Abstract
Background
With the rising burden of cardiovascular disease (CVD) and the need for cost-effective interventions, evaluating the economic implications of Evolocumab becomes crucial.
Objectives
This study aimed to systematically review and evaluate the cost-effectiveness of Evolocumab in adults at risk of CVD.
Methods
We performed an extensive search in Cochrane Library, EMBASE, PubMed, ProQuest, and Web of Science. The reference lists of chosen literature reviews were also examined to find suitable cost-effectiveness analyses (CEAs) of Evolocumab in patients with CVD published until March 2023. The Consolidated Health Economic Evaluation Reporting Standards statement (CHEERS) was used to assess the reporting quality. Cost-related findings were adjusted to reflect 2023 purchase power parity (PPP) values in US dollars to enable cross-study comparisons.
Results
This systematic review comprised 16 studies, published between 2016 and 2023, mostly from the USA and China. Compliance with the CHEERS checklist was high in sections like abstracts, backgrounds, and objectives. However, areas like perspective (71.4%), time horizon (57.1%), and engagement with patients (14.3%) showed lower reporting rates. All studies evaluated the cost-effectiveness of Evolocumab in combination with other lipid-lowering treatments (LLTs). Notably, all studies employed model-based economic evaluations using a Markov cohort state-transition model, with a majority adopting a lifetime horizon. Most studies (10 cases) simultaneously reported both the Incremental Cost-Effectiveness Ratio (ICER) per Quality Adjusted Life Years (QALY) and the ICER per Life-Years Saved (LYS). Four studies exclusively reported ICER/QALY, and 2 studies solely focused on ICER/LYS. The ICER/ QALY exhibited a wide range (3,342.57 to 2,687,920.13 USD), with one study presenting as an outlier. Sensitivity analyses revealed factors influencing cost-effectiveness outcomes, including Low-Density Lipoprotein Cholesterol (LDL-C) levels, Evolocumab costs, and disease type, while several studies reported accepted thresholds for cost-effectiveness analysis.
Conclusions
Our systematic review concludes that Evolocumab could be a cost-effective treatment, particularly for high-risk patient groups, but this varies by disease category, risk level, and evaluation methods. Future studies should investigate the economic impact's certainty and uncertainty, and consider different countries' income levels. LDL-C levels, medication costs, and CVD types are important factors affecting cost-effectiveness analysis.
Keywords: cardiovascular diseases, cost-effectiveness analysis, evolocumab, hypercholesterolemia, LDL-C, lipid-lowering drugs, PCSK9 inhibitors
Introduction
Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, resulting in escalating healthcare expenditures. The anticipated global expenditure attributed to CVDs is expected to rise to $1044 billion by 2030.1 Highlighting the severity of the issue, a 2019 report identified high levels of Low-Density Lipoprotein Cholesterol (LDL-C) as the third most critical modifiable risk factor for CVD.2 This emphasizes the necessity of utilizing interventions aimed at addressing risk factors associated with CVD to reduce the resulting economic burden.
Despite the existence of effective medications, such as statins or ezetimibe, further reduction in LDL-C levels may be necessary, particularly for individuals unresponsive to or intolerant of current therapies. Protease convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as Evolocumab, offer an alternative approach for lowering LDL-C levels and reducing the risk of CVD. Evolocumab plays a significant role in preserving LDL receptors on liver cells, enhancing their effectiveness in removing LDL-C from the bloodstream and subsequently lowering overall LDL-C levels. This reduction significantly decreases the risk of CVD events, especially in individuals with high LDL-C levels and a prior history of CVD.3, 4, 5
However, the high cost of Evolocumab has sparked debates about its cost-effectiveness in practical medical use. Numerous studies have examined the cost-effectiveness of Evolocumab compared to standard CVD treatments, but the results are inconsistent and contingent upon a multitude of factors.6, 7, 8, 9 Given the rising expenditures and resource scarcity in the healthcare sector, the cost-effectiveness of novel treatments has gained paramount importance.10 A systematic review of economic evaluations helps identify factors influencing cost-effectiveness estimates, including the modeling used in the analysis, as well as factors such as patient population, treatment duration, drug pricing, and treatment scenarios. By synthesizing multiple economic evaluations, a systematic review also highlights areas requiring further investigation.11
In this study, our primary aim was to conduct a systematic review of the cost-effectiveness of Evolocumab in adult patients with a risk of CVD. This inquiry has the potential to enhance understanding regarding the affordability of Evolocumab and offer valuable insights to inform healthcare policy and decision-making.
