Publications by authors named "Carsten Henneges"

37 Publications

Dynamics of Left Ventricular Myocardial Work in Patients Hospitalized for Acute Heart Failure.

J Card Fail 2021 Jul 29. Epub 2021 Jul 29.

Comprehensive Heart Failure Center, University Hospital and University of Würzburg, Würzburg, Germany; Department of Medicine I, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Background: The left ventricular ejection fraction (LVEF) is the most commonly used measure describing pumping efficiency, but it is heavily dependent on loading conditions and therefore not well-suited to study pathophysiologic changes. The novel concept of echocardiography-derived myocardial work (MyW) overcomes this disadvantage as it is based on LV pressure-strain loops. We tracked the in-hospital changes of indices of MyW in patients admitted for acute heart failure (AHF) in relation to their recompensation status and explored the prognostic utility of MyW indices METHODS AND RESULTS: We studied 126 patients admitted for AHF (mean 73 ± 12 years, 37% female, 40% with a reduced LVEF [<40%]), providing pairs of echocardiograms obtained both on hospital admission and prior to discharge. The following MyW indices were derived: global constructive and wasted work (GCW, GWW), global work index (GWI), and global work efficiency. In patients with HF with reduced ejection fraction with decreasing N-terminal prohormone B-natriuretic peptide levels during hospitalization, the GCW and GWI improved significantly, whereas the GWW remained unchanged. In patients with HF with preserved ejection fraction, the GCW and GWI were unchanged; however, in patients with no decrease or eventual increase in N-terminal prohormone B-natriuretic peptide, we observed an increase in GWW. In all patients with AHF, higher values of GWW were associated with a higher risk of death or rehospitalization within 6 months after discharge (per 10-point increment hazard ratio 1.035, 95% confidence interval 1.005-1.065).

Conclusions: Our results suggest differential myocardial responses to decompensation and recompensation, depending on the HF phenotype in patients presenting with AHF. The GWW predicted the 6-month prognosis in these patients, regardless of LVEF. Future studies in larger cohorts need to confirm our results and identify determinants of short-term and longer term changes in MyW.
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http://dx.doi.org/10.1016/j.cardfail.2021.07.004DOI Listing
July 2021

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

Eur Heart J 2021 04;42(16):1569-1578

Comprehensive Heart Failure Center Würzburg, University and University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany.

Aims: We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years.

Methods And Results: A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with 'intensity of attention' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29).

Conclusion: In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.
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http://dx.doi.org/10.1093/eurheartj/ehab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060058PMC
April 2021

Impact of Ixekizumab Treatment on Itch and Psoriasis Area and Severity Index in Patients with Moderate-to-Severe Plaque Psoriasis: An Integrated Analysis of Two Phase III Randomized Studies.

Dermatol Ther (Heidelb) 2018 Dec 21;8(4):621-637. Epub 2018 Nov 21.

Department of Dermatology, University of Muenster, Muenster, Germany.

Introduction: We evaluated baseline itch and its impact on the efficacy of ixekizumab (IXE) in clearing psoriasis and improving quality-of-life measures, and we explored the relationship between itch and psoriatic skin improvement.

Methods: Data were analyzed from two double-blind, randomized, controlled phase III studies (UNCOVER-2/3) comparing etanercept (ETN), IXE, and placebo (PBO) in patients with moderate-to-severe plaque psoriasis. Long-term analysis included UNCOVER-3 data from week 0 to week 156.

Results: At week 12, a clinically meaningful improvement in itch [Itch Numeric Rating Scale (NRS) reduction ≥ 4] was seen in 70.0%, 88.6%, and 90.8% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively (all itch severity groups p < 0.001 versus ETN and PBO). Also, 68.9%, 67.1%, and 73.6% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively, showed an improvement of ≥ 90.0% in the Psoriatic Area and Severity Index (PASI) at week 12 as compared to the baseline (PASI 90) (all itch severity groups p < 0.001 versus ETN and PBO). For most patients, itch reduction preceded psoriatic plaque improvement. Sustained effects of IXE on itch and PASI were observed during 3 years of treatment.

Conclusions: Regardless of baseline itch severity, IXE treatment provided a rapid improvement in itch followed by clinically meaningful improvements in psoriasis.

Funding: Eli Lilly and Company.

Trial Registration: ClinicalTrials.gov identifiers, NCT01597245 and NCT01646177.
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http://dx.doi.org/10.1007/s13555-018-0267-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261114PMC
December 2018

Ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment: Results from IXORA-S, a phase 3 study.

J Am Acad Dermatol 2019 Jan 30;80(1):70-79.e3. Epub 2018 Jun 30.

Dermatologikum Berlin and Georg-August-University Göttingen, Göttingen, Germany.

Background: Biologics targeting interleukin 17A (IL-17A) allow for rapid clearance of psoriatic plaques, with a clinically favorable safety profile.

Objectives: To compare the safety and efficacy of ixekizumab, an IL-17A antagonist, with the safety and efficacy of the IL-12/23 inhibitor ustekinumab through 52 weeks of treatment in the head-to-head trial IXORA-S.

Methods: Patients were randomized to ixekizumab (n = 136) or ustekinumab (n = 166) and dosed per the approved labels. After 1 year, efficacy was assessed via improvements in Psoriasis Area and Severity Index (PASI) score (with PASI 90 indicating a 90% or greater improvement from baseline PASI score) and a static Physician's Global Assessment (sPGA) response of either 0 or 0 or 1, with dropouts counted as nonresponders. Safety analyses included treatment-emergent adverse events (AEs).

Results: At week 52, significantly more ixekizumab-treated patients (P < .01) reported PASI 90 (104 [76.5%]), an sPGA response of 0 (72 [52.9%]), or an sPGA response of 0 or 1 (110 [82.1%]) responses than did ustekinumab-treated patients (PASI 90, 98 [59.0%]; sPGA response of 0, 60 [36.1%]; and sPGA response of 0 or 1, 108 [65.1%]). Treatment-emergent AEs, serious AEs, and discontinuation rates were not different between the treatment groups. Injection site reactions occurred more frequently in the ixekizumab-treated group (ixekizumab, 22 [16.3%]; ustekinumab, 2 [1.2%]) (P < .001).

Limitations: This study was not designed to compare safety end points related to rare events.

Conclusions: Compared with ustekinumab, ixekizumab showed superior efficacy and comparable safety outcomes through 52 weeks of treatment.
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http://dx.doi.org/10.1016/j.jaad.2018.06.039DOI Listing
January 2019

Prevalence of genital psoriasis in patients with psoriasis.

J Dermatolog Treat 2018 Dec 28;29(8):754-760. Epub 2018 Mar 28.

f Baylor University Medical Center , Dallas , TX , USA.

Background: Psoriatic lesions in the genital area (GenPs) can cause considerable physical and emotional distress. To increase physician awareness, we estimated the GenPs prevalence among patients with psoriasis.

