Influence of timing of seasonal influenza vaccination on effectiveness and cost-effectiveness in pregnancy.

The purpose of this review was to estimate the impact of timing of seasonal influenza vaccination during pregnancy on health and economic outcomes. Cost-effectiveness analysis with a dynamic model of the US population of pregnant women and infants who were <6 months incorporated seasonal variation in influenza incidence. Compared with no vaccination, seasonal influenza vaccination in pregnancy costs $70,089 per quality-adjusted life year. Most of the benefit for infants was limited to those whose mothers were vaccinated within the first 4 weeks of vaccine availability. Once all women who were pregnant at the time of vaccine availability were vaccinated, vaccination of newly pregnant women had benefits for mothers but not infants. Delay of vaccination beyond November reduced both effectiveness and cost-effectiveness. The greatest population benefit from seasonal influenza vaccination in pregnancy was realized if pregnant women were vaccinated as soon as possible after trivalent inactivated influenza vaccine became available. Efforts to increase vaccine rates should be concentrated early in the influenza season.

Direct medical costs for type 2 diabetes mellitus complications in the US commercial payer setting: a resource for economic research.

BACKGROUND: Medical complications are the key drivers of the direct medical costs of treating patients with type 2 diabetes mellitus. However, the published literature shows great variability across studies in the number and type of sources from which these costs for diabetes are obtained. OBJECTIVE: To provide to researchers a set of costs for type 2 diabetes complications, originally developed for input into an established diabetes model, that are empirically based, clearly and consistently defined and applicable to a large segment of managed care patients in the US. METHODS: Patients with 1 of 24 diabetes-related complications between 1 January 2003 and 31 December 2004 and with evidence of type 2 diabetes were identified using a nationally representative US commercial insurance claims database. Therapy utilization and complication cost data were extracted for all patients for the 12 months following the first identified complication; data for months 13-24 were obtained for a subset of patients with at least 24 months of follow-up enrollment. Medical costs included both the amounts charged by medical providers and the health plan contracted allowed amounts. Costs were expressed as $US, year 2007 values. RESULTS: A total of 44 021 patients with a minimum of 12 months of continuous follow-up enrollment were identified, with a mean age of 56 years; a subset of 32 991 patients with at least 24 months of continuous health-plan enrollment was also identified. Among the aggregate sample, 74% of patients were receiving oral antidiabetics, 26% were receiving insulin, 43% were receiving ACE inhibitors and 50% were receiving antihyperlipidaemics/HMG-CoA reductase inhibitors (statins) during the first 12 months following the index complication. The majority of patients had at least one physician office visit (99.8%), laboratory diagnostic test (96.2%) and other outpatient visit (97.5%). Six complications (angina pectoris, heart failure, peripheral vascular disease, renal disease, nonproliferative retinopathy and neuropathy) had a prevalence of at least 10%. Allowed amounts for most complications were 30-45% of charges. Myocardial infarction, heart failure and renal disease had the greatest fiscal impact because of the total number of patients experiencing them (7.2%, 14.0% and 11.0%, respectively) and their associated costs; 12-month mean allowed amounts were $US 14,853, $US 11,257 and $US 13,876, respectively, and 12-month mean charged amounts were $US 41,695, $US 30, 066 and $US 34,987, respectively. Similarly, in the subset of 32 991 patients, these three complications had higher allowed and charged amounts over months 13-24 compared with the majority of other complications of interest. CONCLUSION: These costing results provide an important resource for economic modelling and other types of costing research related to treating diabetes-related complications within the US managed care system.

Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis.

