Determinants of functional outcome and healthcare costs in bipolar disorder: a high-intensity follow-up study.

BACKGROUND: Review of published studies reveals few data regarding determinants of the poor functional outcome and high healthcare costs that are characteristic of bipolar disorder. In order to identify potential mechanisms, critical to designing optimal treatment strategies, this longitudinal study investigated (a) the degree to which disease outcome is correlated with functional outcome and direct treatment costs, and (b) whether similar demographic or clinical characteristics predict disease and functional outcome and healthcare costs. METHODS: Disease and functional outcome were assessed in bimonthly structured interviews over 48 weeks in 43 outpatient veterans with bipolar disorder. Direct mental health treatment costs from the VA perspective were determined from the VA database and patient interview. Regression analysis was used to determine association among the three outcome domains, and to identify clinical or demographic variables that predicted each of the three domains. RESULTS: Functional outcome was correlated with depressive, but not manic, symptoms during follow-up. Costs were not correlated with any measure of disease or functional outcome. Several demographic, but not clinical, characteristics predicted functional outcome. In contrast, several clinical, but not demographic, characteristics predicted symptom status. No predictors were associated with direct treatment costs. LIMITATIONS: Subjects were predominantly male veterans of relatively homogeneous social class, followed prospectively for approximately one year in a clinic designed specifically to minimize barriers to care. CONCLUSIONS: Data from this and prior studies indicate that ongoing depressive symptoms are strongly associated with functional outcome, although substantial variance remains unexplained. Optimal models to explain functional outcome and healthcare costs will need to address factors besides simply disease severity and chronicity. The authors present a heuristic paradigm for understanding both the research and therapeutic aspects of these findings.

Effect of age on mortality, hospitalizations and response to digoxin in patients with heart failure: the DIG study.

OBJECTIVES: This study was designed to determine the effect of increasing age on mortality, hospitalizations and digoxin side effects in patients with heart failure (HF), and to determine whether the effect of digoxin on clinical outcomes varies as a function of age. BACKGROUND: The incidence and prevalence of HF increase with advancing age, but there are limited data on the clinical course and response to specific therapeutic interventions in elderly patients with HF. METHODS: The Digitalis Investigation Group (DIG) study was a prospective, randomized clinical trial involving 7,788 patients with HF randomized to digoxin or placebo and followed for an average of 37 months. In the present analysis, patients were stratified into five age categories: <50 years (n = 841), 50 to 59 years (n = 1,545), 60 to 69 years (n = 2,885), 70 to 79 years (n = 2,092) and > or =80 years (n = 425). Interactions between age and the following clinical outcomes were examined: total mortality, all-cause hospitalizations, HF hospitalizations, the composite of HF death or HF hospitalization, hospitalization for suspected digoxin toxicity and withdrawal from therapy because of side effects. RESULTS: Increasing age was an independent risk factor for total mortality, all-cause hospitalization, HF hospitalization, HF death or hospital admission, hospitalization for suspected digoxin toxicity and withdrawal from digoxin therapy (all p < 0.001). However, there were no significant interactions between age and digoxin treatment with respect to any of the major clinical end points. CONCLUSIONS: Increasing age is associated with progressively worse clinical outcomes in patients with HF. However, the beneficial effects of digoxin in reducing all-cause admissions, HF admissions, and HF death or hospitalization are independent of age. Thus, digoxin remains a useful agent for the adjunctive treatment of HF due to impaired left ventricular systolic function in patients of all ages.

Principles of effectiveness trials and their implementation in VA Cooperative Study #430: 'Reducing the efficacy-effectiveness gap in bipolar disorder'.