Methods
We conducted and reported our systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.12 Additionally, the protocol for our systematic review was registered on PROSPERO [CRD42022356613].
Eligibility Criteria
This systematic review adheres to the following inclusion criteria: studies published in the English language with full-text availability, focusing on the cost-effectiveness or cost-utility of Evolocumab, and constituting comprehensive economic evaluations that reported the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) and/or life years saved (LYS). We excluded Case reports or case series studies, conference abstracts, studies that are not specifically focused on CVDs, or reported partial health economic analyses. The PICO is as follow: Population: Patients with CVDs, Intervention: Evolocumab, Comparison: Other Lipid-Lowering Therapies (LLTs) drugs or placebo with or without Evolocumab, Outcome: ICER) per QALY and/or LYS.
Search Strategy and Sources
A comprehensive search was conducted of electronic databases from their inception up to March 2023, including the Cochrane Library, EMBASE, PubMed, ProQuest, and Web of Science.
The search strategy was designed to address the research question, incorporating terms such as Evolocumab, economic evaluation, and cost-effectiveness analysis. Medical Subject Headings (MeSH) terms were combined with relevant keywords, using Boolean operators to ensure comprehensive coverage of the literature. The detailed search strategy for PubMed is provided in the supplementary material (Online Resource 1).
The eligibility of all studies was independently evaluated by 2 authors. In cases of disagreement, they discussed and resolved the disparities. If necessary, a third author served as an arbitrator.
Data Extraction
A standardized data extraction form was employed to collect pertinent data. Whenever discrepancies arose, they collaborated to reconcile their differences through discussion. If a resolution could not be met, a third author intervened as a mediator.
The extracted data encompassed bibliographic information (study title and year, first author, country), drug specifics (name and dosage), type of the disease, ICER, time horizon, model type, discount rates, currency and reference year, perspective (e.g., payer, societal or healthcare perspective), thresholds, and funding sources. To determine the ICER, the incremental costs of regimen A (total costs of regimen A minus costs of regimen B) were divided by the difference in effects of regimen A and B (incremental LYS or QALYs). The ICERs were reported in their respective reference year, without accounting for inflation at a country-specific level.
Quality Assessment
The methodological quality of the studies that met the inclusion criteria was assessed using the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) Statement, which comprises 28 items across 7 categories.13 The CHEERS 2022 Statement provides a comprehensive set of criteria to ensure transparent and consistent reporting across studies.
For each item within the CHEERS Checklist, the studies were rated as “Yes,” “No,” or “Partial.” A “Yes” rating indicated that the study fully met the criterion, providing a clear and comprehensive response. A “No” rating meant that the study did not meet the criterion, lacked the necessary information or transparency. Meanwhile, a “Partial” rating reflected a partial fulfillment of the criterion, where the study addressed the item to some extent but could have provided more detailed or clearer information. An overall quality score was calculated based on the proportion of “Yes” ratings for each study. A thorough evaluation of each study was independently conducted by 2 reviewers, ensuring a comprehensive assessment of the methodological quality. Disagreements were resolved through constructive discussions, and if necessary, a third reviewer was consulted to reach a consensus.
Effect Measures and Synthesis Methods
A meta-analysis was deemed inappropriate due to the considerable heterogeneity of the data derived from the included studies. The sources of heterogeneity stemmed from variations in the comparator arms. Therefore, the data underwent a comprehensive analysis utilizing a combination of narrative analysis and descriptive statistics, including numerical values and percentages.
Both ICER per QALY and ICER per LYS, when reported, undergo inflation adjustment to reflect 2023 values and are converted to US dollars using the purchase power parity (PPP) estimated by the Organization for Economic Co-operation and Development (OECD). This process enables meaningful comparisons to be made across various countries and timeframes.14
Ethics Approval
Ethical approval was not required as the analysis involved data from previously published studies.
Results
A total of 282 records were identified and screened. After removing 53 duplicate articles, 176 were excluded based on their titles and abstracts. Subsequently, the full texts of 53 studies were evaluated, and ultimately, 16 studies were included in the final review. To present the study selection process, a PRISMA flowchart was utilized (Figure 1). Table 1 presents the characteristics of the included studies.
