Lasmiditan for Patients with Migraine and Contraindications to Triptans: A Post Hoc Analysis.

INTRODUCTION: As 5-HT1B receptor agonists, triptans produce vasoconstriction and have cardiovascular contraindications and precautions. Lasmiditan, a selective 5-HT1F receptor agonist, has a low affinity for 5-HT1B receptors, does not cause vasoconstriction, and is free of cardiovascular contraindications and precautions. The objective of this post hoc analysis was to evaluate the efficacy and safety of lasmiditan in patients with and without at least one triptan contraindication. METHODS: Patient subgroups, with and without triptan contraindications, were analyzed from pooled patient data from four randomized, double-blind, placebo-controlled clinical trials (SAMURAI, SPARTAN, CENTURION, and MONONOFU). Patients experiencing a single migraine attack of moderate or severe intensity were treated with lasmiditan 50 mg (SPARTAN and MONONOFU only), 100 mg, 200 mg, or placebo, and efficacy data were recorded in an electronic diary. RESULTS: Of 5704 patients, 207 (3.6%) patients had at least one contraindication to triptans. Overall subgroup analysis revealed that the effects of lasmiditan on pain freedom, pain relief, freedom from most bothersome symptom, disability freedom, and Patient Global Impression of Change at 2 h post-dose did not differ in patient groups with and without triptan contraindications. These outcomes generally showed a similar benefit pattern for lasmiditan in both subgroups, with all results being statistically significant in patients without contraindications, and pain relief being statistically significant in patients with contraindications. The safety and tolerability profiles of patients with triptan versus without triptan contraindications were similar, including dizziness in 18.3 to 22.8% and somnolence in 7.9 to 9.9% of patients at the highest dose of lasmiditan. CONCLUSIONS: In pooled analyses from four trials, patients with and without triptan contraindications did not differ in their patterns of lasmiditan efficacy. Lasmiditan may be a treatment option in patients with contraindications to triptans. TRIAL REGISTRATION NUMBERS: SAMURAI, NCT:02439320; SPARTAN, NCT:02605174; CENTURION, NCT:03670810; and MONONOFU, NCT:03962738.

Migraine history and response to lasmiditan across racial and ethnic groups.

OBJECTIVE: The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT1F) receptor agonist, in racial and ethnic subgroups. METHODS: Descriptive data from racial (White [W](n = 3471) and Black or African American [AA](n = 792)) and ethnic (Hispanic or Latinx [HL](n = 775) and Non-Hispanic or Latinx [Non-HL](n = 3637)) populations are presented on pooled data from two double-blind, placebo-controlled, randomized Phase 3 studies (SAMURAI [NCT02439320] and SPARTAN [NCT2605174]). Patients were treated with lasmiditan (50 (SPARTAN only), 100, or 200 mg) or placebo for a single migraine attack of moderate-to-severe intensity. Efficacy data were recorded in an electronic diary at baseline, 30, 60, 90, and 120 min. Safety was evaluated and reported by occurrences of adverse events. RESULTS: Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes. CONCLUSIONS: There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

A close association of freedom from pain, migraine-related functional disability, and other outcomes: results of a post hoc analysis of randomized lasmiditan studies SAMURAI and SPARTAN.

BACKGROUND: While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing. METHODS: Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom. RESULTS: Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time. CONCLUSIONS: This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint. TRIAL REGISTRATION: SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 ).

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

PURPOSE: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population. METHODS: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing). FINDINGS: Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period. IMPLICATIONS: The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain.

OBJECTIVE: To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. METHODS: Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. RESULTS: In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. CONCLUSIONS: Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Lasmiditan in patients with common migraine comorbidities: a post hoc efficacy and safety analysis of two phase 3 randomized clinical trials.

OBJECTIVE: Determine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT1F receptor agonist approved in the United States for the acute treatment of migraine. METHODS: In SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). RESULTS: Across all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments. CONCLUSIONS: The efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

Method of Blood Pressure Measurement in Neonates and Infants: A Systematic Review and Analysis.