Despite the availability of efficacious treatments for bipolar disorder, their effectiveness in general clinical practice is greatly attenuated, resulting in what has been called an 'efficacy-effectiveness gap'. In designing VA Cooperative Studies Program (CSP) Study #430 to address this gap, nine principles for conducting an effectiveness (in contrast to an efficacy) study were identified. These principles are presented and discussed, with specific aspects of CSP #430 serving as illustrations of how they can be implemented in an actual study. CSP #430 hypothesizes that an integrated, clinic-based treatment delivery system that emphasizes (1) algorithm-driven somatotherapy, (2) standardized patient education, and (3) easy access to a single primary mental health care provider to maximize continuity-of-care, will address the efficacy-effectiveness gap and improve disease, functional, and economic outcome. It is an 11-site, randomized controlled clinical trial of this multi-modal, clinic-based intervention versus usual VA care running from 1997 to 2003. The trial has enrolled 191 subjects in each arm, using minimal exclusion criteria to maximize the external validity of the study. Subjects are followed for 3 years. The intervention is highly specified in a series of operations manuals for each of the three components. Several continuous quality improvement (CQI) interventions, process measures, and statistical techniques deal with drift of care in both the intervention and usual care arms to ensure the internal validity of the study. CSP #430 is designed to have impact well beyond the VA, since it evaluates a basic health care operational principle: that augmenting ambulatory access for major mental illness will improve outcome and reduce overall treatment costs. If results are positive, this study will provide a reason to reconsider the prevailing trend toward limitation of ambulatory services that is characteristic of many managed care systems today.

Filling and voiding symptoms in the American Urological Association symptom index: the value of their distinction in a Veterans Affairs randomized trial of medical therapy in men with a clinical diagnosis of benign prostatic hyperplasia.

PURPOSE: We used data from a large Veterans Affairs trial of medical therapy for men with benign prostatic hyperplasia to evaluate the value of calculating separate filling and voiding subscores of the American Urological Association (AUA) symptom index. MATERIALS AND METHODS: We performed factor analysis to assess the psychometric validity of separating the 7 items of the AUA symptom index into filling and voiding subsets. To assess the clinical usefulness of calculating these subscores we correlated them against baseline measurements of symptom interference as well as urodynamic and anatomical measures of disease severity, and used them for predicting the response to medical therapy. RESULTS: Factor analysis confirmed the psychometric validity of separating the AUA symptom index into a 3-item filling and a 4-item voiding subscale. However, calculating filling and voiding subscores did not result in differential correlations with measures of disease interference or severity. It also did not enable us to predict a better symptomatic or uroflowmetry response to medical therapy. CONCLUSIONS: Calculating separate filling and voiding subscores of the AUA symptom index is psychometrically valid but not clinically useful.

Effect of finasteride and/or terazosin on serum PSA: results of VA Cooperative Study #359.

BACKGROUND: Medical management of benign prostatic hyperplasia (BPH) giving rise to lower urinary tract symptomatology (LUTS) has emerged as the mainstay for first-line therapy. Prostate-specific antigen (PSA) is the most important method of detecting prostate carcinoma. The effect of finasteride on PSA has been widely reported. Little data exist with respect to alpha-adrenergic blocking therapy in men treated for BPH. In the present investigation we set out to evaluate the effect of these two forms of therapy. METHODS: Patients enrolled in the VA Cooperative Study #359 trial were evaluated. This study evaluated men with moderate LUTS owing to BPH in four treatment groups: placebo (P), finasteride (F), terazosin (T), and combination of finasteride plus terazosin (C). Men were recruited at 31 VA medical centers and had a baseline in 52-week PSA determination at the respective sites. RESULTS: There was no significant difference in baseline PSA between four groups (mean range, 2.0-2.9 ng/ml). Statistically significant reduction in PSA levels was observed at 52 weeks in the F and C arms (P < 0.001), whereas significant increases were observed in the T and P arms (P < 0.01). Additionally, there was no significant difference in PSA response between the T and P arms. Thirty percent of men in the C or F arms had more than 40-60% reduction of PSA. In contrast, the majority of men on T or P had less than 40% change in PSA. Only 35% of men on F or C had the expected 40-60% reduction in PSA level. CONCLUSIONS: These data demonstrate no clinically significant effect of T on PSA level. The heterogeneity of PSA response to F may make monitoring patients for the development of prostate cancer problematic.

