Cost–Utility Analysis of Inclisiran Added to Standard of Care for Secondary Prevention of Cardiovascular Disease in Egypt: A Public Payer Perspective

Cost–Utility Analysis of Inclisiran Added to Standard of Care for Secondary Prevention of Cardiovascular Disease in Egypt: A Public Payer Perspective | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cost–Utility Analysis of Inclisiran Added to Standard of Care for Secondary Prevention of Cardiovascular Disease in Egypt: A Public Payer Perspective Mahmoud Almezayen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9066799/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Inclisiran, a novel siRNA therapy, offers significant LDL-C reduction, yet its economic value in the Egyptian healthcare system remains unquantified. This study evaluated the cost-utility of adding Inclisiranto standard of care (SoC) for the secondary prevention of cardiovascular disease (CVD) in Egypt. Methods: A Markov cohort model with a lifetime horizon was developed from a public payer perspective. Clinical efficacy was derived from ORION trials, while costs were sourced from local Egyptian hospital tariffs. Uncertainty was explored through deterministic and probabilistic sensitivity analyses (PSA). Results: The base-case ICER was 11,623,189 EGP per QALY gained , far exceeding the Egyptian willingness-to-pay (WTP) threshold of 150,000–450,000 EGP per QALY (1–3× GDP per capita) . Probabilistic sensitivity analysis demonstrated that the probability of Inclisiran being cost-effective remained 0% across the evaluated WTP range . The tornado analysis identified the drug acquisition cost as the primary driver of cost-effectiveness outcomes . Conclusion: At its current list price, Inclisiranis not a cost-effective strategy for the Egyptian public payer. To achieve the 1x GDP threshold (150,000 EGP), a price reduction exceeding 90% (to approximately 3,000–5,000 EGP per dose) is required. Strategic value-based pricing is essential for sustainable integration into the national formulary. Inclisiran · Cost-effectiveness · ICER · PCSK9 inhibitor Atherosclerotic cardiovascular disease LDL-C Markov model Egypt Health technology assessment Willingness-to-pay Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Cardiovascular disease (CVD) represents the leading cause of morbidity and premature mortality worldwide and disproportionately affects low- and middle-income countries, including Egypt 1 National and regional data reveal that ischemic heart disease and stroke constitute a large share of premature mortality in the Egyptian population, hence substantially impacting healthcare consumption and economic burden 2 . Elevated low-density lipoprotein cholesterol (LDL-C) is a recognized causative risk factor for atherosclerotic cardiovascular disease (ASCVD), and aggressive LDL-C reduction is fundamental to secondary prevention. In Egypt, despite the prevalent use of statins, Observational data indicate that a substantial proportion of individuals with established cardiovascular disease in Egypt fail to achieve guideline-recommended LDL-C targets despite statin therapy. 3 Globally lipid management guidelines advocate for high-intensity statin medication as the primary treatment, supplemented by ezetimibe for patients failing to achieve LDL-C targets. 4 Inclisiran is an innovative small interfering RNA (siRNA) therapy that suppresses hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to prolonged decreases in LDL-C levels when administered alongside traditional lipid-lowering treatment. The twice-yearly maintenance schedule, following initial loading doses at baseline and three months, may confer adherence advantages relative to daily oral therapies, particularly in resource-constrained settings. 5 . Several large-scale randomized controlled studies conducted in phase III have shown evidence that Inclisiran is effective in clinical settings. In the ORION-10 and ORION-11 trials, the addition of Inclisiran to maximally tolerated statin medication resulted in around fifty percent decreases in LDL-C levels when compared with placebo 5 . These reductions were observed across patients who had established ASCVD as well as those who were at high cardiovascular risk 5 . As a component of combination lipid-lowering medication, these clinical trials offer substantial evidence that Inclisiran is effective in decreasing LDL-C levels. The clinical efficacy of Inclisiran has been established in extensive randomized studies 6 , although its economic value in the Egyptian healthcare system remains unassessed. Considering limited healthcare budgets and the rising prevalence of cardiovascular disease in Egypt, data on the cost-utility of innovative lipid-lowering medicines is crucial for guiding reimbursement and resource allocation decisions. Regarding the secondary prevention of cardiovascular disease in Egypt, the purpose of this study was to evaluate the cost–utility of Inclisiran added to standard of treatment in comparison with standard of care alone. This evaluation was conducted from the point of view of public payers. Methods Study Design and Perspective A cohort-based Markov model was developed to evaluate the cost-utility of Inclisiran added to standard of care (SOC) compared with SOC alone for the secondary prevention of cardiovascular disease in Egypt. SOC was defined as maximally tolerated high-intensity statins combined with ezetimibe (10 mg), in accordance with international lipid management protocols 7 . For the cost analysis, SOC was specifically modeled as Atorvastatin 40 mg daily plus ezetimibe 10 mg, representing the most frequently prescribed regimen in Egyptian clinical practice 8 . The analysis was conducted from the perspective of a public payer, capturing direct medical costs borne by the Egyptian healthcare system. The model adopted a lifetime horizon to capture long-term clinical and economic outcomes. Future costs and health outcomes were discounted at an annual rate of 3.5%. 9 Willingness-to-Pay Threshold In the absence of an official fixed cost-effectiveness threshold for Egypt, a willingness-to-pay (WTP) range of one to three times the Egyptian Gross Domestic Product (GDP) per capita was adopted, consistent with World Health Organization (WHO) recommendations and recent local health economic guidelines Accordingly, the analysis utilized a WTP threshold range of 150000 to 450000 Egyptian Pounds (EGP) per QALY gained. 10 Target population: The model simulated a hypothetical cohort of adult patients with diagnosed atherosclerotic cardiovascular disease (ASCVD) ideal for secondary prevention. Patients were presumed to exhibit consistently higher low-density lipoprotein cholesterol (LDL-C) values despite undergoing maximally tolerated high-intensity statin medication, with or without ezetimibe, in accordance with the inclusion criteria of the ORION clinical trials. 5 The base-case population was presumed to accurately reflect patients typically treated inside the Egyptian public healthcare system. Upon model entrance, the cohort's mean age was established at 65 years, aligning with the baseline characteristics of the key Phase III trials. 4 , 7 Interventions and Comparator Strategies: The study evaluated two therapy regimens for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients with uncontrolled LDL-C levels. Intervention Arm (Inclisiran with Standard of Care) Patients in the intervention arm received Inclisiran (284 mg) alongside standard of care (SOC). Inclisiran administration was structured according to the approved dosing regimen, comprising a subcutaneous injection at baseline, a subsequent dose at month 3, followed by maintenance doses every 6 months thereafter. This regimen entails two doses in the first year of treatment and two doses annually in subsequent years. Comparator Arm (Standard of Care Alone) The comparator arm represented the prevailing standard of clinical practice. Patients were administered standard of care (SOC) exclusively, characterized as the highest tolerable dosage of high-intensity statin medication in conjunction with ezetimibe (10 mg daily). For cost analysis, statin therapy was presumed to involve atorvastatin 40 mg administered daily. This therapeutic approach aligns with the 2019 ESC/EAS Guideline 4 , which advocate for the incorporation of ezetimibe in patients who do not meet LDL-C objectives with statin therapy alone. 7 Model Structure : A Markov cohort state-transition model was created to assess the cost-utility of Inclisiran in conjunction with standard of care (SOC) against SOC alone in patients with established atherosclerotic cardiovascular disease (ASCVD) within the Egyptian healthcare context. The research was performed over a lifetime horizon to assess the long-term clinical and economic implications of lipid-lowering therapy. 11 Model Health States : The model consisted of five mutually exclusive health states, as depicted in Fig. 1: Stable ASCVD (Event-Free): The initial condition for all patients, denoting individuals with confirmed cardiovascular disease who have not encountered a new event during the current cycle. Post-Myocardial Infarction (Post-MI): Refers to people who have undergone a non-fatal myocardial infarction and have survived. Post-Stroke: Refers to patients who have endured a non-fatal ischemic stroke and have survived. Cardiovascular Death (CV Death): A definitive state denoting fatalities resulting from cardiovascular causes. Non-Cardiovascular Death (Non-CV Death): A definitive state denoting fatalities from all other causes, derived from age- and sex-specific mortality rates in Egypt. 