Figure 1.
Study flow diagram.
Table 1.
General characteristics of included studies.
| Study | Country | Type of Intervention | Type of Comparator | Targeted Population | Time Horizon | Discount Rate | Reference Year |
Perspective |
|---|---|---|---|---|---|---|---|---|
| Alghamdi et al.15 | KSA | evolocumab + LLT therapy (with or without ezetimibe) | conventional LLT alone | ASCVD or HeFH | lifetime | 3% | 2020 | public healthcare perspective |
| Borissov et al.16 | Bulgaria | evolocumab + SoC | SoC | HeFH | lifetime | 5% | NR | payer perspective |
| Fonarow et al.17 | US | evolocumab + SoC (moderate- to high-intensity statin with(out) ezetimibe) | SoC | ASCVD | lifetime | 3% | 2017 | societal perspective |
| Fonarow et al.6 | US | evolocumab + SoC (moderate- to high-intensity statin with(out) ezetimibe) | SoC | ASCVD | lifetime | NR | 2018 | societal perspective |
| Gandra et al.7 | US | evolocumab + SOC | SoC |
|
lifetime | 3% | NR | payer perspective |
| Gre´goire et al.18 | Canada | evolocumab when used as an add-on treatment | conventional LLTs | ASCVD | lifetime | 1.5% | 2021 | public healthcare and societal perspective |
| Kodera et al.19 | Japan | evolocumab+statin | SoC (statin monotherapy) | ASCVD | 30 year | 2% | NR | public healthcare payer |
| Kumar et al.20 | Australia | evolocumab+statin | Placebo | ASCVD | 25-year time | 5% | 2017 | Health care system |
| Landmesser et al.8 | Sweden | evolocumab + SoC LLT | placebo | ASCVD | lifetime | NR | 2019 | willingness-to pay |
| Lee et al.2 | Canada | evolocumab + statin | statin | ASCVD | lifetime | 3% | 2017 | NR |
| Liang et al.22 | China | Evolocumab + statin | placebo | MI | 25 years | 5% | 2019 | Health care system |
| Tobias Michaeli et al.23 | UK | icosapent ethyl, fenofibrate, ezetimibe, evolocumab, and alirocumab + statins | statin monotherapy | dyslipidaemia patients | lifetime | 3.5% (± 1.5%) |
2021 | Health care system |
| Michaeli et al.24 | Germany | icosapent ethyl, ezetimibe, evolocumab, and alirocumab | statin monotherapy | dyslipidaemia patients | lifetime | 3% | 2021 | Health care system |
| Villa et al.25 | Spain | evolocumab + (SoC; statins) | statins | (1) FH (2) patients with prior CVD event history (secondary prevention [SP]) with or without prior CVD event history |
lifetime | 5% | 2016 | Health care system |
| Xi et al.26 | China | evolocumab+statin | ezetimab+statin | recent ACS event (in the last 12 months) | lifetime | 5% | 2020 | Health care system |
| Xie et al.27 | China | evolocumab + statins | placebo+statins (atorvastatin 40 mg/day or rosuvastatin 20 mg/day, oral administration, daily use |
ASCVD and LDL-C levels 70 mg/dl | lifetime | 5% | 2020 | Health care system |
ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; acute coronary syndrome; FH = familial hypercholesterolemia; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; LLT = lipid lowering therapy; MI = myocardial infarction; NR = not reported; SoC = standard of care.
Results of Syntheses
The articles chosen for our analysis were published between 2016 and 2023. The majority of the studies were conducted in the USA17,28,29 and China.22,26,27 Two articles originated from Canada.18,21 Additionally, one study was included from each of the following countries: Bulgaria,30 the Kingdom of Saudi Arabia,15 Japan,19 Sweden,31 Australia,20 the United Kingdom,23 Spain,25 and Germany.24
The intervention arm comprised Evolocumab, either in combination with statins or with other LLTs, such as Ezetimibe. For clarity, we refer to the intervention as “Evolocumab” throughout the manuscript, understanding that this includes its use in combination with other LLTs. The comparator arms consisted of placebo in 3 studies,8,20,22 while the remaining used statins with or without Ezetimibe.
