Original article

Cost-effectiveness of sacubitril/valsartan in chronic heart-failure patients with reduced ejection fraction

DOI: https://doi.org/10.4414/smw.2017.14533
Publication Date: 15.11.2017
Swiss Med Wkly. 2017;147:w14533

Ademi Zanfinaae, Pfeil Alena Ma, Hancock Elizabethb, Trueman Davidc, Haroun Rolad, Deschaseaux Célined, Schwenkglenks Matthiasa

a Institute of Pharmaceutical Medicine (ECPM), University of Basel, Switzerland

b PHMR, London, United Kingdom

c Source HEOR, Oxford, United Kingdom

d Novartis Pharma AG, Basel, Switzerland

e Monash Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

Summary

AIMS

We aimed to assess the cost effectiveness of sacubitril/valsartan compared to angiotensin-converting enzyme inhibitors (ACEIs) for the treatment of individuals with chronic heart failure and reduced-ejection fraction (HFrEF) from the perspective of the Swiss health care system.

METHODS

The cost-effectiveness analysis was implemented as a lifelong regression-based cohort model. We compared sacubitril/valsartan with enalapril in chronic heart failure patients with HFrEF and New York-Heart Association Functional Classification II–IV symptoms. Regression models based on the randomised clinical phase III PARADIGM-HF trials were used to predict events (all-cause mortality, hospitalisations, adverse events and quality of life) for each treatment strategy modelled over the lifetime horizon, with adjustments for patient characteristics. Unit costs were obtained from Swiss public sources for the year 2014, and costs and effects were discounted by 3%. The main outcome of interest was the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life years (QALYs) gained. Deterministic sensitivity analysis (DSA) and scenario and probabilistic sensitivity analysis (PSA) were performed.

RESULTS

In the base-case analysis, the sacubitril/valsartan strategy showed a decrease in the number of hospitalisations (6.0% per year absolute reduction) and lifetime hospital costs by 8.0% (discounted) when compared with enalapril. Sacubitril/valsartan was predicted to improve overall and quality-adjusted survival by 0.50 years and 0.42 QALYs, respectively. Additional net-total costs were CHF 10 926. This led to an ICER of CHF 25 684. In PSA, the probability of sacubitril/valsartan being cost-effective at thresholds of CHF 50 000 was 99.0%.

CONCLUSION

The treatment of HFrEF patients with sacubitril/valsartan versus enalapril is cost effective, if a willingness-to-pay threshold of CHF 50 000 per QALY gained ratio is assumed.

Keywords: cost-effectiveness, chronic heart failure, drug treatment

Introduction

Heart failure is a progressive and incurable disease, with high morbidity and mortality in high-income countries including Switzerland. The reported prevalence of heart failure varies from between 1 and 2%, and increases for individuals aged above 65 years [1]. Estimates for 2010 expected 15 million people with heart failure in Europe and 6.6 million in the United States [2, 3]. Chronic heart failure has a prevalence of 1 to 2% and heart failure with reduced ejection fraction (HFrEF) accounts for about 50% of all heart failure cases [4]. In general, the condition requires complex management and treatment protocols that require substantial effort from patients, care givers, and healthcare services, and therefore poses a high cost burden on society [5]. Morbidity is very prominent in terms of severity of symptoms, reduced quality of life, hospitalisations and continuous need for treatment [6, 7]. Previous guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers as initial treatment, as well as diuretics if there is a fluid overload [8]. These treatments appear to reduce the risk of death and improve exercise capacity. Angiotensin receptor blockers (ARBs) are controversial and less well tolerated than ACEIs, but remain a treatment option where ACEIs are not tolerated. Other treatments such as anti-platelets and lipid-lowering agents are added if necessary [9]. Advances in chronic heart failure treatment have been quite limited in the last decade.

Sacubitril/valsartan, an angiotensin-receptor-neprilysin-inhibitor (ARNI), is a novel oral therapy proposed in the current guidelines for the treatment of heart failure in patients with reduced left ventricular ejection fraction (LVEF) [9]. The phase-III prospective double-blind randomised controlled trial PARADIGM-HF (prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure) compared morbidity and mortality between sacubitril/valsartan and the ACEI enalapril in a population with HFrEF [10]. The primary outcome was a composite of death from cardiovascular causes or hospitalisation for heart failure. After a median follow-up of 27 months, sacubitril/valsartan was associated with a significant reduction in time to the primary outcome (hazard ratio [HR] 0.80, 95% confidence interval [95% CI] 0.73–0.87; p <0.001), all-cause mortality (HR 0.84, 95% CI 0.76–0.93; p <0.001) and cardiovascular mortality (HR 0.80, 95% CI 0.71–0.89; p <0.001). In addition, sacubitril/valsartan was also associated with a reduced risk of hospitalisation for heart failure of 21% (p <0.001) and a reduction in the symptoms and physical limitations of heart failure (p = 0.001) [10].

The aim of this study was to assess the clinical effectiveness in terms of quality-adjusted life years (QALYs) gained, the direct medical cost, and the cost-effectiveness of sacubitril/valsartan (in addition to standard care) compared to ACEIs (in addition to standard care) from the perspective of the Swiss healthcare system.

Methods

Overview of approach and model

A model-based cost-utility analysis was undertaken comparing sacubitril/valsartan and standard care to ACEI and standard care. The incremental cost-effectiveness ratio (ICER) was expressed as cost per QALY gained. The analysis was conducted from the perspective of the Swiss healthcare system. Costs and effects occurring after one year were discounted by 3% in the base-case analysis.

A two-state Markov model [11] was implemented for the current analyses. In brief, the model is structured as a two-state Markov model (with health states “alive” and “dead”). Regression models were used to predict events and outcomes such as mortality, hospitalisations, adverse events and health-related quality of life over the lifelong time horizon of the model, based on patient characteristics and treatment received (fig. 1). This type of model was chosen as the benefits of treatment and costs continue to accrue beyond the observation period of the PARADIGM-HF trial. Cycle length is one month and a half-cycle correction is applied. The model permits both deterministic (DSA) and probabilistic sensitivity analyses (PSA). Death can occur at any point in time. Model outcomes include survival time (i.e., life years), QALYs, medical resource utilisation, accrued lifetime and total and disaggregated costs, and other clinical events such as number of hospitalisations and adverse events.

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Figure 1
Model structure.
AEs = adverse events; QALYs = quality adjusted life years

Patient population

The patient population considered for the economic model was the same as that enrolled on the PARADIGM-HF trial [10] i.e., adult HErEF and a mean age of 64 years. The following eligibility criteria were applied: age of at least 18 years, NYHA class II–IV symptoms, ejection fraction of 40% or less (which was changed to 35% or less) [12], and plasma B-type natriuretic peptide (BNP) level of at least 150 pg/ml or hospitalisation for heart failure within the previous 12 months and a BNP of at least 100 pg/ml. Patients taking stable doses of ACEIs or ARBs four weeks before screening were considered for participation in the study. Implantable cardioverter-defibrillators (ICDs) and cardiac resynchronisation therapy (CRT) are increasingly used in patients with HFrEF. In the PARADIGM-HF trial [10], 1,857 (22%) of the eligible patients used either ICDs or CRT at baseline. After screening, patients had a run-in phase with enalapril or sacubitril/valsartan, which was followed by the main double-blind randomised treatment phase [13]. Of 8,442 patients randomised, 43 patients were excluded for the full analysis set (FAS) due to invalid randomisation (n = 6) and good clinical practice (GCP) violations (n = 37). The analysis population consisted of 4187 patients receiving sacubitril/valsartan and 4212 patients receiving enalapril. The baseline characteristics of the trial population are presented in supplementary table S1 in appendix 2.

Treatment strategies

The average daily dose at the end of the PARADIGM-HF trial [10] for sacubitril/valsartan (in addition to standard care) was 375 mg compared to a treatment strategy with a daily dose of the ACEI enalapril (in addition to standard care) of 18.9 mg. Standard care included the use of diuretics, beta-blockers, aldosterone antagonists, digoxin, anticoagulants, aspirin, adenosine diphosphate antagonists and lipid-lowering medications. The choice of standard care is based on medication classes observed in the PARADIGM-HF trial [10].

Clinical model inputs

Clinical information regarding all-cause mortality, hospitalisation rates, health-related quality of life and adverse events was obtained from the PARADIGM-HF trial [10].

Mortality

The base-case analysis used a multivariable parametric survival model of all-cause mortality, which was based on the treatment arm, baseline characteristics of the patients, and time since randomisation (supplementary table S2 in appendix 2).

An alternative scenario analysis used multivariable parametric survival for cardiovascular mortality from the PARADIGM-HF trial [10] (supplementary table S3), and non-cardiovascular mortality from Swiss national life-tables (table S6). The monthly probability of non-cardiovascular mortality was obtained by subtracting the probability of cardiovascular mortality from the probability of all-cause mortality as calculated with data provided by the Swiss Federal Office of Public Health (SFOPH) [14] and the Swiss Federal Office of Statistics (SFOS) tables [15]. A death rate including cardiovascular death for five-year age bands was calculated by dividing the number of deaths obtained from Swiss life tables [15] by the number of persons in the relevant age group sourced from the SFOPH [14]. The death rates were converted to yearly probabilities of death using the formula p = 1 − ecentral death rate*time (time is 1/12 years in this case, as we derived monthly probabilities). All-cause mortality and cardiovascular mortality were assumed to be constant within the 5-year age bands provided by the SFOS, and constant in the age group of persons aged 85 years or above, as we had no additional data for this age category. Additional information about Swiss population and related mortality is available in tables S4, S5 and S6.

Hospitalisation and adverse events

The model predicted the risk of all-cause hospitalisation beyond the PARADIGM-HF trial using negative binomial regression [11]. Briefly, predicted hospitalisation rates were adjusted for baseline characteristics of the subjects included in the PARADIGM-HF trial such as age, race, and region, and were dependent on the treatment arm. The model for all-cause hospitalisation showed that a treatment strategy with a daily dose of sacubitril/valsartan compared to ACEI treatment reduced all-cause hospitalisation (supplementary table S7).

