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Background: Because of concerns of cost-effectiveness and low utilization, in 2018, manufacturers initiated a 60% price reduction for PCSK9 inhibitors, reducing the list price from more than $14,000 to $5,850. The goal of the reduction was to increase access and lower patient cost sharing for PCSK9 inhibitors., Objective: To determine whether list price reductions resulted in a statistically significant decrease in patient cost sharing for PCSK9 inhibitors. The secondary objective is to quantify the change in monthly out-of-pocket (OOP) cost in the years following the price reduction policies., Methods: This analysis uses a cross-sectional quasi-experimental design, with 2 time periods, to estimate the change in monthly OOP cost. A 2-stage cost model was used to quantify the difference in mean monthly OOP cost between the preprice and postprice reduction periods. This analysis was completed using IQVIA PharMetrics Plus for Academics health plan claims for PSCK9 inhibitors between January 2016 and December 2021 for commercially insured individuals in the United States. The primary exposure of interest is a manufacturer-initiated list price reduction in October 2018. The primary outcome of interest is the difference in the predicted monthly OOP cost between the prereduction and postreduction periods., Results: There was a 50% decrease in the predicted monthly OOP cost, from $235.22 (SD = $241) in the prereduction period to $116.75 (SD = $152) in the postreduction period., Conclusions: This claims level analysis used robust statistical modeling techniques to quantify the effect of manufacturer-initiated price reductions on monthly OOP cost. This unique manufacturer decision resulted in a statistically significant decrease in the monthly OOP cost for beneficiaries using PCSK9 inhibitors. Manufacturer-initiated price reductions could be a strategy to reduce the cost for other therapies with access and cost concerns. Further research is needed on the downstream patient-level effects of cost reductions, particularly among individuals who experience multiple barriers to care.

Objective: We aim to explore the concept of distance and journey to goal, and consideration of these 2 elements a priori when choosing LLT., Methods: Modelling of expected % LDL-C reductions was carried out on a range of hypothetical patients' baseline LDL-C values prior to any LLT being commenced. Therapies were then added in a stepwise manner based on the pathway demonstrated in current national guidance and compared with goal achievement on a novel LLT optimization pathway implemented in Morecambe Bay NHS Trust., Results: Modelling of a stepwise lipid management pathway shows that high-intensity statin monotherapy is not sufficient in most modelled baseline LDL-C scenarios to achieve guideline-recommended goals. Furthermore, ezetimibe second line may preclude 3 rd line injectable prescribing and lead to "ezetimibe limbo" where the patient is now below the reimbursement threshold for injectable prescribing but still not achieving their LDL-C target. Overall goal achievement is poor across the spectrum of modelled LDL-C levels. In contrast, by following the Morecambe Bay pathway all patients on statin for the range of hypothetical baseline LDL-C levels can reach an LDL-C target of < 1.8 mmol/L., Conclusions: This study identifies a therapeutic gap when following a stepwise approach highlighted by recent national guidance. Our proposal of a novel pathway highlights that the order in which drugs are added is important in the context of national reimbursement thresholds and allows LDL-C goal to be reached in a timely manner, regardless of the starting baseline LDL-C level.

Background: PCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China's National Reimbursement Drug List through the National Drug Price Negotiation (NDPN) policy. This study aims to evaluate the impact of the NDPN policy on the utilization and accessibility of these two PCSK9 inhibitors., Methods: The procurement data of evolocumab and alirocumab were collected from 1,519 hospitals between January 2021 and December 2022. We determined the monthly availability, utilization, cost per daily defined dose (DDDc), and affordability of the two medicines. Single-group interrupted time series (ITS) analysis was performed to assess the impact of the NDPN policy on each drug, and multiple-group ITS analysis was performed to compare the differences between them., Results: The NDPN policy led to a significant and sudden increase in the availability and utilization of PCSK9 inhibitors, along with a decrease in their DDDc. In the year following the policy implementation, there was an increase in the availability, utilization, and spending, and the DDDc remained stable. The affordability of PCSK9 inhibitors in China have been significantly improved, with a 92.97% reduction in out-of-pocket costs. The availability of both PCSK9 inhibitors was similar, and the DDDc of alirocumab was only $0.23 higher after the intervention. The market share of evolocumab consistently exceeded that of alirocumab. Regional disparities in utilization were observed, with higher utilization in the eastern region and a correlation with per capita disposable income., Conclusions: The NDPN policy has successfully improved the accessibility and utilization of PCSK9 inhibitors in China. However, regional disparities in utilization indicate the need for further interventions to ensure equitable medicine access., (© 2024. The Author(s).)

Introduction: Familial hypercholesterolemia is a common genetic condition that significantly increases an individual's risk of cardiovascular events such as heart attack, stroke, and cardiac death and is a candidate for population-wide screening programs. Economic analyses of strategies to identify and treat familial hypercholesterolemia are limited by a lack of real-world cost estimates for screening services and medications for reducing cardiovascular risk in this population., Methods: We estimated the cost of lipid panel testing in patients with hyperlipidemia and the cost of statins, ezetimibe, and PCKS9 inhibitors in patients with familial hypercholesterolemia from a commercial claims database and report costs and charges per panel and prescription by days' supply., Results: The mean cost for a 90-day supply for statins was $183.33, 2.3 times the mean cost for a 30-day supply at $79.35. PCSK9 inhibitors generated the highest mean costs among medications used by patients with familial hypercholesterolemia., Conclusions: Lipid testing and lipid-lowering medications for cardiovascular disease prevention generate substantial real-world costs which can be used to improve cost-effectiveness models of familial hypercholesterolemia screening and care management., (© 2024. Italian Society of Hypertension.)

Introduction: Proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) are monoclonal antibodies that lower lipid levels. Although several cardiovascular outcome trials reported the effectiveness of PCSK9i, the evidence on cost-effectiveness is mixed. We systematically reviewed the evidence and synthesized incremental net benefit (INB) to quantify pooled cost-effectiveness., Methods: We systematically searched for full economic evaluation studies reporting outcomes of PCSK9i compared with other lipid-lowering pharmacotherapies. We searched PubMed, Embase, Scopus, and Tufts Registry for eligible studies up to August 2021, adhering to preferred reporting items for systematic reviews and meta-analyses guidelines. We pooled INB in US$ with a 95% confidence interval using a random-effects model. We assessed heterogeneity using the Cochran Q test and I 2 statistics. We used the modified economic evaluations bias (ECOBIAS) checklist to evaluate the quality of selected studies., Results: Twenty-three studies were eligible, mainly from high-income countries (HIC). The pooled INB (INBp) of PCSK9i versus other lipid-lowering pharmacotherapies were estimated from n = 24 comparisons, with high heterogeneity (I 2  = 99.99). The INBp (95% CI) was $ - 78,207 (- 120,422; - 35,993) or € - 52,526 (- 80,879; - 24,174) (conversion factor 1 US$ = 0.67€) which shows that PCSK9i was not significantly cost-effective when compared to other standard therapies. On subgroup analysis PCSK9i was significantly not cost-effective [$ - 23,672 (- 24,061; - 23,282)] compared to other lipid-lowering pharmacotherapies in HICs, upper-middle-income countries [$ - 158,412 (- 241,738; - 75,086)] or when the target population was CVD [$ - 109,343 (- 158,968; - 59,717)]; and for treatment subgroup: against placebo or no treatment [$ - 79,018 (- 79,649; - 78,388 PCSK9)] and standard statin therapies [$ - 131,833 (- 173,449; - 90,216)]. The sensitivity analysis revealed that the findings are not robust for HICs and the treatment subgroups., Conclusion: PCSK9 inhibitors are not cost-effective compared to other lipid-lowering pharmacotherapies in HICs. Further, current pieces of evidence are predominantly from HICs with largely lacking evidence from other economies., Prospero Registration: ID CRD42020206043., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Hypertrophic cardiomyopathy (HCM) and left ventricular hypertrophy (LVH) secondary to systemic hypertension (HTN) may be associated with left atrial (LA) functional abnormalities., Objectives: We aimed to characterize LA mechanics in HCM and HTN and determine any correlation with the extent of left ventricular (LV) fibrosis measured by cardiac magnetic resonance (CMR) in HCM patients., Methods: Two-dimensional speckle tracking-derived longitudinal LA function was acquired from apical views in 60 HCM patients, 60 HTN patients, and 34 age-matched controls. HCM patients also underwent CMR, with measurement of late gadolinium enhancement (LGE) extension. Association with LA strain parameters was analyzed. Statistical significance was set at p<0.05., Results: Mean LV ejection fraction was not different between the groups. The E/e' ratio was impaired in the HCM group and preserved in the control group. LA mechanics was significantly reduced in HCM, compared to the HTN group. LA strain rate in reservoir (LASRr) and in contractile (LASRct) phases were the best discriminators of HCM, with an area under the curve (AUC) of 0.8, followed by LA strain in reservoir phase (LASr) (AUC 0.76). LASRr and LASR-ct had high specificity (89% and 91%, respectively) and LASr had sensitivity of 80%. A decrease in 2.79% of LA strain rate in conduit phase (LASRcd) predicted an increase of 1cm in LGE extension (r2=0.42, β 2.79, p=0.027)., Conclusions: LASRr and LASRct were the best discriminators for LVH secondary to HCM. LASRcd predicted the degree of LV fibrosis assessed by CMR. These findings suggest that LA mechanics is a potential predictor of disease severity in HCM.

