SciELO - Scientific Electronic Library Online

 
vol.33 número2Fitoquímicos del cacao en la prevención de muerte por enfermedad cardiovascular: comentario sobre el estudio COSMOSUtilidad de la ecocardiografía en deportistas: experiencia de un centro portugués índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Servicios Personalizados

Revista

Articulo

Indicadores

Links relacionados

  • No hay artículos similaresSimilares en SciELO

Compartir


Cardiovascular and metabolic science

versión On-line ISSN 2954-3835versión impresa ISSN 2683-2828

Cardiovasc. metab. sci vol.33 no.2 Ciudad de México abr./jul. 2022  Epub 29-Mayo-2023

https://doi.org/10.35366/105819 

Original research

Economic evaluation of evolocumab in uncontrolled patients with high-risk cardiovascular disease affected by primary hypercholesterolemia and mixed dyslipidemia

Evaluación económica de evolocumab en pacientes con enfermedad cardiovascular de alto riesgo con hipercolesterolemia primaria y dislipidemia mixta no controlados

Fernando Carlos-Rivera1  * 

Jorge Antonio Guzmán-Caniupan2 

Adolfo Gabriel Hernández-Garduño3 

Mónica Alva-Esqueda4 

Luis Miguel Camacho-Cordero5 

Therese Aubry-de Maraumont6 

1 Master in Health Economics. Pharmacoeconomics Department. AHS Health Consulting, S.A.S. de C.V. Huixquilucan, State of Mexico, Mexico.

2 Master in Health Economics. Access Department. AHS Health Consulting, S.A.S. de C.V. Huixquilucan, State of Mexico, Mexico.

3 MD, MSc., Dr. Sc. Medical Area. AHS Health Consulting, S.A.S. de C.V. Huixquilucan, State of Mexico, Mexico.

4 Master in Health Economics. Health Economics Amgen Mexico, Mexico City, Mexico.

5 MD. Health Economics Amgen Mexico, Mexico City, Mexico.

6 PharmD, MSc. Health Economics Amgen Mexico, Mexico City, Mexico.


Abstract:

Introduction:

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, imposing an enormous clinical and financial burden on healthcare systems. An elevated level of low-density lipoprotein cholesterol (LDL-C) constitutes one of the most important modifiable risk factors for CVDs.

Objectives:

To assess the economic and health outcomes of evolocumab (EVO) added to standard of care (SoC, high-intensity statin with/without ezetimibe) in uncontrolled high-risk adult patients with primary hypercholesterolemia and mixed dyslipidemia (PHMD) in the Mexican Institute of Social Security.

Material and methods:

Using a lifetime Markov model comprising seven health states with annual cycles, we compared the direct medical costs (acquisition of lipid-lowering therapies besides the costs associated with each health state and costs for a transitory event called revascularization), and life-years (LY) expected with EVO+SoC vs SoC alone. The target population was categorized into two groups: PHMD with a history of either myocardial infarction or ischemic stroke and heterozygous familial hypercholesterolemia (HeFH). Both future costs and LY were discounted at a 5% annual rate.

Results:

EVO+SoC had a higher acquisition cost than SoC but was also more effective. The cost per LY additionally gained by using EVO was modeled as $348,629 (MXN) in the first subpopulation and $298,148 (MXN) in patients with HeFH. The model remained robust to plausible changes in the parameters. The probability of EVO+SoC being cost-effective under a willingness to pay threshold of 3 times the gross domestic product per capita estimated for 2020 in Mexico was close to 100% in both subpopulations.

Conclusions:

EVO+SoC may provide a cost-effective intervention.

Keywords: Economic evaluation; cost-effectiveness; economic impact; evolocumab; cardiovascular disease; hypercholesterolemia

Resumen:

Introducción:

Las enfermedades cardiovasculares (ECVs) son la principal causa de mortalidad mundial, imponiendo una enorme carga clínica/financiera a los sistemas de salud. Un nivel elevado de colesterol de lipoproteínas de baja densidad (C-LDL) constituye uno de los factores de riesgo modificables más importantes para ECVs.

Objetivos:

Evaluar desenlaces económicos y de salud de evolocumab (EVO) agregado al estándar de atención (SoC, estatina de alta intensidad con/sin ezetimiba) en adultos de alto riesgo no controlados, con hipercolesterolemia primaria y dislipidemia mixta (HPDM) en el Instituto Mexicano del Seguro Social.

Material y métodos:

Usando un modelo Markov de siete estados de salud, de por vida con ciclos anuales, comparamos costos directos (adquisición de terapias hipolipemiantes, costos según estados de salud y del evento transitorio «revascularización») y años de vida (AV) esperados con EVO+SoC vs SoC. La población objetivo se dividió en dos grupos: HPDM con antecedentes de infarto de miocardio o accidente cerebrovascular isquémico; hipercolesterolemia familiar heterocigótica (HFHe). Costos y AV futuros se descontaron 5% anualmente.

Resultados:

EVO+SoC fue más costoso y más efectivo que SoC. El costo por AV ganado por el uso de EVO fue $348,629 (MXN) en la primera subpoblación y $298,148 (MXN) en pacientes con HFHe. El modelo se mantuvo robusto ante cambios plausibles en los parámetros. La probabilidad de que EVO+SoC sea costo-efectivo para un umbral de aceptabilidad igual a tres veces el producto interno bruto per cápita estimado para 2020 en México fue cercana a 100% en ambas subpoblaciones.

