Eric J. Stanek

Extended-Release Niacin or Ezetimibe and Carotid Intima–Media Thickness

BACKGROUND Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein (HDL) cholesterol level or further lower the low-density lipoprotein (LDL) cholesterol level. METHODS We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively) had been achieved. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial. RESULTS The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter (P < 0.001), and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter) (P < 0.001). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months (P = 0.003), leading to significant reduction of both mean (P = 0.001) and maximal carotid intima-media thickness (P < or = 0.001 for all comparisons). Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness (R = -0.31, P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test). CONCLUSIONS This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe. (ClinicalTrials.gov number, NCT00397657.)

The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis): Final Results and the Impact of Medication Adherence, Dose, and Treatment Duration

OBJECTIVES This report describes the final results of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis) trial. BACKGROUND The ARBITER 6-HALTS trial was terminated early on the basis of a pre-specified interim analysis showing superiority of niacin over ezetimibe on change in carotid intima-media thickness (CIMT). After termination, an additional 107 subjects completed a close-out assessment. METHODS Patients with coronary heart disease (CHD) or CHD equivalent with low-density lipoprotein cholesterol <100 mg/dl and high-density lipoprotein cholesterol <50 mg/dl for men or 55 mg/dl for women while receiving stable statin treatment were randomly assigned to ezetimibe (10 mg/day) or extended-release niacin (target dose, 2,000 mg/day). The primary end point was change in mean CIMT, analyzed according to a last observation carried forward method. The relationships of study medication adherence, dosage, and cumulative exposure (product of adherence, dose, and time) with change in CIMT were explored. RESULTS Results in 315 patients included 208 with 14-month follow-up and 107 after mean treatment of 7 +/- 3 months. Niacin (n = 154) resulted in significant reduction (regression) in mean CIMT (-0.0102 +/- 0.0026 mm; p < 0.001) and maximal CIMT (-0.0124 +/- 0.0036 mm; p = 0.001), whereas ezetimibe (n = 161) did not reduce mean CIMT (-0.0016 +/- 0.0024 mm; p = 0.88) or maximal CIMT (-0.0005 +/- 0.0029 mm; p = 0.88) compared with baseline. There was a significant difference between ezetimibe and niacin treatment groups on mean changes in CIMT, favoring niacin, for both mean CIMT (p = 0.016) and maximal CIMT (p = 0.01). Increased cumulative drug exposure was related to regression of CIMT with niacin, and progression of CIMT with ezetimibe. CONCLUSIONS Niacin induces regression of CIMT and is superior to ezetimibe for patients taking statins. (Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis; NCT00397657).

Impact of Proton Pump Inhibitors on the Effectiveness of Clopidogrel After Coronary Stent Placement: The Clopidogrel Medco Outcomes Study

Study Objective. To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement.

Opportunity for Intervention to Achieve American Heart Association Guidelines for Optimal Lipid Levels in High-Risk Women in a Managed Care Setting

Background—The American Heart Association (AHA) recently established evidence-based recommendations for cardiovascular disease (CVD) prevention in women, including lipid management. This study evaluated optimal lipid-level attainment and treatment patterns on the basis of these guidelines in high-risk women in a managed care setting. Methods and Results—We conducted a historical prospective cohort analysis of a 1.1-million-member, integrated, managed-care database. Eligible high-risk women were those with evidence of previous CVD or risk equivalent who had a full lipid panel available between October 1, 1999, and September 30, 2000; were naive to lipid therapy; and had a minimum of 12 months health plan eligibility preindex and postindex lipid panel. Optimal lipid levels were defined as LDL cholesterol (LDL-C) <100 mg/dL, HDL cholesterol (HDL-C) >50 mg/dL, non–HDL-C <130 mg/dL, and triglycerides <150 mg/dL. Laboratory values and lipid pharmacotherapy were assessed longitudinally over the postindex follow-up (up to 36 months). A total of 8353 high-risk women (mean age, 66±14 years) with a mean follow-up of 27±8 months were included. Only 7% attained optimal combined lipid levels initially, and this increased to 12% after 36 months. Lipid-modifying therapy was initiated in 32% of patients, including 35% of women with LDL-C ≥100 mg/dL and 15% with LDL-C <100 mg/dL. Conclusions—Among high-risk women, few attained the AHA’s standards for all lipid fractions, and only one third received recommended drug therapy, highlighting significant opportunities to apply evidence-based recommendations to manage lipid abnormalities in high-risk women.

Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis

BACKGROUND Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis. METHODS We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response. RESULTS The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias. CONCLUSIONS In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).