More serious adverse events were considered to be covered by all-cause hospitalisations (table S7), whereas less serious adverse events were considered independently. Rates of these adverse events (hypotension, elevated serum creatinine and potassium, cough and non-severe angio-oedema) were estimated from the PARADIGM-HF trial) [10]. Occurrence of less serious adverse events can be found in the additional material provided in table S8.

Health-related quality of life (HRQoL)

A mixed-effects regression model derived from the PARADIGM-HF trial based on patient-level EQ-5D data was estimated to allow the prediction of the EQ-5D-based utility values as a function of baseline characteristics (including baseline EQ-5D), hospitalisations, adverse events, treatment arm and time since randomisation. The EQ-5D 3-level questionnaire was administered at baseline and at months 4, 8, 12, 24, 36, and end of study. The UK EQ-5D tariff published by Dolan et al. was applied to EQ-5D patient responses [16]. Details are available in table S9. Hospitalisations in the 30 days before EQ-5D measurement (to capture the acute effect of hospitalisation), and hospitalisations 30–90 days before EQ-5D measurement (to capture any long term effect during rehabilitation) were implemented. Utility decrements in the model were applied to subjects experiencing hospitalisations or adverse events.

Resource use

Drug dosage (primary and background drug therapy) data from the PARADIGM-HF trial were validated by using the recommendations of the Swiss Heart Failure Working Group of the Swiss Society of Cardiology [17], which are based on 2012 European Society of Cardiology (ESC) guidelines [8]. Drug dosages used for the Swiss model can be found in supplementary table S10. The proportional occurrence of hospitalisations for surgical procedures (4.0%), interventional procedures (8.0%), or medical management only (88.0%), was obtained from the Western European population of the PARADIGM-HF trial (table S11).

A background medical resource utilisation per unit of time was assumed to be the same in both treatment strategies of the model. We assumed that patients with heart failure would need to have at least 12 primary-care physician (PCP) visits per year. This was based on an article by Muntwyler et al. [18], which measured the quality of the diagnosis and management of heart failure in primary care in 1999 in Switzerland. Over 82 PCPs from all over Switzerland participated in the study. A total of 474 patients were included.

Milder adverse events reported in the PARADIGM-HF trial [10] were modelled separately, as mentioned previously. The following assumptions were applied for resource use associated with adverse events; (a) if a patient experiences hypotension, he/she needs 2 additional PCP visits, (b) if a patient experiences cough, he/she needs 2 additional PCP visits and blood tests, (c) in the case of angio-oedema, patients can experience milder or severe angio-oedema. Milder angio-oedema patients require use of antihistamines and 2 additional outpatient visits, while patients experiencing more severe angio-oedema need 2 additional outpatient visits and use of glucocorticoids, (d) if patients show signs of elevated serum creatinine, they need 2 additional PCP visits and a blood test, (e) if patients show signs of elevated serum potassium, they need 2 additional PCP visits and a blood test.

Unit costs

The cost of sacubitril/valsartan per day in the base-case analyses was CHF 5.79 (375 mg per day), and unit costs of background therapies were sourced from SFOPH data (Spezialitätenliste) relevant to 2015 [19]. For each reported therapeutic substance used in the PARADIGM-HF trial, we collected and mapped drugs representing the same substance, based on the number of available producers in the Swiss pharmaceutical market. For example, if there were three pharmaceutical producers of enalapril 10 mg on the market, then the average cost per tablet strength was calculated. Monthly costs were calculated by multiplying the daily costs by 365.25/12. Daily costs of primary therapies and background therapies can be found in supplementary table S10.

Unit costs of hospitalisations were estimated on the basis of diagnosis-related group (DRG) costs, and by mapping each reported hospitalisation in the PARADIGM-HF trial to relevant Swiss DRG codes [20]. For this mapping procedure, we used the proportional occurrence of hospitalisations involving surgery, interventional procedures or medical management. Where several suitable Swiss DRG codes were identified, the weighted mean was used based on their activity and cost as reported for 2012, which is when the latest data was published [20]. Details about hospitalisations, the proportional occurrence of diagnoses reported in the PARADIGM-HF trial, and Swiss DRGs assigned are provided in table S11. The weighted mean cost per hospitalisation provided information on the unit cost per hospitalisation event rather than cost per day in hospital. For the year 2012, the average cost per hospitalisation was CHF 13 847; these costs were then updated to 2014 values using the Swiss consumer price index [21]. The consumer price index values for 2012 and 2014 were 99.9 and 98.1. The resulting cost per hospitalisation in 2014 was CHF 13 598.

As described previously, the estimated number of PCP visits per year was informed by the European IMPROVEMENT-HF study [18]. The unit costs of a PCP visit were derived from the santésuisse web page, and amounted to CHF 113 in 2007. Based on the consumer price index [21] the updated value for one PCP visit in 2014 was CHF 110.30. Unit costs for the treatment of each relevant type of adverse event were estimated from Swiss literature and information publicly available from the SFOPH, Tarmed, and santésuisse websites [19] [22].

Subgroup analyses

Subgroup analyses based on the a priori subgroups in PARADIGM-HF were undertaken to understand variation of the main results between subgroups of patients enrolled in the PARADIGM-HF trial.

Sensitivity analysis

To assess the impact of different assumptions on the model results, a series of scenario analyses were performed. Some were of general relevance. Additional analyses were regarded as specifically relevant for the Swiss setting (see appendix 1 for description). A series of deterministic sensitivity analyses (DSA) were performed to assess the impact of uncertainty surrounding key input parameters. Important parameters were varied independently over plausible ranges determined by the 95% confidence intervals (CI) surrounding point estimates. Where 95% CIs were not available, upper and lower values of ±25% surrounding point estimates were used (supplementary table S12). The ICERs resulting from each analysis were recorded for the upper and lower value and are presented in a Tornado diagram.

Probabilistic sensitivity analysis was undertaken to explore joint parameter uncertainty (details about their respective distributions in table S12). A total of 10 000 iterations were run and the results are shown as a cost-effectiveness plan.

Results

Base-case analyses

In the base-case analysis, the sacubitril/valsartan strategy compared to enalapril showed a decrease in the number of hospitalisations (6.0%/year absolute reduction) and lifetime hospital costs by 8.0% (discounted). Total QALYs per person over a lifetime horizon were 4.99 and 4.56 in the sacubitril/valsartan and ACEI treatment strategies respectively (table 1). This led to an incremental difference of 0.425 QALYs. The total incremental costs difference was CHF 10 926 (table 1) and the ICER for sacubitril/valsartan treatment versus ACEI was CHF 25 684 per QALY gained. Alternatively, the use of Swiss life-tables for non-cardiovascular mortality and cardiovascular mortality rates from the PARADIGM-HF trial led to an ICER of CHF 24 490.

Table 1

Base case results (all costs are expressed in CHF).

ParameterSacubitril/valsartanACEIDifference
Clinical effectiveness parameters (discounted)
Total life years6.676.170.50
Total QALYs4.994.5650.4254
Cost parameters (discounted)
Primary therapy14 119175712 362
Titration2200.00220
Adverse events30729017
Background drug therapy80727467605
Management of HF by physicians88308168662
Hospitalisation32 85735 797−2940
Total costs69 68353 47910 926
Cost-effectiveness parameters
Cost per LYG  CHF21 855
Cost per QALY gained  CHF25 684

ACEI = angiotensin-converting enzyme; HF = chronic heart failure patients; LYG = life year gained; QALY = quality adjusted life year

Cost-effectiveness results for subgroups of patients are presented in full in supplementary table S13 in appendix 2. The ICER was quite stable, with ±1–11% variation from the base-case result. In brief, if the baseline eGFR was <60, the ICER decreased by 8.0%. No use of beta-blockers at baseline decreased the ICER by 11.0%, and where ≤1 year since diagnosis of heart failure was recorded, this increased the ICER by 8.0%.

Sensitivity analysis

The most influential parameters in univariate sensitivity analysis were related to all-cause mortality, hospitalisations and HRQoL (fig. 2). Table 2 shows the scenario analysis results. An ICER of > CHF 48 000 per QALY occurred if all treatment effects of sacubitril/valsartan were assumed to cease after year 5 (while the treatment costs of sacubitril/valsartan continued for life). An analysis based on two years of follow-up led to an increased ICER of CHF 58 679. An ICER of CHF 30 812 per QALY gained was observed where there was assumed to be no effect of sacubitril/valsartan on HRQoL. Using the German and French EQ-5D value sets instead of that for the UK led to slightly more favourable ICER results. Other scenario analyses did not have a major impact on the ICER.

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Figure 2
Tornado diagram summarising univariate sensitivity analysis results.

Table 2

Results of scenario analyses.

Area of uncertaintyScenarioICER
(cost per QALY in CHF)
Base case (patient level data) 25 684
Discount rateDiscount rate: 1.5% benefits; 6% costs18 951
Time horizon2 years58 679
CV mortality PARADIGM, non-CV mortality life tables 24 490
HRQL time trendTime trend halved24 648
HRQL time trendTime trend doubled28 041
HRQL time trendNo decrease in HRQL23 693
HRQL time trendHRQL constant at 5 years24 648
HRQL time trendHRQL constant at 10 years25 311
Treatment effect on HRQLNo absolute benefit in HRQL for sacubitril/valsartan30 812
Treatment effect on hospitalisationsacubitril/valsartan treatment effect applied only to HF hospitalisations (rather than CV mortality and utility)36 472
Effect of hospitalisation on HRQLDecrements for hospitalisation set to zero25 810
Extrapolation of treatment effectsAll treatment effects cease at year 547 062
Extrapolation of treatment effectsAll treatment effects cease at year 1030 132
DiscontinuationInclude discontinuation as seen in PARADIGM-HF25 242
DiscontinuationNo discontinuation after year 325 455
Hospitalisation costsDouble cost per hospitalisation25 684
Adverse event ratesAll adverse event rates set to zero25 621
Cost of primary therapiesCost of ACEI/ sacubitril/valsartan based on PARADIGM-HF target doses26 245
French EQ-5D tariff usedUsing EQ-5D tariff instead of UK tariffs23 359
German EQ-5D tariff usedUsing EQ-5D German tariffs instead of UK tariff24 038
NT-pronBNP test inclusion 26 159
HF management outpatient visits (40)4.6 visits per year25 200

CV = cardiovascular; HF = heart failure; EQ-5D = European quality of life-5 dimensions; HQRL = health-related quality of life; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; NT-pronBNP = N-terminal pro-brain natriuretic peptide; PCP = primary care physician

PSA results are presented in figure 3 as a cost-effectiveness plane. All simulation fell within the northeast quadrant of the cost-effectiveness plane (meaning in all simulations sacubitril/valsartan was both more effective and costlier than enalapril), with a 95% confidence interval range of CHF 18 798 to CHF 43 974 per QALY gained. The cost-effectiveness threshold of CHF 30 000 per QALY gained was met in 78.0% of 10 000 runs, and threshold of CHF 50 000 per QALY gained was met in 99.0% of 10 000 runs.