Purpose: There is limited real-world evidence around use of proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) among US older adults. This study examined baseline characteristics of fee-for-service (FFS) Medicare beneficiaries newly initiating PCSK9i therapy during the period immediately following market availability., Methods: This cross-sectional study used Medicare claims (2013-2016) to identify 5051 FFS Medicare beneficiaries who filled ≥ 1 PCSK9i prescription between August 2015 and December 2016. We analyzed patient demographics, clinical characteristics, and baseline healthcare expenditures in the 12-month period prior to PCSK9i initiation, for these beneficiaries., Results: Most beneficiaries initiating PCSK9i were female (57%), < 75 years of age (61%), white (89%), and lived in metropolitan areas (83%). At baseline, these PCSK9i initiators had 6 chronic conditions on average, with conditions such as hyperlipidemia, hypertension, and ischemic heart disease being most prevalent. Approximately 88% had a diagnosis of atherosclerotic cardiovascular disease (ASCVD), and 14% experienced acute cardiovascular events during the 12-month baseline period. Use of any statin and/or ezetimibe ranged from 54 to 76% in the 6-month and 24-month baseline period. Their total annual Medicare expenditures averaged US$17,552, of which most were attributable to ambulatory care and prescription use, in the 12-month baseline period., Conclusion: High burden of cardiovascular conditions and prescription expenditures at baseline were common among FFS beneficiaries initiating PCSK9i therapy. These findings suggest that physicians prescribe PCSK9i to elderly patients at high risk for adverse cardiovascular events. Considering the evolving treatment landscape, PCSK9i utilization might increase in Medicare., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Financial incentives may improve health behaviors. It is unknown whether incentives are more effective if they target a key process (eg, medication adherence), an outcome (eg, low-density lipoprotein cholesterol [LDL-C] levels), or both., Objective: To determine whether financial incentives awarded daily for process (adherence to statins), awarded quarterly for outcomes (personalized LDL-C level targets), or awarded for process plus outcomes induce reductions in LDL-C levels compared with control., Design, Setting, and Participants: A randomized clinical trial was conducted from February 12, 2015, to October 3, 2018; data analysis was performed from October 4, 2018, to May 27, 2021, at the University of Pennsylvania Health System, Philadelphia. Participants included 764 adults with an active statin prescription, elevated risk of atherosclerotic cardiovascular disease, suboptimal LDL-C level, and evidence of imperfect adherence to statin medication., Interventions: Interventions lasted 12 months. All participants received a smart pill bottle to measure adherence and underwent LDL-C measurement every 3 months. In the process group, daily financial incentives were awarded for statin adherence. In the outcomes group, participants received incentives for achieving or sustaining at least a quarterly 10-mg/dL LDL-C level reduction. The process plus outcomes group participants were eligible for incentives split between statin adherence and quarterly LDL-C level targets., Main Outcomes and Measures: Change in LDL-C level from baseline to 12 months, determined using intention-to-treat analysis., Results: Of the 764 participants, 390 were women (51.2%); mean (SD) age was 62.4 (10.0) years, 310 (40.6%) had diabetes, 298 (39.0%) had hypertension, and mean (SD) baseline LDL-C level was 138.8 (37.6) mg/dL. Mean LDL-C level reductions from baseline to 12 months were -36.9 mg/dL (95% CI, -42.0 to -31.9 mg/dL) among control participants, -40.0 mg/dL (95% CI, -44.7 to -35.4 mg/dL) among process participants, -41.6 mg/dL (95% CI, -46.3 to -37.0 mg/dL) among outcomes participants, and -42.8 mg/dL (95% CI, -47.4 to -38.1 mg/dL) among process plus outcomes participants. In exploratory analysis among participants with diabetes and hypertension, no spillover effects of incentives were detected compared with the control group on hemoglobin A1c level and blood pressure over 12 months., Conclusions and Relevance: In this randomized clinical trial, process-, outcomes-, or process plus outcomes-based financial incentives did not improve LDL-C levels vs control., Trial Registration: ClinicalTrials.gov Identifier: NCT02246959.

Objective: To analyse utilisation patterns of lipid-lowering drugs and the related costs in Switzerland between the years 2013 and 2019., Methods: We conducted a retrospective descriptive study using administrative claims data of persons aged ≥18 years enrolled with the health insurance company Helsana. To enable statements at the Swiss population level, results were extrapolated according to age, sex and canton of residence., Results: The overall prevalence of patients taking lipid-lowering drugs rose from 8.9% (n = 736,174) in 2013 to 11.6% (n = 841,682) in 2019, but varied markedly across regions, with highest values in Ticino and lowest values in Zurich. More than every third individual aged ≥65 years was treated with a lipid-lowering drug in 2019. Statins were by far the most commonly used drugs (>90% of prescriptions), followed by ezetimibe, fibrates and PCSK9 inhibitors. We observed a trend towards the prescription of more potent statins (atorvastatin, rosuvastatin) in recent years. Total costs of lipid-lowering drugs increased from CHF 222 million in 2013 to CHF 230 million in 2019 (+3.5%), whereas annual per capita costs decreased from CHF 302 in 2013 to CHF 273 in 2019 (-9.4%)., Conclusion: The increasing use of lipid-lowering drugs reflects current therapeutic guidelines, but results in high costs for the healthcare system.

