Network meta-analysis combining individual patient and aggregate data from a mixture of study designs with an application to pulmonary arterial hypertension.

BACKGROUND: Network meta-analysis (NMA) is a methodology for indirectly comparing, and strengthening direct comparisons of two or more treatments for the management of disease by combining evidence from multiple studies. It is sometimes not possible to perform treatment comparisons as evidence networks restricted to randomized controlled trials (RCTs) may be disconnected. We propose a Bayesian NMA model that allows to include single-arm, before-and-after, observational studies to complete these disconnected networks. We illustrate the method with an indirect comparison of treatments for pulmonary arterial hypertension (PAH). METHODS: Our method uses a random effects model for placebo improvements to include single-arm observational studies into a general NMA. Building on recent research for binary outcomes, we develop a covariate-adjusted continuous-outcome NMA model that combines individual patient data (IPD) and aggregate data from two-arm RCTs with the single-arm observational studies. We apply this model to a complex comparison of therapies for PAH combining IPD from a phase-III RCT of imatinib as add-on therapy for PAH and aggregate data from RCTs and single-arm observational studies, both identified by a systematic review. RESULTS: Through the inclusion of observational studies, our method allowed the comparison of imatinib as add-on therapy for PAH with other treatments. This comparison had not been previously possible due to the limited RCT evidence available. However, the credible intervals of our posterior estimates were wide so the overall results were inconclusive. The comparison should be treated as exploratory and should not be used to guide clinical practice. CONCLUSIONS: Our method for the inclusion of single-arm observational studies allows the performance of indirect comparisons that had previously not been possible due to incomplete networks composed solely of available RCTs. We also built on many recent innovations to enable researchers to use both aggregate data and IPD. This method could be used in similar situations where treatment comparisons have not been possible due to restrictions to RCT evidence and where a mixture of aggregate data and IPD are available.

Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review.

BACKGROUND: Interactions between spirometry and patient-reported outcomes in COPD are not well understood. This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy. METHODS: Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations. Mean and standard deviations of treatment effects were extracted for each arm of each study. Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling. The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score. RESULTS: Thirty-six studies (≥ 3 months) were included. Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data. Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ. The correlation strengthened with increasing study duration from 3 to 12 months. Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1. The association between change in FEV1 and other patient-reported outcomes was generally weak. CONCLUSIONS: Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status.

Psychometric validation of the overactive bladder satisfaction with treatment questionnaire (OAB-SAT-q).

AIMS: Valid and reliable questionnaires must be used to accurately assess patients' satisfaction with overactive bladder (OAB) treatment. This study evaluated the reliability and validity of the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q). METHODS: This was a secondary analysis of clinical study data of patients randomized to darifenacin or darifenacin plus Behavioral Modification Program. Patients completed the Overactive Bladder Questionnaire (OAB-q) and a 3-day bladder diary at Baseline and Week 12 and the OAB-SAT-q at Week 12. Internal consistency reliability was assessed by Cronbach's alpha. Concurrent validity was assessed through correlations with OAB-q change scores and adverse events (AEs). Discriminant validity was assessed among subgroups using general linear models. RESULTS: Analyses utilized a per-protocol population (completion of OAB-q at Baseline and OAB-q and OAB-SAT-q at Week 12) (n = 375). Exploratory factor analysis of the OAB-SAT-q revealed three 3-item subscales (Satisfaction, Side Effects, Endorsement) and two single items (Convenience, Preference). Cronbach's alphas = 0.84-0.95. Subscale-to-subscale correlations = 0.10-0.67 (all P < 0.01 except Side Effects and Convenience). The Side Effects subscale significantly correlated with number of treatment-related AEs (r = 0.27; P < 0.01) and discriminated between patients with/without dry mouth and patients with/without constipation. The Satisfaction and Endorsement subscales discriminated between patients who worsened or had no change in micturition frequency and urinary urgency and patients who had a reduction of >3 episodes (all P < 0.001). The OAB-SAT-q does not appear to discriminate by incontinence episodes. CONCLUSION: The OAB-SAT-q demonstrated good psychometric properties in this initial evaluation-including internal consistency reliability and concurrent and discriminant validity-and appears to be a useful assessment of OAB treatment satisfaction. Neurourol. Urodynam. 28:416-422, 2009. (c) 2008 Wiley-Liss, Inc.

Is drug therapy for urinary incontinence used optimally in long-term care facilities?

