Safety of Intravenous Pantoprazole Sodium in Pediatric Patients Aged 1 Month to < 1 Year: A Real-World Retrospective Cohort Study.

OBJECTIVE: To estimate the incidence rates (IR) of prespecified outcomes of interest in pediatric patients (1 month to < 1 year) treated with intravenous (IV) pantoprazole using Optum's longitudinal electronic health records database (Optum Market Clarity) from the United States (US). METHODS: This real-world, non-interventional, retrospective cohort study was conducted from 01 January 2007 to 31 December 2020 in patients who received IV pantoprazole. Premature patients and those weighing < 2.36 kg were excluded. Patients were categorized based on diagnosis of gastroesophageal reflux disease (GERD) and erosive esophagitis (EE) into: Subgroup 1 (GERD and EE), Subgroup 2 (GERD and no EE), and Subgroup 3 (absence of GERD and EE). Overall IRs (per 1000 person-years [PY]) and 95% confidence intervals (CI) of outcomes were estimated (overall and subgroups) and stratified by duration of IV pantoprazole treatment (< 4 days versus ≥ 4 days). RESULTS: Of 1879 eligible patients, none were identified in Subgroup 1; 851 (45.3%) and 1028 (54.7%) patients were identified in Subgroups 2 and 3, respectively. IRs of outcomes of interest ranged from 0.0 to 742.8 per 1000 PY. IRs were highest for vomiting (742.80), diarrhea (377.77), abdominal distension (214.31), hyponatremia (204.99), and hypokalemia (203.49). IRs were comparable between Subgroups 2 and 3. For most outcomes, IRs were higher among patients treated with IV pantoprazole for ≥ 4 days versus those treated for < 4 days. CONCLUSION: These results are consistent with the known safety profile of pantoprazole and emphasize the utility of using real-world data from pediatric populations for assessment of safety outcomes.

Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database).

Dronedarone may increase exposure and the risk of major bleeding when prescribed with a direct oral anticoagulant (DOAC). This retrospective cohort study examined the risk of the first occurrence of major bleeding (hospitalization or emergency room visit for gastrointestinal [GI] bleeding, intracranial hemorrhage [ICH], or bleeding at other sites) among new users of apixaban, dabigatran, and rivaroxaban in patients with AF ≥18 years (January 1, 2007 to September 30, 2017) from the United States Truven Health MarketScan claims, comparing concomitant users of dronedarone to DOAC alone users in patients with atrial fibrillation (AF). No increased risk of major bleeding was associated with use of dronedarone and apixaban (adjusted Hazard Ratio [aHR]: 0.69 [95% confidence interval [CI]: 0.40, 1.17], p = 0.16), a modestly increased risk of GI bleeding but not overall bleeding was associated with use of dronedarone and dabigatran (aHR bleeding: 1.18 [95% CI: 0.89, 1.56], p = 0.26; aHR GI bleeding: 1.40 [95% CI: 1.01, 1.93]; p = 0.04) and an increased risk of overall bleeding, driven by GI bleeding, was associated with use of dronedarone and rivaroxaban (aHR bleeding: 1.31 [95% CI: 1.01, 1.69]; p = 0.04; aHR GI bleeding: 1.39 [95% CI: 0.98, 1.95]; p = 0.06), compared to each DOAC respectively. There was no increased risk of ICH associated with combined use of dronedarone and any DOAC. Prospective analyses, preferably randomized controlled studies, are needed to further explore the risk of major bleeding with concomitant use of DOACs and CYP3A4/P-gp inhibitors such as dronedarone.

Evaluating the Risk of Digitalis Intoxication Associated With Concomitant Use of Dronedarone and Digoxin Using Real-World Data.