The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group.

PURPOSE: We determine the effect of placebo, finasteride, terazosin and a combination of drugs on bother due to symptoms, quality of life and patient perception of improvement, and identify baseline clinical factors that predict clinical response to medical therapy. MATERIALS AND METHODS: A total of 1,229 subjects with clinical benign prostatic hyperplasia (BPH) were randomized to 1 year of placebo, finasteride, terazosin or drug combination. The primary outcome measures were American Urological Association (AUA) symptom score and peak flow rate. Relevant secondary outcome measures were symptom problem score, BPH impact score and global rating of improvement. RESULTS: Group mean differences in symptom problem and BPH impact scores between the finasteride versus placebo, and terazosin versus combination groups were not statistically or clinically significant. Group mean differences in all outcome measures were highly statistically significant between the terazosin and finasteride, and combination and finasteride groups. The percentage of subjects who rated improvement as marked or moderate with placebo, finasteride, terazosin and combination was 39, 44, 61 and 65%, respectively. In the subsets of men in the placebo, finasteride, terazosin and combination groups with prostates greater than 50 cm.3 group mean decrease from baseline in AUA symptom score was -2.5, -3.6, -6 and -7, group mean increase in peak flow rate was 0.6, 2.7, 3.6 and 3.7 ml. per second, group mean decrease in symptom problem score was -2.2, - 1.9, -3.1 and -4.5, and group mean decrease in BPH impact score was -0.6, -0.3, -1.1 and -1.5, respectively. A correlational analysis failed to show a significant relationship between baseline prostate volume and treatment response to finasteride. There was a significant but weak relationship between change in AUA symptom score and peak flow rate in the finasteride and combination groups. The symptom responses with terazosin were independent of baseline peak flow rate. CONCLUSIONS: In men with clinical BPH finasteride and placebo are equally effective, while terazosin and combination are significantly more effective. In men with clinical BPH and large prostates the advantage of finasteride over placebo in terms of symptom reduction, impact on bother due to symptoms and quality of life is small at best, while the advantage of terazosin and combination over finasteride and placebo is highly significant. Baseline prostate volume was not a predictor of response to finasteride in the overall study population. On the basis of our results alpha1 blockers, such as terazosin, should be first line medical treatment for BPH.

The relationship between cardiothoracic ratio and left ventricular ejection fraction in congestive heart failure. Digitalis Investigation Group.

BACKGROUND: Left ventricular ejection fraction (EF) is a valuable prognostic index in patients with congestive heart failure (CHF). Although EF can be readily measured, many clinicians use roentgenographic heart size as a clue to differentiate systolic from diastolic dysfunction, even in the absence of solid supportive data. OBJECTIVE: To test the hypothesis that the cardiothoracic ratio (CTR) measured from the chest roentgenogram can be used to estimate left ventricular EF in individuals with CHF. METHODS: To answer this question, the database of the Digitalis Investigation Group trial was used. The CTR, determined using the Danzer method, and quantitative EF, measured locally using angiographic, radionuclide, or 2-dimensional echocardiographic techniques, were compared in 7476 patients with clinical CHF (New York Heart Association functional classes I-IV) due to acquired left-sided cardiac disease of ischemic, hypertensive, idiopathic, and alcohol-related causes. RESULTS: Mean (+/-SD) CTR for the cohort was 0.53+/-.07. Mean (+/-SD) EF was 31.7%+/-12.2%. A weak, negative correlation between CTR and EF was observed (r=-0.176). Similar findings were obtained when the results were stratified by cause of CHF, presence of clinically defined right ventricular dysfunction, and method of EF measurement. Categorical analysis failed to yield a CTR cutoff point that facilitated useful segregation of individuals with an EF greater than 35% or 35% and below; greater than 40% or 40% and below; and greater than 45% or 45% and below in any patient group. CONCLUSIONS: Although a weak, negative correlation exists between CTR and EF, this relationship does not allow for accurate determination of systolic function in individual patients with CHF. Considering the morbidity and mortality associated with CHF, and the clinical implications of systolic function in this syndrome, direct measurement of EF is recommended.

