Use of Contrave, Naltrexone with Bupropion, Bupropion, or Naltrexone and Major Adverse Cardiovascular Events: A Systematic Literature Review.

Naltrexone/Bupropion extended release (ER; Contrave) is an extended-release, fixed-dose combination medication of naltrexone (8 mg) and bupropion (90 mg) for patients with obesity or overweight with at least one weight-related comorbidity. Obese and overweight patients with or without comorbidities are at increased cardiovascular (CV) risk. Due to the increased CV risk profile in this patient population, this systematic literature review was conducted to assess human studies reporting major adverse CV events (MACE) and other CV events. A priori eligibility criteria included clinical studies (randomized and observational) published from January 1, 2012, to September 30, 2021, with data comparing users of naltrexone/bupropion ER, naltrexone with bupropion, bupropion without naltrexone, or naltrexone without bupropion versus comparator groups (placebo or other treatments), and with sufficient information to determine the frequency of MACE or other CV adverse events by treatment group. Among 2539 English-language articles identified, 70 articles met the eligibility criteria: seven studies of naltrexone/bupropion ER or naltrexone with bupropion, 32 studies of bupropion, and 31 studies of naltrexone. No studies reported an increased risk of MACE among users of naltrexone/bupropion ER, naltrexone with bupropion, or bupropion or naltrexone individually compared with nonusers. One-half of the available studies (n = 35) reported no (zero) CV events and the other half (n = 35) reported that a non-zero frequency of CV events occurred. Four studies reported data on MACE, including three studies of bupropion and one study of naltrexone/bupropion ER. For composite MACE and its components, the difference in proportions between naltrexone/bupropion ER-, bupropion-, or naltrexone-treated patients compared with active comparators or placebo-treated patients did not exceed 2.5%. In conclusion, the available human evidence does not indicate an increased risk of CV events or MACE following use of naltrexone/bupropion ER, naltrexone with bupropion, or the individual components.

Risk of interstitial lung disease in patients treated for atrial fibrillation with dronedarone versus other antiarrhythmics.

PURPOSE: To compare risks of interstitial lung disease (ILD) between patients treated with dronedarone versus other antiarrhythmics. METHODS: Parallel retrospective cohort studies were conducted in the United States Department of Defense Military Health System database (DoD) and the HealthCore Integrated Research Database (HIRD). Study patients were treated for atrial fibrillation (AF) with dronedarone, amiodarone, sotalol, or flecainide. Propensity score matching was employed to create analysis cohorts balanced on baseline variables considered potential confounders of treatment decisions. The study period of July 20, 2008 through September 30, 2014 included a 1-year baseline and minimum 6 months of follow-up, for patients with drugs dispensed between July 20, 2009 and March 31, 2014. Suspect ILD outcomes were reviewed by independent adjudicators. Cox proportional hazards regression compared risk of confirmed ILD between dronedarone and each comparator cohort. A sensitivity analysis examined the effect of broadening the outcome definition. RESULTS: A total 72 ILD cases (52 DoD; 20 HIRD) were confirmed among 27 892 patients. ILD risk was significantly higher among amiodarone than dronedarone initiators in DoD (HR = 2.5; 95% CI = 1.1-5.3, p = 0.02). No difference was detected in HIRD (HR = 1.0; 95% CI = 0.4-2.4). Corresponding risks in sotalol and flecainide exposure groups did not differ significantly from dronedarone in either database. CONCLUSIONS: ILD risk among AF patients initiated on dronedarone therapy was comparable to or lower than that of amiodarone initiators, and similar to that of new sotalol or flecainide users. This finding suggests that elevated ILD risk associated with amiodarone does not necessarily extend to dronedarone or other antiarrhythmic drugs.

