Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Safety and tolerability of cariprazine for the adjunctive treatment of major depressive disorder: a pooled analysis of phase 2b/phase 3 clinical trials.

To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d [approved doses for MDD]). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.

Cariprazine for the Adjunctive Treatment of Major Depressive Disorder in Patients With Inadequate Response to Antidepressant Therapy: Results of a Randomized, Double-Blind, Placebo-Controlled Study.

Objective: To assess the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive treatment for patients with major depressive disorder (MDD) and inadequate response to ongoing antidepressant therapy (ADT).Methods: This randomized, double-blind, placebo-controlled study was conducted from November 2018 to September 2021. Adults with MDD per DSM-5 criteria were randomized (1:1:1) to cariprazine 1.5 mg/d or 3 mg/d plus ADT, or placebo plus ADT. The primary and secondary endpoints were change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively.Results: A total of 249 placebo-, 250 cariprazine 1.5 mg/d-, and 251 cariprazine 3 mg/d-treated patients were included in the modified intent-to-treat population. At week 6, the least squares mean change in MADRS total score was -13.8 for cariprazine 1.5 mg/d, -14.8 for cariprazine 3 mg/d, and -13.4 for placebo; differences versus placebo were not statistically significant. Mean change from baseline in CGI-S scores at week 6 was not significant for cariprazine versus placebo, although a trend toward significance was observed for 3 mg/d (P = .0573 [not adjusted for multiplicity]). Common treatment-emergent adverse events (≥ 5% either cariprazine group and twice placebo) were akathisia and insomnia.Conclusions: There were no statistically significant differences for cariprazine 1.5 or 3 mg/d versus placebo on the primary or secondary outcomes. Cariprazine was generally well tolerated, and no new safety concerns were detected.Clinical Trials Registration: ClinicalTrials.gov identifier NCT03739203.

Adjunctive Cariprazine for the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

OBJECTIVE: The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy. METHODS: In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons. RESULTS: The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea. CONCLUSIONS: Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.

A pooled post hoc analysis evaluating the safety and tolerability of cariprazine in bipolar depression.

BACKGROUND: The safety and efficacy of cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was evaluated in 4 randomized, double-blind, placebo-controlled trials in patients with bipolar depression. METHODS: Safety and tolerability were evaluated in 2 post hoc analyses. Modal dose analysis: pooled data from all 4 flexible/fixed-dose trials (dose groups: <1.5, 1.5, 3 mg/d). Fixed-dose analysis: pooled data from 2 identically designed fixed-dose trials (1.5 and 3 mg/d dose groups). RESULTS: The modal dose and fixed-dose analyses evaluated data from 1775 and 970 patients, respectively. Cariprazine was generally safe and well tolerated; study completion rates were 78% and 82% in the modal dose and fixed-dose analyses, respectively. In modal dose analysis, treatment-emergent adverse events (TEAEs) occurred in 60% of overall cariprazine- and 55% of placebo-treated patients; nausea (8% vs 3%) and akathisia (7% vs 2%) occurred in ≥5% of cariprazine patients and twice the rate of placebo. Metabolic changes were small and generally similar for cariprazine and placebo; mean increase in glucose was 3.1 mg/dL for cariprazine and 2.6 mg/dL for placebo. Fixed-dose and modal dose findings were generally consistent; values for most metabolic parameters were slightly higher for fixed-dose 3 mg/d versus 1.5 mg/d. LIMITATIONS: Post hoc analyses, modal dose groups, short treatment duration. CONCLUSIONS: In modal dose (0.25-3 mg/d) and fixed-dose (1.5 and 3 mg/d) analyses, cariprazine was generally safe and well tolerated in the treatment of bipolar depression. Slightly improved tolerability was observed with fixed-dose cariprazine 1.5 mg/d versus 3 mg/d. TRIAL REGISTRATION: clinicaltrials.gov NCT00852202, NCT01396447, NCT02670538, NCT02670551.

Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538). METHODS: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored. RESULTS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups. CONCLUSIONS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Randomized Trial of Ceftazidime-Avibactam vs Meropenem for Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia (REPROVE): Analyses per US FDA-Specified End Points.

