Increased Risk of New-Onset Hypertension in Patients With Narcolepsy Initiating Sodium Oxybate: A Real-World Study.

OBJECTIVE: To compare intermediate-term risk of new-onset hypertension between normotensive patients with narcolepsy initiating sodium oxybate (SXB cohort) and those not initiating sodium oxybate (control cohort). PATIENTS AND METHODS: This retrospective cohort study used MarketScan administrative claims data from January 1, 2014, to February 29, 2020. Eligible patients were 18 years of age or older with continuous enrollment (≥180 days before and after cohort entry), had one or more narcolepsy claims or a prescription fill for sodium oxybate, had no history of hypertension or antihypertensive medication use, and had no use of sodium oxybate within 13 months before cohort entry. Patients in the SXB and control cohorts were matched 1:2 for the propensity score to balance baseline characteristics. End points were (1) a composite of new-onset hypertension diagnosis or antihypertensive medication initiation and (2) new-onset hypertension diagnosis. Patients were monitored for 180 days, until outcome occurrence, sodium oxybate discontinuation (SXB cohort), or sodium oxybate initiation (control cohort). Risk per 100 patients was reported; differences were evaluated using logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The SXB and control cohorts included 954 and 1908 patients, respectively. Risk of new-onset hypertension diagnosis or antihypertensive medication initiation was higher in the SXB cohort than in the control cohort (6.60 vs 4.20 per 100 patients; OR, 1.61; 95% CI, 1.15 to 2.27). Risk of a new-onset hypertension diagnosis only in the SXB cohort was 0.94 per 100 patients and 0.52 per 100 patients in the control cohort (OR, 1.81; 95% CI, 0.73 to 4.46). CONCLUSION: In this study, sodium oxybate use was associated with a new-onset hypertension diagnosis or antihypertensive medication initiation in normotensive patients with narcolepsy.

Cardiovascular Burden of Narcolepsy Disease (CV-BOND): a real-world evidence study.

STUDY OBJECTIVES: Narcolepsy is associated with cardiovascular risk factors; however, the risk of new-onset cardiovascular events in this population is unknown. This real-world study evaluated the excess risk of new-onset cardiovascular events in U.S. adults with narcolepsy. METHODS: A retrospective cohort study using IBM MarketScan administrative claims data (2014-2019) was conducted. A narcolepsy cohort, comprising adults (≥18 years) with at least two outpatient claims containing a narcolepsy diagnosis, of which at least one was non-diagnostic, was matched to a non-narcolepsy control cohort (1:3) based on cohort entry date, age, sex, geographic region, and insurance type. The relative risk of new-onset cardiovascular events was estimated using a multivariable Cox proportional hazards model to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: The narcolepsy and matched non-narcolepsy control cohorts included 12 816 and 38 441 individuals, respectively. At baseline, cohort demographics were generally similar; however, patients with narcolepsy had more comorbidities. In adjusted analyses, the risk of new-onset cardiovascular events was higher in the narcolepsy cohort compared with the control cohort: any stroke (HR [95% CI], 1.71 [1.24, 2.34]); heart failure (1.35 [1.03, 1.76]); ischemic stroke (1.67 [1.19, 2.34]); major adverse cardiac event (1.45 [1.20, 1.74]); grouped instances of stroke, atrial fibrillation, or edema (1.48 [1.25, 1.74]); and cardiovascular disease (1.30 [1.08, 1.56]). CONCLUSION: Individuals with narcolepsy are at increased risk of new-onset cardiovascular events compared with individuals without narcolepsy. Physicians should consider cardiovascular risk in patients with narcolepsy when weighing treatment options.

Transferability of real-world data across borders for regulatory and health technology assessment decision-making.