OBJECTIVES: To determine the recommended blood pressure (BP) measurement methods in neonates after systematically analyzing the literature regarding proper BP cuff size and measurement location and method. STUDY DESIGN: A literature search was conducted in MEDLINE, PubMed, Embase, Cochrane Library, and CINAHL from 1946 to 2017 on BP in neonates <3 months of age (PROSPERO ID CRD42018092886). Study data were extracted and analyzed with separate analysis of Bland-Altman studies comparing measurement methods. RESULTS: Of 3587 nonduplicate publications identified, 34 were appropriate for inclusion in the analysis. Four studies evaluating BP cuff size support a recommendation for a cuff width to arm circumference ratio of approximately 0.5. Studies investigating measurement location identified the upper arm as the most accurate and least variable location for oscillometric BP measurement. Analysis of studies using Bland-Altman methods for comparison of intra-arterial to oscillometric BP measurement show that the 2 methods correlate best for mean arterial pressure, whereas systolic BP by the oscillometric method tends to overestimate intra-arterial systolic BP. Compared with intra-arterial methods, systolic BP, diastolic BP, and mean arterial pressure by oscillometric methods are less accurate and precise, especially in neonates with a mean arterial pressure <30 mm Hg. CONCLUSIONS: Proper BP measurement is critical in neonates with naturally lower BP and attention to BP cuff size, location, and method of measurement are essential. With decreasing use of intra-arterial catheters for long-term BP monitoring in neonates, further studies are urgently needed to validate and develop oscillometric methodology with enhanced accuracy.

Treatment satisfaction of men and partners following switch from on-demand phosphodiesterase type 5 inhibitor therapy to tadalafil 5 mg once daily.

INTRODUCTION: Treatment satisfaction of men receiving phosphodiesterase 5 inhibitors (PDE5) for erectile dysfunction (ED) and their partners is essential to successful long-term therapy. AIM: This study aims to assess treatment satisfaction, in men with a partial response to on-demand (PRN) PDE5 and their female partners, following tadalafil 5 mg once daily or placebo. METHODS: The study was randomized, double-blind, parallel, and placebo-controlled in men primarily with mild to moderate ED. Treatment satisfaction was assessed following a 4-week maximum dose PRN lead-in, 4-week nondrug washout, and treatment through 12 weeks. Men were ≥18 years old with ED for ≥3 months and International Index of Erectile Function Erectile Function score of ≥17 and <26 at screening and <26 following PRN lead-in. MAIN OUTCOME MEASURES: Treatment satisfaction was assessed using the Treatment Satisfaction Scale (TSS) for patients and partners. TSS domain scores range from 0 to 100, with higher values indicating greater satisfaction. Statistical comparisons were made using analysis of covariance. RESULTS: Treatment satisfaction was significantly greater with tadalafil once daily vs. placebo across all TSS domains for both patients and their partners (all P < 0.001). For patients, mean scores for the TSS domains Confidence to Complete Sexual Activity and Satisfaction with Orgasm ranged from 53.7 to 57.8 after the PRN lead-in and 26.7 to 31.9 following the nondrug washout. Following randomized treatment, scores for tadalafil and placebo were 55.4 and 32.6, respectively, for Confidence to Complete Sexual Activity and 57.5 and 37.9, respectively, for Satisfaction with Orgasm. Results were comparable for other TSS domains and between men and their partners. CONCLUSIONS: Treatment satisfaction was comparable for tadalafil 5 mg once daily and PRN PDE5 for both patients and female partners, suggesting that tadalafil once daily is a viable therapy option for men with ED who had a partial response to PRN PDE5 therapy.

Time to onset of clinically meaningful improvement with tadalafil 5 mg once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: analysis of data pooled from 4 pivotal, double-blind, placebo controlled studies.