Conclusiones:

EVO+SoC puede proveer una intervención costo-efectiva.

Palabras clave: Evaluación económica; costo-efectividad; impacto económico; evolocumab; enfermedad cardiovascular; hipercolesterolemia

Introduction

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, taking an estimated 17.8 million lives (31.8% of all global deaths) in 2017, with coronary heart disease as well as stroke comprising 85% of the total CVD-related deaths.1 In addition, CVDs constitute the top cause of disability-adjusted life years (DALYs) around the world, with an approximate loss of 366 million DALYs in 2017, which represents 14.64% of the global burden of disease.2 Since 1990, CVDs have remained the leading grouped cause of death in Mexico.3 Almost 150,000 people died from CVDs in Mexico in 2018, for a mortality rate of 119 per 100,000 individuals.4 The crude incidence and prevalence numbers of CVDs in Mexico in 2017 were estimated at 808,600 and 7.2 million, respectively.5 The financial impact of CVDs is substantial due to the high number of acute episodes in addition to their chronic stages. The annual cost for hypercholesterolemia per patient in Mexico was estimated at $258,761 (MXN), leading to an economic burden of more than $115,000 million (MXN) in 2016.6

Statins are the first treatment choice for primary (heterozygous-familial and non-familial) hypercholesterolemia and mixed dyslipidemia (PHMD), as well as for the reduction of low-density lipoprotein cholesterol (LDL-C) levels and cardiovascular (CV) events.7-10 However, despite the availability of statins and other lipid-lowering therapies such as ezetimibe, used either alone or in combination, many high-risk patients fail to achieve their LDL-C goals.7,9 Evolocumab, a Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitor, has been evaluated in several clinical trials, showing a significant reduction of LDL-C levels in different groups of patients. Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of CV events and is also associated with atherosclerotic plaque regression.11

It is important to assess the economic value of evolocumab in Mexico. We used an economic model to evaluate the cost-effectiveness of evolocumab added to the standard of care of high-intensity statin therapy with or without ezetimibe (hereinafter referred to as SoC) in high-risk adult patients with PHMD with uncontrolled LDL-C levels with SoC alone from the perspective of the Mexican Institute of Social Security (IMSS).

Material and methods

A lifetime Markov cohort state-transition model, adapted from previous publications,12-15 was built in Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). The model comprises seven health states (Figure 1): myocardial infarction (MI); ischemic stroke (IS); other atherosclerotic CVD (oASCVD) that captures less severe CV events, namely peripheral artery disease, angina, transient ischemic attack, and carotid stenosis; post-MI; post-IS; CV death; and non-CV death. Only post-MI, post-IS, and oASCVD were considered as initial states. The states for MI and IS cover the first year period after the event, while post-event health states cover the subsequent years. Revascularization (RV), either urgent or elective, is included as a procedure (i.e., cost) and not as a separate health state because the baseline rates already incorporate the impact of RV on subsequent event rates. The model considers annual cycles and half-cycle correction. The effectiveness is reported in terms of life-years (LY).

CV = cardiovascular; IS = ischemic stroke; MI = myocardial infarction; oASCVD = other atherosclerotic cardiovascular disease.

Figure 1: Model structure. 

Target population

The target population comprises adult patients with PHMD and high CV risk who have not met their LDL-C goals despite receiving SoC. The patients were categorized into two distinct subpopulations: (i) individuals with PHMD plus a history of either MI or IS and (ii) individuals with heterozygous familial hypercholesterolemia (HeFH).

Model inputs

Baseline characteristics: main baseline characteristics for individuals with PHMD plus a history of either MI or IS were defined according to the data available in the FOURIER trial (Table 1).16 Baseline LDL-C in this subpopulation (175 mg/dL) corresponds to the midpoint of the range (160 to 190 mg/dL) considered as «high» in the CARMELA study.17 Likewise, the main baseline characteristics for individuals with HeFH (Table 2) were defined according to data from the RUTHERFORD-2 trial.18 Distribution among initial health states for individuals with HeFH (35.56% post-MI, 3.33% post-IS, 61.11% oASCVD) is also based on the RUTHERFORD-2 trial,18 with specific values derived from Borissov et al.15 Baseline LDL-C in this subpopulation (217.8 mg/dL) was estimated as the weighted average for patients with definite/probable HeFH diagnosis off and on treatment, as reported by Benn et al.19

Table 1: Main model inputs in the primary hypercholesterolemia and mixed dyslipidemia plus history of either myocardial infarction or ischemic stroke subpopulation. 

Description Base-case value Source
Baseline characteristics
Mean age (years) 62.5 FOURIER trial(16)
Proportion of females (%) 24.6 FOURIER trial(16)
Mean LDL-C (mg/dL) 175.0 CARMELA study(17)
Concomitant use of ezetimibe (%) 5.2 FOURIER trial(16)
Distribution among initial health state Based on the proportions of patients with a history of MI (81.1%) or of previous stroke (19.4%) in the FOURIER trial(16)
Post-MI (%) 80.7
Post-IS (%) 19.3
oASCVD (%) 0.0
Baseline annual CV event rate* 10.0 Toth et al.(13)
Relative reduction of LDL-C with evolocumab (%) 59.0 FOURIER trial(16)

LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; IS = ischemic stroke; oASCVD = other atherosclerotic cardiovascular disease; CV = cardiovascular.