11 Transitions and Cycle length The model utilized a 1-year cycle length, aligning with the chronic characteristics of ASCVD and established pharmacoeconomic methodology .A half-cycle correction was applied to account for the discrete approximation of continuous event timing within each annual cycle. 12 During each cycle, people in the Stable ASCVD state may remain free of events, have a non-fatal myocardial infarction or non-fatal stroke, or progress to death (cardiovascular or non-cardiovascular). Patients in the post-myocardial infarction or post-stroke phases may persist in their existing conditions, have a recurrent cardiovascular event, or progress to a state of mortality. 13 Clinical Inputs, Transition Probabilities, and Treatment Efficacy Patient movement within the Markov model was determined by annual transition probabilities governing progression between health states 14 . In each cycle, patients in the Stable ASCVD state were at risk of experiencing a non-fatal myocardial infarction (MI), a non-fatal ischemic stroke, cardiovascular death (CV death), or non-cardiovascular death (non-CV death). For the standard of care (SOC) arm, baseline annual transition probabilities representing underlying disease progression were obtained from established cardiovascular risk models and previously published economic evaluations in secondary prevention settings. 4 , 7 Age-specific non-cardiovascular mortality was incorporated using Egyptian life-table data derived from the World Health Organization (WHO), thereby ensuring consistency with local population demographics. 2 , 11 Cardiovascular mortality was modeled as a proportion of total mortality based on published epidemiologic evidence 15 . For the intervention arm (Inclisiran added to SOC), treatment efficacy was modeled through its effect on low-density lipoprotein cholesterol (LDL-C) reduction. The mean percentage reduction in LDL-C was derived from the pooled phase III ORION-10 and ORION-11 trials. 5 , 16 To translate LDL-C reduction into cardiovascular event risk modification, a log-linear relationship between LDL-C reduction and major vascular events was applied using rate ratios reported by the Cholesterol Treatment Trialists’ (CTT) Collaboration. 16 This approach assumes that each 1 mmol/L reduction in LDL-C confers a proportional relative risk reduction in major cardiovascular events 17 . The corresponding relative risk reductions were applied multiplicatively to the baseline transition probabilities in the SOC arm to estimate event risks under Inclisiran therapy. 3 , 18 Table 1 Clinical Inputs and Annual Transition Probabilities Parameter Base-Case Value Reference Annual Baseline Risk (Standard of Care) - Non-fatal Myocardial Infarction 0.025 Assumed based on established CVD models 16 , 18 - Non-fatal Ischemic Stroke 0.015 Assumed based on established CVD models 16 , 18 - Cardiovascular Death (CV Death) 0.018 Assumed based on established CVD models 16 , 18 - Background Mortality (Non-CV Death) 0.02 Calibrated to Egyptian WHO Life Tables 1 1 Treatment Efficacy (Relative Risk with Inclisiran) - RR for Myocardial Infarction 0.76 CTT Collaboration / NICE TA733 16,18 - RR for Ischemic Stroke 0.84 CTT Collaboration / NICE TA733 16,18 Health-State Utilities and Quality of Life Health outcomes were expressed in quality-adjusted life-years (QALYs), calculated by assigning preference-based utility weights to each health state. Utility values ranged from 0 (equivalent to death) to 1 (perfect health). Health-state utility values and acute event disutilities applied in the model are presented in Table 2 .The baseline health-related quality of life (HRQoL) associated with the Stable ASCVD state was sourced from published literature reporting EQ-5D index scores in patients with established cardiovascular disease. 19 Table 2 Health-State Utility Values Applied in the Economic Model Health State / Event Utility Source Stable ASCVD (event-free) 0.78 Sullivan & Ghushchyan (2006) 19 Post-Myocardial Infarction 0.72 Sullivan & Ghushchyan (2006) 19 Post-Stroke 0.62 Sullivan & Ghushchyan (2006) 19 Death 0 Assumption Acute cardiovascular events were associated with temporary decrements in HRQoL. Accordingly, transient disutilities were applied during the cycle in which a non-fatal MI or non-fatal ischemic stroke occurred, reflecting short-term deterioration in health status. 1 , 18 Patients surviving an acute event transitioned to the chronic Post-MI or Post-Stroke states. These post-event states were assigned lower long-term utility weights compared with the Stable ASCVD state, capturing persistent functional impairment and reduced quality of life following cardiovascular events. Utility inputs and disutility estimates were aligned with validated cardiovascular economic evaluations and relevant National Institute for Health and Care Excellence (NICE) technology appraisals. 18 Cost Inputs and Resource Use The economic evaluation was conducted from the perspective of the Egyptian public healthcare system. Direct medical costs incorporated into the model were classified into three primary categories: drug acquisition and administration costs, acute cardiovascular event costs, and annual routine health-state management costs. All costs were calculated and reported in Egyptian Pounds (EGP) for the year 2024. Drug Acquisition and Administration Costs The unit acquisition cost for the novel siRNA therapy, Inclisiran (284 mg per pre-filled syringe), was based on the current local Egyptian market price (58,500 EGP per dose). Administration costs per outpatient visit were estimated utilizing standard local public hospital tariffs. For the standard of care (SoC) arm, the annual cost was calculated using the observed local monthly price range for a combination of high-intensity atorvastatin (40 mg) and ezetimibe (10 mg), which ranges from 166 to 807 EGP. A midpoint annualized value of 5,838 EGP was utilized for the base-case analysis, with the minimum and maximum annualized market prices informing the lower and upper bounds for sensitivity testing. Acute Event and Health-State Costs To accurately reflect the current economic burden within the Egyptian healthcare system, the costs associated with acute cardiovascular events and subsequent chronic health states were derived from real-world billing data and standard tariffs of a local tertiary public hospital. The acute event costs for non-fatal myocardial infarction (MI) and non-fatal ischemic stroke encompassed emergency room admission, intensive care unit (ICU) stays, diagnostic procedures (e.g., angiography, MRI), and acute procedural interventions (e.g., percutaneous coronary intervention). Similarly, the annual health-state follow-up costs (for Stable ASCVD, Post-MI, and Post-Stroke states) were estimated based on local clinical practice. These annual costs account for ongoing outpatient specialist visits, routine laboratory investigations (e.g., lipid panels), and necessary cardiovascular rehabilitation services. Table 3 Direct Medical Costs Applied in the Economic Model (in EGP) Cost Parameter Base-case Value (EGP) Lower Bound Upper Bound Reference / Source Drug Acquisition & Administration Inclisiran (per dose) 58500 46800 70200 Local Egyptian market price Inclisiran Administration (per visit) 250 200 300 MOH standard outpatient tariff Standard of Care (Annual) 5838 1992 9684 Local market price range Acute Event Costs (One-off) Acute Myocardial Infarction 45000 36000 54000 Local tertiary hospital billing data Acute Ischemic Stroke 32000 25600 33400 Local tertiary hospital billing data Annual Health-State Costs Stable ASCVD Routine Care 2500 2000 3000 Local clinical expert estimation Post-Myocardial Infarction 4800 3840 5760 Local tertiary hospital billing data Post-Ischemic Stroke 5500 4400 6600 Local tertiary hospital billing data Sensitivity Analyses Both deterministic and probabilistic sensitivity analyses (DSA and PSA) were systematically conducted to evaluate the robustness of the model and account for parameter uncertainty. A one-way DSA was performed to identify the key drivers of the model's outcomes by varying individual parameters—including drug acquisition costs, disease management costs, health-state utilities, and transition probabilities—by ± 20% around their base-case estimates. The impact of these variations on the incremental cost-effectiveness ratio (ICER) was visualized using a Tornado diagram. Furthermore, to assess joint parameter uncertainty, a PSA was executed utilizing a second-order Monte Carlo simulation with 1,000 iterations. In this analysis, all model inputs were varied simultaneously by randomly drawing from predefined statistical distributions (gamma distributions for cost parameters, and beta distributions for utilities and probabilities). Finally, a cost-effectiveness acceptability curve (CEAC) was generated to illustrate the probability of the Inclisiran strategy being cost-effective across a continuum of willingness-to-pay (WTP) thresholds relevant to the Egyptian healthcare context. Results Base-Case Cost-Effectiveness Analysis The deterministic base-case analysis was conducted over a 35-year lifetime horizon for a cohort of 1,000 patients with established ASCVD, comparing the addition of Inclisiran to standard of care (SoC) versus SoC