Article Text

Original research article
Cost-effectiveness of sacubitril/valsartan in the treatment of heart failure with reduced ejection fraction
1. John J V McMurray1,
2. David Trueman2,3,
3. Elizabeth Hancock2,3,
4. Martin R Cowie4,
5. Andrew Briggs5,
6. Matthew Taylor6,
7. Juliet Mumby-Croft2,
8. Fionn Woodcock2,
9. Michael Lacey7,
10. Rola Haroun8,
11. Celine Deschaseaux8
1. 1 British Heart Foundation (BHF) Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
2. 2 Health Economics, DRG Abacus Ltd, Bicester, UK
3. 3 Health Economics, PHMR Ltd, London, UK
4. 4 National Heart and Lung Institute, Imperial College London, London, UK
5. 5 Health Economics & Health Technology Assessment, Institute of Health & Wellbeing, University of Glasgow, Glasgow, UK
6. 6 York Health Economics Consortium Ltd, University of York, York, UK
7. 7 Global Economic Value & Market Access Life Sciences, IBM Watson Health, Cambridge, MA, USA
8. 8 Cardio Metabolic Franchise, Novartis Pharma AG, Basel, Switzerland
1. Correspondence to Rola Haroun, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland; Rola.Haroun{at}novartis.com

## Abstract

Objective Chronic heart failure with reduced ejection fraction (HF-REF) represents a major public health issue and is associated with considerable morbidity and mortality. We evaluated the cost-effectiveness of sacubitril/valsartan (formerly LCZ696) compared with an ACE inhibitor (ACEI) (enalapril) in the treatment of HF-REF from the perspective of healthcare providers in the UK, Denmark and Colombia.

Methods A cost-utility analysis was performed based on data from a multinational, Phase III randomised controlled trial. A decision-analytic model was developed based on a series of regression models, which extrapolated health-related quality of life, hospitalisation rates and survival over a lifetime horizon. The primary outcome was the incremental cost-effectiveness ratio (ICER).

### Probabilistic sensitivity analysis (PSA)

In the UK, the expected ICER from the PSA was £18 000 (95% CI £8900 to £34 700). At cost-effectiveness thresholds of £20 000 and £30 000 per QALY gained, the probabilities that sacubitril/valsartan was cost-effective were 68% and 94%, respectively (figure 3).

Figure 3

Cost-effectiveness acceptability curves.

In Denmark, the expected ICER from PSA was Kr176 700 (95% CI Kr76 200 to Kr367 300). The probability that sacubitril/valsartan was cost-effective at Kr250 000 was 84% (figure 3).

In Colombia, the expected ICER from the PSA was COP$33.8 million. The probability of being cost-effective at a WTP threshold of COP$52.4 million (three times the average per capita income) was 95% (figure 3).

## Discussion

The base-case analysis for the UK indicates that sacubitril/valsartan was cost-effective at a WTP threshold of £20 000 per QALY, compared with an ACEI, with an ICER of £17 100. This result was not only mainly driven by reductions in mortality but also by improvements in HRQL and reductions in hospitalisation. The findings of the analysis were robust to changes in most structural assumptions, and a PSA suggested that the probability that sacubitril/valsartan was cost-effective at a WTP threshold of £20 000 was 68%. Three analyses from the perspective of third-party healthcare payers in the USA have also suggested that sacubitril/valsartan is cost-effective at commonly accepted WTP thresholds.21–23

Our findings were consistent across all three countries. The base-case analysis for Denmark, another high-income country, found that sacubitril/valsartan was cost-effective at a WTP threshold of Kr250 000 per QALY, compared with an ACEI, with an ICER of Kr174 000. The base-case analysis for Colombia, a middle-income country, found that sacubitril/valsartan was cost-effective at a WTP threshold of COP$52.4 million per QALY, with an ICER of COP$39.5 million.

These results are in line with National Institute for Health and Care Excellence (NICE) guidance, which recommends sacubitril/valsartan as a cost-effective option for the treatment of HF-REF in patients with NYHA class II–IV, a left ventricular ejection fraction of ≤35% and who are already taking a stable dose of ACEI or ARB.24

The UK analysis predicted (discounted) gains in life years and QALYs with sacubitril/valsartan of 0.62 (9%) and 0.52 (10%), respectively. These are comparatively large benefits in terms of absolute and relative gains compared with the benefits of other treatments for HF-REF, especially as PARADIGM-HF was an active-controlled rather than placebo-controlled trial. The statistical models of mortality presented here were developed to align with the methods outlined by the NICE Decision Support Unit.25 This approach provides shorter estimates of survival in both arms of the model than have been estimated using non-parametric methods from PARADIGM-HF and correspondingly lower gains in life expectancy.26 Given the importance of mortality as a determinant of cost-effectiveness in the present analysis, such estimates may provide a conservative estimate of cost-effectiveness for sacubitril/valsartan.

