Cost effectiveness analysis of fesoterodine compared to mirabegron in first-line therapy setting for overactive bladder with urge urinary incontinence, from the Spanish National Health System perspective. / Análisis de coste efectividad de fesoterodina comparado con mirabegron en el marco de tratamiento de primera línea para vejiga hiperactiva con incontinencia urinaria de urgencia, desde la perspectiva del Sistema Nacional de Salud español.

OBJECTIVES: To evaluate the cost-effectiveness of first-line treatment of Overactive Bladder (OAB) with fesoterodine relative to mirabegron, from the Spanish National Health System (NHS) perspective. METHODS: A decision tree model was developed to represent a typical clinical process of 52-week of treatment for an OAB patient with urge urinary incontinence (UUI) initiating first-line therapy with fesoterodine 4mg, including optional titration to 8mg, vs.mirabegron 50mg. Efficacy data were obtained from a Bayesian indirect treatment meta-analysis. Patients with UUI of less than one episode/day were defined as treatment responder and persistence was assessed at weeks 4, 12 and 24. At week 12, non-responders discontinued treatment permanently. Quality-adjusted life years (QALYs) were calculated based on time spent in responder and non-responder states. OAB-related drug and medical care costs including physician visits, laboratory tests, incontinence pads, and comorbidities (fracture, skin infection, urinary tract infections and depression) were modeled and expressed in €2015. RESULTS: At week 52, the percentage of responders was 20.8% for patients starting on fesoterodine 4mg who optionally titrated to 8mg and 19.4% for patients treated with mirabegron. QALYs were slightly higher with fesoterodine than mirabegron (0.7703vs. 0.7668, difference=0.0035). Fesoterodine treatment also had slightly higher total costs than mirabegron (3,296€vs. 3,217, difference=79€), resulting in a cost of 22,523/QALY€ gained for fesoterodine versus mirabegron. Probabilistic sensitivity analysis confirmed the slight advantage of fesoterodine with a 61.1% probability of being cost-effective at the 30,000€ willingness-to-pay for 1QALY threshold. CONCLUSIONS: Given the relatively small 1-year cost difference between the two treatments, fesoterodine can be considered a cost-effective option relative to mirabegron for the first-line management of OAB with UUI in Spain.

Systematic review and meta-analysis of pharmacological therapies for pain associated with postherpetic neuralgia and less common neuropathic conditions.

OBJECTIVE: To estimate the relative efficacy of pharmacological therapies for the treatment of postherpetic neuralgia (PHN), multiple sclerosis (MS)-related pain, posttraumatic pain, central poststroke pain (CPSP) and human immunodeficiency virus (HIV)-related neuropathic pain (NeP). METHODS: This systematic review (through June 2011) identified randomised, controlled trials of treatments for these conditions. Bayesian mixed treatment comparison (MTC) methods were used to determine the relative efficacy and safety among the treatments within each pain condition. RESULTS: Fifty studies were identified: 33 PHN, 2 MS-related pain, 3 CPSP, 3 posttraumatic pain and 9 HIV-related NeP. Data from 28 PHN studies including 21 interventions and 4317 patients were included into the PHN MTC. Of treatments studied in ≥ 50 patients, opioids had the greatest mean pain reduction of -1.70 vs. placebo on an 11-point numeric rating scale. Pregabalin ≥ 300 mg/day was most effective for ≥ 30% and ≥ 50% pain reduction [relative risk (RR) vs. placebo = 2.44 and 2.13, respectively]. Data identified for MS-related pain, CPSP, posttraumatic pain and HIV-related NeP were sparse; only 7 of 17 studies had ≥ 50 patients. Adverse events (AEs) and discontinuations for most treatments were not significantly greater than placebo except in PHN, where 8 of 12 treatments had higher risks of AEs compared with placebo and tricyclic antidepressants and opioids had higher risk of discontinuation compared with placebo. CONCLUSIONS: Guideline-recommended treatments for PHN were more effective than placebo on the pain NRS and for ≥ 30% and ≥ 50% pain reduction. Although guidelines exist for the management of less common NeP conditions, little published evidence supports them. These results highlight the need for additional evaluations and more complete reporting of outcomes to help guide physicians' treatment selections.

