Onset of Efficacy Following Oral Treatment With Lasmiditan for the Acute Treatment of Migraine: Integrated Results From 2 Randomized Double-Blind Placebo-Controlled Phase 3 Clinical Studies.

OBJECTIVE: To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms. BACKGROUND: Lasmiditan is a novel selective 5-hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose. METHODS: Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine-related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed. RESULTS: Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100- and 200-mg lasmiditan-treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100- and 200-mg lasmiditan-treated groups. A significantly higher percentage of patients in the 200-mg lasmiditan-treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200-mg lasmiditan-treated group achieved freedom from migraine-related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001). CONCLUSIONS: Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100- or 200-mg lasmiditan treatment.

Prospective Case-crossover Study Investigating the Possible Association Between Nonarteritic Anterior Ischemic Optic Neuropathy and Phosphodiesterase Type 5 Inhibitor Exposure.

OBJECTIVE: To evaluate the association between intermittent phosphodiesterase type 5 inhibitor (PDE5i) exposure and risk of acute nonarteritic anterior ischemic optic neuropathy (NAION) using a case-crossover design. METHODS: Male adults with suspected NAION were enrolled at 41 US ophthalmology sites from 2010 to 2015 and were interviewed regarding risk factors for NAION, medical history, and PDE5i use before NAION onset (index date of onset [IDO]). An adjudication committee confirmed the NAION cases. The primary analysis, using the person-time method, examined the rate of PDE5i exposure within 5 half-lives of NAION onset relative to PDE5i exposure over a 30-day study period preceding the IDO in men exposed to PDE5i intermittently as a measure of NAION risk associated with PDE5i exposure. Rate ratios were estimated using the Mantel-Haenszel estimator. Secondary analyses included person-time analyses over the 12-months preceding the IDO and matched-interval analyses over 42 days preceding the IDO. RESULTS: Of 279 men with confirmed NAION, 22 were exposed to PDE5i intermittently within 30 days of IDO. The Mantel-Haenszel rate ratio for risk of NAION associated with PDE5i exposure within 5 half-lives of IDO was 2.27 (95% confidence interval [CI]: 0.99-5.20) over the 30-day period (n = 22) and 3.52 (95% CI: 1.59-7.79) over the 12-month period (n = 26). Sensitivity analyses showed similar results and were statistically significant. The matched-interval method found no association (hazard ratio = 1.64 [95% CI: 0.60-4.51]). CONCLUSION: Overall, the study suggests an increased risk of NAION associated with PDE5i use. Patients and health-care providers should continue to weigh the risks and benefits of PDE5i use, including the potential for NAION.

The prevalence, burden, and treatment of urinary incontinence among women in a managed care plan.

OBJECTIVE: Urinary incontinence (UI) symptoms are common among women, yet only a small proportion of women with incontinence receive a diagnosis and treatment. We used survey and utilization data to determine the prevalence, burden, and treatment use for incontinence among women at Kaiser Permanente in Northern California. METHODS: In 2002, we surveyed 6726 female health plan members about health issues, including incontinence. We assessed type and bothersomeness of incontinence symptoms in the previous 7 days. For survey respondents and a 10% sample of female plan members (n = 108,825), we assessed use from 1997 to 2003. RESULTS: The survey response rate was 49.7% (3344 of 6726); 44% of respondents reported incontinence symptoms in the previous 7 days, with over half of these women reporting that these symptoms bothered them. Fifteen percent of women with incontinence symptoms had a diagnosis consistent with incontinence in the previous 5 years. One third of the women reporting current bothersome incontinence and 14 or more incontinence episodes in the last 7 days had a diagnosis consistent with incontinence in the previous 5 years. Among women who had received medical or surgical treatment for incontinence in the previous 5 years, approximately half currently report being bothered by their symptoms. CONCLUSIONS: Prevalence of bothersome incontinence symptoms among females in a prepaid health plan is high. However, only a small proportion of these women received a diagnosis or treatment for incontinence symptoms in the last 5 years. Efforts to improve the detection and treatment of bothersome incontinence symptoms are needed.

The direct cost of stress urinary incontinence among women in a Medicaid population.

OBJECTIVE: To describe health care utilization and costs for women diagnosed with stress urinary incontinence in a Medicaid population. STUDY DESIGN: We utilized a pooled database of claims for women enrolled in Medicaid in 1 of 3 states. Health care utilization and costs were compared for 12 months before and 12 months after a woman's urinary incontinence diagnosis. Additional analyses utilized data from a fourth state. RESULTS: Of 13,672 women with diagnosed stress urinary incontinence, average urinary incontinence-related costs were approximately 800 dollars in the 12-month study period, less than 0.1% of total Medicaid spending. Thirteen percent of women underwent a surgery for stress urinary incontinence in the study period, with sling procedures performed most commonly. CONCLUSION: Although population prevalence estimates of any stress urinary incontinence symptoms often are high, diagnosis and health care utilization in the Medicaid population is low. Overall costs of stress urinary incontinence treatment in Medicaid currently are minimal. Further efforts to understand the appropriate detection, diagnosis, and treatment of women with stress urinary incontinence are needed.

