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Background Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes. Objective To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs. Design Prospective cohort. (ClinicalTrials.gov: NCT02411396). Setting 4 U.S. sites, with recruitment between April 2015 and December 2016. Participants Adults with SCD living within 60 miles of a study site. Measurements Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment. Results Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED. Limitation The study was restricted to participants with uncomplicated VOCs. Conclusion In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED. Primary funding source Patient-Centered Outcomes Research Institute.

BACKGROUND: Older adults have many comorbidities contributing to mortality. OBJECTIVE: To develop a summary Elixhauser (S-Elixhauser) comorbidity score to predict 30-day, in-hospital, and 1-year mortality in older adults using the 38 comorbidities operationalized by the Agency for Healthcare Research and Quality (AHRQ). DESIGN: Retrospective cohort study. SETTING: Medicare beneficiaries from 2017 to 2019. PATIENTS: Persons hospitalized in 2018 (n = 899 844) and 3 disease-specific hospitalized cohorts. MEASUREMENTS: Weights were derived for 38 comorbidities to predict 30-day, in-hospital, and 1-year mortality. The S-Elixhauser score was internally validated and calibrated. Individual Elixhauser comorbidity indicators (38 comorbidities), the modified application of the AHRQ-derived Elixhauser summary score, the Charlson comorbidity indicators (17 comorbidities), and the Charlson summary score were externally validated. The c-statistic was used to evaluate discrimination of a comorbidity score model. RESULTS: The S-Elixhauser score was well calibrated and internally validated, with a c-statistic of 0.705 (95% CI, 0.703 to 0.707) in predicting 30-day mortality, 0.654 (CI, 0.651 to 0.657) for in-hospital mortality, and 0.743 (CI, 0.741 to 0.744) for 1-year mortality. In external validation of other comorbidity indices for 30-day mortality, the c-statistic was 0.711 (CI, 0.709 to 0.713) for the individual Elixhauser comorbidity indicators, 0.688 (CI, 0.686 to 0.690) for the AHRQ Elixhauser score, 0.696 (CI, 0.694 to 0.698) for the Charlson comorbidity indicators, and 0.690 (CI, 0.688 to 0.693) for the Charlson summary score. In 3 disease-specific populations, the discrimination of the S-Elixhauser score in predicting 30-day mortality ranged from 0.657 to 0.732. LIMITATIONS: Validation of the S-Elixhauser comorbidity score and head-to-head comparison with other comorbidity scores in an external population are needed to evaluate comparative performance. CONCLUSION: The S-Elixhauser comorbidity score is well calibrated and internally validated but its advantage over the AHRQ Elixhauser and Charlson summary scores is unclear. PRIMARY FUNDING SOURCE: National Institute on Aging.

Summary Background Many individuals take long-term immunosuppressive medications. We evaluated whether these individuals have worse outcomes when hospitalised with COVID-19 compared with non-immunosuppressed individuals. Methods We conducted a retrospective cohort study using data from the National COVID Cohort Collaborative (N3C), the largest longitudinal electronic health record repository of patients in hospital with confirmed or suspected COVID-19 in the USA, between Jan 1, 2020, and June 11, 2021, within 42 health systems. We compared adults with immunosuppressive medications used before admission to adults without long-term immunosuppression. We considered immunosuppression overall, as well as by 15 classes of medication and three broad indications for immunosuppressive medicines. We used Fine and Gray's proportional subdistribution hazards models to estimate the hazard ratio (HR) for the risk of invasive mechanical ventilation, with the competing risk of death. We used Cox proportional hazards models to estimate HRs for in-hospital death. Models were adjusted using doubly robust propensity score methodology. Findings Among 231 830 potentially eligible adults in the N3C repository who were admitted to hospital with confirmed or suspected COVID-19 during the study period, 222 575 met the inclusion criteria (mean age 59 years [SD 19]; 111 269 [50%] male). The most common comorbidities were diabetes (23%), pulmonary disease (17%), and renal disease (13%). 16 494 (7%) patients had long-term immunosuppression with medications for diverse conditions, including rheumatological disease (33%), solid organ transplant (26%), or cancer (22%). In the propensity score matched cohort (including 12 841 immunosuppressed patients and 29 386 non-immunosuppressed patients), immunosuppression was associated with a reduced risk of invasive ventilation (HR 0·89, 95% CI 0·83–0·96) and there was no overall association between long-term immunosuppression and the risk of in-hospital death. None of the 15 medication classes examined were associated with an increased risk of invasive mechanical ventilation. Although there was no statistically significant association between most drugs and in-hospital death, increases were found with rituximab for rheumatological disease (1·72, 1·10–2·69) and for cancer (2·57, 1·86–3·56). Results were generally consistent across subgroup analyses that considered race and ethnicity or sex, as well as across sensitivity analyses that varied exposure, covariate, and outcome definitions. Interpretation Among this cohort, with the exception of rituximab, there was no increased risk of mechanical ventilation or in-hospital death for the rheumatological, antineoplastic, or antimetabolite therapies examined. Funding None.

Clinical trials investigating cardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) among patients with cardiovascular and renal disease rarely recruit patients with renal impairment, despite associations with increased risk for major adverse cardiovascular events (MACE). We investigated the risk of MACE associated with the use of DPP-4i among these high-risk patients. Using a new-user, retrospective, cohort design, we analyzed 2010–2015 IBM MarketScan Commercial Claims and Encounters for patients with diabetes, comorbid with cardiovascular disease and/or renal impairment. We compared time to first MACE for DPP-4i versus sulfonylurea and versus metformin. Of 113,296 individuals, 9146 (8.07%) were new DPP-4i users, 17,481 (15.43%) were new sulfonylurea users, and 88,596 (78.20%) were new metformin users. Exposure groups were not mutually exclusive. DPP-4i was associated with lower risk for MACE than sulfonylurea (aHR 0.84; 95% CI 0.74, 0.93) and similar risk for MACE to metformin (aHR 1.07; 95% CI [1.04, 1.16]). DPP-4i use was associated with lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin. This association was most evident in the first year of therapy, suggesting that DPP-4i is a safer choice than sulfonylurea for diabetes treatment initiation in high-risk patients.

Background and aims Multiple direct-acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. Approach and results We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician-recorded adverse events, patient-reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%-97.6%) and 97.4% (95% CI, 95.5%-99.2%), respectively, with a difference estimate of 2.2% (-0.5% to 4.7%), falling within the "equivalence" interval (-5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient-reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow-up after treatment, limiting the ability to measure SVR12. Conclusions This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin-free EBR/GZR and LDV/SOF.