Recently, there has been increased consideration of real-world data (RWD) and real-world evidence (RWE) in regulatory and health technology assessment (HTA) decision-making. Due to challenges in identifying high-quality and relevant RWD sources, researchers and regulatory/HTA bodies may turn to RWD generated in locales outside of the locale of interest (referred to as "transferring RWD"). We therefore performed a review of stakeholder guidance as well as selected case studies to identify themes for researchers to consider when transferring RWD from one jurisdiction to another. Our review highlighted that there is limited consensus on defining decision-grade, transferred RWD; certain stakeholders have issued relevant guidance, but the recommendations are high-level and additional effort is needed to generate comprehensive guidance. Additionally, the case studies revealed that RWD transferability has not been a consistent concern for regulatory/HTA bodies and that more focus has been put on the evaluation of internal validity. To help develop transferability best practices (alongside internal validity best practices), we suggest that researchers address the following considerations in their justification for transferring RWD: treatment pathways, nature of the healthcare system, incidence/prevalence of indication, and patient demographics. We also recommend that RWD transferability should garner more attention as the use of imported RWD could open doors to high-quality data sources and potentially reduce methodological issues that often arise in the use of local RWD; we thus hope this review provides a foundation for further dialogue around the suitability and utility of transferred RWD in the regulatory/HTA decision-making space.

Predicting waist circumference from body mass index.

BACKGROUND: Being overweight or obese increases risk for cardiometabolic disorders. Although both body mass index (BMI) and waist circumference (WC) measure the level of overweight and obesity, WC may be more important because of its closer relationship to total body fat. Because WC is typically not assessed in clinical practice, this study sought to develop and verify a model to predict WC from BMI and demographic data, and to use the predicted WC to assess cardiometabolic risk. METHODS: Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES) and the Atherosclerosis Risk in Communities Study (ARIC). We developed linear regression models for men and women using NHANES data, fitting waist circumference as a function of BMI. For validation, those regressions were applied to ARIC data, assigning a predicted WC to each individual. We used the predicted WC to assess abdominal obesity and cardiometabolic risk. RESULTS: The model correctly classified 88.4% of NHANES subjects with respect to abdominal obesity. Median differences between actual and predicted WC were -0.07 cm for men and 0.11 cm for women. In ARIC, the model closely estimated the observed WC (median difference: -0.34 cm for men, +3.94 cm for women), correctly classifying 86.1% of ARIC subjects with respect to abdominal obesity and 91.5% to 99.5% as to cardiometabolic risk.The model is generalizable to Caucasian and African-American adult populations because it was constructed from data on a large, population-based sample of men and women in the United States, and then validated in a population with a larger representation of African-Americans. CONCLUSIONS: The model accurately estimates WC and identifies cardiometabolic risk. It should be useful for health care practitioners and public health officials who wish to identify individuals and populations at risk for cardiometabolic disease when WC data are unavailable.

Direct and indirect costs of patients treated with extended-release oxymorphone HCl or controlled-release oxycodone HCl.

OBJECTIVE: Compare direct and indirect costs of oxymorphone extended-release ('oxymorphone') and oxycodone controlled-release ('oxycodone') users. METHODS: Patients, aged 18+, with ≥1 claim for oxymorphone/oxycodone, Q2:2006-Q4:2009, were selected from a de-identified private payer claims database and observed from the first such claim ('index date') until the earliest of: use of comparator drug; end of continuous eligibility; 12 months ('study period'). Patients with claims for any formulation of the comparator drug during the first 30 days of the study period were excluded. Direct (medical and drug) costs paid by private insurers were reported for patients aged 18-64 (n = 8354) and 65+(n = 3515), as well as sub-sets without cancer (n = 7090 and n = 2444, respectively). Indirect costs (medically-related absenteeism and disability) were reported for all employees, aged 18-64 (n = 1313), and employees without cancer (n = 1146). Multivariate models were used to estimate risk-adjusted costs controlling for patient characteristics. RESULTS: Oxymorphone users, aged 18-64, had lower drug costs ($693 vs $763, p = 0.0035) and similar medical costs ($1875 vs $1976, p = 0.3570) per patient-month compared with oxycodone users (mean follow-up 236 and 280 days, respectively). Indirect costs were not different ($662 vs $670, p = 0.9370). Oxymorphone users, aged 65+, had similar Medicare supplemental drug costs ($533 vs $588, p = 0.0840) and lower medical costs ($459 vs $747, p < 0.0001). Results were comparable for subsets without cancer. LIMITATIONS: Patients with concomitant use of oxymorphone and oxycodone were excluded. CONCLUSIONS: Oxymorphone users incur lower risk-adjusted costs in several cost categories, compared with oxycodone users, and no higher costs in any of the examined categories.

Daily average consumption of 2 long-acting opioids: an interrupted time series analysis.

