Heart failure (HF) is a highly prevalent syndrome that significantly affects morbidity and mortality, as well as the patients' quality of life.

Although the incidence of HF has stabilized, its prevalence continues to increase, mainly due to population aging and the emergence of treatments that improve patient survival. There are an estimated 56 million patients with HF worldwide (prevalence between 1% and 3%)1. In Spain, its prevalence is around 1.89%2 and increases with age, rising to 8% among individuals aged 65–74 years and reaching 16.1% in those aged 75 or older3.

Heart failure is considered a public health issue due to its high prevalence and its impact on survival and quality of life. The average annual cost per patient is estimated to be around €3000/year, with hospitalisations being the main cost component4.

Sacubitril/valsartan (Sac/Val) is a molecular combination of an angiotensin II receptor blocker (ARB) and a neprilysin inhibitor (ARNI). It is indicated for the treatment of HF with reduced ejection fraction (HFrEF). During its development, the PARADIGM-HF trial compared Sac/Val with enalapril, an angiotensin-converting enzyme inhibitor (ACEI), in an outpatient setting. The PIONEER-HF study compared the same medications in hospitalized patients with HFrEF who had been stabilized after an episode of acute decompensated HF. Both studies demonstrated the superiority of Sac/Val in reducing mortality, hospital admissions, and other parameters that could lead to greater resource utilization. However, since Sac/Val is an innovative drug with a higher cost than enalapril (a generic pharmaceutical product), determining its incremental cost-utility ratio (ICUR) in these settings is essential to inform prescribing decisions.

The objective of this study was to evaluate the cost-effectiveness and cost-utility of Sac/Val treatment in outpatient and inpatient settings for patients with HFrEF, from the perspective of the Spanish healthcare system, in order to determine the treatment option and setting most likely to be cost-effective, thereby supporting informed decision-making in the selection of the most appropriate treatment.

Table 2 shows the base-case results of the three comparisons. Compared to enalapril, Sac/Val yielded benefits in LYG and QALYs, with ICURs below €20,000 per QALY. The ratio was more favorable in scenarios where Sac/Val was initiated in the hospital setting once decompensation had been resolved.

The tornado diagrams in Fig. 2 show that, regarding the one-way sensitivity analyses, the parameter with the greatest impact on the model is the HR for mortality in the Sac/Val arm within the first two months following admission for decompensated HF.

Figure 2.

Tornado diagrams of the 3 comparisons: (i) Comparison of Sac/Val at discharge vs enalapril; (ii) Comparison of Sac/Val at admission vs enalapril; (iii) Comparison of Sac/Val at admission vs Sac/Val at discharge.

The base-case results are supported by those from the probabilistic sensitivity analyses shown in Table 2 and Fig. 3.

Figure 3.

Scatter plots from the probabilistic sensitivity analysis of the 3 comparisons: (i) Comparison of Sac/Val at discharge vs enalapril; (ii) Comparison of Sac/Val at admission vs enalapril; (iii) Comparison of Sac/Val at admission vs Sac/Val at discharge.

The results of this study show that treatment options with Sac/Val are cost-effective compared to ACEIs, and more efficient when Sac/Val is initiated in hospital once the patient has been stabilized, rather than delaying initiation until after hospital discharge in the outpatient setting. These findings were consistent across both deterministic and probabilistic analyses.

When reviewing the results of the probabilistic analyses to determine the scenarios in which Sac/Val exceeded the efficiency threshold (defined as €25,000/QALY), it was observed that the variables influencing this outcome were similar to those identified in the probabilistic sensitivity analyses: mortality-related variables in Sac/Val vs enalapril comparisons, and hospitalization-related variables in the comparisons between initiating ARNI during hospitalization or after discharge. This finding was expected in the case of the comparisons with enalapril, as an HR value of 1 indicates equal effectiveness between the drugs being compared. This means that the most efficient option is also the least costly. The same applies to comparisons between Sac/Val initiation timing strategies, where, with mortality rates similar in both arms, the differentiating factor is the number of hospital admissions, which is reduced by early initiation of ARNI. This finding is in line with those reported in the systematic review by Proudfoot et al8.

