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Aims: High resting heart rate (HR ≥70 b.p.m.) is associated with worse clinical outcomes in heart failure with reduced ejection fraction (HFrEF). Heart rate, guideline-directed medical therapy (GDMT) with beta-blocker (BB), and cardiovascular outcomes were evaluated in a large integrated health network. Methods and results: Using electronic health records we examined patients with chronic HFrEF (ejection fraction ≤35%) in sinus rhythm with at least 1 year of follow-up and available serial HR and medication data between 1 January 2000 and 31 December 2014. Among 6071 patients followed for median of 1330 days across 73 586 total visits, median HR remained stable over time with 61.2% of the follow-up period with HR ≥70 b.p.m. At baseline, 27.9% of patients were on ≥ 50% GDMT target BB dose, 16.2% subjects at baseline, and 19.4% at the end of follow-up had HR ≥70 b.p.m. despite receiving ≥50% of target BB dose. In adjusted analyses, baseline HR was associated with all-cause mortality/heart failure (HF) hospitalization (hazard ratio 1.28 per 15 b.p.m. Heart rate increase; P < 0.001). In comparison, hazard ratio for BB dose was 0.97 (per 77.2 mg increase; P = 0.36). When evaluating patients based on HR and BB dose there was a significant difference in the cumulative hazard for all-cause mortality or HF hospitalization (P < 0.001). For HF hospitalization, hazard appeared to be more closely associated with HR rather than BB dose (P = 0.01). Conclusion: In a real-world analysis, high resting HR was common in HFrEF patients and associated with adverse outcomes. Opportunities exist to improve GDMT and achieve HR control.

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PURPOSE: Compare medical expenditures among adults with statin-associated adverse effects (SAAE) and high statin adherence (HSA) following myocardial infarction (MI). METHODS: We analyzed expenditures in 2016 US dollars among Medicare beneficiaries with SAAE (n = 1741) and HSA (n = 55,567) who were ≥ 66 years of age and initiated moderate/high-intensity statins following an MI in 2007-2013. SAAE were identified through a claims-based algorithm, which included down-titrating statins and initiating ezetimibe, switching to ezetimibe monotherapy, having a rhabdomyolysis or antihyperlipidemic adverse event followed by statin down-titration or discontinuation, or switching between ≥ 3 statin types within 365 days following MI. HSA was defined by having a statin available to take for ≥ 80% of the days in the 365 days following MI. RESULTS: Expenditures among beneficiaries with SAAE and HSA were $40,776 (95% CI $38,329-$43,223) and $26,728 ($26,482-$26,974), respectively, in the 365 days following MI, and $34,238 ($31,396-$37,080) and $29,053 ($28,605-$29,500), respectively, for every year after the first 365 days. Multivariable-adjusted ratios comparing expenditures among beneficiaries with SAAE versus HSA in the first 365 days and after the first 365 days following MI were 1.51 (95% CI 1.43-1.59) and 1.23 (1.12-1.34), respectively. Inpatient and outpatient expenditures were higher among beneficiaries with SAAE versus HSA during and after the first 365 days following MI. Compared to beneficiaries with HSA, medication expenditures among those with SAAE were similar in the 365 days following MI, but higher afterwards. Other medical expenditures were higher among beneficiaries with SAAE versus HSA. CONCLUSION: SAAE are associated with increased expenditures following MI compared with HSA.