OBJECTIVES: To examine the management of urinary incontinence (UI) among nursing home (NH) residents in the United States, particularly drug therapy for UI in those who may be suitable candidates for such treatment based on their functional status. DESIGN: Retrospective analysis of admissions (between January 2, 2002, and December 31, 2003) to a total of 373 skilled nursing facilities and assisted living centers operated by a single provider of long-term care. PARTICIPANTS: Residents identified as incontinent according to at least one Minimum Data Set (MDS) assessment during their NH stay who had adequate mobility and/or cognitive ability to toilet, as determined by a toileting score of < or =2 on the 5-point MDS scale, and/or a score of < or =3 on the 7-point scale, the Cognitive Performance Score (CPS). MEASUREMENTS: MDS assessments for individual residents were obtained from a central database linked to a physician order database that captured the dose, frequency, and start and stop dates of all medications prescribed. Residents were stratified into treated or untreated groups according to whether or not they were prescribed medications used to treat UI (including tolterodine, oxybutynin [oral and transdermal patch formulations], desmopressin, and flavoxate). RESULTS: During the study period, there were 58,216 admissions to the 373 participating facilities; 31,219 (54%) were identified as incontinent of urine on the MDS. The study population comprised 25,140 NH residents who met MDS criteria for UI (80.5% of the total identified as incontinent of urine) and who had adequate mobility to toilet and/or did not have severe cognitive impairment. They were typically over 60 years of age (95.2%), female (65.1%), and frequently or completely incontinent (63.1%). Nonpharmacologic treatment (as recorded in the MDS) included pads/briefs (76.8%), scheduled toileting (31.9%), and/or bladder retraining (2.8%). Only 1752 (7.0%) of eligible residents received medication for their UI. Using a multivariate analysis, factors that were significantly associated with drug treatment for UI included female gender, frequent or complete urinary incontinence (MDS category 3-4), constipation, and use of incontinence appliances/programs and walking aids. Older residents and those with severe cognitive impairment were less likely to receive drug therapy. CONCLUSIONS: Only a small proportion of incontinent NH residents with mobility and cognitive function potentially suitable for specific treatment for incontinence receives drug therapy for their condition. Further research is needed to determine whether low drug use reflects an unmet need for treating UI, or appropriate prescribing practices based on the multiple and interacting factors that influence decisions on drug therapy in the NH population.

Direct medical costs of constipation in the United States.

This study estimated the total medical cost of care and described characteristics of patients with constipation in the United States. The 2001 National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, and National Hospital Discharge Survey were used to provide national estimates. Patients diagnosed with constipation, or whose constipation was a reason for the visit, were identified. Medicare reimbursement rates based on recognized diagnostic and procedural codes were used to value each visit related to constipation. Constipation was a diagnosis or reason for seeking care in an estimated 5.7 million ambulatory visits and was the primary diagnosis or reason for 2.7 million of those visits. Of these visits, 1,838,493 were outpatient physician, 297,927 were outpatient hospital, and 555,432 were emergency department. Constipation was the primary diagnosis in 38,361 additional inpatient visits. Total cost was dollar 235 million per year, with 55% incurred from inpatient care and 23%, 16%, and 6% from ED, outpatient physician, and outpatient hospital settings, respectively. Constipation is treated primarily in ambulatory settings, but the costs of inpatient care exceed those of ambulatory care.

Use of valsartan for the treatment of heart-failure patients not receiving ACE inhibitors: a budget impact analysis.

BACKGROUND: Heart failure is a widespread and costly malady. It represents the leading single diagnosis for hospitalized patients. For many heart failure patients, angiotensin-converting enzyme (ACE) inhibitors are either not tolerated or contraindicated, but angiotensin receptor blockers such as valsartan may be a therapeutic option for them. OBJECTIVE: The aim of this study was to prepare a budget impact analysis to assist health plans in evaluating the financial impact of adding valsartan therapy to usual care for heart failure patients not receiving ACE inhibitors. METHODS: A budget impact analysis was developed for a hypothetical US health plan. Model inputs included demographic data, estimates of the prevalence of heart failure and proportion of heart-failure patients not on ACE inhibitors, prevalence of heart failure-related hospitalization, cost data, and resultant health care utilization from the Valsartan Heart Failure Trial (Val-HeFT). Costs and cost savings were reported as year-2001 US dollars. RESULTS: An estimated 1207 of hypothetical 250,000 enrollees were projected to have heart-failure diagnoses, with 603 (50.0%) not receiving ACE inhibitors, and 160 (26.5%) of such patients being hospitalized each year. For valsartan-treated patients, savings due to reduced hospitalizations and shorter length of hospital stay were 1,083,938 US dollars and 221,364 US dollars, respectively. Subtracting the cost of valsartan treatment (629,472 US dollars) from savings yielded projected net savings of 675,830 US dollars per year. Varying patient, treatment, and payer-mix characteristics resulted in projected net savings of $409,598 to 1,350,617 US dollars per year. CONCLUSIONS: Addition of valsartan therapy to usual care in this model analysis resulted in net cost savings among hypothetical heart-failure patients not receiving ACE inhibitors. Substantial cost savings were realized, regardless of variation in model parameters.