alone. In terms of health outcomes, the model projected that the Inclisiran strategy yielded a total of 9.57 discounted Quality-Adjusted Life Years (QALYs) per patient, whereas the SoC strategy generated 9.44 discounted QALYs. This translates to a marginal incremental health benefit of 0.13 QALYs per patient for the Inclisiran arm, driven by the reduction in non-fatal cardiovascular events. Economically, the total discounted direct medical costs over the lifetime horizon were estimated at 1,608,424 EGP for the Inclisiran arm compared to 127,351 EGP for the SoC arm. The substantial incremental cost associated with the Inclisiran strategy was 1,481,072 EGP. Dividing the incremental costs by the incremental QALYs yielded an Incremental Cost-Effectiveness Ratio (ICER) of 11,623,189 EGP per QALY gained. When compared against the willingness-to-pay (WTP) threshold of one to three times the Egyptian GDP per capita, this ICER significantly exceeds the acceptable limits. Consequently, at its current list price, the addition of Inclisiran to SoC is not considered a cost-effective strategy within the Egyptian public healthcare setting. Table 4 Base-Case Cost-Effectiveness Results (Discounted per patient) Strategy Total Costs (EGP) Incremental Costs (EGP) Total QALYs Incremental QALYs ICER (EGP/QALY) Standard of Care (SoC) 127,351 - 9.44 - - Inclisiran + SoC 1,608,424 1,481,072 9.57 0.13 11,623,189 Probabilistic Sensitivity Analysis (PSA) The results of the probabilistic sensitivity analysis, comprising 1,000 Monte Carlo iterations, were plotted on a cost-effectiveness plane (Fig. 2). The scatter plot demonstrates that 100% of the simulated iterations fell into the North-East (NE) quadrant. This unequivocally indicates that, across all variations of parameter uncertainty, the addition of Inclisiran consistently yielded greater health benefits (higher QALYs) but at a substantially higher cost compared to the standard of care. There were no iterations in the South-East quadrant (dominant strategy), reaffirming that while Inclisiran is clinically superior, its economic viability is entirely dependent on the willingness-to-pay (WTP) threshold and necessitates a substantial price reduction. To further contextualize the probabilistic results against local affordability, a Cost-Effectiveness Acceptability Curve (CEAC) was generated (Fig. 3) The CEAC illustrates the probability of the Inclisiran strategy being cost-effective across a continuum of willingness-to-pay (WTP) thresholds. According to the World Health Organization (WHO) guidelines, a cost-effective intervention in developing countries should fall within one to three times the gross domestic product (GDP) per capita. In the Egyptian context, this acceptable WTP threshold translates to approximately 150,000 to 450,000 EGP per QALY gained 10 . As depicted in the curve, at this locally relevant WTP range (0.15 to 0.45 million EGP), the probability of Inclisiran being cost-effective is absolute zero (0%). The intervention only begins to register a > 0% probability of cost-effectiveness as the threshold unrealistically approaches the base-case ICER of approximately 11.6 million EGP/QALY. This visually reinforces the conclusion that Inclisiran, at its current acquisition list price, is not an economically viable option for the Egyptian public healthcare payer and necessitates a massive price reduction. One-way Deterministic Sensitivity Analysis (DSA) The robustness of the base-case results was further explored through a one-way deterministic sensitivity analysis, presented in the Tornado diagram (Fig. 4). This analysis illustrates the relative impact of individual parameter uncertainty on the incremental cost-effectiveness ratio (ICER). Primary Drivers The acquisition cost of Inclisiran was identified as the most significant driver of the model outcomes. Varying this cost by ± 20% resulted in the widest fluctuation in the ICER, ranging from approximately 9.3 million to 13.9 million EGP per QALY. Secondary Influencers The discount rate (varied between 3% and 5%) and the baseline utility of the stable ASCVD state were the next most influential parameters. High discount rates and lower utility weights adversely impacted the cost-effectiveness profile of the intervention. Robust Parameters The model remained remarkably robust to changes in acute event costs (MI and stroke event costs) and administrative costs, as indicated by the narrow bars at the bottom of the diagram. Conclusion of DSA Across all tested ranges for all parameters, the ICER consistently remained significantly above any plausible willingness-to-pay threshold for the Egyptian healthcare system. This confirms that the current high acquisition price of Inclisiran is the definitive barrier to its cost-effectiveness, regardless of variations in other clinical or economic inputs. Discussion In this first cost-utility analysis of Inclisiran for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) conducted from an Egyptian public payer perspective, the base-case ICER of 11,623,189 EGP per QALY gained exceeded the locally accepted willingness-to-pay (WTP) upper bound of 450,000 EGP per QALY (3× GDP per capita) by approximately 26-fold, and the lower bound of 150,000 EGP per QALY (1× GDP per capita) by approximately 77-fold, 10,11 unequivocally demonstrating that Inclisiran, at its current ex-manufacturer list price, is not cost-effective for the Egyptian public payer. These findings are consistent with an emerging international consensus. In the United Kingdom, NICE (TA733) initially assessed Inclisiran as not cost-effective at list price, ultimately recommending it only following a confidential Patient Access Scheme discount estimated at 70–80%. 20 In Canada, CADTH similarly concluded Inclisiran could not be recommended without substantial price reduction, citing an ICER exceeding the implicit WTP threshold of CAD 50,000 per QALY. 21 In Singapore, the Agency for Care Effectiveness reached an analogous conclusion. 7 This convergence across jurisdictions with markedly different healthcare systems and WTP thresholds strongly suggests the economic challenge is structural and inherent to the current global pricing of Inclisiran. Threshold analysis indicates that achieving cost-effectiveness at the 1× GDP WTP threshold would require a price reduction exceeding 97% from the current list price, to approximately 3,000–5,000 EGP per biannual dose; attaining the 3× GDP threshold would still necessitate a reduction exceeding 90%. 10,11 While these magnitudes appear substantial, they are consistent with confidential rebates negotiated in the United Kingdom, Italy, and Sweden.²¹ The Egyptian Unified Procurement Authority is well-positioned to leverage the country’s considerable epidemiological scale an estimated 2.4 million patients with established ASCVD and suboptimal LDL-C control 3 to negotiate comparable terms through a volume-based pricing agreement. A conditional listing mechanism for a high-priority sub-population, with expansion contingent upon real-world outcomes data, represents a pragmatic framework for the Universal Health Insurance Authority to consider. 22 The incremental health benefit of 0.13 QALYs per patient reflects important methodological constraints. The model derives treatment efficacy exclusively from surrogate endpoint data specifically, the approximately 50% LDL-C reduction observed in the ORION-10 and ORION-11 trials 5 , 6 translated to cardiovascular event-rate reductions using the log-linear relationship established by the Cholesterol Treatment Trialists’ Collaboration. 16 This methodology, employed also in NICE TA733, 18 introduces uncertainty given that Inclisiran currently lacks a dedicated cardiovascular outcomes trial. The ORION-4 trial is anticipated to report primary results in 2025–2026 20 and its data should be incorporated into updated analyses prior to any final formulary decision. Study Limitations: This analysis is subject to several limitations. First, baseline transition probabilities for the Stable ASCVD health state were derived from published international cardiovascular risk models and clinical trial data 13 , 16 due to the absence of validated Egyptian-specific cohort data; population-level cardiovascular event rates in Egypt may differ materially from predominantly European and North American trial populations, representing the most consequential source of structural uncertainty. Second, the health-state utility values were derived from US-based EQ-5D tariff data reported by Sullivan and Ghushchyan 19 as Egyptian-specific preference weights for cardiovascular health states are not currently available in the published literature; the transferability of these US utility tariffs to an Egyptian context has not been validated, introducing additional uncertainty into QALY estimates. Third, the model assumes full treatment adherence and sustained LDL-C reduction across the 35-year horizon. Real-world evidence from PCSK9 inhibitor programmes consistently reports one-year discontinuation rates of 30–40%, 23 and the absence of an adherence discount in the base case likely results in an overestimate of incremental QALY gain and an underestimate of the true ICER. Fourth, this analysis does not include a Budget Impact Analysis (BIA), which is a mandatory component of a complete market access dossier for UPA/UHIA submission per national pharmacoeconomic reporting guidance. 