The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group.

BACKGROUND: Men with benign prostatic hyperplasia can be treated with alpha 1-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS: We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS: The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS: In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Benign prostatic hyperplasia specific health status measures in clinical research: how much change in the American Urological Association symptom index and the benign prostatic hyperplasia impact index is perceptible to patients?

PURPOSE: We assessed the relationship between changes in scores for the American Urological Association (AUA) symptom index and benign prostatic hyperplasia (BPH) impact index with patient global ratings of improvement in a large Veterans Affairs trial comparing different pharmacological therapies for BPH. MATERIALS AND METHODS: The primary analyses compared absolute score changes from baseline with global ratings of improvement at 13 weeks for 1,218 men. RESULTS: Subjects who rated themselves as being slightly improved had a mean decrease in AUA symptom index and BPH impact index scores of 3.1 and 0.4 points, respectively. However, the baseline scores strongly influenced this relationship. CONCLUSIONS: These data provide guidance for investigators using the AUA symptom index and BPH impact index as outcome measures.

The effects of antireflux therapy on pulmonary function in patients with severe gastroesophageal reflux disease. Department of Veterans Affairs Gastroesophageal Reflux Disease Study Group.

OBJECTIVES: Gastroesophageal reflux can induce bronchospasm, and antireflux therapy has been shown to improve pulmonary function in patients who have gastroesophageal reflux disease (GERD) associated with asthma. Our objective was to study the pulmonary effects of antireflux therapy in patients who had severe GERD without clinically apparent lung disease. METHODS: In a Department of Veterans Affairs Cooperative Study, patients who had complicated GERD without important lung disease were randomly assigned to receive one of three types of antireflux treatment, including two kinds of medical therapy and a surgical therapy. Patients had pulmonary function tests (PFTs), including total lung capacity, residual volume, forced vital capacity, forced expiratory volume in 1 s, maximal midexpiratory flow, and diffusing capacity for carbon monoxide. RESULTS: Two hundred forty-seven patients (243 men, four women; mean age 58 yr) entered the randomized trial, and 151 returned for PFTs at 1 yr. For the entire study group and for all three treatment groups, mean values for PFTs at 1 yr did not differ significantly from those at baseline. Even in subgroups of patients whose baseline PFTs were abnormal and whose esophagitis had healed completely, there were no significant changes in results of PFTs. CONCLUSIONS: For veteran patients with severe GERD and no obvious lung disease, 1 yr of antireflux therapy had no important effect on pulmonary function. These findings suggest that GERD is not commonly associated with inapparent, reversible pulmonary dysfunction.

Development for and results of the use of a gastroesophageal reflux disease activity index as an outcome variable in a clinical trial. VA Cooperative Study Group on Gastroesophageal Reflux Disease (GERD).

Due to the significant expense of obtaining frequent endoscopy and pH monitoring measures as outcome variables available for use in a multihospital clinical trial of gastroesophageal reflux disease, and the lack of a suitable inexpensive index of disease activity, evaluated for both reliability and validity, the study planning committee decided to develop an index of gastroesophageal reflux disease activity in a pilot study--to precede the clinical trial. In particular, the purpose of the pilot study was to find a reliable, valid, and inexpensive index of gastroesophageal reflux disease which could be obtained independently of the treating physician and used as an outcome variable in the clinical trial. This paper describes the pilot study and the statistical methodology used to derive and evaluate a gastroesophageal reflux disease activity index model. In addition, the results of the activity index's use in the subsequent clinical trial's longitudinal analyses are presented. Comparisons with the more expensive, and thus less frequently obtained, endoscopy and pH monitoring outcome variables are described.

Diagnostic inconsistencies in Barrett's esophagus. Department of Veterans Affairs Gastroesophageal Reflux Study Group.