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Figure 3
Cost-effectiveness scatterplot and 95% confidence range (10 000 simulations).

Discussion

Given limited healthcare budgets throughout the world, the health economic aspects of new drug evaluations can be as important as efficacy, safety and the ability to serve important medical needs under routine clinical practice. In most developed countries, heart failure poses a great economic burden. Estimates show that management of heart failure accounts for 2–5% [2, 3] of total healthcare budgets. Long-term drug treatment is a cornerstone of heart failure therapy.

The cost-effectiveness of sacubitril/valsartan plus standard care compared to enalapril plus standard care has been assessed, from the perspective of the Swiss health care system. The base-case analysis indicated an ICER of CHF 25 684 per QALY gained.

The findings presented were robust to changes in assumptions, and the ICER results were similar across multiple patient subgroups. When model input parameters were varied on the basis of their 95% confidence intervals (as observed in the PARADIGM-HF trial or estimated in regression analyses based thereupon), the ICER remained below CHF 50 000 per QALY gained in most of the cases. In the scenario analyses performed, the ICER also remained below CHF 50 000 per QALY gained, except in the extreme scenarios of the treatment effect of sacubitril/valsartan that persisted for only two or five years.

It should be noted that there is no formally accepted cost-effectiveness threshold in Switzerland. In this study, we tentatively assume a threshold of CHF 30 000 and CHF 50 000 per QALY gained to distinguish between favourable and unfavourable ICER results [23, 24]. This threshold level is similar to the upper limit of the threshold range of £20 000–£30 000 accepted in the United Kingdom (UK) [25]. A few years ago, a court in Switzerland hinted at a CHF 100 000 per QALY threshold [26].

Findings were similar to the results of three previously published cost-effectiveness analyses in the United States [2729]. These studies (Gaziano et al., King et al. and Sandhu et al.) found sacubitril/valsartan to be cost-effective. The first published economic analysis for the US [27] used the same analytical framework over a 30-year time horizon and displayed an ICER of US$45 017 per QALY gained. Differences observed with our study affected costs and quality of life. Incremental costs and effects were higher in the US population. For example, the monthly cost for sacubitril/valsartan in the US was $375, whereas in Switzerland it was CHF 176. The cost of heart failure hospitalisation were $18 158 in the US and CHF 13 599 in Switzerland. Incremental QALYs gained were 0.78 for the US population and 0.42 for the Swiss population.

The second set of cost-effectiveness analyses undertaken by King et al. [28] found similar results with an ICER of $50 959 per QALY gained over a lifetime. However, their model included population with NYHA class I [28], whereas NYHA class I population was excluded from the PARADIGM-HF trial. The third economic evaluation by Sadhu et al. [29] displayed a cost per QALY gained of $47 053, and differences with our study were mainly due to modelling techniques and input parameters. Monthly cost for sacubitril/valsartan in the study by Sadhu et al. [29] was assumed to be $380, and heart failure hospitalisation costs were assumed as $11 829. In terms of health outcomes, the study by Sadhu et al. [29] displayed a higher incremental QALY gained of 0.62, as compared to that of the Swiss population (0.42).

Another recent study from the Netherlands, using a Markov model and using the effectiveness data from the PARADIGM-HF trial over a lifetime horizon, showed that sacubitril/valsartan was considered cost effective at an ICER of 19 113 per QALY gained [30]. Differences observed with our study were mainly in terms of model structure, but also in terms of input parameters, such as quality of life. The Dutch study was not able to utilise patient level PARADIGM-HF trial data. The reported incremental QALY gained was 0.29 for the Dutch population, which was lower than that for the Swiss population (0.42). However, the monthly cost for sacubitril/valsartan in the Dutch and Swiss models was quite similar; the amounts were €161.7 and CHF 176 respectively.

In recent years, there have been a number of cost-effectiveness studies undertaken for heart failure patients. The interventions considered included ivabradine, eplerenone, ACEI, and beta blockers. These were compared with placebo or standard of care. In particular, ivabradine was one of the most studied drugs in heart failure patients. Lifetime ICERs ranged from €7634 in Poland [31] to $53 710 in Mexico [32] within these studies [31, 3338]. ICERs for sacubitril/valsartan appear to be in a comparable range.

Strengths and limitations

Patient-level data from a large international randomised clinical trial formed the basis of this analysis. Use of data from PARADIGM-HF, a large randomized controlled trial comparing sacubitril/valsartan to a real-world standard of care, allowed for a high level of internal consistency in the model. Multivariate risk equations allowed us to characterise and take into account between-patient heterogeneity. A relatively novel approach was used to predict quality of life, by extrapolating EQ-5D utility values based on time trends observed in PARADIGM-HF. The use of local data with regards to non-cardiovascular deaths and unit costs allowed for adjustment to the Swiss healthcare environment. Consistency across countries with regards to medical resource use was partially improved by using the Western European part of the PARADIGM-HF population for the calculation of some parameters, such as hospitalisations. However, the transferability of clinical trial results is necessarily affected by simplifications and assumptions, as these are required in all health economic models.

The main limitation was extrapolation of the treatment effect beyond the observation period of the PARADIGM-HF trial. This is a common limitation shared by most economic evaluation studies when the lifetime impact of an emerging treatment is assessed. Assumptions made with regards to the long-term effects of treatment on mortality, health-related quality of life and all-cause hospitalisation were addressed by performing state-of-the-art sensitivity and scenario analyses. When these assumptions were changed one at a time, they were found to have a relatively modest impact on the final results. Hence, results derived in the base-case analysis seem to be realistic based upon assumptions in the economic evaluation.

The mean age of patients treated in the PARADIGM–HF trial was 64 years, while the mean age of patients in the Swiss population might be higher. This may have led to an over- or underestimation of the true differences between sacubitril/valsartan and standard treatment to be expected for Switzerland, with unclear implications for the ICER. However, in a subgroup analysis including only PARADIGM-HF [39] patients aged at least 75 at baseline, the resulting ICER was very similar to the base case ICER.

The model used Swiss input data where relevant and available, but some approximations were required due to lack of data. One related limitation was the lack of information with regards to medical resource use in heart failure patients. This highlights the need for high-quality Swiss data to cover the aspects of resource utilisation. In the absence of such data, we have adopted resource-use estimates from the UK and verified these with the Swiss literature published as far as possible. This approach may have led to an underestimation of the medical resource use of Swiss CHF patients, which is expected to have a relatively unclear impact on this ICER. In addition, we were not able to capture out-of-pocket expenses incurred by patients themselves with regards to heart failure, and this information should be included in future assessments of costs from the perspective of the Swiss healthcare system.

Conclusion

From the perspective of the Swiss healthcare system, sacubitril/valsartan represents a cost-effective treatment option in patients with HFrEF versus enalapril if a willingness-to-pay threshold of CHF 50 000 per QALY gained is assumed.

Disclosure statement

This analysis and the PARADIGM-HF study were funded by Novartis AG. Elizabeth Hancock and David Trueman acted as paid consultants for Novartis Pharma AG. Céline Deschaseaux was employee at Novartis Pharma AG at study time. For the work under consideration, Matthias Schwenglenks has received research funding (via employment institution) from Novartis Pharma Schweiz AG.

Correspondence

Zanfina Ademi, Pharm, MPH, PhD, Institute of Pharmaceutical Medicine (ECPM), University of Basel, Klingelbergstrasse 61, CH-4056 Basel, zanfina.ademi[at]unibas.ch

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39 Jhund PS, Fu M, Bayram E, Chen CH, Negrusz-Kawecka M, Rosenthal A, et al.; PARADIGM-HF Investigators and Committees. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015;36(38):2576–84. doi:. http://dx.doi.org/10.1093/eurheartj/ehv330 PubMed

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Appendix 1

Scenario analyses

Basing non-cardiovascular death from Swiss life tables, observations from the PARADIGM-HF trial were used for cardiovascular (CV) mortality. Towards this end, CV mortality parametric survival model was used where an effect of sacubitril/valsartan on CV mortality was considered.

Sacubitril/valsartan showed a small positive effect on European Quality of Life-5 Dimensions (EQ-5D) score (0.011, p = 0.001). To test the impact of this assumption, in the scenario analysis this effect was set to zero.

The treatment effect of sacubitril/valsartan was applied to heart failure (HF) hospitalisations only, whereas the base-case analyses modelled the observed impact of sacubitril/valsartan treatment on all cause hospitalisations.

Hospitalisation-related utility decrements were set to zero whereas in the base-case analyses, utility decrements for hospitalisation in the previous 30 days and in the previous 30-90 days were incorporated.

The median follow-up time in the PARADIGM-HF trial was 27 months. In the absence of long term follow up data, the base-case analyses assumed that the treatment effect of sacubitril/valsartan on mortality, hospitalisations and health-related quality of life (HRQoL) would continue over a lifetime horizon. In scenario analyses, all sacubitril/valsartan treatment effects were assumed to cease after 5 or 10 years (but the accrual of sacubitril/valsartan treatment costs was assumed to continue).