22 A separate BIA quantifying the 3–5-year cumulative budget impact of Inclisiran under a range of uptake and pricing scenarios must be conducted before any formulary submission is advanced. Fifth, the model relies on surrogate endpoint data in the absence of a completed cardiovascular outcomes RCT for Inclisiran; the pending ORION-4 trial results will substantially improve the evidentiary basis for future analyses. 20 Conclusion In conclusion, this economic evaluation demonstrates that Inclisiran, while clinically superior to standard of care alone, does not currently represent a cost-effective use of resources within the Egyptian public healthcare sector. The current ICER of over 11.6 million EGP per QALY is economically unsustainable for the national budget. To facilitate equitable patient access to this innovative therapy, significant strategic interventions are required. We strongly recommend that the Egyptian Ministry of Health and the Universal Health Insurance Authority (UHIA) and Unified Purchasing Authority (UPA) engage in rigorous price-volume negotiations or implement value-based purchasing agreements 22 . A substantial reduction in the acquisition cost is the only viable pathway to integrate Inclisiran into the national formulary without compromising the financial stability of the healthcare system. Declarations Conflicts of Interest : The author declares no conflicts of interest. Funding : This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution M.A.A. conceived the study, developed the economic model, performed all analyses, interpreted the results, and wrote the manuscript. The author reviewed and approved the final version of the manuscript." Data Availability "All data used in this study are derived from published literature, publicly available sources, and local Egyptian hospital tariffs, all of which are fully cited within the manuscript. The model structure, input parameters, and assumptions are transparently reported in the manuscript tables. 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Front Pharmacol. 2025;16:1449712. 10.3389/fphar.2025.1449712 . Inclisiran. (Leqvio): CADTH Reimbursement Recommendation: Indication: For Use as an Adjunct to Lifestyle Changes, Including Diet, to Further Reduce Low-Density Lipoprotein Cholesterol (LDL-C) Level in Adults with Non-Familial Hypercholesterolemia with Atherosclerotic Cardiovascular Disease Who Are on Maximally Tolerated Dose of a Statin, with or without Other LDL-C-Lowering Therapies . Canadian Agency for Drugs and Technologies in Health; 2024. Accessed March 8, 2026. http://www.ncbi.nlm.nih.gov/books/NBK604817/ Gamal M, Sedrak AS, Elsisi GH, et al. National Recommendations for Pharmacoeconomic Evaluations Reporting for Reimbursement and Procurement of New Pharmaceutical Applications in Egypt. Global J Qual Saf Healthc. 2024;7(4):216–23. 10.36401/JQSH-24-12 . Colantonio LD, Rosenson RS, Deng L, et al. Adherence to Statin Therapy Among US Adults Between 2007 and 2014. JAHA. 2019;8(1):e010376. 10.1161/JAHA.118.010376 . 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Almezayen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYDCCAwwMzAwV/+UYGHhI0nKG2ZhELYxtzIkNRGvhu3068XPBGbb0DcfPHnzwgcFOTreBgBbJc7mbpWdU8ORuOJOXbDiDIdnY7AABLQZneDdI85yRyN1wIMdMmofhQOI2IrRs/s3bZpBucP4N8Vq2SfO2JSQY3CDWFkmgFmueMwcMZ954Y2w4w4AIv/ABHXabp+KAPN/5HMMHHyrs5AhqgQMFsEoDYpWDgHwDKapHwSgYBaNgRAEADJVE/iugKHIAAAAASUVORK5CYII=","orcid":"","institution":"Mansoura University","correspondingAuthor":true,"prefix":"","firstName":"Mahmoud","middleName":"","lastName":"Almezayen","suffix":""}],"badges":[],"createdAt":"2026-03-08 22:53:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9066799/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9066799/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104342489,"identity":"8597f7a0-73b0-4d94-b5e8-e7fa9a220326","added_by":"auto","created_at":"2026-03-10 17:03:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69884,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic representation of the Markov model structure for patients with established ASCVD.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9066799/v1/df1e8c1debe1d9f92ab8e7c7.png"},{"id":104405418,"identity":"54fa09ad-402d-4714-bf02-b291a5ac20af","added_by":"auto","created_at":"2026-03-11 12:22:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":93893,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of the probabilistic sensitivity analysis (1,000 iterations) on the cost-effectiveness plane comparing Inclisiran plus standard of care (SoC) versus SoC alone.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9066799/v1/23d8ed2efd4d507222ecfb31.png"},{"id":104342486,"identity":"81e3a01f-7e92-4fd9-8d83-c8054554d228","added_by":"auto","created_at":"2026-03-10 17:03:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":77158,"visible":true,"origin":"","legend":"\u003cp\u003eCost-Effectiveness Acceptability Curve (CEAC) illustrating the probability of Inclisiranplus standard of care being cost-effective across various willingness-to-pay (WTP) thresholds.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9066799/v1/3e297f5ba31eef3369e9a47b.png"},{"id":104342488,"identity":"7b58ea56-5534-40e0-b97e-7017e4e0bc09","added_by":"auto","created_at":"2026-03-10 17:03:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":194659,"visible":true,"origin":"","legend":"\u003cp\u003eTornado diagram of the one-way deterministic sensitivity analysis.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9066799/v1/0a8ced3cb261a3791a089ebc.png"},{"id":107340191,"identity":"73782095-c711-4445-832b-59f00f86884a","added_by":"auto","created_at":"2026-04-20 14:13:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":950907,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9066799/v1/cc0734ac-e3a0-48f7-92b5-3967b49e4af8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cost–Utility Analysis of Inclisiran Added to Standard of Care for Secondary Prevention of Cardiovascular Disease in Egypt: A Public Payer Perspective","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCardiovascular disease (CVD) represents the leading cause of morbidity and premature mortality worldwide and disproportionately affects low- and middle-income countries, including Egypt\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e National and regional data reveal that ischemic heart disease and stroke constitute a large share of premature mortality in the Egyptian population, hence substantially impacting healthcare consumption and economic burden\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eElevated low-density lipoprotein cholesterol (LDL-C) is a recognized causative risk factor for atherosclerotic cardiovascular disease (ASCVD), and aggressive LDL-C reduction is fundamental to secondary prevention. In Egypt, despite the prevalent use of statins, Observational data indicate that a substantial proportion of individuals with established cardiovascular disease in Egypt fail to achieve guideline-recommended LDL-C targets despite statin therapy.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Globally lipid management guidelines advocate for high-intensity statin medication as the primary treatment, supplemented by ezetimibe for patients failing to achieve LDL-C targets. \u003csup\u003e4\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eInclisiran is an innovative small interfering RNA (siRNA) therapy that suppresses hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), leading to prolonged decreases in LDL-C levels when administered alongside traditional lipid-lowering treatment. The twice-yearly maintenance schedule, following initial loading doses at baseline and three months, may confer adherence advantages relative to daily oral therapies, particularly in resource-constrained settings.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSeveral large-scale randomized controlled studies conducted in phase III have shown evidence that Inclisiran is effective in clinical settings. In the ORION-10 and ORION-11 trials, the addition of Inclisiran to maximally tolerated statin medication resulted in around fifty percent decreases in LDL-C levels when compared with placebo\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. These reductions were observed across patients who had established ASCVD as well as those who were at high cardiovascular risk\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. As a component of combination lipid-lowering medication, these clinical trials offer substantial evidence that Inclisiran is effective in decreasing LDL-C levels.\u003c/p\u003e \u003cp\u003eThe clinical efficacy of Inclisiran has been established in extensive randomized studies\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, although its economic value in the Egyptian healthcare system remains unassessed. Considering limited healthcare budgets and the rising prevalence of cardiovascular disease in Egypt, data on the cost-utility of innovative lipid-lowering medicines is crucial for guiding reimbursement and resource allocation decisions.\u003c/p\u003e \u003cp\u003eRegarding the secondary prevention of cardiovascular disease in Egypt, the purpose of this study was to evaluate the cost\u0026ndash;utility of Inclisiran added to standard of treatment in comparison with standard of care alone. This evaluation was conducted from the point of view of public payers.