Variations in erythropoiesis-stimulating agent administration in transfusion-dependent myelodysplastic syndromes impact response.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) reduce red blood cell (RBC) transfusions in approximately 40% of patients with myelodysplastic syndrome (MDS) in clinical trials. We studied the association of timing of ESA initiation, agent (epoetin alfa, darbepoetin) and number of weeks of ESA use with response in MDS patients in routine practice. METHODS: Patients diagnosed with MDS from 2001 to 2005 were identified in the Surveillance Epidemiology and End Results-Medicare linked database. The study cohort consisted of patients with new-onset transfusion dependence (TD). All patients received an ESA at least once during the study period, which began the week that criteria for TD were met and continued until transfusion independence (TI). Kaplan-Meier statistics and Cox Proportional Hazard models were used to assess relationships between time to ESA initiation, agent and number of weeks of ESA use and TI attainment. RESULTS: Of 610 TD patients treated with ESAs, 210 (34.4%) achieved TI. Median time from ESA initiation to TI was 13 weeks. Shorter time from TD to ESA initiation and use of darbepoetin were associated with higher probability of achieving TI. The probability of achieving TI decreased beyond 8 weeks of treatment, and was very low beyond 16 weeks (8-15 weeks: HR=0.64, 16-31 weeks: HR=0.25, 32+ weeks HR=0.10). CONCLUSIONS: In this observational, population-based study, variations in ESA administration impacted response in transfusion-dependent MDS patients, with higher response rates with early administration and use of darbepoetin, and low response likelihood in non-responders beyond 16 weeks of therapy.

Adverse event reporting patterns of newly approved drugs in the USA in 2006: an analysis of FDA Adverse Event Reporting System data.

BACKGROUND: The Weber effect states that adverse event (AE) reporting tends to increase in the first 2 years after a new drug is placed onto the market, peaks at the end of the second year, and then declines. However, since the Weber effect was originally described, there has been improvement in the communication of safety information and new policies regarding the reporting of AEs by healthcare professionals and consumers, prompting reassessment of the existence of the Weber effect in the current AE reporting scenario. OBJECTIVES: To determine the AE reporting patterns for new molecular entity (NME) drugs and biologics approved in 2006 and to examine these patterns for the existence of the Weber effect. METHODS: Publicly available FDA Adverse Event Reporting System data were used to assess the AE reporting patterns for a 5-year period from the drug's approval date. The total number of annual reports from all sources, based on the report date, was plotted against time (in years). RESULTS: In the period from 2006 to 2011, a total of 91,187 AE reports were submitted for 19 NMEs approved in 2006. The highest number of AE reports were submitted for varenicline tartrate (N = 47,158) and the lowest number for anidulafungin (N = 161). Anidulafungin was reported to have the highest proportion of death reports (36 %) and varenicline tartrate the lowest proportion (1.7 %). The classic Weber pattern was not observed for any of the 19 NMEs approved in 2006. While there was no one predominant pattern of AE report volume, we grouped the drugs into four general categories; the majority of drugs had either a continued increase in reports (Category A 31.6 %) or an N-pattern with reporting reaching an initial peak in year 2 or 3, declining and then beginning to climb again (Category B 42.1 %). CONCLUSIONS AND RELEVANCE: There have been numerous changes in AE reporting, particularly a huge increase in overall annual report volume, since the Weber effect was first reported. Our results suggest that a Weber-type reporting pattern should not be assumed in the design or interpretation of analyses based on AE reports.

Patterns of erythropoiesis-stimulating agent use among Medicare beneficiaries with myelodysplastic syndromes and consistency with clinical guidelines.

Erythropoiesis-stimulating agents (ESA) are used commonly to reduce symptomatic anemia in patients with myelodysplastic syndromes (MDS). We assessed population-based patterns of ESA use relative to treatment guidelines using data from the Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data from 2001 through 2005. The study found widespread use (62%) of ESA in Medicare beneficiaries with MDS. Similar ESA use rates regardless of risk status, low frequency (45%) of serum erythropoietin determination prior to ESA initiation, and high prevalence (60.4%) of short-duration ESA episodes suggest clinically important discrepancies between actual practice and guideline-recommended therapy.

Risk areas for pediatric acute care: asthma differs from upper and lower respiratory illness.

