Measuring Costs of Cardiovascular Disease Prevention for Patients with Familial Hypercholesterolemia in Administrative Claims Data.

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.

Incremental net benefit of lipid-lowering therapy with PCSK9 inhibitors: a systematic review and meta-analysis of cost-utility studies.

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 I2 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 (I2 = 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.

Cost-Effectiveness Analysis of Evolocumab Therapy in Patients at High Risk of Cardiovascular Events in the Context of the Brazilian Unified Health System. / Análise de Custo-Efetividade da Terapia com Evolocumabe em Pacientes com Alto Risco de Eventos Cardiovasculares no Contexto do SUS ­ Brasil.

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, ß 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.

FUNDAMENTO: Em associação às estatinas, os inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) demonstraram ser eficazes na redução de eventos cardiovasculares em pacientes de alto risco. OBJETIVO: Analisar a custo-efetividade da implementação de evolocumabe para pacientes com alto risco de eventos cardiovasculares no contexto do Sistema Único de Saúde (SUS) no Brasil. MÉTODOS: Um modelo de Markov foi utilizado, baseando-se em uma amostra ambulatorial de pacientes com doença arterial coronariana. Os desfechos primários analisados foram infarto agudo do miocárdio, acidente vascular cerebral isquêmico (AVCi), revascularização do miocárdio e morte cardiovascular. O resultado foi expresso por meio da razão de custo-efetividade incremental (RCEI), considerando-se uma taxa de desconto de 5% ao ano, e uma análise de sensibilidade foi realizada, tendo em vista a imprecisão de valores. RESULTADOS: Selecionaram-se 61 pacientes com risco cardiovascular estimado em 35% em 10 anos, se em uso de atorvastatina 80mg/dia, e em 22,75%, se adicionado o evolocumabe. O custo global por paciente no período de 10 anos foi de R$ 46.522,44 no grupo em monoterapia com atorvastatina versus R$ 236.141,85 na terapia combinada, com uma efetividade global de 0,54 e 0,73, respectivamente. Isso resultou em uma RCEI R$ 1.011.188,07 (R$ 864.498,95 a R$ 1.296.748,43) por desfecho cardiovascular evitado. CONCLUSÕES: Apesar de não existirem padrões nacionais para custo-efetividade, os dados encontrados sugerem que a estratégia de associação do evolocumabe à terapia com estatina não é, no momento, custo-efetiva.

Análise de Custo-Efetividade da Terapia com Evolocumabe em Pacientes com Alto Risco de Eventos Cardiovasculares no Contexto do SUS - Brasil / Cost-Effectiveness Analysis of Evolocumab Therapy in Patients at High Risk of Cardiovascular Events in the Context of the Brazilian Unified Health System

Resumo Fundamento: Em associação às estatinas, os inibidores da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) demonstraram ser eficazes na redução de eventos cardiovasculares em pacientes de alto risco. Objetivo: Analisar a custo-efetividade da implementação de evolocumabe para pacientes com alto risco de eventos cardiovasculares no contexto do Sistema Único de Saúde (SUS) no Brasil. Métodos: Um modelo de Markov foi utilizado, baseando-se em uma amostra ambulatorial de pacientes com doença arterial coronariana. Os desfechos primários analisados foram infarto agudo do miocárdio, acidente vascular cerebral isquêmico (AVCi), revascularização do miocárdio e morte cardiovascular. O resultado foi expresso por meio da razão de custo-efetividade incremental (RCEI), considerando-se uma taxa de desconto de 5% ao ano, e uma análise de sensibilidade foi realizada, tendo em vista a imprecisão de valores. Resultados: Selecionaram-se 61 pacientes com risco cardiovascular estimado em 35% em 10 anos, se em uso de atorvastatina 80mg/dia, e em 22,75%, se adicionado o evolocumabe. O custo global por paciente no período de 10 anos foi de R$ 46.522,44 no grupo em monoterapia com atorvastatina versus R$ 236.141,85 na terapia combinada, com uma efetividade global de 0,54 e 0,73, respectivamente. Isso resultou em uma RCEI R$ 1.011.188,07 (R$ 864.498,95 a R$ 1.296.748,43) por desfecho cardiovascular evitado. Conclusões: Apesar de não existirem padrões nacionais para custo-efetividade, os dados encontrados sugerem que a estratégia de associação do evolocumabe à terapia com estatina não é, no momento, custo-efetiva.

Abstract 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.

Effect of Financial Incentives for Process, Outcomes, or Both on Cholesterol Level Change: A Randomized Clinical Trial.

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.

Utilisation patterns and costs of lipid-lowering drugs in Switzerland 2013-2019.

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.

Trends in Utilization and Cost of Low-Density Lipoprotein Cholesterol-Lowering Therapies Among Medicare Beneficiaries: An Analysis From the Medicare Part D Database.

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.

Patient Characteristics and Treatment Patterns among Medicare Beneficiaries Initiating PCSK9 Inhibitor Therapy.

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.

The cost-effectiveness of intensive low-density lipoprotein cholesterol lowering in people with peripheral artery disease.

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.

A regional analysis of payer and provider views on cholesterol management: PCSK9 inhibitors as an illustrative alignment model.

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.

Inclisiran, the billion-dollar drug, to lower LDL cholesterol - is it worth it?

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.

A Retrospective Chart Review Evaluating Efficacy, Tolerability, and Cost of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i) in Older Adults.

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.

Trends and Factors Associated With Insurer Approval of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Prescriptions.

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.

Cost-Effectiveness Analysis of Ezetimibe as the Add-on Treatment to Moderate-Dose Rosuvastatin versus High-Dose Rosuvastatin in the Secondary Prevention of Cardiovascular Diseases in China: A Markov Model Analysis.

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.

Generic atorvastatin and rosuvastatin in the South Korean market: time of introduction in relation to manufacturer characteristics.

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.

Cost effectiveness of lifelong therapy with PCSK9 inhibitors for lowering cardiovascular events in patients with stable coronary artery disease: Insights from the Ludwigshafen Risk and Cardiovascular Health cohort.

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.

Cost-Effectiveness Analysis of Non-Statin Lipid-Modifying Agents for Secondary Cardiovascular Disease Prevention Among Statin-Treated Patients in Thailand.

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.