While the base-case analyses included discontinuation as seen in PARADIGM-HF, scenario analysis assumed an exponential survival model of treatment discontinuation, implying a constant rate of discontinuation. Upon discontinuation, costs and efficacy for sacubitril/valsartan patients were assumed to revert to that of angiotensin converting-enzyme inhibitors (ACEIs). This change in efficacy was assumed for all treatment effects, i.e. mortality, hospitalisations, HRQoL and adverse event occurrence. Costs for discontinued ACEI patients were based on angiotensin receptor blocker (ARB) costs, with efficacy assumed to be the same for ACEI and ARBs. (ARBs were shown to have comparable efficacy to ACEI [40].) Another scenario assumed there would be no discontinuation after 3 years.

Given geographical proximity, we additionally applied utility estimates based on the French and German EQ-5D value sets. The former was based on a French time trade-off study by Chevalier et al. [41]. This study recruited a total of 452 respondents aged over 18 years who were representative of the French population with regard to age, gender, and socio-professional group [41]. Secondly, Greiner et al. provided a German value set for the EQ-5D [42] based on the stated preferences of the German general public. A sample of 339 individuals in northern Germany valued 15 different health states from a sample of 36 states. Similarly as described for the base-case model, mixed-effects regression models based on patient-level EQ-5D utility values were estimated to predict EQ-5D utility as a function of baseline characteristics (including baseline EQ-5D), hospitalisations, adverse events, treatment arm and time since randomisation [42].

Another scenario analysis assumed that N-terminal pro-brain natriuretic peptide tests would be routinely performed in heart failure patients.

A last scenario analysis, assumed 4.6 times HF outpatient visits per year, instead of 12 times per year as per base case analysis. 4.6 times HF outpatient visits per year as per Agvall et al. 2005 [43].

Appendix 2

Supplementary tables

Table S1

Baseline characteristics of the PARADIGM-HF trial population (full analysis set).

VariableEnalapril 10 mg twice dailySacubitril/valsartan 200 mg twice dailyp-value
No.42124187 
Age (years), mean (SD)63.8 (11.3)63.8 (11.5)0.93
Female, n (%)953 (22.6%)879 (21.0%)0.070
Race, n (%)   
          White2781 (66.0%)2763 (66.0%)0.97
          Black215 (5.1%)213 (5.1%) 
          Asian750 (17.8%)759 (18.1%) 
          Other      466 (11.1%)      452 (10.8%) 
Region, n (%)   
    North America292 (6.9%)310 (7.4%)0.90
    Latin America720 (17.1%)713 (17.0%) 
    Western Europe and other1025 (24.3%)1026 (24.5%) 
    Central Europe1433 (34.0%)1393 (33.3%) 
    Asia-Pacific742 (17.6%)745 (17.8%) 
Systolic blood pressure (mm Hg), mean (SD)121.2 (15.4)121.6 (15.2)0.31
Heart rate (bpm), mean (SD)72.5 (12.1)72.2 (12.0)0.26
Body mass index (kg/m2), mean (SD)28.2 (5.5)28.1 (5.5)0.65
Serum creatinine (mg/l), mean (SD)1.1 (0.3)1.1 (0.3)0.39
Ischaemic aetiology, n (%2530 (60.1%)2506 (59.9%)0.84
Ejection fraction (%), mean (SD)29.4 (6.3)29.6 (6.1)0.30
NT-proBNP (pg/ml), median (IQR)188.4 (104.8–390.8)192.8 (104.7–373.0)0.94
BNP (pg/ml), median (IQR)72.4 (44.4–134.1)73.6 (44.6–136.6)0.57
NYHA class, n (%)   
    I209 (5.0%)180 (4.3%)0.077
    II2921 (69.3%)2998 (71.6%) 
    III1049 (24.9%)969 (23.1%) 
    IV27 (0.6%)33 (0.8%) 
    Missing6 (0.1%)7 (0.2%) 
Hypertension status, n (%)2971 (70.5%)2969 (70.9%)0.71
Diabetic status, n (%)1450 (34.4%)1446 (34.5%)0.92
Atrial fibrillation based on history, n (%)1574 (37.4%)1517 (36.2%)0.28
Prior HF hospitalisation, n (%)2667 (63.3%)2607 (62.3%)0.32
Prior myocardial infarction, n (%)1816 (43.1%)1818 (43.4%)0.78
Prior stroke, n (%)370 (8.8%)355 (8.5%)0.62
Prior use of ACEI, n (%)3266 (77.5%)3266 (78.0%)0.61
Prior use of ARB, n (%)963 (22.9%)929 (22.2%)0.46
Diuretic use, n (%)3375 (80.1%)3363 (80.3%)0.83
Beta-blocker use, n (%)3912 (92.9%)3899 (93.1%)0.66
Digoxin use, n (%)1316 (31.2%)1223 (29.2%)0.042
Use of mineralocorticoid receptor antagonist, n (%)2400 (57.0%)2271 (54.2%)0.011
Cardioverter-defibrillator implanted, n (%)620 (14.7%)623 (14.9%)0.84
Use of cardiac resynchronisation therapy, n (%)282 (6.7%)292 (7.0%)0.61

ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; BNP = brain natriuretic peptide; HF = heart failure; IQR = interquartile range; NT-pro-BNP = N-terminal pro-brain natriuretic peptide

Table S2

Gompertz regression model for all-mortality (n = 8399).

 CoefficientSEzP>z95% LCI95% UCI
Sacubitril/valsartan−0.1610.051–3.1500.002–0.261–0.061
Age–0.1010.016–6.2200.000–0.133–0.069
Age squared0.0010.0006.7800.0000.0010.001
Female–0.3890.070–5.6000.000–0.525–0.253
Region - Latin America (vs North America)0.5270.1274.1500.0000.2780.776
Region - Western Europe (vs North America)0.1280.1121.1400.254–0.0910.346
Region - Central Europe (vs North America)0.3480.1153.0300.0020.1230.573
Region - Other (vs North America)–0.2110.298–0.7100.479–0.7960.373
Race - Black (vs Caucasian)0.2850.1302.1900.0290.0300.540
Race - Asian (vs Caucasian)0.7090.2832.5000.0120.1541.265
Race - Other (vs Caucasian)0.0830.1100.7600.449–0.1320.298
NYHA class III/IV (vs I/II)0.2020.0613.3000.0010.0820.322
LVEF–0.0140.004–3.3000.001–0.022–0.006
Heart rate0.0050.0022.5400.0110.0010.010
log(eGFR)–0.2360.095–2.4700.013–0.422–0.049
log(NT-proBNP)0.3870.02714.1400.0000.3330.440
Sodium–0.0310.009–3.4300.001–0.048–0.013
QRS duration0.0020.0013.0800.0020.0010.003
Diabetes0.2150.0543.9500.0000.1080.321
Beta-blocker use–0.2870.088–3.2600.001–0.460–0.115
Lipid lowering medication use–0.0860.057–1.5200.129–0.1970.025
1–5 years since HF diagnosis (vs ≤1 year)0.2050.0673.0400.0020.0730.337
>5 years since HF diagnosis (vs ≤1 year)0.2900.0724.0100.0000.1480.432
Ischaemic aetiology0.1860.0593.1400.0020.0700.302
Prior stroke0.1710.0832.0700.0390.0090.333
Previously hospitalised for HF0.1520.0552.7500.0060.0440.261
EQ-5D–0.5410.115–4.7000.000–0.767–0.315
Constant–12.7600.583–21.8900.000–13.902–11.617
Gamma0.0000.0004.5600.0000.0000.001

eGFR = estimated glomerular filtration rate; EQ-5D, European Quality of Life-5 Dimensions; HF = heart failure; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA II–IV = New York Heart Association class II–IV; SE = standard error

Table S3

Gompertz regression model for CV mortality (n = 8399).

MortalityHazard ratioCoefficientSEzP>z95% CI
Sacubitril/valsartan0.81–0.2160.0570–3.790.000–0.328–0.104
Age0.91–0.0920.0180–5.130.000–0.128–0.057
Age squared1.000.0010.00015.350.0000.0000.001
Female0.70–0.3570.0766–4.670.000–0.508–0.207
Region       
      Latin America1.870.6250.14554.30.0000.3400.910
      Western Europe1.180.1680.13071.280.200–0.0890.424
      Central Europe1.700.5290.13194.010.0000.2700.787
      Asia-Pacific0.83–0.1870.3172–0.590.556–0.8090.435
Race       
      Black1.500.4090.14402.840.0050.1260.691
      Asian2.620.9620.29893.220.0010.3771.548
      Other1.180.1680.12261.370.169–0.0720.409
NYHA III/IV1.340.2960.06694.420.0000.1650.427
Ejection fraction0.98–0.0170.0046–3.60.000–0.026–0.008
Log(eGFR)0.79–0.2380.1054–2.260.024–0.444–0.031
Log(NT-proBNP)1.560.4430.029914.840.0000.3850.502
Sodium0.97–0.0270.0099–2.690.007–0.046–0.007
QRS duration1.000.0020.00073.040.0020.0010.003
Diabetes1.260.2290.05993.820.0000.1110.346
Beta-blocker use0.73–0.3200.0964–3.320.001–0.509–0.131
Time since diagnosis of HF       
      1–5 years1.230.2100.07482.80.0050.0630.356
      >5 years1.410.3440.08054.280.0000.1860.502
Ischaemic disease1.170.1560.06262.480.0130.0330.278
Prior HF hospitalisation1.170.1590.06172.570.0100.0380.280
Baseline EQ-5D0.57–0.5630.1275–4.420.000–0.813–0.313
Constant0.00–12.6650.6477–19.550.000–13.934–11.395
Gamma§1.000.0000.00012.560.0100.0000.000

eGFR = estimated glomerular filtration rate; EQ-5D, European Quality of Life-5 Dimensions; HF = heart failure; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA II–IV = New York Heart Association class II–IV; SE = standard error
† Variable centred on mean
‡ Constant term in Gompertz regression
§ The ancillary parameter that controls the shape of the baseline hazard

Table S4

All-cause mortality of the Swiss population in 2012.