The efficacy of extracorporeal life support in premature and low birth weight newborns.

Based on data obtained early in the development of neonatal extracorporeal life support (ECLS), contraindications to the use of ECLS have included low estimated gestational age (EGA) and low birth weight (BW). However, multiple improvements in the technical and management aspects of neonatal ECLS have been implemented since those early data were evaluated. The purpose of this study, therefore, is to assess in the "modern era" the efficacy of prolonged extracorporeal support in premature and low birth weight newborns. Examination of the Extracorporeal Life Support Organization (ELSO) Registry showed that between 1988 and 1991 ECLS was utilized in 158 premature (PREM, EGA < or = 34 weeks), 4,128 full-term (FT, EGA > or = 35 weeks), 26 low birth weight (LBW, BW < 2.0 kg), and 4,333 normal birth weight (NBW, BW > or = 2.0 kg) patients with respiratory failure. Data were evaluated for variables thought to be associated with a decrease in survival or an increase in the incidence of intracranial hemorrhage (ICH). A logistic regression model was developed to evaluate the ability of EGA and BW to predict survival. The incidence of survival (SURV) was decreased (63% v 84%) and ICH increased (37% v 14%) significantly in PREM when compared with FT newborns (P < .001). However, respectable survival rates in PREM patients with EGA > 32 weeks were documented. In addition, both survival and ICH in PREM patients have improved substantially when compared with past reports (Past: SURV = 25% and ICH = 100%; current: SURV = 63% and ICH = 37%; ICH P < .001; SURV P = .056). Survival was significantly decreased in LBW when compared to NBW neonates (65% v 83%, P < .05), but there was no significant difference in ICH.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal membrane oxygenation in term newborns. A prospective cost-benefit analysis.

Clinicians reserve ECMO for neonates at > 80% predicted mortality risk. The authors hypothesized that ECMO instituted at lower (50%) mortality risk would result in fewer intensive care unit days and a lower hospital cost compared with conventional therapy (including ECMO at high mortality risk). This was a randomized control trial, cost-benefit analysis in an academic newborn intensive care unit. The patients were a prospectively studied, consecutive sample of 41 term neonates with 1) age 24-72 hours, 2) "maximal medical management" for > 6 hours, 3) oxygenation index (OI) values > 25 but < 40. (Severity of illness measured by OI = ((mean airway pressure x FiO2 x 100) PaO2)). All eligible patients entered. Thirty-two of 37 survivors were evaluated at 1 year. Intervention occurred when OI = 25. Patients were randomized to ECMO or continued medical management (ECMO possible at OI = 40). Planned primary outcome measures were ICU days and hospital charges. Secondary measures were pulmonary and neurologic outcomes at discharge and 1 year. Twenty-two early ECMO patients, 19 controls, 14/19 met late ECMO criteria. Four patients died (two each group). No statistically significant difference was seen in hospital charges (early ECMO = $49,500 versus control = $53,7000), (95% confidence intervals = -$3200 to +$5100 more for controls) or ICU days (early = 14 + 5 days versus control = 19 + 12 days) (95% CI = -0.8 to +10 more for controls). At 1 year the early group had a higher mental developmental index score (115 + 11) versus (103 + 18), (p = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal membrane oxygenation: support for overwhelming pulmonary failure in the pediatric population. Collective experience from the extracorporeal life support organization.

Data from the Extracorporeal Life Support Organization (ELSO) regarding the use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with respiratory failure are reviewed. Two hundred eighty-five children between the ages of 14 days and 18 years were supported with ECMO between January 1982 and September 1991. Although these data represent the experience of 52 ECMO centers, seven centers accounted for over 50% of the total. The patients had a mean age of 33 +/- 48 months with a median age of 13 months: 137 (48%) were male and 148 (52%) were female. There were numerous primary pulmonary diagnoses: the two most common were presumed viral pneumonia (32%) and adult respiratory distress syndrome (28%). Entry criteria for ECMO, although poorly defined and specific to each institution, attempted to identify children with an 85% to 100% predicted mortality. The survival rate with ECMO was 47% (135/285). Pre-ECMO mechanical ventilatory support was extreme with an FIO2 .97 +/- .07 and a mean airway pressure (MAP) 23.6 +/- 8 cm H2O used to achieve PaO2 of 50 +/- 39 and PaCO2 51 +/- 22 mm Hg. The MAP was significantly higher in nonsurvivors versus survivors (25.3 +/- 8.7 v 22.0 +/- 7.1 cm H2O, P < .01). The duration of ECMO was 4 hours to 35.5 days with a mean of 245 +/- 165 hours, which is approximately 10 days. Duration for survivors was 222 +/- 151 hours compared with 266 +/- 176 hours for nonsurvivors. ECMO complications are divided into two categories: mechanical (directly related to the ECMO circuit) and medical (patient related).(ABSTRACT TRUNCATED AT 250 WORDS)

