Is Intention to Treat Still the Gold Standard or Should Health Technology Assessment Agencies Embrace a Broader Estimands Framework?: Insights and Perspectives From the National Institute for Health and Care Excellence and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E9 (R1) Addendum.

OBJECTIVES: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E9 (R1) addendum will have an important impact on the design and analysis of randomized controlled clinical trials, which represent crucial sources of evidence in health technology assessments, and on the intention-to-treat (ITT) principle in particular. This article brings together a task force of health economists and statisticians in academic institutes and the pharmaceutical industry, to examine the implications of the addendum from the perspective of the National Institute for Health and Care Excellence (NICE) and the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) and to address the question of whether the ITT principle should be considered the gold standard for estimating treatment effects. METHODS: We review the ITT principle, as introduced in the ICH E9 guideline. We then present an overview of the ICH E9 (R1) addendum and its estimand framework, highlighting its premise and the proposed strategies for handling intercurrent events, and examine some cases among submissions to IQWiG and NICE. RESULTS: IQWiG and NICE appear to have diverging perspectives around the relevance of the ITT principle and, in particular, the acceptance of hypothetical strategies for estimating treatment effects, as suggested by examples where the sponsor proposed an alternative approach to the ITT principle when accounting for treatment switching for interventional oncology trials. CONCLUSIONS: The ICH E9 (R1) addendum supports the use of methods that depart from the ITT principle. The relevance of estimands using these methods depends on the perspectives and objectives of payers. It is challenging to design a study that meets all stakeholders' research questions. Different estimands may serve to answer different relevant questions or decision problems.

Changes in overactive bladder medication following bariatric surgery: segmented regression analysis.

PURPOSE: Bariatric surgery has shown reductions in overactive bladder (OAB) symptoms; however, the impacts on OAB treatment is unknown. The goal of our study is to evaluate the impact of bariatric surgery on OAB medication utilization. METHODS: We used IBM® MarketScan® commercial databases from 2005 to 2018. We included patients aged ≥ 18 years with 360 days of continuous enrollment before and after bariatric surgery (Roux-en-Y Gastric Bypass and Sleeve Gastrectomy) with at least one fill of an OAB medication in the 360 days prior to bariatric surgery. We evaluated all included patients and stratified by surgery type and patient sex. Segmented regression analyses were used to assess the proportion of patients on OAB medications before and after bariatric surgery. We replicated our findings using hip or knee replacement surgery as a negative control. RESULTS: Among the included patients (n = 3069), 92.2% were females, 58.6% underwent Roux-en-Y Gastric Bypass. Immediately following bariatric surgery, the proportion of patients treated with an OAB medication reduced from 34.8 to 14.1% (p < 0.001) resulting in a 59.5% relative reduction. Patients who underwent Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy (63.8% vs. 55.1%) relative reduction (p = 0.009)) and females versus males [62.3% vs. 52.9% relative reduction (p < 0.001)] had a more pronounced reduction in OAB medication use. There was slight decrease in OAB medication use in the negative control analysis. CONCLUSIONS: A reduction in OAB medication use following bariatric surgery may be associated with a reduction in OAB symptoms suggesting an additional benefit of bariatric surgery.

Association between gabapentinoids and oedema treated with loop diuretics: A pooled sequence symmetry analysis from the USA and Denmark.

AIMS: To assess the gabapentinoid-oedema-loop diuretic prescribing cascade in adults using large administrative health care databases from the USA and Denmark. METHODS: This study used a sequence symmetry analysis to assess loop diuretic initiation before and after the initiation of gabapentinoids among patients aged 20 years or older without heart failure or chronic kidney disease. Data from MarketScan Commercial and Medicare Supplemental Claims databases (2005 to 2019) and Danish National Prescription Register (2005 to 2018) were analyzed. Use of loop diuretics associated with initiation of selective norepinephrine reuptake inhibitors (SNRI) was used as a negative control. We assessed the pooled temporality of loop diuretic initiation relative to gabapentinoid or SNRI initiation across the 2 countries. Secular trend-adjusted sequence ratios (aSRs) with 95% confidence intervals (CIs) were calculated using data from 90 days before and after initiation of gabapentinoids. Pooled ratio of aSRs were calculated by comparing gabapentinoids to SNRIs. RESULTS: Among the 1 511 493 gabapentinoid initiators (Denmark [n = 338 941]; USA [n = 1 172 552]), 20 139 patients had a new loop diuretic prescription 90 days before or after gabapentinoid initiation, resulting in a pooled aSR of 1.33 (95% CI 1.06-1.67). The pooled aSR for the negative control (i.e., SNRI) was 0.84 (95% CI 0.75-0.94), which resulted in a pooled ratio of aSRs of 1.58 (95% CI 1.23-2.04). Pooled estimated incidence of the gabapentinoid-loop diuretic prescribing cascade was 8.14 (95% CI, 1.92-34.49) events per 1000 patient-years. CONCLUSION: We identified evidence of the gabapentinoid-oedema-loop diuretic prescribing cascade in 2 countries.