BACKGROUND: Hospital-acquired and ventilator-associated pneumonia (HAP/VAP; nosocomial pneumonia) due to Gram-negative pathogens are associated with significant morbidity and mortality; treatment options for multidrug-resistant infections are limited. The pivotal phase III REPROVE trial evaluated the efficacy of ceftazidime-avibactam (CAZ-AVI) vs meropenem in the treatment of patients with HAP/VAP. Study results for prespecified analyses per US Food and Drug Administration-recommended trial end points are reported here. METHODS: Hospitalized adults with HAP/VAP proven or suspected to be caused by a Gram-negative pathogen were randomized 1:1 to receive CAZ-AVI or meropenem for 7 to 14 days. The primary outcome was 28-day all-cause mortality in the intent-to-treat (ITT) population. Secondary outcomes included clinical cure at test of cure (TOC) in the ITT and microbiological ITT (micro-ITT) populations, and safety and tolerability throughout the study. RESULTS: hundred seventy randomized patients received treatment and were included in the ITT population (CAZ-AVI, n = 436; meropenem, n = 434). CAZ-AVI was noninferior to meropenem for the primary end point (28-day all-cause mortality; ITT) based on the prespecified 10% noninferiority margin (CAZ-AVI, 9.6%; meropenem, 8.3%; difference, 1.5%; 95% confidence interval [CI], -2.4% to 5.3%) and for the clinical cure end point in the ITT population based on a prespecified -10% noninferiority margin (CAZ-AVI, 67.2%; meropenem, 69.1%; difference, -1.9%; 95% CI, -8.1% to 4.3%). Clinical cure rates at TOC for patients infected with CAZ-nonsusceptible pathogens were similar (CAZ-AVI, 75.5%; meropenem, 71.2%; micro-ITT). Safety data were consistent with established safety profiles for both agents. CONCLUSIONS: CAZ-AVI provides an important new treatment option for HAP/VAP due to Gram-negative pathogens, including CAZ-nonsusceptible strains.

Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study.

OBJECTIVE: Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression. METHODS: In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity. RESULTS: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups. CONCLUSIONS: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

Effect of Roflumilast and Inhaled Corticosteroid/Long-Acting ß2-Agonist on Chronic Obstructive Pulmonary Disease Exacerbations (RE(2)SPOND). A Randomized Clinical Trial.

RATIONALE: Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease. OBJECTIVES: To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting ß2-agonist with or without a long-acting muscarinic antagonist (LAMA). METHODS: In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting ß2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 µg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use. MEASUREMENTS AND MAIN RESULTS: Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants. CONCLUSIONS: Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

Preference, satisfaction and critical errors with Genuair and Breezhaler inhalers in patients with COPD: a randomised, cross-over, multicentre study.

BACKGROUND: The specific attributes of inhaler devices can influence patient use, satisfaction and treatment compliance, and may ultimately impact on clinical outcomes in patients with chronic obstructive pulmonary disease (COPD). AIMS: To assess patient preference, satisfaction and critical inhaler technique errors with Genuair (a multidose inhaler) and Breezhaler (a single-dose inhaler) after 2 weeks of daily use. METHODS: Patients with COPD and moderate to severe airflow obstruction were randomised in a cross-over, open-label, multicentre study to consecutive once-daily inhalations of placebo via Genuair and Breezhaler, in addition to current COPD medication. The primary end point was the proportion of patients who preferred Genuair versus Breezhaler after 2 weeks (Patient Satisfaction and Preference Questionnaire). Other end points included overall satisfaction and correct use of the inhalers after 2 weeks, and willingness to continue with each device. RESULTS: Of the 128 patients enrolled, 127 were included in the safety population (male n=91; mean age 67.6 years). Of the 110 of the 123 patients in the intent-to-treat population who indicated an inhaler preference, statistically significantly more patients preferred Genuair than Breezhaler (72.7 vs. 27.3%; P<0.001). Mean overall satisfaction scores were also greater for Genuair than for Breezhaler (5.9 vs. 5.3, respectively; P<0.001). After 2 weeks, there was no statistically significant difference in the number of patients who made ⩾1 critical inhaler technique error with Breezhaler than with Genuair (7.3 vs. 3.3%, respectively). CONCLUSIONS: Patient overall preference and satisfaction was significantly higher with Genuair compared with Breezhaler. The proportion of patients making critical inhaler technique errors was low with Genuair and Breezhaler.

ACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patients.

BACKGROUND AND OBJECTIVES: Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 µg in patients with moderate-to-severe COPD. METHODS: In this double-blind study, 544 patients with COPD were randomized to placebo or twice-daily aclidinium 200 or 400 µg administered by Genuair(®)/Pressair(®). Lung function, health status [measured by the St. George's Respiratory Questionnaire (SGRQ)], dyspnea [measured using the Transition Dyspnea Index (TDI)], and safety were assessed throughout the study. RESULTS: Mean changes from baseline in morning trough forced expiratory volume in 1 s (FEV(1)) at week 12 (primary endpoint) were significantly higher for aclidinium than for placebo (200 µg, 51 mL; 400 µg, 72 mL; both p < 0.05). Aclidinium also significantly improved other lung function outcomes. At week 12, improvements from baseline were observed with aclidinium in SGRQ total score (200 µg, -6.0; 400 µg, -5.4) and TDI focal score (200 µg, 1.0; 400 µg, 1.3). Furthermore, clinically important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients, respectively, who received aclidinium 400 µg, with a significant difference versus placebo for TDI (p < 0.05). Anticholinergic-related adverse events (e.g., dry mouth) were infrequent, occurring <2 % for any event in any treatment group. Both aclidinium doses were well tolerated. CONCLUSION: This study demonstrates efficacy and safety of aclidinium in COPD patients. Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study.