Multicenter comparison of conventional venoarterial access versus venovenous double-lumen catheter access in newborn infants undergoing extracorporeal membrane oxygenation.

A multicenter trial was designed to compare standard venoarterial (VA) access versus single-catheter, venovenous access using the double-lumen catheter (VV-DLC) for newborns with respiratory failure undergoing extracorporeal membrane oxygenation (ECMO). Twenty-seven ECMO centers participated, each submitting data from the center's most recent VA cases, and data from VV-DLC cases completed upon entering the study. Data from 135 VA ECMO cases and 108 VV-DLC cases were submitted. All diagnoses resulting in neonatal respiratory failure were submitted, including patients with congenital diaphragmatic hernia (24 patients VA bypass, 11 patients VV-DLC bypass). Overall survival in patients undergoing VA bypass was 87%, while survival in patients undergoing VV-DLC bypass was 95%. Eleven patients required conversion from VV-DLC bypass to VA bypass because of insufficient support--10 of these patients survived (91% survival). Average bypass time for newborns undergoing VA bypass was 132 +/- 7.4 hours versus 100 +/- 5.1 hours for those undergoing VV-DLC bypass. Neurologic complications were more common in the VA bypass patients, although the VV patients were more stable. Hemorrhagic, cardiopulmonary, and mechanical complications, other than kinking of the DLC, occurred with approximately equal frequency in each group. In conclusion, in newborns with adequate cardiac function, venovenous ECMO using the DLC can provide the same level of support as conventional VA ECMO, without ligation of the carotid artery.

Extracorporeal life support for pediatric respiratory failure.

OBJECTIVES: The purposes of this report are to a) describe the University of Michigan experience with venoarterial or venovenous extracorporeal life support for severe pediatric pulmonary rescue therapy, and b) examine survivors and nonsurvivors for differences that might be useful for examination in future, prospective studies. DESIGN: Case series report. Phase I study of safety and effectiveness of extracorporeal life support for pediatric respiratory failure. SETTING: University of Michigan Medical Center. PATIENTS: Non-neonatal pediatric patients treated with extracorporeal life support for severe respiratory failure at the University of Michigan. INTERVENTIONS: Extracorporeal life support for pulmonary failure. MEASUREMENTS AND MAIN RESULTS: From November 1982 until May 1991, 25 pediatric patients underwent extracorporeal life support for severe pulmonary failure. Twenty patients were treated in the last 36 months. Sixty percent (15/25 patients) survived their life-threatening respiratory illness, were weaned from mechanical ventilation, and were discharged home. The mean patient age was 4.1 yrs, and mechanical ventilation duration before extracorporeal life support was 5.9 days. Mean blood gas data and mechanical ventilation pressures before extracorporeal life support were: peak inspiratory pressure of 48.6 cm H2O, mean airway pressure of 21.9 cm H2O, positive end-expiratory pressure of 9.7 cm H2O, PaCO2 of 43 torr (5.7 kPa), PaO2 of 69 torr (9.1 kPa), estimated alveolar-arterial oxygen gradient of 563 torr (75 kPa), and FIO2 of 0.98. Variables associated with survival included: age of survivors vs. nonsurvivors, 2.1 vs. 7.1 yrs (p less than .02); peak inspiratory pressure of survivors vs. nonsurvivors, 43.1 vs. 57.9 cm H2O (p less than .03); mean airway pressure of survivors vs. nonsurvivors, 18.4 vs. 27.2 cm H2O (p less than .03); and positive end-expiratory pressure of survivors vs. nonsurvivors, 8.1 vs. 12.1 cm H2O (p less than .01). There were no differences detectable in the blood gas values (PaO2, PaCO2, P[A-a]O2) in survivors and nonsurvivors before extracorporeal life support. The number of days mechanical ventilation was used before extracorporeal life support in survivors and in nonsurvivors was similar. CONCLUSION: Extracorporeal life support is an effective rescue therapy for pediatric patients with severe respiratory failure (University of Michigan survival rate of 60%).