Co-utilization of opioids and nonbenzodiazepine hypnotic drugs in U.S. ambulatory care visits, 2006-2016.

OBJECTIVE(S): This study aimed to characterize the co-utilization of non-benzodiazepine sedative 'Z'-drugs with opioids at ambulatory care visits in the United States. DESIGN: A cross-sectional analysis of the National Ambulatory Medical Care Survey (NAMCS) from 2006 to 2016 was completed. SETTING AND PARTICIPANTS: Ambulatory care visits in the United States involving adult patients with an opioid prescription were included in the analysis. OUTCOME MEASURES: The primary outcome was initiation or continuation of a Z-drug (zolpidem, eszopiclone, or zaleplon) in a patient visit in conjunction with an opioid medication. RESULTS: The authors analyzed 564,090,296 visits (weighted from a sample of 28,773) with a reported opioid prescription. Co-utilization of opioids with Z-drugs fluctuated during the study period beginning at 4.0% in 2006 (95% CI 2.2%-5.7%), 6.3% in 2012 (3.7%-8.9%), and 4.7% in 2016 (2.8%-6.5%). Among all opioid visits in the study period, co-utilization with a Z-drug was not significantly different among female patients compared with male patients (5.26% vs. 4.63%, P = 0.26). Among visits with concomitant opioid and Z-drugs, 7.0% reported new initiation of both medications in the same visit. CONCLUSION: At ambulatory care visits between 2006 and 2016, co-utilization of opioids and Z-drugs fluctuated with some differences by sex. Major regulatory advisories and policy changes during this period may have contributed to these varying rates of utilization. Additional work is needed to identify predictors of co-utilization and downstream consequences more widely.

Use of negative controls in a prescription sequence symmetry analysis to reduce time-varying bias.

PURPOSE: There is an increased use in the (prescription) sequence symmetry analysis (PSSA); however, limited studies have incorporated a negative control, and no study has formally quantified and controlled for within-patient time-varying bias using a negative control. Our aim was to develop a process to incorporate the effect of negative controls into the main analysis of a PSSA. METHODS: Using a previously assessed dihydropyridine calcium channel blocker (DH-CCB) and loop diuretic PSSA, we directly compared the adjusted sequence ratios (aSRs) of DH-CCBs to each of the two negative control index drugs (levothyroxine and angiotensin converting enzyme [ACE] inhibitor/angiotensin-2 receptor blocker [ARB]) using the ratio of the aSRs to estimate a relative aSR with a Z test. Further, we utilized the relative aSR in stratum-specific analyses and varying exposure windows. RESULTS: The relative aSR of DH-CCBs decreased from 1.87 to 1.72 (95% CI 1.66-1.78) using levothyroxine as a negative control index drug. ACE inhibitor/ARB negative control index drug resulted in an aSR of 1.27 thus reducing the relative aSR for DH-CBB from 1.84 to 1.45 (95% CI 1.41-1.49). When restricting the exposure window to 180 and 90 days, the relative aSR of DH-CCBs increased to 1.68 (95% CI 1.62-1.74) and 1.86 (95% CI 1.78-1.94), respectively, relative to the ACE inhibitor/ARB negative control index drug. CONCLUSION: We illustrated how to incorporate negative control index drugs into a PSSA and generate relative aSRs. Stratum-specific assessments and varying the exposure windows while using negative control index drugs can yield more informative results.

Changes in Quantity of Opioids Dispensed following Florida's Restriction Law for Acute Pain Prescriptions.