PURPOSE: Tadalafil once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia consistently shows statistically significant I-PSS improvements. However, physicians and patients wish to know whether tadalafil provides rapid, clinically meaningful improvement in lower urinary tract symptoms. In this post hoc analysis we integrated results from 4 placebo controlled studies to determine the duration of tadalafil once daily required to achieve clinically meaningful improvement. MATERIALS AND METHODS: We performed post hoc analysis of data integrated from 4 double-blind studies of tadalafil 5 mg and placebo once daily in 742 and 735 men, respectively, 45 years old or older with total I-PSS 13 or greater. Two clinically meaningful improvement categories were assessed, including 1) 3-point or greater baseline to end point total I-PSS improvement and 2) 25% or greater baseline to end point total I-PSS improvement. I-PSS was assessed at weeks 4, 8 and 12 in all studies, week 1 in 2 and week 2 in 1. Results in men treated with tadalafil who showed clinically meaningful improvement (responders) were further examined to determine the earliest time to clinically meaningful improvement. RESULTS: Of 742 tadalafil treated patients 513 (69.1%) and 444 (59.8%) demonstrated category 1 and 2 clinically meaningful improvement, respectively, at the study end point. Of 234 category 1 responders with week 1 assessments 140 (59.8%) achieved clinically meaningful improvement by week 1 and 407 of the total of 513 category 1 responders (79.3%) showed it by week 4. Of the 205 category 2 responders with week 1 assessments 103 (50.2%) achieved clinically meaningful improvement by week 1 while 322 of the 444 category 2 responders (72.5%) did so by week 4. CONCLUSIONS: Tadalafil 5 mg once daily led to clinically meaningful improvement in approximately two-thirds of men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. More than half of this group of tadalafil treated responders achieved clinically meaningful improvement after 1 week of therapy and more than 70% did so within 4 weeks.

A short-term, multicenter, placebo-controlled, randomized withdrawal study of a metabotropic glutamate 2/3 receptor agonist using an electronic patient-reported outcome device in patients with schizophrenia.

This 6-week, multicenter, randomized withdrawal, placebo-controlled trial sought to determine whether symptoms of physical dependence occur after abrupt cessation of pomaglumetad methionil (LY2140023 monohydrate), a metabotropic glutamate 2/3 receptor agonist, in patients with schizophrenia. Eligible outpatients, 18 to 65 years old who required a modification or initiation of antipsychotic medication received 4 weeks of pomaglumetad methionil during open-label treatment and then were randomized, double-blind, to continue pomaglumetad methionil or receive placebo for 2 weeks. The primary outcome compared results of the 3-day moving mean of the total score on the Discontinuation Symptom Checklist-Modified Rickels for pomaglumetad methionil-treated patients with those on placebo during the randomized withdrawal phase. An electronic patient-reported outcome (ePRO) device was used daily to record these results. During the withdrawal phase, 103 patients were randomized, and 98 patients completed the trial. There was no statistically significant evidence of withdrawal symptoms associated with placebo compared with pomaglumetad methionil continuation as measured by Discontinuation Symptom Checklist-Modified Rickels (P = 0.170). The results are supported by secondary analyses with the clinician-rated, Clinical Institute Withdrawal Assessment of Alcohol Scale Revised, which showed no statistically significant differences between treatment groups. Using the ePRO device, 82.5% of the patients achieved 75% to 100% of compliance. No discontinuations due to worsening of schizophrenia, serious adverse events, deaths, or seizures were reported during either phase of the study. These findings suggest that there is no evidence of withdrawal symptoms associated with the abrupt discontinuation of pomaglumetad methionil and that an ePRO device can be successfully used in a multicenter schizophrenia trial.

Impact of low testosterone on response to treatment with tadalafil 5 mg once daily for erectile dysfunction.