Background: People with peripheral artery disease are at a high risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Randomized controlled trials suggest that intensive lowering of low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is an effective strategy to prevent these events. This study estimated the potential benefit and cost-effectiveness of administrating PCSK9 inhibitors to a cohort of participants with peripheral artery disease., Methods: A total of 783 participants with intermittent claudication (IC; n = 582) or chronic limb-threatening ischemia (CLTI; n = 201) were prospectively recruited from three hospitals in Australia. Serum LDL-C was measured at recruitment, and the occurrence of MACE and MALE was recorded over a median (interquartile range) follow-up of 2.2 years (0.3-5.7 years). The potential benefit of administering a PCSK9 inhibitor was estimated by calculating the absolute risk reduction and numbers needed to treat (NNT) based on relative risk reductions reported in published randomized trials. The incremental cost-effectiveness ratio per quality-adjusted life year gained was estimated., Results: Intensive LDL-C lowering was estimated to lead to an absolute risk reduction in MACE of 6.1% (95% confidence interval [CI], 2.0-9.3; NNT, 16) and MALE of 13.7% (95% CI, 4.3-21.5; NNT, 7) in people with CLTI compared with 3.2% (95% CI, 1.1-4.8; NNT, 32) and 5.3% (95% CI, 1.7-8.3; NNT, 19) in people with IC. The estimated incremental cost-effectiveness ratios over a 10-year period were $55,270 USD and $32,800 USD for participants with IC and CLTI, respectively., Conclusions: This analysis suggests that treatment with a PCSK9 inhibitor is likely to be cost-effective in people with CLTI., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: PCSK9 inhibitors were approved by the Food and Drug Administration in 2015 to lower low-density lipoprotein cholesterol (LDL-C) levels. In the years following, additional research findings, changes in national guideline recommendations, and price reductions have occurred., Objective: The goal of the study is to describe the characteristics and trends in PCSK9 inhibitor prescription fills and price, from initial FDA approval in Quarter 3 2015 through Quarter 4 2019, at the national and state levels., Methods: Cross-sectional study of fills obtained using the IQVIA National Prescription Audit®, Extended Insights, New to Brand, and Regional databases. Prescription fills included injections that provided cholesterol-lowering therapy from 14 to 90 days for the two PCSK9 inhibitors: alirocumab (75 mg/mL and 150 mg/mL) or evolocumab (140 mg/mL and 420 mg/3.5 mL). Quarterly prescription fills obtained nationally for Quarter 3 2015 through Quarter 4 2019, by sex, age, and state during 2019., Results: Over the time period examined, 2.75 million PCSK9 inhibitor prescriptions were filled nationally (alirocumab: 38%; evolocumab: 62%), and the average retail price per fill (unadjusted $US) from retail pharmacies decreased by 40% from $1502 to $896 per fill. Year-over-year percent change in new PCSK9 inhibitor users increased throughout the observation period, with 9611 new alirocumab users and 25,381 new evolocumab users in Q4 2019. PCSK9 inhibitor fill rates ranged from 5.6 per 1000 in the Northeast to 3.4 per 1000 in the West in 2019, with the highest rate per 1000 in Louisiana (9.1), and lowest in Wyoming (1.3)., Conclusions: PCSK9 inhibitor prescriptions have increased nationally since 2015, coinciding with additional evidence supporting their use for LDL-C lowering and cardiovascular event reduction. Although the retail price has decreased since introduction, cost and delivery mode likely continue as barriers., (Copyright © 2021 National Lipid Association. All rights reserved.)

Importance: Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are a cornerstone of prevention in atherosclerotic cardiovascular disease. With the introduction of generic formulations and the release of new therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, contemporary Medicare utilization of these therapies remains unknown., Objective: To determine trends in utilization and spending on brand-name and generic LDL-C-lowering therapies and to estimate potential savings if all Medicare beneficiaries were switched to available therapeutically equivalent generic formulations., Design, Setting, and Participants: This cross-sectional study analyzed prescription drug utilization and cost trend data from the Medicare Part D Prescription Drug Event data set from 2014 to 2018 for LDL-C-lowering therapies. A total of 11 LDL-C-lowering drugs with 25 formulations, including 16 brand-name and 9 generic formulations, were included. Data were collected and analyzed from October 2019 to June 2020., Main Outcomes and Measures: Number of Medicare Part D beneficiaries, annual spending, and spending per beneficiary for all formulations., Results: The total number of Medicare Part D beneficiaries ranged from 37 720 840 in 2014 to 44 249 461 in 2018. The number of Medicare beneficiaries taking LDL-C-lowering therapies increased by 23% (from 20.5 million in 2014 to 25.2 million in 2018), while the associated Medicare expenditure decreased by 46% (from $6.3 billion in 2014 to $3.3 billion in 2018). Lower expenditure was driven by greater uptake of generic statin and ezetimibe and a concurrent rapid decline in the use of their brand-name formulations. Medicare spent $9.6 billion on brand-name statins and ezetimibe and could have saved $2.1 billion and $0.4 billion, respectively, if brand-name formulations were switched to equivalent generic versions when available. The number of beneficiaries using PCSK9 inhibitors since their introduction in 2015 has been modest, although use has increased by 144% (from 25 569 in 2016 to 62 476 in 2018) and total spending has increased by 199% (from $164 million in 2016 to $491 million in 2018)., Conclusions and Relevance: Between 2014 and 2018, LDL-C-lowering therapies were used by 4.8 million more Medicare beneficiaries annually, with an associated $3.0 billion decline in Medicare spending. This cost reduction was driven by the rapid transition from brand-name formulations to lower-cost generic formulations of statins and ezetimibe. Use of PCSK9 inhibitions, although low, increased over time and could have broad implications on future Medicare spending.

BACKGROUND: Multiple barriers exist for appropriate use of the proprotein convertase subtilisin/kexin type 9 enzyme inhibitors (PCSK9i) in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH) with inadequately controlled hypercholesterolemia despite standard therapies. Among these barriers, high payer rejection rates and inadequate prior authorization (PA) documentation by providers hinder optimal use of PCSK9i. OBJECTIVES: To (a) identify and discuss provider and payer discordances on barriers to authorization and use of PCSK9i based on clinical and real-world evidence and (b) align understanding and application of clinical, cost, safety, and efficacy data of PCSK9i. METHODS: Local groups of 3 payers and 3 providers met in 6 separate locations across the United States through a collaborative project of AMCP and PRIME Education. Responses to selected pre- and postmeeting survey questions measured changes in attitudes and beliefs regarding treatment barriers, lipid thresholds for considering PCSK9i therapy, and tactics for improving PA processes. Statistical analysis of inter- and intragroup changes in attitudes were performed by Cox proportional hazards test and Fisher's exact test for < 5 variables. RESULTS: The majority of providers and payers (67%-78%) agreed that high patient copayments and inadequate PA documentation were significant barriers to PCSK9i usage. However, payers and providers differed on beliefs that current evidence does not support PCSK9i cost-effectiveness (6% providers, 56% payers; P = 0.003) and that PA presents excessive administrative burden (72% providers, 44% payers; P = 0.09) Average increases pre- to postmeeting were noted in provider beliefs that properly documented PA forms expedite access to PCSK9i (22%-50% increase) and current authorization criteria accurately distinguish patients who benefit most from PCSK9i (6%-22%). Payers decreased in their belief that current authorization criteria accurately distinguish benefiting patients (72%-50%). Providers and payers increased in their belief that PCSK9i are cost-effective (44%-61% and 28%-50%, respectively) and were more willing to consider PCSK9i at the low-density lipoprotein cholesterol threshold of > 70 mg/dL for patients with ASCVD (78%-83% and 44%-67%, respectively) or FH (22%-39% and 22%-33%). Payers were more agreeable to less stringent PA requirements for patients with FH (33%-72%, P = 0.019) and need for standardized PA requirements (50%-83%, P = 0.034); these considerations remained high (89%) among providers after the meeting. Most participants supported educational programs for patient treatment adherence (83%) and physician/staff PA processes (83%-94%). CONCLUSIONS: Provider and payer representatives in 6 distinct geographic locations provided recommendations to improve quality of care in patients eligible for PCSK9i. Participants also provided tactical recommendations for streamlining PA documentation processes and improving awareness of PCSK9i cost-effectiveness and clinical efficacy. The majority of participants supported development of universal, standardized patient eligibility criteria and PA forms. DISCLOSURES: The study reported in this article was part of a continuing education program funded by an independent educational grant awarded by Sanofi US and Regeneron Pharmaceuticals to PRIME Education. The grantor had no role in the study design, execution, analysis, or reporting. AMCP received grant funding from PRIME to assist in the study, as well as in writing the manuscript. McCormick, Bhatt, Bays, Taub, Caldwell, Guerin, Steinhoff, and Ahmad received an honorarium from PRIME for serving as faculty for the continuing education program. McCormick, Bhatt, Bays, Taub, Caldwell, Guerin, Steinhoff, and Ahmad were involved as participants in the study. Bhatt discloses the following relationships: Advisory board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice chair , ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology ), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention ), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease ); Site co-investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. Bays' research site has received research grants from 89Bio, Acasti, Akcea, Allergan, Alon Medtech/Epitomee, Amarin, Amgen, AstraZeneca, Axsome, Boehringer Ingelheim, Civi, Eli Lilly, Esperion, Evidera, Gan and Lee, Home Access, Janssen, Johnson and Johnson, Lexicon, Matinas, Merck, Metavant, Novartis, Novo Nordisk, Pfizer, Regeneron, Sanofi, Selecta, TIMI, and Urovant. Bays has served as a consultant/advisor for 89Bio, Amarin, Esperion, Matinas, and Gelesis, and speaker for Esperion. McCormick, Caldwell, Guerin, Ahmad, Singh, Moreo, Carter, Heggen, and Sapir have nothing to disclose.

