Cost-Effectiveness of Icosapent Ethyl, Evolocumab, Alirocumab, Ezetimibe, or Fenofibrate in Combination with Statins Compared to Statin Monotherapy

A Markov model simulating the progression of CVD in dyslipidaemia patients was adapted from existing cost-effectiveness studies (Fig. 1) [23]. Patients transitioned between three distinct health states: “Alive without CVD”, “Alive with CVD”, and “Dead”. The occurence of non-fatal MI and non-fatal strokes transitioned patients without prior CVD history to the “Alive with CVD” state. Within each health state, patients were at risk of acute events, including coronary revascularisation and hospitalisation for unstable angina pectoris. Patients without CVD entered the model in the “Alive without CVD” state (primary prevention cohort), whereas patients with documented CVD commenced in the “Alive with CVD” state (secondary prevention cohort). Patients were channelled to the “Dead” state by dying from CVD or non-CVD causes. The model was constructed from the perspective of the UK's NHS, entailing a 20-year time horizon (lifetime) and a 3.5% (± 1.5%) discount rate [24].

For the purpose of our analyses, we considered all lipid-lowering therapies that were approved by the European Medicines Agency (EMA) for primary or secondary cardiovascular prevention after the introduction of statins. Nicotinic acid in combination with laropiprant was excluded based on a negative EMA recommendation after the results of the HPS2-THRIVE study in 2013 [9]. For each drug, we selected the largest cardiovascular outcomes trial (CVOT) in dyslipidaemia patients (Supplementary Table e1). We therefore considered five drugs (ezetimibe, icosapent ethyl, evolocumab, alirocumab, fenofibrate) in our analyses. Only icosapent ethyl and fenofibrate were analysed for primary cardiovascular prevention as ezetimibe, evolocumab, and alirocumab were not yet evaluated in patients without established CVD. Until this point there were no completed CVOT for bile acid sequestrants, inclisiran, bempedoic acid, and other investigational new drugs.

The European Society of Cardiology guidelines recommend to escalate lipid-lowering treatments from moderate-/high-intensity statins to moderate-/high-intensity statins in combination with an adjunct therapeutic for patients with refractory elevated blood lipids [11]. Therefore, moderate-/high-intensity statin monotherapy, e.g., simvastatin (20–40 mg), atorvastatin (40–80 mg), rosuvastatin (20–40 mg), was set as the comparator. This also reflects the average baseline patient population in each drug’s underlying CVOT (Supplementary Table e1).

Transition probabilities were calculated based on the CVOT results for icosapent ethyl (REDUCE-IT), evolocumab (FOURIER), alirocumab (ODYSSEY), ezetimibe (IMPROVE-IT), and fenofibrate (ACCORD) [5‐8, 10]. First, hazard ratios for each acute event, non-CVD death, and CVD death were extracted from the respective trials (Table 1). Second, endpoints were converted to annual transition probabilities using the median follow-up of each CVOT (Supplementary Table e2), coherent with previous cost-effectiveness studies [16, 25].

For icosapent ethyl and fenofibrate, CVOT reported distinct endpoints in patients with and without established CVD. Consequently, separate transition probabilities for primary and secondary cardiovascular prevention were estimated based on the underlying CVD prevalence, the overall MACE reduction, and the occurrence of acute events in patients with and without established CVD [16]. For ezetimibe, evolocumab, and alirocumab, CVOT only reported endpoints in patients with established CVD. Therefore, these therapies were only evaluated for secondary cardiovascular prevention setting. Similar to previous studies, baseline transition probabilities were multiplied by + 10% and + 14% annually to model the age-dependent increased risk of non-CVD and CVD events, respectively [23].

Patients commenced the simulation at 63 years of age, which equals to the weighted-average age of the patient population studied in all considered CVOT.

