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.

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 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.

Application of PCSK9 Inhibitors in Practice.

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.

Lipid-lowering therapy with PCSK9-inhibitors in the real-world setting: Two-year experience of a regional lipid clinic.

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.

PCSK9 inhibitor valuation: A science-based review of the two recent models.

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.

Prior Authorization Requirements for Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Across US Private and Public Payers.

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.

Rectal indomethacin or intravenous gabexate mesylate as prophylaxis for acute pancreatitis post-endoscopic retrograde cholangiopancreatography.

OBJECTIVE: We aimed to evaluate the results in our case series of AP ERCP over the last three years. The prophylaxis for acute pancreatitis (AP) post-endoscopic retrograde cholangiopancreatography (ERCP) consists of rectal indomethacin, but some studies are not concordant. PATIENTS AND METHODS: We compared 241 ERCP performed from January 2014 to February 2015 with intravenous gabexate mesylate (Group A), with the 387 ERCP performed from March 2015 to December 2016 with rectal indomethacin (Group B) as prophylaxis for AP post-ERCP. RESULTS: There were 8 (3.31%) AP post-ERCP in Group A vs. 4 (1.03%) in Group B. CONCLUSIONS: Rectal indomethacin shows a better statistically significant performance than intravenous gabexate mesylate in the prophylaxis of AP post-ERCP, besides being cheaper.

Therapeutics: Alpha-1 Antitrypsin Augmentation Therapy.

Subjects with alpha-1 antitrypsin deficiency who develop pulmonary disease are managed following general treatment guidelines, including disease management interventions. In addition, administration of intravenous infusions of alpha-1 proteinase inhibitor (augmentation therapy) at regular schedules is a specific therapy for individuals with AATD with pulmonary involvement.This chapter summarizes the manufacturing differences of commercially available formulations and the available evidence of the effects of augmentation therapy. Biologically, there is clear evidence of in vivo local antiprotease effects in the lung and systemic immunomodulatory effects. Clinically, there is cumulative evidence of slowing lung function decline and emphysema progression. The optimal dose of augmentation therapy is being revised as well as more individualized assessment of who needs this therapy.

Clinical efficacy and safety of evolocumab for low-density lipoprotein cholesterol reduction.

Multiple categories of medications have been developed to manage lipid profiles and reduce the risk of cardiovascular events in patients with heart disease. However, currently marketed medications have not solved the problems associated with preventing and treating cardiovascular diseases completely. A substantial population of patients cannot take advantage of statin therapy due to statin intolerance, heart failure, or kidney hemodialysis, suggesting a need for additional effective agents to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was discovered in 2003 and subsequently emerged as a novel target for LDL-C-lowering therapy. Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) directed against human PCSK9. By inactivating PCSK9, evolocumab upregulates LDL receptors causing increased catabolism of LDL-C and the consequent reduction of LDL-C levels in blood. Overall, evolocumab has had notable efficacy, with LDL-C reduction ranging from 53% to 75% in monotherapy and combination therapies, and is associated with minor adverse effects. However, studies regarding the ability of evolocumab to reduce mortality as well as long-term safety concerns are limited. The fact that the drug was introduced at a cost much higher than the existing medications and shows a low incremental mortality benefit suggests that many payers will consider evolocumab to have an unfavorable cost-benefit ratio.

Effect and cost of treatment for acute pancreatitis with or without gabexate mesylate: a propensity score analysis using a nationwide administrative database.

OBJECTIVES: Despite a lack of evidence, gabexate mesylate (GM) is routinely used for the treatment of acute pancreatitis (AP) in some countries. The present study examined the effect and cost of GM for AP treatment using the Japanese Diagnosis Procedure Combination database. METHODS: We performed a propensity score analysis to compare inhospital mortality, length of stay (LOS), and total costs between patients with AP treated with GM and those without GM in 2010. RESULTS: We identified 2483 patients treated with GM and 890 patients without GM. Overall, 77% of the patients treated with GM were nonsevere AP cases. The propensity-matched 707 pairs showed no significant difference between GM users and nonusers in inhospital mortality or median length of stay in nonsevere AP (1.0% vs 1.2%, P = 0.789; 10 vs 10 days, P = 0.160) and severe AP (8.4% vs 5.0%, P = 0.438; 12 vs 14 days, P = 0.487) cases. Total costs were significantly different between the GM users and the nonusers in nonsevere AP cases (US$4982 vs US$4373, P < 0.001), but not in severe AP cases ($6605 vs $6490, P = 0.764). CONCLUSIONS: Using GM for nonsevere AP cannot be justified because of higher costs without significant effects. Gabexate mesylate use is also not justifiable for severe AP because it does not reduce mortality or length of stay.

Boceprevir and treatment of chronic hepatitis C.

The addition of boceprevir to peginterferon and ribavirin has improved sustained response rates markedly. Boceprevir is effective in treatment naïve, relapsers, partial responders, and null responders. Those with advanced fibrosis require 44 weeks of boceprevir therapy after a 4-week peg/ribavirin lead-in. The main side effect with boceprevir is anemia and ribavirin dose reduction is an effective strategy. This review examines the current treatment paradigm of boceprevir-based treatment of chronic hepatitis C, examining treatment paradigms, predictors of response, futility rules, as well as preliminary results from studies examining boceprevir efficacy in additional populations. Further follow-up in these cohorts will be required.

alpha1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note.

