Comparative efficacy of opioids for older adults presenting to the emergency department with acute pain: Systematic review.

OBJECTIVE: To systematically review the literature for studies comparing the efficacy of opioid analgesics for older adults (≥ 65 years) presenting to the emergency department (ED) with acute pain. DATA SOURCES: The Cochrane Library, MEDLINE, EMBASE, Web of Science, and CINAHL were searched up to August or September 2017. Reference lists were searched for potential articles and ClinicalTrials.gov was searched for unpublished trials. STUDY SELECTION: Randomized controlled trials (RCTs) were sought that compared the efficacy of 2 or more opioid analgesics for acute pain in older patients (≥ 65 years) in the ED. Two reviewers independently screened abstracts, assessed study quality, and extracted data. SYNTHESIS: After screening titles and abstracts of 1315 citations, the full texts of 63 studies were reviewed and 1 RCT met the inclusion criteria. This study randomized older adult patients presenting to an urban academic ED with acute, severe pain to receive a single dose of either 0.0075 mg/kg intravenous hydromorphone or 0.05 mg/kg intravenous morphine. This study found no clinical or statistical difference between the 2 treatments. CONCLUSION: The lack of published research in this area demonstrates a considerable gap in knowledge of the comparative efficacy of opioid analgesics in the growing older adult patient population. Physicians are often uncertain in their choice of analgesia, potentially contributing to the undertreatment of pain. It is clear that well designed RCTs are urgently needed.

Management of priapism with a trial of exercise in the emergency department.

Priapism is characterized by persistent penile erection in the absence of sexual arousal or desire that does not subside with orgasm. Although relatively uncommon, it is a genitourinary emergency that necessities prompt work-up and appropriate management, as there is a time-dependent relationship between total duration of erection and an increasing risk of permanent erectile dysfunction. Confirming the type of priapism is key to proper management, but the majority of cases presenting to the emergency department are ischemic in nature. Conservative management strategies for ischemic priapism are sparsely described in the literature but generally include ice pack application to the area, cold showers, masturbation and rarely, exercise. These strategies lack sound evidence, but the risks of attempting them are minimal as long as access to more definitive treatment is not delayed. Lower-limb exercise as a first-line treatment warrants further study in the undifferentiated emergency department priapism population. The case we present and discuss here illustrates the potential benefits of a trial of acute lower-limb exercise, specifically stair climbing, as a treatment for medication-induced priapism. If effective, this simple non-invasive management strategy may decrease the time to effective treatment, requires minimal resource utilization, and ultimately, avoids the need for more invasive treatment.

Incremental direct and indirect costs of untreated vasomotor symptoms.

OBJECTIVE: Most women with moderate to severe vasomotor symptoms (VMS) are untreated. This retrospective matched-cohort study aims to evaluate the healthcare resource utilization, work loss, and cost burden associated with untreated VMS. METHODS: Health insurance claims (1999-2011) were used to match (1:1) women with untreated VMS with control women using propensity score. Healthcare resource utilization, work productivity loss (disability + medically related absenteeism), and associated costs were compared between cohorts. RESULTS: During the 12-month follow-up, women with untreated VMS (n = 252,273; mean age, 56 y) had significantly higher healthcare resource utilization than women in the control cohort: 82% higher for all-cause outpatient visits (95% CI, 81-83; P < 0.001) and 121% higher (95% CI, 118-124; P < 0.001) for VMS-related outpatient visits. Mean direct costs per patient per year were significantly higher for VMS women (direct cost difference, US$1,346; 95% CI, 1,249-1,449; P < 0.001). VMS women had 57% (95% CI, 51-63; P < 0.001) more indirect work productivity loss days than controls, corresponding to an incremental indirect cost per patient per year associated with untreated VMS of US$770 (95% CI, 726-816; P < 0.001). CONCLUSIONS: This study shows that untreated VMS are associated with significantly higher frequency of outpatient visits and incremental direct and indirect costs.

Economic simulation of canagliflozin and sitagliptin treatment outcomes in patients with type 2 diabetes mellitus with inadequate glycemic control.

