cardiotoxicity, Stroke Volume, Prospective Studies, Follow-Up Studies, Anthracyclines, Angiotensin-Converting Enzyme Inhibitors, Observer Variation, Confidence Intervals, Hypovolemia, Receptors, Angiotensin, Intention to Treat Analysis, Goals, Sample Size, Ventricular Function, Left, Ventricular Function, Left, Echocardiography, Neoplasms, Magnetic Resonance Imaging, Risk Factors, Angiotensin Receptor Antagonists, Informed Consent, Heart Failure

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