Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial.

BACKGROUND: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2). CONCLUSIONS: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups.

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics.

BACKGROUND: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. TRIAL REGISTRATION: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

Concept Elicitation Within Patient-Powered Research Networks: A Feasibility Study in Chronic Lymphocytic Leukemia.

OBJECTIVES: To explore the feasibility of using social media-based patient networks to gather qualitative data on patient-reported outcome (PRO) concepts relevant to chronic lymphocytic leukemia (CLL). METHODS: Between August and November 2013, US-residing members of the PatientsLikeMe online CLL patient community completed open-ended web-based surveys designed to elicit descriptions of CLL symptoms, impacts, and treatment-related perceptions. Qualitative telephone follow-up interviews were conducted with a subsample of respondents. Survey responses and interview transcripts were coded for qualitative analysis using Atlas.ti. RESULTS: Fifty survey responses were included in the analyses. Participants were age 60.5 ± 6.9 years, 54% female, and 96% white. When surveyed, 20% were receiving current treatment, 16% were in remission, and 64% were treatment-naïve. Among respondents, 369 descriptions of CLL symptoms were coded. Fatigue-related symptoms were expressed most frequently, with 54% reporting "fatigue," "tiredness," or both in their responses. These concepts were followed by night sweats (38%), swollen lymph nodes (32%), and frequent infections (28%). Among impacts of CLL, worry and fear (66% of respondents), depressed feelings (52%), and work limitations (50%) were noted most frequently. CONCLUSIONS: Survey results identified constitutional symptoms of CLL included in existing PRO instruments and the literature. Although the findings suggest that qualitative data obtained through social media applications can be potentially useful in supporting concept identification for newly developed PRO instruments, they also indicate that online approaches alone may not be sufficient to achieve efficient and exhaustive concept elicitation. Further research is needed to identify whether the results can support content validity in the same way as established qualitative research methods.

Efficacy and safety of dapoxetine in men with premature ejaculation and concomitant erectile dysfunction treated with a phosphodiesterase type 5 inhibitor: randomized, placebo-controlled, phase III study.

INTRODUCTION: Men with comorbid erectile dysfunction (ED) and premature ejaculation (PE) may be concomitantly prescribed a phosphodiesterase type 5 (PDE5) inhibitor and dapoxetine. AIM: Evaluate efficacy and safety of dapoxetine 30 mg and 60 mg on demand (prn) in men with PE and ED who were being treated with PDE5 inhibitors. METHODS: This randomized, double-blind, placebo-controlled, flexible-dose, multicenter study enrolled men ≥18 years who met diagnostic criteria for PE including intravaginal ejaculatory latency time (IELT) of ≤2 minutes in ≥75% of sexual intercourse episodes; were on stable regimen of a PDE5 inhibitor; and had International Index of Erectile Function-erectile function domain score ≥21. Subjects received placebo, dapoxetine 30 mg, or dapoxetine 60 mg prn (1-3 hours before intercourse) for 12 weeks. MAIN OUTCOME MEASURE: Stopwatch-measured average IELT, Clinical Global Impression of Change (CGIC) in PE, Premature Ejaculation Profile (PEP), and treatment-emergent adverse events (TEAEs). RESULTS: Of 495 subjects randomized, 429 completed the study. Arithmetic mean average IELT significantly increased with dapoxetine vs. placebo at end point (5.2 vs. 3.4 minutes) and weeks 4, 8, and 12 (P ≤ 0.002 for all). Men who described their PE at least "better" using the CGIC were significantly greater with dapoxetine vs. placebo at end point (56.5% vs. 35.4%) and weeks 4, 8, and 12 (P ≤ 0.001 for all). Significantly better outcomes were also reported with dapoxetine vs. placebo on PEP measures. Incidence of TEAEs was 20.0% and 29.6% in placebo- and dapoxetine-treated subjects, respectively (P = 0.0135). TEAEs led to discontinuation in 1.6% of subjects in both groups. Most frequent TEAEs were known adverse drug reactions of dapoxetine treatment including nausea (9.2%), headache (4.4%), diarrhea (3.6%), dizziness (2.4%), and dizziness postural (2.4%). CONCLUSIONS: In men with PE and comorbid ED on a stable regimen of PDE5 inhibitor, dapoxetine provided meaningful treatment benefit and was generally well tolerated.