Aim There is conflicting evidence regarding the safety and effectiveness of warfarin for atrial fibrillation (AF) treatment among older end-stage renal disease (ESRD) patients, and differences among subgroups are unclear. Methods Older dialysis patients who were newly diagnosed with AF (7/2007-12/2011) were identified in the United States Renal Data System. The adjusted hazard ratios (HR) of the outcomes (any stroke, ischaemic stroke, major bleeding, severe gastrointestinal bleeding, and death) by time-varying warfarin use were estimated using Cox regression accounting for the inverse probability of treatment weight. Results Among 5765 older dialysis patients with incident AF, warfarin was associated with significantly increased risk of major bleeding (HR = 1.50, 95% CI 1.33-1.68), but was not statistically associated with any stroke (HR = 0.92, 95% CI 0.75-1.12), ischaemic stroke (HR = 0.88, 95%CI 0.70-1.11) or gastrointestinal bleeding (HR = 1.03, 95% CI 0.80-1.32). Warfarin use was associated with a reduced risk of mortality (HR = 0.72, 95%CI 0.65-0.80). The association between warfarin and major bleeding differed by sex (male: HR = 1.29; 95%CI 1.08-1.55; female: HR = 1.67; 95%CI 1.44-1.93; P-value for interaction = 0.03). Conclusion Older ESRD patients with AF who were treated with warfarin had a no difference in stroke risk, lower mortality risk, but increased major bleeding risk. The bleeding risk associated with warfarin was greater among women than men. The risk/benefit ratio of warfarin may be less favourable among older women.

Background It is unclear whether chronic use of immunosuppressive drugs worsens or improves the severity of coronavirus disease 2019 (COVID-19), with plausible mechanisms for both. Methods Retrospective cohort study in 2121 consecutive adults with acute inpatient hospital admission between 4 March and 29 August 2020 with confirmed or suspected COVID-19 in a large academic health system, with adjustment for confounding with propensity score–derived stabilized inverse probability of treatment weights. Chronic immunosuppression was defined as prescriptions for immunosuppressive drugs current at the time of admission. Outcomes included mechanical ventilation, in-hospital mortality, and length of stay. Results There were 2121 patients admitted with laboratory-confirmed (1967, 93%) or suspected (154, 7%) COVID-19 during the study period, with a median age of 55 years (interquartile range, 40–67). Of these, 108 (5%) were classified as immunosuppressed before COVID-19, primarily with prednisone (>7.5 mg/day), tacrolimus, or mycophenolate mofetil. Among the entire cohort, 311 (15%) received mechanical ventilation; the median (interquartile range) length of stay was 5.2 (2.5–10.6) days, and 1927 (91%) survived to discharge. After adjustment, there were no significant differences in the risk of mechanical ventilation (hazard ratio [HR], .79; 95% confidence interval [CI], .46–1.35), in-hospital mortality (HR, .66; 95% CI, .28–1.55), or length of stay (HR, 1.16; 95% CI, .92–1.47) among individuals with immunosuppression and counterparts. Conclusions Chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19 in one US health system., Among adults with confirmed or suspected coronavirus disease 2019 (COVID-19), chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes such as mechanical ventilation, in-hospital mortality, or length of stay.

Rigorous evidence about the broad range of harms that might be experienced by a patient in the course of testing and treatment is sparse. We aimed to generate recommendations for how researchers might more comprehensively evaluate potential harms of healthcare interventions, to allow clinicians and patients to better include this evidence in clinical decision-making. We propose seven domains of harms of tests and treatments that are relevant to patients: (1) physical impairment, (2) psychological distress, (3) social disruption, (4) disruption in connection to healthcare, (5) labeling, (6) financial impact, and (7) treatment burden. These domains will include a range of severity of harms and variation in timing after testing or treatment, attributable to the service itself or a resulting care cascade. Although some new measures may be needed, diverse data and tools are available to allow the assessment of harms comprehensively across these domains. We encourage researchers to evaluate harms in sub-populations, since the harms experienced may differ importantly by demographics, social determinants, presence of comorbid illness, psychological state, and other characteristics. Regulators, funders, and editors might require either assessment or reporting of harms in each domain or require justification for inclusion and exclusion of different domains. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-06597-9.

PURPOSE: Delays in initiating adjuvant endocrine therapy (AET) are a cause for concern among women with breast cancer and clinicians, but the impact of delayed AET on overall survival (OS) is unclear. This study seeks to describe the relationship between delayed AET and OS. METHODS: Retrospective cohort study of women with stage II and III hormone receptor positive, human epidermal receptor 2 negative, invasive breast cancer, identified from the National Cancer Database. The primary exposure delayed AET, was defined as initiation of AET more than 12 months after breast cancer diagnosis. Using logistic regression we examined predictors of delayed AET. The survival analysis with Cox proportional hazards regression adjusted for patient, tumor, and treatment characteristics. RESULTS: Among the 391,594 included women, 12,162 (3.1%) had delayed AET. Predictors of delayed AET included Black race (adjusted odds ratio [aOR]=1.61, 95% confidence interval [CI], 1.52-1.70) or Hispanic ethnicity (aOR=1.25, 95% CI 1.16-1.35) vs white race, Medicare (aOR=1.13, 95% CI 1.06-1.20) or Medicaid (aOR=1.41, 95% CI 1.32-1.50) versus private insurance, and cancer stage III (aOR=1.24, 95% CI 1.19-1.30) vs stage II. With median follow-up of 67.4 months, 67,335 (17.2%) patients died. Delayed AET had no statistically significant effect on the hazard of death (adjusted hazards ratio=1.01; 95% CI, 0.96-1.06) compared to initiation within 12 months of diagnosis. CONCLUSION: This study suggests that there may be no adverse impact on survival if initiation of AET occurs 12 to 24 months after initial diagnosis compared to within 12 months of diagnosis as currently recommended.

BACKGROUND: Overuse of health care resources has been identified as the leading contributor to waste in the US health care system. OBJECTIVE: To explore health care system factors associated with regional variation in systemic overuse of health care resources as measured by the Johns Hopkins Overuse Index (JHOI) which aggregates systemic overuse of 20 health care services. DESIGN: Using Medicare fee-for-service claims data from beneficiaries age 65 or over in 2008, we calculated the JHOI for the 306 hospital referral regions in the United States. We used ordinary least squares regression and multilevel models to estimate the association of JHOI scores and characteristics of regional health care delivery systems listed in the Area Health Resource File and Dartmouth Atlas. KEY RESULTS: Regions with a higher density of primary care physicians had lower JHOI scores, indicating less systemic overuse (P

Background: Excessive breast cancer screening with mammography or other modalities often burdens patients with false-positive results and costs. Yet, screening patients beyond the age at which they will benefit or at too frequent intervals persists. This review summarizes the factors associated with overuse of breast cancer screening. Methods: We searched Medline and Embase from January 1998 to March 2017 for articles addressing the overuse of breast cancer screening and hand-searched the reference lists of included articles. Studies were included if they were written in English, pertained to a U.S. population, and identified a factor associated specifically with overuse of breast imaging. Paired reviewers independently screened abstracts, extracted data, and assessed quality. Results: We included 15 studies: 3 cohort, 5 cross-sectional, 6 surveys, and 1 in-depth interview. White women (non-Hispanic) were less vulnerable than other racial groups to overuse in 3 of 5 studies. Physician specialty was consistently associated with screening overuse in three of three studies. Abundant access to primary care and a patient desire for screening were associated with breast cancer screening overuse. Lower self-confidence, lower risk taking tendencies, higher perception of conflict in expert recommendations, and a belief in screening effectiveness were clinician traits associated with overuse of screening in the surveys. Conclusions: The literature supports that liberal access to care and clinicians' recommendations to screen, possibly influenced by conflicting guidelines, increase excessive breast cancer screening. Overuse might conceivably be reduced with more concordance across guidelines, physician education, patient involvement in decision-making, thoughtful insurance restrictions, and limitations on the supply of services; however, these will need careful testing regarding their impact.

