Association between bronchiectasis exacerbations and longitudinal changes in FEV1 in patients from the US bronchiectasis and NTM research registry.

BACKGROUND: This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV1 associated with exacerbation frequency (objective 2). METHODS: This was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV1 and FEV1 % predicted over 24 months stratified by baseline exacerbation frequency. RESULTS: Objective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV1 was significantly lower in patients who had more exacerbations; however, decline in FEV1 from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV1 % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001). CONCLUSIONS: Patients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV1 at baseline, although FEV1 decline may not differ by baseline exacerbation frequency.

Pulmonary exacerbations in insured patients with bronchiectasis over 2†years.

Background: Patients with bronchiectasis experience persistent symptoms and frequent pulmonary exacerbations; this study investigated the frequency of exacerbations and all-cause hospitalisation. Methods: This longitudinal, retrospective, claims database study (IBM® MarketScan®) identified patients aged ≥18 years from 1 July 2015 through 30 September 2018. Exacerbations were identified by bronchiectasis inpatient claim or a healthcare interaction, followed by antibiotic prescription within 7 days. Patients with ≥36 months of continuous health plan enrolment (12 months preceding the first bronchiectasis claim, i.e., baseline period and ≥24 months of follow-up) were included. Patients with cystic fibrosis at baseline were excluded. A multivariable logistic regression model identified baseline factors associated with having ≥2 exacerbations over the 2-year follow-up period. Results: In total, 14 798 patients with bronchiectasis were identified; 64.5% were female, 82.7% were aged ≥55 years and 42.7% had ≥2 exacerbations at baseline. Having ≥2 exacerbations after 2 years was positively associated with chronic macrolide use, long-acting ß2 agonist use, gastro-oesophageal reflux disease, heart failure and Pseudomonas aeruginosa. Frequent exacerbations (≥2) at baseline were significantly associated with greater likelihood of experiencing ≥2 exacerbations during the first and second year's follow-up (unadjusted odds ratios 3.35 (95% CI 3.1-3.6) and 2.96 (95% CI 2.8-3.2), respectively). The proportion of patients experiencing ≥1 all-cause hospitalisation cumulatively increased from 41.0% in the first year of follow-up to 51.1% over 2 years' follow-up. Conclusion: Frequent exacerbations in patients with bronchiectasis may increase the likelihood of future exacerbations over 2 years of follow-up, with increased hospitalisation rates over time.

Impact of initiation of amikacin liposome inhalation suspension on hospitalizations and other healthcare resource utilization measures: a retrospective cohort study in real-world settings.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) is an infection that is increasing in frequency, associated with substantial disease burden, and often refractory to treatment. Amikacin liposome inhalation suspension (ALIS) is the first therapy approved for refractory MAC-LD. In the CONVERT study of adult patients with refractory MAC-LD, adding ALIS to a multidrug background regimen showed evidence of MAC infection elimination in sputum by month 6, which was maintained in most patients through the end of treatment (≤ 12 months post-conversion). This study assessed changes in healthcare resource utilization (HCRU) among patients initiating ALIS in real-world settings. METHODS: This retrospective cohort study of the All-Payer Claims Database (October 2018-April 2020) included patients aged ≥ 18 years with ≥ 1 pharmacy claim for ALIS and ≥ 12 months of continuous health plan enrollment pre- and post-ALIS initiation. Respiratory disease-related (and all-cause) HCRU (hospitalizations, length of stay [LOS], emergency department [ED] visits, and outpatient office visits) were compared 12 months pre- and post-ALIS initiation. Outcomes were reported at 6-month intervals; 0-6 months pre-ALIS initiation was the reference period for statistical comparisons. RESULTS: A total of 331 patients received ALIS, with HCRU highest in the 6 months pre-ALIS initiation. Compared with 26.9% during the reference period, respiratory-related hospitalizations decreased to 19.3% (P < 0.01) and 15.4% (P < 0.0001) during 0-6 and 7-12 months post-ALIS initiation, respectively. Mean number of respiratory disease-related hospitalizations per patient/6-month period decreased from 1.0 (reference period) to 0.6 (P < 0.0005) at both timepoints post-ALIS initiation. A similar pattern was observed for all-cause hospitalizations and hospitalizations per patient/6-month period (both P < 0.005). Reductions in all-cause and respiratory disease-related LOS post-ALIS initiation were significant (both P < 0.05). ED visits were few and unchanged during the study. Significant reductions per patient/6-month period in all-cause and respiratory-related outpatient office visits were observed post-ALIS initiation (all P < 0.01). CONCLUSIONS: In this first real-world study of ALIS, respiratory disease-related (and all-cause) hospitalizations and outpatient visits were reduced in the 12 months following ALIS initiation. The results of this study provide HCRU-related information to better understand the impact of initiating ALIS treatment. TRIAL REGISTRATION: Not appliable.