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStudy Design and Perspective\u003c/h2\u003e\n \u003cp\u003eA cohort-based Markov model was developed to evaluate the cost-utility of Inclisiran added to standard of care (SOC) compared with SOC alone for the secondary prevention of cardiovascular disease in Egypt. SOC was defined as maximally tolerated high-intensity statins combined with ezetimibe (10 mg), in accordance with international lipid management protocols\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. For the cost analysis, SOC was specifically modeled as Atorvastatin 40 mg daily plus ezetimibe 10 mg, representing the most frequently prescribed regimen in Egyptian clinical practice\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The analysis was conducted from the perspective of a public payer, capturing direct medical costs borne by the Egyptian healthcare system. The model adopted a lifetime horizon to capture long-term clinical and economic outcomes. Future costs and health outcomes were discounted at an annual rate of 3.5%.\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eWillingness-to-Pay Threshold\u003c/h3\u003e\n\u003cp\u003eIn the absence of an official fixed cost-effectiveness threshold for Egypt, a willingness-to-pay (WTP) range of one to three times the Egyptian Gross Domestic Product (GDP) per capita was adopted, consistent with World Health Organization (WHO) recommendations and recent local health economic guidelines Accordingly, the analysis utilized a WTP threshold range of 150000 to 450000 Egyptian Pounds (EGP) per QALY gained.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eTarget population:\u003c/h3\u003e\n\u003cp\u003eThe model simulated a hypothetical cohort of adult patients with diagnosed atherosclerotic cardiovascular disease (ASCVD) ideal for secondary prevention. Patients were presumed to exhibit consistently higher low-density lipoprotein cholesterol (LDL-C) values despite undergoing maximally tolerated high-intensity statin medication, with or without ezetimibe, in accordance with the inclusion criteria of the ORION clinical trials.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e The base-case population was presumed to accurately reflect patients typically treated inside the Egyptian public healthcare system. Upon model entrance, the cohort\u0026apos;s mean age was established at 65 years, aligning with the baseline characteristics of the key Phase III trials.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eInterventions and Comparator Strategies:\u003c/h3\u003e\n\u003cp\u003eThe study evaluated two therapy regimens for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients with uncontrolled LDL-C levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention Arm (Inclisiran with Standard of Care)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients in the intervention arm received Inclisiran (284 mg) alongside standard of care (SOC). Inclisiran administration was structured according to the approved dosing regimen, comprising a subcutaneous injection at baseline, a subsequent dose at month 3, followed by maintenance doses every 6 months thereafter. This regimen entails two doses in the first year of treatment and two doses annually in subsequent years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparator Arm (Standard of Care Alone)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe comparator arm represented the prevailing standard of clinical practice. Patients were administered standard of care (SOC) exclusively, characterized as the highest tolerable dosage of high-intensity statin medication in conjunction with ezetimibe (10 mg daily). For cost analysis, statin therapy was presumed to involve atorvastatin 40 mg administered daily. This therapeutic approach aligns with the 2019 ESC/EAS Guideline\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, which advocate for the incorporation of ezetimibe in patients who do not meet LDL-C objectives with statin therapy alone.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eModel Structure :\u003c/h3\u003e\n\u003cp\u003eA Markov cohort state-transition model was created to assess the cost-utility of Inclisiran in conjunction with standard of care (SOC) against SOC alone in patients with established atherosclerotic cardiovascular disease (ASCVD) within the Egyptian healthcare context. The research was performed over a lifetime horizon to assess the long-term clinical and economic implications of lipid-lowering therapy.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eModel Health States :\u003c/h2\u003e\n \u003cp\u003eThe model consisted of five mutually exclusive health states, as depicted in Fig. 1:\u003c/p\u003e\n \u003cp\u003eStable ASCVD (Event-Free): The initial condition for all patients, denoting individuals with confirmed cardiovascular disease who have not encountered a new event during the current cycle.\u003c/p\u003e\n \u003cp\u003ePost-Myocardial Infarction (Post-MI): Refers to people who have undergone a non-fatal myocardial infarction and have survived.\u003c/p\u003e\n \u003cp\u003ePost-Stroke: Refers to patients who have endured a non-fatal ischemic stroke and have survived.\u003c/p\u003e\n \u003cp\u003eCardiovascular Death (CV Death): A definitive state denoting fatalities resulting from cardiovascular causes.\u003c/p\u003e\n \u003cp\u003eNon-Cardiovascular Death (Non-CV Death): A definitive state denoting fatalities from all other causes, derived from age- and sex-specific mortality rates in Egypt.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eTransitions and Cycle length\u003c/p\u003e\n \u003cp\u003eThe model utilized a 1-year cycle length, aligning with the chronic characteristics of ASCVD and established pharmacoeconomic methodology .A half-cycle correction was applied to account for the discrete approximation of continuous event timing within each annual cycle.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e During each cycle, people in the Stable ASCVD state may remain free of events, have a non-fatal myocardial infarction or non-fatal stroke, or progress to death (cardiovascular or non-cardiovascular). Patients in the post-myocardial infarction or post-stroke phases may persist in their existing conditions, have a recurrent cardiovascular event, or progress to a state of mortality.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eClinical Inputs, Transition Probabilities, and Treatment Efficacy\u003c/h3\u003e\n\u003cp\u003ePatient movement within the Markov model was determined by annual transition probabilities governing progression between health states\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In each cycle, patients in the Stable ASCVD state were at risk of experiencing a non-fatal myocardial infarction (MI), a non-fatal ischemic stroke, cardiovascular death (CV death), or non-cardiovascular death (non-CV death).\u003c/p\u003e\n\u003cp\u003eFor the standard of care (SOC) arm, baseline annual transition probabilities representing underlying disease progression were obtained from established cardiovascular risk models and previously published economic evaluations in secondary prevention settings.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Age-specific non-cardiovascular mortality was incorporated using Egyptian life-table data derived from the World Health Organization (WHO), thereby ensuring consistency with local population demographics.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003eCardiovascular mortality was modeled as a proportion of total mortality based on published epidemiologic evidence\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eFor the intervention arm (Inclisiran added to SOC), treatment efficacy was modeled through its effect on low-density lipoprotein cholesterol (LDL-C) reduction. The mean percentage reduction in LDL-C was derived from the pooled phase III ORION-10 and ORION-11 trials.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e To translate LDL-C reduction into cardiovascular event risk modification, a log-linear relationship between LDL-C reduction and major vascular events was applied using rate ratios reported by the Cholesterol Treatment Trialists\u0026rsquo; (CTT) Collaboration.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e This approach assumes that each 1 mmol/L reduction in LDL-C confers a proportional relative risk reduction in major cardiovascular events\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The corresponding relative risk reductions were applied multiplicatively to the baseline transition probabilities in the SOC arm to estimate event risks under Inclisiran therapy.