Rationale: Diabetes and metabolic syndrome have been associated with worsened asthma control. Metformin improves insulin resistance and metabolic function. Experimental studies suggest that metformin may improve pathologic features of asthma, but evidence of clinical benefit is limited. Objectives: To determine if treatment with metformin in a cohort of individuals with asthma and diabetes is associated with lower risk of asthma exacerbation. Methods: A 6-year retrospective cohort of individuals over age 18 with asthma and diabetes was assembled from a national administrative claims database. New users of metformin were matched to nonusers by propensity score on the basis of demographic, comorbidity, and medication-use characteristics. An exacerbation was defined as an asthma-related hospitalization, emergency department visit, or filling of a systemic corticosteroid prescription within 14 days of an asthma-related ambulatory visit. Cox proportional hazards estimated the change in hazard of asthma exacerbation associated with metformin initiation. Results: In a cohort of 23,920 individuals with asthma and diabetes, metformin initiation was associated with lower hazard of asthma exacerbation (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.86–0.98), driven by lower hazards of asthma-related emergency department visits (HR, 0.81; 95% CI, 0.74–0.88) and hospitalization (HR, 0.67; 95% CI, 0.50–0.91), without differences in corticosteroid use (HR, 0.96; 95% CI, 0.86–1.03). Conclusions: In an administrative cohort of individuals with asthma and diabetes, metformin initiation was associated with a lower hazard of asthma-related emergency department visits and hospitalizations. These findings suggest a possible benefit of metformin in more severe asthma exacerbations. Investigation within cohorts with more detailed participant characterization is necessary.

Purpose In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015. Methods We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE. Results Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset. Conclusions Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Objective To examine the use of antimuscarinics for treating urinary incontinence (UI) in older adults with varying levels of cognition. Design Cross-sectional. Setting National Alzheimer's Coordinating Center from 2005 through 2015. Participants Community-dwelling men and women aged 65 and older (N = 24,106). Measurements Clinicians and staff evaluated each participant's dementia status during annual in-person assessments. Participants or their informants reported all medications taken in the 2 weeks before each study visit. Results Overall, 5.2% (95% confidence interval (CI) = 4.9–5.5%) of the cohort took a bladder antimuscarinic. Participants with impaired cognition were more likely to be taking an antimuscarinic than those with normal cognition. Rates of bladder antimuscarinic use were 4.0% (95% CI = 3.6–4.4%) for participants with normal cognition, 5.6% (95% CI = 4.9–6.3%) for those with mild cognitive impairment, and 6.0% (95% CI = 5.5–6.4%) for those with dementia (p < .001). Of 624 participants with dementia who took antimuscarinics, 16% (95% CI = 13–19%) were simultaneously taking other medicines with anticholinergic properties. Conclusion Use of bladder antimuscarinics was more common in older adults with impaired cognition than in those with normal cognition. This use is despite guidelines advising clinicians to avoid prescribing antimuscarinics in individuals with dementia because of their vulnerability to anticholinergic-induced adverse cognitive and functional effects. A substantial proportion of cognitively impaired individuals who took antimuscarinics were simultaneously taking other anticholinergic medications. These findings suggest a need to improve the treatment of UI in individuals with impaired cognition.

Objectives To quantify prescription analgesic use of elderly nursing home (NH) residents with persistent noncancer pain and to identify individual and facility traits associated with no treatment. Design Cross-sectional study. Setting Linked Minimum Data Set (MDS) assessments; Online Survey, Certification and Reporting (OSCAR) records; and Medicare Part D claims. Participants Individuals aged 65 and older with persistent noncancer pain were identified from a cross-section of all long-stay U.S. NH residents with an MDS assessment and Medicare Part D enrollment in 2008, excluding those who were terminally ill, those with Alzheimer's disease, and those with the most-severe cognitive impairment. Measurements Residents with moderate to severe daily pain on consecutive assessments at least 90 days apart constituted the cohort with persistent pain. Part D dispensing for an opioid or nonsteroidal anti-inflammatory drug (NSAID) within 30 days of persistent pain onset was identified. Information on resident and facility characteristics was obtained from MDS and OSCAR records. Associations between resident and facility attributes and pain treatment were estimated using multilevel mixed-effects logistic regression analyses. Results Of the study sample of 18,526 residents with persistent pain, 3,094 (16.7%) did not receive prescription analgesics, 12,815 (69.2%) received a prescription opioid, 485 (2.6%) received a prescription NSAID, and 2,132 (11.5%) received a prescription opioid and NSAID. After adjusting for potentially confounding covariates, residents who were older (≥95, odds ratio (OR) = 2.06, 95% confidence interval (CI) = 1.70–2.49), more cognitively impaired (moderately severe cognitive impairment, OR = 2.12, 95% CI = 1.71–2.62), or black (OR = 1.20, 95% CI = 1.03–1.39) or Asian (OR = 1.97, 95% CI = 1.22–3.20) were less likely to receive a prescription analgesic. Conclusion Through 2008, pain remained undertreated in NHs, especially in certain subpopulations, including cognitively impaired and older residents. Changes in pain management practice and policies may be necessary to target these vulnerable residents.

OBJECTIVE Appropriate glycemic control is fundamental to diabetes care, but aggressive glucose targets and intensive therapy may unintentionally increase episodes of hypoglycemia. We quantified the burden of severe hypoglycemia requiring medical intervention in a well-defined population of insured individuals with diabetes receiving care in integrated health care delivery systems across the U.S. RESEARCH DESIGN AND METHODS This observational cohort study included 917,440 adults with diabetes receiving care during 2005 to 2011 at participating SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) network sites. Severe hypoglycemia rates were based on any occurrence of hypoglycemia-related ICD-9 codes from emergency department or inpatient medical encounters and reported overall and by age, sex, comorbidity status, antecedent A1C level, and medication use. RESULTS Annual rates of severe hypoglycemia ranged from 1.4 to 1.6 events per 100 person-years. Rates of severe hypoglycemia were higher among those with older age, chronic kidney disease, congestive heart failure, cardiovascular disease, depression, and higher A1C levels, and in users of insulin, insulin secretagogues, or β-blockers (P < 0.001 for all). Changes in severe hypoglycemia occurrence over time were not clinically significant in the cohort as a whole but were observed in subgroups of individuals with chronic kidney disease, congestive heart failure, and cardiovascular disease. CONCLUSIONS Risk of severe hypoglycemia in clinical settings is considerably higher in identifiable patient subgroups than in randomized controlled trials. Strategies that reduce the risk of hypoglycemia in high-risk patients are needed.