Introduction: If statins are unsuccessful at achieving the LDL cholesterol level goal in subjects with hypercholesterolemia, non-statin therapy should be added to reduce cardiovascular morbidity and mortality. The first inhibitors of proprotein convertase substilisin-kexin type 9 (PCSK9) were human monoclonal antibodies and these reduced LDL cholesterol and cardiovascular events. Inclisiran is a small interfering RNA molecule (siRNAs) directed against PCSK9., Areas Covered: This key paper evaluation focuses on Phase 3 trials that assess inclisiran in the treatment of hypercholesterolemia and heterozygous familial hypercholesterolemia., Expert Opinion: To date, the findings with inclisiran have been very promising as it causes large decreases in LDL cholesterol with few adverse effects. However, there are some limitations to its widespread use. Firstly, cardiovascular outcomes trials have not been completed, so we do not know how inclisiran compares to the PCSK9 monoclonal antibodies, which, seem to me, to only have a modest effect on cardiovascular outcomes. Secondly, a major problem with the PCSK9 monoclonal antibodies is that they are expensive, and their use is often discontinued or not pursued, which can leave the subjects intended for treatment at high cardiovascular risk. At present, it is not clear whether similar problems around cost will apply to inclisiran.

Background : The competition for and market dynamics of generic medicines can be understood by analyzing manufacturers' behavior. In this study, we analyzed the various types of generic atorvastatin and rosuvastatin that were introduced onto the South Korean market from 2002 to 2018 and their corresponding manufacturers. Methods : Based on publicly available data, we selected drugs containing atorvastatin and rosuvastatin as active ingredients for the analysis. We calculated the time between the date of marketing approval for the first generic and that of the remaining generics. Then, we categorized manufacturers that marketed generics into first movers and latecomers. Results : We confirmed that many manufacturers have marketed generic drugs in South Korea and that manufacturers can be categorized as first movers and latecomers. Interestingly, latecomers account for a large portion of the manufacturers of generics, and they have entered the market steadily, even after the market matured with a number of manufacturers. Additionally, the characteristics of the manufacturers were closely related to manufacturers' behaviors in the market. Conclusions : The order-of-entry effect, which is commonly observed in other markets, is marginal in the South Korean market, and this phenomenon is mainly explained by the rare price competition among generic manufacturers.

Introduction: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are proven to have profound lowering of low-density lipoprotein cholesterol (LDL-C) in patients with clinical atherosclerotic cardiovascular disease or familial hypercholesterolemia., Aim: The primary purpose of this study was to evaluate PCSK9i utilization in older adults, with a focus on efficacy outcomes within 6 months of initiation. Secondary outcomes included tolerability, out-of-pocket expenses (OPE), and barriers to initiation of therapy., Methods: We conducted a retrospective chart review of patients ≥ 65 years prescribed PCSK9i therapy by a pharmacist-run lipid clinic within a cardiology practice., Results: A total of 136 older adults were prescribed PCSK9i therapy for a Food and Drug Administration-approved indication between September 2015 and March 2019 with 98 patients included in the analyses. In terms of efficacy, 51 patients who took ≥ 3 doses of PCSK9i with baseline and follow-up lipid panels were assessed. On average, LDL-C reduced by 60% (169-67 mg/dL, p < 0.001). For tolerability, 15 patients reported treatment-emergent side effects, resulting in 10 therapy discontinuations. For the cost analysis, 72 patients reported anticipated OPE for 1 month of therapy. Ultimately 17 patients were approved for manufacturer patient assistance with $0 OPE and 31 patients utilized insurance coverage to obtain therapy reporting a median OPE of $9 United States Dollars ($0-$450). The main barrier to initiation was high OPE., Conclusions: PCSK9i are effective at lowering LDL-C in older adults. Tolerability was high among patients without a history of statin intolerance. PCSK9i remain high-cost medications to both insurance companies and patients in terms of cost-sharing responsibilities.

Objectives: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is)-innovative yet costly cholesterol-lowering agents-have been subject to substantial prior authorization (PA) requirements and low approval rates. We aimed to investigate trends in insurer approval and reasons for rejection for PCSK9i prescriptions as well as associations between patients' demographic, clinical, pharmacy, payer, and PCSK9i-specific plan/coverage factors and approval., Methods: We examined trends in PCSK9i approval rates and reasons for rejection using medical and prescription claims from 2015 to 2017 for individuals who received a PCSK9i prescription. We used multinomial logistic regression to estimate quarterly risk-adjusted approval rates for initial PCSK9i prescriptions and approval for any PCSK9i prescription within 30, 90, and 180 days of the initial PCSK9i prescription. For a 2016 subsample for whom we had PCSK9i-specific plan policy data, we examined factors associated with approval including PCSK9i-specific plan formulary coverage, step therapy requirements, and number of PA criteria., Results: The main sample included 12 309 patients (mean age 64.8 years [SD = 10.8], 52.1% female, 51.5% receiving Medicare) and was similar in characteristics to the 2016 subsample (n = 6091). Approval rates varied across quarters but remained low (initial prescription, 13%-23%; within 90 days, 28%-44%). Over time, rejections owing to a lack of formulary coverage decreased and rejections owing to PA requirements increased. Lack of formulary coverage and having ≥11 PA criteria in the plan policy were associated with lower odds of PCSK9i prescription approval., Conclusions: These findings confirm ongoing PCSK9i access issues and offer a baseline for comparison in future studies examining the impact of recent efforts to improve PCSK9i access., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: For patients with inadequate control of cholesterol using moderate-dose statins in the secondary prevention of cardiovascular diseases (CVD), either doubling the dose of statins or adding ezetimibe should be considered. The cost-effectiveness of them is unknown in the Chinese context. The aim of this study is to compare the cost and effectiveness of the two regimens, and estimate the incremental cost-effectiveness ratio (ICER)., Methods: A Markov model of five health statuses were used to estimate long-term costs and quality-adjusted life-years (QALYs) of the two treatment regimens from the healthcare perspective. The effectiveness data used to calculate the transition probability was based on a previously published randomized trial. The utility data was gathered from literature and the costs were gathered from the electronic medical record system of West China Hospital in Chinese Yuan (CNY) in 2017 price. One-way sensitivity analysis and probabilistic sensitivity analysis were conducted., Results: The ICER for ezetimibe plus moderate-dose rosuvastatin was 47,102.99 CNY per QALY for 20 years simulation, which did not reach the threshold of per capita gross domestic product (GDP) of 59,660 CNY per QALY in 2017 in China. Non-CVD-related mortality and CVD-related mortality contributed most to the ICER., Conclusion: Adding ezetimibe to the moderate-dose statin in secondary prevention for CVD is cost-effective, compared with the high-dose statin in the Chinese context whose low-density lipoprotein cholesterol (LDL-c) was not inadequately controlled by moderate-dose statin alone., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Yang et al.)