Unsuspected congenital heart disease in neonates receiving extracorporeal life support: a review of ninety-five cases from the Extracorporeal Life Support Organization Registry.

The purpose of this study was to determine the frequency of patients with congenital heart disease who were given extracorporeal life support (ECLS) for respiratory failure. Underlying congenital heart disease "masked" by respiratory failure occurred in 2%. The most frequent pre-ECLS diagnosis that "masked" congenital heart disease was persistent fetal circulation. Of neonates with a pre-ECLS diagnosis of persistent fetal circulation, congenital heart disease was found in 56 (9%) of 623 patients.

New method for describing the performance of cardiac surgery cannulas.

Cardiac surgery cannulas are characterized by external diameter only, which provides little information about the pressure-flow characteristics of a cannula. A system has been developed to describe pressure-flow characteristics with a single, unitless number, M, which is patterned after a Reynolds friction factor correlation. A cannula with a lower M number has a more favorable pressure-flow relationship. The M number was determined for 16 arterials cannulas ranging in size from 10F to 26F and 27 venous cannulas sized 12F to 36F. Pressure-flow characteristics vary considerably among cannulas from different manufacturers despite having similar French sizes. Clinical decisions regarding choice of cannula can be simplified by using the M number, which gives a more accurate description of the performance characteristics of a cannula than the French size designation.

Extracorporeal life support for cardiac assist in pediatric patients. Review of ELSO Registry data.

The collected data on extracorporeal membrane oxygenation (ECMO), now referred to as extracorporeal life support (ECLS), for pediatric cardiac support has not been analyzed. The purpose of this study was to review the Extracorporeal Life Support (ELSO) Registry data to evaluate the results, identify possible predictors of outcome, and attempt to establish criteria. From 1981 to June of 1990, 189 patients were placed on ECLS for cardiac assist. The age range was 0-204 months (median, 7 months). Mean time on ECLS was 115 +/- 75 hours. Fourteen patients were placed on ECLS as a bridge to transplant or for management of transplant rejection. All of the remaining 175 patients were treated in the postoperative period. The causes of mortality included lack of improvement in cardiovascular function in 69 (37%) of the patients, major central nervous system damage in 28 (15%), uncontrollable hemorrhage in three (2%), sepsis in three (2%), and pulmonary interstitial disease in two (1%). The Registry data were examined for predictors of outcome. There was no significant difference between survivors and nonsurvivors when compared for duration of ECLS, mechanical complications, arterial or venous blood gases, ventilation settings, or hemodynamics. Forty-three percent of 189 pediatric patients treated with ECLS for cardiac failure survived. The highest survival, 61%, occurred in right-sided lesions and the lowest, 18%, in post-Fontan. Mediastinal bleeding, cardiac arrest, renal failure, and prolonged intubation were all associated with a poor outcome. Most deaths were attributed to irreversible cardiac or brain injury, suggesting that results could be improved by earlier identification of high-risk patients and earlier institution of ECLS.

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation.

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Extracorporeal membrane oxygenation and neonatal respiratory failure: experience from the extracorporeal life support organization.