Most of the studies included in the research were financially supported by a pharmaceutical company,15,17,18,26, 27, 28, 29, 30, 31 while 5 investigations acquired funding from their corresponding nations.21, 22, 23, 24, 25 Notably, 2 studies did not receive any financial assistance or grants.19,20
All the studies included in the analysis were model-based economic evaluations using a Markov cohort state-transition model. Among the studies included in our systematic review, a significant majority (81.25%) utilized a lifetime horizon for their economic evaluations. The remaining studies adopted either a 25-year (2 studies) or 30-year time horizon (1 study). Regarding perspective, the healthcare system perspective was the most frequently preferred approach, employed in 9 out of 16 studies. Additionally, a subset of studies incorporated payer and societal perspectives to assess the economic implications of the interventions under investigation.
With the exception of 2 studies,21,30 the remaining studies included in this analysis reported the ICER per QALY. Additionally, 4 studies6,8,19,22 did not provide the ICER per LYS. The summarized findings of these studies are presented in Table 2, offering a comprehensive overview of the cost-effectiveness results. When converted to 2023 American dollars using PPP, the range of ICER per QALY, spanned from a low of 3342.57 in Xi et al.’s study26 to a high of 2687920.13 reported in Liang et al.’s study.22 Liang et al.’s study is notable as an outlier, with a significantly higher ICER value compared to other studies, as illustrated in Figure 2.
Table 2.
Results of ICER per QALY and LYS in different disease categories.
| Study | category of disease | ICER per Lys | converted ICER per LYs to 2023 $ US (PPP) | ICER per QALY | converted ICER per QALY to 2023 $ US (PPP) | Overall Results |
|---|---|---|---|---|---|---|
| Alghamdi et al.15 | Clinically evident ASCVD, LDL-C ≥ 70 mg/dL | 110853.26 | 81046.22 | 109,274 | 78717.12 | cost effective |
| Clinically evident ASCVD, LDL-C ≥ 100 | 74,700 | 54614.12 | 75,163 | 54144.76 | cost effective | |
| HeFH | 21654.52 | 15831.89 | 22,391 | 16129.68 | cost effective | |
| Fonarow et al.17 | Base case, full list price, US clinical practice: LDL ≥ 70 mg/dL and the cardiovascular event rate was 6.4 per 100 patient-years | 257068.29 | 290469.93 | 268,637 | 303541.79 | not cost effective |
| Full list price, ASCVD | NR | NR | 413,579 | 467316.53 | not cost effective | |
| Fonarow et al.6 | Base cases involving treatment with or without ezetimibe Patients at VHR in US clinical practice, event rate of 6.4 events per 100 patient-years |
NR | NR | 56,655 | 62604.75 | cost effective |
| Base cases involving treatment with or without ezetimibe Patients at VHR in US clinical practice, event rate of 12.3 events per 100 patient-years |
NR | NR | 7667 | 8472.17 | cost effective | |
| Scenarios involving treatment with ezetimibe Patients at VHR in US clinical practice, event rate of 6.4 events per 100 patient-years | NR | NR | 59,331 | 65561.77 | cost effective | |
| Scenarios involving treatment with ezetimibe patients at VHR in US clinical practice, event rate of 6.4 events per 100 patient-years | NR | NR | 10,584 | 11695.5 | cost effective | |
| Scenario involving treatment with or without ezetimibe Patients at VHR in FOURIER trial, event rate of 4.4 events per 100 patient-years | NR | NR | 91,610 | 101230.62 | cost effective | |
| Borissov et al.16 | HeFH LDL≥ 100 | 129386.02 | 222511.19 | NR | NR | cost effective |