Background: Using non-statin lipid-modifying agents in combination with statin therapy provides additional benefits for cardiovascular disease (CVD) risk reduction, but their value for money has only been evaluated in high-income countries (HICs). Furthermore, studies mainly derive effectiveness data from a single trial or older meta-analyses., Objectives: Our study used data from the most recent network meta-analysis (NMA) and local parameters to assess the cost effectiveness of non-statin agents in statin-treated patients with a history of CVD., Methods: A published Markov model was adopted to investigate lifetime outcomes: (1) number of recurrent CVD events prevented, (2) quality-adjusted life-years (QALYs) gained, (3) costs and (4) incremental cost-effectiveness ratios (ICERs) of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and ezetimibe added to statin therapy. Event rates and effectiveness inputs were obtained from the NMA. Cost and utility data were gathered from published studies conducted in Thailand. A series of sensitivity analyses were performed., Results: Patients receiving PCSK9i and ezetimibe experienced fewer recurrent CVD events (number needed to treat [NNT] 17 and 30) and more QALYs (0.168 and 0.096 QALYs gained per person). However, under the societal perspective and at current acquisition costs in 2018, ICERs of both agents were $US1,223,995 and 27,361 per QALY gained, respectively. Based on threshold analyses, the costs need to be reduced by 97 and 85%, respectively, for PCSK9i and ezetimibe to be cost-effective., Conclusions: Despite the proven effectiveness of PCSK9i and ezetimibe, the costs of these agents need to reduce to a much greater extent than in HICs to be cost-effective in Thailand.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cardiovascular events in coronary artery disease (CAD). Their costs exceed that of established oral lipid-lowering agents. Previous cost-effectiveness assessments have been inconsistent. Markov cohort state transitions models for stable CAD patients were calculated using information from 1530 participants of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) with known causes of deaths. Non-fatal to fatal event rates, drug prices, direct treatment costs, and utility weights were from public sources. At an assumed relative risk reduction of 32.5% and an annual drug price of 8500 Euros, QALYs gained were 1.23 and 1.20, savings were 2390 and 2410 Euros, and ICERs were 112,530 and 108,660 Euros in women and men, respectively. When the annual cost of this medication was set at 1600 Euros, corresponding ICERs were 21,180 and 20,450 Euros. PCSK9i treatment is cost-effective in stable CAD at a threshold of 150,000 Euro and annual costs of 8500 Euros. As the broad use of PCSK9i therapy in CAD would have a disruptive impact on the healthcare budget, treatment should be focused on very high risk patients (≥3 comorbidities, annual risk of 10%); alternatively, and for lower risk, significant cost reductions would be needed., (Copyright © 2019. Published by Elsevier Inc.)

Importance: In October 2018, evolocumab was made available at a reduced annual list price of $5850 in the United States. This 60% reduction was aimed at improving patient access by lowering patient copays. Shortly thereafter, the 2018 American College of Cardiology/American Heart Association cholesterol management guideline was released. An updated cost-effectiveness analysis of evolocumab in the United States may be therefore of interest to payers and prescribers., Objective: To present an updated cost-effectiveness analysis of evolocumab added to standard background therapy compared with standard background therapy alone in patients with very high-risk atherosclerotic cardiovascular disease, reflecting the 2018 ACC/AHA guideline definition and using the new evolocumab list price., Design, Setting, and Participants: This study used the Markov model originally used in a previous study by Fonarow et al in 2017. A US societal perspective was considered, and a range of baseline cardiovascular event rates were modeled to reflect varying risk profiles in clinical practice within patients with very high-risk atherosclerotic cardiovascular disease., Exposures: Addition of evolocumab to standard background therapy, including maximally tolerated statin therapy (ie, the maximum intensity of statin therapy a patient can safely receive), with or without ezetimibe., Main Outcomes and Measures: Major cardiovascular events (myocardial infarction, ischemic stroke, and cardiovascular death), costs, quality-adjusted life-years, and incremental cost-effectiveness ratios., Results: Evolocumab was associated with both increased costs and improved outcomes when added to standard background therapy. Incremental costs ranged from $22 228 to $3411, depending on the varying level of risk within the defined population. Incremental quality-adjusted life years ranged from 0.39 to 0.44. Incremental cost-effectiveness ratios ranged from $56 655 to $7667 per quality-adjusted life-year gained. For a range of baseline cardiovascular event rates in patients with very high-risk atherosclerotic cardiovascular disease, incremental cost-effectiveness ratios were below the generally accepted willingness-to-pay thresholds. Moreover, the ratios were below the threshold of $50 000 per quality-adjusted life-years gained for any baseline rate of 6.9 or more events per 100 patient-years., Conclusions and Relevance: At its current list price, the addition of evolocumab to standard background therapy meets accepted cost-effectiveness thresholds across a range of baseline cardiovascular event rates in patients with very high-risk atherosclerotic cardiovascular disease as defined by the 2018 ACC/AHA guideline.

A group of experts convened by the Spanish Society of Arteriosclerosis (SEA) has been in charge of updating the SEA document on the indications of PCSK9 inhibitors (PCSK9i) in clinical practice that was published in 2016. This update is justified by the fact that the data from clinical trials carried out on a large scale with PCSK9i have shown that in addition to their high potency to lower atherogenic cholesterol, they reduce the risk of atherosclerotic cardiovascular disease, both in patients with stable disease, and with recent disease, and with a high degree of security. This update provides the recommendations and level of evidence for the prescription of iPCSK9 in patients with homozygous and heterozygous familial hypercholesterolemia, with atherosclerotic cardiovascular disease, and in primary prevention in patients with very high cardiovascular risk. These recommendations have been established taking into account the concentration of LDL-C, the clinical situation of the patient, the additional risk factors and the cost-effectiveness of their use., (Copyright © 2019 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol was a landmark document guiding health care professionals around the globe on how to administer lipid-lowering therapies. Those guidelines were primarily focused on statin therapy benefit groups. The writing committee found insufficient evidence for specific low-density lipoprotein cholesterol (LDL-C) treatment targets. There have been many important updates in the lipid literature since the publication of that document. Most importantly, clinical trials have provided definitive evidence for the pivotal role of LDL-C in atherogenesis and the improvement in clinical outcomes by means of aggressive LDL-C reduction. Ezetimibe, evolocumab, and alirocumab treatment resulted in substantial reductions in major adverse cardiovascular outcomes. These data encourage a discussion on whether LDL-C targets are warranted in primary and/or secondary prevention, and if so, how low should those targets be. In order to answer such questions, the costs and safety of such therapies, as well as the safety of very low levels of LDL-C need to be addressed. This review discusses the relationship between LDL-C lowering and cardiovascular risk reduction, the efficacy, safety, and cost-effectiveness of high-intensity lipid-lowering therapies, and the recommendations from the most recent lipid guidelines., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: The ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial included participants with a recent acute coronary syndrome. Compared with participants receiving statins alone, those receiving a statin plus alirocumab had lower rates of a composite outcome including myocardial infarction (MI), stroke, and death., Objective: To determine the cost-effectiveness of alirocumab in these circumstances., Design: Decision analysis using the Cardiovascular Disease Policy Model., Data Sources: Data sources representative of the United States combined with data from the ODYSSEY Outcomes trial., Target Population: U.S. adults with a recent first MI and a baseline low-density lipoprotein cholesterol level of 1.81 mmol/L (70 mg/dL) or greater., Time Horizon: Lifetime., Perspective: U.S. health system., Intervention: Alirocumab or ezetimibe added to statin therapy., Outcome Measures: Incremental cost-effectiveness ratio in 2018 U.S. dollars per quality-adjusted life-year (QALY) gained., Results of Base-Case Analysis: Compared with a statin alone, the addition of ezetimibe cost $81 000 (95% uncertainty interval [UI], $51 000 to $215 000) per QALY. Compared with a statin alone, the addition of alirocumab cost $308 000 (UI, $197 000 to $678 000) per QALY. Compared with the combination of statin and ezetimibe, replacing ezetimibe with alirocumab cost $997 000 (UI, $254 000 to dominated) per QALY., Results of Sensitivity Analysis: The price of alirocumab would have to decrease from its original cost of $14 560 to $1974 annually to be cost-effective relative to ezetimibe., Limitation: Effectiveness estimates were based on a single randomized trial with a median follow-up of 2.8 years and should not be extrapolated to patients with stable coronary heart disease., Conclusion: The price of alirocumab would have to be reduced considerably to be cost-effective. Because substantial reductions already have occurred, we believe that timely, independent cost-effectiveness analyses can inform clinical and policy discussions of new drugs as they enter the market., Primary Funding Source: University of California, San Francisco, and Institute for Clinical and Economic Review.