Methods: An English language literature search was performed. Articles reporting GenPs prevalence met the search criteria and were included. Because GenPs is rarely reported in demographics of prospective clinical trials, GenPs prevalence and baseline demographics of patients with and without GenPs in two prospective randomized phase 3b trials (NCT02561806 and NCT02634801) involving patients with moderate-to-severe psoriasis are reported.

Results: Overall, 600 references were screened. Eighteen articles met the search criteria. Patient populations were highly heterogeneous across articles. Broadly, the presence of GenPs was either physician-reported (physical examinations) or patient-reported (questionnaires). In the literature, GenPs prevalence at the time of reporting ranged from 7% to 42% and the prevalence of GenPs at any time during the course of psoriasis ranged from 33% to 63%. In the two prospective clinical trials, the prevalence of GenPs at the time of enrollment was 35-42%.

Conclusion: A substantial proportion of patients experience genital lesions at some time during the course of psoriasis. Increased awareness of GenPs prevalence may drive improved assessment and treatment.
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http://dx.doi.org/10.1080/09546634.2018.1453125DOI Listing
December 2018

Use of Structural Equation Modeling to Demonstrate the Differential Impact of Storage and Voiding Lower Urinary Tract Symptoms on Symptom Bother and Quality of Life during Treatment for Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia.

J Urol 2016 Sep 19;196(3):824-30. Epub 2016 Apr 19.

Department of Urology, Hannover Medical School, Hannover, Germany.

Purpose: Lower urinary tract symptoms associated with benign prostatic hyperplasia typically respond well to medical therapy. While changes in total I-PSS (International Prostate Symptom Score) are generally accepted as measurement for treatment response, I-PSS storage and voiding subscores may not accurately reflect the influence of symptom improvement on patient bother and quality of life.

Materials And Methods: Structural equation modeling was done to evaluate physiological interrelationships measured by I-PSS storage vs voiding subscore questions and measure the magnitude of effects on bother using BII (Benign Prostatic Hyperplasia Impact Index) and quality of life on I-PSS quality of life questions. Pooled data from 4 randomized, controlled trials of tadalafil and placebo in 1,462 men with lower urinary tract symptoms/benign prostatic hyperplasia were used to investigate the relationship of storage vs voiding lower urinary tract symptoms on BII and quality of life.

Results: The final structural equation model demonstrated a sufficient fit to model interdependence of storage, voiding, bother and quality of life (probability for test of close fit <0.0001). Storage aspects had a twofold greater effect on voiding vs voiding aspects on storage (0.61 vs 0.28, each p <0.0001). The direct effect of storage on bother was twofold greater than voiding on bother (0.64 vs 0.29, each p <0.0001). Bother directly impacted quality of life by the largest magnitude of (-0.83), largely driven by storage lower urinary tract symptoms (p <0.0001).

Conclusions: Total I-PSS is a reliable instrument to assess the therapeutic response in lower urinary tract symptoms/benign prostatic hyperplasia cases. However, an improvement in storage lower urinary tract symptoms is mainly responsible for improved bother and quality of life during treatment. Care should be taken when evaluating the accuracy of I-PSS subscores as indicators of the response to medical therapy.
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http://dx.doi.org/10.1016/j.juro.2016.04.062DOI Listing
September 2016

Describing the Sequence of Cognitive Decline in Alzheimer's Disease Patients: Results from an Observational Study.

J Alzheimers Dis 2016 ;52(3):1065-80

Lilly Deutschland GmbH, Bad Homburg, Germany.

Background: Improved understanding of the pattern of cognitive decline in Alzheimer's disease (AD) would be useful to assist primary care physicians in explaining AD progression to patients and caregivers.

Objective: To identify the sequence in which cognitive abilities decline in community-dwelling patients with AD.

Methods: Baseline data were analyzed from 1,495 patients diagnosed with probable AD and a Mini-Mental State Examination (MMSE) score ≤ 26 enrolled in the 18-month observational GERAS study. Proportional odds logistic regression models were applied to model MMSE subscores (orientation, registration, attention and concentration, recall, language, and drawing) and the corresponding subscores of the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), using MMSE total score as the index of disease progression. Probabilities of impairment start and full impairment were estimated at each MMSE total score level.

Results: From the estimated probabilities for each MMSE subscore as a function of the MMSE total score, the first aspect of cognition to start being impaired was recall, followed by orientation in time, attention and concentration, orientation in place, language, drawing, and registration. For full impairment in subscores, the sequence was recall, drawing, attention and concentration, orientation in time, orientation in place, registration, and language. The sequence of cognitive decline for the corresponding ADAS-cog subscores was remarkably consistent with this pattern.

Conclusion: The sequence of cognitive decline in AD can be visualized in an animation using probability estimates for key aspects of cognition. This might be useful for clinicians to set expectations on disease progression for patients and caregivers.
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http://dx.doi.org/10.3233/JAD-150852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927893PMC
July 2017

Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy--Results from a Randomized Controlled Trial (REACTT).

J Sex Med 2016 Apr 25;13(4):679-83. Epub 2016 Mar 25.

Biomedicines BU, Lilly Deutschland GmbH, Bad Homburg, Germany.

Introduction And Aim: The multicenter, randomized, double-blind, double-dummy, placebo-controlled REACTT trial suggested that treatment with tadalafil once daily (OaD) started early after bilateral nerve-sparing radical prostatectomy (nsRP) for prostate cancer may contribute to erectile function (EF)-recovery, which was predefined as achieving an International Index of Erectile Function (IIEF)-EF score ≥22. Here, we report descriptive post-hoc analyses, using the more strict definition for EF-recovery of returning back to the pre-surgery IIEF-EF-level ("back-to-baseline analysis").

Methods: REACTT included 422 men <68 years with adenocarcinoma of the prostate and preoperative IIEF-EF ≥22 who underwent nsRP at 50 centers from 9 European countries and Canada. Patients were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg OaD (n = 139), tadalafil 20 mg on-demand (pro-re-nata, PRN; n = 142), or placebo (n = 141), followed by 6-week drug-free washout (DFW) and 3-month open-label tadalafil OaD treatment (OLT).

Main Outcome Measures: Proportion of patients returning to their preoperative IIEF-EF category (22-25 or ≥26) at the end of DBT, DFW, and OLT.

Results: Overall, 92.4% of patients had pre-surgery (baseline) IIEF-EF scores ≥26 (tadalafil OaD 94.2%, PRN 91.6%, placebo 91.5%), 7.4% had IIEF-EF 22-25. At the end of DBT, 22.3% of patients on tadalafil OaD had achieved "back-to-baseline" IIEF-EF, compared with 11.3% on tadalafil PRN and 7.8% on placebo. Of all 58 patients "back-to-baseline" at the end of DBT, only 1 PRN-group patient had started from a baseline IIEF-EF <26. The treatment-group difference at the end of DBT was not maintained after DFW. After 3 months of OLT with tadalafil OaD, the proportion of patients with "back-to-baseline" IIEF-EF had almost doubled in all 3 groups.

Conclusion: Changing the definition for EF-recovery from IIEF-EF ≥22 to the more strict definition of "returning back-to-baseline IIEF-EF" had no major impact. Tadalafil OaD started early after nsRP improved drug-assisted EF, but had no effect on unassisted EF following treatment cessation after 9 months.
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http://dx.doi.org/10.1016/j.jsxm.2016.01.022DOI Listing
April 2016

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy.