| Gandra et al.7 | HeFH LDL≥ 100 | 67232.02 | 77411.96 | 75,863 | 87349.8 | cost effective |
| ASCVD LDL≥ 100 | 122718.60 | 141300.05 | 141699 | 163154.36 | cost effective | |
| ASCVD (statin-intolerant) LDL≥ 100 | 92502.03 | 106508.22 | 100,309 | 115497.29 | cost effective | |
| Gre´goire et al.18 | ASCVD prior MI, LDL-C ≥ 1.8 mmol/L | 60,349 | 52108.98 | 66,453 | 57379.54 | cost effective |
| Kodera et al.19 | patients with triple-vessel CAD | NR | NR | 13,454,814 | 151502.95 | not cost effective |
| Kumar et al.20 | ASCVD | 347,164 | 272028.05 | 308,558 | 241777.46 | not cost effective |
| Landmesser et al.8 | Recent MI LDL-C of 2.5 mmol/L | NR | NR | 623,367 | 76255.05 | cost-effective |
| MI with a risk factor LDL-C of 2.5 mmol/L | NR | NR | 460,241 | 56300.22 | cost-effective | |
| MI with a second event LDL-C of 2.5 mmol/L | NR | NR | 458,380 | 56072.57 | cost-effective | |
| Lee et al.21 | ASCVD | 261637 | 243445.64 | NR | NR | cost-effective |
| Liang et al.22 | MI | NR | NR | 894771 | 276518.37 | not cost effective |
| Michaeli et al.23 | dyslipidaemia patients/ secondary prevention evolocumab | 75,283 | 112624.27 | 85,193 | 127449.75 | not cost effective |
| Michaeli et al.24 | dyslipidaemia patients/ secondary prevention evolocumab | 96,243 | 128859.32 | 114,639 | 153489.65 | not cost effective |
| Villa et al.25 | familial hypercholestromia | 36931.64 | 22524.92 | 30,893 | 53890.94 | cost effective |
| patients with prior CVD event history (Secondary prevention) | 41437.25 | 25272.93 | 45,340 | 79092.84 | cost effective | |
| Xi et al.26 | patients with recent ACS events | 79849.66 | 24141.05 | 87,050 | 26317.94 | cost effective |
| Recent MI (second-line) | 94789.51 | 28657.83 | 102,642 | 31031.89 | cost effective | |
| Recent ACS (third-line) | 63191.96 | 19104.91 | 69,338 | 20963.05 | cost effective | |
| VHR ASCVD (third-line) | 103016.36 | 31145.07 | 111,056 | 3342.57 | cost effective | |
| HeFH Population (third-line) | 63795.09 | 19287.25 | 74,350 | 22478.33 | cost effective | |
| Xie et al.27 | ASCVD and LDL-C levels 70 mg/dl | 13965.67 | 4222.26 | 14,969 | 4525.6 | cost effective |
ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; CVD = cardiovascular disease; HeFH = heterozygous familial hypercholesterolemia; ICER = incremental cost-effectiveness ratio; LDL-C = low-density lipoprotein cholesterol; LYs = life years saved; MI = myocardial Infarction; NR = not reported; PPP = public private partnership; QALY = quality adjusted life years; VHR = very high-risk.
Figure 2.
Overall results of converted ICER per QALY to 2023 $ US (PPP) among included studies.
With the exception of 3 studies, the remaining studies reported their accepted threshold for cost-effectiveness analysis. Among these, 7 studies employed the threshold of ICER per QALY, while one study used ICER per LYS. Additionally, 4 studies set their thresholds at 3 times the Gross Domestic Product (GDP) of their respective countries or equal to the GDP itself. One study adopted a more comprehensive approach by conducting the analysis based on 2 distinct thresholds, namely the World Health Organization (WHO) recommendation and the statement on the level of value put forth by the American College of Cardiology/American Heart Association (ACC/AHA). It was observed that the majority of studies that employed the GDP per QALY threshold were from Asian countries, while the remaining studies originated from Europe and America (see Table 3).
Table 3.
Summary of Cost-Effectiveness Thresholds and Results in Included Studies.