Background In the South African private sector context, generically similar products are grouped together and the reimbursement rate is set at the average price of the generically equivalent products. Very little evidence exists in low and middle-income countries with regards to the impact of this policy over time. Objectives To determine the impact of the introduction of generics and generic reference pricing on candesartan and rosuvastatin in the South African private health care sector in terms of medicine utilisation, medicine price and medicine expenditure. Setting South African private health sector. Method Medicine claims for candesartan and rosuvastatin was obtained from a Pharmacy Benefit Manager in South Africa. The claims covered a 48-month period from January 2012 to December 2015 and provided a pre- and post-reference price period for analysis. Medicine utilisation was measured as the number of Defined Daily Doses dispensed per 100,000 beneficiaries. Medicine price and expenditure was calculated as the average per Defined Daily Dose. Main outcome measure Medicine utilisation, price and expenditure. Results Candesartan experienced an average 7.0% year-on-year decline in utilisation and rosuvastatin a 5.0% increase. Medicine expenditure reduced by an additional 34.6% and 20.9% for candesartan and rosuvastatin respectively. The total savings was 54.8% for candesartan and 31.9% for rosuvastatin. Conclusion The introduction of generics and generic reference pricing did not have an impact on medicine utilisation, but reduced the price and expenditure of both candesartan and rosuvastatin.

PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are set to revolutionize the treatment of hypercholesterolemia in the management of atherosclerotic risk, but numerous reports have detailed unprecedented barriers to access for these drugs. To overcome these challenges, our group created a model to facilitate provision of this new therapy for patients who qualify according to Food and Drug Administration criteria. This report details the real-world follow-up experience of PCSK9i use in a large patient cohort structured to ensure rigor in data collection, analysis, and interpretation. The 271 patients approved and actively followed in our PCSK9i clinic between July 2015 and August 2018 represent a 97% approval rate from insurance, with 28% of prescriptions requiring at least one appeal. Over 50% of patients were statin intolerant. On average, there was a median lapse of 15 days between initial visit and insurance approval. PCSK9i therapy was affordable for most patients, with an average monthly out-of-pocket expense of $58.05 (median $0). Only 2.3% of patients were unable to initiate or continue therapy because of cost. Reductions from baseline in LDL (low-density lipoprotein) cholesterol and Lp(a) (lipoprotein [a])were comparable to published reports with median reductions of 60% and 23% at 1 year, respectively. PCSK9i therapy was well-tolerated overall, though 9% of patients reported adverse events, and 5% of patients discontinued due mostly to musculoskeletal and flu-like symptoms. Our practice model demonstrates that PCSK9i therapy can be accessed easily and affordably for the majority of eligible patients, resulting in dramatic improvement in lipid profile results. Moreover, our registry data suggest that results from the prospective clinical trials of PCSK9i on LDL and Lp(a) reduction and on tolerability are applicable to a real-world cohort.

Introduction and Objectives: To analyze the cost-effectiveness ratio and budget impact of treatment with evolocumab (PCSK9 inhibitor) for patients in secondary prevention in the Spanish National Health System., Methods: A budget impact analysis, decision tree and Markov models were designed under the public health system perspective, based on the only study with morbidity and mortality data (FOURIER). The alternatives compared were evolocumab vs statins, and dual therapy with ezetimibe in 5% of the population. The measure of effectiveness used was the number of cardiovascular events avoided. Univariate and probabilistic sensitivity analyses were performed., Results: The average annual cost of patients receiving evolocumab was 11 134.78€ and 393.83€ for standard treatment (statins plus ezetimibe). The incremental cost-effectiveness ratio was > 600 000 € per avoided cardiovascular event for both assessed outcomes (first: cardiovascular death, myocardial infarction, stroke, and hospitalization due to unstable angina or coronary revascularization; second: includes the first 3 events). To perform the 10-year Markov model, the average cost of standard treatment was 13 948.45€ vs 471 417.37€ with evolocumab. Treatment with evolocumab for patients with familial hypercholesterolemia would cost between 3 and 6.1 million euros, assuming a difference of 2.5 and 5.1 million euros with the standard treatment (2017). This difference would be between 204.3 and 1364.7 million euros (2021) for those with nonfamiliar hypercholesterolemia (secondary prevention)., Conclusions: Treatment with evolocumab is associated with a lower frequency of cardiovascular events, but is inefficient for patients suitable to receive this drug in the Spanish National Health System., (Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Prescribing of lipid-lowering agents (LLAs) has increased worldwide including in Scotland with increasing prevalence of coronary heart disease, and higher dose statins have been advocated in recent years. There have also been initiatives to encourage prescribing of generic versus patented statins to save costs without compromising care. There is a need to document these initiatives and outcomes to provide future direction., Method: Assessment of utilization (items dispensed) and expenditure of key LLAs (mainly statins) between 2001 and 2015 in Scotland alongside initiatives., Results: Multiple interventions over the years have increased international nonproprietary name prescribing (99% for statins) and preferential prescribing of generic versus patented statins, and reduced inappropriate prescribing of ezetimibe. This resulted in a 50% reduction in expenditure of LLAs between 2001 and 2015 despite a 412% increase in utilization, increased prescribing of higher dose statins (71% in 2015) especially atorvastatin following generic availability, and reduced prescribing of ezetimibe (reduced by 72% between 2010 and 2015). As a result, the quality of prescribing has improved., Conclusion: Generic availability coupled with multiple measures has resulted in appreciable shifts in statin prescribing behavior and reduced ezetimibe prescribing, resulting in improvements in both the quality and efficiency of prescribing.

Background: The American College of Cardiology and American Heart Association (ACC/AHA) issued new cholesterol treatment guidelines in 2013. Two of the groups designated for primary prevention were analyzed: patients with a low-density lipoprotein cholesterol (LDL-C) level ≥ 190 mg per dL and diabetic patients aged 40-75 years., Objective: To estimate the effects of primary prevention as specified in the 2013 guidelines on cardiovascular event risk and cost., Methods: Primary prevention patients were identified using laboratory and diagnostic data for Humana members from 2007 to 2013. Potential study patients were classified into 3 risk groups: elevated LDL-C, diabetes, and elevated LDL-C and diabetes. Patients receiving cholesterol-lowering medications before their index date were excluded. Eligible patients were divided into 2 treatment groups: (1) primary prevention patients who initiated treatment before experiencing any cardiovascular disease (CVD)-related event, and (2) patients who either did not initiate treatment until after experiencing a CVD event or never initiated treatment. The associations between initiating cholesterol-lowering medications for primary prevention and the risk for acute myocardial infarction, stroke, coronary angioplasty, or coronary artery bypass graft surgery were estimated using Cox proportional hazards models. The effect of primary prevention on health care costs was estimated using generalized linear models., Results: 91,066 patients met study selection criteria. Primary prevention rates were the lowest in diabetic patients (35%), who were newly designated for treatment in the 2013 guidelines. Primary prevention rates were higher for patients designated for treatment under earlier guidelines: 65% for patients with elevated LDL-C and 78% for the combined LDL-C and diabetes group. Primary prevention treatment was associated with significant reductions in cardiovascular event risk (up to 37%) and lower total all-cause costs (by $673) in the first post-index year., Conclusions: Initiating cholesterol-lowering medications for primary prevention, as specified in the ACC/AHA 2013 guidelines, for patients with high LDL-C and diabetes is associated with reduced CVD event risks and lower health care costs., Disclosures: No outside funding supported this study. Han received fellowship support from the Pharmaceutical Research and Manufacturers Association Foundation (PhRMA) during the conduct of this study. Dougherty is employed by PhRMA. The authors have nothing to disclose.

Introduction: Evolocumab is fully human monoclonal antibody which binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), and prevents its blocking effect on recycling of liver low-density lipoprotein (LDL) receptors. Areas covered: The aim of this review is to assess efficacy, safety, and cost-effectiveness of evolocumab in adult patients with high cardiovascular risk. Major research databases MEDLINE, EBSCO, and CENTRAL were systematically searched for relevant study reports. Expert commentary: Even when given in full doses, statins augmented with ezetimibe and cholesterol-binding resins could not reduce cholesterol baseline level for more than 66%, while evolocumab reduces cholesterol level for 75% or even more. Up to now, evolocumab showed good safety profile, and patents tolerate it very well. The abovementioned advantages of evolocumab made it almost ideal drug for hypercholesterolemia, and probably in the future the best drug for secondary prevention of major cardiovascular events. Evolocumab is borderline cost-effective for the treatment of patients with high cardiovascular risk in European countries, while in the U.S.A. it is under debate where the underlying assumption (risk of cardiovascular disease events) determine the true value.