BACKGROUND: Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010. OBJECTIVE: To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR. METHODS: This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugs-oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed. RESULTS: The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced. CONCLUSION: The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER.

A comparison of daily average consumption (DACON) of oxycodone and oxymorphone long-acting oral tablets.

BACKGROUND: The utilization of high-potency opioids is an important component of chronic pain management, and appropriate utilization of these medicines is a common concern of payers. Two of the most commonly prescribed oral long-acting opioids, oxycodone controlled-release (CR) and oxymorphone extended-release (ER), are FDA-approved for twice-daily dosing, which equates to a theoretical average consumption (DACON) of 2 tablets per day. DACON values greater than 2 have budget and policy implications for managed care pharmacists. OBJECTIVES: To assess from the perspective of the pharmacy benefit decision maker the DACONs of oxycodone CR and oxymorphone ER. METHODS: The main outcome measure for the analysis was DACON. Pharmacy and medical claims data from a large commercially insured population (i3 InVision Data Mart database) were analyzed to identify patients with at least 1 pharmacy claim for either oxycodone CR or oxymorphone ER from July 1, 2007, to September 30, 2009. After an initial 30-day titration period, all subjects included in the study had 1 or more claims totaling at least a 90-day supply of either study drug during the subsequent 90 days (DACON measurement period). Patients were excluded if there was evidence of a switch from one to the other study opioid during the 90-day measurement period. There were no limitations on the use of other opioids, either short- or long-acting, during either the DACON measurement period or the previous 6 months (baseline period). In addition, patients were excluded if the enrollee was younger than 18 years old, pregnant, did not have continuous insurance coverage for the 6 months before and after the start of the 90-day DACON measurement, or were enrolled in an HMO plan. Bivariate analyses were performed with between-group differences in DACON values assessed using t-tests and Wilcoxon rank sum tests. Patient characteristics including age, sex, geographic location, and baseline Charlson Comorbidity Index (CCI) for each drug group were evaluated descriptively using either the Pearson chi-square test or t-test. Multivariate analyses were conducted using generalized linear models (GLM) to adjust for the observed heterogeneity among patients in the observational database. For the GLMs, the gamma distribution and log link function were chosen to account for non-normal distributions of DACON. Independent variables included study drug, tablet strengths, age, sex, CCI, the maximum days gap between prescription refills during the DACON measurement period, and other opioid medication use. Several sensitivity analyses were conducted to verify all findings. RESULTS: The final analyses were conducted on 6,567 oxycodone CR patients and 796 oxymorphone ER patients. The unadjusted DACON mean value for the highest strength of oxycodone CR 80 milligrams (mg) was 3.9, compared with 2.9 for oxymorphone ER 40 mg (P < 0.001); mean DACON values were 3.0 versus 2.4, respectively, for lower strengths (P < 0.001) and 3.1 versus 2.5 for all strengths (P < 0.001). After adjusting for age, sex, CCI, maximum gap days, and other opioid medication use, a risk-adjusted mean difference in DACON remained, with oxycodone CR patients receiving on average 0.6 tablets more per day than those dispensed oxymorphone ER (P < 0.001). The direction, magnitude, and statistical significance of these differences were essentially unchanged in sensitivity analyses. CONCLUSIONS: On average during a 90-day time period, patients taking oxymorphone ER consumed 0.6 fewer tablets per day than did patients taking oxycodone CR. Further research is necessary to see if this difference amounts to cost savings for health plans that provide prescription reimbursement for patients with chronic pain syndromes.

Prevalence of exposure to potential CYP450 pharmacokinetic drug-drug interactions among patients with chronic low back pain taking opioids.

Drug-drug interactions (DDIs) have been defined as two or more drugs interacting in such a way that the effectiveness and/or toxicity of one or all drugs are changed. Patients taking more than one drug metabolized through the cytochrome P450 (CYP450) enzyme system, including some, but not all, opioids experience a drug-drug exposure (DDE), which may result in a potentially dangerous DDI. Using a retrospective analysis of a large commercial claims database and a Medicare database, we evaluated DDEs that have the potential to cause DDIs among chronic low back pain (cLBP) patients on long-term opioid analgesia, which metabolizes through the CYP450 enzyme system, concomitant with other CYP450-metabolized drug(s). The overall prevalence of DDEs among cLBP patients was 27%. Women had a higher prevalence of DDEs (30.6% vs. 22% for men). Patients aged 45 to 55 and 56 to 64 years had the highest prevalence of DDEs (30.4% and 29.8%, respectively), followed by patients 34 to 45 years (27.9%). For patients>65 years, the prevalence of DDEs was 23.1%. In general, the prevalence of DDEs was fairly consistent across age ranges in this population. This study suggests that DDEs are common in the cLBP population. When selecting an opioid to treat cLBP, physicians should consider the potential for exposure of these patients to drugs that might unfavorably interact and, for that reason, the use of opioids that do not rely on the CYP450 system as their primary means of metabolism might be worthy of consideration.

