Sacubitril/Valsartan Curbs Cardiotoxicity From Chemotherapy

CHICAGO — Sacubitril/valsartan (Entresto) was effective at keeping cardiotoxicity at bay in high-risk people receiving anthracycline chemotherapy in the SARAH trial.

Cancer patients were less likely to have a greater than 15% reduction in global longitudinal strain (GLS) of the left ventricle if they had been randomly assigned the angiotensin receptor-neprilysin inhibitor (ARNI) treatment for 24 weeks instead of placebo (7.1% vs 25%, OR 0.23, 95% CI 0.07-0.75), according to Marcely Gimenes Bonatto, MD, of University of São Paulo.

This translated to a number needed to treat of 5.59, she said, adding that sacubitril/valsartan’s benefit was consistent regardless of anthracycline dose, HER2 positivity, hypertension, and age.

“The SARAH trial is the first study to demonstrate the cardioprotective potential of ARNI in high-risk patients receiving anthracycline therapy,” Bonatto told the audience here at the American Heart Association (AHA) annual conference.

Anthracyclines are used to treat many types of cancer, including breast cancer, leukemia, and lymphoma.

One of the downsides is that these chemotherapy drugs are known to carry a dose-dependent risk of cardiotoxicity that can limit treatment or increase morbidity. The cardiotoxicity can progress from initial troponin release and decreased GLS, to a drop in left ventricular ejection fraction (LVEF), and ultimately heart failure symptoms, Bonatto explained.

A key aspect of the trial was its selection of participants at high risk for cardiotoxicity. From 2022 to 2024, investigators sought adults with cancer who had an increase in high-sensitivity troponin I above the 99th percentile after any anthracycline chemotherapy session. In the placebo arm of SARAH, patients ultimately had LVEF drop below 50% in 17.0% of cases per cardiac MRI and 10.7% of cases on echocardiograms.

“It’s important to note that our strategy selected patients with evidence of cellular injury and therefore were at a high risk of developing cardiotoxicity, which may benefit from this [ARNI] strategy. This helps to avoid unnecessary [exposure] to adverse events and costs [to] lower-risk patients,” Bonatto said during an AHA press conference.

Besides the reduction in GLS, study authors also reported improvements in echocardiographic and cardiac MRI parameters related to LV remodeling after ARNI therapy. On cardiac MRI, for example, LVEF stayed in the 60%-61% range in the sacubitril/valsartan group, while it dropped from just over 60% to 57% after 24 weeks on placebo (P=0.016).

Meanwhile, clinical events trended lower with ARNI without the difference reaching statistical significance at 24 weeks (1.8% vs 7.0%, P=0.364).

As for safety, adverse event rates were generally comparable between sacubitril/valsartan and placebo groups, but ARNI was associated with excess hypotension (14% vs 1.8%, P=0.032) and higher potassium (4.31 vs 4.16 mmol/L, P=0.047).

Session discussant Bonnie Ky, MD, MSCE, of the University of Pennsylvania in Philadelphia, thus found sacubitril/valsartan to be “well-tolerated” and that it “attenuated declines in GLS and LVEF at 24 weeks.”

Still, Ky commented on the need to both validate the SARAH findings in larger populations and “to define sustainability of this response and impact on clinical outcomes in the longer term.”

For sacubitril/valsartan to progress further as cardioprotection in cancer patients, “we need hard outcomes like heart failure, hospitalizations, cardiovascular and overall mortality,” added Tochi Okwuosa, DO, of Rush University Medical Center in Chicago, commenting during the press conference. “We need real-world studies, and then cost and bioavailability is also an issue.”

SARAH was a randomized double-blind trial conducted at one center in Brazil: the Erasto Gaertner Hospital in Curitiba.

Patients with cardiomyopathy, coronary artery disease, and moderate to severe valve disease were excluded.

Towards the end of chemotherapy, 114 patients were selected for randomization to sacubitril/valsartan (97/103 mg twice daily) or placebo, with a dose titration at 2 weeks and 4 weeks. Randomization was stratified by higher- and lower-dose anthracycline cohorts. Assigned interventions ended at 24 weeks.

At baseline, the ARNI and placebo groups both averaged just over 51 years of age and were around 90% women. Approximately 80% had breast cancer. The cumulative anthracycline dose reached around 240 mg/m².

Bonatto acknowledged the short follow-up and limited sample size of SARAH.