Aim: PCSK9 inhibitors (PCSK9i) effectively lower cholesterol levels in randomized trials with reduction in cardiovascular outcomes and favorable safety profile. However, the access to PCSK9i is limited due to high cost and data regarding the use of PCSK9i in real-world practice is limited., Methods: Data on all patients submitted for approval of PCSK9i at a regional lipid clinic, outside of clinical trials. Patients' profile, approval rates, low-density lipoprotein cholesterol (LDL-C) reduction rates, and adverse events were evaluated., Results: Recommendation for PCSK9i was given to 133 patients; 16 did not receive insurance approval and additional 16 were approved but did not initiate therapy. Of the 101 treated patients (47% females; mean age 61 ± 11 years), 52 had probable/definite familial hypercholesterolemia (FH) (peak LDL-C level 305 ± 87 mg/dL vs non-FH 204 ± 39 mg/dL) and 62% had an established cardiovascular disease. Statin intolerance was reported by 77%. Follow-up lipid panel was available in 66/101 patients: mean LDL-C reduction was 59% ± 19. Subjects with heterozygous FH had similar LDL-C decrease than those with non-FH (59% ± 22 vs 60% ± 14, P = .792). LDL-C < 100 mg/dL was achieved by 76%, LDL-C < 70 mg/dL by 58% and LDL-C < 40 mg/dL by 18% of those with follow-up data. Side effects were reported by 10%, mainly musculoskeletal complaints and flu-like symptoms, and 15% have discontinued treatment., Conclusions: Patient selection by a regional lipid clinic resulted in a high real-world PCSK9i insurance approval, with efficacy and safety comparable to randomized clinical trials. Cost and medication nonadherence are potential barriers to successful implementation of therapy in routine clinical care., (© 2018 John Wiley & Sons Ltd.)

The objective of this study was to review available health economic evaluations of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. These drugs reduce low-density lipid cholesterol levels and cardiovascular risk, but their cost effectiveness has been questioned. We searched Medline and Embase for economic evaluations in any language at any time. Studies were included if they analysed any PCSK9 inhibitor compared with either statin alone or in combination with ezetimibe or any other therapy considered standard prior to the introduction of PCSK9 inhibitors. We found ten full health economic evaluations of PCSK9 inhibitors, two from Europe and eight from the United States (US). Six of the eight from the US were from two different consortia that analysed PCSK9 inhibitors at different stages through the development of evidence. All studies generally reported incremental cost-effectiveness ratios above suggested thresholds for cost effectiveness, except one study from Spain. The results of this review indicate that PCSK9 inhibitors in general are not cost effective at the current prices, but lower prices may change the results.

Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, and/or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream. The levels of apoB are regulated by endoplasmic reticulum (ER) associated degradation as well as by a post ER degradation pathway in model systems, and we suggest that these events provide novel therapeutic targets. We discuss first how cardiovascular disease arises and how cholesterol is regulated, and then summarize the mechanisms of action of existing treatments for cardiovascular disease. We then review the apoB biosynthetic pathway, focusing on steps that might be amenable to therapeutic interventions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Simvastatin plus ezetimibe reduced the risk of cardiovascular events in the IMProved Reduction of Outcomes: Vytorin Efficacy International (IMPROVE-IT) study. The aim of this study is to investigate the cost-effectiveness of adding ezetimibe to simvastatin treatment for patients with ACS based on the recently completed IMPROVE-IT trial., Methods: We constructed a Markov state-transition model to evaluate the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness (ICER) associated with co-therapy compared with simvastatin alone from a health care perspective. We ran separate base-case analyses assuming a trial-length and longer term follow-up. One-way sensitivity analyses were used to explore uncertainty in model parameters., Results: In the trial-length model, the ICERs compared with simvastatin alone were $114,400 per QALY for the combination therapy. In 5- and 10-year time horizons, the ICERs remained above the cost-effectiveness threshold of $50,000 per QALY. In the lifetime horizon model, The ICER was $45,046 per QALY for combination treatment compared with simvastatin alone. The combination therapy is cost-effective at an 80% decrease in the current branded simvastatin and ezetimibe cost. Probabilistic sensitivity analysis suggested simvastatin and ezetimibe co-therapy would be a cost-effective alternative to simvastatin monotherapy 60.7% of the time., Conclusions: In our trial-length, 5-year, and 10-year models, the co-therapy was not a cost-effective alternative; however, as follow-up was extended to lifetime, the co-therapy became a cost-effective treatment compared with the simvastatin monotherapy in patients with histories of ACS., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Purpose of Review: This review aims to explore and summarize the current literature on the cardiovascular disease (CVD) healthcare burden and determine the cost-effectiveness of the PCSK9 inhibitors., Recent Findings: The CVD remain the largest cause of mortality in the USA presenting substantial healthcare cost burden reaching $555 billion in 2016 and projected to rise to $1.1 trillion by 2035. The PCSK9 inhibitors have shown strong efficacy in LDLC lowering, but its price of ~ 14,000-14,600 per patient per year coupled with ~ 2.2-2.8 years of cardiovascular outcome data has created many controversies surrounding its cost-effectiveness. To determine the cost-effectiveness of the PCSK9 inhibitors, various simulation models and risk-based stratification and case-by-case patient approachs have yielded divisive data which need to be reassessed as per the ODYSSEY and long-term CVD outcomes. Further studies are warranted to evaluate the long-term CVD event rates of patients on the PCSK9 inhibitors to determine its true cost-effectiveness.

The present investigation was aimed to study the effect of detoxification on the nutrients and antinutrients of wild apricot kernel followed by its hypocholesterolemic effect in male Wistar albino rats. The results revealed a non-significant (p > 0.05) effect of detoxification on the proximate composition except total carbohydrates and protein content. However, detoxification led to a significant (p < 0.05) decrease in l-ascorbic acid (76.82%), β-carotene (25.90%), dietary fiber constituents (10.51-28.92%), minerals (4.76-31.08%) and antinutritional factors (23.92-77.05%) (phenolics, tannins, trypsin inhibitor activity, saponins, phytic acid, alkaloids, flavonoids, oxalates) along with the complete removal (100%) of bitter and potentially toxic hydrocyanic acid (HCN). The quality parameters of kernel oil indicated no adverse effects of detoxification on free fatty acids, lipase activity, acid value and peroxide value, which remained well below the maximum permissible limit. Blood lipid profile demonstrated that the detoxified apricot kernel group exhibited significantly (p < 0.05) increased levels of HDL-cholesterol (48.79%) and triglycerides (15.09%), and decreased levels of total blood cholesterol (6.99%), LDL-C (22.95%) and VLDL-C (7.90%) compared to that of the raw (untreated) kernel group. Overall, it can be concluded that wild apricot kernel flour could be detoxified efficiently by employing a simple, safe, domestic and cost-effective method, which further has the potential for formulating protein supplements and value-added food products.

Low-density lipoprotein cholesterol (LDL-C) has been extensively evaluated. Prospective cohort studies, randomized controlled trials, biology, pathophysiology, genetics, and Mendelian randomization studies, have clearly taught us that LDL-C causes atherosclerotic cardiovascular disease. The newest class of drugs to lower LDL-C, the proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, have been found to safely reduce LDL-C approximately 60% when added to high-intensity statin therapy. Because their cost is much greater than that of the currently available agents, their value has been questioned. In late August, 2017, two groups assessed the value of this class of drugs looking at cost-effectiveness; however, the Institute for Clinical and Economic Review and Fonarow and colleagues found disparate results when assessing PCSK9 valuation. Herein, we review the evolution of LDL-C from hypothesis to fact, and then attempt to adjudicate the 2 models, shedding light on the complex modeling process. We find that models of cost-effectiveness are helpful adjuncts to decision making, but that their conclusions depend on many assumptions. Ultimately, clinician judgment regarding their clinical benefit, balanced by some estimation of cost, may be more productive to target the right patients for whom the benefits can be well-justified., (© 2018 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.)