Dabigatran is a direct thrombin inhibitor approved by the FDA in October 2010 for the treatment of nonvalvular atrial fibrillation. Little is known regarding patient adherence to this therapy.To examine adherence and persistence to dabigatran among adults with atrial fibrillation.We used IMS Health's LifeLink Health Plan Claims Database from 2010 to 2012 to identify patients with atrial fibrillation who were new users of dabigatran. We derived adherence and persistence for continuously enrolled patients at 6 months, 9 months, and 12 months of follow-up. We measured adherence using the medication possession ratio (MPR), defined as individuals with MPRs of 0.80 or greater as adherent, and examined persistence by identifying individuals with gaps in drug possession of 60 days or greater.Of 5,951 adults with atrial fibrillation who were new users of dabigatran, 49% had prevalent atrial fibrillation and at least 6 months of continuous follow-up. Of these, 89% used dabigatran as the only oral anticoagulant, whereas the remainder filled prescriptions for at least 1 other oral anticoagulant during the follow-up period. Among those using dabigatran alone (n = 2,713), the mean MPR was 0.73 (standard error = 0.30), 41% were nonadherent with therapy, and 32% had gaps of 60 days or greater. Among those observed for 9 (or 12) months who used dabigatran alone, rates of nonadherence were 47% (49%), whereas 48% (49%) discontinued therapy during follow-up. Rates of adherence and persistence were similar for patients with incident atrial fibrillation.Nonadherence to dabigatran was common among patients with atrial fibrillation. Future studies are needed to understand the reasons for nonadherence.

BackgroundCardiovascular safety of dipeptidyl peptidase-IV inhibitors (DPP-4i) in patients without cardiovascular or renal disease, a majority of newly diagnosed patients with type 2 diabetes often excluded from clinical trials on this association, is poorly understood. Thus, we investigate the risk of major adverse cardiovascular events (MACE) associated with DPP-4i in low-risk patients with diabetes.MethodsUsing a new-user retrospective cohort derived from IBM MarketScan Commercial Claims and Encounters (2010-2015), we identified patients aged 35-65 with type 2 diabetes, without cardiovascular or renal disease, initiating DPP-4i, sulfonylureas, or metformin. Primary composite outcome of time to first MACE was defined as the first of any of the following: myocardial infarction, cardiac arrest, coronary artery bypass graft, coronary angioplasty, heart failure, and stroke. Secondary outcomes were time to first heart failure, acute myocardial infarction, and stroke. We compared outcomes for DPP-4i versus sulfonylurea and DPP-4i versus metformin using propensity score weighted Cox proportional hazards, adjusting for demographics, baseline comorbidities, concomitant medications, and cumulative exposure.ResultsOf 445,701 individuals, 236,431 (53.0%) were male, median age was 51 (interquartile range: [44, 57]), 30,267 (6.79%) initiated DPP-4i, 52,138 (11.70%) initiated sulfonylureas, and 367,908 (82.55%) initiated metformin. After adjustment, DPP-4i was associated with lower risk of MACE than sulfonylurea (adjusted hazard ratio (aHR) = 0.87; 95% confidence interval (CI): 0.78-0.98), and similar risk to metformin (aHR = 1.07; 95% CI: 0.97-1.18). Risk for acute myocardial infarction (aHR = 0.70; 95% CI: 0.51-0.96), stroke (aHR = 0.57; 95% CI: 0.41-0.79), and heart failure (aHR = 0.57; 95% CI: 0.41-0.79) with DPP-4i was lower compared to sulfonylureas.ConclusionOur findings show that for this cohort of low-risk patients newly treated for type 2 diabetes, DPP-4i exhibited 13% lower risk for MACE compared to sulfonylureas and similar risk for MACE compared to metformin, suggesting DPP-4i is a low cardiovascular risk option for low-risk patients initiating antihyperglycemic treatment.

537 Background: Time to adjuvant endocrine therapy concerns patients and clinicians, but its impact on overall survival is not clear. There are no population level studies that address this question. Our primary objective is to describe the relationship between time from diagnosis of breast cancer to start of adjuvant endocrine therapy and overall survival. Methods: This is a population-based cohort study using prospectively collected population level data from the National Cancer Database (NCDB). The NCDB prospectively collects data on incident cancer cases from over 1500 Commission on Cancer-accredited facilities nationally. NCDB captures approximately 70% of incident cases of cancer in the United States. The participants are women with Stage II and III estrogen or progesterone receptor positive, human epidermal receptor 2 negative, invasive breast cancer who underwent definitive surgical treatment. Results: Of the 391,594 women in this study, 12,162 (3.1%) began treatment with adjuvant endocrine therapy more than 12 months after initial diagnosis of hormone receptor positive, invasive breast cancer. Mean age at diagnosis was 59.7 years (SD 13.4). Predictors of delayed initiation of adjuvant endocrine therapy include Black race or Hispanic ethnicity (adjusted odds ratio [aOR] of Black vs White, 1.57; 95% CI, 1.48-1.66; P < .001, Hispanic vs White, aOR 1.22, 95% CI 1.13-1.32; P < .001), Insurance other than private insurance (Medicare vs Private, aOR 1.09, 95% CI 1.01-1.17; P = .007, Medicaid vs Private, aOR 1.36, 95% CI 1.28-1.45; P < .001), higher stage of disease at diagnosis (Stage III vs II, aOR 1.24, 95% CI 1.19-1.30; P < .001), and delayed surgery or chemotherapy (Delayed surgery vs On-time lumpectomy, aOR 2.76, 95% CI 2.60-2.93; P < .001 and Delayed chemotherapy vs no chemotherapy, aOR 11.5, 95%CI 10.6-12.5). With median follow-up of 63.2 months, 67,335 (17.2%) patients died by the end of follow-up. Delayed initiation of AET resulted in no change in the hazard of death (HR, 1.00; 95% CI, 0.95-1.05; P = .97) compared to initiation within 12 months of diagnosis after adjusting for age, race and ethnicity, insurance type, urban vs rural residence, neighborhood income and education, comorbidity, cancer grade, stage, and receipt of timely or delayed surgery, chemotherapy, and/or radiation therapy. Conclusions: These results suggest that there may be no detriment to survival if initiation of adjuvant endocrine therapy occurs 12 to 24 months after initial diagnosis compared to within 12 months of diagnosis, as currently recommended.

With expanding therapeutic options for type 2 diabetes, the treatment of older adults requires special care to balance safety and complexity with glucose control. We compared national trends in type 2 diabetes treatment among older (≥65 years) and younger adults (30-64 years) using the 2006-2015 National Ambulatory Medical Care Survey (NAMCS), an annual probability sample of visits to U.S. outpatient providers. We included all visits of patients with type 2 diabetes using ≥1 diabetes medication. Analyses were weighted to yield nationally-representative estimates. In the most recently available data, 2014-2015, there were 23.3 million and 20.1 million annual treated diabetes visits for older and younger adults, respectively. The most frequently used medications in older and younger adult visits were metformin (50.4% vs. 62.3% respectively, p In conclusion, the outpatient treatment of type 2 diabetes differs between older and younger adults driven in part by a marked increase in the use of long-acting insulin among older adults, which may have implications for risk of hypoglycemia. Disclosure S.J. Pilla: None. J.B. Segal: None. G. Alexander: Other Relationship; Self; See disclosure. C. Boyd: None. N. Maruthur: None.