Clinical outcomes in high-hypoglycaemia-risk patients with type 2 diabetes switching to insulin glargine 300 U/mL versus a first-generation basal insulin analogue in the United States : Results from the DELIVER High Risk real-world study.

AIMS: To compare 12-month clinical effectiveness of insulin glargine 300 units/mL (Gla-300) versus first-generation basal insulin analogues (BIAs) (insulin glargine 100 units/mL [Gla-100] or insulin detemir [IDet]) in patients with type 2 diabetes (T2D) who were at high risk of hypoglycaemia and switched from one BIA to a different one (Gla-300 or Gla-100/IDet) in a real-world setting. METHODS: DELIVER High Risk was a retrospective observational cohort study of 2550 patients with T2D who switched BIA to Gla-300 (Gla-300 switchers) and were propensity score-matched (1:1) to patients who switched to Gla-100 or IDet (Gla-100/IDet switchers). Outcomes were change in glycated haemoglobin A1c (HbA1c), attainment of HbA1c goals (<7% and <8%), and incidence and event rates of hypoglycaemia (all-hypoglycaemia and hypoglycaemia associated with an inpatient/emergency department [ED] contact). RESULTS: HbA1c reductions were similar following switching to Gla-300 or Gla-100/IDet (-0.51% vs. -0.53%; p = .67), and patients showed similar attainment of HbA1c goals. Patients in both cohorts had comparable all-hypoglycaemia incidence and event rates. However, the Gla-300 switcher cohort had a significantly lower risk of inpatient/ED-associated hypoglycaemia (adjusted odds ratio: 0.73, 95% confidence interval: 0.60-0.89; p = .002) and experienced significantly fewer inpatient/ED-associated hypoglycaemic events (0.21 vs. 0.33 events per patient per year; p < .001). CONCLUSION: In patients with T2D at high risk of hypoglycaemia, switching to Gla-300 or Gla-100/IDet achieved similar HbA1c reductions and glycaemic goal attainment, but Gla-300 switchers had a significantly lower risk of hypoglycaemia associated with an inpatient/ED contact during 12 months after switching.

How many people with type 2 diabetes fulfil the eligibility criteria for randomized, controlled trials of insulin glargine 300 U/mL in a real-world setting?

Randomized controlled trial (RCT) populations often do not reflect those typically seen in clinical practice. This retrospective, observational cohort study analysed the real-world data of people with type 2 diabetes (T2DM) prescribed basal insulin analogues from electronic medical records (EMRs) in the Explorys database, which includes data from 39 integrated healthcare systems in the United States, to determine how representative selected RCTs investigating insulin glargine 300 U/mL (Gla-300) are of T2DM populations in a real-world setting. Applying eligibility criteria derived from the EDITION 1, 2 and 3 (Gla-300 vs. insulin glargine 100 U/mL [Gla-100]) and BRIGHT (Gla-300 vs. insulin degludec) RCTs, we observed that only 17% (33 345/191 218) of people captured in the real-world database would have been eligible for such trials. Those who were ineligible tended to be older, had more comorbidities and a higher baseline hypoglycaemia rate than the eligible group. Using another large US EMR database (Optum Humedica) as corroboration, we found that 15% (36 285/235 697) would have been eligible to participate in the EDITION/BRIGHT RCTs. Furthermore, only 7% (1734/24 547) would have been eligible for the CONCLUDE (insulin degludec vs. Gla-300) RCT. Our findings remind us of the value of real-world data studies, complementing the results of RCTs, and providing additional insights into groups who would typically be excluded from RCTs.

Reduced Hypoglycemia Risk in Type 2 Diabetes Patients Switched to/Initiating Insulin Glargine 300 vs 100 U/ml: A European Real-World Study.