Baseline characteristics and treatment outcomes for men with acquired or lifelong premature ejaculation with mild or no erectile dysfunction: integrated analyses of two phase 3 dapoxetine trials.

INTRODUCTION: Premature ejaculation (PE) is classified as an acquired or lifelong condition but data on baseline characteristics and response to treatment of men with acquired or lifelong PE and mild erectile dysfunction (ED) or normal erectile function (EF) is limited. AIM: To present integrated analyses of baseline characteristics and treatment outcomes from phase 3 dapoxetine trials in men with acquired or lifelong PE and mild or no ED. METHODS: Data were analyzed from two randomized, double-blind, placebo-controlled, phase 3 clinical trials (International and Asia-Pacific) that evaluated efficacy and safety of dapoxetine (30 mg or 60 mg as needed [PRN]) in patients with PE. Men were ≥18 years, in a stable monogamous relationship for ≥6 months, met DSM-IV-TR criteria for PE for ≥6 months, had an International Index of Erectile Function EF domain score ≥21, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: Demographics, sexual history, and PE symptomatology at baseline, and mean IELT and patient-reported outcomes (PROs) at study end (week 12), were analyzed for men with acquired or lifelong PE and mild or no ED (EF score 21-25 vs. ≥26). RESULTS: Baseline characteristics except duration of PE were similar in men with acquired and lifelong PE, with no other differentiating features by ED status. Dapoxetine treatment improved significantly mean IELT (arithmetic and geometric) and PRO responses (perceived control over ejaculation, satisfaction with sexual intercourse, ejaculation-related personal distress, and interpersonal difficulty) for acquired and lifelong subtypes, but presence of mild ED diminished PRO responsiveness in both subtypes, particularly those with lifelong PE. CONCLUSIONS: Baseline characteristics and treatment outcomes were generally similar in men with acquired and lifelong PE. The presence of mild ED appears to be associated with a more modest treatment response, irrespective of lifelong or acquired PE subtype.

Validity of the patient-reported Clinical Global Impression of Change as a measure of treatment response in men with premature ejaculation.

INTRODUCTION: The Clinical Global Impression of Change (CGIC) measures have high utility in clinical practice. However, it is unknown whether the CGIC is valued for assessing premature ejaculation (PE) symptoms and/or the relationship between CGIC and other validated PE patient-reported measures. AIM: The study aims to assess the validity of the patient-reported CGIC measure in men with PE and to examine the relationship between CGIC ratings and assessments of control, satisfaction, personal distress, and interpersonal difficulty. METHODS: Data from a randomized, double-blind, 24-week phase 3 trial in 1,162 men with PE who received dapoxetine (30 mg or 60 mg) or placebo on demand provided the basis for the analysis. Patients were ≥18 years, in a stable monogamous relationship for ≥6 months, met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision criteria for PE for ≥6 months, and had an intravaginal ejaculatory latency time (IELT) ≤2 minutes in ≥75% of intercourse episodes. MAIN OUTCOME MEASURES: The CGIC asked patients to rate improvement or worsening of their PE compared with the start of the study using a 7-point response scale; other patient-reported measures were control over ejaculation, satisfaction with sexual intercourse, interpersonal difficulty, and personal distress related to ejaculation. Stopwatch-measured IELT was recorded. Associations between CGIC and change in other measures at study end point were assessed. RESULTS: The magnitude of IELT increased for each category of improvement on the CGIC: 1.63, 4.03, and 7.15 minutes for slightly better, better, and much better, respectively. Higher CGIC ratings were correlated with greater improvement in control (r = 0.73), satisfaction (r = 0.62), greater reduction in distress (r = -0.52), and interpersonal difficulty (r = -0.39). Total variance accounted for was 57.4%: control (48.7%), satisfaction (4.5%), IELT (2.8%), and distress (1.15%). CONCLUSIONS: The analyses support the validity of the CGIC measure in men with PE. The CGIC can provide clinicians in practice with a valid and brief outcome assessment of their patient's condition.

Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine.

