Ventricular assist devices as bridge to heart transplantation: impact on post-transplant infections.

BACKGROUND: Ventricular assist devices (VAD) are valuable options for patients with heart failure awaiting cardiac transplantation. We assessed the impact of pre-transplant VAD implantation on the incidence of post-transplant infections in a nationwide cohort of heart transplant recipients. METHODS: Heart transplant recipients included in the Swiss Transplant Cohort Study between May 2008 and December 2012 were analyzed. Cumulative incidence curves were used to calculate the incidence of bacterial or Candida infections (primary endpoint) and of other infections (secondary endpoint) after transplant. Cox regression models treating death as a competing risk were used to identify risk factors for the development of infection after transplant. RESULTS: Overall, 119 patients were included in the study, 35 with a VAD and 84 without VAD. Cumulative incidences of post-transplant bacterial or Candida infections were 37.7 % in VAD patients and 40.4 % in non-VAD patients. In multivariate analysis, the use of cotrimoxazole prophylaxis was the only variable associated with bacterial/Candida infections after transplant (HR 0.29 [95 % CI 0.15-0.57], p < 0.001), but presence of a VAD was not (HR 0.94, [95 % CI 0.38-2.32], p = 0.89, for continuous-flow devices, and HR 0.45 [0.15 - 1.34], p = 0.15, for other devices). Risk for post-transplant viral and all fungal infections was not increased in patients with VAD. One-year survival was 82.9 % (29/35) in the VAD group and 82.1 % (69/84) in the non-VAD group. All 6 patients in the VAD group that died after transplant had a history of pre-transplant VAD infection. CONCLUSION: In this nationwide cohort of heart transplant recipients, the presence of VAD at the time of transplant had no influence on the development of post-transplant infections.

Pain assessment for chronic lower back pain: performance of the PAL-S and PAL-I patient-reported measures for symptoms and impacts.

Objective: The Patient Assessment for Low Back Pain-Symptoms (PAL-S) and the Patient Assessment for Low Back Pain-Impacts (PAL-I) were developed to incorporate patient perspective of treatment benefit in chronic low back pain (cLBP) trials. This study documents psychometric measurement properties of the PAL-S and PAL-I.Methods: In this multicenter, observational study, eligible participants clinically diagnosed with cLBP provided sociodemographic information and completed PAL measures and other patient-reported outcome measures of pain and/or disability. Confirmatory factor analyses (CFA), construct validity, and reliability were assessed.Results: The 104 participants were 61% female, 89% white, and mean age of 55 years; mean cLBP duration was 11.4 (range 0-47) years. Using painDETECT scores, 36.5% reported small likelihood of neuropathic pain, 30.8% reported unclear likelihood, and 32.7% reported definite likelihood. Persistent pain with pain attacks was reported by 38.5% of participants. CFA confirmed single components with adequate fit indices. Cronbach's alpha was 0.83 (PAL-S) and 0.87 (PAL-I), indicating reliable scales. Intraclass correlation coefficients (test-retest reproducibility, n = 44) were 0.81 (PAL-S) and 0.85 (PAL-I). PAL-S score correlation was 0.49 with Roland-Morris Disability Questionnaire (RMDQ) and 0.77 with Neuropathic Pain Symptom Inventory (NPSI). PAL-I correlated at 0.73 with RMDQ and -0.60 with Medical Outcomes Study (MOS)-36 Bodily Pain. Both measures significantly differentiated between pain intensity levels (based on numeric response scale) and painDETECT groups.Conclusion: The PAL-S and PAL-I generated highly reliable scores with substantial evidence of construct validity. Routine use of these measures in treatment trials will enhance comparability of LBP-related symptom and impact results, including patient perspective of treatment benefit.

Cancer-related chronic pain: Investigation of the novel analgesic drug candidate cebranopadol in a randomized, double-blind, noninferiority trial.