INTRODUCTION: Randomized controlled trials and real-world data from the USA have shown similar glycemic control with insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) and reduced hypoglycemia risk with Gla-300. This real-world study describes the efficacy and safety of Gla-300 and Gla-100 in patients with type 2 diabetes (T2D) in France, Spain, and Germany. METHODS: This retrospective chart review analysis used anonymized data for adults with T2D switching basal insulin analog (BIA) therapy to Gla-300 or Gla-100, or insulin-naïve patients initiating Gla-300 or Gla-100. Outcomes included change from baseline to 6-month follow-up in glycated hemoglobin A1c (A1C), total and severe hypoglycemia incidences and events, insulin dose, and reasons for BIA choice. RESULTS: Six hundred sixty-five physicians (33.8% Spain, 31.7% France, 34.4% Germany) provided chart data for patients switching to Gla-300 (n = 679) or Gla-100 (n = 429) or initiating Gla-300 (n = 719) or Gla-100 (n = 711). After adjustment for baseline characteristics, A1C reductions from baseline were similar for patients switching to Gla-300 or Gla-100 (- 0.87% vs. - 0.93%; p = 0.326) while those switched to Gla-300 vs. Gla-100 had a significantly greater mean reduction in hypoglycemic events (- 1.29 vs. - 0.81 events during 6 months; p = 0.012). Mean insulin doses after titration were 0.43 ± 0.36 and 0.40 ± 0.28 U/kg in Gla-300 and Gla-100 switchers, respectively. Factors that significantly influenced BIA choice included a lower risk of hypoglycemia (for Gla-300) and physician familiarity (for Gla-100). Outcomes for insulin-naïve patients were broadly similar to those of switchers. CONCLUSIONS: In this real-world European study, patients with T2D who switched therapy to Gla-300 or Gla-100 had improved glycemic control and reduced hypoglycemia at 6 months, with significant hypoglycemia advantages with Gla-300.

Use of real-world evidence in regulatory decisions for rare diseases in the United States-Current status and future directions.

Following the release of the framework for the Real-World Evidence (RWE) Program, the US Food and Drug Administration (FDA) is actively evaluating and exploring ways to optimize the utility of real-world data (RWD) and RWE to support regulatory decision making. For rare conditions, conducting traditional randomized clinical trials may not always be feasible, and RWD and RWE have played and will continue to play an important role. We use three case examples-cerliponase alfa, asfotase alfa, and uridine triacetate-to illustrate how RWD from disease registries, medical records with chart review, and literature, respectively, have been used to generate RWE to support regulatory decisions for selected rare diseases. These examples highlight the need for improving data reliability and quality in existing data to expand use of RWD and RWE beyond "hard endpoints" and standardizing data collection for outcome measures in patient registries to expand its utility. We also discuss a recent FDA guidance for using RWE in supporting rare disease drug development, including its recommendations about using natural history studies as external control groups for single-arm interventional trials. The external control group needs to be comparable with the treated group. Selection bias and confounding are major concerns because of lack of randomization and unrecognized baseline differences. Use of valid epidemiological approaches can reduce these biases. Lastly, we discuss future directions to expand the use of RWD and RWE to support orphan drug approvals, including the need for including patient experience data as an important source of RWD.

Switching to insulin glargine 300 units/mL in real-world older patients with type 2 diabetes (DELIVER 3).

AIM: To compare the second-generation basal insulin glargine 300 units/mL (Gla-300) and first-generation basal insulins on glycaemic control and hypoglycaemia risk in older adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER 3 was a retrospective observational cohort study of electronic medical records. A total of 1176 older adults (aged ≥ 65 years) with T2D and ≥1 HbA1c value during 6 month baseline and 3 to 6 month follow-up who switched from basal insulin to Gla-300 were propensity score-matched to 1176 older adults who switched to a first-generation basal insulin [insulin detemir (IDet) or insulin glargine 100 units/mL (Gla-100)]. Outcomes were follow-up HbA1c, achievement of HbA1c <7% and <8%, hypoglycaemia incidence and event rates, and healthcare resource utilization. RESULTS: Following basal insulin switching, HbA1c reductions were greater/similar with Gla-300 versus IDet/Gla-100 (variable follow-up: -0.45% ± 1.40% vs. -0.29% ± 1.57%; P = .021; fixed follow-up: -0.48% ± 1.49% vs. -0.38% ± 1.59%; P = .114), while HbA1c goal attainment was similar in both cohorts. Gla-300 was associated with less hypoglycaemia [event rate: adjusted rate ratio (aRR): 0.63, 95% CI: 0.53-0.75; P < .001] and inpatient/emergency department-associated hypoglycaemia (adjusted hazard ratio: 0.58, 95% CI: 0.37-0.90; P = .016; aRR: 0.43, 95% CI: 0.31-0.60; P < .001) by variable follow-up. By fixed follow-up, hypoglycaemia results significantly or numerically favoured Gla-300. CONCLUSION: Among older adults with T2D, switching to Gla-300 versus Gla-100/IDet was associated with greater/similar improvements in glycaemic control, and generally less hypoglycaemia.

