Heart failure is a clinical syndrome responsible for considerable morbidity and mortality on a global scale.1 It represents a growing clinical dilemma with profound impact on public health and social expenditure. It is estimated that between 1% and 3% of adults are affected by heart failure worldwide, with direct and indirect costs, soaring to more than $100 billion,1 with a projected increase in health care burden because the disease trajectory is shaped by transforming practice.

Thanks to the progression of our understanding on heart failure risk factors and molecular determinants; novel pathophysiological insights have emerged and allowed the expansion of actionable therapeutic targets.

With the release of the 2021 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure,2,3 closely followed by the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guideline for the Management of Heart Failure,4 medical therapy for chronic heart failure with reduced ejection fraction now rests on 4 medication categories, fundamental for reducing the risk of heart failure hospitalizations and mortality. These 4 pillars are the angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor, beta-blockers, mineralocorticoid receptor antagonists, and the sodium–glucose cotransporter-2 (SGLT2) inhibitors. These latter walked a revolutionary road5 from its 19th century isolation from the apple tree root bark to the European Medical Agency and Food and Drug Administration approval as antidiabetic agents, reaching the inclusion in heart failure guidelines as the fourth component of combined medical therapy.

It would be expected that a similar cursus honorum would lead to a swift, ubiquitous implementation of these 4 pillars. Nevertheless, adoption of guideline recommendations can be gradual, partially owing to the balance of prospected benefits, adverse events, and costs. Regional disparities often stem from ethnic, economic, and social factors that clinical trial designs might not fully encompass.6

In this issue of the Journal, Huang et al7 assessed the cost-effectiveness of SGLT2 inhibitors on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction in China. Cost-effectiveness analysis is useful to examine costs and health outcomes of one or more interventions, by comparing one intervention with another (or to the standard of care) and approximating the costs required to gain a unit of a health outcome as a life year gained or a death prevented.8 Therefore, cost-effectiveness helps identify ways to redirect economic resources by demonstrating not only the benefit of allocating them to effective interventions but also the utility of choosing more cost-effective interventions.8

The analysis was performed according to China's health care perspective.7 As the first step, the authors conducted a meta-analysis, pooling the results of 6 pivotal studies in the field. The included trials were DECLARE-TIMI 58, EMPA-REG OUTCOME, DAPA-HF, SUGAR-DM-HF, EMPEROR-Reduced, and REFORM. This comprehensive approach included approximately 11,000 patients in total. The combined trials' data were used to estimate the rates of heart failure hospitalization and readmission, as well as of cardiovascular death. These rates were then used to calculate transition probabilities within a 20-year horizon simulation, using a Markov model. Costs and utility values for the chosen heart failure states were derived from published literature and Chinese official documentation. Baseline results showed high cost-effectiveness for SGLT-2 inhibitors. The quadruple therapy saved a mean of 21.44 quality-adjusted life years (QALYs; vs. 18.60 QALYs of the standard regimen), with an Incremental Cost-Effectiveness Ratio of $124.03 per QALY gained, well below the chosen willingness to pay threshold of $37,663 per QALY gained.

The robustness of this model results persisted through the one-way sensitivity analysis proposed in the study, leading the authors to conclude that SGLT-2 inhibitors are cost-effective from the perspective of the Chinese public health care.

Main study characteristics are presented in Figure 1.

FIGURE 1.:

Graphical representation of main study features and results.

This study represents, to the best of our knowledge, the cost-effectiveness analysis with the lowest reported Incremental Cost-Effectiveness Ratio of the entire drug class, providing great hope for prompt introduction into clinical practice.7 Despite most studies showcasing a favorable economic value for SGLT-2 inhibitors, it is clear that the results have exhibited significant heterogeneity.9

Nonetheless, heterogeneity should be welcome in the field because it is inherent in the imperfect world of cost estimation in public health. Early stages of clinical adoption of a drug for a novel clinical indication pose significant challenges to the inevitable need of assessing sustainability in all modern health care systems. Available data initially come from highly selected populations that inherently lack the complexity clinicians face in routine practice.

Randomized controlled clinical trials, in being a crystallized, tailored portrayal of reality, may be exposed to the intrinsic hurdles of trial design, striving to strike a balance between internal validity and external applicability of findings.

Relevant to this work, it must be acknowledged that for the studies included in the meta-analysis, Asian patients were listed in only 4 of the studies (DECLARE-TIMI 58, EMPA-REG OUTCOME, DAPA-HF, and EMPEROR-Reduced),10 exceeding 20% of the trial cohort only in the DAPA-HF and EMPA-REG OUTCOME trials. A recent meta-analysis suggests a greater benefit for Asian patients of SGLT2 inhibitors, with comparable tolerability.11,12 This assumed advantage could translate in more favorable cost estimates and consequent underestimation of economic value if left unaccounted.

A second challenge derives from the typical follow-up times used in trial designs. Although these times are often optimal for efficient and relatively safe use of a drug in the target population, they fall short of the lifetime horizon which is required for optimal cost-effectiveness analysis.

Specifically, the median follow-up of 4.2 years awards the Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes (DECLARE-TIMI 58), the longest follow-up duration among the aforementioned trials.13

Though long term, postmarketing surveillance is ongoing, modeling steps in as a dependable tool to bridge the gap. However, the adoption of modeling introduces a level of uncertainty pertaining key parameters, such as transition probabilities, utility values, and monitoring cycle length.

The authors of this study used 2 powerful analytical approaches, namely meta-analysis and sensitivity analysis, to address these limitations to some extent, showing overall robustness of findings within the model. Indirect costs and out-of-pocket expenses, which were not considered in this study, might vary based on societal conditions.

Thus, variability of results between similar works primarily stems from the complex interplay of the steps taken to manage these factors and compute treatment expenses. In fact, the determination of health care costs is influenced not only by the health care environment selected but also by the temporal aspect, considering that drug prices often exhibit a downward trajectory over time.

Understanding the economic value of novel therapies is important for health systems to prioritize implementation in the context of more limited budgets always. However, cost-effectiveness should remain only 1 consideration when evaluating the overall importance of novel therapies, particularly in the context of the heart failure pandemic. Furthermore, new dares are waiting for us: the costs of adopting SGLT2 inhibitors as the sole effective drug for heart failure with preserved ejection fraction and considerations on the implementation of vericiguat or omecamtiv mecarbil use for patients with advanced heart failure.

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