The healthcare expenditure of cardiovascular events in patients with dyslipidaemia was obtained from peer-reviewed literature. Costs for the “Alive without CVD” state of £2497 per year were based on healthcare expenditure in dyslipidaemia patients without history of any cardiovascular event [26]. These costs are based on a retrospective cohort study of 24,093 patients over 6 years in the UK. Costs for acute events amounted to £7842 for non-fatal MI, £11,512 for non-fatal stroke, £3517 for unstable angina, and £7337 for coronary revascularisation [27, 28]. Spending for the “Alive with CVD” state of £3466 per year was based on the treatment cost of patients with established CVD, e.g., after MI, stroke, angina pectoris, and associated comorbidities, e.g., arterial hypertension, diabetes mellitus, and chronic kidney diseases [27, 28]. Costs for non-CVD deaths were estimated at £2734 based on the NHS expense during the last 90 days of life weighted by the location of death [29, 30]. The incremental cost of dying from CVD compared to non-CVD causes was estimated at £3558 [28]. All costs are presented in 2021 Great British Pounds (£).

List prices for all lipid-lowering drugs were obtained from the British National Formulary to calculate annual treatment costs [31], which amounted to £357 for statin (weighted-average cost of generic statins for high-intensity treatment), £346 for ezetimibe, £2064 for icosapent ethyl (manufacturer guidance), £4423 for evolocumab, £4412 for alirocumab, and £141 for fenofibrate.

Health-related quality of life (HRQoL) values, measured by the EQ-5D-5L index, were assigned to each health state. Patients in the “Alive without CVD” state were assigned an average age-specific HRQoL value of the overall English population obtained from the longitudinal General Practice Patient Survey (GPPS) with 1,416,793 responses [32]. The HRQoL was reduced by − 0.08 in the “Alive with CVD” state [33]. A HRQoL of 0 was allocated to the “Dead” state. HRQoL values were further reduced contingent on the incidence of acute cardiovascular events: − 0.04 for non-fatal MI, − 0.12 for non-fatal stroke, − 0.09 for hospitalisation for angina, and − 0.01 for coronary revascularisation [16].

We calculated the incremental cost-effectiveness ratios (ICERs) per quality-adjusted life years (QALY) and life years (LY) for each adjunct lipid-lowering drug compared to statin monotherapy. We also contrasted numbers needed to treat (NNT) for each cardiovascular event across treatment alternatives.

Several sensitivity analyses were conducted to assess the robustness of calculated outcomes. First, a univariate (deterministic) sensitivity analysis evaluates the impact of variations in a distinct input parameter on ICERs. Variability in drug prices, discount rates, time horizon, and mortality trends were assessed in a scenario analysis. Drugs' differential efficacy in patient populations was explored in a subgroup analysis. A probabilistic sensitivity analysis (PSA) evaluates the impact of simultaneous variations in input parameters on results. Base case point estimates were therefore sampled 1000 times from their defined distribution (Table 1) to estimate 95% confidence intervals (CI) for ICERs. Based on the PSA, we estimated the probability that a treatment is cost effective at the UK’s willingness-to-pay (WTP) threshold of £20,000 to £30,000 per QALY. Finally, the impact of drug prices on the calculated ICERs was investigated in a pricing analysis.

Univariate, scenario, probabilistic, WTP, and pricing analyses were conducted to evaluate the robustness of base case results under varying input values and different settings.

Protein convertase subtilisin/kexin type 9 serine protease inhibitors reduce the risk of MACE by 15%, in contrast to an observed risk reduction of 6% provided by ezetimibe [5‐7]. However, PCSK9 inhibitors are costly with list prices around £4400 per year in the UK, causing ICERs to exceed the NHS’ established cost-effectiveness threshold of £20,000 to £30,000 per QALY. Consequently, PCSK9 inhibitors are a “double edged sword” in the treatment of dyslipidaemia patients. Whilst increasing available therapeutic options to patients, pharmaceutical companies demand steep prices for the limited observed efficacy [6].