| Study | Country | Type of Cost-Effectiveness Threshold | Reported measure of threshold | Result of study |
|---|---|---|---|---|
| Alghamdi et al.15 | KSA | WHO range | 3GDP=SAR 264,813 in 2019 | cost effective |
| Borissov et al.16 | Bulgaria | ICER per QALY | NR | cost effective |
| Fonarow et al.17 | US | WHO range/ the statement on level of value from the ACC/AHA | ICER of $150 000 per QALY | not cost effective |
| Fonarow et al.6 | US | NR | $50 000 per QALY | cost effective |
| Gandra et al.7 | US | WHO range/ the statement on level of value from the ACC/AHA |
The WHO thresholds were based on 2014 US GDP per capita (US$54,629.50, World Bank): highly cost-effective, <US$55,000/QALY; cost-effective, US$55,000 to US$165,000/QALY; and not cost-effective, >US$165000/QALY gained. The ACC/AHA thresholds were based on the level of value to society: high, <US$50,000/QALY gained; intermediate, US$50,000 to < US$150,000/QALY; and low, ≥US$150,000/QALY. |
cost effective |
| Gre´goire et al.18 | Canada | ICER per QALY | CAD$100,000 per QALY | cost effective |
| Kodera et al.19 | Japan | ICER per QALY | 5 million JPY per QALY | Not cost effective |
| Kumar et al.20 | Australia | ICER per QALY | AU $50,000 per QALY | Not cost effective |
| Landmesser et al.8 | Sweden | ICER per QALY | SEK 700 000 (€66,500) per QALY | cost effective |
| Lee et al.21 | Canada | NR | $50 000 per QALY | cost effective |
| Liang et al.22 | China | 3 times GDP per capita | 70,892 CNY × 3 = 212,676 CNY in 2019 | Not cost effective |
| Michaeli et al.23 | UK | NHS’ established cost-effectiveness threshold | £20,000 to £30,000 per QALY |
Not cost effective |
| Michaeli et al.24 | Germany | NR | NR | Not cost effective |
| Villa et al.25 | Spain | ICER per QALY | €30,000 to €45,000 per ΔQALY. | cost effective |
| Xi et al.26 | China | ICER per QALY | CNY 217,341 per QALY | cost effective |
| Xie et al.27 | China | One times GDP per capita | 1 GDP= 80,976 | cost effective |
ACC = American College of Cardiology; AHA = American Heart Association; AU = Australian dollar; CAD = Canadian dollar; CNY = Chinese yuan; GDP = gross domestic product; ICER = incremental cost effectiveness ratio; JPY = Japanese yen; NHS = National Health Services; NR = not reported; QALY = quality adjusted life years; SAR = Saudi riyal; SEK = The Swedish crown; WHO = World Health Organization.
The sensitivity analysis of the included studies provided insights into factors that could influence the cost-effectiveness results. Specifically, 7 studies reported LDL-C levels,7,8,15,17,18,25,26 while 5 studies identified the cost of Evolocumab19, 20, 21, 22,30 as a significant variable. Additionally, 4 studies reported utility measures,20, 22, 26,27 and 3 reported the type of CVD15,18,25 played a role in the sensitivity analysis. Additionally, a few studies mentioned discount rates21,25 as factors that impacted the final results of the cost-effectiveness analysis (CEA).
Quality Assessment Results
The identified studies underwent evaluation for potential bias using the CHEERS Checklist 2022. The objective was to comprehensively assess all relevant studies and gain an in-depth understanding of the literature on this topic. No study was excluded from this review based on its quality assessment score, provided it was relevant to the specific question being addressed (Online resource 2).
Overall, the studies generally excelled in providing clear and transparent abstracts, backgrounds, objectives, and descriptions of study populations and settings, with a high level of reporting across these sections (100%). However, the perspective was reported in only 71.4% of the studies, the time horizon in 57.1%, and the discount rate in 71.4%. Engagement with patients or individuals impacted by the study was infrequently documented, with only 14.3% of studies mentioning it. The rationale and description of chosen models, as well as the handling of uncertainty, were generally well-reported (85.7%). However, the studies varied in their reporting of assumptions (42.9%), heterogeneity (71.4%), and the impact of engagement activities, indicating room for improvement in providing comprehensive explanations and ensuring consistency across studies.
Discussion
This systematic review provides a comprehensive analysis of existing economic evaluations on the cost-effectiveness of Evolocumab, a lipid-lowering intervention, without limiting the scope to a specific type of CVD. A total of 16 economic evaluations published between 2016 and 2023 were systematically reviewed and their quality assessed. It is essential to acknowledge that all studies in our review evaluated the cost-effectiveness of Evolocumab when used alongside other LLTs, which is consistent with its standard clinical application.32 This systematic review revealed that 10 out of the 16 studies (62.5%) demonstrated the cost-effectiveness of Evolocumab. Conversely, 6 studies reported scenarios where Evolocumab was not cost-effective, such as in patients with triple-vessel coronary artery disease (CAD) or in the context of secondary prevention (SP) in dyslipidemia patients.