Early hypoglycaemia and adherence after basal insulin initiation in a nationally representative sample of Medicare beneficiaries with type 2 diabetes.

AIMS: To estimate risk factors associated with early hypoglycaemia and its impact on adherence to and persistence with therapy in Medicare Part D beneficiaries with type 2 diabetes who are initiating basal insulin (BI). MATERIALS AND METHODS: This retrospective analysis used a 5% sample of Medicare files from 2007-2013, identifying beneficiaries with type 2 diabetes initiating BI from 1 January 2008 to 31 December 2012. Early hypoglycaemia was defined as ≥1 hypoglycaemic event ≤6 months postindex. Outcomes included medication adherence and persistence over 12- and 36-month follow-up. Multivariable logistic and Cox regression analyses were conducted to examine factors associated with early hypoglycaemia and BI adherence/persistence. RESULTS: Of the 14 466 included patients, 1315 (9.1%) experienced hypoglycaemia ≤6 months after initiating BI. Factors associated with early hypoglycaemia were female sex (odds ratio [OR] 1.16 [95% confidence interval [CI] 1.02-1.32]), receipt of a low-income subsidy under Medicare Part D (OR 1.20 [95% CI 1.01-1.43]), high diabetes complication score index (OR 1.08 [95% CI 1.01-1.15]), and hypoglycaemia during the baseline period (OR 4.24 [95% CI 3.63-4.96]). At 12 months, patients with baseline hypoglycaemia were less likely to be adherent to (OR 0.81 [95% CI 0.70-0.93]) and more likely to discontinue (OR 1.33 [95% CI 1.07-1.66]) their insulin therapy. Results were similar at 36 months. CONCLUSIONS: Within 6 months of BI initiation, almost 1 in 10 Medicare Part D beneficiaries experienced hypoglycaemia. Early hypoglycaemia was associated with decreased adherence to BI treatment over 12- and 36-month follow-up.

Comparable glycaemic control and hypoglycaemia in adults with type 2 diabetes after initiating insulin glargine 300 units/mL or insulin degludec: The DELIVER Naïve D real-world study.

AIM: To compare glycaemic control, hypoglycaemia and treatment discontinuation of insulin glargine 300 units/mL (Gla-300) and insulin degludec (IDeg) in a real-world study of insulin-naïve adults with type 2 diabetes (T2D). MATERIALS AND METHODS: DELIVER Naive D was a retrospective observational study that used electronic medical record data from the IBM Watson Health Explorys database. Insulin-naïve adults with T2D who started Gla-300 or IDeg between March 2015 and September 2017 were identified. Patients were active in the system for ≥12 months before and ≥6 months after starting Gla-300 or IDeg and had HbA1c measurements during 6-month baseline and 3- to 6-month follow-up. Outcomes were compared among 1:1 propensity score-matched cohorts. RESULTS: In the matched cohorts (n = 638 each), the mean age was 59 years, approximately 53% were male, and mean HbA1c was 9.67% (82 mmol/mol). Mean (SD) HbA1c decreases were comparable in the Gla-300 and IDeg cohorts (-1.67% [2.22] and -1.58% [2.20]; P = 0.51), as were HbA1c target attainment [<7% (53 mmol/mol): 23.8% and 27.4%; P = 0.20; <8% (64 mmol/mol): 55.0% and 57.1%; P = 0.63] and treatment discontinuation (29.2% and 32.6%; P = 0.14). Overall and inpatient/emergency department-associated hypoglycaemia incidences and event rates were similar in both cohorts using fixed 6-month or variable on-treatment follow-up. CONCLUSIONS: Among real-world insulin-naïve adults with T2D, initiation of Gla-300 or IDeg resulted in comparable improvements in glycaemic control and similar rates of hypoglycaemia. These real-world data complement and confirm a randomized trial and other real-world studies.