Consistent with our results, the NHS concluded that both PCSK9 inhibitors are not cost effective at annual treatment costs around £4400 [34, 35]. The committee demanded discounts in undisclosed magnitude alongside prescribing restrictions. Our analyses suggest that discounts beyond − 37% are necessary for PCSK9 inhibitors to be cost effective. Prescription is restricted to patients with established CVD, a high risk of acute cardiovascular events, and LDL-C levels above 135 mg/dL (3.5 mmol/L). Incremental cost-effectiveness ratios can be substantially lowered by reducing prices and restricting prescription to at-risk patients as analyses in the USA demonstrate [22, 36]. Similarly, our subgroup analysis demonstrates lower ICERs among patients with baseline LDL-C levels of ≥ 100 mg/dL for evolocumab (ICER = £63,600 per QALY) and alirocumab (ICER = £44,851 per QALY).

In line with our results, meta-analyses reviewing the cost effectiveness of lipid-lowering therapeutics across the globe concluded that ezetimibe is cost effective, in contrast to PCSK9 inhibitors, which are not cost-effective [25, 37‐39]. Only one of ten studies (10%) evaluated PCSK9 inhibitors as cost effective, compared to five out of eight (63%) for ezetimibe [25]. Previous studies required discounts of − 20% to − 88% on PCSK9 inhibitors' list prices to achieve cost effectiveness [39]. Although the clinical economics of PCSK9 inhibitors are well established in developed nations, evidence from low-income countries is scarce [37].

The REDUCE-IT and JELIS trials alongside recent meta-analyses demonstrate that icosapent ethyl reduces the risk of MACE by up to 25% in patients with elevated triglyceride levels despite statin therapy in a dose-dependent manner [8, 40, 41]. Informed by these CVOT, studies evaluated the cost-effectiveness of icosapent ethyl in Germany, the USA, Australia, Canada, and Japan [16‐21, 23].

In Germany, Michaeli et al assessed icosapent ethyl as a cost-effective use of resources compared to statin monotherapy based on ICERs of €18,133 per QALY for primary and €14,485 per QALY for secondary cardiovascular prevention [23]. The US Institute for Clinical and Economic Review and Weintraub et al concluded icosapent ethyl is cost effective at the US WTP threshold of USD50,000 per QALY with ICERs ranging from USD18,000 to 36,118 per QALY [17, 19]. Ademi et al considered icosapent ethyl cost effective at the Australian WTP threshold of AUD50,000 per QALY, especially for secondary prevention [16]. They calculated an ICER of AUD45,036 per QALY using a Markov model simulation based on annual treatment costs of AUD1637. In contrast, Gao et al calculated an ICER of AUD59,036 per QALY based on annual treatment costs of AUD3768 [18].

Similar to Australia, icosapent ethyl’s clinical economics remain disputed in Canada. Lachaine et al calculated an ICER of CAD42,797 per QALY, whilst the Canadian Agency for Drugs and Technologies in Health (CADTH) calculated an ICER of CAD105,053 per QALY and therefore demanded a price discount of − 43% to reach the Canadian WTP threshold of CAD50,000 per QALY [20, 21]. Kodera et al assessed icosapent ethyl as cost effective for primary, yet not secondary prevention in Japan [42]. However, they derive transition probabilities based on a MACE reduction of 19% observed in the Japanese JELIS trial, which treated patients with 1.8 g eicosapentaenoic acid (EPA) per day [40, 42]. Consequently, icosapent ethyl's ICER is likely lower at treatment doses of 4 g per day in Japan considering the observed dose-dependent MACE reduction [41].

Cost-effectiveness studies conducted in Germany, the USA, Australia, Canada, and Japan are coherent with our results in the UK. Icosapent ethyl is cost effective for cardiovascular prevention at the UK’s WTP of £25,000 per QALY. The clinical and economic value is especially favourable in secondary prevention (ICER = £13,285 per QALY). Furthermore, the conducted subgroup analysis demonstrates that an early therapeutic intervention in patients younger than 65 years substantially lowers ICERs. Additionally, targeting at-risk patients with elevated triglycerides (≥ 200 mg/dL) at low HDL-C levels (≤ 35 mg/dL) reduces icosapent ethyl's ICERs.