Regarding efficiency (cost-utility), the results are consistent with Proudfoot's findings8, and are similar to those of the models developed by Gaziano5,6, which were adapted to the Spanish setting in this study. They are also in line with other models published in Europe, such as those in Switzerland9, Germany10, the Netherlands11, and, closer to home, Portugal12. All of these results are consistent with the assessment conducted by the UK's NICE13. A similar result in favor of Sac/Val efficiency was also found in studies using a societal perspective14, although it should be assessed whether the findings of this US study can be extrapolated to the Spanish healthcare system.

Cost-effectiveness (cost-utility) studies are a key source of information to inform funding decisions. This study identifies the most efficient option for the healthcare system (i.e., the option that offers the greatest benefit for each monetary unit). These studies complement budget impact analyses, which only consider treatment costs and exclude those arising from other aspects of healthcare provision.

As with all analyses of this nature, the main limitation of pharmacoeconomic models is the data used to populate them. In this case, the efficacy data for the drugs were obtained from clinical trials, which may differ from real-world clinical practice due to inclusion and exclusion criteria or the limited duration of the studies. Therefore, modeling requires extrapolating efficacy data to the broader population eligible for funding and over a lifetime horizon.

To mitigate the uncertainty introduced by this extrapolation, a probabilistic sensitivity analysis was conducted, generating different efficacy scenarios based on probability distributions. The results of this analysis show that Sac/Val is the cost-effective option in most scenarios. Moreover, it can be assumed that the impact of temporal extrapolation is minimal in this instance, given that HFrEF typically affects older patients with relatively short life expectancies.

Additionally, a conservative approach was adopted by not including other potential savings attributable to Sac/Val. These include those associated with avoiding implantable cardioverter-defibrillators (ICDs), which have a unit cost exceeding €20,000 (average of official tariffs across Spain's autonomous communities). In this regard, an Italian cost-effectiveness study showed that treatment with Sac/Val was the dominant strategy compared to ICD implantation15.

It is also worth noting that the benefits of Sac/Val vs enalapril are likely due to the fact that, while ACEIs act solely on the angiotensin II pathway, Sac/Val also targets the neprilysin pathway. The pathophysiology of HFrEF involves five distinct pathways: the angiotensin II and neprilysin pathways, as previously mentioned, plus the norepinephrine, aldosterone, and sodium-glucose cotransporter type 2 (SGLT-2) pathways. Accordingly, the latest international guidelines recommend early intervention across all five pathways using quadruple therapy, which includes an ARNI targeting two pathways. In this context, and to adapt the US cost-effectiveness study on this topic16 to the Spanish setting, a cost-effectiveness analysis should be conducted to compare the full five-pathway quadruple therapy—ARNI, beta-blocker (BB), mineralocorticoid receptor antagonist (MRA), and SGLT-2 inhibitor—with the current treatment recommended by Spanish funding criteria. The latter involves a stepwise approach targeting only three pathways (ACEI, BB, and MRA). Clinical trials show that patients treated with Sac/Val from hospital admission experience a very early reduction in clinical events, which would explain the favorable cost-effectiveness outcomes observed.

The results of this study show that, under the assumptions used in the model, initiating treatment with Sac/Val from hospital admission onwards in patients with HFrEF is cost-effective, is the most efficient option for the SNS, and is superior to treatment with Sac/Val at discharge or treatment with enalapril.

This study demonstrates the efficiency of sacubitril/valsartan—where earlier initiation yields greater benefit—for treating patients with heart failure with reduced ejection fraction within the Spanish National Health System. Although sacubitril/valsartan has been available for some time, this is the first study to be conducted and published from the perspective of the Spanish National Health System. The results of this type of study are useful in supporting the decision-making process for drug funding.

Antonio García-Quintana: Writing – review & editing, Visualization, Validation, Supervision, Methodology, Formal analysis, Conceptualization. Héctor Alonso Ramos: Writing – review & editing, Visualization, Validation, Methodology, Formal analysis, Conceptualization. Javier Parrondo: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

The authors declare that this study was funded by Novartis Farmacéutica SA.