The US Food and Drug Administration's Risk Evaluation and Mitigation Strategy (REMS) Program - Current Status and Future Direction.

The US Food and Drug Administration (FDA) Amendments Act of 2007 granted the FDA new authorities to enhance drug safety by requiring application holders to submit a proposed Risk Evaluation and Mitigation Strategy (REMS). A REMS is a required risk management plan that uses tools beyond the package insert. REMS elements may include a medication guide and patient package insert for patients and a communication plan focused on health care professionals. Elements to assure safe use (ETASUs) are put in place to mitigate a specific known serious risk when other less restrictive elements of a REMS are not sufficient to mitigate such risk. An implementation system is required for an REMS that includes the ETASUs. With approximately eight years of experience with REMS programs, many health care settings have created systems to manage REMS and also to integrate REMS into their practice settings. At the same time, there are issues associated with the development and implementation of REMS. In 2011, FDA created the REMS Integration Initiative to develop guidance on how to apply statutory criteria to determine when a REMS is required, to improve standardization and assessment of REMS, and to improve integration of REMS into the existing healthcare system. A key component of the REMS Integration Initiative is stakeholder outreach to better understand how existing REMS programs are working and to identify opportunities for improvement. This review attempts to share our company's experience with the REMS program, and to provide updates on FDA's efforts to improve REMS communication, to standardize REMS process, to reduce REMS program burdens and to build a common REMS platform.

Risk of Wernicke's encephalopathy and cardiac disorders in patients with myeloproliferative neoplasm.

The objectives of the study were to estimate the incidence of Wernicke's encephalopathy (WE) and cardiac disorders among patients with myeloproliferative neoplasms (MPN), and compare it with those without MPN. A total of 39,761 MPN patients were identified from the US Marketscan database. Approximately 27% of them were 65+ years of age, and 51% were male. Patients with MPN had higher rates of WE, compared to those without MPN (MPN vs. non-MPN: 1.09 vs. 0.39/1000 person-year, adjusted HR=2.19, 95%CI 1.43-3.34). Patients with MPN also had higher rates of cardiac events (congestive heart failure: MPN vs. non-MPN: 9.27 vs. 3.70/1000 person-year, adjusted HR=1.64, 95%CI 1.42-1.88; acute myocardial infarction: MPN vs. non-MPN: 10.45 vs. 5.02/1000 person-year, adjusted HR=1.44, 95%CI 1.27, 1.63; cardiac arrhythmia: MPN vs. non-MPN: 106.5 vs. 53.9/1000 person-year, adjusted HR=1.42, 95%CI 1.36-1.48). Physicians who care for patients with MPN should be aware of increased risk of WE and cardiac disorders in this population.

Assessment of dronedarone utilization using US claims databases.

BACKGROUND: A dronedarone utilization study using US MarketScan and InVision Data Mart databases was conducted to estimate the prevalence of the following: (1) dronedarone use in contraindicated patients with worsening heart failure (HF) or hospitalization for HF within 1 month before dronedarone prescription; (2) concomitant prescribing of contraindicated drugs; and (3) recommended creatinine testing after dronedarone initiation among dronedarone users. METHODS: In this retrospective cohort study, data in the MarketScan database between July 20, 2009, and December 31, 2011, and in the InVision Data Mart database between July 20, 2009, and March 31, 2012, were analyzed. The study population included patients who received ≥1 dronedarone prescription during the study period. The following variables were reported: worsening of or hospitalization for HF, concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors or QT-prolonging drugs, and creatinine testing. RESULTS: There were 31,408 and 7025 dronedarone users identified in the MarketScan and InVision Data Mart databases, respectively. Approximately 86% to 90% of patients had a diagnosis of atrial fibrillation in each database. In the MarketScan database, 40% were women and 54% were aged ≥65 years. In the InVision Data Mart database, 31% were women and 32% were aged ≥65 years. The corresponding prevalence of worsening or hospitalization for HF was 6.4% (95% CI, 6.2-6.7) and 4.7% (95% CI, 4.2-5.2) in each database, respectively. The corresponding estimates of concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors and QT-prolonging drugs within 30 days before initiation or refilling of dronedarone were 2.0% (95% CI, 1.8-2.1) and 10.0% (95% CI, 9.7-10.4), respectively, in the MarketScan database, and 2.3% (95% CI, 2.0-2.7) and 11.2% (95% CI, 10.5-12.0) in the InVision Data Mart database. More than 50% of patients in each database had serum creatinine tests conducted after dronedarone initiation. CONCLUSIONS: The results of the present analysis based on a long-term follow-up (nearly 3 years) were consistent with the previous findings that dronedarone has mostly been used appropriately in compliance with US prescribing in the target populations.