PURPOSE: Dronedarone may increase digoxin plasma levels through inhibition of P-glycoprotein. Using real-world data, we evaluated the risk of digitalis intoxication in concomitant users of dronedarone and digoxin compared digoxin-alone users. METHODS: We used the Clinformatics DataMart, a US claims database, to identify adult patients with atrial fibrillation (AF) or atrial flutter (AFL) who concomitantly used dronedarone and digoxin and those who used digoxin alone between July 2009 and March 2016. Digitalis intoxication during follow-up until March 2016 was ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Adjusted hazard ratios (HR) for digitalis intoxication in concomitant users versus users of digoxin alone were estimated, controlling for age, sex, cohort entry year, number of medical encounters for AF or AFL, history of congestive heart failure, diabetes, hypertension, stroke, myocardial infarction, renal failure, use of drugs interacting with digoxin, and digoxin dose. FINDINGS: Overall, 524 concomitant users and 32,459 users of digoxin alone were identified, among which 3 and 301 events of digitalis intoxication occurred during follow-up, respectively. Incidence rates were 17.25 and 9.17 cases per 1000 person-years, respectively. The adjusted HR for digitalis intoxication in concomitant users versus users of digoxin alone was 1.56 (95% CI, 0.50-4.88; P = 0.45). When digitalis intoxication was defined by ICD-9-CM and ICD-10-CM codes accompanied by laboratory testing for digoxin/digitoxin or hospitalization within 30 days, no events occurred in the concomitant users and 40 events occurred in the users of digoxin alone (incidence rate of 1.22 cases per 1000 person-years). IMPLICATIONS: Concomitant use of dronedarone and digoxin was uncommon in this study, and no significant increase in the risk of digitalis intoxication with concomitant use was found.

Age- and sex-specific incidence of non-traumatic lower limb amputation in patients with type 2 diabetes mellitus in a U.S. claims database.

AIM: To estimate age- and sex-specific incidence rates (IRs) of non-traumatic lower limb amputations (LLA) in patients with type 2 diabetes mellitus (T2DM) using a claims database from the United States (US). METHODS: Patients with T2DM 18 years and older were identified using the Truven Health MarketScan database from January 1, 2007 to September 30, 2018. The overall and age- and sex-specific IRs of all non-traumatic LLA, minor LLA (amputation at or below the ankle), and major LLA (amputation above ankle) were calculated. RESULTS: Among the 6,117,981 patients with T2DM, 14,627 LLA events occurred (minor LLA; 72.8%; major LLA: 27.2%). The IRs (95% CI) of all LLA, minor LLA, and major LLA per 1000 person-years or PY were 0.86 (0.85, 0.88), 0.63 (0.62, 0.64), and 0.23 (0.23, 0.24), respectively. The IR (95% CI) of all LLA per 1000 PY in males was higher compared to females [1.24 (1.22, 1.26) vs. 0.46 (0.45, 0.48)]. The incidence of all LLA increased with an increasing age (highest IR in age-group of ≥80 years). CONCLUSIONS: This study identified males and older patients with T2DM at higher risk of developing LLA in the US, warranting further exploration of risk factors of LLA in these subgroups.

Assessing the Risk for Peripheral Neuropathy in Patients Treated With Dronedarone Compared With That in Other Antiarrhythmics.

PURPOSE: There are few data on the risk for peripheral neuropathy associated with dronedarone, a newer antiarrhythmic medicine. The objective of this study was to assess whether dronedarone is potentially associated with an increased risk for peripheral neuropathy compared with other antiarrhythmics, including amiodarone, sotalol, flecainide, and propafenone. METHODS: The MarketScan database was used for identifying patients who were at least 18 years of age, had atrial fibrillation or flutter, and had not been diagnosed with peripheral neuropathy in the 180-day period prior to or on the date of the first prescription of an antiarrhythmic between July 20, 2009, and December 31, 2011. Peripheral neuropathy that occurred during the treatment period for a study drug was ascertained using ICD-9-CM diagnostic codes. For each antiarrhythmic, the incidence rate of peripheral neuropathy was calculated. The adjusted hazard ratio (aHR) for peripheral neuropathy for dronedarone compared with another antiarrhythmic was obtained, with control for age, sex, diabetes mellitus status, and the presence of other comorbidities. FINDINGS: The study population included 106,933 patients treated with dronedarone (n = 12,989), amiodarone (n = 45,173), sotalol (n = 22,036), flecainide (n = 14,244), or propafenone (n = 12,491). The incidence rates (per 1000 person-years) of peripheral neuropathy were 1.33 for dronedarone, 2.38 for amiodarone, 1.20 for sotalol, 1.08 for flecainide, and 1.97 for propafenone. The aHRs for peripheral neuropathy for dronedarone relative to other drugs ranged from 0.53 (95% CI, 0.21-1.34) compared with propafenone, to 0.94 (95% CI, 0.38-2.30) compared with sotalol. A new-user analysis showed similar results. IMPLICATIONS: The risks for peripheral neuropathy were not significantly different between dronedarone and other antiarrhythmics.

Gender disparity in the use of drug-eluting stents during percutaneous coronary intervention for acute myocardial infarction.