Eur Urol 2016 09 3;70(3):529-37. Epub 2016 Mar 3.

Biomedicines BU, Lilly Deutschland GmbH, Bad Homburg, Germany.

Background: Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies.

Objective: To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT).

Design, Setting, And Participants: Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada.

Intervention: Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment.

Outcome Measurements And Statistical Analysis: Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group.

Results And Limitations: The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and open-label treatment identified high presurgery intercourse satisfaction as the key predictor.

Conclusions: Exploratory decision-tree analyses identified high presurgery sexual desire, confidence, and intercourse satisfaction as key predictors for EF recovery. Patients meeting these criteria might benefit the most from conserving surgery and early postsurgery EF rehabilitation. Strategies for improving EF after surgery should be discussed preoperatively with all patients; this information may support expectation management for functional recovery on an individual patient level.

Patient Summary: Understanding how patient characteristics and different treatment options affect the recovery of erectile function (EF) after radical surgery for prostate cancer might help physicians select the optimal treatment for their patients. This analysis of data from a clinical trial suggested that high presurgery sexual desire, sexual confidence, and intercourse satisfaction are key factors predicting EF recovery. Patients meeting these criteria might benefit the most from conserving surgery (robot-assisted surgery, perfect nerve sparing) and postsurgery medical rehabilitation of EF.

Trial Registration: ClinicalTrials.gov, NCT01026818.
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http://dx.doi.org/10.1016/j.eururo.2016.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478190PMC
September 2016

Tadalafil 5 mg once daily for the treatment of erectile dysfunction during a 6-month observational study (EDATE): impact of patient characteristics and comorbidities.

BMC Urol 2015 Nov 12;15:111. Epub 2015 Nov 12.

Lilly Deutschland GmbH, Bad Homburg, Germany.

Background: To explore the impact of patient-characteristics and relevant comorbidities on treatment continuation rates, effectiveness, and satisfaction in patients with erectile dysfunction (ED) who started or switched to tadalafil 5 mg once daily (TAD-OaD) at baseline.

Methods: In the EDATE observational study, phosphodiesterase-type-5 (PDE5)-inhibitor pretreated or naïve ED patients who started or switched to TAD-OaD were prospectively followed for 6 months. Time to discontinuation of TAD-OaD was estimated using the Kaplan-Meier product-limit method at Months 2, 4, and 6 in subgroups stratified by age (18 - 65 years and >65 years), PDE5-inhibitor pretreatment, ED-severity (mild, moderate, severe), and presence or absence of relevant comorbidities (BPH, diabetes, CVD, hypertension, dyslipidemia). LSmean change from baseline in International Index of Erectile Function (IIEF) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores and associated 95 % CIs were assessed using a mixed-model for repeated measures. Visit, ED etiology, and subgroups were included as fixed-effects.

Results: Overall, 778 patients received prescriptions for initiating or switching to TAD-OaD at baseline. At Month 2, >90 % of patients remained on TAD-OaD, except those aged >65 years (86.7 %) and patients with severe ED (89.0 %). More than 80 % of patients in all subgroups, except those aged >65 years (75.0 %), continued TAD-OaD at Month 6. There was a significant LSmean negative effect on IIEF- EF domain-score improvement for BPH (LSmean effect [95 % CI]: -2.77 [-4.98, -0.55], p = 0.014), previous PDE5-inhibitor treatment (-2.13 [-3.33,-0.94], p < 0.001), and mild vs moderate ED (-2.00 [-3.54,-0.46], p = 0.011); the latter possibly linked with a bigger treatment-effect in those with more severe ED at baseline. The LSmean effect on change in IIEF-EF was significantly positive for diabetes (2.28 [0.64,3.92], p = 0.007), most likely because those with diabetes had more severe ED at baseline. For all other parameters, no statistically significant LSmean effects in IIEF-EF changes were observed. No comorbidity or baseline-characteristic except age (18 - 65 years vs >65 years: 11.25 [2.96,19.54], p = 0.008) affected changes in EDITS.

Conclusions: Under routine clinical conditions, treatment continuation rate or satisfaction does not seem to be significantly affected by the presence of comorbidities in men who choose ED-treatment with TAD-OaD. The magnitude of treatment effectiveness was affected by certain baseline characteristics and comorbid conditions.

Trial Registration: The study (H6D-EW-LVIU) is registered in the German VfA Registry of Non-Interventional Studies (Verband Forschender Arzneimittelhersteller) since 06 December 2011; available at: http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_741 .
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http://dx.doi.org/10.1186/s12894-015-0107-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643510PMC
November 2015

Predictors of Individual Response to Placebo or Tadalafil 5mg among Men with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: An Integrated Clinical Data Mining Analysis.

PLoS One 2015 18;10(8):e0135484. Epub 2015 Aug 18.

Department of Urology, Queen's University, Kingston, Ontario, Canada.

Background: A significant percentage of patients with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) achieve clinically meaningful improvement when receiving placebo or tadalafil 5mg once daily. However, individual patient characteristics associated with treatment response are unknown.

Methods: This integrated clinical data mining analysis was designed to identify factors associated with a clinically meaningful response to placebo or tadalafil 5mg once daily in an individual patient with LUTS-BPH. Analyses were performed on pooled data from four randomized, placebo-controlled, double-blind, clinical studies, including about 1,500 patients, from which 107 baseline characteristics were selected and 8 response criteria. The split set evaluation method (1,000 repeats) was used to estimate prediction accuracy, with the database randomly split into training and test subsets. Logistic Regression (LR), Decision Tree (DT), Support Vector Machine (SVM) and Random Forest (RF) models were then generated on the training subset and used to predict response in the test subset. Prediction models were generated for placebo and tadalafil 5mg once daily Receiver Operating Curve (ROC) analysis was used to select optimal prediction models lying on the ROC surface.

Findings: International Prostate Symptom Score (IPSS) baseline group (mild/moderate vs. severe) for active treatment and placebo achieved the highest combined sensitivity and specificity of 70% and ~50% for all analyses, respectively. This was below the sensitivity and specificity threshold of 80% that would enable reliable allocation of an individual patient to either the responder or non-responder group.

Conclusions: This extensive clinical data mining study in LUTS-BPH did not identify baseline clinical or demographic characteristics that were sufficiently predictive of an individual patient response to placebo or once daily tadalafil 5mg. However, the study reaffirms the efficacy of tadalalfil 5mg once daily in the treatment of LUTS-BPH in the majority of patients and the importance of evaluating individual patient need in selecting the most appropriate treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135484PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540425PMC
May 2016

Effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy: quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized, placebo-controlled phase IV study.

BMC Urol 2015 Apr 12;15:31. Epub 2015 Apr 12.

Lilly Deutschland GmbH, Bad Homburg, Germany.