UNLABELLED: Increases in lumbar spine BMD account for 30-41% of the vertebral fracture risk reduction with teriparatide treatment. The remaining fracture risk reduction is caused by improvements in non-BMD determinants of bone strength. INTRODUCTION: Changes in BMD account for a small percentage of the fracture risk reduction seen in patients treated with antiresorptive drugs. The relationship between changes in lumbar spine BMD and vertebral fracture risk reduction with teriparatide treatment has not been assessed. MATERIALS AND METHODS: The relationship between spine BMD and the risk of new vertebral fractures after teriparatide treatment was assessed using data from the Fracture Prevention Trial. Postmenopausal women with osteoporosis (n = 1637) were randomized to placebo or teriparatide 20 or 40 microg/day for a median of 19 months. Spine BMD was assessed at baseline and 18 months. Vertebrae whose fracture status changed during the trial were removed from the calculation of BMD. Baseline and endpoint lateral spine radiographs were assessed using a visual semiquantitative technique. RESULTS: Both the baseline and change in spine BMD were contributors to vertebral fracture risk. The mean spine BMD increase in teriparatide-treated patients was 0.09 g/cm(2) across tertiles of baseline spine BMD. Compared with placebo, teriparatide significantly reduced the risk of new vertebral fracture for all endpoint BMD values. Teriparatide-mediated increases in spine BMD accounted for 30% (in the low baseline spine BMD tertile) to 41% (in the high baseline spine BMD tertile) of the reduction in vertebral fracture risk. CONCLUSIONS: Increases in BMD account for approximately one third of the vertebral fracture risk reduction seen with teriparatide. The majority of the risk reduction, however, results from improvements in non-BMD determinants of bone strength.

Initial experience with teriparatide in the United States.

Teriparatide has been commercially available in the United States (US) for over 3 years. This summary spans the early experience with this therapy. As of December 31, 2005, over 235 000 patients had filled a prescription for teriparatide world-wide. Data collected from July to December 2004, from 15,000 retail pharmacies in the US, indicated that the mean age of patients was 67.5 years, and more recent data collected from January through October 2005 indicated that 90% of patients were female. According to market research conducted with prescribing physicians from February through March of 2005, it is estimated that over 80% of patients receiving prescriptions for teriparatide had already experienced one or more prior fractures. Since teriparatide is administered subcutaneously, it is important that patients receive training on the use of the teriparatide injection device (i.e., the pen device). Educational programs are available for those who have been prescribed teriparatide therapy. Patients may also contact a customer care program regarding a variety of topics, including pen device use. Based on patient feedback, design changes have been implemented in the pen device to facilitate optimal use. Updates have also been made to the prescribing information to reflect the post-marketing surveillance experience. Adverse experiences reported to date have been consistent with the current product label and with cumulative teriparatide clinical trial experience. As of December 31, 2005 no reports of pathology-confirmed osteosarcoma have been received for individuals who have been treated with teriparatide, either with the commercially available drug or in clinical trials. We are unaware of any reports of osteosarcoma in association with other preparations of teriparatide, or other peptides of parathyroid hormone, either in the setting of clinical trials or from marketed drug experience.

New or worsening lumbar spine vertebral fractures increase lumbar spine bone mineral density and falsely suggest improved skeletal status.

Changes in lumbar spine bone mineral density (BMD) are determined by follow-up dual-energy x-ray absorptiometry (DXA) assessments. Inclusion of new or worsening vertebral fractures in follow-up measurements may increase BMD. To test this hypothesis, we examined pooled data from the placebo groups of two clinical trials that involved postmenopausal women with osteoporosis. DXA measurements of lumbar spine BMD, bone mineral content (BMC), and area were obtained at baseline and at two years in the Multiple Outcomes of Raloxifene Evaluation (MORE) Trial and at baseline and study endpoint in the Fracture Prevention Trial. In these trials, fractured vertebrae identified by expert radiologists during posterioranterior (PA) spine DXA assessment were excluded from the BMD assessment. Lateral spine radiographs were graded using a semi-quantitative (SQ) scale. Most new or worsening vertebral fractures (84%) diagnosed from lateral spine radiographs were not identified by PA spine DXA. While the follow-up BMD of vertebrae without new or worsening fractures did not change significantly, each unit increase in SQ grade was associated with an approximate 7.0% increase in the BMD of affected vertebrae (p < 0.001). Increases in BMD were highly correlated with increases in BMC (r = 0.87, p < 0.001). Inclusion of new or worsening vertebral fractures increased PA spine BMD measurements at follow-up, with the impact being related to the magnitude of change in SQ score. It is difficult to reliably identify vertebral fractures from PA spine DXA assessments. Inclusion of new or worsening vertebral fractures in follow-up DXA measurements may falsely suggest an improvement in spine BMD. Our suggestion is to perform lateral spine imaging concurrently with any assessment of PA spine BMD in patients who, in the opinion of the health care provider, may have vertebral fractures.