* Represents the rate per 100 patient-years under standard of care, calculated for a mean age of 67 years and mean LDL-C level of 103.2 mg/dL.

Table 2: Main model inputs in the heterozygous familial hypercholesterolemia subpopulation. 

Description Base-case value Source
Baseline characteristics
Mean age (years) 51.0 RUTHERFORD-2 trial(18)
Proportion of females (%) 42.2 RUTHERFORD-2 trial(18)
Mean LDL-C (mg/dL) 217.8 Benn et al. 2012(19)
Concomitant use of ezetimibe (%) 62.0 RUTHERFORD-2 trial(18)
Distribution among initial health state Derived from Borissov et al.(15) which used data collected in the RUTHERFORD-2 trial(18)
Post-MI (%) 35.56
Post-IS (%) 3.33
oASCVD (%) 61.11
Baseline annual CV event rate* 7.99 Derived from Borissov et al.(15)
Relative reduction of LDL-C with evolocumab (%) 59.2 RUTHERFORD-2 trial(18)

LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; IS = ischemic stroke; oASCVD = other atherosclerotic cardiovascular disease; CV = cardiovascular.

* Represents the rate per 100 patient-years under standard of care, calculated as -LN (1 - 0.55) / 10; where LN is natural logarithm and 0.55 is the predicted 10-year risk for mean age of 51.16 years and mean LDL-C level of 155.46 mg/dL.

Baseline risks: the baseline CV event rates represent the rates for patients treated with SoC. The rates are adjusted by age and LDL-C level to reflect the risk in the target population, using the formula:

ra=r0 × HR(age/age) ×RR(LDL)

where ra is the adjusted baseline rate; r0 is the baseline rate at mean age (see below); HRage is the hazard ratio (HR) for age, taking a value of 1.03 from the model developed by Wilson et al.;20 ∆age is the age difference between cycle age and the mean age of the cohort from which the baseline rate was obtained; RR is the rate ratio (RR) per 1 mmol/L of LDL-C reduction (equal to 0.78, which is the RR for any major vascular event in the CTTC trial),21 and ∆LDLc is the LDL-C difference in mmol/L after subtracting the mean LDL-C of the population being evaluated from the cohort LDL-C from which the baseline rate was obtained. The cohort baseline annual CV event rate for a mean age of 67 years and mean LDL-C level of 103.2 mg/dL for the PHMD with a history of either MI or IS subpopulation is 10.0 per 100 patient-years (Table 1). These three parameters were obtained from an observational study conducted in the United Kingdom13 that applied inclusion criteria similar to those used in the FOURIER trial.16 The parameters for the cohort used as a reference in the HeFH subpopulation are shown in Table 2. The baseline CV event rates are further adjusted in the model once patients experience additional CV events based on the study by Wilson et al., where HRs due to two and three vascular beds involved (vs only one) were 1.35 and 1.83, respectively, and a CV event in the previous year increased the rate by 46%.20 All rates were converted to risks assuming a constant rate over time (exponential survival function).14

Non-CV mortality: mortality from non-CVD causes was assumed to be the same as that of the IMSS adult beneficiary population. The age- and sex-specific non-CV mortality rates were estimated as the difference between the corresponding rates for all-cause and CV mortality, both calculated from the number of deaths (classified by cause) that occurred in individuals aged ≥ 18 years affiliated to IMSS in 2018 according to the National Institute of Statistics and Geography (INEGI)22 and the IMSS adult beneficiary population in the middle of 2018, based on the Mexican population projections elaborated by the National Population Council (CONAPO)23 and the IMSS coverage of social security data found in the National Survey of Employment and Social Security (ENESS) 2017.24

Treatment effect: The predicted effectiveness of evolocumab on reducing CV event rates in each subpopulation is based on the relative LDL-C reduction observed with evolocumab in the FOURIER16 and RUTHERFORD-218 trials. In particular, the model draws on the treatment differences between the mean percentage reduction of LDL-C levels with evolocumab administered subcutaneously once every two weeks and placebo (both on top of SoC): at week 48 in the FOURIER trial (59.0%,16 applied to PHMD plus a history of either MI or IS) and at week 12 in the RUTHERFORD-2 trial (59.2%,18 applied to HeFH). The absolute reductions in LDL-C levels with evolocumab were calculated as the product of the corresponding baseline LDL-C level and the relative reduction in LDL-C. Further, the absolute reductions were converted from mg/dL to mmol/L by dividing them by 38.67.12 For SoC, the relative reduction in LDL-C was set to zero because patients were assumed to be treated with SoC at baseline.14

Absolute LDL-C reductions from baseline were converted into reductions in CV events based on the relationship between LDL-C level and occurrence of CV events reported in the FOURIER trial. Specifically, the model employs the RRs per 1 mmol/L of LDL-C reduction estimated from the HRs for the key secondary endpoint, which consists of CV death, MI, or IS: 0.84 (95% confidence interval, 0.74-0.96) in the first year and 0.75 (0.66-0.85) for subsequent years.16 The RR of CV events per 1 mmol/L of LDL-C reduction was defined as:

RR =HR(1/LDLc)

where HR as it was previously referred, while ∆LDLc indicates the mean LDL-C reduction in the FOURIER trial16 after the imputation for missing values (1.38 mmol/L, equal to 53.4 mg/dL).25 Hence, the adjusted rate of CV events for patients treated with evolocumab (ra_EVO) is given by the following formula:14,15

ra_EVO =ra * RRLDLc

where ra is the baseline CV rate adjusted by age and LDL-C level, calculated for SoC (see above).