OBJECTIVE: To assess the impact of Florida's 3-day opioid prescription supply law, effective July 2018, on opioids dispensed for acute pain patients. METHODS: Pharmacy claims from a health plan serving a large Florida employer from January 2015 through March 2019 were analyzed. We used an interrupted time series study design accounting for autocorrelation of trends before and after policy change. Acute pain patients met inclusion criteria if they had not received any opioid containing medications in the past 180 days. Patients could contribute to additional new use time if subsequent opioid claims occurred ≥180 days since the previous claim. Outcomes included mean number of units dispensed of the initial opioid prescription, mean morphine milligram equivalents (MMEs) per day of initial prescription by month, and mean total MMEs per initial prescription by month. RESULTS: A total of 8,375 enrollees had 10,583 unique opioid starts in the given timeframe. Following the policy, there was an immediate significant decrease in the units dispensed per prescription of 4.9 (95% confidence interval [CI] -8.95, -.82 units). Additionally, there was a significant immediate reduction in total MMEs dispensed per prescription of 25.6 (95% CI -44.76, -6.44 MMEs). CONCLUSIONS: Among a group of privately-insured plan enrollees in Florida, and as a result of the law, there were significant decreases in the number of units dispensed, and total MMEs of opioid prescriptions. The immediate reduction in new opioid utilization following policy implementation suggests effective policy; however, impacts on chronic pain patients were not assessed.

Effects of hydrocodone rescheduling on opioid use outcomes: A systematic review.

OBJECTIVE: To evaluate opioid prescribing, dispensing, and use in relation to hydrocodone-containing product (HCP) rescheduling. METHODS: Seven biomedical databases and grey literature sources were searched with keywords and database-specific controlled vocabulary relevant to HCP rescheduling for items published between January 2014 and July 2019. We included English-language quasi-experimental studies that assessed changes in HCP and other opioid prescribing, dispensing, utilization, and opioid-related health outcomes before and after HCP rescheduling. A data extraction sheet was created for this review. Two authors evaluated risk of bias for each included study. Two of 4 authors each independently extracted patient demographics and opioid-related outcomes from the included studies. Conflicts were resolved by a third author. RESULTS: All studies identified (n = 44) were quasi-experimental in design with 10 using an interrupted time series approach. A total of 24 studies reported a decrease in HCP prescribing by 3.1%-66.0%. Six studies reported a decrease in HCP days' supply or doses by 14.0%-80.8%. There was increased prescribing of oxycodone-containing products by 4.5%-13.9% in 5 studies, tramadol by 2.7%-53.0% in 9 studies, codeine-containing products by 0.8%-1352.9% in 8 studies). Five studies reported a decrease in morphine equivalents by at least 10%, whereas 2 studies reported an increase in morphine equivalents. Differences in populations, sample sizes, and approaches did not allow for a meta-analysis. Details regarding approach and findings were limited in published conference abstracts (n = 16). CONCLUSIONS: Hydrocodone rescheduling was associated with reductions in prescribing and use of HCPs but was also associated with increased prescribing and use of other opioids, both schedule II and nonschedule II.

Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: The THUNDER study.

INTRODUCTION: The THUNDER study provides an analysis of treatment patterns and outcomes in UK patients with severe or moderate haemophilia A (SHA/MHA) in 2015. METHODS: Patients with SHA or MHA registered with the UK National Haemophilia Database (NHD) were segregated by severity, inhibitor status and age. Haemophilia joint health score (HJHS) was derived from NHD records and treatment regimen and annualized bleed/joint-bleed rate (ABR/AJBR) from Haemtrack (HT) in HT-compliant patients. RESULTS: We report 1810 patients with SHA and 864 with MHA. Prophylaxis was used in 94.9% (n = 130/137) of HT-compliant children <12 years with SHA, falling to 74.1% (n = 123/166) aged ≥40 years. Median ABR increased with age (1.0, IQR 0.0-5.0, <12 years; 3.0 IQR, 1.0-8.0, ≥40 years). Inhibitors were present in 159 (8.8%) SHA and 34 (3.9%) MHA. Median ABR increased from 2.0 (<12 years) to 21.0 (≥40 years) in SHA inhibitor patients using prophylaxis. Prophylaxis was used by 68.8% of HT-compliant MHA patients (n = 106) (median FVIII baseline 0.01 IU/mL) associated with a median (IQR) ABR of 3.0 (1.0-7.0). Median HJHS (n = 453) increased with age in SHA and MHA. Median (IQR) HJHS was higher in SHA inhibitor (17.0, 0.0-64.5) than non- or past inhibitor patients (7.0, 0.0-23.0). CONCLUSIONS: Increasing ABR with age persists despite current prophylaxis regimens. SHA and MHA had similar ABR/AJBR and HJHS, leading to a suspicion that a subgroup of MHA may be relatively undertreated. More intensive prophylaxis may improve outcomes, but this requires further study.