OBJECTIVE: To determine if emergency department utilization for pediatric respiratory illness varies across small geographic jurisdictions within a large urban city. DESIGN: A retrospective analysis of Maryland Health Services Cost Review Commission Emergency Department discharge data. SETTING/PATIENTS: All non-neonatal, Baltimore City residents <18 years old with valid diagnoses admitted and discharged from emergency departments (ED) in the state of Maryland from April 1, 1997 to December 31, 2000 (n=245,339). MAIN OUTCOME MEASURES: Crude and adjusted ED visit rates for asthma, upper and lower respiratory illnesses (per 1000 population). To evaluate the effect of geography on pediatric ED visit rates, odds of an asthma ED visit, URI, or LRI vs. non-respiratory ED visit were compared across regions of the city. RESULTS: We determined that residential areas with high ED utilization rates for upper and lower respiratory illnesses, as well as non-respiratory illnesses correlate with regions of high ED utilization for asthma, even after adjusting for race, gender and age of the population. The regions with high odds ratios that an ED visit was for asthma were different from those with high ORs for URI and LRI after also controlling for poverty. CONCLUSIONS: This suggests that poverty accounts for high utilization of the ED in urban settings, but suggests that environmental exposures that increase the risk of ED care for asthma differ from those that lead to URI and LRI.

Looking beyond urban/rural differences: emergency department utilization by asthmatic children.

Asthma causes pediatric morbidity throughout the US with substantial regional variability. Emergency department (ED) utilization data were studied to determine if geographic variability of pediatric asthma cases exists within a state. Records for non-neonatal Maryland children less than 18 years of age seen and discharged from Maryland EDs from April 1997 through March 2001 were analyzed. While Baltimore City had the highest rates of asthma visits, adjusted odds ratios identified the wealthiest suburban county to have a higher risk of an asthma ED visit. Children from rural counties, for the most part, had fewer ED asthma visits than children from urban and suburban counties.

National patterns of medication use during pregnancy.

PURPOSE: To describe patterns of medication use during pregnancy in ambulatory care settings according to the U.S. Food and Drug Administration (FDA) pregnancy risk classification. METHODS: A cross-sectional study of two national ambulatory care surveys, sampling all office visits made by pregnant women in 1999 and 2000, was conducted. Using the FDA pregnancy risk classification, patterns of medication use and predictive factors for FDA pregnancy risk D or X (D/X) medications were evaluated. RESULTS: In 1999 and 2000, about half of all pregnant visits had one or more medications. Among the total visits, FDA Class A was the majority (private = 65.7%; hospital = 79.5%; p < 0.05) followed by Class C (private = 26.5%; hospital = 36.4%; p < 0.05). Class D/X medications accounted for 6.4% and 2.9% of visits in private and hospital, respectively (p < 0.05). Medications with unknown pregnancy categories were predominant in the private setting (12.0% and 3.9%; p < 0.05). Age, insurance type, region, physician specialty, and number of medications were associated with a category D/X prescription. Among hospital visits, those from the West region and with private insurance were more likely to receive category D/X prescriptions. Number of medications was strongly associated with high-risk drugs in both settings. CONCLUSIONS: This study shows considerable medication use among pregnant women. The prevalence of visits with FDA pregnancy category D/X drugs was moderate, but still indicates exposure to high-risk medications.

Antidiabetic therapy and the risk of heart failure in type 2 diabetic patients: an independent effect or confounding by indication.