Many studies use glucose values from electronic medical record data to identify patients with prediabetes and diabetes (1–3). Since diagnostic criteria are based on fasting glucose (4), investigators often choose to assume that patients were fasting if phlebotomy was performed in the morning. We sought to assess the validity of the assumption that outpatient morning measurements are fasting measures. We surveyed adult patients (age ≥18 years) presenting for phlebotomy at the Johns Hopkins Outpatient Center between 7:00 a.m. and noon over 2 weeks in November 2018. Patients responded to a four-question written survey provided by the registration staff. The survey asked 1 ) about their fasting status, 2 ) whether the ordering provider instructed them to fast, 3 ) whether they were getting a glucose and/or cholesterol test (“If you know which blood test(s) you are getting done, please select ones that are included on the list below,” with answer options of “glucose” and “cholesterol panel”), and 4 ) what …

OBJECTIVE The objective of this study was to assess the incidence of major cardiovascular (CV) hospitalization events and all-cause deaths among adults with diabetes with or without CV disease (CVD) associated with inadequately controlled glycated hemoglobin (A1C), high LDL cholesterol (LDL-C), high blood pressure (BP), and current smoking. RESEARCH DESIGN AND METHODS Study subjects included 859,617 adults with diabetes enrolled for more than 6 months during 2005–2011 in a network of 11 U.S. integrated health care organizations. Inadequate risk factor control was classified as LDL-C ≥100 mg/dL, A1C ≥7% (53 mmol/mol), BP ≥140/90 mm Hg, or smoking. Major CV events were based on primary hospital discharge diagnoses for myocardial infarction (MI) and acute coronary syndrome (ACS), stroke, or heart failure (HF). Five-year incidence rates, rate ratios, and average attributable fractions were estimated using multivariable Poisson regression models. RESULTS Mean (SD) age at baseline was 59 (14) years; 48% of subjects were female, 45% were white, and 31% had CVD. Mean follow-up was 59 months. Event rates per 100 person-years for adults with diabetes and CVD versus those without CVD were 6.0 vs. 1.7 for MI/ACS, 5.3 vs. 1.5 for stroke, 8.4 vs. 1.2 for HF, 18.1 vs. 40 for all CV events, and 23.5 vs. 5.0 for all-cause mortality. The percentages of CV events and deaths associated with inadequate risk factor control were 11% and 3%, respectively, for those with CVD and 34% and 7%, respectively, for those without CVD. CONCLUSIONS Additional attention to traditional CV risk factors could yield further substantive reductions in CV events and mortality in adults with diabetes.

Summary Background Venous thromboembolism (VTE) has been recently recognized as a complication of sickle cell disease (SCD); however, the incidence of VTE in SCD is unknown. Objectives The primary objective of this study was to determine the incidence of first VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), among SCD patients age ≥ 15 years. We also evaluated genotypic differences in VTE risk and determined the relationship between VTE and mortality. Patients/methods In this retrospective cohort study, we used data from the Cooperative Study of Sickle Cell Disease (CSSCD) to calculate incidence rates for first VTE. We used Cox proportional hazard models to estimate hazard ratios (HRs) for time to VTE by genotype and time to death by VTE status. Results We included 1523 SCD patients aged ≥ 15 years with 8862 years of follow-up in this analysis. The incidence rate for first VTE was 5.2 events/1000 person-years (95% confidence interval [CI] 3.8–6.9) with a cumulative incidence of 11.3% (95% CI 8.3–15.3) by age 40 years. Individuals with the SS/Sβ0-thalassemia genotype had the highest rate of VTE (7.6 events/1000 person-years [95% CI 5.3–10.6]). The incidence of PE exceeded that of isolated DVT (3.6 [95% CI 2.5–5.1] events/1000 person-years vs. 1.6 [95% CI 0.9–2.7] events/1000 person-years), although this difference was not statistically significant. SCD patients with VTE had a higher mortality rate (adjusted HR 2.32 [95% CI 1.20–4.46]) than those without VTE. Conclusions Patients with SCD are at substantial risk for VTE, and individuals with VTE are at higher risk of death than those without VTE.

BACKGROUND: Overuse of healthcare is pervasive in the United States, often exposing patients to harm with little likelihood of benefit. Older Americans are particularly vulnerable to overuse and impacted by it, yet it is unknown whether older patients perceive overuse as a consequential problem. OBJECTIVE: To explore the experiences and perspectives of older adults with respect to healthcare overuse in order to develop a framework for understanding and reducing overuse in older adults. DESIGN: Qualitative study using focus group methodology. PARTICIPANTS: Five focus groups were held with people ≥65 years of age (N = 38) in four senior centers in Baltimore, Maryland, in 2016. APPROACH: Transcripts were analyzed using qualitative content analysis to identify major themes. KEY RESULTS: Of the 38 participants, 28 were women and 29 were African-American; 31 had at least a 12th grade education. While virtually all reported experience with what they perceived to have been healthcare overuse, some expressed concern that they had been denied appropriate care. They perceived overuse to have occurred when interventions were applied in the absence of symptoms (excluding cancer screening), did not improve symptoms, were discordant with their preferences, or were duplicative. Some defined overuse as interventions that were offered before less intensive options or too early in the course of disease. Suggested contributors to overuse were poor quality communication between patients and healthcare providers, and between different healthcare providers. Participants reported suffering from treatment effects, high costs, worry, and inconvenience from what they perceived to be overuse. They suggested that overuse may be reduced when the patient is involved in decision making and has a trusted primary care doctor. CONCLUSIONS: The experience of older adults highlights potential sites of intervention to reduce healthcare overuse. Engaging patients in shared decision making and enhancing communication and knowledge transfer should be tested as interventions to reduce perceived overuse. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-017-4264-y) contains supplementary material, which is available to authorized users.

In a comment (1) on our article in Diabetes Care (2), Dr. Philip Home posits that the association of severe hypoglycemic events with other medical conditions and the use of diagnoses from hospitalized patients could explain the high event rate noted in our study compared with other reports based in the …

Background Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection. Purpose To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection. Data Sources MEDLINE and EMBASE from inception through 1 November 2016. Study Selection 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. Data Extraction Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently. Data Synthesis Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (

OBJECTIVES To identify patient demographics and characteristics associated with compliance to statin therapy after switching from branded to generic agents

Purpose The purpose of this study was to evaluate the impact of switching from branded to generic statins on medication compliance. Methods In this historic cohort study, we identified patients taking branded statins between January 2003 and December 2012 from Sutter Health's electronic health records in Northern California. Patients with ≥2 consecutive pharmacy claims for generic statins after initiating branded statins were classified as switchers. Switchers and non-switchers were matched 1:1 on the propensity for switching. Medication possession ratio (MPR) was calculated as the sum of days supply of therapy divided by treatment duration. We assessed between-group differences in compliance (MPR ≥ 0.80) by logistic regression. Results Among 16,364 patients meeting eligibility criteria, 8470 were retained in the matched cohort. No significant differences in compliance with statin therapy were observed for non-switchers versus switchers, overall, or versus patients switched from a branded to generic statin of the same agent (generic substitutions). Patients switched from a branded to generic statin of a different agent (therapeutic substitutions) more frequently received less potent statin dosing relative to those with generic substitutions (42.2% vs.