OBJECTIVE: We examined gender disparity in the use of drug-eluting stents (DES) versus bare metal stents (BMS) during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), and gender disparity in all-cause mortality after coronary stent implantation for AMI. BACKGROUND: Gender disparities in AMI managements have been well documented, but it is unclear whether these disparities are seen in the type of coronary stent implantation for AMI and outcomes. METHODS: Hospital discharge data from January 1, 2003 through December 31, 2010 in New Jersey from the Myocardial Infarction Data Acquisition System were used to identify 40,215 patients (12,878 women and 27,337 men) with coronary stent implantation for AMI. The in-hospital, short term (30 days) and long term (1 and 5 year) all-cause mortality rates, unadjusted and adjusted for demographics and comorbidities, were determined. RESULTS: Women were older than men and had a higher prevalence of co-morbidities. Men had higher prevalence of prior coronary revascularizations. After adjustment for co-morbidities, there was no significant gender difference in the use of DES versus BMS for AMI, except in 2003 and 2006 where women were found to be more likely to receive a DES versus a BMS. After adjustment, women had higher odds of in-hospital deaths but no difference in short and long-term all-cause mortality rates. CONCLUSIONS: There was no significant gender difference in the proportion of DES implantation versus BMS for AMI in contemporary years. Women treated with either BMS or DES for AMI had higher in-hospital death than men.

Challenges in implementing and maintaining osteoporosis therapy.

In the United States, an estimated 19% of older men and 30% of older women are at elevated risk of osteoporotic fracture and considered to be eligible for treatment. The burden of osteoporosis is similar in Europe and is projected to rise worldwide, with aging populations and increasing fracture rates accompanying urbanization. Notwithstanding its high prevalence, osteoporosis is often underdiagnosed and undertreated. Moreover, even when the diagnosis is made and the decision is taken to treat, there are remaining challenges in implementing therapy for osteoporosis. Several patient populations are particularly challenging for clinicians to treat and require further study with regard to osteoporosis therapy. These include the very elderly, who face challenges relating to adherence; men, in whom osteoporosis remains under-recognized; patients with glucocorticoid-induced osteoporosis or renal impairment, who are at increased risk of fracture; patients with preexisting gastrointestinal problems who cannot tolerate existing orally administered osteoporosis therapies; and high-risk patients who show inadequate response to therapy. Moreover, poor adherence and poor persistence with osteoporosis medications are common and result in an increased risk of fracture, higher medical costs, and increased hospitalizations. Once the decision to institute therapy is made, patient education about osteoporosis and fracture risk should be provided. This is particularly important for men, who may not be aware that osteoporosis can be a concern. Secondary prevention programs, including fracture liaison services and bone therapy groups, can help to improve adherence to therapy. Further study is needed to guide the treatment of men, the very elderly, patients with glucocorticoid-induced osteoporosis and renal impairment, high-risk patients not well-controlled despite therapy, and patients with preexisting gastrointestinal conditions. Moreover, therapies are needed that are viewed as effective and safe by both physicians and patients, and as convenient to take by patients.

Plasma nitrite is an indicator of acute changes in ambient air pollutant concentrations.

CONTEXT: Endothelial dysfunction has been suggested as a potential mechanism by which ambient air pollution may cause acute cardiovascular events. Recently, plasma nitrite has been developed as a marker of endothelial dysfunction. OBJECTIVES: We examined the changes in plasma nitrite concentration associated with increases in ambient air pollutant concentrations in the previous 7 d. MATERIALS AND METHODS: We linked up to three measurements of plasma nitrite concentrations obtained from 49 students to 24-h average concentrations of five criteria air pollutants [particle mass < 2.5 µm in aerodynamic diameter (PM(2.5)), carbon monoxide (CO), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3)] measured at two monitoring sites closest to Rutgers University campus (6-15 miles) in New Jersey during the years 2006-2009. We examined the change in plasma nitrite associated with each interquartile-range (IQR) increase in pollutant concentration in the previous 24 h and six preceding 24- h periods, using linear mixed models. RESULTS: IQR increases in mean PM(2.5) (7.0 µg/m³) and CO (161.7 parts per billion) concentrations in the first 24 h before the plasma nitrite measurement were associated with increased plasma nitrite concentrations (PM(2.5): 15.5 nanomolar; 95% confidence interval (CI): 2.4, 28.5; CO: 15.6 nanomolar; 95% CI: 2.4, 28.9). Increased plasma nitrite associated with IQR increases in O3 and SO2 concentrations over longer lags were observed. DISCUSSION AND CONCLUSION: Rapid increases in plasma nitrite following exposure to ambient air pollutants support the hypothesis that ambient air pollution is associated with inducible nitric oxide synthase-mediated systemic inflammation in humans.