Preference, satisfaction and errors with two dry powder inhalers in patients with COPD.

OBJECTIVE: To assess preference, satisfaction and critical errors with a novel, breath-actuated, multi-dose dry powder inhaler (DPI; Genuair®/Pressair™), versus a widely used, single-dose DPI (HandiHaler®) in patients with moderate-to-severe chronic obstructive pulmonary disease. METHODS: In this randomised, open-label, multicentre, cross-over study, patients (aged ≥ 40 years) inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication. The primary end point was percentage of patients who preferred Genuair to HandiHaler. Overall patient satisfaction (5-point scale: 1 = very dissatisfied; 5 = very satisfied), critical errors and willingness to continue using each inhaler (0 = not willing; 100 = definitely willing) were assessed. RESULTS: Of 130 patients randomised, 105 were included in the intent-to-treat population (71.4% male; mean age 65.7 years). After 2 weeks, significantly more patients preferred Genuair than HandiHaler (79.1 vs 20.9%; p < 0.0001). Overall satisfaction scores (4.6 vs 3.8; p < 0.0001) and willingness to continue use scores (84.0 vs 62.5; p < 0.0001) were significantly higher with Genuair versus HandiHaler. Significantly fewer patients made ≥ 1 critical error with Genuair only compared with HandiHaler only (2.9 vs 19.0%; p < 0.0001). CONCLUSION: After 2 weeks' practice, patients preferred and were more willing to continue using Genuair than HandiHaler. Genuair was associated with higher patient satisfaction and fewer critical errors than HandiHaler.

Evaluation of the effect of a supratherapeutic dose of intravenous ceftaroline fosamil on the corrected QT interval.

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, crossover study with tolterodine and darifenacin in healthy participants > or = 50 years.

Antimuscarinics, used commonly to treat overactive bladder, may differ in their potential to increase heart rate via effects on cardiac muscarinic M2 receptors. This prospective, 3-way crossover, randomized, double-blind study assessed the heart rate effects of 7 days' exposure to a nonselective M2/M3 receptor blocker (tolterodine; 4 mg/d), a highly selective M3 receptor blocker (darifenacin; 15 mg/d), and placebo in 162 healthy participants > or = 50 years. Heart rate was measured by 24-hour Holter monitoring. Tolterodine significantly increased heart rate versus darifenacin and heart rate versus placebo, while darifenacin did not affect heart rate versus placebo. The proportion of participants with an increase in mean heart rate per 24 hours of > or =5 beats per minute was higher with tolterodine than with darifenacin (P = .0004) or with placebo (P = .0114) but did not differ between darifenacin and placebo. The results show that antimuscarinics exert differential effects on heart rate depending on their muscarinic receptor profile. This should be considered when selecting a treatment.

Differential effects of the antimuscarinic agents darifenacin and oxybutynin ER on memory in older subjects.

OBJECTIVES: To investigate the effects of darifenacin controlled-release (CR) and oxybutynin extended-release (ER) on cognitive function (particularly memory) in older subjects. METHODS: Healthy subjects (n=150) >/=60 years were randomised to darifenacin, oxybutynin ER or placebo in a multicentre, double-blind, double-dummy, parallel-group, 3-week study. Doses were administered according to US labels: oxybutynin ER 10mg once daily (od), increasing to 15mg od then 20mg od by week 3; darifenacin 7.5mg od in weeks 1 and 2, then 15mg od in week 3. The primary end point was accuracy on the Name-Face Association Test (delayed recall) at week 3. RESULTS: Results of the Name-Face Association Test at week 3 showed no significant difference between darifenacin and placebo on delayed recall (mean difference, -0.06, p=0.908). In contrast, oxybutynin ER resulted in memory impairment, with significantly lower scores than placebo and darifenacin (mean differences, -1.30, p=0.011 and -1.24, p=0.022, respectively) for delayed recall on the Name-Face Association Test at week 3. Additional tests of delayed recall indicated significant memory impairment with oxybutynin ER versus placebo at certain time points, whereas darifenacin was similar to placebo. No between-treatment differences were detected in self-rated memory, demonstrating that subjects were unaware of memory deterioration. CONCLUSIONS: While darifenacin had no significant effects on memory versus placebo, oxybutynin ER caused significant memory deterioration (magnitude of effect comparable to brain aging of 10 years). The results also demonstrate that subjects may not recognise/report memory deterioration.