OBJECTIVES: To assess the utility of perceived control over ejaculation ('control') in the evaluation of treatment benefit in men with premature ejaculation (PE), and to compare effects associated with a two-category or greater increase in this variable between men receiving dapoxetine and placebo. PATIENTS AND METHODS: This subanalysis used combined data from all treatment groups in an integrated analysis of two identically designed, 12-week, double-blind, randomized, placebo-controlled trials of dapoxetine. Men (2614) met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision) criteria for PE, had a stopwatch-measured intravaginal ejaculatory latency time (IELT) of < or =2 min in > or =75% of events in a 2-week baseline period, and self-reported moderate or severe PE. Men received placebo or dapoxetine 30 or 60 mg, 1-3 h before intercourse. The stopwatch-measured IELT was recorded for each episode; the patient-reported global impression of change (PGI; 7-point scale, 'much worse' to 'much better'), control and satisfaction with sexual intercourse (5-point scales, 'very poor' to 'very good') were assessed monthly. The utility of a two-category or greater increase in control was evaluated by examining the relationship of this variable with IELT and satisfaction with sexual intercourse. RESULTS: Of 2341 men with baseline and endpoint assessments, 96.8% reported 'very poor' or 'poor' control at baseline, and 748 (32%) reported a two-category or greater increase in control after treatment. More than 95% of those men rated their PE as 'slightly better', 'better', or 'much better' on the PGI; 67.1% gave ratings of 'better' or 'much better.' They also had greater improvements in IELT than men with less than a two-category increase in control, with a mean (sd) change from baseline of 3.7 (4.3) vs 0.77 (1.8) min, respectively, and a greater percentage reported good or very good satisfaction with sexual intercourse than men with less than a two-category increase in control (74% vs 19%, respectively). Nausea, headache and upper respiratory tract infection were the most common adverse events reported by men with a two-category or greater increase in control (15.8%, 7.4% and 6.6%, respectively) and those without (8.5%, 5.5% and 6.5%, respectively). The proportions of men with a two-category or greater increase in control with dapoxetine 30 and 60 mg were 36.3% and 44.5%, respectively (vs 15% with placebo). CONCLUSIONS: A two-category or greater increase in control (5-point scale) is useful for assessing the treatment benefit in men with PE; it corresponds with improvements in the man's perception of his condition, substantially greater prolongation of IELT, and higher levels of satisfaction with sexual intercourse.

Canagliflozin: a sodium glucose co-transporter 2 inhibitor for the treatment of type 2 diabetes mellitus.

The sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin is a novel treatment option for adults with type 2 diabetes mellitus (T2DM). In patients with hyperglycemia, SGLT2 inhibition lowers plasma glucose levels by reducing the renal threshold for glucose (RTG ) and increasing urinary glucose excretion (UGE). Increased UGE is also associated with a mild osmotic diuresis and net caloric loss, which can lead to reductions in body weight and blood pressure (BP). After promising results from preclinical and phase I/II studies, the efficacy and safety of canagliflozin was evaluated in a comprehensive phase III development program in over 10,000 patients with T2DM on various background therapies. Canagliflozin improved glycemic control and provided reductions in body weight and BP versus placebo and active comparators in studies of up to 2 years' duration. Canagliflozin was generally well tolerated, with higher incidences of adverse events (AEs) related to the mechanism of action, including genital mycotic infections and AEs related to osmotic diuresis. Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT2 inhibitor approved in the United States, and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with T2DM.

Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are widely used as the first-line treatment for depression. Information regarding their side effects is mostly based on controlled clinical trials. METHOD: Patients who received an SSRI for a new or recurrent case of depression (ICD-9 code 296.2 or 311) between December 15, 1999, and May 31, 2000 were interviewed by telephone 75 to 105 days after initiation of SSRI therapy. Using closed-ended questions, investigators asked patients if they experienced any of 17 side effects commonly associated with SSRIs, how bothersome they were, and what their duration was. Prescribing physicians completed a written survey providing their estimates about frequency of side effects associated with SSRIs and how bothersome those side effects are. RESULTS: Of 401 patients who completed the phone interview, 344 patients (86%) reported at least 1 side effect, and 219 patients (55%) experienced 1 or more bothersome side effect(s). The most common bothersome side effects were sexual dysfunction and drowsiness (17% each). While most side effects first occurred within the first 2 weeks of treatment, the majority of patients were still experiencing the same side effects at the time of interview, most notably blurred vision (85%) and sexual dysfunction (83%). Overall, physicians (N = 137) significantly underestimated the occurrence of the 17 side effects explored, and they tended to underrate how bothersome those side effects were to their patients. CONCLUSION: Side effects associated with SSRIs are common and bothersome to patients. Treatment-emergent side effects tend to persist during the first 3 months of treatment.