Purpose Antihyperglycemic medication intensification practices among patients with incident diabetes are incompletely understood. We characterized the first intensification the year after oral antihyperglycemic medication initiation among incident diabetes patients. Methods This retrospective cohort study across 11 US health systems included adults identified with incident diabetes between 2005 and 2009 who started oral antihyperglycemic monotherapy or combination therapy within 6 months after diabetes identification. We determined intensification, defined as increased index medication dosage, addition of another oral medication, or switch to/addition of insulin 31–365 days after initial antihyperglycemic dispensing. Cox regression was used to assess intensification for patient, temporal, and system covariates, adjusting for glycosylated hemoglobin (HbA1c) as a time-dependent variable. Results Among 41 233 patients, 33.5% and 45.3% had treatment intensified within 6 and 12 months, respectively. This first intensification was most often with increased index medication dosage (78%), least often with insulin (

To minimize bias, clinical practice guidelines (CPG) for managing patients with multiple conditions should be informed by well-planned syntheses of the totality of the relevant evidence by means of systematic reviews and meta-analyses. However, deficiencies along the entire evidentiary pathway hinder the development of evidence-based CPGs. Published reports of trials and observational studies often do not provide usable data on treatment effect heterogeneity, perhaps because their design, analysis and presentation is seldom geared towards informing on how multimorbidity modifies the effect of treatments. Systematic reviews and meta-analyses inherit all the limitations of their building blocks and introduce additional of their own, including selection biases at the level of the included studies, ecological biases, and analytical challenges. To generate recommendations to help negotiate some of the challenges in synthesizing the primary literature, so that the results of the evidence synthesis is applicable to the care of those with multiple conditions. Informal group process. We have built upon established general guidance, and provide additional recommendations specific to systematic reviews that could improve the CPGs for multimorbid patients. We suggest that following the additional recommendations is good practice, but acknowledge that not all proposed recommendations are of equal importance, validity and feasibility, and that further work is needed to test and refine the recommendations.

OBJECTIVE This study uses novel methods to examine the frequency of diagnosis and treatment of prediabetes in real-world clinical settings using electronic health record (EHR) data. RESEARCH DESIGN AND METHODS We identified a cohort of 358,120 adults with incident prediabetes (fasting plasma glucose [FPG] 100–125 mg/dL or glycated hemoglobin 5.7–6.4% [39–46 mmol/mol]) between 2006 and 2010 and examined rates of diagnosis and treatment in the 6 months after identification. RESULTS In the 6 months after identification of prediabetes, 18% of patients had their blood glucose levels retested; 13% received a physician diagnosis of prediabetes/hyperglycemia; 31.0% had prediabetes, diabetes, or lifestyle documented in the clinical notes; and CONCLUSIONS Documented rates of follow-up and treatment for prediabetes are low. EHR data may be a valuable tool to improve identification and treatment of prediabetes in the U.S.

OBJECTIVE Since 2010, several non-vitamin K antagonist oral anticoagulants (NOACs) have been brought to the U.S. market, yet little is known regarding their evolving adoption for prophylaxis of atrial fibrillation (AF)-related stroke. We examined temporal trends in choice of oral anticoagulants (OACs) among incident OAC users with AF and its association with patient demographic and clinical characteristics. METHODS We conducted a serial cross-sectional analysis of medical and pharmacy claims for commercial and Medicare Advantage enrollees in a large, private, U.S. health plan. We identified 112,187 adults with nonvalvular AF starting OACs between October 2010 and March 2017. Multivariable logistic regression was used to examine the associations of patient characteristics with prescription of NOACs versus warfarin. Multinomial logistic regression was used to test the associations of patient characteristics with choice among NOACs. RESULTS The prescription of NOACs has increased dramatically since their introduction in October 2010. In the first quarter of 2017 (2017Q1), 7502 patients started OACs, of whom 78.9% used NOACs and 21.1% warfarin. For NOACs, 3.8% used dabigatran, 25.0% rivaroxaban, and 50.1% apixaban. In multivariable analyses, factors associated with choice of NOACs versus warfarin included younger age, lower stroke or bleeding risk, fewer comorbidities, higher education level or household net worth, and prescription by cardiologists (all p

Among adults with incident diabetes, data are lacking about first antihyperglycemic initiation and whether medication choice aligns with recommendations.To identify predictors of initiating any antihyperglycemic, and specifically sulfonylurea versus metformin.This retrospective cohort study included 241 327 patients from 11 US health systems, 2005 through 2010. Assessments included antihyperglycemic initiation within 6 months of diabetes identification, first medication initiated, and initiation predictors.Only 40.3% (n = 97 350) started any antihyperglycemic; 75.2% (n = 73 221) started metformin. Glycosylated hemoglobin (HbA1c) predicted initiating any antihyperglycemic (HbA1c9%, relative risk [RR] = 3.94, 95% CI = 3.82, 4.07, vs HbA1c6.5%-7%). Age modified the HbA1c effect: at higher HbA1c, likelihood of starting antihyperglycemics differed little across ages; at lower HbA1c, older patients were less likely to start antihyperglycemics (P.001). Individuals with elevated serum creatinine (SCr) were more likely to started on sulfonylurea (SCr = 1.4-2, RR = 2.21 [2.05, 2.39]; SCr2, RR = 2.75 [2.30, 3.29] vs normal SCr), particularly as HbA1c increased: patients with HbA1c 8%-9% and SCr2 were 5.59 times (2.94, 10.65) more likely to start sulfonylurea versus those with HbA1c6.5%-7% and normal SCr. Age predicted sulfonylurea initiation (20-39 years, RR = 0.87 [0.79, 0.95]; ≥ 80 years, RR = 2.41 [2.20, 2.65] vs 50-59 years).Among adults with incident diabetes, metformin was generally the first antihyperglycemic initiated. However, 59.7% did not start any antihyperglycemic at diabetes identification. HbA1c and age predict antihyperglycemic initiation; SCr and age predict sulfonylurea initiation.

Background Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear. Objective We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma. Methods MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article. Results Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT. Conclusion Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making.

SummaryWhat is known and objective The prevalence of diabetic nephropathy continues to rise and it remains a strong predictor of morbidity and mortality in diabetic patients. Patients diagnosed with diabetic nephropathy are actively excluded from most trials involving diabetic medications and it is important to understand the prescription patterns in this subset of patients with diabetes. Methods Using the IMS Health's National Disease and Therapeutic Index, we analysed the medication prescription patterns for six classes of medications from 2010 to 2014 among patients, 35 years or older, with diabetic nephropathy. Results Annual office visits increased from 772 860 (95% confidence interval (CI), 755, 470–790, 249) in 2010 to 1 868 618 (95% CI, 1 834 422–1 902 814) in 2013 and declined to 830 596 (95% CI, 809 167–852 025) in 2014. Sulfonylureas and dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were the most frequently used of the four classes of diabetic medications included in this study. DPP-4 inhibitors use increased gradually and was used in 54% (95% CI 49–58) of treatment visits by the last quarter of 2014. Across these years, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs and ARBs) were prescribed in the majority of treatment visits with peaks above 90%. However, there were some periods when utilization of these antihypertensives was low. What is new and conclusions Significant increases occurred in the uptake of new diabetic medications; DPP-4 inhibitors and SGLT-2 inhibitors and in the utilization of ACEIs and ARBs compared to the findings reported in other studies with increased complexity in the treatment of patients with diabetic nephropathy. Improved and continued used of these medications may be beneficial in improving patient outcomes.