Exposure to potentially dangerous drug-drug interactions involving antipsychotics.

OBJECTIVE: Antipsychotic drug therapy is the cornerstone of treatment of persons with schizophrenia. Because most antipsychotics are metabolized by the hepatic cytochrome P450 system, concomitant use of an antipsychotic and medications that are competitively metabolized by the same system may cause a potentially harmful drug-drug interaction. This study used a large state's Medicaid claims database to examine the proportion of patients exposed to such interactions and the risk factors associated with exposure. METHODS: Claims from January 2000 through December 2003 for adult patients with a diagnosis of schizophrenia and at least one prescription for an antipsychotic (N=27,909) were examined for pairs of medications identified as potentially causing moderate or severe adverse drug effects. Logistic regression models were estimated to determine potential risk factors associated with exposure to the interaction pairs. RESULTS: A total of 6,417 (23%) patients were exposed to 14,213 potentially harmful interactions; 4,725 patients had at least one exposure from the same pharmacy, and 4,032 patients were exposed by the same physician. The greatest number of exposures (N=1,353) to potentially harmful combinations involved olanzapine and haloperidol. Patients prescribed risperidone were most likely to be exposed to an interaction (13.1%), followed by patients prescribed olanzapine (10.3%), quetiapine (3.3%), and clozapine (3.2%). A higher risk of exposure was associated with being female (odds ratio [OR]=.94), being white (OR=1.43), having depression (OR=1.21), or having impulse-control disorder (OR=1.98). CONCLUSIONS: Interventions by physicians and pharmacies to reduce the prescribing and dispensing of potentially harmful pairs of medications to patients with schizophrenia are recommended.

Incidence of serious upper and lower gastrointestinal events in older adults with and without Alzheimer's disease.

OBJECTIVES: To estimate and compare the incidence of serious upper and lower gastrointestinal (GI) events in individuals aged 65 and older with and without Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING: PharMetrics, a large population-based health insurance claims database was used for the study. PARTICIPANTS: Individuals aged 65 and older with a diagnosis of AD (International Classification of Diseases, Ninth Revision, Clinical Modification Code 331.0) were identified between January 1, 2003, and December 31, 2006, using the PharMetrics database. The control cohort consisted of a random sample of health plan enrollees matched to the AD cohort according to age, sex, location, and index year in a 1:1 ratio. MEASURES: The outcomes of interest were serious GI events, including ulceration, perforation, and bleeding in the upper or lower GI tract. RESULTS: Twenty-seven thousand seventy-six individuals with AD were identified. Approximately 66% of them were age 80 and older, and 65% were female. Participants with AD had higher incidence of serious GI events (upper GI: AD vs non-AD: 27.4 vs 17.1/1000 person-years, HR = 1.49, 95%CI = 1.34-1.65; lower GI: AD vs non-AD: 9.4 vs 6.9/1000 person-years, HR = 1.26, 95%CI = 1.06-1.48). The association was also present in participants without a history of GI bleeding (upper GI: HR = 1.54, 95%CI = 1.37-1.73; lower GI: HR = 1.37, 95%CI = 1.14-1.64). CONCLUSION: Participants with AD had higher incidence of serious upper and lower GI events, compared to those without AD. Physicians should recognize the high risk of serious GI events that exists in individuals with AD.