The observation that cost-effectiveness in this analysis was mainly driven by improvements in mortality is consistent with the results of some, but not all, prior analyses.27 However, other model-based studies concluded that reductions in hospitalisation are the key determinant of cost-effectiveness.28 This difference may be a consequence of the different analytical approaches. This model considered independent statistical models of mortality, hospitalisation and long-term HRQL changes, and the relationships between these outcomes were contained implicitly in the analysis. In contrast, the model of Lee et al 28 considered mortality and long-term HRQL to be direct functions of the number of hospitalisations experienced by an individual, and therefore model outcomes were conditional on the rate of hospitalisation itself. Nevertheless, both this model and that of Lee et al predicted that the proportions of QALY gains attributable to life extension were of similar magnitude for their respective interventions (88% and 80% in this model and in Lee et al, respectively). The cost savings attributable to reduced hospitalisation were also of a similar magnitude (8% and 12% in this model and in Lee et al, respectively). These differences in the conclusions therefore appear to reflect decisions made in the conceptual design of the respective analyses.

The present evaluation used methods consistent with a recently published economic evaluation in HF,27 but incorporated a novel approach to the prediction of HRQL, in which EQ-5D was extrapolated based on time trends observed in PARADIGM-HF. A key strength of this analysis was that PARADIGM-HF collected EQ-5D at multiple time points, permitting this longitudinal analysis. This allowed the direct modelling of EQ-5D over time, rather than predicting HRQL based on intermediate clinical measures such as NYHA class.

The key limitation of this analysis was the extrapolation beyond the follow-up of PARADIGM-HF (with median follow-up of 27 months). This is a cause of uncertainty which cannot readily be characterised in sensitivity analysis, but is common to all modelling exercises, particularly in HRQL estimates. However, the assumption of an annual decline in EQ-5D of 0.008 appears consistent with data from other studies; 1-year longitudinal data presented by Berg et al in patients with chronic HF suggests an annual decrease in EQ-5D of 0.006.29

PARADIGM-HF was a geographically diverse study, and the patient population may not be generalisable to individual countries. Although there is no evidence that the treatment effect differed across subgroups in PARADIGM-HF,10 cost-effectiveness is driven by absolute benefit, which is dependent on patients’ absolute risk of events, reflecting their baseline clinical characteristics. If patient characteristics differ between PARADIGM-HF and the HF-REF population in the UK, Denmark or Colombia, then absolute benefit, and therefore cost-effectiveness, would be expected to differ too. However, the results of the subgroup and scenario analyses suggest that the conclusions of the base-case analysis would not change to any meaningful extent.

In conclusion, this analysis suggests that sacubitril/valsartan likely represents a cost-effective option in the treatment of HF-REF for the NHS in the UK, the Danish healthcare system and for the Colombian healthcare system.

### Key messages

#### What is already known on this subject?

Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in  Heart Failure trial showed that sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor, was superior to the ACE inhibitor enalapril in reducing the risks of death and heart failure hospitalisation in patients with heart failure with reduced ejection fraction. Published analyses from the perspective of third-party healthcare payers in the USA have suggested that sacubitril/valsartan is cost-effective at commonly accepted willingness-to-pay thresholds.

#### What might this study add?

We evaluated the cost-effectiveness of sacubitril/valsartan compared with enalapril in the treatment of heart failure with reduced ejection fraction from the perspectives of the UK National Health Service, the Danish healthcare system (high-income countries) and the Colombian healthcare system (middle-income country). We found sacubitril/valsartan to be cost-effective at conventional willingness-to-pay thresholds in all three country settings.

#### How might this impact on clinical practice?

This analysis, which shows sacubitril/valsartan to be a cost-effective use of resources, should aid decision-makers and may enhance availability of this efficacious treatment for patients with heart failure with reduced ejection fraction.

## Acknowledgments

The authors are grateful to Morten Størling Hedegaard, Vera Gielen and Elizabeth Karpf of Novartis AG for providing inputs to the Danish, UK and Colombian model adaptations, respectively.

View Abstract

## Footnotes

• i Results presented here use the reweighted population to remain in line with Danish HTA submissions. Costs and QALYs increase in both arms when using an unweighted population; however, the ICER remains similar at Kr170 000.

• Contributors JJVM, DT, EH, MRC, AB, MT, JMC, RH and CD contributed to the design of the evaluations. DT, EH, FW and ML were responsible for data collection, development of the economic model and performing the analysis. CD and RH were responsible for overseeing the content. All authors contributed to the writing of the manuscript.

• Funding This analysis and the PARADIGM-HF study were funded by Novartis AG.

• Competing interests CD and RH are permanent employees of Novartis AG. CD and RH oversaw the all stages of the economic evaluation and contributed to the design and reporting of the economic model. DRG Abacus received funding from Novartis AG to undertake the analysis and has supported EH, DT JJVM and FW through salary payments. York Health Economics Consortium received funding from Novartis AG to provide consulting input and has supported MT through salary payments. MRC and AB have received consulting fees from Novartis AG. JJVM’s employer, Glasgow University, has received consulting fees and research grant support from Novartis AG.

• Provenance and peer review Not commissioned; externally peer reviewed.

• Correction notice Since this paper has been published online an update has been made to the paragraph Colombian setting. The ICER value of €15 975 has been changed to € 11 200.

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