Background: This multicenter, randomized, double-blind, double-dummy, placebo-controlled trial primarily evaluated the efficacy of tadalafil once-daily (OaD) or on-demand ("pro-re-nata"; PRN) treatment, started early post-nsRP. Secondary outcome-measures on quality-of-life (QoL) and treatment satisfaction are reported.

Methods: Patients, aged <68 yrs, with adenocarcinoma of the prostate (Gleason ≤ 7, normal preoperative erectile function [EF]) were randomized post-nsRP 1:1:1 to 9-month treatment with tadalafil 5 mg OaD, tadalafil 20 mg PRN, or placebo, followed by 6-week drug-free washout and 3-month open-label tadalafil OaD treatment (OLT). The main outcome measures were Changes in Expanded Prostate Cancer Index Composite (EPIC-26), Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS), and Self-Esteem and Relationship (SEAR) questionnaires (mixed-model-for-repeated-measures, including terms for treatment, visit, treatment-by-visit interaction, age-group, country, baseline-score). LS means with 95% confidence interval (CI) are reported.

Results: 423 patients were randomized to 3 treatment-groups: tadalafil OaD (N = 139), PRN (N = 143), or placebo (N = 141). In each group, 57 (41.0%), 58 (40.6%), and 50 (35.5%) patients were aged 61-68 yrs. At the end of double-blind treatment (DBT), patients' EPIC sexual domain-scores improved significantly with tadalafil OaD versus placebo (treatment effect [95% CI]: 9.6 [3.1,16.0]; p = 0.004); comparisons of PRN versus placebo at end of DBT, and comparisons of tadalafil OaD and PRN versus placebo after OLT were not significant. Only in older patients (61-68 yrs; age-by-treatment p ≤ 0.1), EPIC urinary incontinence domain-scores also improved significantly with tadalafil OaD versus placebo (overall treatment effect across all visits, 8.3 [0.4,16.1]; p = 0.040). Treatment satisfaction increased significantly in both tadalafil groups, EDITS total-scores increased significantly with OaD and PRN versus placebo during DBT (p = 0.005 and p = 0.041, respectively). At the end of OLT, improvement was significant for tadalafil OaD versus placebo only (p = 0.035). No significant differences were observed for SEAR.

Conclusions: These results suggest that chronic dosing of tadalafil improves QoL of patients post-nsRP. The improvement of urinary incontinence in elderly patients randomized to tadalafil OaD may contribute to this effect.

Trial Registration: www.clinicaltrials.gov , NCT01026818.
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http://dx.doi.org/10.1186/s12894-015-0022-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419565PMC
April 2015

Treatment satisfaction and clinically meaningful symptom improvement in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: Secondary results from a 6-month, randomized, double-blind study comparing finasteride plus tadalafil with finasteride plus placebo.

Int J Urol 2015 Jun 31;22(6):582-7. Epub 2015 Mar 31.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

Objectives: To report the secondary analyses of treatment satisfaction and clinically meaningful improvements in a randomized study comparing coadministration of tadalafil 5 mg with finasteride 5 mg versus finasteride alone in men with prostatic enlargement secondary to benign prostatic hyperplasia.

Methods: An international, randomized, double-blind, parallel study was carried out in men aged ≥45 years who were 5-alpha reductase inhibitor naïve, and had an International Prostate Symptom Score ≥13 and prostate volume ≥30 mL; 350 men received placebo/finasteride and 345 received tadalafil/finasteride over 26 weeks. Treatment satisfaction was assessed per protocol using the Treatment Satisfaction Scale-Benign Prostatic Hyperplasia. Responder cut-offs, analyzed post-hoc were total International Prostate Symptom Score improvement ≥3 points or ≥25% from randomization.

Results: Baseline patient characteristics were generally comparable between responders and non-responders. The proportion of patients with an International Prostate Symptom Score improvement ≥3 points with tadalafil/finasteride and placebo/finasteride, respectively, at week 4 was 57.0% and 47.9% (OR 1.45, 95% confidence interval 1.07-1.97), at week 12 was 68.8% and 60.7% (OR 1.48, 95% confidence interval 1.07-2.05) and at week 26 was 71.4% and 70.2% (OR 1.14, 95% confidence interval 0.81-1.61); for IPSS change ≥25%, the corresponding proportions were 44.8% and 32.9% (OR 1.66, 95% confidence interval 1.21-2.28), 55.5% and 51.9% (OR 1.18, 95% confidence interval 0.87-1.62), and 62.0% and 58.3% (OR 1.23, 95% confidence interval 0.89-1.70). Treatment satisfaction at week 26 was significantly greater with tadalafil/finasteride versus placebo/finasteride for total treatment satisfaction scale score (P=0.031) and satisfaction with efficacy subscore (P = 0.025); scores were not significantly different between treatments for satisfaction with dosing or side-effects (both P ≥ 0.371).

Conclusions: Tadalafil/finasteride results in significantly more patients achieving early clinical meaningful improvements in symptoms, and in greater treatment satisfaction versus placebo/finasteride.
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http://dx.doi.org/10.1111/iju.12741DOI Listing
June 2015

Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial.

Urology 2015 May 24;85(5):1090-1096. Epub 2015 Mar 24.

Therapeutic Area Men's Health, Lilly Deutschland GmbH, Bad Homburg, Germany.

Objective: To report penile integrity measures, including stretched penile length (SPL), from a randomized, double-blind, double-dummy, placebo-controlled trial evaluating treatment with tadalafil initiated after nerve-sparing radical prostatectomy (nsRP).

Methods: Patients aged ≤ 68 years were randomized after nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg once daily (OaD), 20-mg tadalafil on-demand ("pro-re-nata"; PRN), or placebo, followed by 6-week drug-free washout and 3-month open-label OaD treatment. Secondary outcome measures included the change in SPL from pre-nsRP to the end of DBT (analysis of covariance adjusting for treatment, country, baseline, age, and nerve-sparing score), responses to Sexual Encounter Profile (SEP) questions 1-3 (mixed models for repeated measures adjusting for treatment, country, visit, visit-treatment-interaction, age), and Standardized Morning Erection Question (Cochran-Mantel-Haenszel test adjusted for age and country).

Results: Four hundred twenty-three patients were randomized to tadalafil OaD (N = 139), tadalafil PRN (N = 143), and placebo (N = 141). Greater retainment of SPL was observed with tadalafil OaD vs placebo at the end of DBT (least-square mean [95% confidence interval] difference OaD vs placebo, 4.1 mm [0.4 to 7.8 mm]; P = .032). No significant effects on SPL were found for tadalafil PRN vs placebo, or for the nerve-sparing score. Penile tumescence (SEP1) and ability for vaginal insertion (SEP2) significantly improved vs placebo at the end of double-blind and open-label treatment for patients randomized to tadalafil OaD only. The ability for successful sexual intercourse (SEP3) significantly improved with tadalafil OaD vs placebo only during DBT. The distribution of Standardized Morning Erection Question responses was different at the end of DBT (P = .045); 34.2% of patients on tadalafil OaD, 50.0% on tadalafil PRN, and 56.5% on placebo reported absence of morning erections.