Population pharmacokinetic analysis of danvatirsen supporting flat dosing switch.

Danvatirsen is a Generation 2.5 antisense oligonucleotide under clinical development. Population PK modelling was conducted using data from 3 available danvatirsen Phase I/II studies in oncology patients to investigate the impact of flat dosing on exposure compared to ideal body weight-based dosing. A total of 126 patients who received danvatirsen doses ranging from 1 to 4 mg/kg as monotherapy or in combination with durvalumab, most at 3 mg/kg (n = 70), was used in the danvatirsen population PK analysis. A 2-compartment model with linear elimination described the data well. Covariate analysis revealed ideal body weight was not a significant covariate on the PK of danvatirsen; nor was age, sex or race. The model-based simulation suggested that steady state weekly AUC and Cmax were very similar between 3 mg/kg and 200 mg flat dosing (geometric mean of AUC: 62.5 vs. 63.4 mg h/L and Cmax: 26.2 vs. 26.5 mg/L for two dose groups) with slightly less overall between-subject variability in the flat dosing regimen. The switch to flat dosing was approved by multiple regulatory agencies, including FDA, EMA, PMDA and ANSM. Several ongoing studies have been evaluating flat dosing. Interim analysis from an ongoing study (D5660C00016, NCT03421353) has shown the observed steady state concentration from 200 mg flat dose is in agreement with the model predictions. The population PK model could be further utilized in subsequent exposure-response efficacy and safety modelling.

An evaluation of a potential calcium channel blocker-lower-extremity edema-loop diuretic prescribing cascade.

OBJECTIVES: Dihydropyridine calcium channel blockers (DH-CCB) are associated with lower-extremity edema (LEE). Loop diuretics have been used inappropriately to treat DH-CCB-associated LEE, constituting a prescribing cascade (PC). The aim of this work was to identify the prevalence and factors associated with potential DH-CCB-LEE-loop diuretic PC. METHODS: The 2014 National Ambulatory Medical Care Survey was used to identify patient visits in which a DH-CCB was continued. The definition of a potential PC was the continuation or initiation of a loop diuretic in the absence of congestive heart failure, cancer, obstructive sleep apnea, chronic kidney disease or end-stage renal disease, obesity, or resistant hypertension. Multivariable logistic regression was used to identify factors related to a potential PC, including demographic information, number of medications, number of patient visits in the previous 12 months, and comorbid conditions. RESULTS: Among the estimated 47.5 million patient visits in which a DH-CCB was continued, 4.6% had a potential PC. Visits in patients 65 to 84 years of age (odds ratio [OR] 2.56, 95% CI 1.20-5.43) and 85 years of age and older (OR 3.89, 95% CI 1.76-8.61) were more likely to have potential PC compared with patients 18 to 64 years of age. Visits in patients with 5 to 7 (OR 3.75, 95% CI 1.72-8.19), 8 to 11 (OR 2.20, 95% CI 1.09-4.44), and 12 or more (OR 5.23, 95% CI 2.29-11.94) medications were more likely to have potential PC compared with patients with 4 or fewer medications. CONCLUSION: A potential DH-CCB-associated LEE loop diuretic PC was present in approximately 2.2 million patient visits in which DH-CCB was continued. Older age and an increasing number of concomitant medications were associated with this potential PC.

Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when?

Gastrointestinal haemorrhage is a common clinical scenario and, in those using antithrombotic agents, the risk is significantly increased. Management of these patients, in terms of initial resuscitation is well established and numerous guidelines exist in this area. However, few studies have addressed the subsequent dilemma of if and when antithrombotic agents should be reintroduced. Consequently, practice is variable and not necessarily evidenced-based. Overall, for patients that are either anticoagulated or using antiplatelet drugs for secondary prophylaxis, there is a clear benefit to restarting these agents. However, there is limited data to guide when this should occur. For individuals at low risk of re-bleeding, current guidelines suggest single agent aspirin can be continued without interruption, assuming haemostatic control has been confirmed endoscopically. For those at higher bleeding risk, aspirin should be withheld, but reintroduced early (within 3 days of index endoscopy). However, randomised evidence is lacking, as are studies including more modern agents or combined anticoagulant/ antiplatelet regimens. As such, guidance statements are limited and management suggestions must be extrapolated from clinical trials, retrospective studies and data relating specifically to warfarin and aspirin. The intention of this review is to summarise what evidence is available and, where this is lacking, suggest pragmatic management options based on a risk-benefit assessment of thromboembolism and recurrent bleeding.

IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response.

The activation of pro-inflammatory gene programs by nuclear factor-kappaB (NF-kappaB) is primarily regulated through cytoplasmic sequestration of NF-kappaB by the inhibitor of kappaB (IkappaB) family of proteins. IkappaBbeta, a major isoform of IkappaB, can sequester NF-kappaB in the cytoplasm, although its biological role remains unclear. Although cells lacking IkappaBbeta have been reported, in vivo studies have been limited and suggested redundancy between IkappaBalpha and IkappaBbeta. Like IkappaBalpha, IkappaBbeta is also inducibly degraded; however, upon stimulation by lipopolysaccharide (LPS), it is degraded slowly and re-synthesized as a hypophosphorylated form that can be detected in the nucleus. The crystal structure of IkappaBbeta bound to p65 suggested this complex might bind DNA. In vitro, hypophosphorylated IkappaBbeta can bind DNA with p65 and c-Rel, and the DNA-bound NF-kappaB:IkappaBbeta complexes are resistant to IkappaBalpha, suggesting hypophosphorylated, nuclear IkappaBbeta may prolong the expression of certain genes. Here we report that in vivo IkappaBbeta serves both to inhibit and facilitate the inflammatory response. IkappaBbeta degradation releases NF-kappaB dimers which upregulate pro-inflammatory target genes such as tumour necrosis factor-alpha (TNF-alpha). Surprisingly, absence of IkappaBbeta results in a dramatic reduction of TNF-alpha in response to LPS even though activation of NF-kappaB is normal. The inhibition of TNF-alpha messenger RNA (mRNA) expression correlates with the absence of nuclear, hypophosphorylated-IkappaBbeta bound to p65:c-Rel heterodimers at a specific kappaB site on the TNF-alpha promoter. Therefore IkappaBbeta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, IkappaBbeta(-/-) mice are resistant to LPS-induced septic shock and collagen-induced arthritis. Blocking IkappaBbeta might be a promising new strategy for selectively inhibiting the chronic phase of TNF-alpha production during the inflammatory response.

Aromatic monomers by in situ conversion of reactive intermediates in the acid-catalyzed depolymerization of lignin.

Conversion of lignin into well-defined aromatic chemicals is a highly attractive goal but is often hampered by recondensation of the formed fragments, especially in acidolysis. Here, we describe new strategies that markedly suppress such undesired pathways to result in diverse aromatic compounds previously not systematically targeted from lignin. Model studies established that a catalytic amount of triflic acid is very effective in cleaving the ß-O-4 linkage, most abundant in lignin. An aldehyde product was identified as the main cause of side reactions under cleavage conditions. Capturing this unstable compound by reaction with diols and by in situ catalytic hydrogenation or decarbonylation lead to three distinct groups of aromatic compounds in high yields acetals, ethanol and ethyl aromatics, and methyl aromatics. Notably, the same product groups were obtained when these approaches were successfully extended to lignin. In addition, the formation of higher molecular weight side products was markedly suppressed, indicating that the aldehyde intermediates play a significant role in these processes. The described strategy has the potential to be generally applicable for the production of interesting aromatic compounds from lignin.

An observational cohort study of patients with newly diagnosed digital ulcer disease secondary to systemic sclerosis registered in the EUSTAR database.

OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.

Transfer Hydrogenation Employing Ethylene Diamine Bisborane in Water and Pd- and Ru-Nanoparticles in Ionic Liquids.

Herein we demonstrate the use of ethylenediamine bisborane (EDAB) as a suitable hydrogen source for transfer hydrogenation reactions on C-C double bonds mediated by metal nanoparticles. Moreover, EDAB also acts as a reducing agent for carbonyl functionalities in water under metal-free conditions.

Changes in Mood in New Enrollees at a Program of All-Inclusive Care for the Elderly.