The use of IV augmentation therapy with plasma-derived alpha1-antitrypsin (AAT) has become the standard of care for the treatment of pulmonary disease associated with the severe genetic deficiency of AAT. The Medical and Scientific Advisory Committee of the Alpha-1 Foundation has become aware that physicians are prescribing this expensive blood product for the treatment of individuals with a single abnormal AAT gene, primarily the PI*MZ genotype. We are aware of no evidence that such therapy is effective in this patient population. The most important therapeutic interventions in such patients remain smoking cessation and elimination of other risk factors for lung disease. This commentary discusses the treatment of AAT deficiency and the concerns regarding treatment of PI*MZ individuals. We conclude that clinicians should avoid prescribing augmentation therapy for this heterozygote population.

Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

OBJECTIVES: To compare patient outcomes, resource use and costs to the NHS and NHS Blood Transfusion Authority (BTA) associated with cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion. DATA SOURCES: Electronic databases covering the period 1996-2004 for systematic reviews and 1994-2004 for economic evidence. REVIEW METHODS: Existing systematic reviews were updated with data from selected randomised controlled trials (RCTs) that involved adults scheduled for elective non-urgent surgery. Any resource use or cost data were extracted for potential use in populating an economic model. Relative risks or weighted mean difference of each outcome for each intervention were assessed, taking into account the number of RCTs included in each outcome and intervention and the presence of any heterogeneity. This allowed indirect comparison of the relative effectiveness of each intervention when the intervention is compared with allogeneic blood transfusion. A decision analytic model synthesised clinical and economic data from several sources, to estimate the relative cost-effectiveness of cell salvage for people undergoing elective surgery with moderate to major expected blood loss. The perspective of the NHS and patients and a time horizon of 1 month were used. The economic model was developed from reviews of effectiveness and cost-effectiveness and clinical experts. Secondary analysis explored the robustness of the results to changes in the timing and costs of cell salvage equipment, surgical procedure, use of transfusion protocols and time horizon of analysis. RESULTS: Overall, 668 studies were identified electronically for the update of the two systematic reviews. This included five RCTs, of which two were cell salvage and three preoperative autologous donation (PAD). Five published systematic reviews were identified for antifibrinolytics, fibrin sealants and restrictive transfusion triggers, PAD plus erythropoietin, erythropoietin alone and acute normovolaemic haemodilution (ANH). Twelve published studies reported full economic evaluations. All but two of the transfusion strategies significantly reduced exposure to allogeneic blood. The relative risk of exposure to allogeneic blood was 0.59 for the pooled trials of cell salvage (95% confidence interval: 0.48 to 0.73). This varied by the type and timing of cell salvage and type of surgical procedure. For cell salvage, the relative risk of allogeneic blood transfusion was higher in cardiac surgery than in orthopaedic surgery. Cell salvage had lower costs and slightly higher quality-adjusted life years compared with all of the alternative transfusion strategies except ANH. The likelihood that cell salvage is cost-effective compared with strategies other than ANH is over 50%. Most of the secondary analyses indicated similar results to the primary analysis. However, the primary and secondary analyses indicated that ANH may be more cost-effective than cell salvage. CONCLUSIONS: The available evidence indicates that cell salvage may be a cost-effective method to reduce exposure to allogeneic blood transfusion. However, ANH may be more cost-effective than cell salvage. The results of this analysis are subject to the low quality and reliability of the data used and the use of indirect comparisons. This may affect the reliability and robustness of the clinical and economic results. There is a need for further research that includes adequately powered high-quality RCTs to compare directly various blood transfusion strategies. These should include measures of health status, health-related quality of life and patient preferences for alternative transfusion strategies. Observational and tracking studies are needed to estimate reliably the incidence of adverse events and infections transmitted during blood transfusion and to identify the lifetime consequences of the serious hazards of transfusion on mortality, health status and health-related quality of life.

Frequency of post-ERCP pancreatitis in a single tertiary referral centre without and with routine prophylaxis with gabexate: a 6-year survey and cost-effectiveness analysis.

BACKGROUND AND STUDY AIMS: Several drugs have been used for the prevention of post-ERCP pancreatitis with conflicting results and no data referring to the routine use of a pharmacological prophylaxis have been published up to now. Aim of the study was to evaluate the frequency of post-ERCP pancreatitis and costs in a series of consecutive patients who have undergone ERCP procedures before and after the introduction of a routine prophylaxis with gabexate in all cases. PATIENTS AND METHODS: Data from 1312 patients who underwent ERCP procedures without gabexate prophylaxis and from 1149 consecutive patients with 1g i.v. gabexate, were retrospectively evaluated during a 6-year period. Patients were also subdivided in standard- and high-risk subjects, on the basis of patient- and technique-related risk factors: 984 subjects (39.9%) had one or more conditions that placed them at high risk for post-ERCP pancreatitis. RESULTS: Post-ERCP pancreatitis was reported in 76 out of 2461 patients (3.1%). The frequency of pancreatitis appeared significantly reduced in the gabexate period in comparison with before gabexate in overall cases (2.2% versus 3.9%; p=0.019); however, the reduction was significant only for high-risk patients (3.8% versus 7.3%; p=0.001). Severe hyperamylasaemia at 4-6h and 24h after the procedure was also significantly reduced only in high-risk patients (p=0.001). Routine prophylaxis with gabexate appeared cost-effective in high-risk patients. CONCLUSIONS: Routine gabexate prophylaxis was associated with a significant reduction of post-ERCP pancreatitis rate, severe hyperamylasaemia and hospitalisation-related costs only in high-risk patients. However, gabexate appeared unable to reduce the incidence of severe pancreatitis.