PURPOSE: This study assesses the effect of the type of antidiabetic treatment on the risk of developing congestive heart failure (CHF) in type 2 diabetes. METHODS: The study was derived from the U.K.-based General Practice Research Database (GPRD) comprised of 3.5 million subjects followed between 1987 and 2001. A total of 21 888 type 2 diabetic patients were identified. A 6:1 matched nested case-control design was employed. Conditional logistic regression was used to derive adjusted odds ratios (ORs) for the association of drug treatment with CHF controlling for diabetes duration and for diseases known to affect the risk of CHF. Antidiabetic drug exposure was defined as the receipt of at least one prescription for an antidiabetic medication within the 3 months prior to the date of CHF diagnosis. RESULTS: There were 1301 incident cases of CHF in the cohort, matched to 7788 controls. After risk factor adjustment, there was a 1.2-fold increase in the risk of CHF for sulphonylureas (SUs) (OR = 1.17; 95%CI = 1.00-1.37) and metformin monotherapies (OR = 1.22; 95%CI = 0.97-1.52), a 1.6-fold increase with combinations of metformin and SUs (OR = 1.62; 95%CI = 1.30-2.02), a 2.2-fold increase with oral tricombinations (OR = 2.16; 95%CI = 0.96-4.86) and a 1.5-fold increase for insulin compared to no exposure (OR = 1.52; 95%CI = 1.06-2.17). Compared to SUs, bicombinations of metformin and SUs showed a statistically significant 1.4-fold increase in the odds of CHF (OR = 1.38; 95%CI = 1.13-1.69). CONCLUSIONS: All antidiabetic medications were associated with an increased likelihood of CHF compared to no antidiabetic exposure. The risk of CHF increased with the complexity of the antidiabetic regimen suggesting that it is the diabetes severity, which imparts risk and not necessarily the antidiabetic regimen itself.

Impact of regulatory labeling for troglitazone and rosiglitazone on hepatic enzyme monitoring compliance: findings from the state of Ohio medicaid program.

PURPOSE: Troglitazone, the first drug of the thiazolidinediones class for type II diabetes, was first marketed in March 1997 and was removed from the U.S. market 36 months later after 90 cases of liver failure were reported despite multiple warnings containing liver enzyme monitoring recommendations. Rosiglitazone has been available since June 1999 and is still on the market. The purpose of this study was to evaluate the impact of labeled hepatic enzyme monitoring for troglitazone and rosiglitazone. METHODS: Drug cohorts were assembled, using population-based fee-for-service Medicaid claims, for patients between 18 and 65 years of age who had received at least one troglitazone (n = 7226) or rosiglitazone (n = 1480) prescription between 1 April, 1997, and 21 March, 2000. The outcome of interest was the percentage of patients, based on their first treatment episode, who had baseline and post-baseline liver enzyme testing. RESULTS: Overall baseline testing was under 9% before regulatory actions, increased to 14% after the first two 'Dear Doctor' letters issued by the FDA in October and December 1997, and peaked to about 26% afterwards. Coincident with the marketing of rosiglitazone and the fourth 'Dear Doctor' letter issued in June 1999, baseline testing dropped to 18%. Baseline testing increased 2.5-fold (race-sex-age adjusted) after regulatory action. Achieving 50% post-baseline testing took approximately 6 months for both drugs. CONCLUSION: Regulatory actions had only modest effects on the incidence of liver monitoring. More effective and timely communication strategies, health provider prescribing interventions and modification of health provider behaviors to enhance compliance with recommended risk management measures need to be identified, evaluated and implemented.

Impact of an educational intervention for secondary prevention of myocardial infarction on Medicaid drug use and cost.

OBJECTIVES: The objectives of this drug utilization review program were (1) to increase beta-blocker prescribing to fee-for-service post-acute myocardial infarction (AMI) Medicaid patients; (2) to improve compliance among patients who were prescribed beta-blockers post-AMI; and (3) to evaluate the economic implications of increased beta-blocker prescribing. STUDY DESIGN: Pre-post nonequivalent group design. PATIENTS AND METHODS: The intervention targeted physicians of Pennsylvania Medicaid recipients who had an AMI between November 1, 1998, and November 1, 1999. Educational materials were sent to the physicians of post-AMI patients not receiving beta-blockers. Preintervention and postintervention rates of beta-blocker prescribing in the Medicaid program within 7 and 30 days of discharge after an AMI hospitalization were compared. Similarly, pre- and postintervention compliance rates were compared for AMI patients who were prescribed beta-blockers. Cost savings and number of avoided deaths also were calculated. RESULTS: There was a 5.5%, to 6.9% increase in beta-blocker prescribing after the intervention, depending on the follow-up period. Postintervention AMI patients were 16% more likely to be prescribed a beta-blocker. There was an 8.3% increase in patient compliance with beta-blocker therapy from preintervention to postintervention. In the first 2 years of the intervention, the estimated cost savings to the Pennsylvania Medicaid program ranged from 71,970 dollars to 76,678 dollars, respectively. An estimated 3 deaths were avoided. CONCLUSIONS: The intervention resulted in increased appropriate prescribing and compliance with beta-blockers among post-AMI patients. There also were estimated cost savings to Pennsylvania Medicaid as a result of reduced hospitalization, and fewer deaths.