Cost-effectiveness analysis of universal influenza vaccination with quadrivalent inactivated vaccine in the United States.

To address influenza B lineage mismatch and co-circulation, several quadrivalent inactivated influenza vaccines (IIV4s) containing two type A strains and both type B lineages have recently been approved in the United States. Currently available trivalent inactivated vaccines (IIV3s) or trivalent live attenuated influenza vaccines (LAIV3s) comprise two influenza A strains and one of the two influenza B lineages that have co-circulated in the United States since 2001. The objective of this analysis was to evaluate the cost-effectiveness of a policy of universal vaccination with IIV4 vs. IIV3/LAIV3 during 1 year in the United States. On average per influenza season, IIV4 was predicted to result in 30,251 fewer influenza cases, 3512 fewer hospitalizations, 722 fewer deaths, 4812 fewer life-years lost, and 3596 fewer quality-adjusted life-years (QALYs) lost vs. IIV3/LAIV3. Using the Fluarix Quadrivalent(TM) (GlaxoSmithKline) prices and the weighted average IIV3/LAIV3 prices, the model predicts that the vaccination program costs would increase by $452.2 million, while direct medical and indirect costs would decrease by $111.6 million and $218.7 million, respectively, with IIV4. The incremental cost-effectiveness ratio (ICER) comparing IIV4 to IIV3/LAIV3 is predicted to be $90,301/QALY gained. Deterministic sensitivity analyses found that influenza B vaccine-matched and mismatched efficacies among adults aged ≥65 years had the greatest impact on the ICER. Probabilistic sensitivity analysis showed that the cost per QALY remained below $100,000 for 61% of iterations. In conclusion, vaccination with IIV4 in the US is predicted to reduce morbidity and mortality. This strategy is also predicted to be cost-effective vs. IIV3/LAIV3 at conventional willingness-to-pay thresholds.

Employer-incurred health care costs and productivity losses associated with influenza.

The primary objective of this study was to assess trends in employer expenditures for both direct medical costs and indirect productivity losses associated with influenza. A retrospective analysis was performed using two of the MarketScan family of databases for 2005-2009. Patients with at least one diagnosis claim for influenza during an influenza season were selected. We estimated seasonal incidence of influenza in the employed population from the MarketScan Commercial Claims and Encounters database. Health care utilization and costs and productivity losses were assessed during the 21-d period following the influenza diagnosis date. Compared with the 2005-2006 season (493 per 100,000 plan members), influenza incidence increased during the 2006-2007 (598 per 100,000 plan members) and 2007-2008 (1,142 per 100,000 plan members) seasons and had a dramatic increase during the pandemic season of 2008-2009 (1,715 per 100,000 plan members) . The total influenza-related employer spending per 100,000 plan members also increased by over 400% during the 2008-2009 influenza season [$623,248; confidence interval (CI]):$601,518-$644,991], compared with 2005-2006 ($145,834; 95% CI: $135,067-$156,603). The primary drivers of the increased costs were emergency room, outpatient and inpatient visits. Total costs associated with influenza-related missed work time per 100,000 plan members increased over 4-fold from $26,479 in the 2005-2006 influenza season to $122,811 in 2008-2009. Overall, as expected, considerably higher direct and indirect costs were observed during the 2008-2009 influenza pandemic season than during other influenza seasons. In recent years, the influenza-related employer burden has increased considerably. In future, employers may need efficient resource allocation in order to address the productivity losses and increasing direct medical costs associated with increased influenza incidence. One of the strategies that employers may consider is increasing influenza vaccination rates among employees, which likely will help lower the influenza incidence and the associated downstream direct and indirect costs.

Influenza-related health care utilization and productivity losses during seasons with and without a match between the seasonal and vaccine virus B lineage.