OBJECTIVE: To evaluate, posthoc, the relationship between serum total testosterone and response to therapy in a study of tadalafil once daily for erectile dysfunction (ED). METHODS: Men were aged ≥18 years, with ≥3-month history of ED and partial prior response to on-demand (PRN) phosphodiesterase type 5 inhibitor (PDE5I) therapy. A 4-week maximum-dose PRN PDE5I run-in was followed by a 4-week nondrug washout period, then randomization to tadalafil 2.5 mg titrated to 5 mg or tadalafil 5 mg (pooled for analyses) or placebo once daily for 12 weeks. Analyses compared endpoint efficacy results between low- (<300 ng/dL) vs normal-testosterone (≥300 ng/dL) level subgroups. RESULTS: Improvements for tadalafil vs placebo were significant for the International Index of Erectile Function (IIEF) Erectile Function domain, Intercourse Satisfaction domain, Overall Satisfaction domain, and Question 15 (confidence in the ability to get and keep an erection; all P<.001), and for the Sexual Encounter Profile Questions 1-5 (all P≤.011). Analysis of covariance modeling identified significant treatment-by-subgroup interactions for the IIEF-Overall Satisfaction domain and erection confidence question and Sexual Encounter Profile Question 3. Comparing between tadalafil-treated testosterone subgroups, the IIEF-Erectile Function domain scores improved significantly more in men with normal vs low testosterone (P=.022); no other significant differences were identified for either placebo or tadalafil. No significant differences in pre-existing conditions were observed between tadalafil and placebo within the normal- and low-testosterone subgroups. CONCLUSION: In men with partial response to a PRN PDE5I, tadalafil 5 mg once daily significantly improved ED and sexual function vs placebo irrespective of testosterone levels.

Treatment satisfaction with tadalafil or tamsulosin vs placebo in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH): results from a randomised, placebo-controlled study.

OBJECTIVES: To assess treatment satisfaction with tadalafil or tamsulosin vs placebo in a 12-week, randomised, double-blind study of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH). PATIENTS AND METHODS: After a 4-week placebo lead-in period, men aged ≥45 years with an International Prostate Symptom Score (IPSS) of ≥13 and a maximum urinary flow rate of ≥4 to ≤15 mL/s received placebo (172 men), tadalafil 5 mg (171), or tamsulosin 0.4 mg (168) once daily for 12 weeks. Treatment Satisfaction Scale-BPH (TSS-BPH) responses were assessed based on median treatment differences using the van Elteren test. RESULTS: Overall treatment satisfaction was greater for tadalafil vs placebo (P = 0.005), based on greater satisfaction with efficacy (P = 0.003); neither overall treatment satisfaction nor satisfaction with efficacy was greater for tamsulosin vs placebo (P ≥ 0.409). For individual questions, 66.5% of men rated tadalafil treatment as 'effective/very effective' (Question 1, Q1) vs placebo (P = 0.011), 72.6% would 'definitely/probably recommend their treatment' (Q3; P = 0.043), 71.8% were generally 'very satisfied/satisfied with their medication' (Q8; P < 0.003), and 65.0% would 'definitely/probably continue therapy' (Q10; P = 0.035). With tamsulosin, differences vs placebo were not statistically significant. Subgroup analyses of overall TSS-BPH by baseline age (≤65/>65 years), history of erectile dysfunction (yes/no), LUTS/BPH severity (IPSS

Duloxetine for the treatment of stress urinary incontinence in women: an integrated analysis of safety.

OBJECTIVE: The objective was to characterize the safety of duloxetine for treatment of stress urinary incontinence (SUI) in women, using an integrated database generated from four published placebo-controlled clinical trials. METHODS: The database included 1913 women randomized to duloxetine (N=958) or placebo (N=955), examining adverse events (AEs), serious adverse events (SAEs), vital signs, electrocardiograms, and laboratory analytes. AEs occurring initially or worsening during the double-blind treatment period were considered treatment-emergent (TEAE). Differences between duloxetine-treated and placebo-treated groups were compared statistically. RESULTS: Common TEAEs included: nausea (23.2%), dry mouth (13.4%), fatigue (12.7%), insomnia (12.6%), constipation (11.0%), headache (9.7%), dizziness (9.5%), somnolence (6.8%), and diarrhea (5.1%). Most TEAEs that emerged early were mild to moderate, rarely worsened, and resolved quickly. Overall AE discontinuation rates were 20.5% for duloxetine and 3.9% for placebo (P<.001). Most discontinuations (83%) occurred within the first month of treatment. SAEs were uncommon and did not differ between treatments. Statistically significant, but clinically unimportant mean increases in heart rate (2.4 bpm) and systolic and diastolic blood pressure (

Pharmacological treatment of women awaiting surgery for stress urinary incontinence.