OBJECTIVES: To examine changes in mood after nine months of enrollment in a Program of All-Inclusive Care for the Elderly (PACE). DESIGN: Cohort study. SETTING: Alexian Brothers PACE, St. Louis, Missouri. PARTICIPANTS: Newly enrolled patients 55 years of age and older, living in the PACE service area, eligible for nursing facility care and able to live safely in the community, with continuous care, for at least nine months (N = 182). MAIN OUTCOME MEASURES: Geriatric Depression Scale (GDS)-15 score at the pre-admission evaluation (PAE) and the nine-month evaluation (9ME). RESULTS: Of the 182 patients evaluated, 27% (n = 49) met the definition of depression as defined by the GDS-15 score of ≥ 6 at the PAE. At the 9ME, only 11% of patients met the depression criteria (P < 0.001). Of the patients who met the criteria for depression at the PAE, 80% of patients (n = 39) no longer met these criteria at the 9ME (P = 0.029). Similar findings were observed by age, gender, and race. Greater improvement was observed among those who were depressed at the PAE; the depressed cohort improved by 5.0 points (P < 0.001) on the GDS-15 scale from the PAE to the 9ME, whereas the nondepressed cohort improved by 0.6 points (P = 0.003). CONCLUSION: The use of PACE as an alternative intervention may be a good option to improve mood in older adults.

Reaction progress kinetic analysis of a copper-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline.

The results from a kinetic investigation of a Cu-catalyzed oxidative coupling reaction between N-phenyl tetrahydroisoquinoline and a silyl enol ether using elemental oxygen as oxidant are presented. By using reaction progress kinetic analysis as an evaluation method for the obtained data, we discovered information regarding the reaction order of the substrates and catalysts. Based on this information and some additional experiments, a refined model for the initial oxidative activation of the amine substrate and the activation of the nucleophile by the catalyst was developed. The mechanistic information also helped to understand why silyl nucleophiles have previously failed in a related Cu-catalyzed reaction using tert-butyl hydroperoxide as oxidant and how to overcome this limitation.

Use of onabotulinumtoxinA for overactive bladder with concomitant warfarin.

The symptoms of overactive bladder (OAB) can be treated with oral medications using a variety of antimuscarinic medications and, more recently, mirabegron, a beta-3 agonist. However, the use of these medications may be limited for patients because of adverse drug reactions, contraindications, and those who are refractory to oral medications. Recently, intravesical injections of onabotulinumtoxinA (onaBoNTA) have been proven to be safe and effective as an alternative to oral OAB medications. Although this procedure is typically thought to be outside the realm of a consultant pharmacist, there are incidences in which a pharmacist can make a substantial impact on patient care. The patient, a 71-year old female, presents to her urologist for evaluation to assess appropriateness of intravesical onaBoNTA injections. She has failed multiple oral medications for the treatment of her OAB with urge incontinence. The procedure is further complicated by the patient's past medical history of atrial fibrillation (A fib), deep vein thrombosis (DVT), and pulmonary embolism (PE) that require anticoagulation with warfarin therapy. This case demonstrates the use of onaBoNTA for OAB in a patient concomitantly receiving warfarin for A fib, PE, and DVT. Specifically, it demonstrates discontinuation, bridge therapy, and reinitiation of warfarin on a patient undergoing intravesical injections of onaBoNTA for OAB, and a collaborative approach to care between a pharmacist and a urologist.

Mirabegron: a Beta-3 agonist for overactive bladder.

OBJECTIVE: To review the literature regarding the efficacy and safety of mirabegron for the treatment of overactive bladder (OAB). DATA SOURCES: A literature search was performed using MEDLINE (PubMed) prior to December 31, 2013, using the terms "mirabegron" and "randomized-controlled trial." STUDY SELECTION/DATA EXTRACTION: All published, double-blind, randomized-controlled trials assessing mirabegron were included. Articles were reviewed and included if mirabegron was used as monotherapy and if the primary outcome analyzed drug efficacy. DATA SYNTHESIS: The efficacy of mirabegron for the treatment of OAB has been demonstrated in the selected five randomized, placebo-controlled trials. The majority of these trials lasted 12 weeks and compared various doses of mirabegron with placebo and/or tolterodine extended-release (ER). Primary efficacy outcomes for the trials included mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Included trials showed statistically significant reductions in both efficacy outcomes for various doses of mirabegron when compared with placebo. CONCLUSION: Based on the trials reviewed, mirabegron has been efficacious in reducing mean number of micturitions and incontinence episodes per 24 hours, as well as in improving other secondary outcomes such as OAB symptoms and quality-of-life measures. Common adverse drug events seen with mirabegron include: hypertension, nasopharyngitis, urinary tract infections, headache, constipation, upper respiratory tract infection, arthralgia, diarrhea, tachycardia, abdominal pain, and fatigue. Given the efficacy and safety data currently available, mirabegron represents a reasonable alternative to antimuscarinics for patients with OAB. Future studies are needed to determine the utility of mirabegron for OAB in a variety of demographics.