Conclusion: These data suggest the early initiation of tadalafil OaD protects from penile length loss and may contribute to protection from structural cavernosal changes after nsRP.
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http://dx.doi.org/10.1016/j.urology.2014.11.058DOI Listing
May 2015

Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial.

Urology 2015 May 24;85(5):1090-1096. Epub 2015 Mar 24.

Therapeutic Area Men's Health, Lilly Deutschland GmbH, Bad Homburg, Germany.

Objective: To report penile integrity measures, including stretched penile length (SPL), from a randomized, double-blind, double-dummy, placebo-controlled trial evaluating treatment with tadalafil initiated after nerve-sparing radical prostatectomy (nsRP).

Methods: Patients aged ≤ 68 years were randomized after nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg once daily (OaD), 20-mg tadalafil on-demand ("pro-re-nata"; PRN), or placebo, followed by 6-week drug-free washout and 3-month open-label OaD treatment. Secondary outcome measures included the change in SPL from pre-nsRP to the end of DBT (analysis of covariance adjusting for treatment, country, baseline, age, and nerve-sparing score), responses to Sexual Encounter Profile (SEP) questions 1-3 (mixed models for repeated measures adjusting for treatment, country, visit, visit-treatment-interaction, age), and Standardized Morning Erection Question (Cochran-Mantel-Haenszel test adjusted for age and country).

Results: Four hundred twenty-three patients were randomized to tadalafil OaD (N = 139), tadalafil PRN (N = 143), and placebo (N = 141). Greater retainment of SPL was observed with tadalafil OaD vs placebo at the end of DBT (least-square mean [95% confidence interval] difference OaD vs placebo, 4.1 mm [0.4 to 7.8 mm]; P = .032). No significant effects on SPL were found for tadalafil PRN vs placebo, or for the nerve-sparing score. Penile tumescence (SEP1) and ability for vaginal insertion (SEP2) significantly improved vs placebo at the end of double-blind and open-label treatment for patients randomized to tadalafil OaD only. The ability for successful sexual intercourse (SEP3) significantly improved with tadalafil OaD vs placebo only during DBT. The distribution of Standardized Morning Erection Question responses was different at the end of DBT (P = .045); 34.2% of patients on tadalafil OaD, 50.0% on tadalafil PRN, and 56.5% on placebo reported absence of morning erections.

Conclusion: These data suggest the early initiation of tadalafil OaD protects from penile length loss and may contribute to protection from structural cavernosal changes after nsRP.
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http://dx.doi.org/10.1016/j.urology.2014.11.058DOI Listing
May 2015

Sexual function in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia: results of a 6-month, randomized, double-blind, placebo-controlled study of tadalafil coadministered with finasteride.

J Sex Med 2015 Jan 29;12(1):129-38. Epub 2014 Oct 29.

Instituto H. Ellis, São Paulo, Brazil; Department of Urology, Ipiranga Hospital, São Paulo, Brazil.

Introduction: Tadalafil (TAD) 5 mg coadministered with finasteride (FIN) 5 mg significantly improves lower urinary tract symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) and prostatic enlargement. However, its effects on erectile/sexual function have yet to be fully described.

Aim: Assess the effects of TAD/FIN coadministration (compared with placebo [PBO]/FIN) on erectile and sexual function in sexually active men with LUTS and prostatic enlargement secondary to BPH with or without baseline comorbid erectile dysfunction (ED).

Methods: A randomized, double-blind, PBO-controlled study of 695 men (610 sexually active; 450 with baseline ED; 404 sexually active with baseline ED) conducted at 70 sites in 13 countries. TAD 5 mg or PBO once daily coadministered with FIN 5 mg once daily for 26 weeks.

Main Outcome Measures: International Index of Erectile Function (IIEF) domain and single-item scores; proportions of patients who demonstrated minimal clinically important differences (MCIDs) in IIEF-Erectile Function domain scores (IIEF-EF; MCID defined as ≥4-point improvement); and sexual dysfunction adverse events (AEs).

Results: Compared with PBO/FIN, TAD/FIN resulted in improvements for all IIEF domain and single-item scores assessed among patients with baseline ED (P ≤ 0.002 for all measures) and among patients without baseline ED (P ≤ 0.041 for all measures). Compared with PBO/FIN, significantly larger percentages of sexually active men with baseline ED treated with TAD/FIN achieved an IIEF-EF MCID after 4, 12, and 26 weeks of therapy (P < 0.001 for odds ratio comparisons between TAD/FIN and PBO/FIN at all 3 three postbaseline timepoints). The incidence of sexual AEs was low: five TAD/FIN patients and seven PBO/FIN patients reported sexual AEs, including ED, decreased/lost libido, and ejaculation disorders.

Conclusions: TAD/FIN coadministration for the treatment of men with LUTS and prostatic enlargement secondary to BPH concurrently leads to statistically significant improvements in erectile/sexual function and is well-tolerated, regardless of the presence/absence of ED at treatment initiation.
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http://dx.doi.org/10.1111/jsm.12714DOI Listing
January 2015

Effect of tadalafil on male lower urinary tract symptoms: an integrated analysis of storage and voiding international prostate symptom subscores from four randomised controlled trials.

Eur Urol 2015 Jan 7;67(1):114-122. Epub 2014 Oct 7.

Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.

Background: The international prostate symptom score (IPSS) evaluates lower urinary tract symptoms (LUTS) in men with suspected benign prostatic hyperplasia (BPH); the total score does not differentiate between storage and voiding and is unevenly weighted (four questions [57%] on voiding, three questions [43%] on storage).

Objective: To evaluate the relative contributions of storage and voiding IPSS subscores to total IPSS at baseline and in response to treatment with tadalafil.

Design, Setting, And Participants: Integrated analysis of data from four placebo-controlled, 12-wk studies of tadalafil (5mg once daily) in 1499 men with LUTS/BPH.

Outcome Measurements And Statistical Analysis: Relationships between total IPSS and the storage and voiding subscores were assessed using graphical exploration and linear regression modelling. Linear modelling was performed for the baseline and endpoint and for changes in subscores. The optimal storage subscore to total IPSS (S:T) ratio for IPSS improvement was identified using nonparametric regression and gradient-descent optimisation.

Results And Limitations: The contribution of storage and voiding subscores at baseline and endpoint was 38.8% and 61.2%, and 39.2% and 60.7%, respectively. This intuitive 40:60 storage-to-voiding ratio was similar at baseline and endpoint by treatment group and for changes in subscores, but spanned the entire range for individuals. Changes in total IPSS were greatest for a storage subscore percentage contribution to total IPSS of 42.7%. There was no statistical association between S:T ratio (≥ 40% vs < 40%) at baseline and response to tadalafil. The main limitation was the use of unvalidated storage and voiding IPSS subscores.

Conclusions: A constant S:T ratio of 4:10 was observed at baseline and endpoint. The greatest effect on total IPSS was noted for an S:T percentage contribution of 42.7%. Tadalafil efficacy was unaffected by the level of storage dysfunction at baseline.