Risk of cardiovascular events in patients at optimal values for combined lipid parameters

ABSTRACT Background: Current prevention guidelines support efforts to achieve optimal high-density lipoprotein (HDL‑C) and triglyceride (TG) values, in addition to low-density lipoprotein (LDL‑C) in order to reduce cardiovascular (CV) events. The study objective was to evaluate the risk of CV events in patients attaining versus not attaining combined (LDL‑C, HDL‑C, and TG) optimal lipid values. Methods/results: This retrospective cohort analysis was conducted using a 1.1 million member managed care database. Eligible patients had a full lipid panel between 10/1/99 and 9/30/00, were naive to lipid therapy, and had health plan eligibility 12 months pre- and post-index (baseline) lipid laboratory value. Optimal lipid values (LDL‑C, HDL‑C, and TG) were established using the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) guidelines, and patients were placed into one of four groups: none, one, two, or three lipid components non-optimal at baseline. The presence of cardiovascular risk, disease, and events were determined by selected International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) and Current Procedural Terminology (CPT codes). The definition of a CV event included: diagnosis of ischemic heart disease, peripheral arterial disease, stroke/TIA, or revascularization procedure. Odds ratios (OR) for a CV event associated with attainment of each optimal lipid fraction were determined by multivariate logistic regression. The study cohort included 30 348 patients, with a mean follow-up of 27 ± 8 months. Mean age was 66 ± 12 years; 16 549 (54%) were male; and 17 289 (57%) patients had coronary heart disease (CHD) or CHD risk equivalent. There were 5955 CV events that occurred in 4059 (13%) study patients. The presence of a single non-optimal lipid value slightly increased CV event risk [OR: 1.06; 95% CI: 0.95–1.18], whereas two or all three non-optimal lipid values significantly increased the risk of a CV event [OR: 1.22; 95% CI: 1.08–1.37; and 1.45; 95% CI: 1.24–1.68, respectively]. Limitations: As with all large observational databases there are potential limitations including: patient selection bias (e.g., more interventions in patients with greater illness, lack of mortality data, and frequency of lipid monitoring), unknown confounding variables, and potential coding errors. Conclusion: Not attaining optimal combined lipid values, independently and significantly, increased the risk of CV events in this large at-risk population with approximately 68 283 patient-years of follow-up. The combination of non-attainment of optimal LDL‑C with non-attainment of optimal HDL‑C or TG values, or both, increased the adjusted risk of CV events by 22–45%. Thus, therapeutic strategies should focus on assessment and management of multiple lipid abnormalities, and not on single lipid risk factor modification.

Twelve-Month Frequency of Drug-Metabolizing Enzyme and Transporter-Based Drug-Drug Interaction Potential in Patients Receiving Oral Enzyme-Targeted Kinase Inhibitor Antineoplastic Agents

OBJECTIVE To describe 12-month rates and patterns of coprescription of drugs that potentially create drug-drug interactions (DDIs) through shared metabolic or transport pathways for 9 enzyme-targeted kinase inhibitor oral antineoplastic drugs (OADs). PATIENTS AND METHODS We used a deidentified pharmacy claims database identifying patients prescribed dasatinib, erlotinib, everolimus, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, or sunitinib between January 1, 2008, and May 31, 2010. Coprescribing was 1 or more overlapping days of supply between the OAD and potential DDI drugs during the 12-month period beginning on the OAD index date. Product labels identified the cytochrome P450 metabolic enzymes used and whether P-glycoprotein was used by the OADs. Drugs that induce and/or inhibit these pathways were identified from the label and online resources. RESULTS Sample sizes ranged from 96 (pazopanib group) to 4617 (imatinib group). Coprescribing rates with drugs that may decrease OAD effectiveness were 359/1546 (23%) (sunitinib group) to 1851/3263 (57%) (erlotinib group). Coprescribing rates with drugs that may increase OAD toxicity were 364/1546 (24%) (sunitinib group) to 71/96 (74%) (pazopanib group). Patients coprescribed DDI drugs had a median of 1 to 4 more medications present on the OAD index date than those not coprescribed a DDI drug. Most groups coprescribed DDI drugs had a median of 180 or more OAD days of supply during follow-up. The proportion of OAD days of supply with overlapping days of DDI drugs ranged from 7% to 85%. Generally, oncologists prescribed the OAD and nononcologists the DDI drug. CONCLUSION Coprescription of drugs that induce or inhibit metabolic pathways used by enzyme-targeted kinase inhibitor OADs is high. The clinical consequences need further study.

Paradoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe

AIMS Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) but has complex actions on cholesterol transport and metabolism, and thus, LDL-C reduction may not solely define its overall effects. We explored the relationship between treatment effects and cumulative exposure to ezetimibe, with its effects on carotid intima-media thickness (CIMT) in ARBITER 6-HALTS. METHODS AND RESULTS This analysis includes the 159 patients randomized to ezetimibe within ARBITER 6-HALTS that completed the final imaging endpoint assessment. Eligibility criteria for ARBITER 6-HALTS included known coronary artery disease (CAD) or high risk for coronary heart disease, and treatment with a statin with LDL-C <100 mg/dL and high-density lipoprotein cholesterol <50 or 55 mg/dL for men and women, respectively. The mean CIMT was measured in the far wall of the distal common carotid artery. We analysed the univariate and multivariate relationships of the change in CIMT with baseline characteristics, on-treatment effects, and cumulative ezetimibe exposure (treatment duration × dose × adherence). Ezetimibe reduced LDL-C from 84 ± 23 to 66 ± 20 mg/dL. No net effect on CIMT was observed (baseline CIMT 0.898 ± 0.151 mm; net change -0.002 mm; P = 0.52). There was an inverse relationship between LDL-C and change in CIMT such that greater reductions in LDL-C were associated with greater CIMT progression (r = -0.266; P < 0.001). Change in CIMT also had univariate associations with baseline LDL-C, triglycerides (TG), high-sensitive C-reactive protein, and systolic blood pressure and was directly associated with the change in TG and inversely associated with the change in high-sensitive C-reactive protein. Multivariable models controlling for change in LDL-C, cumulative ezetimibe exposure, and baseline and on-treatment variables showed that both increased LDL-C reduction (P = 0.005) and cumulative drug exposure (P = 0.02) were associated with ezetimibe-associated CIMT progression. CONCLUSION Among CAD and high-risk patients on statin therapy in the ARBITER-6 trial, ezetimibe leads to paradoxical progression of CIMT in association with both greater LDL-C reduction and cumulative drug exposure. These findings may suggest the presence of off-target actions of ezetimibe. TRIAL REGISTRATION ClinicalTrials.gov number: NCT00397657.

Statin use in asthmatics on inhaled corticosteroids is associated with decreased risk of emergency department visits.

Abstract Objective: Statins are hypothesized to have beneficial effects in asthma management through their pleiotropic anti-inflammatory effects. Several studies have examined this relationship, but have yielded conflicting results. This study investigates the effect of statin use on asthma-related hospitalizations and/or emergency department (ED) visits, and whether this relationship varies by concomitant inhaled corticosteroid (ICS) in a large cohort of asthma patients. Methods: Subjects with asthma, a recent history of asthma exacerbation, and who were 18 years or older were selected from the population-based Medco Health Solutions administrative database over a 1 year period. Prescription claims for statins and asthma medications, and asthma-related hospitalizations and/or ED visits were ascertained over a 12 month follow-up period. Subjects were stratified into two groups based on their ICS use. Results: A total of 3747 ICS users and 2905 non-ICS users were included in this study. Statin users represented 21% of ICS users and 11% of non-users. Among ICS users, statin use was significantly associated with decreased odds of asthma-related ED visits (OR = 0.77, 95% CI 0.64–0.94, p = 0.008), but not with asthma-related hospitalizations (OR = 1.09, 95% CI 0.92–1.30, p = 0.31). No significant associations were found among non-ICS users (for asthma-related ED visits: OR = 0.92, 95% CI 0.57–1.49, p = 0.73; asthma-related hospitalizations: OR = 1.10, 95% CI 0.85–1.41, p = 0.48). The statistical interactions between ICS and statin use on asthma-related hospitalizations and/or ED visits were not significant. Conclusion: Statin use is associated with fewer ED visits in asthma patients who are using ICS.

On pharmacogenomics in pharmacy benefit management.

Recently, the separate trajectories of pharmacy benefit management and pharmacogenomics converged. Pharmacogenomic tests have become more widely available for clinical use and at costs within the range of typical health care services. Pharmacy benefit payers continue to seek the precision they can apply to their coverage policies and clinical programs that pharmacogenomics offers. We describe how pharmacogenomics can now make sense as part of a pharmacy benefit and also how pharmacogenomics can be applied in a benefit coverage policy and clinical programs. Detail is provided on clinical program development and implementation processes featuring pharmacogenomics. We also discuss the research needed to support ongoing program development involving pharmacogenomics and describe the current roles of benefit payers and administrators in these research efforts. The legal and ethical dimensions of applying pharmacogenomics in pharmacy benefits are covered and in particular how benefit payers and administrators need to navigate between genetic exceptionalism and applicable laws and regulations. Finally, some thoughts are provided on future opportunities and challenges for pharmacogenomics in pharmacy benefit management and pharmacy in general.