Extracorporeal membrane oxygenation (ECMO) has rescued moribund infants with respiratory failure from a variety of causes. We report the experience from 58 United States and 7 overseas ECMO centers between 1980 and 1989. Voluntarily submitted data forms provided details of diagnosis, clinical condition, ECMO indications, morbidity, and mortality. Of 3,528 infants with a predicted mortality greater than 80% treated with ECMO, 83% survived. Entry diagnoses and aggregate survival were: meconium aspiration syndrome (MAS) 1,356 (93%), persistent pulmonary hypertension of the newborn (PPHN) 480 (83%); congenital diaphragmatic hernia (CDH) 585 (62%); hyaline membrane disease (HMD) 532 (84%); sepsis 416 (77%); and other 185 (77%). ECMO indications were a-AdO2 greater than 600 for 6 to 8 hours (22%), oxygenation index greater than 40 for 4 hours (18%), acute deterioration (14%), maximal therapy failure (34%), and barotrauma (1%). Annual survival improved over 9 years except for CDH, which decreased from 70% (1987) to 56% (1989) P less than .01). Survivors differed from non-survivors (P less than .05) by birth weight (greater than 2 kg), gestational age (greater than 37 weeks), entry diagnosis (MAS, PPHN, HMD, sepsis v CDH), inborn versus outborn, pre-ECMO pH, and ECMO duration. Technical complications in 25% of patients and medical complications in 75% adversely affected survival. Annual sepsis survival improved to 75% (1989) but had significantly greater complication rates (P less than .05) than other diagnoses. Multicenter data yield information not available from single institution experience. Although entry criteria and conventional therapy continue to evolve, ECMO currently improves survival from an estimated 20% to 83% overall. Individual prognosis depends on entry diagnosis, clinical condition, and complications.

Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration.

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.

National experience with extracorporeal membrane oxygenation for newborn respiratory failure. Data from 715 cases.

In a national registry, data were collected on 715 newborn patients with severe respiratory failure supported by extracorporeal membrane oxygenation (ECMO) in 18 neonatal centers. This represents almost all infants treated with ECMO between 1980 and 1987. Eighty-one percent of the patients survived. This result is statistically significantly better than any other treatment which produces less than 78.4% survival. The most common diagnoses were meconium aspiration (310 patients, 91% survived), respiratory distress syndrome (96 patients, 78% survived), diaphragmatic hernia (121 patients, 65% survived), and sepsis (64 patients, 72% survived). Average pre-ECMO characteristics were: age 59 hours; PaO2 42 torr, PaCO2 41 torr, pH 7.40; ventilator settings FiO2 1.0, pressure 45/4 cmH2O, rate 93. Technical complications occurred in 23.1%, and physiologic complications occurred in 65.6%. Results improved with experience. Survival rate for the first ten patients from each center was 73.5% compared to 83.7% for all subsequent patients. Survival rate did not, however, significantly differ after an institutional experience of 20 patients. These observations were made on a large cohort that could not be accumulated at an individual center. These results indicate that ECMO and lung rest is appropriate and successful treatment for newborn respiratory failure unresponsive to other means of management, and that almost all respiratory failure is reversible in near-term neonates.

Recruitment experience in the Nocturnal Oxygen Therapy Trial.

The Nocturnal Oxygen Therapy Trial was a randomized controlled clinical trial sponsored by the National Heart, Lung, and Blood Institute and carried out by six clinics. The primary objective was to compare, in patients with advanced chronic obstructive pulmonary disease, the effectiveness of 24 hours of oxygen administration to that of 12 hours of oxygen administration including the patient's usual period of sleep. Some patients entering the period of baseline observation were not eligible for randomization at the end of the baseline period. Such attrition is discussed relative to setting goals for the number of patients to enter such an observation period. The impact of an enrollment rate less than what was originally projected is discussed relative to changes in the eligibility criteria and relative to the decision as to whether to extend the recruitment period.

Long-term prognosis (15 to 26 years) after repair of tetralogy of Fallot: I. Survival and symptomatic status.

One hundred eighty-two patients with tetralogy of Fallot repaired before or during 1967 were studied by interview, physical examination, and noninvasive testing. Twenty were excluded from the final analysis because review of cineangiograms and operative reports disclosed that they had had double-chambered right ventricle rather than tetralogy of Fallot. On follow-up ranging from 15 to 26 years (mean, 20.2 years), there were 86 patients in New York Heart Association Functional Class I, 53 in Class II, 5 in Class III, and none in Class IV. There were 9 late deaths. Functional classification was not ascertained in the remaining 9 patients. Cumulative survival at 25 years postoperatively was 94.4%. There was no significant relationship between survival and year of operation, age at operation, sex, or presence of a prior shunt. The 9 late deaths occurred between 6 and 23 years after operation and were due to late-onset complete heart block in 2 patients, congestive failure in 4, suicide in 1, accident in 1, and an unknown cause in 1. We conclude that long-term survival after repair of tetralogy of Fallot is excellent and not influenced by prior shunt.