BACKGROUND: Cancer-related pain is a growing health problem given the increasing life expectancy of cancer patients. Opioids are commonly used to treat cancer-related pain, but carry the risk of severe side effects, limiting their use. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. This trial examined the analgesic efficacy of cebranopadol compared with morphine prolonged release (PR) in patients with moderate-to-severe cancer-related pain. METHODS: This double-blind, parallel-group, multiple-dose trial was designed as noninferiority trial for efficacy of cebranopadol versus morphine PR. Planned with 524 patients, finally 126 patients were treated for up to 7 weeks (low accrual). The primary efficacy endpoint was the average amount of daily rescue medication intake (morphine immediate release) over the last 2 weeks of treatment. RESULTS: For the primary endpoint, noninferiority of cebranopadol with and superiority over morphine PR were demonstrated (Full Analysis Set: ∆[95%CI] = -7.48 mg [-12.05, -2.92]; Per Protocol Set: ∆[95%CI] = -4.67 mg [-9.25, -0.10]). The vast majority of patients (≥75%, either treatment) had clinically relevant pain reduction, and noninferiority on this secondary endpoint was not shown. Mostly used doses were ≤800 µg cebranopadol or ≤120 mg morphine PR daily. A total of 83.1% of patients on cebranopadol and 82.0% on morphine PR experienced treatment-emergent adverse events. CONCLUSIONS: Cebranopadol was effective, safe and well tolerated in the dose range tested (200-1,000 µg) in patients suffering from chronic moderate-to-severe cancer-related pain and was superior to morphine PR on the primary endpoint. SIGNIFICANCE: Cebranopadol presents a new approach to treat cancer pain. The drug candidate was easy to titrate, safe and well tolerated, and as effective as morphine PR in patients suffering from chronic moderate-to-severe cancer-related pain.

Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks.

CONTEXT: Pain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose. OBJECTIVES: We assessed the safety and tolerability of prolonged treatment with oral cebranopadol for up to 26 weeks in patients suffering from chronic moderate-to-severe cancer-related pain. METHODS: This was a non-randomized, multi-site, open-label, single-arm clinical trial with patients who had completed a double-blind trial comparing morphine prolonged release with cebranopadol. In this extension trial, patients were treated with oral cebranopadol for up to 26 weeks. RESULTS: Cebranopadol was safe and well tolerated in patients with chronic moderate-to-severe pain related to cancer in the dose range tested (200-1000 µg once daily). The median and mean pain levels remained in the range of mild pain during the treatment period. CONCLUSION: Our data suggest that cebranopadol was safe and well tolerated when administered for up to 26 weeks in patients with chronic cancer-related pain who were previously treated with cebranopadol or morphine prolonged release.

An investigation of dose titration with darifenacin, an M3-selective receptor antagonist.

OBJECTIVES: To evaluate the efficacy, tolerability and safety of a flexible-dosing strategy with darifenacin, an M(3)-selective receptor antagonist, in patients with symptoms of overactive bladder (OAB). PATIENTS AND METHODS: In this multicentre double-blind 12-week study, 395 patients (aged 22-89 years; 84% female) with OAB symptoms for >6 months were randomized (2 : 1) and received once-daily treatment with darifenacin controlled-release tablets 7.5 mg (268 patients) or matching placebo (127). After 2 weeks of treatment, the efficacy, safety and tolerability were assessed and the dose increased to 15 mg once daily (pseudo-increase for placebo recipients) if additional efficacy was required by both the patient and physician. In the week before clinic visits (at 2 and 12 weeks), patients recorded incontinence episodes (primary efficacy endpoint) and several secondary efficacy variables in an electronic daily diary. Safety and tolerability were evaluated from withdrawal rates and adverse-event reports. RESULTS: The treatment groups had comparable baseline characteristics. Similar proportions of darifenacin (59%) and placebo (68%) recipients increased the dose at 2 weeks; at 12 weeks patients on darifenacin (overall group) had a significantly greater reduction in the median number of incontinence episodes per week than had those on placebo, at - 8.2 (-62.9%) and - 6.0 (-48.1%), respectively (P = 0.035). There were also significant improvements in voiding frequency (P = 0.001), bladder capacity (volume voided; P = 0.036), frequency of urgency (P < 0.001), severity of urgency (P = 0.013) and number of significant leaks/week (i.e. incontinence episodes needing a change of clothing or pads, per week; P = 0.010) for darifenacin over placebo. Subset analysis suggested that some patients (those remaining on darifenacin 7.5 mg) were more sensitive to darifenacin than those who increased the dose, based on both efficacy and adverse events. Continued treatment with 7.5 mg for 'sensitive' patients, and an increased dose (to 15 mg) for remaining patients, resulted in comparable outcomes by 12 weeks. The most common treatment-related adverse events were mild-to-moderate dry mouth and constipation, which led to discontinuation in < 3.0% of darifenacin-treated patients and < 1.0% of the placebo group. Central nervous system and cardiovascular adverse events were comparable to those with placebo. CONCLUSIONS: Darifenacin appears to be an effective, well-tolerated and flexible treatment for patients with OAB, allowing individualized dosing according to patient needs.

Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist.

AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: 317 patients aged > or =65 years with OAB symptoms (urge incontinence, urgency and frequency) received up to 12 weeks' oral treatment with darifenacin 7.5 mg or 15 mg once daily or matching placebo. Efficacy was evaluated from daily electronic diary records. Safety endpoints included withdrawal rates and treatment-related adverse events. RESULTS: Darifenacin treatment of patients aged > or =65 years was associated with a dose-related, significant improvement of all the major symptoms of OAB. At week 12, the median reduction in incontinence episodes/week was greater with darifenacin 7.5 mg or 15 mg than in the corresponding placebo arms (66.7% vs. 34.8% and 75.9% vs. 44.8%, respectively, both p < 0.001). Both doses were also significantly superior to placebo in improving micturition frequency (both p < 0.001), bladder capacity (volume voided) (darifenacin 7.5 mg, p = 0.018, darifenacin 15 mg, p < 0.001), and the frequency of urgency episodes (both p < 0.001). Darifenacin was well tolerated. The most common treatment-related adverse events were dry mouth (7.5 mg, 20.6%; 15 mg, 30.9%; placebo, 4.5%) and constipation (7.5 mg, 18.6%; 15 mg, 23.6%; placebo, 6.4%), typically mild or moderate. Use of constipation remedies (laxatives, stool softeners or fibre supplements) was low and similar between groups (7.5 mg, 10.3%; 15 mg, 16.4%; placebo, 10.0%). There were few withdrawals due to treatment-related adverse events (7.5 mg, 1.0%; 15 mg, 9.1%; placebo, 2.7%), and no nervous system or cardiovascular safety concerns. CONCLUSIONS: The results demonstrate excellent efficacy, tolerability and safety with darifenacin 7.5 mg and 15 mg once-daily treatment for OAB in older patients.

A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder.

OBJECTIVE: To evaluate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), from an analysis of pooled data from three phase III, multicentre, double-blind clinical trials in patients with overactive bladder (OAB). PATIENTS AND METHODS: After a 4-week washout/run-in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for > or = 6 months were randomized to once-daily oral treatment with darifenacin (7.5 mg, 337; or 15 mg, 334) or matching placebo (388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, voiding frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of adverse events (AEs), withdrawal rates and laboratory tests. RESULTS: Relative to baseline, 12 weeks of treatment with darifenacin resulted in a significant reduction in the median (% change, interquartile range) number of incontinence episodes per week; 7.5 mg (-8.8, -68.4%, -15.1 to -4.4); 15 mg; (-10.6, -76.8%, -17.3 to -5.8: both P < 0.01 vs placebo). There was a significant dose-response trend in each study for which darifenacin 7.5 and 15 mg were evaluated (P < 0.01). There were also significant decreases in the frequency and severity of urgency, voiding frequency, and number of significant leaks (incontinence episodes resulting in a change of clothing or pads; both P < or = 0.001 vs placebo), together with an increase in bladder capacity (both P < 0.01 vs placebo). Darifenacin was well tolerated; the most common AEs were dry mouth and constipation, although together these resulted in few discontinuations (darifenacin 7.5 mg 0.6% of patients; 15 mg 2.1%; placebo 0.3%). The incidence of peripheral/central nervous system and cardiovascular AEs were comparable with those on placebo. CONCLUSIONS: Darifenacin (7.5 and 15 mg once daily) is effective in the treatment of patients with OAB. As predicted by its M3 selectivity and associated M1/M2-sparing profile, darifenacin was well tolerated with no central nervous system or cardiovascular safety concerns.

Long-term results of surgery for urethral stricture: a statistical analysis.

PURPOSE: We assessed the long-term results of surgery for urethral stricture by statistical methods using guidelines for survival analysis. MATERIALS AND METHODS: Of the 267 patients who underwent surgery for urethral strictures between March 1993 and December 1999, 238 (89%) were followed prospectively. The primary end point was success rate of urethroplasty. Secondary end points were variables that might influence success rates. Survival data were analyzed by the Kaplan-Meier method and Cox regression using guidelines for survival analysis. RESULTS: The success rate of all urethroplasties was 82% (95% CI 66 to 89) at 7.5 years. A 6.5-year success rate of 86% (95% CI 70 to 95) was achieved by flap, of 86% (95% CI 66 to 100) by anastomotic, of 79% (95% CI 64 to 94) by mesh graft and of 56% (95% CI 20 to 100) by graft urethroplasty. No significant difference was found among the surgical procedures using the log rank (p = 0.269) or Gehan-Wilcoxon (p = 0.259) test. Multivariate analysis showed an increased risk of failed urethroplasty in patients previously treated with urethral stents (HR 3.69, 95% CI 1.27 to 10.8) and by 2 or more urethrotomies (HR 2.25, 95% CI 1.05 to 4.8). CONCLUSIONS: Using standardized success criteria and statistical methods that applied guidelines for survival analysis conclusions were drawn. Excellent results are achievable by all forms of urethroplasty, justifying a more liberal indication for urethral reconstruction.