OBJECTIVE: To assess and compare direct medical costs (incurred by payers) and indirect productivity losses (incurred by employers) associated with influenza seasons with matched or mismatched circulating and vaccine containing influenza B lineages. METHODS: A retrospective analysis, using two MarketScan databases, for the years 2000-2009. Each influenza season was categorized as matched or mismatched after comparing that season's circulating influenza B lineage and the vaccine influenza B lineage. Patients selected had at least one diagnosis claim for influenza (ICD-9-CM code 487.xx [influenza] or 488.1 [H1N1]) during an influenza season. We assessed the incidence of influenza (overall and influenza B), influenza-related medical utilization and associated costs, and productivity losses for each season. RESULTS: The four matched seasons had lower average influenza incidence (overall incidence per 100,000 plan members: 509; 95% confidence interval [CI]: 505-512) than the five mismatched seasons (748; 95% CI: 745-751). The mismatched seasons had lower influenza B incidence (average incidence per 100,000 plan members: 126; 95% CI: 125-128) than the matched seasons (165; 95% CI: 163-167). The average, per-patient, total influenza-related medical costs in the mismatched seasons ($300.83; range: $245.38-$371.58) were approximately $61.00 higher than in the matched seasons ($239.43; range: $201.49-$264.01). The mismatched seasons had greater average per-patient, influenza-related productivity-loss costs than the matched seasons (mean: $237.31 vs. $175.10). CONCLUSION: CDC data showed that influenza A was the predominant circulating strain during seasons in which the circulating influenza B lineage did not match the vaccine influenza B lineage. This resulted in lower influenza B incidence during the mismatched seasons. However, the average, per-patient, influenza-related direct medical costs and indirect productivity losses were higher during the mismatched seasons. Additional research is required to determine if these higher costs can be attributed to influenza B infections and if the influenza severity varies during mismatched seasons.

Inappropriate antibiotic prescribing in managed care subjects with influenza.

OBJECTIVES: To evaluate costs of inappropriate oral antibiotic prescribing in a managed care population with influenza. METHODS: This was a retrospective (January 1, 2005, through December 31, 2009) analysis of the US Impact National Benchmark Database. Patients with an influenza diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 487.xx) and continuous health plan enrollment for >12 months before and 1 month after the index influenza diagnosis date were included. We identified patients with an antibiotic prescription claim within 3 days before or 3 days after the index influenza diagnosis date. Patients were classified as having received appropriate antibiotic treatment if a secondary respiratory infection was observed within the 2-week postindex period or if there was a previous comorbid diagnosis of diabetes, congestive heart failure, chronic obstructive pulmonary disease, asthma, acute myocardial infarction, or sickle cell anemia as identified by ICD-9-CM codes. RESULTS: We identified 270,057 subjects with influenza (mean age, 31.6 years). Antibiotics were prescribed in 58,477 (21.65%) patients. Among patients receiving antibiotics, 99% did not have a follow-up diagnosis for a respiratory bacterial infection and 79% had neither a secondary infection nor evidence of a comorbidity (ie, received inappropriate antibiotic treatment). Based on a conservative annual seasonal influenza rate of 10%, we estimated that inappropriate antibiotic prescribing for influenza costs the United States approximately $211 million annually. CONCLUSIONS: Empiric antibiotics were inappropriately prescribed in a high percentage of influenza patients. This represents a significant financial burden to the US healthcare system and may contribute to increased antibiotic resistance.

Hospital costs, length of stay and mortality associated with childhood, adolescent and young adult meningococcal disease in the US.