Comparing healthcare costs of Medicaid patients with postherpetic neuralgia (PHN) treated with lidocaine patch 5% versus gabapentin or pregabalin.

OBJECTIVE: To compare healthcare resource utilization and costs of postherpetic neuralgia (PHN) patients initiating lidocaine patch 5% (lidocaine patch) or oral gabapentin/pregabalin. METHODS: Patients with PHN diagnosis, or herpes zoster diagnosis and ≥30 days PHN-recommended treatment were selected from de-identified Medicaid claims data from Florida, Iowa, Missouri, and New Jersey, 1999-2007. Patients initiated monotherapy with lidocaine patch or gabapentin/pregabalin after PHN diagnosis, had continuous eligibility 6 months before (baseline) and 6 months after (study period) medication index date, and were ≥18 years old. Lidocaine patch patients were matched to gabapentin/pregabalin patients based on their propensity to initiate treatment. Study period resource utilization and costs from a Medicaid perspective were compared between treatment groups using univariate analysis. RESULTS: Matched patients were on average 61.3 years old, approximately 73% were women, and 55% had other painful conditions during the baseline period. 6-month per patient PHN-related prescription drug costs were similar for matched lidocaine patch (n=312) and gabapentin/pregabalin (n=312) patients ($854 vs. 820, p=0.75), while PHN-related medical costs appeared lower in the lidocaine patch group ($145 vs. 353, p=0.12). Furthermore, there were no statistically significant differences between treatment groups during the observation period in overall resource utilization, total prescription drug costs, and total medical costs per patient. CONCLUSIONS: In spite of higher list prices, PHN patients treated with lidocaine patch cost no more than patients treated with gabapentin or pregabalin in terms of overall healthcare costs over the 6-month study period. The study suggests that PHN-related medical costs may be lower among lidocaine patch patients. LIMITATIONS: Findings are based on a Medicaid sample and may not be generalizable to all PHN patients.

Descriptive analysis of Medicaid patients with postherpetic neuralgia treated with lidocaine patch 5%.

OBJECTIVES: To compare demographic and comorbidity profiles and healthcare costs of Medicaid patients with postherpetic neuralgia (PHN) treated with lidocaine patch 5% (lidocaine patch) versus patients not treated with the lidocaine patch. Repeat comparison for the subset of patients treated in long-term care (LTC) settings. METHODS: Patients, age≥18 years, with PHN diagnosis, or PHN-likely patients with herpes zoster diagnosis and ≥30 days of PHN-recommended treatment, were identified in Medicaid claims from Florida, Iowa, Missouri, and New Jersey (1999-2007). Patients had continuous eligibility 6 months before (baseline) and 12 months after (study period) the PHN index date. Patients with ≥1 claim for a lidocaine patch during the study period (n=872) were compared to patients without a lidocaine patch claim (comparison group). Baseline characteristics, study period treatment and healthcare costs (reimbursements by Medicaid for medical services and prescription drugs) were compared between groups using univariate analyses. RESULTS: PHN patients in the lidocaine patch group were older (64.5 vs. 62.2 years; p=0.002) and had higher rates of pain-related comorbidities (e.g., back/neck pain, osteoarthritis) than comparison patients. Average PHN-related drug costs per patient were higher ($1994 vs. 1137; p<0.0001) among lidocaine patch patients, with lidocaine patch accounting for $505 of the difference. PHN-related medical costs appeared lower in the lidocaine patch group, although not statistically significant ($983 vs. 1294; p=0.1348). No significant differences were found in total healthcare costs ($20,175 vs. 19,124; p=0.3720) across groups, despite higher total prescription drug costs among lidocaine patch patients. A similar pattern was observed among LTC patients. CONCLUSIONS: Despite higher rates of comorbidities and prescription drug costs, lidocaine patch patients had similar study period healthcare costs as comparison patients. The cost of the lidocaine patch represented a small fraction of overall costs incurred over the study period. LIMITATIONS: Findings are based on a Medicaid sample and may not be generalizable to all PHN patients.