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical Inputs and Annual Transition Probabilities\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBase-Case Value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAnnual Baseline Risk (Standard of Care)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- Non-fatal Myocardial Infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssumed based on established CVD models \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- Non-fatal Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssumed based on established CVD models \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- Cardiovascular Death (CV Death)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssumed based on established CVD models \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- Background Mortality (Non-CV Death)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCalibrated to Egyptian WHO Life Tables\u0026nbsp;1\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment Efficacy (Relative Risk with Inclisiran)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- RR for Myocardial Infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCTT Collaboration / NICE TA733 \u003csup\u003e16,18\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e- RR for Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCTT Collaboration / NICE TA733 \u003csup\u003e16,18\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eHealth-State Utilities and Quality of Life\u003c/h3\u003e\n\u003cp\u003eHealth outcomes were expressed in quality-adjusted life-years (QALYs), calculated by assigning preference-based utility weights to each health state. Utility values ranged from 0 (equivalent to death) to 1 (perfect health). Health-state utility values and acute event disutilities applied in the model are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.The baseline health-related quality of life (HRQoL) associated with the Stable ASCVD state was sourced from published literature reporting EQ-5D index scores in patients with established cardiovascular disease.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eHealth-State Utility Values Applied in the Economic Model\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHealth State / Event\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUtility\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSource\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStable ASCVD (event-free)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan \u0026amp; Ghushchyan (2006)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-Myocardial Infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan \u0026amp; Ghushchyan (2006)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSullivan \u0026amp; Ghushchyan (2006)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAssumption\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAcute cardiovascular events were associated with temporary decrements in HRQoL. Accordingly, transient disutilities were applied during the cycle in which a non-fatal MI or non-fatal ischemic stroke occurred, reflecting short-term deterioration in health status.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003ePatients surviving an acute event transitioned to the chronic Post-MI or Post-Stroke states. These post-event states were assigned lower long-term utility weights compared with the Stable ASCVD state, capturing persistent functional impairment and reduced quality of life following cardiovascular events. Utility inputs and disutility estimates were aligned with validated cardiovascular economic evaluations and relevant National Institute for Health and Care Excellence (NICE) technology appraisals.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eCost Inputs and Resource Use\u003c/h2\u003e\n \u003cp\u003eThe economic evaluation was conducted from the perspective of the Egyptian public healthcare system. Direct medical costs incorporated into the model were classified into three primary categories: drug acquisition and administration costs, acute cardiovascular event costs, and annual routine health-state management costs. All costs were calculated and reported in Egyptian Pounds (EGP) for the year 2024.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDrug Acquisition and Administration Costs\u003c/strong\u003e The unit acquisition cost for the novel siRNA therapy, Inclisiran (284 mg per pre-filled syringe), was based on the current local Egyptian market price (58,500 EGP per dose). Administration costs per outpatient visit were estimated utilizing standard local public hospital tariffs. For the standard of care (SoC) arm, the annual cost was calculated using the observed local monthly price range for a combination of high-intensity atorvastatin (40 mg) and ezetimibe (10 mg), which ranges from 166 to 807 EGP. A midpoint annualized value of 5,838 EGP was utilized for the base-case analysis, with the minimum and maximum annualized market prices informing the lower and upper bounds for sensitivity testing.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAcute Event and Health-State Costs\u003c/strong\u003e To accurately reflect the current economic burden within the Egyptian healthcare system, the costs associated with acute cardiovascular events and subsequent chronic health states were derived from real-world billing data and standard tariffs of a local tertiary public hospital. The acute event costs for non-fatal myocardial infarction (MI) and non-fatal ischemic stroke encompassed emergency room admission, intensive care unit (ICU) stays, diagnostic procedures (e.g., angiography, MRI), and acute procedural interventions (e.g., percutaneous coronary intervention).\u003c/p\u003e\n \u003cp\u003eSimilarly, the annual health-state follow-up costs (for Stable ASCVD, Post-MI, and Post-Stroke states) were estimated based on local clinical practice. These annual costs account for ongoing outpatient specialist visits, routine laboratory investigations (e.g., lipid panels), and necessary cardiovascular rehabilitation services.\u003c/p\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDirect Medical Costs Applied in the Economic Model (in EGP)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCost Parameter\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBase-case Value (EGP)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLower Bound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eUpper Bound\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eReference / Source\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDrug Acquisition \u0026amp; Administration\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInclisiran (per dose)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e58500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal Egyptian market price\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInclisiran Administration (per visit)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e250\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e300\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMOH standard outpatient tariff\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStandard of Care (Annual)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1992\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9684\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal market price range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAcute Event Costs (One-off)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAcute Myocardial Infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e36000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e54000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal tertiary hospital billing data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAcute Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e25600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal tertiary hospital billing data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnnual Health-State Costs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStable ASCVD Routine Care\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal clinical expert estimation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-Myocardial Infarction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4800\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3840\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5760\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal tertiary hospital billing data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePost-Ischemic Stroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4400\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocal tertiary hospital billing data\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003eSensitivity Analyses\u003c/h2\u003e\n \u003cp\u003eBoth deterministic and probabilistic sensitivity analyses (DSA and PSA) were systematically conducted to evaluate the robustness of the model and account for parameter uncertainty. A one-way DSA was performed to identify the key drivers of the model\u0026apos;s outcomes by varying individual parameters\u0026mdash;including drug acquisition costs, disease management costs, health-state utilities, and transition probabilities\u0026mdash;by \u0026plusmn;\u0026thinsp;20% around their base-case estimates. The impact of these variations on the incremental cost-effectiveness ratio (ICER) was visualized using a Tornado diagram.\u003c/p\u003e\n \u003cp\u003eFurthermore, to assess joint parameter uncertainty, a PSA was executed utilizing a second-order Monte Carlo simulation with 1,000 iterations. In this analysis, all model inputs were varied simultaneously by randomly drawing from predefined statistical distributions (gamma distributions for cost parameters, and beta distributions for utilities and probabilities). Finally, a cost-effectiveness acceptability curve (CEAC) was generated to illustrate the probability of the Inclisiran strategy being cost-effective across a continuum of willingness-to-pay (WTP) thresholds relevant to the Egyptian healthcare context.