Patient Summary: This analysis shows that for men with BPH, improvements during treatment with tadalafil apply to both storage and voiding symptoms at a constant ratio. The extent of storage dysfunction before treatment did not affect the response to treatment.
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http://dx.doi.org/10.1016/j.eururo.2014.08.072DOI Listing
January 2015

Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia – integrated data from 1,499 study participants.

BJU Int 2015 May 7;115(5):815-21. Epub 2015 Mar 7.

Department of Urology, Queen's University, Kingston, UK.

Objectives: To evaluate the proportion of patients achieving clinically meaningful improvement of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) with tadalafil using two definitions of response.

Patients And Methods: Post hoc integrated analysis of four placebo-controlled studies in men (aged ≥45 years; International Prostate Symptom Score [IPSS] of ≥13; maximum urinary flow rate [Q(max)] of ≥4 to ≤15 mL/s) with BPH-LUTS randomised to tadalafil 5 mg (752 patients) or placebo (747) for 12 weeks after a 4-week placebo run-in. Responders were defined as having a total IPSS improvement of ≥3 points or ≥25% from randomisation to endpoint (Week 12). Response status was calculated per patient, and relative benefit and odds ratio (OR) with 95% confidence interval (CI) of tadalafil vs placebo was calculated using a logistic Generalised Mixed Model for Repeated Measures.

Results: Tadalafil 5 mg once daily resulted in a significantly greater proportion of patients achieving a ≥3-point IPSS improvement (71.1% and 56.0% for tadalafil and placebo patients, respectively [OR 1.9, 95% CI 1.5, 2.4; P < 0.001]) and achieving a ≥25% improvement in total IPSS randomisation to endpoint (61.7% and 45.5% for tadalafil and placebo patients, respectively [OR 2.0, 95% CI 1.6, 2.5; P < 0.001]).

Conclusion: About two-thirds of tadalafil-treated patients achieve a clinically meaningful improvement in BPH-LUTS symptoms, based on two different definitions of responder status.
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http://dx.doi.org/10.1111/bju.12926DOI Listing
May 2015

Effects of tadalafil once daily or on demand versus placebo on time to recovery of erectile function in patients after bilateral nerve-sparing radical prostatectomy.

World J Urol 2015 Jul 26;33(7):1031-8. Epub 2014 Aug 26.

Department of Urology, Hospital La Zarzuela, Madrid, Spain,

Purpose: We report time to erectile function (EF)-recovery data from a multicenter, randomized, double-blind, double-dummy, placebo-controlled trial evaluating tadalafil started after bilateral nerve-sparing radical prostatectomy (nsRP).

Methods: Patients ≤68 years were randomized post-nsRP 1:1:1 to 9-month double-blind treatment (DBT) with tadalafil 5 mg once daily (OaD), 20 mg tadalafil on demand ("pro-re-nata"; PRN), or placebo, followed by 6-week drug-free washout (DFW) and 3-month open-label OaD treatment. Secondary outcome measures included Kaplan-Meier estimates of time to EF-recovery (IIEF-EF ≥ 22) during DBT (Cox proportional hazard model adjusting for treatment, age, and country).

Results: A total of 423 patients were randomized to tadalafil OaD (N = 139), PRN (N = 143), and placebo (N = 141); 114/122/155 completed DBT. The proportion of patients achieving IIEF-EF ≥22 at some point during DBT with OaD, PRN, and placebo was 29.5, 23.9, and 18.4 %, respectively. DBT was too short to achieve EF-recovery (IIEF-EF ≥ 22) in >50 % of patients; median time to EF-recovery was non-estimable. Time for 25 % of patients to achieve EF-recovery (95 % CI) was 5.8 (4.9, 9.2) months for OaD versus 9.0 (5.5, 9.2) and 9.3 (9.0, 9.9) months for PRN and placebo, respectively. Showing a significant overall treatment effect (p = 0.038), the probability for EF-recovery was significantly higher for OaD versus placebo [hazard ratio (HR); 95 % CI 1.9; 1.2, 3.1; p = 0.011], but not for PRN versus placebo (p = 0.140). Of 57 OaD patients (41.0 %) with ED improved (by ≥1 IIEF-EF severity grade) at the end of DBT, 16 (28.1 % of 57) maintained this improvement through DFW and 27 (47.4 %) declined but maintained improvement from baseline after DFW.

Conclusions: Data suggest that the use of tadalafil OaD can significantly shorten the time to EF-recovery post-nsRP compared with placebo.
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http://dx.doi.org/10.1007/s00345-014-1377-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480825PMC
July 2015

Decision tree analyses of key patient characteristics in Middle Eastern/North African and Latin American men treated with long-acting and short-acting PDE5 inhibitors for erectile dysfunction.

Curr Med Res Opin 2015 Feb 29;31(2):367-78. Epub 2014 Jul 29.

Asociación Mexicana para la Salud Sexual, AC (AMSSAC) , Mexico City , Mexico.

Background: Phosphodiesterase type 5 (PDE5) inhibitors have discontinuation rates as high as 60% in men with erectile dysfunction. Treatment satisfaction has been significantly associated with treatment continuation. Understanding key characteristics in terms of treatment preference, relationship, and lifestyle issues could provide direction on how to improve compliance with PDE5 inhibitor treatment globally.

Objective: The objective was to identify subgroups of interest in the pooled database of two observational studies conducted in Latin America (LA) and Middle East/North Africa (MENA) exploring patient characteristics and prescription of either a long- or short-acting PDE5 inhibitor at baseline.

Methods: Two identical prospective, non-interventional, observational, studies in MENA (N = 493) and LA (N = 511) treated men with an 'on demand' (pro re nata, PRN) PDE5 inhibitor (sildenafil, tadalafil, vardenafil, or lodenafil) during 6 months. In this post-hoc meta-analysis of two observational studies with equal design, pooled data were analyzed to determine patient characteristics and PDE5 inhibitor prescribed/used most likely to be associated with patient expectations, satisfaction, self-esteem, and patient-partner relationships. Decision tree analyses, with and without weighting, were used to identify and describe key features.

Results: In each analysis of patient expectations, patient-partner relationship, and self-esteem, we describe the two major subgroups at baseline for each decision tree. Analyses of patient expectations and sexual self-esteem revealed that patients prescribed long-acting PDE5 inhibitors (59%) highlighted the importance of treatment effect duration, second to partner satisfaction with treatment, while patients prescribed short-acting PDE5 inhibitors (32%) placed less importance on treatment effect duration but considerable importance on treatment effect lasting until intercourse completion. Further insights regarding patients, partner relationship characteristics, and treatment expectations were identified.

Conclusion: Our analyses have described key characteristics, such as self- and partner perceptions, sexual attitudes, and treatment expectations in relation to the patients' country and prescribed treatment, which might guide treatment decisions in MENA and LA men with ED.
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http://dx.doi.org/10.1185/03007995.2014.946125DOI Listing
February 2015

PDE5 inhibitor treatment persistence and adherence in Brazilian men: post-hoc analyses from a 6-month, prospective, observational study.

Int Braz J Urol 2014 May-Jun;40(3):390-9

Lilly Research Laboratories, Eli Lilly and Company, IN, USA.