Incremental burden of disease in patients diagnosed with pulmonary arterial hypertension receiving monotherapy and combination vasodilator therapy.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare, severely debilitating disease with high mortality. There are limited data available on treatment patterns and burden of disease from conditions of actual care. METHODS: This analysis assesses the burden of disease for patients with PAH treated with monotherapy and combination therapies excluding and including intravenous (IV) prostacyclin analogues (PGI2). Data were drawn from the Adelphi PAH Disease Specific Programme, a cross sectional survey of consulting patients undertaken in the US, Germany, Italy and the UK in 2010. Outcomes included demographics, clinical characteristics, health-care resource utilization, and quality of life measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR). RESULTS: Data were analyzed from 446 patients receiving ≥1 of 3 PAH-specific treatment classes. Physicians comprised mainly pulmonologists and cardiologists. The symptoms, functioning and quality of life scales of the CAMPHOR instrument were completed by 218, 229, and 214 patients, respectively. Although 46.2% of patients were classified as World Health Organization (WHO) functional class III or IV, only 24.4% of the population received combination therapy. Combination therapy including IV PGI2 was used in 4.7% of all patients. Patients on monotherapy had the lowest pulmonary vascular resistance values, the highest recorded 6-min walk distance and the lowest recorded levels of dyspnea. Patients on combination therapy including IV PGI2 scored worse on all three variables and had more hospitalizations than patients on less aggressive combination therapy. With increasing therapeutic regimens, the CAMPHOR scores were higher, indicating worse states of health. CONCLUSIONS: Combination treatment and particularly the use of prostacyclins remain underused in an unselected population of PAH patients surveyed under conditions of actual care. The disease burden is substantial and increases with greater severity of disease and more aggressive treatments. This necessitates improvement in optimizing current therapy, as well as novel and innovative combination options.

Treatment patterns and healthcare system burden of managed care patients with suspected pulmonary arterial hypertension in the United States.

OBJECTIVES: To describe treatment patterns and healthcare burden among individuals with suspected pulmonary arterial hypertension (PAH), as identified through a practice guideline-based healthcare claims algorithm. METHODS: Adults with evidence of PAH from 1 January 2004 (commercial and Medicaid) or 1 July 2006 (Medicare Advantage) through 30 June 2008 were identified. Given the lack of an ICD-9 code for PAH, an algorithm was developed requiring: (1) ≥ 1 claim for PAH medication (index date); (2) ≥ 1 claim with a pulmonary hypertension diagnosis code in the 6-month pre-index period (baseline) or within 90 days post-index; (3) a right heart catheterization or pulmonary hypertension-related inpatient stay during baseline or within 90 days post-index; and (4) continuous health plan enrollment for 6 months pre-index and ≥ 6 months post-index. Patients with PAH-specific medications during baseline were excluded. Treatment patterns, healthcare utilization, and costs were assessed during the period ending with the earlier of health plan disenrollment or 31 December 2008. RESULTS: Among the 521 included patients, 69% were female. Most patients (94%) initiated treatment with monotherapy (most commonly sildenafil or bosentan), and 12.7% of all patients augmented their therapy by the end of the observation period. The medication possession ratio was 0.96 each for ambrisentan (SD=0.04), bosentan (SD=0.04), and sildenafil (SD=0.05). Overall, 72.6% of patients discontinued therapy with a mean of 149 (SD=170) days until discontinuation. A mean (SD) of 2.14 (1.82) all-cause office and 1.64 (1.98) outpatient visits occurred per patient per month. Mean PAH-related healthcare costs were $6617 per patient per month, comprising 71% of all-cause costs. The guideline-based algorithm may not have perfectly captured patients with PAH. CONCLUSIONS: Patients with suspected PAH were likely to initiate treatment with oral monotherapy, had high compliance rates, and received close ambulatory follow-up. PAH-related costs constituted the majority of all-cause healthcare costs.

The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.

Oral corticosteroids (OCS) are a key part of therapy regimens for a diverse variety of conditions. Despite their efficacy, they are associated with a wide variety of adverse events. The purpose of this review was to identify the range of adverse events that have been reported to be related to oral corticosteroids, examine the factors that influence their incidence and estimate the economic burden caused by these adverse events. In 61 identified studies, 21 different categories of OCS related adverse events were reported with increased fracture risk being the category most frequently described. Most studies that examined factors linked to the incidence of OCS related adverse events found that dose, age, gender, duration of use, treatment history, smoking habits or cholesterol level were influential in determining risk. Additionally, a cumulative economic analysis of selected adverse events found the annual cost of treating these events in the UK to be at least 165 pounds per patient taking OCS. The clinical and economic burden of OCS related adverse events highlights the need for OCS sparing therapies to be developed.