Patient-rated troubling symptoms of depression instrument results correlate with traditional clinician- and patient-rated measures: a secondary analysis of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The Patient-Rated Troubling Symptoms of Depression (PaRTS-D) instrument assesses the presence and troublesomeness of 8 commonly reported depression-related symptoms from the patient's perspective. A post hoc analysis of a double-blind, randomized risperidone augmentation to antidepressant therapy trial in patients with major depressive disorder explored the relationship between the PaRTS-D instrument and other clinician- and patient-rating scales. METHODS: Patients completed the PaRTS-D; the Patient Global Improvement Scale (PGIS), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS), while clinicians completed the Hamilton Rating Scale for Depression (HRSD-17), and the Clinical Global Impressions of Severity (CGI-S) at baseline and at pre-determined study weeks. RESULTS: In the PaRTS-D instrument, the four most frequently reported and troublesome symptoms were sadness (73.5%, severity 6.8), trouble concentrating (70.9%, 7.3), reduced involvement in pleasurable activities (61.9%, 7.3), and being tense or uptight (56.0%, 6.7). The improvement in PaRTS-D total score was significantly greater in risperidone-augmented compared with placebo-augmented patients at week 4 (p=0.034) and week 6 (p=0.007). Pearson correlations between the PaRTS-D scores and the measures of HRSD-17, CGI-S, PGIS, Q-LES-Q, and SDS were significant at both baseline and at week 6 LOCF (p<0.001 for each comparison). LIMITATIONS: Results are from a post hoc analysis. CONCLUSIONS: Significant correlations were observed between the PaRTS-D and other clinician- and patient-rated measures, with PaRTS-D being sensitive to the effects of treatment. These findings suggest that the PaRTS-D instrument is a reliable scale to assess antidepressant activity as experienced by the patients.

Potential bias in testing for hyperprolactinemia and pituitary tumors in risperidone-treated patients: a claims-based study.

BACKGROUND: A reporting association of risperidone with pituitary tumors has been observed. Because such tumors are highly prevalent, there may be other reasons why they were revealed in association with risperidone treatment. We assessed two potential explanations: disproportionately more prolactin assessment and head/brain imaging in risperidone-treated patients vs patients treated with other antipsychotics. METHODS: Treatment episodes with risperidone, clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole, haloperidol, perphenazine and 'other typical' antipsychotics were identified in two databases (large commercial, Medicaid). Comparisons used proportional hazards regression to determine whether prolactin testing was disproportionate with risperidone, regardless of prior potentially prolactin-related adverse events (PPAEs). Logistic regression determined whether magnetic resonance imaging (MRI)/computed tomography (CT) were disproportionate in risperidone-treated patients vs other patients, regardless of hyperprolactinemia or PPAEs. In each regression, the 'other typical' antipsychotic category served as the comparator. Regression models controlled for age, gender, and other factors. RESULTS: Altogether, 197,926 treatment episodes were analyzed (63,878 risperidone). Among patients with or without preceding PPAEs, risperidone treatment was associated with a significantly greater likelihood of prolactin assessment (hazard ratio (HR) 1.34, 95% confidence interval (CI) = 1.09 to 1.66, p = 0.007). Among patients with hyperprolactinemia or PPAEs, those treated with risperidone (odds ratio (OR) 1.66, 95% CI 1.23 to 2.23, p = 0.001) or ziprasidone (OR 1.66, 95% CI 1.06 to 2.62, p = 0.028) had a higher likelihood of MRI/CT. CONCLUSION: Risperidone-treated patients are more likely to undergo prolactin assessment regardless of prior PPAEs, and more likely to undergo MRI/CT in association with hyperprolactinemia or PPAEs. Thus, a predisposition for more evaluations in risperidone-treated patients may contribute to disproportionate identification and reporting of prevalent pituitary adenoma.

Psychometric evaluation of a patient-rated troubling symptom scale for generalized anxiety disorder clinical trials.

BACKGROUND: The majority of clinical outcome assessments developed for generalized anxiety disorder (GAD) may not efficiently and sensitively reflect heterogeneous symptom clusters from a patient perspective. The Patient-Rated Troubling Symptoms Scale for Anxiety (PaRTS-A) instrument was developed to provide an individualized assessment of patient relevant GAD symptoms. OBJECTIVE: The objective of this analysis was to evaluate the psychometric characteristics of the PaRTS-A. METHODS: Data were taken from a 6-week clinical trial evaluating the efficacy of adjunctive risperidone therapy in GAD patients undergoing standard treatment. Patients completed the PaRTS-A, the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and the Sheehan Disability Scale (SDS) as well as impressions of improvement. Physicians completed the Hamilton Anxiety Rating Scale (HAM-A). A instrument characteristics were assessed through statistical tests of reliability, reproducibility, construct and discriminant validity, and responsiveness. RESULTS: In the item response theory (IRT) analysis, the PaRTS-A items fit into a single construct of anxiety. Internal consistency reliability exceeded 0.70. The PaRTS-A total score was moderately correlated with the Q-LES-Q and the SDS. The PaRTS-A distinguished between patients with high and low HAM-A scores (p<0.001). The PaRTS-A was responsive to changes in clinical status and the minimal important difference was identified. CONCLUSION: The PaRTS-A provides a unique patient-rated assessment of anxiety symptoms. The instrument may provide clinicians with useful information regarding patient's self-rated anxiety disorder symptoms and the hierarchy of symptoms that they considered most troubling. Our analysis suggests that the PaRTS-A is an internally consistent, valid, and responsive instrument that may be a beneficial adjunct to other instruments in clinical trials.