Impact of duloxetine on quality of life for women with symptoms of urinary incontinence.

The objective of this study was to evaluate the effectiveness of duloxetine in improving quality of life among women with stress and mixed urinary incontinence. The study included 451 women with self-reported stress incontinence episodes (>or=1/week) who were randomized to duloxetine (40 mg BID) or placebo in a double-blind, usual care design. Patients and physicians were allowed to titrate, augment, and/or discontinue treatment. Concomitant treatments were permitted. The primary outcome was the Incontinence Quality of Life Questionnaire (I-QOL) score, with assessments at 3, 6, and 9 months. Other measures included the Patient Global Impression of Improvement (PGI-I) and adverse events. The adjusted mean change in I-QOL total score was greater in the duloxetine group than in the placebo group and at a level comparable to that found in previous clinical trials, but the difference between placebo and duloxetine was not statistically significant in the intent-to-treat, last observation carried forward (LOCF) analysis. The difference approached statistical significance in favor of duloxetine at 3 months (p=0.07). PGI-I ratings did not demonstrate significant superiority for duloxetine in LOCF analysis; however, study completers taking duloxetine were significantly more likely to rate themselves as "better" (70.2%) than completers taking placebo (50.8%, p<0.05). Women utilized a variety of treatment methods including pelvic floor muscle training, estrogen, anticholinergic medication, weight reduction, and smoking cessation. In this study, while mean I-QOL change scores were numerically higher for the duloxetine group than mean change scores for the placebo group, this difference was not statistically significant. Among women who completed the study on study drug, a significantly greater proportion of duloxetine women versus placebo women rated their condition to be better.

The impact of international medical graduate status on primary care physicians' choice of specialist.

BACKGROUND: Approximately one fourth of practicing physicians in the United States graduated from medical schools in other countries. It is unknown how the role of international medical graduate status affects physician decision-making. OBJECTIVE: The objective of this study was to determine whether a primary care physicians' knowledge of a specialist's international medical graduate status affects his or her decision to refer patients to that specialist. RESEARCH DESIGN AND SUBJECTS: We studied a national, cross-sectional study of primary care physicians who see adult patients. The sample was drawn from the American Medical Association Physician's Professional Data. Each physician received 2 clinical case vignettes describing a patient for whom referral to a specialist was considered necessary. Each vignette was followed by 5 vignette specialist descriptions with medical school graduate status varied randomly alongside other physician characteristics. MEASURE: We measured the decision to refer to an international versus U.S. medical graduate specialist. RESULTS: Of 1054 eligible physicians, 623 (59.1%) responded. Respondents were significantly more likely to refer to a U.S. medical graduate (USMG) compared with an international medical graduate (IMG) (63% vs. 54%, P <0.05). After adjustment for age, race, sex, and referral characteristics of the vignette specialists, a positive referral decision was noted in a higher proportion of vignettes in which the vignette specialist was described as a USMG versus an IMG (63% vs. 51%, P <0.05). CONCLUSION: With other factors being equal, vignette specialists described as IMGs versus USMGs were significantly less likely to be associated with a positive referral decision. Although specialist IMG status, relative to other factors, might not have a major effect on referral decisions, it is possible that negative views of international medical graduates could lead to suboptimal choices in referral decisions. Potentially, a patient could be referred to an USMG who happens to have inferior clinical skills than an IMG with superior clinical skills.

Referral of patients to specialists: factors affecting choice of specialist by primary care physicians.