BACKGROUND: Assessments of vaccination programmes should account for several important factors, including efficacy, safety and costs of preventing and treating the disease. Because patients with invasive meningococcal disease (IMD) are managed primarily in an inpatient setting, hospital costs and outcomes are central endpoints in health economic evaluations of IMD. OBJECTIVE: The aim of the study was to estimate hospital costs, length of stay (LOS) and mortality associated with IMD among children, adolescents and young adults in the US. METHODS: The study design was a retrospective analysis of discharges from the 2006 Healthcare Cost and Utilization Project Kids' Inpatient Database. Infant (<1 year), childhood (1-10 years), adolescent (11-18 years) and young adult (19-20 years) IMD-related hospitalizations (International Classification of Diseases, Ninth Edition, Clinical Modification [ICD-9-CM] code 036) were selected. Regression-adjusted costs ($US, year 2009 values), LOS and mortality risk were compared between IMD hospitalizations and demographically matched (5 : 1) controls. RESULTS: A weighted total of 735 IMD admissions were identified. Among children, adjusted mean LOS and cost per admission was highest for infants (9.0 days and $US36 454 among cases vs 1.9 days and $US5041 for controls; all p < 0.0001). Adjusted costs and case fatality was highest among infants with meningococcal sepsis ($US49 626 and 11.6%, respectively). Versus controls, adjusted risks of death in IMD cases were 4.6- and 10.3-fold higher, respectively, for infants and adolescents (both p < 0.05). CONCLUSIONS: While the advent of vaccines for Haemophilus influenzae and Streptococcus pneumoniae has curtailed invasive bacterial infection rates, IMD continues to be a public health concern that presents greatly increased hospital costs, LOS and mortality risk, particularly for infants and adolescents.

Comparison of costs among patients with type 2 diabetes treated with exenatide or sitagliptin therapy.

INTRODUCTION: Exenatide (Byetta, Amylin Pharmaceuticals Inc., CA, USA) and sitagliptin (Januvia, Merck & Co, NJ, USA) are two antidiabetic agents recently approved by the US Food and Drug Administration. The purpose of this analysis was to compare costs among patients with type 2 diabetes (T2D) treated with either of these agents. METHODS: Data with dates of service from September 1, 2005 through August 31, 2007, were obtained from a large US retrospective claims database. Intent-to-treat cohorts of adults diagnosed with T2D who began taking either exenatide (n=1885) or sitagliptin (n=2482) and did not use the alternate medication in the 6-month follow-up period were created. Six-month total medical costs were estimated using stepwise multivariate regressions. Six-month total diabetes-related medical costs, a component of total medical costs, were also estimated using stepwise multivariate regressions. In addition, other cost components were examined using either stepwise multivariate regressions or a two-part model that controlled for the probability of using the medical service. Smearing estimates were used to transform estimated log costs into costs. The analysis controlled for the potential impact of patient demographics, general health, prior resource use, comorbidities, and timing of treatment initiation. RESULTS: Exenatide was associated with lower total 6-month direct medical costs ($9340 vs. $9995; P<0.0001), despite some component costs being slightly higher with exenatide: diabetes-related drug costs ($1765 vs. $1743; P=0.0062), diabetes-related medical costs ($4142 vs. $4002; P<0.0001), and emergency room costs ($43 vs. $29; P=0.0388). Exenatide was associated with lower outpatient costs ($4498 vs. $5942; P<0.0001). CONCLUSIONS: Compared with the use of sitagliptin, exenatide was associated with lower total medical costs (difference of $655) despite higher total diabetes-related costs (difference of $140). As a result, there appears to be overall cost savings associated with the use of exenatide relative to sitagliptin.

Relationship of health related quality of life to prevalent and new or worsening back pain in postmenopausal women with osteoporosis.

OBJECTIVE: To examine the association between back pain and health related quality of life (HRQOL) in postmenopausal women with osteoporosis. METHODS: The Fracture Prevention Trial was a prospective double blinded, placebo controlled study designed to compare the proportion of women receiving teriparatide who experienced a new fracture to the proportion of women receiving placebo who experienced a new fracture. Subjects were ambulatory postmenopausal women with osteoporosis and prior vertebral fracture. As part of this trial, English-speaking women from Canada, New Zealand, Australia, and the United States participated in a HRQOL substudy using the Osteoporosis Assessment Questionnaire (OPAQ). OPAQ was administered at baseline, 12 months, and at study termination (median treatment duration 19 mo). Back pain data were collected as part of the adverse event monitoring during the trial. Subjects considered to have experienced back pain reported this event spontaneously and were not queried specifically. We examined the influence of prevalent back pain on HRQOL after controlling for spine deformity index score, and the influence of new or worsening back pain on HRQOL after controlling for incident vertebral fracture. RESULTS: Of 471 women who completed OPAQ at baseline, 172 reported back pain that was associated with a mean decrease in all OPAQ dimension scores (p < 0.05). Of 429 women who completed OPAQ at all timepoints, 88 experienced new or worsening back pain that was associated with a mean decrease in physical function, emotional status, and symptoms scores (p < 0.01 for each). In a subset of 65 women who experienced moderate to severe back pain, all OPAQ dimensions were significantly reduced (p < 0.05). CONCLUSION: Both prevalent back pain and new or worsening back pain affected HRQOL negatively. Osteoporosis therapies that prevent the development of back pain in postmenopausal women may also prevent decreases in HRQOL.