Hospitalization rates before and after initiation of paliperidone ER in patients with schizophrenia: results from open-label extensions of the US double-blind trials.

OBJECTIVE: To assess differences in the number of days hospitalized among schizophrenic patients receiving paliperidone extended-release (paliperidone ER) during the open-label extension (OLE) phases, compared to a similar time period prior to the screening for entry into the double-blind (DB) trials conducted in the United States. METHODS: Mental health-related hospital days during the 52 weeks before entering the DB trials and during the OLE phases were compared. The mean number of hospital days per person per year in the pre- and post-periods was calculated and the statistical significance of pre-post differences was assessed using bootstrap resampling methods. Total person-years were also calculated for the pre- and post-periods to account for different lengths of observation. RESULTS: Patients' (n=215) mean (+/-SD) age was 41.2 (+/-11.0) years; most were male (73.0%); and black (52.1 vs. 45.1% white). The mean (+/-SD) paliperidone ER treatment duration during the OLE phase was 167.0 (+/-145.0) days and the mean (+/-SD) daily dose was 10.5 (+/-2.0) mg. Overall, paliperidone ER patients spent an average (+/-SD) of 13.2 (+/-1.6) and 3.1 (+/-0.7) hospital days per person-year in the pre-and post-periods, respectively (mean +/-SD change 10.0+/-1.8, 95% CI 6.5, 13.4, p<0.001). Using the 2007 Federal Per Diem Base Rate (i.e., $595.09 per day), this reduction in hospital days would result in an average (+/-SD) cost savings of $5951 (+/-1071) per person per year. CONCLUSIONS: Patients had significantly fewer hospital days in the OLE phase compared to the 1-year period prior to entering the DB trial. Paliperidone ER may play a role in reducing mental health-related hospital days and associated costs. Important study limitations include the lack of a control group, the pre-post design comparing historical data with data collected in the trials which could create a bias due to the mismatch in settings, and patients having more frequent contact with treating physicians and investigators during the trial period, which could favor the outcomes in the OLE phase. Further studies are needed to confirm these findings.

Comparative costs of ertapenem and piperacillin-tazobactam in the treatment of diabetic foot infections.

PURPOSE: To evaluate potential cost savings, trial data were used to determine the clinical outcomes for i.v. ertapenem given once daily and i.v. piperacillin-tazobactam given every six hours daily in treating diabetic foot infections. METHODS: A cost-minimization analysis (CMA) was conducted on the drug-dosing data of the subset of patients enrolled in a recent double-blind randomized trial who were treated solely as inpatients and were clinically evaluable at fi nal assessment (n = 99). Cost per dose was calculated from (a) average hospital acquisition price per dose for ertapenem ($40.52) or piperacillin-tazobactam ($13.58), (b) average U.S. wages and benefits for labor, based on nine published time-and-motion studies of i.v. antibiotic preparation and administration ($3.10), and (c) consumable supplies, using a 40% discount off the manufacturer list price ($2.90). For each patient, the actual number of antibiotic doses given was multiplied by total cost per dose. RESULTS: There were no significant differences between antibiotic groups with respect to patient demographics, percentage with a severe wound, and mean days of i.v. therapy. Compared with piperacillin-tazobactam, patients treated with ertapenem received significantly fewer mean doses (25.5 versus 7.5; p < 0.0001) and lower antibiotic-related costs ($502.76 versus $355.55, respectively; p < 0.001). The $147.21 difference between groups accounts for approximately 3% of total hospital Medicare reimbursements for these infections. CONCLUSION: A CMA of treatment of diabetic foot infections showed that, compared with piperacillin-tazobactam given four times daily i.v., ertapenem given once daily i.v. was associated with lower drug acquisition and supply costs and less time and labor devoted to preparation and administration of i.v. therapy.