In order to better interpret and compare these results, it is important to consider the perspective and methodology used in each study. Most studies adopted a healthcare system perspective, but only 2 included a societal perspective,6,17 which may capture additional costs and benefits. Conversely, the remaining studies utilized a national healthcare system perspective in Australia,20 Japan,19 the UK,23 Germany,24 and China.22 The time horizon varied across studies, with some focusing on short-term outcomes and others considering lifetime horizons, which can significantly impact the cost-effectiveness results. Additionally, the choice of comparators and the inclusion of different treatment scenarios, such as the use of ezetimibe, can also influence the findings.
The analysis revealed that a critical factor affecting the cost-effectiveness of Evolocumab is the underlying risk to the patient population. Several studies have highlighted that Evolocumab was more cost-effective in high-risk patients, such as those with established CVD or Heterozygous Familial Hypercholesterolemia (HeFH), compared to lower-risk individuals. This is reflected in the ICERs, where higher ICERs were generally observed in lower-risk populations, indicating that the additional cost per QALY gained was higher in these groups. The study conducted by Villa et al. in Spain25 reported the highest QALYs. This study included 2 categories of patients at high risk of cardiovascular (CV) events. The first category comprised individuals with Familial Hypercholesterolemia (FH), with or without a history of previous CV events, who were given Evolocumab in conjunction with standard-of-care (SoC), specifically the maximally tolerated dose (MTD) of statin therapy. They were compared to patients who received SoC alone. The second category included patients with a history of previous CV events (SP) who received Evolocumab in addition to SoC (MTD of statin therapy), and they were compared to patients receiving SoC alone. The lowest QALY was reported by Xi et al. in China.26 In the mentioned study, patients were included if they had a history of recent Acute Coronary Syndrome (ACS) event within the previous 12 months and, despite receiving statin treatment, their LDL-C levels stayed at or above 100 mg/dL. The variation between the 2 studies can be elucidated by the distinct Phase III clinical trials of Evolocumab upon which they were based.25,26
Considering the factors previously mentioned, the choice of time horizon can significantly impact the ICER. Different time horizons may yield varied outcomes in cost-effectiveness assessments. In our review, the majority of studies adopted a lifetime horizon,15, 16, 17, 18,21,23, 24, 25, 26, 27, 28, 29,31 though the definitions varied, ranging from 20 years to a maximum of 30 years. However, this research found no significant differences in cost-effectiveness based on the time horizon. Therefore, it is reasonable to conclude that the variations in cost-effectiveness across the studies are not predominantly driven by differences in time horizons.10 Other factors, such as the chosen perspective (societal or health system) and the specific healthcare contexts of the countries where the studies were conducted, appear to have a more significant influence on determining cost-effectiveness outcomes.33
Furthermore, the geographical distribution of studies highlights regional variations in cost-effectiveness thresholds due to differences in healthcare systems, economic conditions, and societal preferences. This diversity underscores the importance of considering regional context when interpreting the economic implications of healthcare interventions. GDP-based thresholds in healthcare decisions reflect a country's economic capacity but may evolve over time. A recent systematic review suggests a more suitable threshold range for setting willingness-to-pay per QALY (WTP/QALY) is 0.5–1.5 times GDP per capita.34 This range is lower than the WHO's recommended range of 1 to 3 times GDP per capita,35 enabling cost-effectiveness thresholds to be tailored to consumer preferences. Some countries use alternative methods, such as willingness-to-pay surveys, to determine cost-effectiveness thresholds, reflecting the nuanced considerations among researchers and decision-makers in health economics.
Within the selected studies, the range of ICER per QALY, when adjusted to PPP using 2023 US dollars, varied widely, from 3342.57 to 276518.37, with both extremes originating from Chinese studies.22,26 Another Chinese study reported a value of 4525.6.27 The primary factor contributing to the variance between these studies appears to be the difference in Evolocumab pricing. However, Liang et al.22 reported the highest ICER per QALY, which can be attributed to variations in the incidence of CV events and the effectiveness rate of Evolocumab. Liang's study22 considered the drug's effectiveness to be 0.73 for MI and 0.79 for stroke, while the other 2 studies26,27 assumed an effectiveness rate of 0.78 for both outcomes. Determining the exact source of the discrepancy is challenging, as it may be influenced by variations in model parameters, costs, efficacy assumptions, study design, patient characteristics, or regional healthcare practices.