BACKGROUND/AIMS: Few studies have compared the precision of various diagnostic tests used to determine the presence of Barrett's esophagus. The aim of this study was to compare the results of histological, endoscopic, and manometric tests for patients with Barrett's esophagus in two closely spaced examinations. METHODS: In a Veterans Administration Cooperative Study, 192 patients with complicated gastroesophageal reflux disease had esophageal manometry and endoscopy performed at baseline and after 6 weeks. At each examination, the endoscopist localized the most proximal level of Barrett's epithelium and the lower esophageal sphincter and obtained esophageal biopsy specimens. RESULTS: One hundred sixteen patients met the criteria for Barrett's esophagus on at least one of the two endoscopic examinations. Among patients with specialized columnar epithelium, 20% had specialized columnar epithelium found on only one of the two examinations. Although the mean lower esophageal sphincter level did not change, approximately 10% of patients had a change > or = 4 cm on endoscopy and manometry between examinations. This led to an apparent change in the diagnosis in 18% of patients with Barrett's esophagus. CONCLUSIONS: From one endoscopic examination to another, inconsistencies in the ability to detect specialized columnar epithelium are common. This may lead to substantial problems in establishing an accurate diagnosis of Barrett's esophagus.

Comparison of eligible randomized patients with two groups of ineligible patients: can the results of the VA Total Parenteral Nutrition clinical trial be generalized?

The recently reported VA Cooperative Study "A Randomized Clinical Trial of Total Parenteral Nutrition (TPN) in Malnourished Surgical Patients" randomized 395 pre-operative patients to TPN treatment or control. The study concluded that the use of perioperative TPN should be limited to the most severely malnourished patients. The study also followed 233 patients eligible for the study who refused to give informed consent for randomization (Eligible Refusers) as well as 1220 patients who were ineligible because they were not sufficiently malnourished (Index Group). Patients in the Index Group were determined to be significantly healthier than those in the two eligible groups of patients. Those in the Eligible Refuser group were shown to be slightly less malnourished than the Randomized Patients. The 395 patients randomized to the study (Randomized Patients) showed the highest rate of septic complications at 30 days and at 90 days (10% and 13% respectively) with rates for the Eligible Refusers slightly lower (8% and 9%) and Index Group rates still lower (4% and 4%). Nonseptic complication rates showed the same pattern (19% and 22% for the Randomized group, 12% and 12% for Eligible Refusers, and 10% and 10% for the Index Group). Because (a) the beneficial effect of TPN is attained only in severely malnourished patients, (b) there is increased risk of septic complications with TPN use in patients not severely malnourished, (c) Index Group patients, and presumably the population of patients from which they are drawn, are not severely malnourished, it follows that unless specifically indicated, TPN should not be used in nonseverely malnourished patients.

Does perioperative total parenteral nutrition reduce medical care costs?

An economic analysis accompanied a multicenter Department of Veterans Affairs randomized, controlled trial of perioperative total parenteral nutrition (TPN). The cost of providing TPN for an average of 16.15 days before and after surgery was $2405, more than half of which ($1025) included costs of purchasing, preparing, and delivering the TPN solution itself; lipid solutions accounted for another $181, additional nursing care for $843, and miscellaneous costs for $356. Prolonged hospital stay added another $764 per patient to the $2405 cost of providing TPN, bringing the total to $3169. The incremental costs attributed to perioperative TPN were highest ($3921) for the patients least likely to benefit, that is, those who were less malnourished and at low risk of nutrition-related complications. Incremental costs were lowest ($3071) for high-risk patients. On the basis of the hospital-based method of administering TPN that was used in the clinical trial, perioperative TPN did not result in decreased costs for any subgroup of patients.

Quality of care and outcomes of chronic mentally ill patients in hospitals and nursing homes.