Age group (years)PopulationDeaths malesDeath rate malesAnnual probability malesDeath femalesDeath rates femalesAnnual probability females
MalesFemales
<141 91439 4951560.003720.0037151400.003540.003538
1–4169 732160 469260.000150.000153150.000090.000093
5–9204 230193 511110.000050.000054170.000090.000087
10–14206 846196 080200.000090.000097110.000050.000056
15–19226 301214 933850.000380.000376260.000120.000121
20–24253 574245 3871120.000440.000442400.000160.000163
25–29274 522268 6851180.000430.000429650.000240.000242
30–34288 145282 5891520.000530.000527710.000250.000251
35–39281 336278 2352040.000730.0007241060.000380.000381
40–44304 469300 8423680.001210.001207080.000690.000691
45–49338 087330 1675900.001750.0017443880.001180.001174
50–54314 108307 3659580.003050.0030455690.001850.001849
55–59266 125261 02313060.004910.0048958030.003080.003071
60–64226 250232 46419600.008660.00862611070.004760.004751
65–69207 158220 26826380.012730.01265416040.007280.007256
70–74159 179181 89330120.018920.01874420200.011110.011044
75–79116 891148 63741240.035280.03466630780.020710.020495
80–8481 364123 18951460.063250.06128854590.044310.043347
85+61 860132 30897110.156980.14528217 7490.134150.125540

Table S5

Cardiovascular mortality of the Swiss population in 2012.

Age group (years)PopulationDeaths malesDeath rate malesAnnual probability malesDeath femalesDeath rates femalesAnnual probability females
MalesFemales
<141 91439 49510.000020.00002410.000030.000025
1–4169 732160 46910.000010.00000610.000010.000006
5–9204 230193 51100010.000010.000005
10–14206 846196 08020.000010.000009000
15–19226 301214 93320.000010.00000920.000010.000009
20–24253 574245 38740.000020.00001630.000010.000012
25–29274 522268 68560.000020.00002250.000020.000019
30–34288 145282,589110.000040.00003870.000020.000025
35–39281 336278 235250.000090.00008990.000030.000032
40–44304 469300 842700.000230.000229260.000090.000086
45–49338 087330 1671150.000340.000340480.000150.000145
50–54314 108307 3652110.000670.000672570.000190.000185
55–59266 125261 0233060.001150.001149890.000340.000341
60–64226 250232 4644560.002020.0020131390.000600.000598
65–69207 158220 2686410.003090.0030892420.001100.001098
70–74159 179181 8937690.004830.0048194480.002460.002459
75–79116 891148 63712650.010820.0107648820.005930.005916
80–8481 364123 18917930.022040.02179619310.015680.015553
85+61 860132 30840670.065750.06363180380.060750.058944

Table S6

Non-cardiovascular mortality of the Swiss population in 2012.

Age group (years)All-cause mortality males (%)All-cause mortality females (%)CV mortality males (%)CV mortality females (%)Non-CV mortality males (%)Non-CV mortality females (%)
<10.37150.35380.00240.00250.36910.3513
1–40.01530.00930.00060.00060.01470.0087
5–90.00540.008700.00050.00540.0082
10–140.00970.00560.000900.00880.0056
15–190.03760.01210.00090.00090.03670.0112
20–240.04420.01630.00160.00120.04260.0151
25–290.04290.02420.00220.00190.04070.0223
30–340.05270.02510.00380.00250.04890.0226
35–390.07240.03810.00890.00320.06350.0349
40–440.12070.06910.02290.00860.09780.0605
45–490.17440.11740.03400.01450.14040.1029
50–540.30450.18490.06720.01850.23730.1664
55–590.48950.30710.11490.03410.37460.2730
60–640.86260.47510.20130.05980.66130.4153
65–691.26540.72560.30890.10980.95650.6158
70–741.87441.10440.48190.24591.39250.8585
75–793.46662.04951.07640.59162.39021.4579
80–846.12884.33472.17961.55533.94922.7794
85+14.528212.55406.36315.89448.16516.6596

Table S7

Negative binomial regression model for all-cause hospitalisation.

 IRRCoefficientSEzP>z95% CI
Sacubitril/valsartan0.84–0.1730.038–4.5400.000–0.248–0.098
Age0.95–0.0550.013–4.1300.000–0.082–0.029
Age squared1.000.0000.0004.3500.0000.0000.001
Female0.74–0.2990.049–6.0500.000–0.396–0.202
Region       
    Latin America0.70–0.3640.085–4.3000.000–0.530–0.198
    Western Europe1.020.0160.0740.2200.828–0.1290.162
    Central Europe0.72–0.3230.076–4.2700.000–0.471–0.175
    Asia-Pacific0.70–0.3520.085–4.1300.000–0.519–0.185
Heart rate1.010.0070.0024.3200.0000.0040.010
Log (eGFR)0.62–0.4790.072–6.6100.000–0.621–0.337
Log (NT-proBNP)1.260.2290.02011.2600.0000.1890.269
Sodium0.98–0.0210.007–3.2200.001–0.035–0.008
QRS duration1.000.0030.0015.3700.0000.0020.004
Diabetes1.400.3340.0408.2500.0000.2550.413
Prior ACEi use0.90–0.1040.047–2.2200.026–0.196–0.012
Beta-blocker use0.72–0.3320.073–4.5600.000–0.475–0.189
Lipid lowering medication use1.070.0720.0431.6800.094–0.0120.157
Time since diagnosis of HF       
    1–5 years1.300.2650.0495.3900.0000.1690.362
    >5 years1.500.4040.0527.7400.0000.3020.506
Ischaemic disease1.090.0860.0441.9400.052–0.0010.173
Prior stroke1.160.1470.0652.2500.0240.0190.275
Atrial fibrillation1.100.0940.0422.2500.0240.0120.176
Prior cancer1.180.1630.0881.8500.064–0.0100.335
Current smoker1.240.2120.0543.9200.0000.1060.318
Prior HF hospitalisation1.400.3340.0418.2300.0000.2550.414
Baseline EQ-5D0.62–0.4850.090–5.4100.000–0.661–0.309
Constant0.06–2.8910.475–6.0900.000–3.821–1.960
ln(exposure)0.84–0.1730.038–4.5400.000–0.248–0.098

ACEi = angiotensin converting-enzyme inhibitor; GFR = estimated glomerular filtration rate; EQ-5D, European Quality of Life-5 Dimensions; HF = heart failure; IRR = incidence rate ratio; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA II–IV = New York Heart Association class II–IV; SE = standard error
† Variable centred on mean

Table S8

Occurrence of less serious adverse events in the PARADIGM-HF trial.

EventSacubitril/valsartan (n = 4187)Angiotensin converting-enzyme inhibitor
(n = 4212)
p-value
NumberMean annual rateMean monthly probabilityNumberMean annual rateMean monthly probability
Hypotension5880.0630.00523880.0420.0035<0.001
Elevated serum creatinine1390.0150.00121880.0200.00170.007
Elevated serum potassium6740.0730.00617270.0790.00660.15
Cough4740.0510.00426010.0650.0054<0.001
Angio-oedema190.0020.0002100.0010.00010.19
0.52§
0.31

† Absolute number of each adverse event taken from McMurray et al (10)
‡ No treatment or use of antihistamines
§ Use of catecholamines or glucocorticoids without hospitalisation
¶ Hospitalisation without airway compromise

Table S9

Mixed model for EQ-5D-based utility values.

 CoefficientSEzP>z95% CI
Sacubitril/valsartan0.0110.0033.350.0010.0040.017
Age–0.0010.000–4.960.000–0.0010.000
Female–0.0310.004–7.80.000–0.039–0.023
Region      
    Latin America0.0410.0075.720.0000.0270.055
    Western Europe0.0130.0071.860.063–0.0010.026
    Central Europe0.0000.007–0.040.969–0.0140.013
    Asia-Pacific0.0410.0085.370.0000.0260.056
NYHA      
      II (vs I)–0.0090.008–1.220.224–0.0240.006
      III (vs I)–0.0510.008–6.050.000–0.067–0.034
      IV (vs I)–0.0920.021–4.460.000–0.132–0.051
Heart rate0.0000.000–1.970.049–0.0010.000
Log(NT-proBNP)–0.0090.002–5.350.000–0.013–0.006
Sodium0.0010.0011.80.0710.0000.002
BMI–0.0020.000–60.000–0.003–0.001
Diabetes–0.0140.003–4.020.000–0.021–0.007
Time since diagnosis of HF      
      1–5 years–0.0170.004–4.210.000–0.024–0.009
      >5 years–0.0230.004–5.340.000–0.031–0.014
Ischaemic aetiology–0.0070.003–2.130.033–0.014–0.001
Prior stroke–0.0120.006–2.060.039–0.023–0.001
Current smoker–0.0130.005–2.80.005–0.022–0.004
Baseline EQ-5D0.4880.00861.390.0000.4730.504
Hosp 0–30 days–0.1050.006–18.310.000–0.116–0.094
Hosp 30–90 days–0.0540.004–12.430.000–0.062–0.045
AE – cough–0.0280.007–4.330.000–0.041–0.015
AE – hypotension–0.0290.006–4.630.000–0.042–0.017
Time (years)–0.0080.001–8.560.000–0.010–0.006
_cons0.8220.01079.670.0000.8020.843

AE = adverse event; BMI = body mass index; CI = confidence interval; eGFR = estimated glomerular filtration rate; EQ-5D, European Quality of Life-5 Dimensions; HF = heart failure; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA II–IV = New York Heart Association class II–IV; SE = standard error
† Variable centred on mean

Table S10

Swiss drug costs of primary and background therapy for heart failure.

