Analyzing the Cost-Effectiveness of Entresto in Heart Failure

Treatment with Entresto (sacubitril-valsartan) was found to be more cost-effective than renin-angiotensin system inhibitors in heart failure patients with below-normal ejection fractions, according to a new economic analysis published online in JAMA Cardiology. The results of that study funded by Novartis, the maker of Entresto, suggest that the drug improves quality-adjusted life-years; the drug’s cost-effectiveness ratio is high for patients with reduced and mildly reduced ejection fractions (50% or lower) while reaching at least intermediate value for patients with an ejection fraction of 60% or lower.

These findings come as the number of people in the U.S. with heart failure (HF) is expected to climb. It is a chronic condition affecting more than 5.7 million adults in the United States. That number is almost certainly going to grow due to both demographic trends — the aging of baby boomers into their eighth, ninth and tenth decades of life — and the expanding proportion of the U.S. population with obesity, diabetes and hypertension, all of which increase the risk of heart failure.The annual cost of caring for patients with HF is substantial at $30.7 billion and is predicted to rise by 120% by 2030.

HF occurs when the heart cannot pump enough blood to meet the body's needs HF is categorized depending on an individual’s ejection fraction (EF), a measurement of how much blood the left ventricle, the heart’s main pumping chart, pumps out with each contraction. For example, an ejection fraction of 60% means that 60% of the blood in the left ventricle is pumped out with each heartbeat.

Entresto is among several new treatment for HF. Previous trials, including PARADIGM-HF, showed that it is effective and cost-effective in reducing the risk of cardiovascular death or hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). Those findings are reflected in U.S. treatment guidelines that now strongly recommend Entresto as a first-line treatment for HFrEF. Another trial, called PARAGON-HF, extended the evaluation of Entresto to patients with heart failure with preserved ejection fraction (HFpEF).

In 2021, the FDA expanded Entresto’s indications to include all adult patients with chronic HF but noted that the benefits are most evident in patients with below-normal ejection fraction. However, it remains unclear what level of ejection fraction is considered too low. Recent guidelines offer weaker recommendations for Entresto in patients with HFpEF or mildly reduced ejection fraction (HFmrEF). Economic analyses for pharmacologic therapies in these patient groups is lacking.

In this JAMA Cardiology study, which was published online in late September, Ankee S. Bhatt, M.D., MBA, Sc.M., a research scientist in Kaiser Permanente’s Division of Research and a practicing cardiologist and intensivist at the Kaiser Permanente San Francisco Medical Center, and his colleagues, set out to compare the cost-effectiveness of Entresto to renin-angiotensin system inhibitors (RASi) across various ejection fractions. The evaluation was conducted using 2021-2023 data from the PARADIGM-HF and PARAGON-HF trials. Hospitalization and medication costs were gathered from national sources, with the wholesale acquisition cost of Entresto at $7,092 per year. Incremental cost-effectiveness ratios (ICERs) and treatment effects were calculated across different levels of EF, ranging from 5% to 60%.

The results showed that for patients with EFs of 60% or less, Entresto added 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40,892 compared to RASi, generating an ICER of $76,852 per QALY. Among chronic heart failure patients with EFs of 60% or less, Entresto was shown to have intermediate economic value at a cost of $10,242 or less per year, of high economic value at $3,673 or less per year, and cost-saving at $338 or less per year.

Bhatt and his colleagues calculated ICERs of:

• $67,331 per QALY for EFs of 55% or less,
• $59,614 per QALY for EFs of 50% or less, and
• $56,786 per QALY for EFs of 45% or less.

Treatment with Entresto in patients with EFs of 45% or greater yielded an ICER of $127,172 per QALY gained. For those with EFs of 45%-55%, the ICER was $100,388 per QALY gained, and for those with EFs of 45%-50%, the ICER was $84,291 per QALY gained. The analysis included a total of 13,264 patients.

Cost-effectiveness modeling provided ICERs for treatment with Entresto consistent with high economic value for patients with reduced and mildly reduced EFs (less than or equal to 50%) and at least intermediate value for those with an EF of 60% or less.

This study had several limitations. Patients were selected based on their ability to tolerate therapy, which may have introduced bias. Adverse events were not considered in the model, but symptomatic hypotension was more common with Entresto. The distribution of EF may not fully reflect HF patients in the US. Value definitions may vary, and different thresholds could change conclusions. The model did not account for variable adherence to treatments, but evidence suggests higher rates of discontinuation of Entresto among older adults.

Entresto treatment was found to be more cost-effective for those with lower ejection fraction. This estimation was based on the current wholesale acquisition cost price of Entresto without any discounts. These findings may have implications for payers’ coverage decisions and updates to current treatment guidelines for clinical practice. Bhatt and his colleagues noted that “costs likely vary significantly across payers, negotiated rebates and discounts, and various arrangements with pharmacy benefit managers and other intermediaries, making it difficult to estimate the actual cost of therapy in the U.S.”