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eBase-Case Cost-Effectiveness Analysis\u003c/h2\u003e\n \u003cp\u003eThe deterministic base-case analysis was conducted over a 35-year lifetime horizon for a cohort of 1,000 patients with established ASCVD, comparing the addition of Inclisiran to standard of care (SoC) versus SoC alone.\u003c/p\u003e\n \u003cp\u003eIn terms of health outcomes, the model projected that the Inclisiran strategy yielded a total of 9.57 discounted Quality-Adjusted Life Years (QALYs) per patient, whereas the SoC strategy generated 9.44 discounted QALYs. This translates to a marginal incremental health benefit of 0.13 QALYs per patient for the Inclisiran arm, driven by the reduction in non-fatal cardiovascular events.\u003c/p\u003e\n \u003cp\u003eEconomically, the total discounted direct medical costs over the lifetime horizon were estimated at 1,608,424 EGP for the Inclisiran arm compared to 127,351 EGP for the SoC arm. The substantial incremental cost associated with the Inclisiran strategy was 1,481,072 EGP.\u003c/p\u003e\n \u003cp\u003eDividing the incremental costs by the incremental QALYs yielded an Incremental Cost-Effectiveness Ratio (ICER) of 11,623,189 EGP per QALY gained. When compared against the willingness-to-pay (WTP) threshold of one to three times the Egyptian GDP per capita, this ICER significantly exceeds the acceptable limits. Consequently, at its current list price, the addition of Inclisiran to SoC is not considered a cost-effective strategy within the Egyptian public healthcare setting.\u003c/p\u003e\n \u003cdiv\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eBase-Case Cost-Effectiveness Results (Discounted per patient)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStrategy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal Costs (EGP)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIncremental Costs (EGP)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal QALYs\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIncremental QALYs\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eICER (EGP/QALY)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStandard of Care (SoC)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e127,351\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclisiran + SoC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1,608,424\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1,481,072\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e11,623,189\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eProbabilistic Sensitivity Analysis (PSA)\u003c/h2\u003e\n \u003cp\u003eThe results of the probabilistic sensitivity analysis, comprising 1,000 Monte Carlo iterations, were plotted on a cost-effectiveness plane (Fig. 2). The scatter plot demonstrates that 100% of the simulated iterations fell into the North-East (NE) quadrant. This unequivocally indicates that, across all variations of parameter uncertainty, the addition of Inclisiran consistently yielded greater health benefits (higher QALYs) but at a substantially higher cost compared to the standard of care. There were no iterations in the South-East quadrant (dominant strategy), reaffirming that while Inclisiran is clinically superior, its economic viability is entirely dependent on the willingness-to-pay (WTP) threshold and necessitates a substantial price reduction.\u003c/p\u003e\n \u003cp\u003eTo further contextualize the probabilistic results against local affordability, a Cost-Effectiveness Acceptability Curve (CEAC) was generated (Fig. 3)\u003c/p\u003e\n \u003cp\u003eThe CEAC illustrates the probability of the Inclisiran strategy being cost-effective across a continuum of willingness-to-pay (WTP) thresholds. According to the World Health Organization (WHO) guidelines, a cost-effective intervention in developing countries should fall within one to three times the gross domestic product (GDP) per capita. In the Egyptian context, this acceptable WTP threshold translates to approximately 150,000 to 450,000 EGP per QALY gained\u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e\n \u003cp\u003eAs depicted in the curve, at this locally relevant WTP range (0.15 to 0.45\u0026nbsp;million EGP), the probability of Inclisiran being cost-effective is absolute zero (0%). The intervention only begins to register a \u0026gt; 0% probability of cost-effectiveness as the threshold unrealistically approaches the base-case ICER of approximately 11.6\u0026nbsp;million EGP/QALY. This visually reinforces the conclusion that Inclisiran, at its current acquisition list price, is not an economically viable option for the Egyptian public healthcare payer and necessitates a massive price reduction.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\"\u003e\n \u003ch2\u003eOne-way Deterministic Sensitivity Analysis (DSA)\u003c/h2\u003e\n \u003cp\u003eThe robustness of the base-case results was further explored through a one-way deterministic sensitivity analysis, presented in the Tornado diagram (Fig. 4). This analysis illustrates the relative impact of individual parameter uncertainty on the incremental cost-effectiveness ratio (ICER).\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Drivers\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe acquisition cost of \u003cstrong\u003eInclisiran\u003c/strong\u003e was identified as the most significant driver of the model outcomes. Varying this cost by ± 20% resulted in the widest fluctuation in the ICER, ranging from approximately 9.3 million to 13.9 million EGP per QALY.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary Influencers\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe discount rate (varied between 3% and 5%) and the baseline utility of the stable ASCVD state were the next most influential parameters. High discount rates and lower utility weights adversely impacted the cost-effectiveness profile of the intervention.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRobust Parameters\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eThe model remained remarkably robust to changes in acute event costs (MI and stroke event costs) and administrative costs, as indicated by the narrow bars at the bottom of the diagram.\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eConclusion of DSA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAcross all tested ranges for all parameters, the ICER consistently remained significantly above any plausible willingness-to-pay threshold for the Egyptian healthcare system. This confirms that the current high acquisition price of Inclisiran is the definitive barrier to its cost-effectiveness, regardless of variations in other clinical or economic inputs.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this first cost-utility analysis of Inclisiran for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) conducted from an Egyptian public payer perspective, the base-case ICER of 11,623,189 EGP per QALY gained exceeded the locally accepted willingness-to-pay (WTP) upper bound of 450,000 EGP per QALY (3\u0026times; GDP per capita) by approximately 26-fold, and the lower bound of 150,000 EGP per QALY (1\u0026times; GDP per capita) by approximately 77-fold,\u003csup\u003e10,11\u003c/sup\u003e unequivocally demonstrating that Inclisiran, at its current ex-manufacturer list price, is not cost-effective for the Egyptian public payer.\u003c/p\u003e \u003cp\u003eThese findings are consistent with an emerging international consensus. In the United Kingdom, NICE (TA733) initially assessed Inclisiran as not cost-effective at list price, ultimately recommending it only following a confidential Patient Access Scheme discount estimated at 70\u0026ndash;80%.\u003csup\u003e20\u003c/sup\u003e In Canada, CADTH similarly concluded Inclisiran could not be recommended without substantial price reduction, citing an ICER exceeding the implicit WTP threshold of CAD 50,000 per QALY.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e In Singapore, the Agency for Care Effectiveness reached an analogous conclusion.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e This convergence across jurisdictions with markedly different healthcare systems and WTP thresholds strongly suggests the economic challenge is structural and inherent to the current global pricing of Inclisiran.\u003c/p\u003e \u003cp\u003eThreshold analysis indicates that achieving cost-effectiveness at the 1\u0026times; GDP WTP threshold would require a price reduction exceeding 97% from the current list price, to approximately 3,000\u0026ndash;5,000 EGP per biannual dose; attaining the 3\u0026times; GDP threshold would still necessitate a reduction exceeding 90%.\u003csup\u003e10,11\u003c/sup\u003e While these magnitudes appear substantial, they are consistent with confidential rebates negotiated in the United Kingdom, Italy, and Sweden.\u0026sup2;\u0026sup1; The Egyptian Unified Procurement Authority is well-positioned to leverage the country\u0026rsquo;s considerable epidemiological scale an estimated 2.4\u0026nbsp;million patients with established ASCVD and suboptimal LDL-C control\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e to negotiate comparable terms through a volume-based pricing agreement. A conditional listing mechanism for a high-priority sub-population, with expansion contingent upon real-world outcomes data, represents a pragmatic framework for the Universal Health Insurance Authority to consider.