BACKGROUND: Plasma exchange, the standard treatment for thrombotic thrombocytopenic purpura (TTP), has significantly decreased disease mortality. However, TTP recurs in 20% to 50% of patients who survive the initial episode. We aimed to describe the clinical spectrum of TTP, to determine the valid endpoint for plasma exchange cessation, and to explore the risk factors for disease relapse. STUDY DESIGN AND METHODS: Using the ICD-9 diagnosis code, we identified patients treated for TTP at the Johns Hopkins Hospital between 1992 and 2008. Complete demographic, clinical, laboratory, treatment, and outcome data were collected from the medical records. RESULTS: A total of 72 patients were treated for 134 episodes of TTP at the Johns Hopkins Hospital during the study period. With standardized combined immunosuppression and plasma exchange treatment, the all-cause mortality rate was 4%. Lactate dehydrogenase (LDH) normalization lagged behind platelet (PLT) recovery by an average of 9 days and did not predict response. Relapse occurred in 36% of patients during a median follow-up of 30 months with most (76%) occurring in the first 24 months. African American ethnicity was associated with increased risk of relapse (odds ratio = 4.8, p = 0.03). CONCLUSIONS: Excellent outcomes in patients with TTP are achievable with multimodality therapy. LDH normalization lags behind PLT recovery and might not be an informative endpoint for plasma exchange cessation. Prospective studies are warranted to confirm the influence of race on relapse and identify additional risk factors for adverse outcomes that could be targeted to improve therapeutic outcomes for patients with TTP.

CONTEXT. Hydroxyurea is the only approved medication for the treatment of sickle cell disease in adults; there are no approved drugs for children. OBJECTIVE. Our goal was to synthesize the published literature on the efficacy, effectiveness, and toxicity of hydroxyurea in children with sickle cell disease. METHODS. Medline, Embase, TOXLine, and the Cumulative Index to Nursing and Allied Health Literature through June 2007 were used as data sources. We selected randomized trials, observational studies, and case reports (English language only) that evaluated the efficacy and toxicity of hydroxyurea in children with sickle cell disease. Two reviewers abstracted data sequentially on study design, patient characteristics, and outcomes and assessed study quality independently. RESULTS. We included 26 articles describing 1 randomized, controlled trial, 22 observational studies (11 with overlapping participants), and 3 case reports. Almost all study participants had sickle cell anemia. Fetal hemoglobin levels increased from 5%–10% to 15%–20% on hydroxyurea. Hemoglobin concentration increased modestly (∼1 g/L) but significantly across studies. The rate of hospitalization decreased in the single randomized, controlled trial and 5 observational studies by 56% to 87%, whereas the frequency of pain crisis decreased in 3 of 4 pediatric studies. New and recurrent neurologic events were decreased in 3 observational studies of hydroxyurea compared with historical controls. Common adverse events were reversible mild-to-moderate neutropenia, mild thrombocytopenia, severe anemia, rash or nail changes (10%), and headache (5%). Severe adverse events were rare and not clearly attributable to hydroxyurea. CONCLUSIONS. Hydroxyurea reduces hospitalization and increases total and fetal hemoglobin levels in children with severe sickle cell anemia. There was inadequate evidence to assess the efficacy of hydroxyurea in other groups. The small number of children in long-term studies limits conclusions about late toxicities.

SummaryThe clinical relevance of heparin-induced antibodies (HIA) in the absence of thrombocytopenia remains to be defined. The aims of this study were (i) to determine the prevalence of HIA in patients treated by dialysis, (ii) to determine the prevalence of thrombocytopenia and heparin-induced thrombocytopenia (HIT), and (iii) to test whether HIA are associated with adverse outcomes. Sera from 740 patients treated by hemodialysis (HD, n=596) and peritoneal dialysis (PD, n=144) were tested for HIA (IgG, IgA or IgM) by masked investigators at approximately six months after enrolment in the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) study. We assessed, with time-to-event Cox proportional hazards models, whether the presence of HIA predicted any of four clinical outcomes: arterial cardiovascular events, venous thromboembolism, vascular access occlusion and mortality. HIA prevalence was 10.3% overall. HIA positivity did not predict development of thrombocytopenia or any of the four clinical outcomes over a mean follow-up of 3.6 years, with hazard ratios for arterial cardiovascular events of 0.98 (95% confidence interval 0.70–1.37), venous thromboembolism 1.39 (0.17–11.5), vascular access occlusion 0.82 (0.40–1.71), and mortality 1.18 (0.85–1.64). Chronic intermittent heparin exposure was associated with a high seroprevalence of HIA. In dialysis patients these antibodies were not an independent risk factor for cardiovascular events and mortality. Our data do not suggest that dialysis patients should be monitored for HIA antibodies in the absence of thrombocytopenia.

Background: When using observational data to compare the effectiveness of medications, it is essential to account parsimoniously for patients' longitudinal characteristics that lead to changes in treatments over time. Objectives: We developed a method of estimating effects of longitudinal treatments that uses subclassification on a longitudinal propensity score to compare outcomes between a new drug (exenatide) and established drugs (insulin and oral medications) assuming knowledge of the variables influencing the treatment assignment. Research Design/Subjects: We assembled a retrospective cohort of patients with diabetes mellitus from among a population of employed persons and their dependents. Methods: The data, from i3Innovus, includes claims for utilization of medications and inpatient and outpatient services. We estimated a model for the longitudinal propensity score process of receiving a medication of interest. We used our methods to estimate the effect of the new versus established drugs on total health care charges and hospitalization. Results: We had data from 131,714 patients with diabetes filling prescriptions from June through December 2005. Within propensity score quintiles, the explanatory covariates were well-balanced. We estimated that the total health care charges per month that would have occurred if all patients had been continually on exenatide compared with if the same patients had been on insulin were minimally higher, with a mean monthly difference of $397 [95% confidence interval (CI), $218-$1054]. The odds of hospitalization were also comparable (relative odds, 1.02; 95% CI, 0.33-1.98). Conclusions: We used subclassification of a longitudinal propensity score for reducing the multidimensionality of observational data, including treatments changing over time. In our example, evaluating a new diabetes drug, there were no demonstrable differences in outcomes relative to existing therapies.