Tab strength (mg)Cost/pack (CHF)Tabs/packCost/tab (CHF)Cost/mg (CHF)Daily doseDaily cost (CHF)Monthly cost (CHF)
Primary therapy
Angiotensin converting-enzyme inhibitor – enalapril
57.30300.2440.0518.9 mg0.7823.72
109.40280.3370.03
2017.80280.6360.03
Angiotensin converting enzyme inhibitor – ramipril
2.511.80200.590.24   
514.40200.720.142 × 5 mg1.4443.75
1015.10200.750.08   
Angiotensin converting enzyme inhibitor – perindopril
212.73300.420.21   
418.27300.610.158 mg0.7923.91
823.57300.790.10   
Angiotensin converting-enzyme inhibitor – lisinopril
57.07300.240.05   
109.42300.310.031 × 20 mg
1 × 10 mg
0.8626.21
2016.42300.550.03
Angiotensin receptor blocker – losartan
2514.00280.500.02   
5017.00280.610.011 × 100 mg
1 × 50 mg
1.2136.96
10017.00280.610.01
Angiotensin receptor blocker – candesartan
45.8570.840.21   
816.00300.530.07   
1617.60300.590.04   
3226.50300.880.031 × 32 mg0.8826.89
Angiotensin receptor blocker – valsartan
8020.20280.720.01   
16026.75280.960.012 × 160 mg1.9658.16
Background therapy
Beta-blocker – carvedilol
3.1256.95300.230.07   
6.257.45220.340.05   
12.517.80300.590.05   
2526.63300.890.042 × 25 mg1.7854.03
Beta-blocker – bisoprolol
515.90300.530.11   
1026.05300.870.091 × 10 mg0.8726.43
Aldosterone antagonist – spironolactone
257.85200.390.021 × 25 mg
1 × 50 mg
0.5817.77
5015.50200.780.02
10035.85301.200.01   
Digoxin
125µg7.101000.070.0011 × 125 µg0.082.42
250µg8.801000.090.0004   
Lipid lowering medication – atorvastatin
1028.20300.940.091 × 10 mg
1 × 20mg
0.9428.61
2028.20300.940.05
4028.20300.940.02   
8028.20300.940.01   
Lipid lowering medication – simvastatin
2037.35281.330.07   
4037.35281.330.031 × 40 mg
1 × 80 mg
1.3340.60
8037.35281.330.02
Loop diuretics – furosemide
404.85120.400.011 × 20 mg
1 × 40 mg
0.4012.30
Aspirin
1006.60280.240.00241 × 100 mg0.247.17
Marcoumar
37.65250.310.11 × 3 mg0.257.61
320.801000.210.07
Clopidogrel
7544.98281.580.021 × 75 mg1.6148.90

Table S11

Swiss DRG codes for hospitalisation costs (description of surgical procedures).

Hospitalisations and related DRG codesPARADIGM-HF frequencyActivityUnit cost
Hospitalisations involving a surgical procedure (4% of total hospitalisations)
Coronary artery bypass grafting
F05Z16.0%88CHF 51 950
F06A28CHF 90 987
F06B42CHF 59 328
F06C119CHF 46 807
F06D160CHF 40 015
F06E CHF 33 424
Mitral valve repair/replacement and other valve surgery
F03A28.0%93CHF 71 993
F03B100CHF 51 165
F03C175CHF 49 118
F03D442CHF 42 270
F07Z217CHF 49 795
F98Z258CHF 61 777
F69Z218CHF 11 203
Other cardiac surgeries
F08Z39.0%58CHF 61 110
F09Z24CHF 38 057
F13A166CHF 42 882
F13B87CHF 21 845
F13C436CHF 14 250
F14A73CHF 33 106
F14B213CHF 22 372
F20Z65CHF 7 844
F28A118CHF 57 969
F28B120CHF 34 680
F28C56CHF 20 726
F30Z36CHF 48 685
F31Z128CHF 34 456
F33A127CHF 43 072
F33B243CHF 25 924
F34A272CHF 37 873
F34B821CHF 20 207
F35A86CHF 27 309
F35B110CHF 15 845
F38Z63CHF 17 622
F39A1965CHF 6397
F39B2873CHF 5097
F54Z1731CHF 12 408
F59A813CHF 20 232
F59B2240CHF 7912
F51A41CHF 35 034
F51B55CHF 38 129
F51C203CHF 29 486
F61A30CHF 34 597
F61B140CHF 26 897
Ventricular assist device (VAD)
ZE-2015-04.0416.0%228 967.45
ZE-2015-04.05157 934.90
ZE-2015-04.08136 439.15
ZE-2015-04.08136,439.15
ZE-2015-04.09-71 839.55
ZE-2015-04.1112115 918.95
ZE-2015-04.1113115 918.95
ZE-2015-04.122182 347.20
Heart transplantation
A05B1.0%51CHF 147 414
A06Z35CHF 545 196
Hospitalisations involving an interventional procedure (8% of total hospitalisations)
Implantable cardioverter/defibrillator
F01A36.0%31CHF 94 070
F01B130CHF 55 862
F01C63CHF 72 725
F01D198CHF 48 903
F02Z54CHF 49 105
F10Z22CHF 41 700
Cardiac pacemaker (biventricular, defibrillating CRT-D), conventional
F12A53.0%64CHF 36 719
F12B46CHF 41 076
F12C147CHF 33 472
F12D902CHF 21 423
F12E581CHF 20 250
F17A227CHF 17 182
F17B101CHF 13 006
F18A49CHF 25 039
F18B170CHF 11 025
Coronary angioplasty, percutaneous coronary intervention single / percutaneous coronary intervention (multiple)
F52A11.0%189CHF 23 547
F52B1322CHF 14 285
F56A187CHF 22 494
F56B1632CHF 14 139
F57A62CHF 14 470
F57B1351CHF 9703
F58Z178CHF 9730
F24A 180CHF 34 746
F24B1338CHF 19 645
F15Z101CHF 39 039
Hospitalisations involving medical management procedures (88.0% of total hospitalisations)
Cardiac failure / pneumonia / chronic obstructive pulmonary disease
F62A65.0%364CHF 19 068
F62B1532CHF 14 350
F62C7112CHF 8656
Ventricular tachycardia / atrial fibrillation
F50A11.0%310CHF 18 850
F50B30CHF 20 239
F50C528CHF 11 921
F50D210CHF 10 889
F71B772CHF 7606
Cerebrovascular accident
B04B2.0%32CHF 30 082
B39A41CHF 63 370
B39B68CHF 37 476
B39C40CHF 27 626
B70A350CHF 25 839
B70B255CHF 19 414
B70C945CHF 15 791
B70D650CHF 14 717
B70E4093CHF 11 456
B70G126CHF 6122
B70H433CHF 3721
Angina pectoris
F71A2.0%374CHF 13 020
F72A144CHF 7495
F72B3584CHF 4444
Acute myocardial infarction
F41A2.0%39CHF 26 184
F41B411CHF 10 447
F60A472CHF 14 707
F60B2301CHF 7635
Syncope
F73Z3.0%4765CHF 4829
Non-cardiac chest pain
F74Z5.0%2462CHF 3400
E65C
Renal failure acute
L60B3.0%128CHF 26 224
Dyspnoea
F43B3.0%208CHF 30 377
Transient ischaemic attack
B69A1.0%
B69B22CHF 10 926
B69C1591CHF 8643
B69D174CHF 9866
Urinary tract infection
L63D1.0%560CHF 5669
Anaemia
Q61D2.0%256CHF 13 030

Proportion of hospitalisations per procedure were derived from the Western European population of the PARADIGM-HF trial, including patients from Belgium, Denmark, Finland, France, Germany, Iceland, Italy, Netherlands, Portugal, Spain, Sweden, UK, Israel and South Africa.

Table S12

Parameters used in univariate and probabilistic sensitivity analyses. Cost parameters are in CHF.