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Importance: Although PCSK9 inhibitors (PCSK9i) were approved in 2015, their high cost has led to strict prior authorization practices and high copays, and use of PSCK9i in clinical practice has been low. Objective: To evaluate patient access to PCSK9i among those prescribed therapy. Design, Setting, and Participants: Using pharmacy transaction data, we evaluated 45 029 patients who were newly prescribed PCSK9i in the United States between August 1, 2015, and July 31, 2016. Main Outcomes and Measures: The proportion of PCSK9i prescriptions approved and abandoned (approved but unfilled); multivariable analyses examined factors associated with approval/abandonment including payor, prescriber specialty, pharmacy benefit manager, out-of-pocket cost (copay), clinical diagnoses, lipid-lowering medication use, and low-density lipoprotein cholesterol levels. Results: Of patients given an incident PCSK9i prescription, 51.2% were women, 56.6% were 65 years or older, and 52.5% had governmental insurance. Of the patients given a prescription, 20.8% received approval on the first day, and 47.2% ever received approval. Of those approved, 65.3% filled the prescription, resulting in 30.9% of those prescribed PCSK9i ever receiving therapy. After adjustment, patients who were older, male, and had atherosclerotic cardiovascular disease were more likely to be approved, but approval rates did not vary by patient low-density lipoprotein cholesterol level nor statin use. Other factors associated with drug approval included having government vs commercial insurance (odds ratio [OR], 3.3; 95% CI, 2.8-3.8), and those filled at a specialty vs retail pharmacy (OR, 1.96; 95% CI, 1.66-2.33). Approval rates varied nearly 3-fold among the top 10 largest pharmacy benefit managers. Prescription abandonment by patients was most associated with copay costs (C statistic, 0.86); with abandonment rates ranging from 7.5% for those with $0 copay to more than 75% for copays greater than $350. Conclusions and Relevance: In the first year of availability, only half of patients prescribed a PCSK9i received approval, and one-third of approved prescriptions were never filled owing to copay.

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OBJECTIVE: The objective of this study was to assess the costs associated with the hospitalization and the cumulative 30-, 60-, and 90-day readmission rates in a cohort of Medicare beneficiaries with heart failure (HF). METHODS: This was a retrospective, observational study based on data from the national 5% sample of Medicare beneficiaries. Inpatient data were gathered for Medicare beneficiaries with at least one HF-related hospitalization between July 1, 2005, and December 31, 2011. The primary end point was the average per-patient cost of hospitalization for individuals with HF. Secondary end points included the cumulative rate of hospitalization, the average length of hospital stay, and the cumulative 30-, 60-, and 90-day readmission rates. RESULTS: Data from 63,678 patients with a mean age of 81.8 years were included in the analysis. All costs were inflated to $2,015 based on the medical care component of the Consumer Price Index. The mean per-patient cost of an HF-related hospitalization was $14,631. The mean per-patient cost of a cardiovascular (CV)-related or all-cause hospitalization was $16,000 and $15,924, respectively. The cumulative rate of all-cause hospitalization was 218.8 admissions per 100 person-years, and the median length of stay for HF-related, CV-related, and all-cause hospitalizations was 5 days. Also, 22.3% of patients were readmitted within 30 days, 33.3% were readmitted within 60 days, and 40.2% were readmitted within 90 days. CONCLUSION: The costs associated with hospitalization for Medicare beneficiaries with HF are substantial and are compounded by a high rate of readmission.

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BACKGROUND: Elevated heart rate of ≥70 beats/min despite ß-blocker use may represent a new treatment target in patients in sinus rhythm with heart failure with reduced ejection fraction. However, little is known about the proportion of patients with elevated heart rate despite ß-blocker therapy. METHODS: We analyzed data from a large clinical registry to describe discharge heart rate as a function of ß-blocker use and dose. We included patients with left ventricular ejection fraction <40% who were admitted with acute heart failure in 2003 and 2004; we excluded patients with a history of atrial arrhythmia or with a pacemaker or cardiac resynchronization therapy. We considered the ß-blockers carvedilol, metoprolol succinate, bisoprolol, atenolol, and metoprolol tartrate and described discharge dose as a percentage of target dose (ie, <25%, 25%-49%, 50%-99%, and ≥100%). RESULTS: Among 10,696 patients, median discharge heart rate was 76 beats/min (interquartile range [IQR] 66-86 beats/min). Of these, 7,826 (73%) were discharged on a ß-blocker. For patients not on a ß-blocker, median discharge heart rate was 80 beats/min (IQR 70-89 beats/min), compared with 78 beats/min (IQR 69-88 beats/min) on <25% of target dose, 75 beats/min (IQR 66-85 beats/min) on 25% to 49% of target dose, 74 beats/min (IQR 66-82 beats/min) on 50% to 99% of target dose, and 72 beats/min (IQR 65% to 80%) on 100% of target dose or greater (P < .001). Most patients, 7,647 (71%), had a discharge heart rate of ≥70 beats/min, including 1,460 (63%) of 2,301 patients discharged on 50% of target dose or greater. CONCLUSIONS: Despite treatment with ß-blockers, a substantial proportion of patients hospitalized with heart failure with reduced ejection fraction have elevated heart rate at discharge.