OBJECTIVES: This study examines the association between changes in diabetes-related quality measures (QMs) (HbA1c, systolic and diastolic blood pressure [BP], low-density lipoprotein cholesterol [LDL-C], and body weight) and healthcare costs in Type 2 diabetes mellitus (T2DM) patients. It also performs an economic simulation that evaluates the cost implications of the changes in QMs and of the incidence rates (IRs) of adverse events (AEs) associated with canagliflozin (CANA) and sitagliptin (SITA) treatments in a real-world setting. METHODS: Health-insurance claims and electronic medical records from the Reliant Medical Group database (2007-2011) were used to identify adult patients with T2DM receiving metformin and sulfonylurea who did not achieve adequate glycemic control. The association between the changes in QMs and healthcare costs was evaluated using multivariate regression and non-parametric bootstrap methods. AE-related costs were taken from the literature. The cost impact of CANA and SITA outcomes was evaluated using the aforementioned costs and the changes in QMs and the IRs of AEs observed in a recent phase 3 trial comparing CANA and SITA as third oral agent (DIA3015). RESULTS: Eight hundred and fifty-six T2DM patients were identified (mean age = 65.8; female 45.4%). The regression analysis found that increases of 1 percentage point in HbA1C and 1% in systolic and diastolic BP, LDL-C, or weight were associated with a per patient per year (PPPY) cost increase of $4476 (p = 0.028) and $566 (p = 0.006), a decrease of $362 (p = 0.070) and $7 (p = 0.817), and an increase of $241 (p = 0.481), respectively. The economic simulation showed that changes in QMs and IRs of AEs equivalent to those reported in DIA3015 would be associated with a reduction in PPPY healthcare costs of $6061 (p = 0.036) for CANA and $2190 (p = 0.098) for SITA. CONCLUSIONS: This study suggests that integrated approaches that manage to control a combination of quality measures are most successful at reducing downstream healthcare costs.

Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma.

INTRODUCTION: Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma. PATIENTS AND METHODS: A systematic literature review identified studies of bortezomib-based retreatment in relapsed/refractory myeloma. Proportions of bortezomib-refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs. RESULTS: Twenty-three studies (n = 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8%-47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (≤ 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%). CONCLUSION: Based on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients.

Quality measure attainment in patients with type 2 diabetes mellitus.

OBJECTIVES: This study examined the demographics, comorbidities, clinical characteristics, and treatments of people with type 2 diabetes mellitus (T2DM) treated with metformin and sulfonylurea as well as an elderly subgroup. Achievement of predefined quality measure goals (glycated hemoglobin [A1C], blood pressure [BP], low-density lipoprotein cholesterol [LDL-C], body mass index [BMI]) and their association with diabetes-related healthcare costs were assessed. STUDY DESIGN: The study applied a retrospective longitudinal cohort design. METHODS: Health insurance claims and electronic medical records from 14,532 adults with T2DM (2007- 2011) were used to identify a sample receiving metformin and sulfonylurea (MET+SU) concomitantly. The index date was the first dispensing of MET+SU after 6 months of eligibility. Clinical characteristics were assessed during baseline. Quality measure attainment (A1C <8%, BP <140/90 mm Hg, LDL-C level <100 mg/dL, BMI <30 kg/m²), was evaluated during the 12 months following the index date. Association between attainment and diabetes-related costs was evaluated using non-parametric bootstrap methods adjusting for imbalance in baseline characteristics between cohorts. RESULTS: Among 2044 patients, including 1283 patients 65 years and older, hyperlipidemia, hypertension, and cardiovascular disease were the most common baseline comorbidities. Quality measure goal attainment was 63.9% for A1C, 33.1% for BP, 68.2% for LDL-C level, and 34.4% for BMI, and was associated with significantly lower diabetes-related costs per patient per year compared with nonattainment (adjusted mean cost differences: -$1445 for A1C; -$1218 for BMI; -$2029 for A1C and BMI; -$2073 for A1C, BMI, and BP; all P <.05). CONCLUSION: This study highlights the high incidence of comorbidities and potential financial implications of attaining T2DM quality outcomes.

Association between consistent omalizumab treatment and asthma control.

BACKGROUND: Omalizumab is indicated for patients with moderate-to-severe allergic asthma with inadequately controlled symptoms. OBJECTIVE: We evaluated the association between consistent omalizumab treatment and asthma control. METHODS: Health insurance claims from the MarketScan database (2002Q1-2011Q2) were analyzed. Asthmatic patients with ≥12 months of continuous insurance coverage after the first omalizumab claim (index date) after 6 months of continuous omalizumab use were included. A 12-month landmark period was used to assess treatment consistency, defined as uninterrupted treatment without a gap of ≥28 days in omalizumab use. The effect of consistent omalizumab treatment on asthma control between months 13 and 24 was evaluated. Multivariate time-varying Cox regressions were also conducted to assess the adjusted effect of treatment interruption on asthma control from month 1 to month 24. RESULTS: A total of 3044 patients (mean age, 48.5 years; female, 62%) formed the study population. Patients consistent with omalizumab treatment at 12 months (39% of patients) were less likely to have an uncontrolled asthma event during months 13 to 24 with only 49% of patients experiencing one event compared with 54% in the non consistent subgroup (P = .02). In addition, consistent omalizumab treatment at 12 months was associated with a 51% reduction in the mean number of asthma-related emergency department (ED) visits per patient and a 28% reduction in asthma-related hospitalizations. Multivariate analyses corroborated these findings (hazard ratio for consistent vs non-consistent: risk of short-acting ß2-agonists prescription, oral corticosteroids prescription, ED visit, or hospitalization, 0.76; 95% CI, 0.69-0.83]). CONCLUSION: This analysis showed that consistent omalizumab treatment was associated with significant reductions in ED visits and hospitalizations.