Temporal dynamics of emergency department and hospital admissions of pediatric asthmatics.

Asthma is a chronic disease that can result in exacerbations leading to urgent care in emergency departments (EDs) and hospitals. We examined seasonal and temporal trends in pediatric asthma ED (1997-1999) and hospital (1986-1999) admission data so as to identify periods of increased risk of urgent care by age group, gender, and race. All pediatric ED and hospital admission data for Maryland residents occurring within the state of Maryland were evaluated. Distinct peaks in pediatric ED and hospital asthma admissions occurred each year during the winter-spring and autumn seasons. Although the number and timing of these peaks were consistent across age and racial groups, the magnitude of the peaks differed by age and race. The same number, timing, and relative magnitude of the major peaks in asthma admissions occurred statewide, implying that the variables affecting these seasonal patterns of acute asthma exacerbations occur statewide. Similar gross seasonal trends are observed worldwide. Although several environmental, infectious, and psychosocial factors have been linked with increases in asthma exacerbations among children, thus far they have not explained these seasonal patterns of admissions. The striking temporal patterns of pediatric asthma admissions within Maryland, as described here, provide valuable information in the search for causes.

Environmental allergens and asthma in urban elementary schools.

BACKGROUND: Asthma in school children is rising, and indoor allergens are very common triggers of asthma attacks; however, the risk of the school environment on asthma has not been well studied. OBJECTIVE: To determine the presence and the levels of common aeroallergens in schools, where asthma prevalence rates are high. METHODS: Settled dust samples were collected from 12 Baltimore City public elementary schools, and they were analyzed for the following allergens: cockroaches (Bla g 1/2), dust mites (Der f 1/p 1), dog (Can f 1), cat (Fel d 1), and mouse (Mus m 1). School asthma prevalence rates were correlated with allergen levels, and association between allergen levels and other risk factors present in the schools' environment was examined. RESULTS: The mean and range levels were 1.49 U/g (0 to 8) for Bla g 1/2; 0.38 microg/g (0 to 11.9) for the Der f 1/p 1; 1.44 microg/g (0.1 to 9.6) for Can f 1; 1.66 microg/g (0.2 to 12) for Fel d 1; and 6.24 microg/g (0.3 to 118.3) for Mus m 1. Dust mite, cat and dog allergens were significantly in rooms with carpet and/or area rugs, compared to rooms with bare floors (P < 0.05). Asthma prevalence rates varied from 11.8 to 20.8% between schools and positively correlation with the mean levels of Bla g 1/2 in the schools (P = 0.001). CONCLUSIONS: Common allergens that are known to trigger asthma were detected in all school environments, where asthma prevalence rates were high. However, the overall allergen levels were low, indicating that other factors, including exposures in the homes of asthmatic patients, may have more relevance to sensitization and symptoms than school exposures.

Reported adverse drug events in infants and children under 2 years of age.