BACKGROUND: We wanted to determine the importance of factors in primary care physicians' choice of specialist when referring patients and to compare importance ratings by physicians' race and sex. METHODS: Using a cross-sectional study design, we surveyed a stratified national sample of 1,252 primary care physicians serving adults to include equal numbers of black women, white women, black men, and white men. We assessed the percentage of physicians rating each of 17 items to be of major importance in choosing a specialist and compared importance ratings by physicians' race and sex. RESULTS: The response rate was 59.1%. Medical skill, appointment timeliness, insurance coverage, previous experience with the specialist, quality of specialist communication, specialist efforts to return patient to primary physician for care, and the likelihood of good patient-specialist rapport were of major importance to most respondents. Compared with black physicians, white physicians were more likely to rate previous experience with the specialist (65% vs 55%, P = .05) and board certification (41% vs 29%, P < .05) to be of major importance. White physicians were somewhat less likely than black physicians (17% vs 26%, P = .06) to rate patient convenience to be of major importance. Compared with male physicians, female physicians were more likely to rate the patient's insurance status to be of major importance (60% vs 44%, P < .01). CONCLUSIONS: Primary care physicians serving adults consider several factors to be of major importance when choosing a specialist. The importance of patient convenience, previous experience with the specialist, specialist board certification, and insurance coverage accepted by specialist varied by physicians' race and sex. A better understanding of factors important to a diverse physician workforce may help to improve the referral process.

Healthcare utilization among women who undergo surgery for stress urinary incontinence.

This study examined patterns of care for women undergoing surgery for stress urinary incontinence (SUI). A retrospective analysis of administrative claims data was performed and we identified 12520 women with a diagnosis of SUI and a subset of 3735 women with a surgical procedure code for SUI. For the main types of surgeries, we examined length of stay, pharmaceutical use, complications, and healthcare utilization related to incontinence greater than 6 months after surgery. Approximately 30% of women with a coded SUI diagnosis underwent surgery. Of the initial procedures, 40% were retropubic suspensions and 25% were sling procedures. Almost 4% of women underwent an additional surgery, and 14.1% had claims related to incontinence 6 or more months after the initial procedure. We examined medical care and pharmaceutical use for women undergoing continence surgery. This information may be important to patients and physicians discussing treatment options.

Medical and self-care practices reported by women with urinary incontinence.

OBJECTIVES: To determine the extent to which women with incontinence have been identified by physicians, the coping and treatment strategies that incontinent women use, and the factors associated with treatment strategy utilization. STUDY DESIGN: A 2-stage, nationwide, cross-sectional survey. METHODS: Survey participants were adult women from representative US households in NFO WorldGroup survey panels. Of 2310 incontinent women who received the second-stage detailed questionnaire, 1970 (85%) responded. Descriptive analyses were performed to determine the impact of incontinence, the proportion of respondents who had talked to a physician about incontinence, the responses of physicians to these incontinent women, and coping strategies used. We conducted logistic regressions to determine factors associated with treatment strategy utilization. RESULTS: Almost half of incontinent women considered their incontinence moderately to extremely bothersome, yet only 56% of the moderately to extremely bothered women had ever talked to a physician about incontinence. In 85% of all cases, the incontinent woman, rather than the physician, raised the issue of incontinence. Coping strategies women reported ever trying included limiting fluid intake (38%) and physical activity (21%). Kegel exercises and prescription medications were used currently by 20% and 6% of this population, respectively. CONCLUSIONS: Among women of all ages, only about half of women bothered by incontinence have ever talked to a physician about it, and many incontinent women rely on strategies to avoid or conceal incontinence. A better understanding of the current use of coping and treatment strategies as well as the interaction between women and physicians regarding incontinence may help to inform efforts to optimize management of incontinence for women bothered by incontinence symptoms.

A retrospective claims analysis of the direct costs of stress urinary incontinence.

The aim of this study was to evaluate direct expenditures associated with urinary incontinence and overall medical expenditures incurred by women diagnosed with stress urinary incontinence (SUI). The study design was a retrospective analysis of administrative claims data. We identified women with a diagnosis of SUI and no stress, urge or mixed urinary incontinence in the preceding 12 months using the MarketScan 1996-1999 databases. Total expenditures, as well as urinary incontinence-related expenditures, were summarized during the 12 months before and after the initial SUI diagnosis. We also compared expenditures for SUI patients receiving surgical treatment to expenditures for those who did not. There were 8126 patients who met the eligibility criteria. Total healthcare expenditures in the year prior to the initial SUI diagnosis were approximately half of those in the year following the initial diagnosis ($4478 vs $9147). For the subset of patients treated with surgery there was a threefold increase ($4575 vs $14129) in costs. A sensitivity analysis in patients with no comorbid urinary diagnoses found somewhat lower costs but a similar rate of increase in costs between the pre-period and the study period ($3884 vs $7075). Among women with no comorbid urinary diagnoses, approximately 11% ($769; SD $1180) of total mean regression-adjusted annual expenditures ($6892; SD $5067) was attributable to UI. Predicted total expenditures for surgery patients without comorbid urinary diagnoses were $13 212 (SD $7967), 28% of which ($3640;SD $681) were for UI-related costs. We concluded that after diagnosis, annual expenditures for patients were roughly twice those in the year prior to diagnosis. Multivariate analysis suggests that in the year after SUI diagnosis, UI treatment costs represented approximately 10% of total expenditures for all SUI patients, and 26%-28% of total expenditures for the subset of surgically treated patients.