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There are limited data describing outcomes associated with an elevated heart rate in patients with heart failure with reduced ejection fraction (HFrEF) in routine clinical practice. We identified patients with HFrEF at Duke University Hospital undergoing echocardiograms and heart rate assessments without paced rhythms or atrial fibrillation. Outcomes (all-cause mortality or hospitalization and medical costs per day alive) were assessed using electronic medical records, hospital cost accounting data, and national death records. Patients were stratified by heart rate (<70 and ≥70 beats/min) and compared using generalized linear models specified with gamma error distributions and log links for costs and proportional hazard models for mortality/hospitalization. Of 722 eligible patients, 582 patients (81%) were treated with ß blockers. The median heart rate was 81 beats/min (25th and 75th percentiles 69 to 96) and 527 patients (73%) had a heart rate ≥70 beats/min. After multivariate adjustment, a heart rate ≥70 beats/min was associated with increased 1-year all-cause mortality or hospitalization, hazard ratio 1.37 (95% CI 1.07 to 1.75) and increased medical costs per day alive, cost ratio 2.03 (95% CI 1.53 to 2.69). In conclusion, at a large tertiary care center, despite broad use of ß blockers, a heart rate ≥70 beats/min was observed in 73% of patients with HFrEF and associated with worse 1-year outcomes and increased direct medical costs per day alive.

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AIMS: Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up-regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression. METHODS: The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6-hydroxychlorzoxazone in serum and urine were analysed by high-performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase-polymerase chain reaction. RESULTS: The mean +/- s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration-time curve was significantly (P

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AIMS: To examine the effects of an oral contraceptive containing ethinyloestradiol and norgestrel on intestinal and hepatic CYP3A activity using midazolam as a probe substrate. METHODS: In a nonblinded sequential study, nine healthy women received simultaneous doses of intravenous midazolam (0.05 mg kg(-1)) and oral 15N3-midazolam (3 mg) on days 0, 4, 6, 8, and 14. On study day 5, Ovral(50 microg ethinyloestradiol/500 microg norgestrel) was administered for 10 days. Serum and urine samples were assayed for midazolam, 15N3-midazolam and metabolites by liquid chromatography-mass spectrometry. A Digit Symbol Substitution Test (DSST) was used to assess changes in the pharmacodynamic activity of midazolam. RESULTS: Moderate (% CV 26-46) interindividual variability in the pharmacokinetics of midazolam were observed. Compared with baseline, AUC(0,infinity)iv ratios (95% CIs) after 2, 4, and 10 days treatment with OC were 89% (79, 101), 96% (85, 109), and 88% (77, 99), respectively. The AUC(0,infinity)oral ratios (95% CIs) were 101% (82, 125), 105% (85, 130), and 114% (92, 141), respectively, after 2, 4, and 10 days OC treatment compared with baseline. Concomitant administration of the oral contraceptive, Ovral for 2, 4 or 10 days did not significantly alter the area under the curve, clearance, or half-life of midazolam after either oral or intravenous administration. No alterations in pharmacodynamic effects of midazolam were observed between treatment days. Mean DSST scores strongly correlated with mean total midazolam blood concentrations (r = -0.936). CONCLUSIONS: Administration of Ovral for 10 days had no impact on intestinal or hepatic CYP3A activity as determined by midazolam metabolism.

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