OBJECTIVE: Quality of care in three types of facilities in which chronic mentally ill patients reside was examined to determine how it was related to patient functioning and to determine how patients' dependency on others for self-care moderated relationships between quality of care and patient functioning. METHODS: Discriminant function analyses and multiple regression analyses were used to examine 12-month follow-up data from a Department of Veterans Affairs (VA) study of 294 chronic mentally ill patients in 52 community nursing homes, nine VA nursing home care units, and 43 VA hospital psychiatric units. RESULTS: The three types of facilities were best differentiated by staff and resident characteristics and facility policies. Residents of community nursing homes were more impaired, and staff were less well trained, than in the VA facilities. The community nursing homes had less restrictive policies. Patients who lived in facilities that gave them more control over their daily lives and that had larger proportions of high-functioning patients reported more life satisfaction and vigor. Patients in facilities with more social and recreational activities reported less life satisfaction. The extent to which facility features were beneficial or harmful was related to patients' self-care dependency. Supportive physical features and living-assistance services tended to aid impaired residents, whereas more experienced staff and policies that promoted control by residents tended to aid independent residents. CONCLUSIONS: Program managers may need to tailor facility environments to patients' level of functioning to maximize beneficial effects.

A randomized clinical trial of total parenteral nutrition in malnourished surgical patients: the rationale and impact of previous clinical trials and pilot study on protocol design.

The rationale for a large-scale clinical trial of preoperative total parenteral nutrition (TPN) is described in the context of previous clinical trials that have attempted to demonstrate reduction of operative morbidity with preoperative TPN. Defects in study design or execution potentially compromising the validity of these studies are analyzed. Results of a single-institution pilot study performed during the planning phase of the multiinstitutional preoperative TPN trial are presented. This literature review and pilot study provided the data necessary to permit appropriate design of many critical elements in the protocol for the clinical trial including sample size, eligibility criteria, duration and intensity of treatment regimens, and end-point criteria. The rationale underlying critical decisions in protocol design are presented in detail to allow more meaningful interpretation of the results of the clinical trial.

Study protocol: a randomized clinical trial of total parenteral nutrition in malnourished surgical patients.

CSP #221 is a randomized multiinstitutional clinical trial to assess the efficacy of 10 d of perioperative total parenteral nutrition (TPN) in reducing morbidity and mortality in malnourished patients undergoing intraperitoneal and/or intrathoracic operations. In this paper a detailed protocol for the clinical efficacy trial is presented primarily as a reference document for use in interpretation of the results of the clinical trial. It is also anticipated, however, that review of this protocol may be useful to other investigators planning future clinical nutrition intervention trials.

The "constant intake rate" assumption in interim recruitment goal methodology for multicenter clinical trials.

A primary concern of any multihospital clinical trial is the recruitment of a predetermined number of patients during a prespecified interval of time. In several recent papers a Poisson based model was used to estimate the time needed to recruit a predetermined number of patients and the probabilities of recruiting specified fractions of the sample during subintervals. The Poisson model requires the assumption that patients be recruited at a constant rate over the entire length of the interval. In this paper we test the adequacy of this model and assumption using patient intake data from nine multihospital VA clinical trials and propose an alternative Bayesian model.

The relationship of serum cholesterol and vitamin A in hospitalized patients with and without cancer.

Interrelationships among circulating levels of cholesterol, vitamin A, and selected transport proteins, as well as other nutritional variables were examined in a large population of hospitalized cancer (CA, n = 94) and noncancer (NONCA, n = 432) patients in order to help clarify a relationship between serum cholesterol and vitamin A. Serum cholesterol and vitamin A levels were positively correlated (r = 0.39; p less than 0.001) in both CA and NONCA groups. One hypothesis that might explain such a relationship was investigated. Results suggest that serum-transport protein levels and nutritional status are important factors that lead to a correlation between serum cholesterol and vitamin A by virtue of their mutual associations with both substances. Results suggest also that NONCA patients may have a more complex relationship of variates to serum-vitamin A levels than CA patients and that low levels of both cholesterol and vitamin A in CA patients may be related more to nutritional status than to the presence of cancer.