Patterns of relapse and associated cost burden in schizophrenia patients receiving atypical antipsychotics.

OBJECTIVE: To identify relapse in schizophrenia and the main cost drivers of relapse using a cost-based algorithm. METHODS: Multi-state Medicaid data (1997-2010) were used to identify adults with schizophrenia receiving atypical antipsychotics (AP). The first schizophrenia diagnosis following AP initiation was defined as the index date. Relapse episodes were identified based on (1) weeks during the ≥2 years post-index associated with high cost increase from baseline (12 months before the index date) and (2) high absolute weekly cost. A compound score was then calculated based on these two metrics, where the 54% of patients associated with higher cost increase from baseline and higher absolute weekly cost were considered relapsers. Resource use and costs of relapsers during baseline and relapse episodes were compared using incidence rate ratios (IRRs) and bootstrap methods. RESULTS: In total, 9793 relapsers were identified with a mean of nine relapse episodes per patient. Duration of relapse episodes decreased over time (mean [median]; first episode: 34 [4] weeks; remaining episodes: 8 [1] weeks). Compared with baseline, resource utilization during relapse episodes was significantly greater in pharmacy, outpatient, and institutional visits (hospitalizations, emergency department visits), with IRRs ranging from 1.9-2.4 (all p < 0.0001). Correspondingly, relapse was associated with a mean (95% CI) incremental cost increase of $2459 ($2384-$2539) per week, with institutional visits representing 53% of the increase. LIMITATIONS: Relapsers and relapse episodes were identified using a cost-based algorithm, as opposed to a more clinical definition of relapse. In addition, their identification was based on the assumption from literature that ~54% of schizophrenia patients will experience at least one relapse episode over a 2-year period. CONCLUSIONS: Significant cost increases were observed with relapse in schizophrenia, driven mainly by institutional visits.

Burden of illness of patients with allergic asthma versus non-allergic asthma.

OBJECTIVE: Allergic and non-allergic asthma share similar symptoms, but differ in that allergic asthma is triggered by inhaled allergens. This study compared healthcare resource utilization (HCRU) and costs between these groups using US employer-based claims data. METHODS: Health insurance claims from Truven Marketscan database (2002Q1-2010Q2) were analyzed. Included patients had ≥2 asthma diagnoses and ≥1 year of eligibility prior to and following the date of first asthma diagnosis. Patients with ≥1 diagnosis for allergic asthma and ≥1 diagnosis for other allergic conditions formed the allergic asthma cohort whereas patients without any of these diagnoses formed the non-allergic asthma cohort. Allergic and non-allergic asthma patients were matched 1:1. HCRU and costs during the study period were compared between cohorts using incidence rate ratios (IRR) and bootstrap methods. RESULTS: Sixty four thousand four hundred and seventy three allergic and non-allergic asthma patients were matched (mean age = 30; 57.1% female; mean CCI = 0.2), with 7.1% and 0.36% having received an allergy test during the baseline period, respectively. During the study period, allergic asthma patients had significantly more asthma-related pharmacy dispensings (IRR[95% CI] = 2.25[2.22-2.28], p < 0.001) and asthma-related outpatient visits (IRR[95% CI] = 2.29[2.27-2.32], p < 0.001). Allergic asthma patients incurred 39% greater per-patient-per-year all-cause costs (allergic: $4008; non-allergic: $2889, p < 0.001) and 79% greater asthma-related costs (allergic: $1063; non-allergic: $592, p < 0.001) than non-allergic asthma patients. CONCLUSIONS: These results indicate, even in a relatively healthy population, allergic asthma is associated with greater HCRU and costs. Guideline-recommended IgE allergy tests should be employed in distinguishing the two forms of asthma, to optimize patient management and reduce costs.

Real-World Corticosteroid Utilization Patterns in Patients with Metastatic Castration-Resistant Prostate Cancer in 2 Large US Administrative Claims Databases.