Burden of stress urinary incontinence for community-dwelling women.

OBJECTIVE: The purpose of this study was to better understand the subjective bothersomeness of stress urinary incontinence symptoms and their impact on the quality of life of community-dwelling women. STUDY DESIGN: We conducted a mail survey of 605 women in the United States who reported symptoms of stress urinary incontinence. RESULTS: More than three fourths of the respondents reported their symptoms to be bothersome, with approximately 29% reporting their symptoms to be moderately to extremely bothersome. The odds of moderate-to-extreme bother decreased with age and increased with symptom severity. Concerns about social embarrassment were evident. CONCLUSION: Stress urinary incontinence symptoms can impose a significant burden on the women who have them. The results reinforce the need for health care professionals to be proactive in questioning and educating patients about this common lower urinary tract symptom.

Factors associated with women's decisions to seek treatment for urinary incontinence.

BACKGROUND: Urinary incontinence is a highly prevalent and burdensome condition among women. However, fewer than half of women with symptoms talk to a physician about incontinence, and the determinants of treatment seeking are not well understood. DESIGN: A two-stage cross-sectional survey of adult U.S. women; 45,000 households participating in NFO Worldgroup survey research received a questionnaire to identify adults with incontinence. Based on stratified random sampling of identified incontinent women, 2310 women received a detailed questionnaire. RESULTS: Among 1970 women with urinary incontinence symptoms, 38% had initiated a conversation with a physician about incontinence. In multivariate logistic regression analysis, some of the factors associated significantly with treatment seeking were symptom duration >3 years (OR 2.33, 95% CI 1.57-3.45), having a history of a noticeable accident (OR 1.41, 95% CI 1.06-1.87), worse disease-specific quality of life scores (OR 1.89, 95% CI 1.32-2.70), not being embarrassed to talk with a physician about urinary symptoms (OR 1.65, 95% CI 1.28-2.14), talking with others about urinary incontinence (OR 3.34, 95% CI 2.49-4.49), and keeping regular appointments for routine/preventive care (OR 2.25, 95% CI 1.54-3.29). CONCLUSIONS: Less than half of community-dwelling adult U.S. women with symptoms of urinary incontinence have talked with a physician about urinary incontinence. In addition to duration of symptoms, factors associated with treatment seeking included the impact of incontinence on quality of life, lack of embarrassment about talking to a physician about urinary symptoms, and attitudes toward healthcare use. Concerns about the meaning of incontinence for overall and future health were important reasons for women choosing to seek treatment.

The timing of specialist evaluation in chronic kidney disease and mortality.

BACKGROUND: Care for chronic renal failure involves management of complications and preparation for possible dialysis. Patients often are not evaluated by nephrologists in a timely manner. OBJECTIVE: To identify factors associated with late evaluation by a nephrologist and to assess whether late evaluation is associated with worse survival once patients develop end-stage renal disease (ESRD). DESIGN: National prospective cohort study. SETTING: 81 dialysis facilities throughout the United States. PATIENTS: 828 patients with new-onset ESRD. MEASUREMENTS: Time from first evaluation by a nephrologist to initiation of dialysis, classified as late (<4 months), intermediate (4 to 12 months), or early (>12 months); rate of death, from initiation of dialysis to an average of 2.2 years of follow-up; and demographic, clinical, and laboratory characteristics. RESULTS: After adjustment for potential confounders, late evaluation was more common among black men than white men (44.8% vs. 24.5%; P < 0.05), uninsured patients than insured patients (56.7% vs. 29.0%; P < 0.05) and patients with severe comorbid disease than those with mild comorbid disease (35.0% vs. 23.0%; P < 0.05). Compared with patients who had early evaluation, the risk for death was greater among patients evaluated late and was graded (hazard ratio, 1.3 [95% CI, 0.87 to 2.06] for patients with intermediate evaluation and 1.8 [CI, 1.21 to 2.61] for those with late evaluation) after adjustment for dialysis method, demographic characteristics, and socioeconomic status in Cox proportional hazards regression analysis. After additional adjustment for such factors as the presence and severity of comorbid conditions, the association remained graded (hazard ratio, 1.2 [CI, 0.73 to 1.82] for patients evaluated at an intermediate point and 1.6 [CI, 1.04 to 2.39] for those evaluated late). CONCLUSIONS: Late evaluation of patients with chronic renal failure by a nephrologist is associated with greater burden and severity of comorbid disease, black ethnicity, lack of health insurance, and shorter duration of survival.