It is important to note that the benefits of evolocumab regarding the reduction of LDL-C and CV events observed in the FOURIER trial16 were largely consistent across major predefined subgroups related to demographic and disease characteristics, including baseline LDL-C level and baseline risk factors (e.g., previous CV events or presence of familial hypercholesterolemia). The benefits of evolocumab were also consistent across levels of intensity of statin therapy, regardless of ezetimibe use.16 Therefore, the treatment effect observed in the overall trial population of FOURIER was applied across all modeled target subpopulations.

Resource use and costs: The model considers the direct medical costs consisting of the acquisition of hypolipemiant therapies plus the management associated with health states and RV procedures. All costs are expressed in Mexican pesos (MXN) at values as of August 2020. The list price of a 140-mg prefilled syringe of evolocumab ($2,983.00 [MXN]) was provided by Amgen Mexico. The acquisition cost for high-intensity statins was calculated as a simple average of atorvastatin 40 and 80 mg/day,7 using a price of $11.20 (MXN) per 10-Tablet pack of atorvastatin 20 mg.26 The daily dose of ezetimibe was a 10 mg Tablet,7 with an acquisition cost (if applied) being calculated from a price of $126.00 (MXN) per pack (each pack containing 28 Tablets).27 Table 3 presents the estimates of costs associated with diverse CV events and RV procedures. They were computed from the 2018 Diagnosis Related Groups (DRG) costs at the operative-substantive level in IMSS28 and Hunt et al.29 The annual cost for the health states denominated MI and IS was calculated as the sum of their corresponding acute care and follow-up costs. The cost of the transitory event named RV corresponds to the weighted average of percutaneous coronary intervention (PCI, DRG code 248) and coronary artery bypass graft surgery (CABG, DRG code 233), considering that most (88.3%) of the RV procedures correspond to PCI. This percentage was derived from the proportional distribution between ST-elevation myocardial infarction (STEMI; 73.2%) and non-ST-elevation myocardial infarction or unstable angina (NSTEMI/UA; 26.8%) reported in the RENASCA-IMSS study,30 and the probabilities of PCI conditional to STEMI (91.8%) and NSTEMI/UA (87.0%) estimated from the RENASICA III study.31 Conservatively, the cost for non-CV death was set to zero.

Table 3: Costs for cardiovascular events and revascularization procedures. 

Item DRG code Cost
Myocardial infarction, acute care 281 $157,844.05
Ischemic stroke, acute care 064 $61,661.16
Non-fatal CV event, follow-up Not applicable $30,343.28*
oASCVD, annual cost Not applicable $30,343.28
Cardiovascular death 284 $173,484.63
Revascularization 248 and 233§ $230,395.20

DRG = diagnosis related groups at the Mexican Institute of Social Security (2018 version);28 CV = cardiovascular; oASCVD = other atherosclerotic cardiovascular disease.

* From Hunt et al.29 This value was also used as annual cost for both the post-MI and post-IS health states.

Assumed to be equal to the follow-up cost of a non-fatal CV event.

§ Weighted average. See description in text. Notes: (1) Costs based on DRG are expressed in operative-substantive level values.28 (2) All costs were updated by inflation to 2020 and are expressed in Mexican pesos.

Discount rates: In the base-case, both costs and LY were discounted at a 5% annual rate, according to Mexican guidelines.32

Sensitivity analyses: Both deterministic and probabilistic sensitivity analyses were conducted to assess uncertainty surrounding the incremental cost-effectiveness ratio (ICER). Deterministic sensitivity analysis comprised the evaluation of five scenarios regarding the price of evolocumab (5% change up/down), discount rates (high/low according to Mexican guidelines32), and use of CTTC21 RRs instead of those derived from the FOURIER trial,16 in addition to the univariate analysis over the costs of CV events and other parameters involved in the risk estimations. Probabilistic sensitivity analysis consisted of 1000 second-order Monte Carlo simulations for each subpopulation, using the distributions recommended by Briggs et al:33 gamma (with assumed standard errors equal to 10% of the mean values) for costs, normal for LDL-C reductions and mortality, and log-normal for the RRs of CV events per 1 mmol/L of LDL-C reduction and the HRs from Wilson et al.20 The 95% confidence intervals were used to define the lower and upper bounds and to parameterize the probability distributions. Results of the scenario analyses are presented in a Table, whereas those for the univariate and probabilistic sensitivity analyses are summarized graphically through tornado diagrams and cost-effectiveness acceptability curves (CEAC).

