Fady Ntanios

Relationship Between Biomarkers of Oxidized Low-Density Lipoprotein, Statin Therapy, Quantitative Coronary Angiography, and Atheroma Volume ‡: Observations From the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) Study

OBJECTIVES This study was designed to test the hypothesis that circulating biomarkers of oxidized low-density lipoprotein (OxLDL) are affected by statin therapy and predict changes in atheroma volume. BACKGROUND Oxidative stress is thought to play an important role in atherogenesis but the relationship between OxLDL, statin therapy, and atheroma volume in humans is not known. METHODS In a subgroup of 214 patients from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes per apolipoprotein B-100 (apoB), immunoglobin (Ig) G and IgM apoB immune complexes, and OxLDL autoantibodies were measured at baseline and after 18 months of treatment with atorvastatin or pravastatin. Relationships between changes of OxLDL biomarkers and quantitative coronary angiography (QCA), total atheroma volume, and percentage atheroma volume were analyzed. RESULTS There were no differences in QCA parameters or atheroma volume in the 2 groups at baseline. Compared with baseline values, OxPL/apoB and MDA/apoB, and lipoprotein (a) levels increased 21% to 48% (p < 0.001 for all) in response to atorvastatin and 17% to 39% (p < 0.001 for all) in response to pravastatin. In contrast, IgG apoB immune complexes, IgM apoB immune complexes, and IgM OxLDL autoantibodies were significantly reduced by both atorvastatin and pravastatin (p value range 0.003 to <0.001). There were no significant differences between the atorvastatin and pravastatin groups. In the entire cohort, there were no correlations between changes in any OxLDL biomarkers and changes in QCA parameters or atheroma volume. CONCLUSIONS Statin therapy results in significant increases in OxPL/apoB, MDA/apoB, and lipoprotein (a) levels and decreases in apoB immune complexes and OxLDL autoantibodies. However, these measures did not correlate with changes in QCA parameters or atheroma volume.

Efficacy and safety of fesoterodine 8 mg in subjects with overactive bladder after a suboptimal response to tolterodine ER

To assess fesoterodine 8 mg efficacy over time and vs. placebo in subjects with overactive bladder (OAB) who responded suboptimally to tolterodine extended release (ER) 4 mg.

Defining response and non-response to treatment in patients with overactive bladder: a systematic review.

Abstract Objective: There is currently a lack of formal guidance for assessing treatment response and non-response in patients with overactive bladder (OAB). Such guidance would be useful for both clinical practice and the design of clinical trials. Our purpose was to review and assess definitions of treatment response and non-response used in patients with OAB. Methods: We conducted a systematic review of articles published between January 1, 2005 and August 8, 2013 using PubMed. Search terms included (overactive bladder) AND (‘treatment response’ OR responder OR success OR satisfied OR goal OR refractory OR nonresponder OR fail OR persistent OR dissatisfied). Limits were ‘humans’ and ‘English’. Studies conducted in subjects with neurogenic detrusor overactivity, conditions other than OAB, or OAB symptoms following lower urinary tract/pelvic surgery were excluded; case reports and letters were also excluded. Results: The literature search returned 423 articles, of which 75 met the inclusion criteria and defined a specific threshold by which treatment response or non-response was determined for patients receiving behavioral therapy and/or treatment with an antimuscarinic, β3-agonist, botulinum toxin, or neural stimulation. One published abstract from congress proceedings and three additional articles that were not identified by the search were included; thus, a total of 79 records were included. A wide variety of symptom-based definitions and patient-reported outcomes (PROs) were used. Symptom-based definitions frequently used a threshold of 50–100% improvement in general or specific symptoms; urgency urinary incontinence (UUI) was often used in studies with incontinent patients. Definitions based on PROs frequently used measures of satisfaction, general improvement, or goal achievement. Studies of patients with refractory OAB often referred to a failure to respond to ≥1 other therapy, or to poor efficacy or unacceptable tolerability, without further specification. Limitations of this review are that only English language articles were included and that only the PubMed database was used for the literature search. Conclusions: There is considerable heterogeneity in the definitions of treatment response and non-response in trials of patients with OAB; some standardization would be beneficial. However, there is also heterogeneity among patients of what constitutes treatment success or failure, and conceptualizations of treatment response and non-response in both clinical trials and clinical practice must take patient characteristics into account. For patients with UUI, it is recommended that the criteria for treatment response include this symptom, as measured by change in the absolute number of UUI episodes or achievement of continence, given its impact on patients’ lives and associated bother. PROs provide important information that confirm symptom-based measures by demonstrating that observed changes in symptoms are meaningful to the patient. In clinical practice, measures of treatment satisfaction and goal achievement can be highly useful.