Association of cardiometabolic risk factors and prevalent cardiovascular events.

BACKGROUND: Although cardiovascular disease causes substantial morbidity and mortality, how individual and groups of risk factors contribute to cardiovascular outcomes is incompletely understood. This study evaluated cardiometabolic risk factors and their relationship to prevalent diagnosis of acute myocardial infarction (AMI) and stroke. METHODS: We used retrospective data from 3 integrated health-care systems that systematically collect and store detailed patient-level data. Adult enrollees were eligible for inclusion if they had all of the following clinical measurements: weight, height, blood pressure, high density lipoproteins, triglycerides, and fasting blood glucose or evidence of diabetes from July 1, 2003, to June 30, 2005. We used National Cholesterol Education Program Adult Treatment Panel III guidelines to determine qualifying levels for cardiometabolic risk factors. RESULTS: A total of 170,648 persons met the inclusion/exclusion criteria; 11,757 had no qualifying risk factors, 25,684 had 1, 38,176 had 2, and 95,031 had 3 or more risk factors. Compared to those without risk factors, persons with any 1 risk factor were 2.21 (95% confidence interval [CI], 1.78-2.74) times more likely to have had a diagnosis of AMI or stroke. The risk increased to 2.79 (95% CI, 2.26-3.42) for persons with 2, 3.45 (95% CI, 2.80-4.24) for persons with 3, 4.35 (95% CI, 3.54-5.35) for persons with 4, and 5.73 (95% CI, 4.65-7.07) for persons with 5 risk factors. The highest risk was conferred by having the combination of risk factors of diabetes, hypertension, and dyslipidemia, with or without weight risk. CONCLUSIONS: This study demonstrates a direct association between an increasing number of cardiometabolic risk factors and prevalent diagnosis of AMI and stroke. The combination of risk factors conferring the highest risk was diabetes, hypertension, and dyslipidemia.

The effect of obesity and cardiometabolic risk factors on expenditures and productivity in the United States.

OBJECTIVE: To examine the effect of obesity and cardiometabolic risk factors on medical expenditures and missed work days. METHODS AND PROCEDURES: The 2000 and 2002 Medical Expenditure Panel Survey (MEPS), a nationally representative survey of the US population, was used to estimate the marginal effect of obesity (BMI > or = 30) on annual per-person medical expenditures and missed work days for patients with diabetes, dyslipidemia, or hypertension using multivariate regression methods controlling for age, sex, race, ethnicity, education, income, insurance, and smoking status. Maximum Likelihood Heckman Selection with Smearing retransformation was used to assess medical expenditures, and Negative Binomial regression was used for missed work days. RESULTS: Normal weight individuals with diabetes, dyslipidemia, or hypertension had significantly greater medical expenditures than those without the respective condition ($6,006 (5,124-6,887), $4,760 (4,102-5,417), $3,911 (3,345-4,476)) and obesity significantly exacerbated this effect ($7,986 (7,397-8,574), $7,636 (7,072-8,200), $6,197 (5,745-6,649); $2007; all P < 0.05). In addition, diabetes, dyslipidemia, and hypertension resulted in greater missed work days (3.1 (0.94-6.21), 3.2 (0.42-7.91), 1.4 (0.0-3.52)) (all P < 0.05 except hypertension), which resulted in greater lost productivity ($433, $451, $199) and obesity significantly exacerbated the deleterious effect on work days (8.7 (4.44-15.2), 5.5 (2.18-10.5), 4.5 (2.92-6.34)) and lost productivity ($1,217, $763, $622) (all P < 0.05). In addition, medical expenditures increased for increasing weight category and increasing number of risk factors. DISCUSSION: Obesity significantly exacerbates the deleterious effect of diabetes, dyslipidemia, and hypertension on medical expenditures and productivity loss in the United States. Obesity is preventable and public health efforts need to be undertaken to prevent its alarming increase in order to reduce the incidence and effect of cardiometabolic risk factors.