ParameterMean valueLower value for univariate SAUpper value for univariate SAReference for uncertaintyDistribution used in PSA
CV mortality (coef.): sacubitril/valsartan–0.2159–0.3275–0.104295% CIMultivariate normal
CV mortality (coef.): Age*–0.0924–0.1277–0.057195% CIMultivariate normal
CV mortality (coef.): Age squared0.00080.00050.001195% CIMultivariate normal
CV mortality (coef.): Female–0.3575–0.5076–0.207395% CIMultivariate normal
CV mortality (coef.): Region – Latin America (vs North America)0.62520.34010.910395% CIMultivariate normal
CV mortality (coef.): Region – Western Europe (vs North America)0.1675–0.08860.423795% CIMultivariate normal
CV mortality (coef.): Region – Central Europe (vs North America)0.52860.27010.787195% CIMultivariate normal
CV mortality (coef.): Region – Other (vs North America)–0.1869–0.80860.434895% CIMultivariate normal
CV mortality (coef.): Race – Black (vs Caucasian)0.40860.12640.690895% CIMultivariate normal
CV mortality (coef.): Race – Asian (vs Caucasian)0.96240.37661.548295% CIMultivariate normal
CV mortality (coef.): Race – Other (vs Caucasian)0.1685–0.07170.408795% CIMultivariate normal
CV mortality (coef.): NYHA class III/IV (vs I/II)0.29590.16480.427095% CIMultivariate normal
CV mortality (coef.): LVEF*–0.0167–0.0257–0.007695% CIMultivariate normal
CV mortality (coef.): log(eGFR)*–0.2377–0.4442–0.031295% CIMultivariate normal
CV mortality (coef.): log(NT–proBNP)*0.44320.38460.501795% CIMultivariate normal
CV mortality (coef.): Sodium*–0.0267–0.0462–0.007295% CIMultivariate normal
CV mortality (coef.): QRS duration*0.00200.00070.003395% CIMultivariate normal
CV mortality (coef.): Diabetes0.22890.11140.346495% CIMultivariate normal
CV mortality (coef.): Beta blocker use–0.3202–0.5092–0.131295% CIMultivariate normal
CV mortality (coef.): 1–5 years since HF diagnosis (vs ≤1 year)0.20960.06300.356295% CIMultivariate normal
CV mortality (coef.): >5 years since HF diagnosis (vs ≤1 year)0.34410.18640.501895% CIMultivariate normal
CV mortality (coef.): Ischaemic aetiology0.15550.03280.278395% CIMultivariate normal
CV mortality (coef.): Previously hospitalised for HF0.15880.03790.279795% CIMultivariate normal
CV mortality (coef.): EQ–5D*–0.5631–0.8129–0.313295% CIMultivariate normal
CV mortality (coef.): Constant–12.6648–13.9344–11.395395% CIMultivariate normal
CV mortality (coef.): Gamma0.00020.00010.000495% CIMultivariate normal
All-cause mortality: sacubitril/valsartan–0.1608–0.2610–0.060695% CIMultivariate normal
All-cause mortality: Age*–0.1011–0.1329–0.069295% CIMultivariate normal
All-cause mortality: Age squared0.00090.00060.001195% CIMultivariate normal
All-cause mortality: Female–0.3891–0.5253–0.252895% CIMultivariate normal
All-cause mortality: Region - Latin America (vs North America)0.52710.27790.776395% CIMultivariate normal
All-cause mortality: Region - Western Europe (vs North America)0.1275–0.09140.346495% CIMultivariate normal
All-cause mortality: Region - Central Europe (vs North America)0.34820.12320.573295% CIMultivariate normal
All-cause mortality: Region - Other (vs North America)–0.2111–0.79560.373495% CIMultivariate normal
All-cause mortality: Race - Black (vs Caucasian)0.28480.02960.540095% CIMultivariate normal
All-cause mortality: Race - Asian (vs Caucasian)0.70930.15391.264895% CIMultivariate normal
All-cause mortality: Race - Other (vs Caucasian)0.0831–0.13220.298495% CIMultivariate normal
All-cause mortality: NYHA class III/IV (vs I/II)0.20210.08210.322195% CIMultivariate normal
All-cause mortality: LVEF*–0.0138–0.0220–0.005695% CIMultivariate normal
All-cause mortality: Heart rate*0.00550.00120.009795% CIMultivariate normal
All-cause mortality: log(eGFR)*–0.2356–0.4225–0.048795% CIMultivariate normal
All-cause mortality: log(NT-proBNP)*0.38660.33300.440295% CIMultivariate normal
All-cause mortality: Sodium*–0.0306–0.0480–0.013195% CIMultivariate normal
All-cause mortality: QRS duration*0.00190.00070.003095% CIMultivariate normal
All-cause mortality: Diabetes0.21490.10840.321495% CIMultivariate normal
All-cause mortality: Beta blocker use–0.2873–0.4598–0.114795% CIMultivariate normal
All-cause mortality: Lipid lowering medication use–0.0860–0.19700.024995% CIMultivariate normal
All-cause mortality: 1-5 years since HF diagnosis (vs ≤1 year)0.20490.07290.336895% CIMultivariate normal
All-cause mortality: >5 years since HF diagnosis (vs ≤1 year)0.29020.14820.432395% CIMultivariate normal
All-cause mortality: Ischaemic aetiology0.18570.06960.301795% CIMultivariate normal
All-cause mortality: Prior stroke0.17110.00880.333595% CIMultivariate normal
All-cause mortality: Previously hospitalised for HF0.15220.04380.260695% CIMultivariate normal
All-cause mortality: EQ-5D*–0.5413–0.7672–0.315495% CIMultivariate normal
All-cause mortality: Constant–12.7596–13.9020–11.617295% CIMultivariate normal
All-cause mortality: Gamma0.00040.00020.000595% CIMultivariate normal
% of deaths with CV cause (Sacubitril/valsartan)0.78480.75270.814595% CIBeta
% of deaths with CV cause (ACEi)0.82990.80270.854895% CIBeta
Discontinuation: Sacubitril/valsartan–0.1115–0.2104–0.012795% CIMultivariate normal
Discontinuation: Region – Latin America (vs North America)–0.2855–0.4783–0.092795% CIMultivariate normal
Discontinuation: Region – Western Europe (vs North America)–0.1076–0.27980.064695% CIMultivariate normal
Discontinuation: Region – Central Europe (vs North America)–0.4092–0.5880–0.230595% CIMultivariate normal
Discontinuation: Region – Other (vs North America)–0.8739–1.0988–0.649195% CIMultivariate normal
Discontinuation: Heart rate*0.00650.00240.010795% CIMultivariate normal
Discontinuation: log(eGFR)*–0.5315–0.7069–0.356195% CIMultivariate normal
Discontinuation: log(NT–proBNP)*0.20450.15170.257295% CIMultivariate normal
Discontinuation: Sodium*–0.0164–0.03380.000995% CIMultivariate normal
Discontinuation: Diabetes0.15460.05000.259295% CIMultivariate normal
Discontinuation: Beta blocker use–0.1750–0.36240.012595% CIMultivariate normal
Discontinuation: Lipid lowering medication use–0.1914–0.3008–0.081995% CIMultivariate normal
Discontinuation: 1–5 years since HF diagnosis (vs ≤1 year)0.1020–0.02990.234095% CIMultivariate normal
Discontinuation: >5 years since HF diagnosis (vs ≤1 year)0.28790.15360.422295% CIMultivariate normal
Discontinuation: Ischaemic aetiology0.13110.01860.243595% CIMultivariate normal
Discontinuation: EQ–5D*–0.4726–0.6869–0.258395% CIMultivariate normal
Discontinuation: Constant–7.9937–8.2645–7.722895% CIMultivariate normal
Hospitalisation (coef.): Sacubitril/valsartan–0.1729–0.2476–0.098395% CIMultivariate normal
Hospitalisation (coef.): Age*–0.0553–0.0816–0.029195% CIMultivariate normal
Hospitalisation (coef.): Age^20.00050.00030.000795% CIMultivariate normal
Hospitalisation (coef.): Female–0.2989–0.3957–0.202295% CIMultivariate normal
Hospitalisation (coef.): Region – Latin America (vs North America)–0.3638–0.5296–0.198095% CIMultivariate normal
Hospitalisation (coef.): Region – Western Europe (vs North America)0.0161–0.12940.161695% CIMultivariate normal
Hospitalisation (coef.): Region – Central Europe (vs North America)–0.3230–0.4714–0.174695% CIMultivariate normal
Hospitalisation (coef.): Region – Other (vs North America)–0.3520–0.5190–0.185095% CIMultivariate normal
Hospitalisation (coef.): Heart rate*0.00700.00380.010295% CIMultivariate normal
Hospitalisation (coef.): log(eGFR)*–0.4791–0.6211–0.337195% CIMultivariate normal
Hospitalisation (coef.): log(NT–proBNP)*0.22900.18910.268895% CIMultivariate normal
Hospitalisation (coef.): Sodium*–0.0215–0.0346–0.008495% CIMultivariate normal
Hospitalisation (coef.): QRS duration*0.00310.00190.004295% CIMultivariate normal
Hospitalisation (coef.): Diabetes0.33400.25470.413495% CIMultivariate normal
Hospitalisation (coef.): Prior use of ACEi–0.1043–0.1962–0.012495% CIMultivariate normal
Hospitalisation (coef.): Beta blocker use–0.3320–0.4747–0.189395% CIMultivariate normal
Hospitalisation (coef.): Lipid lowering medication use0.0722–0.01220.156795% CIMultivariate normal
Hospitalisation (coef.): 1–5 years since HF diagnosis (vs ≤1 year)0.26510.16870.361695% CIMultivariate normal
Hospitalisation (coef.): >5 years since HF diagnosis (vs ≤1 year)0.40380.30160.506195% CIMultivariate normal
Hospitalisation (coef.): Ischaemic aetiology0.0862–0.00090.173495% CIMultivariate normal
Hospitalisation (coef.): Prior stroke0.14690.01910.274695% CIMultivariate normal
Hospitalisation (coef.): Prior atrial fibrillation/ flutter0.09420.01230.176195% CIMultivariate normal
Hospitalisation (coef.): Prior cancer0.1629–0.00950.335395% CIMultivariate normal
Hospitalisation (coef.): Current smoker0.21190.10600.317895% CIMultivariate normal
Hospitalisation (coef.): Previously hospitalised for HF0.33450.25480.414295% CIMultivariate normal
Hospitalisation (coef.): EQ–5D*–0.4855–0.6615–0.309595% CIMultivariate normal
Hospitalisation (coef.): Constant–2.8905–3.8207–1.960395% CIMultivariate normal
Utility (coef.): Sacubitril/valsartan0.01060.00440.016895% CIMultivariate normal
Utility (coef.): Age*–0.0008–0.0011–0.000595% CIMultivariate normal
Utility (coef.): Female–0.0309–0.0387–0.023195% CIMultivariate normal
Utility (coef.): Region – Latin America (vs North America)0.04120.02710.055395% CIMultivariate normal
Utility (coef.): Region – Western Europe (vs North America)0.0126–0.00070.025995% CIMultivariate normal
Utility (coef.): Region – Central Europe (vs North America)–0.0003–0.01350.013095% CIMultivariate normal
Utility (coef.): Region – Other (vs North America)0.04100.02610.056095% CIMultivariate normal
Utility (coef.): NYHA class II (vs I)–0.0093–0.02420.005795% CIMultivariate normal
Utility (coef.): NYHA class III (vs I)–0.0509–0.0674–0.034495% CIMultivariate normal
Utility (coef.): NYHA class IV (vs I)–0.0917–0.1319–0.051495% CIMultivariate normal
Utility (coef.): Heart rate*–0.0003–0.00050.000095% CIMultivariate normal
Utility (coef.): log(NT–proBNP)*–0.0093–0.0127–0.005995% CIMultivariate normal
Utility (coef.): Sodium*0.0010–0.00010.002295% CIMultivariate normal
Utility (coef.): BMI–0.0020–0.0026–0.001395% CIMultivariate normal
Utility (coef.): Diabetes–0.0140–0.0208–0.007295% CIMultivariate normal
Utility (coef.): 1–5 years since HF diagnosis (vs ≤1 year)–0.0165–0.0242–0.008895% CIMultivariate normal
Utility (coef.): >5 years since HF diagnosis (vs ≤1 year)–0.0226–0.0309–0.014395% CIMultivariate normal
Utility (coef.): Ischaemic aetiology–0.0073–0.0140–0.000695% CIMultivariate normal
Utility (coef.): Prior stroke–0.0118–0.0230–0.000695% CIMultivariate normal
Utility (coef.): Current smoker–0.0130–0.0220–0.003995% CIMultivariate normal
Utility (coef.): EQ–5D*0.48850.47290.504195% CIMultivariate normal
Utility (coef.): Hospitalised within previous 30 days–0.1047–0.1159–0.093595% CIMultivariate normal
Utility (coef.): Hospitalised 30–90 days previously–0.0539–0.0624–0.045495% CIMultivariate normal
Utility (coef.): Adverse event – cough–0.0282–0.0410–0.015495% CIMultivariate normal
Utility (coef.): Adverse event – hypotension–0.0292–0.0415–0.016895% CIMultivariate normal
Utility (coef.): Annual change–0.0079–0.0097–0.006195% CIMultivariate normal
Utility (coef.): Constant0.82240.80220.842695% CIMultivariate normal
Adverse events: hypotension, annual rate, Sacubitril/valsartan0.06300.05800.068095% CINone
Adverse events: hypotension, annual rate, ACEi0.04200.03800.046095% CINone
Adverse events: hypotension, mean duration (days)64.872158.890070.9000± 25%Log
Adverse events: cough, annual rate, Sacubitril/valsartan0.05100.04600.056095% CILog
Adverse events: cough, annual rate, ACEi0.06500.06000.070095% CILog
Adverse events: cough, mean duration (days)73.332866.020080.6500± 25%Log
Adverse events: angio-oedema, annual rate, Sacubitril/valsartan0.00200.00100.003095% CINone
Adverse events: angio-oedema, annual rate, ACEi0.00100.00000.002095% CINone
Adverse events: elevated serum creatinine, annual rate, Sacubitril/valsartan0.01500.01200.017095% CILog
Adverse events: elevated serum creatinine, annual rate, ACEi0.02000.01700.023095% CILog
Adverse events: elevated serum potassium, annual rate, Sacubitril/valsartan0.07300.06700.078095% CILog
Adverse events: elevated serum potassium, annual rate, ACEi0.07900.07300.085095% CILog
Costs, primary therapy, enalapril, cost per pack: 57.325.499.15± 25%None
Costs, primary therapy, enalapril, cost per pack: 109.437.0711.79± 25%None
Costs, background therapy, carvedilol, cost per pack: 3.1256.955.218.69± 25%None
Costs, background therapy, carvedilol, cost per pack: 6.257.455.599.31± 25%None
Costs, background therapy, carvedilol, cost per pack: 12.517.8013.3522.25± 25%None
Costs, background therapy, carvedilol, cost per pack: 2526.6319.9733.28± 25%None
Costs, background therapy, bisoprolol, cost per pack: 515.9011.9319.88± 25%None
Costs, background therapy, bisoprolol, cost per pack: 1026.0519.5432.56± 25%None
Costs, background therapy, spironolactone, cost per pack: 257.855.899.81± 25%None
Costs, background therapy, spironolactone, cost per pack: 5015.5011.6319.38± 25%None
Costs, background therapy, spironolactone, cost per pack: 10035.8526.8944.81± 25%None
Costs, background therapy, digoxin, cost per pack: 1257.105.338.88± 25%None
Costs, background therapy, digoxin, cost per pack: 2508.806.6011.00± 25%None
Costs, background therapy, atorvastatin, cost per pack: 1028.2021.1535.25± 25%None
Costs, background therapy, atorvastatin, cost per pack: 2028.2021.1535.25± 25%None
Costs, background therapy, atorvastatin, cost per pack: 4028.2021.1535.25± 25%None
Costs, background therapy, atorvastatin, cost per pack: 8028.2921.2235.36± 25%None
Costs, background therapy, simvastatin, cost per pack: 2037.3528.0146.69± 25%None
Costs, background therapy, simvastatin, cost per pack: 4037.3528.0146.69± 25%None
Costs, background therapy, simvastatin, cost per pack: 8037.3528.0146.69± 25%None
Costs, background therapy, furosemide, cost per pack: 404.853.646.06± 25%None
Costs, background therapy, aspirin, cost per pack: 1006.604.958.25± 25%None
Costs, background therapy, warfarin, cost per pack: 37.655.749.56± 25%None
Costs, background therapy, clopidogrel, cost per pack: 7544.9833.7456.23± 25%None
Beta blockers, % of patients0.93000.92000.940095% CIBeta
Mineralocorticoid receptor antagonist, % of patients0.55610.55000.570095% CIBeta
Digoxin, % of patients0.30230.29000.310095% CIBeta
Lipid lowering medications, % of patients0.56300.55000.570095% CIBeta
Diuretics, % of patients0.80220.79000.810095% CIBeta
Aspirin, % of patients0.51780.51000.530095% CIBeta
Anticoagulants, % of patients0.31970.31000.330095% CIBeta
ADP antagonists, % of patients0.15000.14000.160095% CIBeta
Costs, monthly cost of HF management110.3082.73137.88± 25%Log
Costs, adverse events – hypotension, cost per PCP visit110.3082.73137.88± 25%Log
Costs, adverse events – hypotension, number of PCP visits required2.001.502.50± 25%Log
Costs, adverse events – elevated serum creatinine, cost per PCP visit110.3082.73137.88± 25%Log
Costs, adverse events – elevated serum creatinine, number of PCP visits required2.001.502.50± 25%Log
Costs, adverse events – elevated serum creatinine, cost per lab test8.006.0010.00± 25%Log
Costs, adverse events – elevated serum potassium, cost per PCP visit110.3082.73137.88± 25%Log
Costs, adverse events – elevated serum potassium, number of PCP visits required2.001.502.50± 25%Log
Costs, adverse events – elevated serum potassium, cost per lab test8.006.0010.00± 25%Log
Costs, adverse events – cough, cost per PCP visit110.3082.73137.88± 25%Log
Costs, adverse events – cough, number of PCP visits required2.001.502.50± 25%Log
Costs, adverse events – cough, cost per lab test8.006.0010.00± 25%Log
Costs, adverse events – angio-oedema, % with milder angio-oedema0.6060%60%± 25%Beta
Costs, adverse events – angio-oedema, cost per outpatient contact110.3082.73137.88± 25%Log
Costs, adverse events – angio-oedema, no. of outpatient visits required2.001.502.50not variedLog
Costs, adverse events – angio-oedema, daily cost of antihistamines0.770.770.77± 25%None
Costs, adverse events – angio-oedema, no. of days on antihistamines14.0010.5017.50± 25%Log
Costs, adverse events – angio-oedema, cost per ER visit492.00369.00615.00± 25%Log
Costs, adverse events – angio-oedema, cost per PCP visit110.3082.73137.88± 25%Log
Costs, adverse events – angio-oedema,no. of PCP visits required1.001.001.00not variedLog
Costs, adverse events – angio-oedema, daily cost of glucocorticoids1.421.421.42± 25%None
Costs, adverse events – angio-oedema, no. of days on glucocorticoids5.003.756.25± 25%Log
Costs, titration, cost per PCP visit110.3082.73137.88± 25%Log
Costs, titration, number of PCP visits required (titration)2.001.502.50± 25%Log
Costs, titration, NT–proBNP testing70.0052.5087.50± 25%Log
Costs, titration, number of outpatient visits required (NT–proBNP testing)1.000.751.25± 25%Log
Costs, titration, cost per outpatient contact132.0299.02165.03± 25%Log