A pooled analysis of the efficacy of fesoterodine for the treatment of overactive bladder, and the relationship between safety, co-morbidity and polypharmacy in patients aged 65 years or older

Background overactive bladder (OAB) is a common condition in older persons. Antimuscarinic treatment remains the mainstay of treatment of OAB but clinicians have been reluctant to prescribe this to older patients. This study examined efficacy and safety information from patients >65 in fesoterodine trials to reaffirm efficacy and to explore the relationships between treatment emergent adverse events (TEAEs), coexisting medication and co-morbidity. Methods data from 10 double-blind, placebo-controlled studies were analysed. A logistic regression analysis, where TEAE incidence was predicted by treatment, prior antimuscarinic treatment, number of coexisting medications, number of concomitant diseases and all possible combinations of two-way interaction terms with treatment was conducted. Results of 4,040 patients who participated in trials; fesoterodine treatment was associated with statistically significant reductions in all disease-related and patient-reported outcomes compared to placebo. There was a significant increase in the likelihood of reporting a TEAE in association with the number of coexistent medications (odds ratio (OR) = 1.028, 95% CI: 1.0143-1.044, P < 0.003). The OR of having a TEAE with increase in the number of concomitant diseases was 1.058 (95% CI: 1.044-1.072, P < 0.0001). Central nervous system (CNS) events were few. Discussion fesoterodine treatment led to clinically meaningful improvements across all included patient reported outcomes. The number of concomitant conditions had the greatest influence on the likelihood of an adverse event being reported. CNS TEAE were not associated with fesoterodine dose and were low across all categories of concomitant disease and coexisting medication.

Do Patient Characteristics Predict Responsiveness to Treatment of Overactive Bladder With Antimuscarinic Agents

OBJECTIVE To determine clinical and demographic characteristics associated with antimuscarinic treatment response using a regression model. METHODS Adults with overactive bladder (OAB) symptoms for >3 months and ≥ 1 urgency urinary incontinence (UUI) episode and ≥ 8 micturitions per 24 hours at baseline were randomized to fesoterodine (8 mg), tolterodine extended-release (4 mg), or placebo in two 12-week, double-blind, head-to-head studies. Fesoterodine-treated patients received 4 mg/d during the first week and 8 mg/d thereafter. Patients completed 3-day bladder diaries and the Overactive Bladder Questionnaire at baseline and week 12. Pooled data for changes from baseline to week 12 in winsorized UUI episodes, micturitions, and urgency episodes per 24 hours and Overactive Bladder Questionnaire Symptom Bother and health-related quality of life scores were analyzed posthoc using a regression model that selects outcome predictors from baseline values and patient characteristics while retaining baseline values and treatment, with stepwise inclusion of significant covariates and assessment of treatment interactions. Logistic regression was used for analysis of diary-dry rates. RESULTS Younger age, lack of previous antimuscarinic treatment, shorter duration of OAB diagnosis, and female gender were common predictors of larger changes in outcomes from baseline to week 12. Baseline measures often interacted with treatment, such that poorer baseline outcomes were predictive of larger treatment differences. Longer duration since OAB diagnosis predicted greater treatment differences for UUI episodes and in diary-dry rate, and increased age predicted greater treatment differences for micturitions. CONCLUSION Symptom severity and duration, age, gender, and previous antimuscarinic pharmacotherapy impact the response to antimuscarinic treatment.

Systematic literature review of clinical trials evaluating pharmacotherapy for overactive bladder in elderly patients: An assessment of trial quality

Overactive bladder (OAB) disproportionately affects older‐aged adults, yet most randomized controlled trials (RCTs) underrepresent patients ≥65. This systematic literature review (SLR) identified RCTs evaluating β‐3 adrenergic agonists or muscarinic antagonists in elderly patients with OAB, and compared study quality across trials.