Treatment patterns and associated symptom improvement during six months of care for overactive bladder: a prospective, observational study.

BACKGROUND: Several pharmacologic and nonpharmacologic interventions are available for the treatment of symptoms of overactive bladder (OAB). The relationship between type of initial intervention and subsequent symptom improvement and resource utilization has not been explored in detail. OBJECTIVE: The purpose of this study was to assess (1) the proportion of patients continuing with their initially prescribed treatment for OAB 3 and 6 months after the initial evaluation and (2) the relationship between actual treatment patterns, symptom improvement. and number of physician office visits. METHODS: A total of 31 physicians enrolled patients with OAB for this 6-month prospective, observational study. Baseline data on OAB symptom severity and OAB management strategies were obtained and initial treatment(s) were prescribed by physicians during a routine office visit. Follow-up data on symptom changes, treatment changes, number of physician office visits, and the frequency of absorbent pad use were collected via telephone interviews with patients 3 and 6 months after the initial visit. Stepwise logistic regression was used to assess the relationship between patient characteristics, prescription of medication, and symptom improvement. RESULTS: A total of 213 patients were enrolled; 122 (57.3%) and 100 (46.9%) patients provided follow-up data at the 3-month and 6-month assessments, respectively. The mean age was 61.2 years; 85.2% of patients were female, and 77.7% were white. OAB symptom improvement was significantly related to being prescribed medication (odds ratio [OR], 4.3; 95% CI, 1.8-9.9) and the mean number of daily leakage incidents at baseline (OR, 3.2; 95% CI, 1.2-8.4). Although patients who were prescribed drugs at baseline tended to have fewer physician office visits and were less likely to be prescribed nondrug interventions than patients who were not treated initially with drugs, these differences were not statistically significant. CONCLUSIONS: Pharmacologic treatment for symptoms of OAB appears to be associated with greater symptom improvement than nonpharmacologic treatment. Larger studies of experimental design are needed to determine whether patients treated with medication use fewer nondrug interventions and require fewer physician office visits than patients treated without medication.

Impact of a collaborative care model on depression in a primary care setting: a randomized controlled trial.

To measure the effects of a collaborative care model that emphasized the role of clinical pharmacists in providing drug therapy management and treatment follow-up to patients with depression, we conducted a randomized controlled trial at a staff model health maintenance organization. We compared the outcomes of subjects treated in this collaborative care model (75 patients, intervention group) with subjects receiving usual care (50 patients, control group). After 6 months, the intervention group demonstrated a significantly higher drug adherence rate than that of the control group (67% vs 48%, odds ratio 2.17, 95% confidence interval 1.04-4.51, p=0.038). Patient satisfaction was significantly greater among members randomly assigned to pharmacists' services than among controls, and provider satisfaction surveys revealed high approval rates as well. Changes in resource utilization were favorable for the intervention group, but differences from the control group did not achieve statistical significance. Clinical improvement was noted in both groups, but the difference was not significant. Clinical pharmacists had a favorable effect on multiple aspects of patient care. Future studies of this model in other health care settings appear warranted.

Impact of a collaborative pharmacy practice model on the treatment of depression in primary care.

The effects of a collaborative pharmacy practice model, in which clinical pharmacy specialists provided medication maintenance and follow-up patient care services at a clinic, on patients' adherence to treatment and satisfaction and costs were studied. A cohort of 13 primary care providers (PCPs) was designated to refer patients diagnosed with depression to the practice model at a staff-model health maintenance organization (HMO) immediately after the initiation of antidepressant medications. Clinical pharmacy specialists proceeded to coordinate follow-up with the patients for six months through a combination of scheduled office visits and telephone calls. Working closely with psychiatric liaisons, pharmacists were granted limited prescribing privileges to provide medication comanagement. These patients' adherence to treatment and satisfaction and costs to the HMO were compared with a control group of patients being treated for depression by the remaining 17 PCPs at the facility. A total of 91 patients were referred to the intervention group and received care from the pharmacists during the 10-month enrollment phase; 129 patients were included in the control group. There were no significant differences between groups regarding age, sex and chronic disease scores. An intent-to-treat analysis of medication adherence revealed that adherence was significantly higher in the intervention group (medication possession ratio, 0.81 versus 0.66) (p = 0.0005). Medication switch rates were higher among intervention patients as well (24% versus 5%) (p = 0.0001). There was a greater decline in the number of visits to PCPs for patients in the intervention group (39% versus 12%) (p = 0.029). A collaborative practice model in which clinical pharmacy specialists managed the medication therapy of patients with mild to moderate depression increased patients' adherence to treatment and their satisfaction and reduced the patients' subsequent visits to PCPs.