Purpose: Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED).

Materials And Methods: Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence.

Results: 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size.

Conclusion: Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment.
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http://dx.doi.org/10.1590/S1677-5538.IBJU.2014.03.14DOI Listing
February 2015

Effects of tadalafil treatment on erectile function recovery following bilateral nerve-sparing radical prostatectomy: a randomised placebo-controlled study (REACTT).

Eur Urol 2014 Mar 13;65(3):587-96. Epub 2013 Oct 13.

Lilly Deutschland GmbH, Bad Homburg, Germany. Electronic address:

Background: The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear.

Objective: The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥ 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length.

Design, Setting, And Participants: Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤ 68 yr of age with adenocarcinoma of the prostate (Gleason ≤ 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada.

Interventions: 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients).

Outcome Measurements And Statistical Analysis: Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥ 22, SEP-3, and penile length.

Results And Limitations: Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥ 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥ 4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032).

Conclusions: Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo.

Trial Registration: ClinicalTrials.gov identifier NCT01026818.
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http://dx.doi.org/10.1016/j.eururo.2013.09.051DOI Listing
March 2014

Screening for protein-DNA interactions by automatable DNA-protein interaction ELISA.

PLoS One 2013 11;8(10):e75177. Epub 2013 Oct 11.

Plant Physiology, Center for Plant Molecular Biology, University of Tuebingen, Tuebingen, Germany.

DNA-binding proteins (DBPs), such as transcription factors, constitute about 10% of the protein-coding genes in eukaryotic genomes and play pivotal roles in the regulation of chromatin structure and gene expression by binding to short stretches of DNA. Despite their number and importance, only for a minor portion of DBPs the binding sequence had been disclosed. Methods that allow the de novo identification of DNA-binding motifs of known DBPs, such as protein binding microarray technology or SELEX, are not yet suited for high-throughput and automation. To close this gap, we report an automatable DNA-protein-interaction (DPI)-ELISA screen of an optimized double-stranded DNA (dsDNA) probe library that allows the high-throughput identification of hexanucleotide DNA-binding motifs. In contrast to other methods, this DPI-ELISA screen can be performed manually or with standard laboratory automation. Furthermore, output evaluation does not require extensive computational analysis to derive a binding consensus. We could show that the DPI-ELISA screen disclosed the full spectrum of binding preferences for a given DBP. As an example, AtWRKY11 was used to demonstrate that the automated DPI-ELISA screen revealed the entire range of in vitro binding preferences. In addition, protein extracts of AtbZIP63 and the DNA-binding domain of AtWRKY33 were analyzed, which led to a refinement of their known DNA-binding consensi. Finally, we performed a DPI-ELISA screen to disclose the DNA-binding consensus of a yet uncharacterized putative DBP, AtTIFY1. A palindromic TGATCA-consensus was uncovered and we could show that the GATC-core is compulsory for AtTIFY1 binding. This specific interaction between AtTIFY1 and its DNA-binding motif was confirmed by in vivo plant one-hybrid assays in protoplasts. Thus, the value and applicability of the DPI-ELISA screen for de novo binding site identification of DBPs, also under automatized conditions, is a promising approach for a deeper understanding of gene regulation in any organism of choice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075177PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795721PMC
July 2014

Tadalafil once daily in men with erectile dysfunction: an integrated analysis of data obtained from 1913 patients from six randomized, double-blind, placebo-controlled, clinical studies.

Eur Urol 2014 Feb 2;65(2):455-64. Epub 2013 Oct 2.

Lilly Deutschland GmbH, Medical Department, Bad Homburg, Germany. Electronic address:

Background: This analysis explores tadalafil once-daily treatment for 12 wk in clinical subpopulations of men with erectile dysfunction (ED).

Objective: Assess the efficacy and safety of once-daily tadalafil 2.5mg and 5mg in patients with different ED characteristics and comorbidities.

Design, Setting, And Participants: This analysis integrated data from six randomized, double-blind, placebo-controlled studies that assigned 1913 men with ≥3-mo history of ED either to once-daily placebo (n=596), tadalafil 2.5mg (n=394), or tadalafil 5mg (n=923). Clinical factors examined included: ethnicity, age, obesity, alcohol consumption, smoking, comorbidities, concomitant medication, and ED characteristics (etiology, duration, severity).

Outcome Measurements And Statistical Analysis: Descriptive statistics were reported for efficacy and safety, including International Index of Erectile Function Erectile Function Domain (IIEF-EF) scores and Sexual Encounter Profile question 3 (SEP3) responses. Clinical factors were included in analysis of covariance models using last observation carried forward for SEP3 and IIEF-EF scores.

Results And Limitations: Both tadalafil doses significantly improved SEP3 responses (least-squares [LS] mean change: 17.8% and 23.6%, respectively) and IIEF-EF scores (LS mean change: 4.2; 5.4) compared with placebo (p<0.01). Treatment with 2.5mg and 5mg tadalafil resulted in IIEF-EF LS mean improvements ≥4 (minimal clinically important difference [MCID]) in patients with hypertension (4.3 [95% confidence interval (CI), 2.9-5.7]; 4.7 [95% CI, 3.5-5.8]), cardiac disorder (7.0 [95% CI, 4.7-9.3]; 6.3 [95% CI, 4.4-8.2]), or hyperlipidemia (5.3 [95% CI, 3.4-7.1]; 5.8 [95% CI, 4.3-7.4]). Obese patients (4.7 [95% CI, 3.4-6.0]), smokers (4.8 [95% CI, 3.0-6.7]), and psychogenic ED (7.3 [95% CI, 5.0-9.6]) reached MCID only after treatment with 5mg tadalafil. Severity-specific MCID (IIEF-EF change ≥7) was achieved by 44.5% of patients with severe baseline ED treated with tadalafil 5mg, compared with 11.6% of placebo-treated patients. No unexpected safety findings were observed. These analyses were performed on integrated data and can only provide descriptive results to guide further investigations.

Conclusions: Treatment with tadalafil 2.5mg or 5mg once daily was well tolerated and resulted in clinically important improvements in patients with mild (54.3% and 74.8%, respectively), moderate (51.3% and 63.1%, respectively), or severe (33.7% and 44.5%, respectively) ED.
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http://dx.doi.org/10.1016/j.eururo.2013.09.037DOI Listing
February 2014

Efficacy and safety of the coadministration of tadalafil once daily with finasteride for 6 months in men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia.

J Urol 2014 Mar 2;191(3):727-33. Epub 2013 Oct 2.

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Electronic address:

Purpose: Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms.

Materials And Methods: In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events.

Results: Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate.

Conclusions: The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.
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http://dx.doi.org/10.1016/j.juro.2013.09.059DOI Listing
March 2014

Effect on platelet reactivity from a prasugrel loading dose after a clopidogrel loading dose compared with a prasugrel loading dose alone: Transferring From Clopidogrel Loading Dose to Prasugrel Loading Dose in Acute Coronary Syndrome Patients (TRIPLET): a randomized controlled trial.

Circ Cardiovasc Interv 2013 Oct 24;6(5):567-74. Epub 2013 Sep 24.