Patterns of medical management of overactive bladder (OAB) and benign prostatic hyperplasia (BPH) in the United States

Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are highly prevalent conditions that place a large burden on the United States (US) health care system. We sought to analyze patterns of prescription medication usage for incident OAB in men and women, and for incident BPH in men using US health insurance claims data.

Development of a predictive model for urgency urinary incontinence.

The ability to set realistic expectations of treatment response in patients with overactive bladder (OAB) can have an impact on patient engagement and adherence to study medication. In order to help set treatment expectations for OAB, a Physician Predictive Tool has been developed based on predictive modelling. Models have been developed utilizing data from eight Phase 3 and 4 fesoterodine clinical trials and these models enable the prediction of individual treatment response in subjects with OAB, based on various baseline characteristics. The data utilized and covariates that were hypothesized to influence treatment response are described. The model selection and development process are also outlined, and the final model and some example results utilizing this model are presented. Finally, we discuss the potential benefits and limitations of such a predictive tool.

MP76-16 PATTERNS OF MEDICAL MANAGEMENT OF OVERACTIVE BLADDER (OAB) AND BENIGN PROSTATIC HYPERPLASIA (BPH) IN THE US: WHO DOES BETTER?

RESULTS: Overall, 46.5% of patients offered an access code logged into their MyChart account. Males (X 1⁄4 10.2; p1⁄4.01); those selfidentifying as “Other” (not White, Asian, or African American) (X 375.0; p<.001); and Hispanic patients (X1⁄4 366.5; p<.001) were less likely to activate their portal account. Patients living in central, urban areas were less likely than those living in suburban areas to activate their accounts (X1⁄4 240.7; p<.001). Using census data for zip code region, patients who activated their account had a significantly higher median household income than those who did not activate, refused, or deactivated their account (F1⁄4 135.6; p<.001). Language was significantly associated with adoption. Those who reported their primary language as Spanish were much less likely to activate the portal (X1⁄4895.9; p<.001) (358 of 1704) than English-speaking patients (4405 of 8480). CONCLUSIONS: Our findings suggest that primary language and socioeconomic factors may be a significant barriers in adopting the portal. Focusing on patient education to reduce these barriers, may increase portal acceptance thereby making the portal a more meaningful tool for patients, parents, and providers.

Characteristics of antimuscarinic responders versus suboptimal responders in a randomized clinical trial of patients with overactive bladder symptoms

Abstract Objective: To assess the characteristics of tolterodine extended-release (ER) 4 mg responders and suboptimal responders (≤50% decrease in UUI episodes/24 h) among patients with overactive bladder (OAB), including urgency urinary incontinence (UUI), and identify predictors of a >50% UUI response with fesoterodine 8 mg in tolterodine suboptimal responders. Methods: Adult patients with OAB symptoms for ≥6 months and ≥8 micturitions, and ≥2 and <15 UUI episodes/24 h at week −2 received open-label tolterodine ER 4 mg during a 2 week run-in. Suboptimal responders after tolterodine treatment (week 0) were randomized to fesoterodine (4 mg for 1 week, 8 mg for weeks 2–12) or placebo once daily. Post-hoc analyses compared the percentage change from week −2 to week 0 in UUI episodes/24 h in tolterodine responders versus suboptimal responders and identified significant predictors of a UUI response at week 12 with fesoterodine 8 mg among tolterodine suboptimal responders. Results: Of 897 patients, 610 (68%) were UUI suboptimal responders during the run-in period. UUI episodes/24 h at week −2 were similar in tolterodine responders and suboptimal responders (4.2 vs. 4.3), but responders showed a significantly greater median percentage decrease in UUI episodes/24 h after tolterodine treatment at week 0 (80.0% versus 15.3%; p < .0001). During double-blind treatment, the percentage of patients with a UUI response at week 12 was significantly greater with fesoterodine (69.9%) than placebo (57.0%; p = .0027). Fesoterodine (vs. placebo), no previous antimuscarinic use before tolterodine run-in, and less UUI severity at baseline were significant predictors of a UUI response. Conclusions: For patients with OAB, including UUI, who were treated initially with tolterodine and showed a suboptimal UUI response, nearly 70% demonstrated a UUI response with second-line fesoterodine 8 mg. No antimuscarinic use before tolterodine and fewer baseline UUI episodes were significant predictors of a UUI response with fesoterodine.