Role of calcium-activated potassium channels in impaired acetylcholine vasodilatory responses in diabetic rats.

Muscarinic agonists produce endothelium-dependent vasodilatation in the presence of nitric oxide synthase (NOS) inhibition. The importance of this mechanism was assessed in the methoxamine-preconstricted perfused mesenteric vascular bed (MVB) of streptozotocin diabetic Sprague-Dawley rats. At 9 weeks of age, male rats were treated with streptozotocin (55 mg/kg in citrate buffer) or with citrate buffer alone. The superior mesenteric artery was cannulated and the MVB was detached from its intestinal borders. Concentration-response curves to acetylcholine were determined in the presence and in the absence of indomethacin, tetrabutylammonium (a calcium-activated potassium channel blocker), high extracellular potassium, or NOS inhibition with Nomega-nitro-l-arginine and l-NG-nitro-l-arginine. There was a rightward shift in the concentration-response curve with an increase in median inhibitory concentration (p < 0.05) and a reduction in acetylcholine IMAX (p < 0.05) values in 14-week streptozotocin rats. The ability of NOS inhibition to attenuate vasodilatation was reduced in the 14-week streptozotocin group relative to the 2-week streptozotocin treatment group (p < 0.05). However, the ability of tetrabutylammonium to block acetylcholine-mediated vasodilatation remained consistent in streptozotocin rats at both stages. The results demonstrate that an alternate pathway involving calcium-activated potassium channels may compensate for diminished nitric oxide bioactivity. This effect is contingent on the duration of diabetes. This study provides insight into the development and progression of altered diabetic vascular responses.

Cysteinyl leukotriene-dependent [Ca2+]i responses to angiotensin II in cardiomyocytes.

With the use of fura 2 measurements in multiple and single cells, we examined whether cysteinyl leukotrienes (CysLT) mediate angiotensin II (ANG II)-evoked increases in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in neonatal rat cardiomyocytes. ANG II-evoked CysLT release peaked at 1 min. The angiotensin type 1 (AT(1)) antagonist losartan, but not the AT(2) antagonist PD-123319, attenuated the elevations in [Ca(2+)](i) and CysLT levels evoked by ANG II. Vasopressin and endothelin-1 increased [Ca(2+)](i) but not CysLT levels. The 5-lipoxygenase (5-LO) inhibitor AA-861 and the CysLT(1)-selective antagonist MK-571 reduced the maximal [Ca(2+)](i) responses to ANG II but not to vasopressin and endothelin-1. While MK-571 reduced the responses to leukotriene D(4) (LTD(4)), the dual CysLT antagonist BAY-u9773 completely blocked the [Ca(2+)](i) elevation to both LTD(4) and LTC(4). These data confirm that ANG II-evoked increases, but not vasopressin- and endothelin-1-evoked increases, in [Ca(2+)](i) involve generation of the 5-lipoxygenase metabolite CysLT. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P(3)] antagonist 2-aminoethoxydiphenyl borate attenuated the [Ca(2+)](i) responses to ANG II and LTD(4). Thus AT(1) receptor activation by ANG II is linked to CysLT-mediated Ca(2+) release from Ins(1,4,5)P(3)-sensitive intracellular stores to augment direct ANG II-evoked Ca(2+) mobilization in rat cardiomyocytes.