Relationship of clinical factors to the use of Cox-2 selective NSAIDs within an arthritis population in a large HMO.

OBJECTIVE: To investigate the degree to which physicians use clinical factors to focus use of Cox-2 selective NSAIDs within an arthritis population. METHODS: Diagnostic codes in the medical records of a large group-model HMO in northern California with approximately 3 million members were examined to identify patients with either rheumatoid arthritis (RA) or non-RA (osteoarthritis or degenerative joint disease). RA and non-RA patients were stratified in deciles of relative risk for gastrointestinal (GI) complications according to patient characteristics identified on the Standardized Calculator of Risk for Events (SCORE) that were associated with use of Cox-2 selective NSAIDs. (The SCORE tool stratifies patients by risk of serious GI complications using patient characteristics that are assigned points during an office visit, including age, health status, diagnosis of rheumatoid arthritis, corticosteroid use, and history of GI ulcer or bleed.) The second stage of analysis examined the percentage of arthritis patients in each SCORE-risk decile who received a Cox-2 selective NSAID, lower-risk NSAID, or traditional NSAID during calendar year 1999. RESULTS: The study population consisted of 144,360 members with an arthritis diagnosis, approximately 4.8% of members in this HMO. The mean age was 62.8 years (SD = 14.1), 61% were female, 10,449 (7%) had rheumatoid arthritis (RA), and 133,911 (93%) had non-rheumatoid arthritis. A diagnosis of RA was the most significant predictor of Cox-2 NSAID use (OR=2.4; 95% CI=1.6-3.5), followed by a history of GI problems (OR=1.5; 95% CI=1.4- 1.6). Female gender, chronic steroid use, and age each increased the odds of receiving a Cox-2 selective NSAID by about 35% (P<0.001 for all). Approximately 8.3% of patients in the highest decile of risk and 1.5% of patients in the lowest decile of risk received a Cox-2 selective NSAID. CONCLUSIONS: Clinical characteristics of patients identified on the SCORE (GI-risk) tool were strongly associated with use of Cox-2-selective NSAIDs in this HMO. A 5.5-fold difference in utilization of Cox-2 selective NSAIDs was found among patients determined to be in the highest-risk decile versus patients in the lowest-risk decile. Future research should investigate how nonclinical factors play a role in the treatment decisions made by physicians.

Results from a prospective observational study of men with premature ejaculation treated with dapoxetine or alternative care: the PAUSE study.

BACKGROUND: Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor and the first drug approved for the on-demand treatment of premature ejaculation (PE). Its safety was established in a thorough clinical development program. OBJECTIVE: To characterize the safety profile of dapoxetine in PE treatment and to report the incidence, severity, and type of adverse events. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-wk, open-label, observational study with a 4-wk, postobservational contact. A total of 10,028 patients were enrolled, with 6712 patients (67.6%) treated with dapoxetine 30-60 mg (group A) and 3316 (32.4%) treated with alternative care/nondapoxetine (group B). INTERVENTIONS: Treatment with dapoxetine or alternative care/nondapoxetine. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Treatment-emergent adverse events (TEAEs) and concomitant therapy use during the 12-wk observational and the postobservational period were reported. RESULTS AND LIMITATIONS: The mean age for all patients was 40.5 yr. In group A, 93.0% of the patients were initially prescribed dapoxetine 30 mg. Treatment options for group B patients included clomipramine, paroxetine, fluoxetine, sertraline, topical drugs, condoms, and behavioral counseling. Both treatment regimens were well tolerated. TEAEs were reported by 12.0% and 8.9% of group A and group B, respectively, with the highest incidence observed in patients aged >65 yr for group A (21.4%) and 30-39 yr (9.8%) for group B. The most commonly reported TEAEs were nausea, headache, and vertigo, with a higher incidence in group A (3.1%, 2.6%, and 1.0%, respectively) than in group B (oral drugs: 2.3%, 1.3%, and 0.9%, respectively). There were no cases of syncope in group A and one case in group B. A major limitation is that this was a nonrandomized, open-label, short-term study lacking efficacy data. CONCLUSIONS: The results of this postmarketing observational study demonstrated that dapoxetine for treatment of PE has a good safety profile and low prevalence of TEAEs. Syncope and major cardiovascular adverse events were not reported. The high level of adherence by healthcare providers to the contraindications, special warnings, and precautions for dapoxetine minimizes the risk for its use in routine clinical practice. The current risk minimization measures for its identified and potential risks are effective.