BACKGROUND: Prostate cancer is the most common noncutaneous malignancy in men in the United States. Patients with metastatic castration-resistant prostate cancer (mCRPC) may be treated with secondary hormonal therapy or with chemotherapy, and potentially with concomitant corticosteroids. Corticosteroids can help manage the side effects of chemotherapy and secondary hormonal therapy and ameliorate prostate cancer-related symptoms, although corticosteroids are also associated with adverse effects. With an increasing number of available treatment options for mCRPC, evaluating the real-world concomitant use of corticosteroids in this patient population is important. OBJECTIVE: To evaluate the utilization patterns of corticosteroids for the treatment of patients with mCRPC based on real-world data from 2 large claim databases. METHODS: This retrospective analysis included medical and pharmacy claims from 2 large publicly available healthcare claims databases covering more than 31 million individuals to identify treatment patterns in adult patients with mCRPC. A total of 2593 patients with mCRPC were identified in data set 1 and 626 patients in data set 2 between 2005 and 2011. The appropriate treatment for castration-resistant prostate cancer (CRPC) was defined as chemotherapy, an antiandrogen, an adrenal androgen blocker, or estrogen. The index date was the date of the first CRPC treatment or the first metastasis diagnosis, whichever occurred later. The observation period spanned from the index date to the end of health insurance eligibility. Study end points included population characteristics, the distribution of mCRPC therapies, and corticosteroid utilization patterns. RESULTS: The study population came from the 2 data sets and included 3219 men who were treated for mCRPC. Bone and lymph nodes were the predominant metastatic sites. Bicalutamide was the most common secondary hormonal therapy, and docetaxel was the most common chemotherapy used for these patients. Overall, 73.4% of the patients in data set 1 received concomitant corticosteroids, as did 71.6% of patients in population 2 during the entire period from the index date to the end of eligibility date. In addition, 62.8% and 60.4% of patients, respectively, received concomitant corticosteroids during the secondary hormonal therapy period, and 93.8% and 95.1% of patients, respectively, received concomitant corticosteroids during the chemotherapy period. Similar patterns of corticosteroid use were observed across geographic areas of the United States. CONCLUSION: This study shows consistently similar utilization patterns of corticosteroids in patients with mCRPC in 2 large national databases. Using real-world data to inform concomitant corticosteroid use in the treatment of patients with mCRPC may assist healthcare providers with treatment selection and with sequencing decision. Future research is warranted to investigate evolving treatment options for patients with mCRPC.

Cardiovascular adaptations of pregnancy in T and B cell-deficient mice.

The pathophysiology of gestational hypertensive disorders is incompletely defined. T lymphocytes are implicated. Both T and natural killer (NK) cells express RAS and, in implantation sites, NK cells are highly enriched. We hypothesized that T cells and/or NK cells contribute to circulatory control during pregnancy. Using radiotelemetry of arterial pressure, heart rate, and activity, mice without T and B cells (genotypes BALB/c-Rag2(-/-) and NOD.scid) were examined at baseline and across pregnancy. These strains differ in NK cell competency, with Rag2(-/-) being normal and NOD.scid impaired. Circulatory features differed between these inbred strains. Rag2(-/-); had blood pressure responses to pregnancy that did not differ from congenic normal mice. NOD.scid had higher midgestational blood pressure compared with normoglycemic NOD mice (3-5 mm Hg greater than NOD; P < 0.004). In comparison to controls, both T and B strains had much higher heart rates after first trimester that did not remit until parturition (>30 bpm greater than control; P < 0.0001). NOD.scid had additional anomalies, including 90% depletion of circulating NK cells and elevated (57%) proliferation of uterine NK cells within implantation sites. These data demonstrate immune control of midgestational heart rate and suggest NK cells contribute to midpregnancy regulation of mean arterial pressure.

Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy.

Reproductive success in mammals involves coordinated changes in the immune and cardiovascular as well as in the neuroendocrine and reproductive systems. This review addresses studies that identify potential links for NK cells and T cells with the local and systemic cardiovascular adaptations of pregnancy. The studies reviewed have utilized immunohistochemisty and in vivo analyses of vascular parameters by ultrasound, chronic monitoring of hemodynamics via radiotelemetric recording and intravital microscopy. At the uterine level, functional subsets of uterine natural killer cells were identified. These included subsets expressing molecules important for vasoregulation, in addition to those previously identified for angiogenesis. Spiral arteries showed conducted responses that could account for conceptus control of vasoactivity and mouse gestational blood pressure 5-phase pattern. Vascular immunology is an emerging transdisciplinary field, critical for both reproductive immunology and cardiovascular disease.