Table S13

Results of subgroup analyses.

Subgroup∆ Costs∆ QALYsICER% change from base-case
Full analysis setCHF 10 9260.425CHF 25 6840%
Baseline age <65 yearsCHF 11 7070.444CHF 26 3753%
Baseline age ≥65 yearsCHF 10 1150.406CHF 24 900–3%
Baseline age <75 yearsCHF 11 3960.437CHF 26 0892%
Baseline age ≥75 yearsCHF 88720.376CHF 23 624–8%
Region - North AmericaCHF 96970.418CHF 23 194–10%
Region - Latin AmericaCHF 10 7660.428CHF 25 164–2%
Region - Western EuropeCHF 10 7710.445CHF 24 229–6%
Region - Central EuropeCHF 11 1530.396CHF 28 13210%
Region - OtherCHF 11 3590.455CHF 24 990–3%
Baseline NYHA class I/IICHF 11 4090.451CHF 25 317–1%
Baseline NYHA III/IVCHF 94560.349CHF 27 1286%
Baseline LVEF ≤ medianCHF 10 3770.420CHF 24,698–4%
Baseline LVEF > medianCHF 11 5650.432CHF 26 8014%
Baseline SBP ≤ medianCHF 10 7920.429CHF 25 127–2%
Baseline SBP > medianCHF 11 0880.420CHF 26 3733%
Baseline eGFR <60CHF 93940.397CHF 23 642–8%
Baseline eGFR ≥60CHF 11 8050.441CHF 26 7384%
Baseline NT-proBNP ≤ medianCHF 12 8410.465CHF 27 5897%
Baseline NT-proBNP > medianCHF 88630.382CHF 23 186–10%
Diabetes at baselineCHF 94770.399CHF 23 762–7%
No diabetes at baselineCHF 11 6890.439CHF 26 6024%
Hypertension at baselineCHF 10 7440.416CHF 25 8010%
No hypertension at baselineCHF 11 3660.447CHF 25 421–1%
Prior use of ACEICHF 11 0050.426CHF 25 8551%
Prior use of ARBCHF 10 6420.425CHF 25 067–2%
Use of beta-blocker at baselineCHF 11 0750.428CHF 25 8791%
No use of beta-blocker at baselineCHF 89440.391CHF 22 856–11%
Use of aldosterone antagonist at baselineCHF 10 8450.422CHF 25 7200%
No use of aldosterone antagonist at baselineCHF 11 0270.430CHF 25 6400%
≤1 year since diagnosis of HFCHF 12 8870.466CHF 27 6748%
1–5 years since diagnosis of HFCHF 10 5360.414CHF 25 464–1%
>5 years since diagnosis of HFCHF 95320.401CHF 23 758–8%
Ischaemic aetiologyCHF 10 5010.413CHF 25 434–1%
Non-ischaemic aetiologyCHF 11 5630.444CHF 26 0331%
Prior atrial fibrillation at baselineCHF 10 0890.404CHF 24 990–3%
No prior atrial fibrillation at baselineCHF 11 4140.438CHF 26 0571%
Prior HF hospitalisationCHF 10 3060.416CHF 24 786–3%
No prior HF hospitalisationCHF 11 9730.442CHF 27 1116%

MRA = mineralocorticoid receptor antagonist; AF = atrial fibrillation; BB = beta-blocker; QALYs = quality-adjusted life years; ICER = incremental cost-effectiveness ratio; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction; SBP = systolic blood pressure; eGFR = estimated glomerular filtration rate; NT-proBNP = N terminal pro-brain natriuretic peptide; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; HF = heart failure.

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