OBJECTIVE: To characterize risks to infants and young children from drugs and biological products that were identified in spontaneous adverse event reports submitted to the US Food and Drug Administration. METHODS: Of >500 000 MedWatch adverse event reports received by the Food and Drug Administration from November 1997 through December 2000, we identified 7111 reports about infants and children younger than age 2. The reports were analyzed for health outcome (eg, death, hospitalization, congenital anomaly), principal suspect drug, and whether the route of drug exposure was direct administration or through the mother in the perinatal period. RESULTS: Drug therapy was associated with an average of 243 reported deaths annually over the 38-month study period, with 100 (41%) occurring during the first month of life and 204 (84%) during the first year. In 1432 (24%) reported adverse event cases of all levels of severity, exposure to the drug was from the mother during pregnancy, delivery, or lactation. Although 1902 different drugs, biological products, and other chemicals were identified in the reports, only 17 drugs or biological products were a suspect in 54% of all serious and fatal adverse events in drugs administered directly. CONCLUSION: Adverse reactions to drug therapy are a significant cause of death and injury in infants and children under 2 years of age. Drugs administered to the mother in the perinatal period constituted a major route of exposure to adverse drug advents. These results underscore the need for additional drug testing in the youngest pediatric patients and for carefully weighing the risks versus benefits of medication.

Patterns of pharmacotherapy and counseling for osteoporosis management in visits to US ambulatory care physicians by women.

BACKGROUND: Women experience rapid bone loss following menopause. Currently available guidelines recommend lifestyle counseling and pharmacotherapy for osteoporosis prevention and treatment in postmenopausal women. METHODS: We analyzed 2 years of National Ambulatory Medical Care Survey data (1997-1998), a national representative survey evaluating recent national patterns of antiosteoporosis medication (AOM) use and lifestyle counseling among office visits made by nonpregnant women 40 years and older. RESULTS: Women 40 years and older made an estimated 267 million office visits annually. Of those visits, about 10% were associated with AOM therapy. Estrogen replacement therapy was the most prevalent form of AOM therapy (80%) followed by therapy with calcium and/or cholecalciferol (vitamin D) supplements (15%). Visits for AOM were more likely to be associated with women in their 50s and 60s, white race, and having private insurance or Medicare. Women at AOM visits were twice as likely to receive concurrent lifestyle counseling than women at visits without AOM therapy. CONCLUSIONS: Women are particularly at risk for osteoporosis as they experience menopause, with estimates of 20 million women with osteoporosis or osteopenia. Despite the high prevalence, our study showed that only 10% of all visits were associated with 1 or more AOM therapy prescribed, provided, or continued in 1997 and 1998. These data also suggest that women with Medicaid or self-pay status were less likely to receive AOMs than women with other forms of insurance. The status of AOM therapy and lifestyle counseling in ambulatory care practice in the United States during 1997 and 1998 was less than optimal.

Using seasonal variations in asthma hospitalizations in children to predict hospitalization frequency.

Asthma hospitalization rates have increased in the United States since 1980. The exposure risk of many environmental factors, which contribute to respiratory disease, vary throughout the year. The objective of this study was to investigate the seasonal variation of pediatric asthma hospitalizations and predict hospitalization frequency. This was a longitudinal analysis of all pediatric asthma hospitalizations in the state of Maryland by age, gender, race, and residence using non-confidential discharge data sets from 1986 to 1999. Of the 631,422 pediatric hospitalizations in the state of Maryland during the years 1986-1999, 45,924 (7%) had a primary admission diagnosis of asthma. Frequency of hospitalization for asthma was lowest in the summer in all age groups, and highest in the fall. Seasonal variation in severe asthma episodes was least striking in children aged 15-18. This was in contrast to non-asthma admissions, which were highest in winter in preschool children, but relatively flat in school- and teenaged children. Using neural network modeling, weekly asthma hospitalizations could be predicted with an R2 between 0.71 and 0.8. Temporal trends in asthma hospitalizations were seen in each age group, gender, race, and location. The seasonal variability in asthma hospitalizations suggests that acute asthma is influenced by variables beyond socioeconomic factors and adherence to medical regimens. Strategies to combat exacerbations of asthma should take into consideration seasonal effects on a population. In addition, temporal trends examined over many years can be used to predict frequency of severe asthma episodes in a population.