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe incremental health benefit of 0.13 QALYs per patient reflects important methodological constraints. The model derives treatment efficacy exclusively from surrogate endpoint data specifically, the approximately 50% LDL-C reduction observed in the ORION-10 and ORION-11 trials \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e translated to cardiovascular event-rate reductions using the log-linear relationship established by the Cholesterol Treatment Trialists\u0026rsquo; Collaboration.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e This methodology, employed also in NICE TA733,\u003csup\u003e18\u003c/sup\u003e introduces uncertainty given that Inclisiran currently lacks a dedicated cardiovascular outcomes trial. The ORION-4 trial is anticipated to report primary results in 2025\u0026ndash;2026\u003csup\u003e20\u003c/sup\u003e and its data should be incorporated into updated analyses prior to any final formulary decision.\u003c/p\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eStudy Limitations:\u003c/h2\u003e \u003cp\u003eThis analysis is subject to several limitations. First, baseline transition probabilities for the Stable ASCVD health state were derived from published international cardiovascular risk models and clinical trial data\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e due to the absence of validated Egyptian-specific cohort data; population-level cardiovascular event rates in Egypt may differ materially from predominantly European and North American trial populations, representing the most consequential source of structural uncertainty.\u003c/p\u003e \u003cp\u003eSecond, the health-state utility values were derived from US-based EQ-5D tariff data reported by Sullivan and Ghushchyan\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e as Egyptian-specific preference weights for cardiovascular health states are not currently available in the published literature; the transferability of these US utility tariffs to an Egyptian context has not been validated, introducing additional uncertainty into QALY estimates.\u003c/p\u003e \u003cp\u003eThird, the model assumes full treatment adherence and sustained LDL-C reduction across the 35-year horizon. Real-world evidence from PCSK9 inhibitor programmes consistently reports one-year discontinuation rates of 30\u0026ndash;40%,\u003csup\u003e23\u003c/sup\u003e and the absence of an adherence discount in the base case likely results in an overestimate of incremental QALY gain and an underestimate of the true ICER.\u003c/p\u003e \u003cp\u003eFourth, this analysis does not include a Budget Impact Analysis (BIA), which is a mandatory component of a complete market access dossier for UPA/UHIA submission per national pharmacoeconomic reporting guidance.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e A separate BIA quantifying the 3\u0026ndash;5-year cumulative budget impact of Inclisiran under a range of uptake and pricing scenarios must be conducted before any formulary submission is advanced.\u003c/p\u003e \u003cp\u003eFifth, the model relies on surrogate endpoint data in the absence of a completed cardiovascular outcomes RCT for Inclisiran; the pending ORION-4 trial results will substantially improve the evidentiary basis for future analyses.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this economic evaluation demonstrates that Inclisiran, while clinically superior to standard of care alone, does not currently represent a cost-effective use of resources within the Egyptian public healthcare sector. The current ICER of over 11.6\u0026nbsp;million EGP per QALY is economically unsustainable for the national budget.\u003c/p\u003e \u003cp\u003eTo facilitate equitable patient access to this innovative therapy, significant strategic interventions are required. We strongly recommend that the Egyptian Ministry of Health and the Universal Health Insurance Authority (UHIA) and Unified Purchasing Authority (UPA) engage in rigorous price-volume negotiations or implement value-based purchasing agreements\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. A substantial reduction in the acquisition cost is the only viable pathway to integrate Inclisiran into the national formulary without compromising the financial stability of the healthcare system.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of Interest :\u003c/h2\u003e \u003cp\u003eThe author declares no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding :\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eM.A.A. conceived the study, developed the economic model, performed all analyses, interpreted the results, and wrote the manuscript. The author reviewed and approved the final version of the manuscript.\"\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003e\"All data used in this study are derived from published literature, publicly available sources, and local Egyptian hospital tariffs, all of which are fully cited within the manuscript. The model structure, input parameters, and assumptions are transparently reported in the manuscript tables. No new primary data were collected, and no datasets were deposited in a public repository.\"\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRoth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990\u0026ndash;2019. J Am Coll Cardiol. 2020;76(25):2982\u0026ndash;3021. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jacc.2020.11.010\u003c/span\u003e\u003cspan address=\"10.1016/j.jacc.2020.11.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. \u003cem\u003eEgypt STEPS Survey 2017: Fact Sheet\u003c/em\u003e. 2017:2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaha HSED, Badran HM, Kandil H, et al. Egyptian practical guidance in lipid management 2020. 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National Institute for Health and Care Excellence; 2021. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nice.org.uk/guidance/ta733\u003c/span\u003e\u003cspan address=\"https://www.nice.org.uk/guidance/ta733\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSullivan PW, Ghushchyan V, Preference-Based. EQ-5D Index Scores for Chronic Conditions in the United States. Med Decis Mak. 2006;26(4):410\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/0272989X06290495\u003c/span\u003e\u003cspan address=\"10.1177/0272989X06290495\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarbi MH. Current usage of Inclisiran for cardiovascular diseases: overview of current clinical trials. 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Adherence to Statin Therapy Among US Adults Between 2007 and 2014. JAHA. 2019;8(1):e010376. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/JAHA.118.010376\u003c/span\u003e\u003cspan address=\"10.1161/JAHA.118.010376\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Inclisiran · Cost-effectiveness · ICER · PCSK9 inhibitor, Atherosclerotic cardiovascular disease, LDL-C, Markov model, Egypt, Health technology assessment, Willingness-to-pay","lastPublishedDoi":"10.21203/rs.3.rs-9066799/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9066799/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Inclisiran, a novel siRNA therapy, offers significant LDL-C reduction, yet its economic value in the Egyptian healthcare system remains unquantified. This study evaluated the cost-utility of adding Inclisiranto standard of care (SoC) for the secondary prevention of cardiovascular disease (CVD) in Egypt.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eA Markov cohort model with a lifetime horizon was developed from a public payer perspective. Clinical efficacy was derived from ORION trials, while costs were sourced from local Egyptian hospital tariffs. Uncertainty was explored through deterministic and probabilistic sensitivity analyses (PSA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The base-case ICER was \u003cstrong\u003e11,623,189 EGP per QALY gained\u003c/strong\u003e, far exceeding the Egyptian willingness-to-pay (WTP) threshold of \u003cstrong\u003e150,000–450,000 EGP per QALY (1–3× GDP per capita)\u003c/strong\u003e. Probabilistic sensitivity analysis demonstrated that the probability of Inclisiran being cost-effective \u003cstrong\u003eremained 0% across the evaluated WTP range\u003c/strong\u003e. The tornado analysis identified the \u003cstrong\u003edrug acquisition cost as the primary driver of cost-effectiveness outcomes\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003eAt its current list price, Inclisiranis not a cost-effective strategy for the Egyptian public payer. To achieve the 1x GDP threshold (150,000 EGP), a price reduction exceeding 90% (to approximately 3,000–5,000 EGP per dose) is required. Strategic value-based pricing is essential for sustainable integration into the national formulary.\u003c/p\u003e","manuscriptTitle":"Cost–Utility Analysis of Inclisiran Added to Standard of Care for Secondary Prevention of Cardiovascular Disease in Egypt: A Public Payer Perspective","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-10 17:03:35","doi":"10.21203/rs.3.rs-9066799/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0b68c098-549f-427d-bf6d-37f6a1371a42","owner":[],"postedDate":"March 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T14:12:04+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-10 17:03:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9066799","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9066799","identity":"rs-9066799","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}