Results

Base case analyses

Table 4:shows the predicted CV event rates per patient, LY (both undiscounted and discounted), and discounted costs disaggregated by item with each intervention for the two subpopulations analyzed. Evolocumab added to SoC decreased the lifetime rate of any major adverse CV event (MACE) by 21 and 24.1% in patients with PHMD plus a history of either MI or IS and in patients with HeFH, respectively. The highest absolute risk reductions were observed for MI, followed by CV death, while the relative reductions in risk varied from 17.5% (CV mortality in HeFH) to 30% (IS in HeFH). The benefit of adding evolocumab is reflected in a higher life expectancy, leading to gains of 3.15 LY for the first subpopulation and 5.58 LY for the second. These values represent relative improvements of 33.7% and 43.8%, respectively. The main cost driver in patients receiving evolocumab and SoC was the acquisition of hypolipemiant therapy, accounting for around half of the total costs in both subpopulations. In the groups of SoC alone, costs owing to RV procedures contributed the most. Overall discounted costs in patients receiving evolocumab as add-on treatment nearly doubled those of the SoC alone, mainly driven by the differences in the acquisition cost of lipid-lowering therapies.

Table 4: Predicted cardiovascular event rates, life years, and discounted costs. 

PHMD plus history of either MI or IS HeFH
Outcomes EVO+SoC SoC Difference EVO+SoC SoC Difference
MACE* 1.35 1.71 -0.36 1.73 2.28 -0.55
MI 0.58 0.76 -0.18 0.82 1.14 -0.31
IS 0.14 0.18 -0.05 0.20 0.29 -0.09
CV death 0.63 0.77 -0.14 0.71 0.85 -0.15
Life years
Undiscounted 12.50 9.35 3.15 18.31 12.73 5.58
Discounted 8.28 6.69 1.59 10.71 8.42 2.29
Discounted costs ($) 1,180,405 625,845 554,560 1,415,406 731,747 683,660
LLT 564,395 8,772 555,623 738,120 18,893 719,227
Acute care 140,074 193,841 -53,767 149,003 228,601 -79,597
Follow-up 237,408 183,550 53,858 308,295 229,128 79,167
Revascularization 238,529 239,683 -1,154 219,988 255,125 -35,137

PHMD = primary hypercholesterolemia and mixed dyslipidemia; HeFH = heterozygous familial hypercholesterolemia; EVO = evolocumab; SoC = standard of care; MACE = major adverse cardiovascular event; MI = myocardial infarction; IS = ischemic stroke; CV = cardiovascular; LLT = lipid-lowering therapies.

* Expressed as per patient rate.

Note: Costs are expressed in Mexican pesos.

Since the addition of evolocumab to SoC was associated with both more costs and more effectiveness in comparison with SoC alone, incremental analyses were warranted (Table 5). The cost per LY gained with evolocumab added to SoC over SoC alone for patients with PHMD plus a history of either MI or IS was $348,629 (MXN). The ICER was lower (i.e., more cost-effective) for the HeFH subpopulation, yielding a value of $298,148 (MXN) per LY gained.

Table 5: Incremental cost-effectiveness analyses: evolocumab added to SoC vs SoC alone. 

PHMD plus history of MI or IS HeFH
Scenarios Δ Cost Δ LY ICER Δ Cost Δ LY ICER
Base-case $554,560 1.59 $348,629 $683,660 2.29 $298,148
5% increase in EVO price $582,237 1.59 $366,029 $719,364 2.29 $313,719
5% decrease in EVO price $526,883 1.59 $331,230 $647,956 2.29 $282,578
High discount rates* $474,304 1.26 $376,837 $560,506 1.70 $329,364
Low discount rates $661,415 3.15 $209,861 $860,832 5.58 $154,371
Use of CTTC rate ratios§ $474,681 1.23 $384,626 $567,491 1.83 $310,261

SoC = standard of care; PHMD = primary hypercholesterolemia and mixed dyslipidemia; HeFH = heterozygous familial hypercholesterolemia; LY = life years; ICER = incremental cost-effectiveness ratio; EVO = evolocumab. The symbol Δ denotes incremental.

* An annual rate of 7% for both costs and LY.32

Annual rates of 3% and 0% (i.e., undiscounted) for costs and LY,32 respectively.

§ 0.73 (myocardial infarction), 0.79 (ischemic stroke), and 0.86 (cardiovascular death) per 1 mmol/L of low-density lipoprotein cholesterol reduction.21 Note: All costs and ICER values are expressed in Mexican pesos.

Scenario analyses

Table 5:shows the incremental values of cost and LY, as well as the ICERs, calculated for the five scenarios evaluated as part of the deterministic sensitivity analysis. All values can be compared to those obtained during the base case analyses. A relative variation of ± 5% in the price of evolocumab resulted in equivalent changes in ICER estimates. When the annual discount rate of 7% for both costs and LY was applied, the ICERs increased moderately (by 8 and 10% in PHMD plus a history of either MI or IS and HeFH subpopulations, respectively). In contrast, low annual discount rates (3% for costs and 0% for LY) led to considerable improvements in ICERs, dropping their values by 40% for the PHMD with a history of either MI or IS subpopulation and 48% for the HeFH subpopulation. Using the CTTC21 RRs of CV events per 1 mmol/L of LDL-C reduction instead of those derived from the FOURIER trial16 produced slightly higher ICERs compared with the ones from the base case.