The clinical importance and benefit of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors appears well established for the high-risk cardiovascular (CV) patient. This applies especially to the statin-intolerant patient or the patient who does not attain an appropriate low-density lipoprotein cholesterol (LDL-C) target. Therefore, the barriers to appropriate clinical use of the PCSK9 inhibitors involve cost and not the documented CV benefit or LDL-C lowering. Multiple roadblocks affect many high-risk CV patients in arranging approval of a PCSK9 inhibitor. Overcoming these roadblocks may require legal pressures, some increased regulation, and facilitation by competitive forces.

Introduction: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is a new treatment option for patients with hypercholesterolemia. The objective of this study was to systematically review the cost-effectiveness of lipid-lowering agents., Areas Covered: Based on Pubmed, Embase, and Cochrane Database of Systematic Reviews, we identified 29 relevant articles. Studies found statins were cost-effective compared with placebo or no treatment in general. Atorvastatin was reported to be cost-effective against simvastatin. In most cases, rosuvastatin was more cost-effective than atorvastatin or simvastatin. Additionally, ezetimibe was considered to be cost-effective compared with no treatment for statin intolerant patients. For patients not meeting treatment goals with their statins, switching to ezetimibe plus simvastatin was consistently reported cost-effective. The cost-effectiveness of ezetimibe plus a hybrid of a statin varied by the source of clinical data and cost of ezetimibe. Finally, the cost-effectiveness of PCSK9 inhibitor plus a statin against statin monotherapy was uncertain. The PCSK9 inhibitor plus a stain was cost-ineffective compared with ezetimibe plus a statin., Expert Commentary: Drug costs and treatment efficacy were the key drivers of the cost-effectiveness results in prior analyses. Future evaluations are warranted to reflect the decreasing drug prices and the long-term treatment effects of PCSK9 inhibitors.

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are an innovative treatment option for patients with familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require further lowering of low-density lipoprotein cholesterol. However, the high costs of these agents have spurred payers to implement utilization management policies to ensure appropriate use. We examined prior authorization (PA) requirements for PCSK9is across private and public US payers., Methods and Results: We conducted an analysis of 2016 formulary coverage and PA data from a large, proprietary database with information on policies governing >95% of Americans with prescription drug coverage (275.3 million lives) within 3872 plans across the 4 major insurance segments (commercial, health insurance exchange, Medicare, and Medicaid). The key measures included administrative PA criteria (prescriber specialty, number of criteria in PA policy or number of fields on PA form, requirements for medical record submission, reauthorization requirements) and clinical/diagnostic PA criteria (approved conditions, required laboratories or other tests, required concomitant therapy, step therapy requirements, continuation criteria) for each of 2 Food and Drug Administration-approved PCSK9is. Select measures (eg, number of PA criteria/fields, medical record submission requirements) were obtained for 2 comparator cardiometabolic drugs (ezetimibe and liraglutide). Between 82% and 97% of individuals were enrolled in plans implementing PA for PCSK9is (depending on insurance segment), and one third to two thirds of these enrollees faced PAs restricting PCSK9i prescribing to a specialist. For patients with familial hypercholesterolemia, diagnostic confirmation via genetic testing or meeting minimum clinical scores/criteria was also required. PA requirements were more extensive for PCSK9is as compared with the other cardiometabolic drugs (ie, contained 3×-11× the number of PA criteria or fields on PA forms and more frequently involved the submission of medical records as supporting documentation)., Conclusions: PA requirements for PCSK9is are greater than for selected other drugs within the cardiometabolic disease area, raising concerns about whether payer policies to discourage inappropriate use may also be restricting access to these drugs in patients who need them., (© 2018 American Heart Association, Inc.)

Background: Considerable interest exists among health care payers and pharmaceutical manufacturers in designing outcomes-based agreements (OBAs) for medications for which evidence on real-world effectiveness is limited at product launch., Objectives: To build hypothetical OBA models in which both payer and manufacturer can benefit., Methods: Models were developed for a hypothetical hypercholesterolemia OBA, in which the OBA was assumed to increase market access for a newly marketed medication. Fixed inputs were drug and outcome event costs from the literature over a 1-year OBA period. Model estimates were developed using a range of inputs for medication effectiveness, medical cost offsets, and the treated population size. Positive or negative feedback to the manufacturer was incorporated on the basis of expectations of drug performance through changes in the reimbursement level. Model simulations demonstrated that parameters had the greatest impact on payer cost and manufacturer reimbursement., Results: Models suggested that changes in the size of the population treated and drug effectiveness had the largest influence on reimbursement and costs. Despite sharing risk for potential product underperformance, manufacturer reimbursement increased relative to having no OBA, if the OBA improved market access for the new product. Although reduction in medical costs did not fully offset the cost of the medication, the payer could still save on net costs per patient relative to having no OBA by tying reimbursement to drug effectiveness., Conclusions: Pharmaceutical manufacturers and health care payers have demonstrated interest in OBAs, and under a certain set of assumptions both may benefit., (Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the budget impact of introducing the proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) alirocumab and evolocumab to market for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular (CV) disease requiring additional lowering of low-density lipoprotein cholesterol (LDL-C)., Methods: A 3-year model estimated the costs of lipid-modifying therapy (LMT) and CV events to a hypothetical US health plan of 1 million members, comparing two scenarios-with and without the availability of PCSK9i as add-on therapy to statins. Proportions of patients with uncontrolled LDL-C despite receiving statins, and at risk of CV events, were estimated from real-world data. Total undiscounted annual LMT costs (2017 prices, including PCSK9i costs of $14,563.50), dispensing and healthcare costs, including the costs of CV events, were estimated for all prevalent patients in the target population, based on baseline risk factors. Maximum PCSK9i utilization of 1-5% over 3 years according to risk group (following the same pattern as current ezetimibe use), and 5-10% as a secondary scenario, were assumed., Results: Total healthcare budget impacts per target patient (and per member) per month for years 1, 2 and 3 were $3.62($0.10), $7.22($0.20) and $10.79($0.30), respectively, assuming 1-5% maximum PCSK9i utilization, and $15.81($0.44), $31.52($0.88) and $47.12($1.31), respectively, assuming 5-10% utilization. Results were sensitive to changes in model timeframe, years to maximum PCSK9i utilization and PCSK9i costs., Conclusions: The budget impact of PCSK9i as add-on therapy to statins for patients with hypercholesterolemia is relatively low compared with published estimates for other specialty biologics. Drug cost rebates and discounts are likely to further reduce budget impact.

Aims: Despite the success of statins, there remains unmet clinical need in cardiovascular disease (CVD) prevention. New proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 55-65%. Two PCSK9 inhibitors, evolocumab, and alirocumab, were approved for use in Norway but not yet for reimbursement through public national insurance. We aim to explore the cost-effectiveness of these compared with available treatments in a Norwegian setting., Methods and Results: A state transition Markov model was developed to model the cost-effectiveness of PCSK9 inhibitors for prevention of coronary heart disease, ischaemic strokes, and death among high-risk patient subpopulations in Norway, in both primary and secondary settings. Evolocumab and alirocumab are compared against ezetimibe and standard treatment. Risk of CVD is based on population incidence rates and adjusted according to baseline risk factors. Preventative effect of treatment was modelled according to absolute reduction in LDL-C. PCSK9 inhibitors were never found to be cost-effective in primary prevention. In secondary prevention they were cost-effective only for older, high-risk patients. The lowest cost-effectiveness ratios were for heterozygous familial hypercholesterolaemia patients and high-risk diabetics, with €63 200 and €68 400 per quality-adjusted life-year, respectively., Conclusion: High lifetime costs of PCSK9 inhibitors may not be offset by estimated health gains for most eligible patients. PCSK9 inhibitors are found in the model only to be cost-effective in secondary prevention for older patients with high absolute risk of CVD. This picture is likely to change as price decreases. Future research is needed to determine the long-term preventative effects of PCSK9 inhibitors., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)