Fenofibrate is an off-patent drug that is available for £141 per year, yet yields additional QALY and LY gains for patients. Consequently, their observed negative ICERs were expected. Clinicians must consider the economic savings that generic drugs offer to the healthcare system in their prescription behaviour.

First, long-term efficacy data are not available for all considered lipid-lowering drugs. We therefore derived annual transition probabilities from aforementioned CVOT with follow-up periods between 2.2 and 6.0 years (Supplementary Table 1), subsequently applied them to a 20-year time horizon, and considered age-specific trends by employing annually increasing CVD risks. Whilst this methodology is widely used in cost-effectiveness studies [16, 25], CVOT with longer follow-up periods are necessary to determine the efficacy and cost of lipid-lowering drugs in clinical practice.

The REDUCE-IT trial compared icosapent ethyl versus mineral oil, raising scientific debate about the potentially overestimated MACE reduction of 25%, which may overvalue its calculated ICER [8, 43]. Nonetheless, icosapent ethyl’s efficacy is underlined by the US Food and Drug Administration (FDA) and EMA regulatory approval.

Our analyses were conducted from the perspective of the UK NHS. Utilities, costs, and WTP thresholds in other countries may vary as previously discussed.

Previous studies evaluated the cost effectiveness of cholesterol-lowering drugs by estimating transition probabilities from national CV observation studies to then simulate each drug’s risk reduction in MACE based on its effect on the surrogate parameter LDL-C. In contrast, we derived transition probabilities and MACE risk reductions from CVOT to adequately capture each drug’s pleiotropic metabolic effects beyond lowering blood lipids, which are particularly important for triglyceride-lowering drugs [8, 10].

Our Markov model assumes immediate treatment intensification. In clinical practice, there remains a significant delay in the intensification and initiation of lipid-lowering treatments, resulting in worse CV outcomes and higher ICER estimates [44].

Finally, adverse events were not considered in our model. Future analyses should evaluate the clinical economics of triple and quadruple lipid-modifying agents. Moreover, the efficacy and costs of therapy sequence require further investigation, given their importance for physicians in clinical practice.

Coherent with previous meta-analyses [45, 46], this study highlights the lack of CVOT data for the use of ezetimibe and PCSK9 inhibitors in primary cardiovascular prevention. Recent market access strategies reveal that pharmaceutical companies first develop new lipid-modifying agents for rare high-risk patient populations, e.g., familial hypercholesterolaemia. This strategy permits companies to finance costly CVOT, which require the enrolment of several thousand patients, for the secondary CV prevention indication. However, companies may be reluctant to fund further CVOT for primary CV prevention, as the lower efficacy in this indication could lead to insurers demanding rebates on a drug’s overall price. Ultimately, this results in unmet needs of robust trials evaluating the efficacy of lipid-modifying drugs in patients without established CVD. More sophisticated indication-specific pricing, coverage, and reimbursement policies, which align a price per drug indication, could help to overcome this unmet need [47, 48]. Otherwise, academic institutes could support trials for primary CV prevention.

Although the new lipid-modifying treatments in this study were proven to significantly reduce the risk of MACE, adherence to these drugs remains low [44]. Particularly impractical administration routes, side-effects, high drug prices resulting in financial toxicity, and lacking physician/patient education pose significant barriers to long-term compliance. Therefore, clinicians are eagerly awaiting trial results from lipid-modifying agents with more convenient administration routes (oral [NNC0385-0434: NCT04992065] or semi-annual [inclisiran: ORION-4] PCSK9 inhibitors), statin alternatives with fewer side effects (bempedoic acid: CLEAR Outcomes), and novel mechanisms of action (vupanorsen, volanesorsen, pelacarsen, olpasiran). More available therapeutics could permit more individualised patient care and drive down prices by increasing competition.