Univariate sensitivity analyses

Figures 2 and 3 present the tornado diagram containing the parameters that have an impact of > 1% on the ICER for the corresponding subpopulations. In both cases, the ICER is mainly sensitive to changes in the RRs of CV events per 1 mmol/L of LDL-C reduction for CV death and MI in year two onwards and to the baseline annual MACE rate.

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; ICER = incremental cost-effectiveness ratio; IS = ischemic stroke; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; PHMD = primary hypercholesterolemia and mixed dyslipidemia (with a history of either MI or IS); SoC = standard of care.

Figure 2: Univariate sensitivity analyses: PHMD. Values in parentheses at the end are 95% confidence intervals. ICER values are expressed in Mexican pesos. 

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HeFH = heterozygous familial hypercholesterolemia; ICER = incremental cost-effectiveness ratio; IS = ischemic stroke; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; noASCVD = without ASCVD; oASCVD = other ASCVD; RV = revascularization; SoC = standard of care.

Figure 3: Univariate sensitivity analyses: HeFH. Values in parentheses at the end are 95% confidence intervals. ICER values are expressed in Mexican pesos. 

Probabilistic sensitivity analyses

Figure 4:displays the CEAC with add-on evolocumab therapy for each subpopulation. The probability of evolocumab added to SoC being cost-effective compared with SoC alone under a willingness to pay threshold of $521,435 (MXN) -which is equivalent to three times the gross domestic product (GDP) per capita for 2020 in Mexico estimated by the authors with data from the International Monetary Fund34,35 available at the time the analyses were done- was 97.7% and 99.3% for PHMD plus a history of either MI or IS and HeFH subpopulations, respectively.

HeFH = heterozygous familial hypercholesterolemia; IS = ischemic stroke; MI = myocardial infarction; MXN = Mexican pesos; PHMD = primary hypercholesterolemia and mixed dyslipidemia (with a history of either MI or IS ).

Figure 4: Cost-effectiveness acceptability curves with add-on evolocumab therapy. 

Discussion

To our knowledge, this is the first economic evaluation of evolocumab in Mexico. The present study found evolocumab added to SoC had ICERs of $298,148 (MXN) in patients with HeFH and $348,629 (MXN) in patients with PHMD plus a history of either MI or IS. These values are equal to 1.72 and 2.00 times, respectively, our estimate of GDP per capita for 2020 in Mexico, meeting international criteria for cost-effectiveness acceptability thresholds.36 Thus, despite significantly higher acquisition cost, the use of evolocumab is cost-effective due to its clinical benefit, characterized by a high potency combined with a simple dosage schedule allowing to achieve a predictable effect in LDL-C reduction, which in turn leads to a considerable decrease in risk of suffering fatal and disabling CV events. It is noteworthy that the model predicted meaningful improvements in survival for patients who received evolocumab added to SoC, yielding gains of 3.15 and 5.58 years in life expectancy over those treated with SoC alone in patients with PHMD plus a history of either MI or IS, and in patients with HeFH, respectively. Sensitivity analyses confirmed the robustness of the cost-effectiveness results.

Because of some methodological differences (e.g., health states considered, characteristics of the target population, type of prevention, sources of clinical information, cost vectors, discount rates), it is difficult to compare the results of our study with those in other published studies. However, there is congruence in several aspects. For example, as other authors have previously reported,12-15,37-39 we found that evolocumab added to SoC may provide a cost-effective intervention when administered to a certain high-risk population, such as in secondary prevention of individuals with PHMD and those with HeFH. In addition, the lower (i.e., better) ICER with HeFH predicted by our model is consistent with that in previous studies.12,14

There are several limitations to this study. First, the relative reduction in LDL-C with evolocumab applied in the model to the HeFH subpopulation is based on a short-term clinical trial.18 Interestingly, the mean percentage reduction in LDL-C levels after 12 weeks of treatment in the RUTHERFORD-2 trial18 (59.2%) is almost identical to the corresponding value in the FOURIER trial16 (59.0%), where the median duration of follow-up was 2.2 years. Second, since the model had a lifetime horizon, the effect of LDL-C lowering on CV events from year two onwards is constant, and it was based on the results of the FOURIER trial.16 Although the limited follow-up time in the FOURIER trial16 may have some uncertainty about the long-term effects of evolocumab. It is worth mentioning that there is evidence of sustained hypolipemiant effect with evolocumab for up to five years.40 In addition, given that the process of atherosclerotic plaque accumulation and its eventual outcome in terms of CV events requires some time, it is possible to hypothesize that the therapeutic benefit of evolocumab from year three onwards will be greater in magnitude than that observed in year 2. It is also worth noting that the ICERs under the scenario considering the RRs of CV events per 1 mmol/L of LDL-C reduction found in the CTTC trial,21 which had a median follow-up of 5.1 years, were similar to those obtained during the base case analyses. A third limitation is that the cost analyses were focused on certain direct medical costs. Incorporation of other sources of costs associated with CV events, such as payment of disability leave and pensions, funeral expenses, and other end-of-life costs, would have led to more favorable results for evolocumab. Regarding this agent, its price was maintained fixed during the whole horizon but if a price erosion eventually occurred, the cost-effectiveness results would improve. Another limitation consisted of the exclusion of supplementary effectiveness measures such as the quality-adjusted life years (QALYs) or DALYs, which presumably would also lead to improved ICERs.