Self-reported premature ejaculation and aspects of sexual functioning and satisfaction.

BACKGROUND: Although premature ejaculation (PE) is a common male sexual dysfunction, its relevant parameters have not been adequately studied in large community-based samples. OBJECTIVE: To examine the diagnostic utility of two self-report questions based on the DSM-IV-TR definition of PE and to investigate the relationship between self-identified PE, sexual functioning, and sexual satisfaction in men. METHODS: An Internet survey of general health and aspects of sexual functioning and satisfaction was conducted in 2,056 males. Subjects were classified as having "probable" or "possible" PE, or as "non-PE" by survey responses. RESULTS: A total of 1158 men met the selection criteria (sexually active in a stable heterosexual relationship), and 189 (16.3%) were classified as having probable PE by reporting they ejaculated before they wished and indicating it was "very much" or "somewhat" a problem. Another 188 (16.2%) men reported ejaculating before they wished but rated their distress lower and were classified as having possible PE. Compared to non-PE men, those with probable and possible PE reported significantly worse sexual functioning in 6 of 8 study measures. Concern about partner satisfaction was high in all groups. The importance of ejaculatory control and the ability to have intercourse for the desired time was significantly higher in men with PE as compared to non-PE men (P < 0.01). CONCLUSIONS: PE was a common problem, was characterized by a lack of ejaculatory control, and was associated with significant effects on sexual functioning and satisfaction. Additional research on the sensitivity and specificity of these self-report questions should be pursued.

Discontinuation of use and switching of antidepressants: influence of patient-physician communication.

CONTEXT: Although current depression treatment guidelines recommend continuing antidepressant therapy for at least 4 to 9 months, many patients discontinue treatment prematurely, within 3 months. OBJECTIVES: To investigate the relationship between patient-physician communication and the continuation of treatment with antidepressants and to explore the demographics, adverse effects, therapeutic response, and frequency of follow-up visits. DESIGN, SETTING, AND PATIENTS: A total of 401 telephone interviews of depressed patients being treated with selective serotonin reuptake inhibitor (SSRI) therapy between December 15, 1999, and May 31, 2000, were conducted and 137 prescribing physicians completed written surveys from Northern California Kaiser Permanente health maintenance organization outpatient clinics. MAIN OUTCOME MEASURES: Patient-physician communication about therapy duration and about adverse effects; therapy discontinuation or medication switching within 3 months after start of SSRI therapy. RESULTS: Ninety-nine physicians (72%) reported that they usually ask patients to continue using antidepressants for at least 6 months, but 137 patients (34%) reported that their physicians asked them to continue using antidepressants for this duration and 228 (56%) reported receiving no instructions. Patients who said they were told to take their medication for less than 6 months were 3 times more likely to discontinue therapy (odds ratio [OR], 3.12; 95% confidence interval [CI], 1.21-8.07) compared with patients who said they were told to continue therapy longer. Patients who discussed adverse effects with their physicians were less likely to discontinue therapy than patients who did not discuss them (OR, 0.49; 95% CI, 0.25-0.95). Patients who reported discussing adverse effects with their physicians were more likely to switch medications (OR, 5.60; 95% CI, 2.31-13.60). Fewer than 3 follow-up visits for depression, adverse effects, and lack of therapeutic response to medication were also associated with patients' discontinuing therapy. CONCLUSIONS: Discrepancies exist between instructions that physicians report they communicate to patients and what patients remember being told. Explicit instructions about expected duration of therapy and discussions about medication adverse effects throughout treatment may reduce discontinuation of SSRI use. Our finding that patients with 3 or more follow-up visits were more likely to continue using the initially prescribed antidepressant medication suggests that frequent patient-physician contact may increase the probability that patients will continue therapy.