Division of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montreal, QC, Canada.

Background: Adding a prasugrel loading dose (LD) to a clopidogrel LD could be desirable because clopidogrel may fail to provide adequate levels of platelet inhibition in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Methods And Results: The pharmacodynamic response of prasugrel 60 mg ld alone was compared with prasugrel 60 mg or 30 mg added 24 hours to clopidogrel 600 mg in Transferring From Clopidogrel Loading Dose To Prasugrel Loading Dose In Acute Coronary Syndrome Patients study: a multicenter, randomized, double-blind, double-dummy, 3-arm, parallel, active-comparator controlled study. Two hundred eighty-two patients were randomized to 3 LD strategies: placebo plus prasugrel 60 mg, clopidogrel 600 mg plus prasugrel 60 mg, or clopidogrel 600 mg plus prasugrel 30 mg. Platelet function was assessed using VerifyNow P2Y12 Reaction Units (PRU) immediately before prasugrel LD, and 2, 6, 24, and 72 hours after prasugrel LD in 149 patients with evaluable platelet function studies. At 6 hours after the prasugrel 60 mg LD, the least squares mean (95% confidence interval) difference between placebo/prasugrel 60 mg and clopidogrel 600 mg/prasugrel 60 mg (primary outcome) was 22.2 (-11.0 to 55.5; P=0.19; least squares mean PRU 57.9 versus 35.6, respectively). For clopidogrel 600 mg/prasugrel 30 mg (least squares mean PRU, 53.9), the difference was 3.9 (-28.2 to 36.1; P=0.81) versus placebo/prasugrel 60 mg. No significant differences in PRU were observed at any time point across the 3 groups. There were few bleeding events observed regardless of treatment.

Conclusions: Platelet reactivity with prasugrel 60 mg LD added to clopidogrel 600 mg LD was not significantly different compared with prasugrel 60 mg LD alone in acute coronary syndrome patients undergoing percutaneous coronary intervention.

Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01115738.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.112.000063DOI Listing
October 2013

Comparably high retention and low relapse rates in different subpopulations of bipolar patients in a German non-interventional study.

BMC Psychiatry 2013 Jul 17;13:193. Epub 2013 Jul 17.

Background: Although a range of pharmacotherapeutical options are available for the treatment of bipolar disorder, patient non-adherence to prescribed treatment regimens and early treatment discontinuation remain among the primary obstacles to effective treatment. Therefore, this observational study assessed time on mood stabilizing medication and retention rates in patients with bipolar disorder (BD).

Methods: In an 18-month, prospective, multicenter, non-interventional study conducted in Germany 761 outpatients (≥18 years) with BD and on maintenance therapy were documented. For analysis, patients were stratified by baseline medication: monotherapy olanzapine (OM, N = 186), lithium (LM, N = 152), anticonvulsants (N = 216), other mood stabilizing medication (OMS, N = 44); combination therapy olanzapine/lithium (N = 47), olanzapine/anticonvulsant (N = 68), other combinations (OC, N = 48). Continuation on medication was assessed as retention rates with 95% confidence intervals. Time to discontinuation and relapse-free time were calculated by Kaplan-Meier analysis. A relapse was defined as increase to CGI-BP >3, worsening of CGI-BP by ≥2 points, hospitalization or death related to BD. A Cox regression was calculated for the discontinuation of mood stabilizing therapy (reference: OM). Logistic regression models with stepwise forward selection were used to explore possible predictors of maintenance of treatment and relapse.

Results: After 540 days (18 months), the overall retention rate of baseline medication was 87.7%, without notable differences between the cohorts. The overall mean time on mood stabilizing treatment was 444.7 days, with a range of 377.5 (OMS) to 481 (LM) by cohort. 74.0% of all patients were without relapse, with rates between the cohorts ranging from 58.4% (OC) to 80.2% (LM).

Conclusions: Retention rates exceeded controlled trial results in all treatment cohorts, in addition to other explanations possibly reflecting that the physicians were expertly adapting treatment regimens to the individual patient's disease characteristics and special needs.
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http://dx.doi.org/10.1186/1471-244X-13-193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724595PMC
July 2013

Adherence to initial PDE-5 inhibitor treatment: randomized open-label study comparing tadalafil once a day, tadalafil on demand, and sildenafil on demand in patients with erectile dysfunction.

J Sex Med 2013 Jun 2;10(6):1592-602. Epub 2013 Apr 2.

Centre d'Etude et de Traitement de la Pathologie de l'Appareil Reproducteur et de la Psychosomatique (Centre ETPARP), Lille, France.

Introduction: Phosphodiesterase type 5 (PDE-5) inhibitor treatment for erectile dysfunction (ED) is frequently discontinued; adherence may vary depending on the initial regimen.

Aim: To evaluate the effects of initiating treatment with tadalafil once a day (OaD), tadalafil on demand (pro re nata [PRN]), or sildenafil PRN on treatment adherence.

Methods: In this multicenter, open-label study, men (≥ 18 years) with ED, naïve to PDE-5 inhibitors, were randomized (1:1:1) to tadalafil 5 mg OaD, tadalafil 10 mg PRN, or sildenafil 50 mg PRN. An 8-week randomized treatment (RT) period (dose adjustment possible) was succeeded by 16 weeks of pragmatic treatment (switches between PDE-5 inhibitors allowed).

Main Outcome Measures: Treatment adherence was measured as time to discontinuation of RT (any cause), estimated by Kaplan-Meier product-limit method. Treatment-group differences were estimated as hazard ratio (HR; Cox proportional hazards).

Results: Seven hundred seventy patients (mean age 53 years) were randomized to tadalafil OaD (N = 257), tadalafil PRN (N = 252), and sildenafil PRN (N = 261). Kaplan-Meier estimates for patients discontinuing RT were 52.2, 42.0, and 66.7%, respectively. Median time to discontinuation of RT was significantly longer for tadalafil OaD and PRN (130 and >168 days) compared with sildenafil (67 days) (HR [97.5% confidence interval]: 0.66 [0.51, 0.85] and 0.49 [0.37, 0.65]; P < 0.001). Reasons for discontinuation with significant differences between groups (P < 0.05) included "lack of efficacy (duration of erection)" (sildenafil 9.2% vs. tadalafil OaD 4.3%, PRN 2.8%), "time constraints due to short window of action" (sildenafil 4.2% vs. tadalafil OaD 0%, PRN 0.4%), and "feel medication controls my sexual life" (sildenafil 2.7% vs. tadalafil OaD 0%). No between-group differences were found in International Index of Erectile Function-Erectile Function domain change from baseline to end of RT (least squares mean: 9.4-10.0, P = 0.359) or discontinuations due to adverse events (1.2-1.6%). The most common adverse event (≥ 4%) was headache.

Conclusions: ED patients assigned to tadalafil OaD or PRN adhered significantly longer to initial treatment than patients assigned to sildenafil PRN. Improvement of erectile function and safety profiles were similar in all three treatment groups.
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http://dx.doi.org/10.1111/jsm.12130DOI Listing
June 2013
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