Finally, it is important to keep in mind that the results of these analyses are only applicable to the subpopulations evaluated, including their specific risk profiles. In the same way, the results are only generalizable to Mexican healthcare institutions with cost vectors like those of the IMSS.

Conclusions

Results from this modeling study found that the addition of evolocumab to SoC may provide a cost-effective intervention for high-risk adult patients with PHMD plus history of either MI or IS as well as for those with HeFH when SoC alone is insufficient to meet their LDL-C goals. The cost-effectiveness of the evolocumab treatment strategy will impact longer survival and fewer complications in this type of patient at high risk of complicated CVDs.

References

1. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392 (10159): 1736-1788. [ Links ]

2. GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392 (10159): 1859-1922. [ Links ]

3. Dávila Cervantes CA. Tendencia e impacto de la mortalidad por enfermedades cardiovasculares en México, 1990-2015. Rev Cub Sal Públ. 2019; 45 (4): e1081. [ Links ]

4. Instituto Nacional de Estadística y Geografía. Características de las defunciones registradas en México durante 2018 [Internet]. 2019 [cited 2020 Aug 13]. Available in: https://www.inegi.org.mx/contenidos/saladeprensa/boletines/2019/EstSociodemo/DefuncionesRegistradas2019.pdfLinks ]

5. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392 (10159): 1789-1858. [ Links ]

6. Baeza-Cruz G, Peniche-Otero G, Alva-Esqueda ME, et al. Análisis de Costo de la Enfermedad, del Tratamiento, las Complicaciones e Intervenciones de la Hipercolesterolemia en México en 2016. Value Health Reg Issues. 2018; 17: 56-63. [ Links ]

7. Diagnóstico y tratamiento de dislipidemias (hipercolesterolemia) en el adulto. México: Secretaría de Salud; 03/11/2016. ISBN: 978-607-7790-62-4. [ Links ]

8. Authors/Task Force Members, Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016; 253: 281-344. [ Links ]

9. Miranda N. Inhibidores de la PCSK9: una nueva era en el control del riesgo cardiovascular. Rev Urug Cardiol. 2019; 34: 369-378. [ Links ]

10. Wilson PWF, Polonsky TS, Miedema MD, et al. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 139 (25): e1144-e1161. [ Links ]

11. Wiggins BS, Senfield J, Kassahun H, Lira A, Somaratne R. Evolocumab: Considerations for the management of hyperlipidemia. Curr Atheroscler Rep. 2018; 20 (4): 17. [ Links ]

12. Gandra SR, Villa G, Fonarow GC, et al. Cost-effectiveness of LDL-C lowering with evolocumab in patients with high cardiovascular risk in the United States. Clin Cardiol. 2016; 39 (6): 313-320. [ Links ]

13. Toth PP, Danese M, Villa G, et al. Estimated burden of cardiovascular disease and value-based price range for evolocumab in a high-risk, secondary-prevention population in the US payer context. J Med Econ. 2017; 20 (6): 555-564. [ Links ]

14. Villa G, Lothgren M, Kutikova L, et al. Cost-effectiveness of evolocumab in patients with high cardiovascular risk in Spain. Clin Ther. 2017; 39 (4): 771-786.e3. [ Links ]

15. Borissov B, Urbich M, Georgieva B, Tsenov S, Villa G. Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years. J Mark Access Health Policy. 2017; 5 (1): 1412753. [ Links ]

16. Sabatine MS, Giugliano RP, Keech AC, et al. FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376 (18): 1713-1722. [ Links ]

17. Escobedo-de la Peña J, de Jesús-Pérez R, Schargrodsky H, Champagne B. Prevalencia de dislipidemias en la ciudad de México y su asociación con otros factores de riesgo cardiovascular. Resultados del estudio CARMELA. Gac Med Mex. 2014; 150 (2): 128-136. [ Links ]

18. Raal FJ, Stein EA, Dufour R, et al. RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomized, double-blind, placebo-controlled trial. Lancet. 2015; 385 (9965): 331-340. [ Links ]

19. Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012; 97 (11): 3956-3964. [ Links ]

20. Wilson PW, D’Agostino R Sr, Bhatt DL, et al. REACH Registry. An international model to predict recurrent cardiovascular disease. Am J Med. 2012; 125 (7): 695-703.e1. [ Links ]

21. Baigent C, Blackwell L, Emberson J, et al. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010; 376 (9753): 1670-1681. [ Links ]

22. Instituto Nacional de Estadística y Geografía. Tabulados interactivos: Defunciones registradas (mortalidad general) para 2018 en IMSS [Internet]. 2019 [cited 2020 Aug 27]. Available in: https://www.inegi.org.mx/sistemas/olap/proyectos/bd/continuas/mortalidad/mortalidadgeneral.asp?s=est&c=11144&proy=mortgral_mgLinks ]

23. Consejo Nacional de Población. Proyecciones de la Población de México y de las Entidades Federativas, 2016-2050: Población a inicio de año [Internet]. 2018 [cited 2020 Jun 5]. Available in: https://datos.gob.mx/busca/dataset/proyecciones-de-la-poblacion-de-mexico-y-de-las-entidades-federativas-2016-2050/resource/ebd3c8a3-93af-4067-a665-2b006db57f4fLinks ]