Substantial under-treatment among women diagnosed with osteoporosis in a US managed-care population: a retrospective analysis.

BACKGROUND: Multiple therapies are approved for the treatment of osteoporosis (OP), but many patients with osteoporosis may not initiate treatment upon osteoporosis diagnosis. OBJECTIVE: To characterize initiation of pharmacologic OP treatment among women within 1 year of OP diagnosis in a US managed care population. RESEARCH DESIGN AND METHODS: The retrospective cohort study included women aged ≥55 years with a claims-documented diagnosis of OP who were naïve to OP medications prior to OP diagnosis (index date) during 2001-2010. Continuous enrollment for 12 months before (baseline) and after (follow-up) the index date was required. Patients who received OP medications but did not have an OP diagnosis were excluded. Differences in baseline characteristics between the treated and untreated cohorts were compared using Wilcoxon rank-sum (continuous variables) and chi-square tests (categorical variables). MAIN OUTCOMES MEASURES: During the follow-up period, the percentages of patients treated with bisphosphonates (alendronate, ibandronate, risedronate, zoledronic acid) and non-bisphosphonates (calcitonin, raloxifene, teriparatide) were determined. RESULTS: A total of 65,344 patients, mean age 65.7 years, met study inclusion exclusion criteria. During the follow-up period, 42,033 patients (64.3%) received no OP medication and 23,311 patients (35.7%) received OP treatment. A total of 20,200 patients (30.9% of total study population) received bisphosphonates and 3111 (4.8% of total) patients received non-bisphosphonates as their index medication. At baseline, untreated patients were slightly older and had higher rates of hypertension, chronic inflammatory joint disease, diabetes mellitus, and gastrointestinal events (p ≤ 0.01) compared with treated patients. CONCLUSIONS: Among women aged ≥55 years in a US managed-care population, 64.3% received no pharmacologic treatment within 1 year after being diagnosed with OP. The authors were not able to determine if untreated patients did not receive or did not fill a prescription. Further research is needed to understand the barriers to OP treatment and reasons for non-treatment.

Cardiovascular outcomes after preeclampsia or eclampsia complicated by myocardial infarction or stroke.

OBJECTIVE: To assess the relationship between preeclampsia or eclampsia and stroke, myocardial infarction (MI), subsequent cardiovascular outcomes, and long-term survival. METHODS: Using the Myocardial Infarction Data Acquisition System in New Jersey (1994-2009), we analyzed cardiovascular outcomes in women with and without preeclampsia or eclampsia and a first MI or stroke but with a hospitalization for a first MI or stroke (analysis 1: MI case group, n=57; MI control group, n=155; stroke case group, n=132; stroke control group, n=379). We also compared these outcomes in women with preeclampsia or eclampsia and a first MI or stroke during pregnancy with women with preeclampsia or eclampsia without MI or stroke during pregnancy (analysis 2: MI case group, n=23; MI control group, n=67; stroke case group, n=90; stroke control group, n=263). A subsequent occurrence of MI, stroke, and cardiovascular death, as well as a combined cardiovascular outcome, was ascertained. RESULTS: In analysis 1, women with preeclampsia or eclampsia were at significantly lower risk for combined cardiovascular outcome with all deaths (frequency of outcome 16.7%) and with cardiovascular deaths (10.6%) compared with women without preeclampsia or eclampsia after a first stroke (33.8% and 23.5%, respectively). In analysis 2, women with preeclampsia or eclampsia and a first stroke during admission were at significantly higher risk of all death (11.1%) and the combined cardiovascular outcome with all deaths (11.1%) compared with women with preeclampsia or eclampsia without a stroke (1.9% and 2.7%, respectively) during that admission. CONCLUSION: Our study indicates that preeclampsia or eclampsia not complicated by MI or stroke during pregnancy may not confer a very high risk for subsequent MI and stroke in up to 16 years of follow-up. Our data suggest that other known risk factors put women at greater risk for stroke than preeclampsia or eclampsia complicated by a stroke. LEVEL OF EVIDENCE: II.

Acute decreases in proteasome pathway activity after inhalation of fresh diesel exhaust or secondary organic aerosol.

