Effects of Sacubitril/Valsartan on Prevention of Cardiotoxicity in High-Risk Patients Undergoing Anthracycline Chemotherapy - SARAH

Nov 18, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD,MPH,FACC
Date Presented:
11/18/2024
Date Published:
11/18/2024
Original Posted Date:
11/18/2024
References

Contribution To Literature:

The SARAH trial showed that in a single-center cohort of patients with cancer receiving anthracycline-based chemotherapy, sacubitril/valsartan reduced the risk of subclinical LV dysfunction at 6 months compared with placebo.

Description:

The goal of the trial was to assess the efficacy of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan in preventing anthracycline-associated cardiotoxicity.

Study Design

  • Single-center
  • Randomized
  • Double-blind

Patients with cancer receiving anthracycline-based chemotherapy and abnormal cardiac biomarkers were randomized in a 1:1 fashion to receive sacubitril/valsartan up-titrated to a target dose of 97/103 mg twice daily (n = 57) or placebo (n = 57).

  • Total number of enrollees: 114
  • Duration of follow-up: 24 weeks
  • Mean patient age: 52 years
  • Percentage female: 90%

Inclusion criteria:

  • Age >18 years
  • Receiving anthracycline-based chemotherapy for malignancy
  • High-sensitivity cardiac troponin I (hs-cTnI) >99th percentile after any anthracycline infusion

Exclusion criteria:

  • Prior chemotherapy or radiotherapy
  • Known cardiomyopathy, coronary artery disease, or at least moderate valvular disease
  • Estimated glomerular filtration rate <30 mL/min/1.73 m2

Other salient features/characteristics:

  • Breast cancer: 81%
  • Mean doxorubicin-equivalent cumulative anthracycline dose: 244 mg/m2
  • Median baseline left ventricular (LV) global longitudinal strain (GLS): -20.1%
  • Mean baseline LV ejection fraction (LVEF): 64%
  • Hypertension: 32%

Principal Findings:

The primary outcome, ≥15% reduction in GLS at 6 months, for sacubitril/valsartan vs. placebo, was: 7.1% vs. 25.0%, hazard ratio (HR) 0.23 (95% confidence interval [CI] 0.07-0.75), p = 0.015.

Secondary outcomes for sacubitril/valsartan vs. placebo at 6 months:

  • Mean change in GLS: +2.5% vs. -7.6%, p < 0.001
  • Mean change in LVEF by cardiac magnetic resonance (CMR) imaging: +0.19% vs. -3.47%, p = 0.011

Exploratory clinical outcomes for sacubitril/valsartan vs. placebo at 6 months:

  • Symptomatic heart failure (HF): 0% vs. 3.5%, p = 0.495
  • HF hospitalization: 0% vs. 1.8%, p = 1.0
  • All-cause death: 1.8% vs. 1.8%, p = 1.0

Safety events for sacubitril/valsartan vs. placebo at 6 months:

  • Any adverse event: 19.3% vs. 15.8%, p = 0.806
  • Hypotension: 14.0% vs. 1.8%, p = 0.032

Cardiac biomarker trends for sacubitril/valsartan vs. placebo:

  • Median baseline hs-cTnI: 1.5 vs. 1.5 ng/L
  • Median hs-cTnI at randomization: 24.9 vs. 19.1 ng/L
  • Median N-terminal pro-B-type natriuretic peptide (NT-proBNP) at randomization: 10 vs. 12 pg/mL
  • Median hs-cTnI at 6 months: 2.9 vs. 2.5 ng/L
  • Median NT-proBNP at 6 months: 17 vs. 17 pg/mL

Interpretation:

The role for neurohormonal agents in the primary prevention of anthracycline-associated cardiotoxicity is uncertain, with larger studies failing to show a significant effect on clinical outcomes despite potentially beneficial effects on LVEF. The current data suggest that sacubitril/valsartan may also prevent subclinical LV systolic dysfunction. Adverse cardiovascular events were rare over a relatively short follow-up period in this small cohort from a single center. High-risk patients more likely to benefit were enrolled based on hs-cTnI elevations after any anthracycline dose. Although this approach has been previously described, it is unclear how differences in timing of ARNI initiation during chemotherapy may affect their potential benefit. The current trial does provide a rationale for future studies of sacubitril/valsartan targeting clinical endpoints in larger cohorts. This may be particularly relevant for patients with even higher risk of cardiotoxicity, such as those with low-normal LVEF or borderline GLS in addition to elevated hs-cTnI.

References:

Presented by Dr. Marcely Gimenes Bonatto at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2024.

Clinical Topics: Cardio-Oncology, Heart Failure and Cardiac Biomarkers, Prevention

Keywords: AHA24, AHA Annual Scientific Sessions, Anthracyclines, Cardio-oncology, Cardiotoxicity, Neoplasms


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