This review updates the American Society of Hematology and British guidelines on immune thrombocytopenic purpura incidence, prevalence, and natural history, with recent observations from the peer-reviewed medical literature.This analysis was conducted using literature-indexing systems to identify relevant articles. Information about the incidence and prevalence of immune thrombocytopenic purpura is limited, with nearly all data coming from Europe. Recent reports have confirmed earlier studies suggesting that the disease occurs in five out of 100,000 children per year, and that spontaneous recovery is typical. Intracranial hemorrhage occurs in 0.5-1.0% of affected children, and half are fatal. The incidence in adults is roughly two in 100,000 per year and may be more common in older adults than previously recognized. A female predominance occurs only among middle-aged patients, and there is no racial variation in incidence. Spontaneous remission rates vary by report and range from 5 to 11%.Spontaneous remission occurs more frequently in children than in adults, and intracranial bleeding is uncommon. The incidence increases with age, with a female predominance only among middle-aged adults. Adult patients with chronic disease may have a better prognosis than previously recognized, although only a small minority recover spontaneously.

Background: Exenatide was approved by the US Food and Drug Administration (FDA) in April 2005 as adjunctive therapy to metformin or a sulfonylurea for the treatment of type 2 diabetes mellitus (DM). Objective: We evaluated whether use of exenatide soon after its approval was consistent with the FDA- approved indications. Methods: We assembled a retrospective cohort of patients with DM using data from a population of employed persons and their dependents, including pharmacy claims and claims for inpatient and outpatient services, provided by i3 Innovus. The data set included patients aged between 18 and 64 years with a diagnosis of DM or a claim for a DM drug from June 1, 2004, to December 31, 2005. Laboratory data were available for a subgroup of patients tested at specific commercial laboratories from June 1, 2003, to December 31, 2005. In addition, we requested data for patients with a diagnosis of obesity, regardless of a diagnosis of DM, to assess early off-label use of this medication. Patients were categorized by DM medication use and by their first fill date for exenatide, and their clinical characteristics were described. Early use was defined as filling a prescription for exenatide in the first 3 months after its approval. For descriptive purposes, we reported the means and percentages for the variables described. Results: The study included data for 206,345 individuals (mean age, 51.3 years), of whom 54.0% were male. Starting in June 2005, prescriptions for exenatide were filled by 3225 (1.6%) individuals. Fifty-three percent of early users were women. Among those who filled a prescription for exenatide, 21.9% were obese, compared with 10.9% to 15.1% of those filling prescriptions for other DM medications. The proportion of patients filling a prescription for exenatide who had not received a prescription for any other DM medication in the preceding year was 14%, suggesting that exenatide was their initial therapy. A prescription for a thiazolidinedione was filled by 29.9% of patients within 60 days of filling a prescription for exenatide. Conclusions: Soon after its approval, exenatide was frequently used as monotherapy or in combination with a thiazolidinedione, neither of which is an FDA- approved indication. The observation that those filling a prescription for exenatide had a higher prevalence of obesity than those receiving prescriptions for other therapies may reflect awareness of the weight-lowering effects of exenatide. ( Clin Ther . 2007;29:1784-1794) Copyright © 2007 Excerpta Medica, Inc.

Purpose: The aim of this study was to evaluate the evidence on the optimal duration of vitamin K antagonist (VKA) therapy for venous thromboembolism (VTE). Methods: Randomized controlled trials of VKA for VTE were identified by a computerized database search. Summary event rates for relevant outcomes were calculated using a random effects model with 95% confidence intervals (95% CI). Results: Ten studies met inclusion criteria. The incidence of recurrent VTE (3 months, 7.9 VTE per 100 patient-years [95% CI, 5.2 to 10] versus 4–12 months, 4.9 VTE per 100 patient-years [95% CI, 3.6 to 6.2] versus continuous therapy, 0.7 VTE per 100 patient-years [95% CI, 0.3 to 1.1]) and total adverse events (3 months, 11.2 events per 100 patient-years [95%CI, 7.1 to 15.4] versus 4–12 months, 7.4 events per 100 patient-years [95%CI, 6.2 to 8.5] versus continuous therapy 3.1 events per 100 patient-years [95%CI, 2.2 to 4.0] declined as VKA therapy duration increased. Continuous reduced intensity therapy (INR 1.5–2) was associated with more recurrent VTE (2.3 VTE per 100 patient-years [95%CI, 1.5 to 3.0]). Continuous VKA therapy (INR 2–3) was beneficial for patients with a second VTE and antiphospholipid antibodies. The incidence of recurrent VTE was similar with 6 or 12 weeks of therapy for isolated calf DVT. Conclusion: Randomized controlled trials indicate that continuous VKA therapy (INR 2–3) for VTE is associated with better clinical outcomes than shorter durations. Patients with a second VTE or antiphospholipid antibodies also benefit from continuous anticoagulation. Patients with calf DVT should be treated for at least 6 weeks. Am. J. Hematol., 2006. © 2006 Wiley-Liss, Inc.

Resistance to inhibition of platelet function by aspirin may contribute to future myocardial infarction and stroke. Adverse cardiovascular outcomes have been associated with aspirin resistance on several different platelet function assays, including the level of urinary 11-dehydro thromboxane B2 (Tx-M), platelet aggregation to arachidonic acid and adenosine diphosphate, and closure time on the platelet function analyzer-100. We examined the concordance of these aspirin-resistance assays and their relation to cardiovascular risk factors in a primary prevention population. Asymptomatic patients (n = 1,311) at increased risk for coronary heart disease were evaluated before and after 2 weeks of aspirin (81 mg/day). Aspirin resistance was defined according to published criteria for these 3 assays of platelet function. Subjects were characterized for the presence of atherosclerosis risk factors. Agreement among the 3 assays was poor. Only 5 patients met aggregation criteria for aspirin resistance. Attenuated suppression of urinary Tx-M by aspirin was associated with a greater atherosclerotic risk profile and Framingham risk score in multivariable regression analysis. Aspirin resistance by platelet function analyzer-100 was associated only with increased von Willebrand factor levels and not with atherosclerotic risk profile. In conclusion, in a primary prevention population, different published criteria for aspirin resistance classify distinct groups of patients as aspirin resistant with very little overlap. Higher Tx-M, which reflects decreased suppression of thromboxane production in vivo, is the only criterion associated with atherosclerosis risk factors, suggesting that this measurement may represent the most relevant approach for identifying asymptomatic subjects whose aspirin treatment will "fail."

Background: Elevated concentration of serum homocysteine contributes to thrombosis, a frequent event in patients with sickle cell anemia. We aimed to test whether children with sickle cell anemia have elevated concentrations of serum homocysteine with diminished levels of folate or B vitamins from accelerated blood cell turnover. Methods: We conducted a case-control study of children with homozygous sickle cell anemia (n = 17) and unaffected children (n = 11). We measured serum and red blood cell folate, vitamin B 6 , vitamin B 12 , and homocysteine concentrations, and assessed micro-nutrient intake. Results: Children with sickle cell anemia had concentrations of homocysteine slightly higher than those of unaffected children. They had lower vitamin B 6 concentrations and comparable concentrations of folate and vitamin B 12 . Homocysteine concentration was inversely related to vitamin B 12 concentration and was not independently associated with levels of vitamin B 6 or folate. Conclusion: Despite comparable intake, children with sickle cell anemia had lower concentrations of vitamin B 6 than unaffected children. Larger studies are needed to determine if chronically low serum vitamin B 6 concentration contributes to hyperhomocysteinemia in this population.