BACKGROUND: Epidemiologic studies consistently demonstrate an association between acute cardiopulmonary events and changes in air pollution; however, the mechanisms that underlie these associations are not completely understood. Oxidative stress and inflammation have been suggested to play a role in human responses to air pollution. The proteasome is an intracellular protein degradation system linked to both of these processes and may help mediate air pollution effects. OBJECTIVES: In these studies, we determined whether acute experimental exposure to two different aerosols altered white blood cell (WBC) or red blood cell (RBC) proteasome activity in human subjects. One aerosol was fresh diesel exhaust (DE), and the other freshly generated secondary organic aerosol (SOA). METHODS: Thirty-eight healthy subjects underwent 2-hr resting inhalation exposures to DE and separate exposures to clean air (CA); 26 subjects were exposed to DE, CA, and SOA. CA responses were subtracted from DE or SOA responses, and mixed linear models with F-tests were used to test the effect of exposure to each aerosol on WBC and RBC proteasome activity. RESULTS: WBC proteasome activity was reduced 8% (p = 0.04) after exposure to either DE or SOA and decreased by 11.5% (p = 0.03) when SOA was analyzed alone. RBCs showed similar 8-10% declines in proteasome activity (p = 0.05 for DE alone). CONCLUSIONS: Air pollution produces oxidative stress and inflammation in many experimental models, including humans. Two experimental aerosols caused rapid declines in proteasome activity in peripheral blood cells, supporting a key role for the proteasome in acute human responses to air pollution.

Acute changes in heart rate variability in subjects with diabetes following a highway traffic exposure.

OBJECTIVE: To pilot a protocol to evaluate acute cardiovascular effects in in-vehicle exposure to traffic air pollutants in people with diabetes. METHODS: Twenty-one volunteers with type 2 diabetes were passengers on 90- to 110-minute car rides on a busy highway. We measured in-vehicle particle number and mass (PM2.5) nitrogen dioxide, and carbon monoxide and heart rate, heart rate variability (HRV), and blood pressure. RESULTS: Compared with pre-ride measurements, we found a decrease in high frequency (HF) HRV from pre-ride to next day (ratio 0.66, 95% CI = 0.47 to 0.93) and an increase in low frequency to HF ratio at post-ride (ratio 1.92, 95% CI = 1.21 to 3.05) at post-ride. Interquartile range increases in measured pollutants were associated with next-day decreases in HR HRV. CONCLUSIONS: This protocol appears useful for assessing acute adverse cardiovascular effects of in-vehicle exposures among people who have diabetes.

Organizational factors and office workers' health after the World Trade Center terrorist attacks: long-term physical symptoms, psychological distress, and work productivity.

OBJECTIVE: To assess if organizational factors are predictors of workers' health and productivity after the World Trade Center attacks. METHODS: We conducted a survey of 750 workers and compared those who had direct exposures to the World Trade Center attacks (south of Canal Street workers; primary victims) with those less directly exposed (north of Canal Street workers; other victims and non-victims). RESULTS: South of Canal Street workers reported headache more frequently than north of Canal Street workers did (P = 0.0202). Primary victims reported headache and cough more frequently than did other victims and non-victims (P = 0.0086 and 0.0043, respectively). Defensive organizational culture was an independent predictor of cough and job stress, and job stress was an independent predictor of on-the-job productivity losses. CONCLUSION: Organizational variables may modify health and productivity outcomes after a large-scale traumatic event in the workplace.

Use of adjuvant systemic therapy for early breast cancer among women 65 years of age and older.

BACKGROUND: The National Institutes of Health (NIH) consensus statement recommends adjuvant therapy for early breast cancer irrespective of age. However, the actual use of such therapy is not well documented among women over 65 years of age. METHODS: We studied the frequency of use of adjuvant therapy and report the receipt of this therapy among 200 women aged > or = 65 years diagnosed with early breast cancer who were identified from the New Jersey State Cancer Registry. RESULTS: In this population, 28% of patients received chemotherapy alone or in combination with hormonal therapy, whereas 42% received hormonal therapy alone. Less than half of the women with estrogen receptor-negative tumors received chemotherapy alone or in combination with hormonal treatment. Adjuvant therapy was not prescribed in 30% of patients. CONCLUSIONS: Despite NIH recommendations, the frequency of use of adjuvant therapy in New Jersey is low among women over 65 years of age, regardless of their receptor status.