24. Encuesta Nacional de Empleo y Seguridad Social (ENESS) 2017. Tabulados predefinidos: Indicadores con precisiones estadísticas [Internet]. 2018 [cited 2020 Aug 27]. Available in: https://www.inegi.org.mx/programas/eness/2017/default.html#TabuladosLinks ]

25. Ference BA, Cannon CP, Landmesser U, et al. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018; 39 (27): 2540-2545. [ Links ]

26. Programa anual de adquisiciones, arrendamientos, servicios y obra pública 2020 en el Instituto Mexicano del Seguro Social [Internet]. 2020 Jul 30 [cited 2020 Aug 17]. Available in: http://compras.imss.gob.mx/pics/pages/bloqrecursos_base/PAAASOP-IMSS-JULIO-2020.zipLinks ]

27. Portal de Compras del Instituto Mexicano del Seguro Social. Ficha del producto: Ezetimiba. Año: 2019 [Internet]. 2020 [cited 2020 Aug 17]. Available in: http://compras.imss.gob.mx/?P=imsscomproprod&pd=01000040240400&pr=2019Links ]

28. Grupos Relacionados con el Diagnóstico: Costo Unitario_2018. Nivel Operativo-Sustantivo. Anexo a la solicitud No. 0064100241520?2 realizada a través de la plataforma del Instituto Nacional de Transparencia, Acceso a la Información y Protección de Datos Personales. [ Links ]

29. Hunt B, Garza JLA, Vázquez CJE, Jain P, Valentine WJ. Evaluating the long-term health economic implications of improving the proportion of patients with type 2 diabetes meeting treatment targets in Mexico. Value Health Reg Issues. 2015; 8: 20-27. [ Links ]

30. Borrayo-Sánchez G, Rosas-Peralta M, Ramírez-Arias E, et al; RENASCA IMSS Group. STEMI and NSTEMI: Real-world Study in Mexico (RENASCA). Arch Med Res. 2018; 49 (8): 609-619. [ Links ]

31. Martinez-Sanchez C, Borrayo G, Carrillo J, et al. RENASICA III Investigators. Clinical management and hospital outcomes of acute coronary syndrome patients in Mexico: The Third National Registry of Acute Coronary Syndromes (RENASICA III). Arch Cardiol Mex. 2016; 86 (3): 221-232. [ Links ]

32. Guía para la Conducción de Estudios de Evaluación Económica para la Actualización del Cuadro Básico y Catálogo de Insumos del Sector Salud en México. Consejo de Salubridad General. Edición diciembre 2017. [ Links ]

33. Briggs AH, Weinstein MC, Fenwick EA, et al. ISPOR-SMDM Modeling Good Research Practices Task Force. Model parameter estimation and uncertainty analysis: a report of the ISPOR-SMDM Modeling Good Research Practices Task Force Working Group-6. Med Decis Making. 2012; 32 (5): 722-732. [ Links ]

34. International Monetary Fund. World Economic Outlook Database, October 2019. Mexico: Gross domestic product per capita 2019 / current prices / national currency [Internet]. 2020 [cited 2020 Aug 11]. Available in: https://www.imf.org/external/pubs/ft/weo/2019/02/weodata/weorept.aspx?sy=2019&ey=2019&scsm=1&ssd=1&sort=country&ds=.&br=1&c=273&s=NGDPPC&grp=0&a=&pr.x=81&pr.y=3Links ]

35. International Monetary Fund. World Economic Outlook Reports. World Economic Outlook Update, June 2020. A Crisis Like No Other, An Uncertain Recovery [Internet]. 2020 Jun 24 [cited 2020 Aug 11]. Available in: https://www.imf.org/en/Publications/WEO/Issues/2020/06/24/WEOUpdateJune2020Links ]

36. Robinson LA, Hammitt JK, Chang AY, Resch S. Understanding and improving the one and three times GDP per capita cost-effectiveness thresholds. Health Policy Plan. 2017; 32(1): 141-145. [ Links ]

37. Carroll C, Tappenden P, Rafia R, et al. Evolocumab for treating primary hypercholesterolaemia and mixed dyslipidaemia: an evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics. 2017; 35 (5): 537-547. [ Links ]

38. Korman M, Wisløff T. Modeling the cost-effectiveness of PCSK9 inhibitors vs. ezetimibe through LDL-C reductions in a Norwegian setting. Eur Heart J Cardiovasc Pharmacother. 2018; 4 (1): 15-22. [ Links ]

39. Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P. Updated cost-effectiveness analysis of evolocumab in patients with very high-risk atherosclerotic cardiovascular disease. JAMA Cardiol. 2019; 4(7): 691-695. [ Links ]

40. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol. 2019; 74 (17): 2132-2146. [ Links ]

1Funding/support: This study was funded by Amgen Mexico. The role of Amgen Mexico as study sponsor included the review of and comment on the draft and final version of the manuscript.

2Conflict of interests: FCR, JAGC and AGHG report partial/full employment with AHS Health Consulting S.A.S. de C.V., which received funding from Amgen Mexico to conduct the study. MAE, LMCC and TAdM are employees of Amgen Mexico.

Received: December 20, 2021; Accepted: May 11, 2022

*Corresponding author: Fernando Carlos-Rivera. E-mail: fernando.carlos@ahs-mex.com

Creative Commons License This is an open-access article distributed under the terms of the Creative Commons Attribution License