OBJECTIVE: Duloxetine, a serotonin/norepinephrine reuptake inhibitor, has been effective in the treatment of mild and moderate stress urinary incontinence. The aim of this trial was to assess its efficacy for women with severe stress urinary incontinence. METHODS: One hundred nine women, aged 33-75 years, enrolled into this double-blind, randomized, placebo-controlled study. Subjects had to have a predominant symptom of stress urinary incontinence with an incontinence episode frequency 14 per week or more, pure urodynamic stress urinary incontinence, and continence surgery already scheduled. Women were randomized to placebo (n = 54) or duloxetine 80 mg/d (n = 55) for 4 weeks, escalated to 120 mg/d for 4 weeks. Assessment variables included incontinence episode frequency, continence pad use, the Incontinence Quality of Life (I-QOL) questionnaire, and the Willingness to Consider Surgery rating. A responder was defined as a subject with an incontinence episode frequency reduction of 50% or more. RESULTS: There were significant improvements with duloxetine compared with placebo in incontinence episode frequency (-60% versus -27%, P <.001), I-QOL score (+10.6 versus +2.4, P =.003), and pad use (-34.5% versus -4.8%, P =.008). At the conclusion of the 8-week study, 10/49 (20%) duloxetine-treated women were no longer interested in surgery, compared with 0/45 placebo-treated women (P =.001). Duloxetine-treated subjects were significantly more likely to be classified as responders (relative risk 4.68, 95% confidence interval 2.27-9.66). The number of subjects-needed-to-treat to gain an additional incontinence episode frequency responder with duloxetine was 2.02. All duloxetine responses were observed within 2 weeks. Side effects and discontinuations because of side effects were significantly more common with duloxetine. CONCLUSION: The data support duloxetine's efficacy in women with severe stress urinary incontinence and suggest that some women responding to duloxetine may reconsider their willingness to undergo surgery.

Baseline characteristics of participants in the Raloxifene Use for The Heart (RUTH) trial.

The Raloxifene Use for The Heart (RUTH) trial is a randomized, placebo-controlled, double-blind trial designed to determine whether raloxifene 60 mg/day compared with placebo lowers the risk of coronary events (coronary death, nonfatal myocardial infarction [MI], or hospitalized acute coronary syndromes other than MI) and reduces the risk of invasive breast cancer in women at risk for a major coronary event. Raloxifene is a selective estrogen receptor modulator that improves cardiovascular risk factors, reduces the risk of vertebral fracture, and is associated with a reduced incidence of invasive breast cancer in postmenopausal women with osteoporosis. Between June 1998 and August 2000, 10,101 women were enrolled at 187 sites in 26 countries. Approximately half of the women had documented coronary heart disease (CHD) (n = 5,031); the remainder had multiple CHD risk factors that increased their risk for a CHD event (n = 5,070). The mean age of participants was 68 years (39% were >70 years old), and did not differ between those with documented CHD and those at increased CHD risk. Most women were Caucasian (84%); 60% had a body mass index >/=27 kg/m(2), 46% had diabetes mellitus, 78% had systemic hypertension, and 14% had low-density lipoprotein cholesterol >160 mg/dl. Compared with women at increased CHD risk, women with documented CHD had higher cardiovascular risk scores, a higher prevalence of abnormal electrocardiograms, greater use of cardiovascular medications, were more likely to have had cardiac rehabilitation, and were more likely to have previously used estrogen or oral contraceptives, but had a slightly lower prevalence of CHD risk factors such as smoking, obesity, diabetes mellitus, and systemic hypertension, and had lower serum levels of total and low-density lipoprotein cholesterol. The RUTH cohort is the largest group of postmenopausal women at increased risk of CHD events ever assembled in a clinical trial, and is the first trial designed to determine the effect of a selective estrogen receptor modulator on the risk of CHD events.