In the present systematic review, the CEA of Evolocumab was not found to be influenced by the income level of the country. One study was conducted in Bulgaria, an upper middle-income country, while the remaining studies were carried out in high-income economies, according to the World Bank country classifications based on income levels.36 The utilization of different cost measures and thresholds can indeed lead to variations in results. Cost-effectiveness thresholds among countries are influenced by factors such as health system characteristics and economic indicators like GDP per capita. Consequently, contrasting annual prices and cost-effectiveness thresholds contribute to Evolocumab being considered cost-effective in some countries, such as Spain, while it may not meet the cost-effectiveness criteria in others, like the United States.
The strength of our systematic review lies in its rigorous and comprehensive approach. Our stringent eligibility criteria focused on high-quality studies with a robust search strategy that covered multiple databases and spanned a significant time frame up to March 2023. Additionally, the methodological quality of the included studies was rigorously assessed using the CHEERS 2022 Statement. This ensured that we systematically evaluated the methodological quality and reporting standards of the included studies. By rigorously assessing each study against these comprehensive criteria, we ensured that our conclusions are based on high-quality evidence. This methodological rigor not only strengthens the credibility of our findings but also provides a clear framework that future studies can adopt to enhance their reporting standards. Our exclusive focus on Evolocumab allowed for a detailed and specific analysis of its cost-effectiveness, providing nuanced insights into its economic value when used alone or in combination with other LLTs.
Limitations
There are also some limitations to this review. We examined only the base case results from the included studies, without considering the results obtained from deterministic or probabilistic sensitivity analysis. Moreover, in cases where certain studies did not specify the reference year for their ICER values, we utilized the publication year instead to convert them to PPP.6,7,19,30 It is important to note that this substitution may introduce a minor impact on the results. Furthermore, language and full-text availability restrictions may have impacted our study, potentially excluding relevant studies published in languages other than those included in the search criteria and leading to the omission of studies that could have contributed valuable insights. Moreover, the majority of studies were conducted in countries classified as high-income, and the cost-effectiveness of the interventions may differ across various nations. Therefore, careful consideration should be given when extrapolating these results to other healthcare contexts. For low-income countries (LIs) and lower-middle-income countries (LMICs), it is advisable to generate primary economic evidence to inform policy decisions.
Conclusion
In conclusion, the findings of this research propose that Evolocumab can be cost-effective, particularly in high-risk patient subgroups. However, its cost-effectiveness profile varies depending on the specific disease category, underlying risk, and methodological choices made in the evaluations. To enhance our understanding of Evolocumab's cost-effectiveness, future research should delve deeper into assessing both the certainty and uncertainty surrounding its economic impact. Additionally, it is essential to conduct evaluations based on countries' income levels, considering the diverse economic contexts of low- and high-income nations. Moreover, factors like LDL-C levels, the cost of medication, and the type of CVD may significantly impact the CEA results.
Declaration of Generative AI and AI-Assisted Technologies in the Writing Process
During the preparation of this work, the authors used ChatGPT in order to improve the language and readability. After using this tool/service, the authors reviewed and edited the content as needed and took full responsibility for the content of the publication.
Availability of Data and Material
All data generated or analyzed during this study is included in the article.
Authors' Contributions
In terms of author contributions, Sara Kaveh was responsible for conceptualization, Sara Kaveh and Nashmil Ghadimi conducted the literature search, all authors were involved in screening and eligibility assessment, data extraction was carried out by Sara Kaveh, Nashmil Ghadimi, Mahshad Goharimehr, Rajabali Daroudi, and Hosein Shabaninejad, and Sara Kaveh and Nashmil Ghadimi collaborated on the first draft. Furthermore, Sara Kaveh, Nashmil Ghadimi, Mahshad Goharimehr, Rajabali Daroudi, and Hosein Shabaninejad collectively conducted the risk of bias assessment, and all authors participated in the critical revision of the paper for significant intellectual content.
Ethics Approval
Ethical approval was not required as the analysis involved data retrieved from previously published studies.
Declaration of competing interest
The authors have indicated that they have no conflicts of interest regarding the content of this article.
Funding
We received funding from the Tehran University of Medical Sciences [1401-3-99-62357]. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.curtheres.2024.100758.
Appendix. Supplementary materials
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data generated or analyzed during this study is included in the article.