Similar Rates Of Adverse Events Research Articles

Abstract WMP41: Risk of 1 Month Stroke, Adverse Events and Mortality following Carotid Endarterectomy (CEA) According to Body Mass Index, Analysis of National Surgical Quality Improvement Program (NSQIP) Registry

Background: Carotid revascularization procedures are increasingly performed in overweight and obese patients. However, whether such procedures are associated with a higher risk of peri-procedural complications is not known. Methods: We studied all patients who underwent CEA in the CEA targeted American College of Surgeons (ACS) NSQIP Registry between years 2011 and 2013. The ACS-NSQIP prospectively collects data on over 300 variables pertaining to patient characteristics, comorbidities, operative details and 30 day post-operative outcomes. Patients were divided into four groups according to body mass index (BMI in kg/m 2 ): underweight (<18.5), normal weight (18.5-24.9), overweight (25-29.9), obese (30-39.9) and morbidly obese (≥40). The odds ratios for selected outcomes were calculated after adjusting for age, gender and symptomatic status using logistic regression. Results: Among the 8576 patients who underwent CEA, 117, 2251, 3339, 2569 and 300 patients were underweight, normal weight, overweight, obese and morbidly obese. Compared with normal weight patients, the risk of stroke within 30 days was not different in overweight (1.6% vs. 2.2%; p=0.17), obese (1.6% vs. 2.4%; p=0.07) and morbidly obese patients (1.6% vs. 1.7%; p>0.999). Compared with normal weight patients, the risk of mortality within 30 days was not different in overweight (0.8% vs. 1.0%; p=0.43) and morbidly obese patients (0.7% vs. 1.0%; p>0.999) but was significantly lower in obese patients (0.5% vs. 1.0%; p=0.04). The one month stroke and/or mortality was not higher in overweight (OR: 1.16; 95% CI: 0.83-1.64; p=0.38), obese (OR: 1.06; 95% CI: 0.88-1.28; p=0.53) and morbidly obese patients (OR: 1.06; 95% CI: 0.81-1.40; p=0.65) after adjusting for potential confounders. There were no differences in the rates of adverse events such as myocardial infarction/arrhythmia, acute renal failure and unplanned intubations according to BMI strata while need for blood transfusions was significantly lower in overweight (2.1% vs. 3.7%; p<0.001) and obese (1.6% vs. 3.7%; p<0.001) patients as compared to normal weight. Conclusions: CEA can be performed with similar rates of stroke, adverse events and mortality in obese and morbidly obese patients as those observed in normal weight patients.

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

BackgroundOsimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC).MethodsIn this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival.ResultsThe median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%).ConclusionsOsimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)

Feasibility of a Collaborative, Prospective Interdisciplinary Review and Pharmacy-Based Dispensing Process for Prothrombin Complex Concentrate.

Therapeutic options for rapid reversal of vitamin K antagonist therapy include 4-factor prothrombin complex concentrate (PCC4) and fresh frozen plasma (FFP). These agents have unique requirements for preparation, potential adverse effects, and cost-effectiveness considerations. To retrospectively assess whether our process for collaborative prospective review and pharmacy preparation facilitates timely and safe warfarin reversal with PCC4 as compared with FFP and to compare effectiveness and safety of the agents in practice. We performed a retrospective, single-center, before and after cohort study of patients requiring warfarin reversal for life-threatening bleeding or urgent invasive procedures over an 18-month period. The primary end point was time from ordering of reversal agent to administration. Secondary end points measured time to therapeutic effect and rates of adverse events. Of 98 patients studied, 72 received FFP, and 26 received PCC4. The median times from ordering to administration of FFP and PCC4 were 69 and 44 minutes, respectively ( P = 0.015). Median time from ordering to end of infusion was significantly shorter for PCC4 compared with FFP (54 vs 151 minutes, respectively; P < 0.0001). In all, 72% of PCC4 patients and 28% of FFP patients achieved the goal international normalized ratio (INR) of ≤1.4 at the first INR check ( P < 0.0001). Adverse reactions occurred in 4% of patients in each group. In routine clinical practice incorporating collaborative prospective review and dispensing from the institution's pharmacy, PCC4 was associated with faster administration, a higher rate of INR correction, and similar rates of adverse events compared with FFP.

Endoscopic submucosal tunnel dissection and endoscopic submucosal dissection for large superficial esophageal squamous cell neoplasm: efficacy and safety study to guide future practice.

ESTD and ESD are currently the two primary treatment options for superficial esophageal squamous cell neoplasm (SESCN) in China. However, in larger cases, ESD proves to be technically challenging and time saving, whereas ESTD exhibits promising efficacy. This study aims to evaluate the efficacy and safety of these two techniques for large SESCN. A total of 150 patients with solitary large SESCN that underwent either ESTD (n = 52) or ESD (n = 98) between August 2011 and June 2016 were included in this study. Both efficacy and safety clinical data were collected and analyzed. All of the 150 patients were found to successfully undergo ESTD or ESD with 92.68 ± 67.96 (mean ± SD) min. The specimen area was measured to be 13.79 ± 7.44 (mean ± SD) cm2 and the dissection speed was 17.99 ± 10.40 (mean ± SD) mm2/min. En bloc resection and R0 resection were achieved in 91.33% (137/150) and 86.00% (129/150) of the cases, respectively. A total of 8.67% (13/150) were found to have intra-operative adverse events. Based on statistical analysis, ESTD was found to have a higher dissection speed and a similar adverse event rate compared with ESD. Moreover, a long operation time was found to be an independent risk factor for intra-operative adverse events. ESTD and ESD both were found to be effective and safe treatment options for the treatment of large SESCN. ESTD appeared to improve operation efficacy, which was reflected in a higher dissection speed compared with ESD. We also demonstrate that long operation times should be avoided as much as possible in order to reduce intra-operative adverse events.

Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials.

Powerful diuretics: A common denominator in landmark hypertension and type 2 diabetes mellitus trials.

An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of hospitalization, functional status, and mortality after mechanical circulatory support in adults with congenital heart disease

Adult congenital heart disease (ACHD) prevalence is increasing worldwide, with advanced heart failure (HF) as a leading cause of death. Limited data are available on durable mechanical circulatory support (MCS) in ACHD patients. ACHD patients from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database were identified and propensity matched with non-ACHD patients using risk factors from the INTERMACS Seventh Annual Report. We compared these groups for the primary outcome of post-MCS mortality. We also investigated adverse event rates, functional status, and health-related quality of life. ACHD (n = 128) and non-ACHD (n = 512) patients were appropriately matched by baseline characteristics. ACHD patients had a longer length of stay at MCS implant (24 vs 19 days, p = 0.006) but similar rates of post-MCS adverse events and hospitalization. There were similar improvements in functional status and health related quality of life post-MCS in both groups. ACHD patients had significantly higher mortality post-MCS exclusively during the first 5 months after implant (p = 0.003) and a lower probability of receiving a transplant (p = 0.003). Risk factors for early mortality were biventricular or total artificial heart device implant and age > 50 years. ACHD patients experience a higher early mortality after MCS but have similar adverse event rates and similar improvements in functional capacity and quality of life compared with non-ACHD patients. These data support expansion of MCS use in selected ACHD patients.

Refractory urgency urinary incontinence treatment in women: impact of age on outcomes and complications

Women with refractory urgency urinary incontinence (ie, unresponsive to behavioral and pharmacological interventions) are treated with onabotulinumtoxinA or sacral neuromodulation. The objective of the study was to compare treatment efficacy and adverse events in women <65 and ≥65 years old treated with onabotulinumtoxinA or sacral neuromodulation. This study was a planned secondary analysis of a multicenter, randomized trial that enrolled community-dwelling women with refractory urgency urinary incontinence to onabotulinumtoxinA or sacral neuromodulation treatments. The primary outcome was a change in mean daily urgency urinary incontinence episodes on a bladder diary over 6 months. Secondary outcomes included ≥75% urgency urinary incontinence episode reduction, change in symptom severity/quality of life, treatment satisfaction, and treatment-related adverse events. Both age groups experienced improvement in mean urgency urinary incontinence episodes per day following each treatment. There was no evidence that mean daily urgency urinary incontinence episode reduction differed between age groups for onabotulinumtoxinA (adjusted coefficient, -0.127, 95% confidence interval, -1.233 to 0.979; P= .821) or sacral neuromodulation (adjusted coefficient, -0.698, 95% confidence interval, -1.832 to 0.437; P= .227). Among those treated with onabotulinumtoxinA, women <65 years had 3.3-fold greater odds of ≥75% resolution than women ≥65 years (95% confidence interval, 1.56 -7.02). Women <65 years had a greater reduction in Overactive Bladder Questionnaire Short Form symptom bother scores compared with women ≥65 years by 7.49 points (95% confidence interval, -3.23 to -11.74), regardless of treatment group. There was no difference between quality of life improvement by age. Women ≥65 years had more urinary tract infections following onabotulinumtoxinA and sacral neuromodulation (odds ratio, 1.9, 95% confidence interval, 1.2-3.3). There was no evidence of age differences in sacral neuromodulation revision/removal or catheterization following onabotulinumtoxinA treatment. Younger women experienced greater absolute continence, symptom improvement, and fewer urinary tract infections; both older and younger women had beneficial urgency urinary incontinence episode reduction, similar rates of other treatment adverse events, and improved quality of life.

Insulin glargine 300 U/ml in type 2 diabetes mellitus patients: results of the EDITION program (review)

Unmet medical needs in basal insulin therapy include late initiation of therapy, hypoglycemia, and low patient compliance. Introduction of new basal insulin may cater to these unmet medical needs.&#x0D; New insulin glargine 300 U/mL (Gla-300) (Toujeo) is a long-acting basal insulin with a more even and prolonged PK/PD profile compared to those of insulin glargine 100 (Lantus). The glucose infusion rate profiles and insulin concentration of Gla-300 were more constant and more evenly distributed over 24 h compared to those of glargine 100 U/mL. Stable blood glucose control (≤ 5.5 mmol/L) was maintained approximately 5 h longer with glargine 300 U/mL compared to glargine 100 U/mL. The difference in PK/PD profiles of glargine 300 U/mL and glargine 100 U/mL may be a key to explanation of the Toujeo® clinical features demonstrated in the EDITION program.&#x0D; This review discusses the EDITION clinical program results in type 2 diabetes mellitus (T2MD) patients, except EDITION JP2: on previous basal-bolus therapy (EDITION 1, n=807), previous basal insulin in combination with oral anti-diabetic drug (EDITION 2, n=811), and insulin naive patients (oral anti-diabetic drug excl. SU) (EDITION 3, n=878). The EDITION program was aimed to assess the efficacy and safety of Gla-300 compared to those of glargine 100 U/mL. EDITION programs were multicenter, 1:1 randomized, open-label, parallel group, phase III, and non-inferiority studies, with similar designs and endpoints. The primary endpoint was the non-inferiority of Gla-300 vs glargine 100 U/mL, which was estimated as a HbA1c reduction at 6 months. The main secondary endpoint was the percentage of participants with one or more nocturnal confirmed (≤3.9 mmol/L) or severe hypoglycemic events from week 9 to month 6 of treatment. Patients were randomized to glargine 300 U/mL or glargine 100 U/mL once a day, with dose titration seeking fasting plasma glucose of 4.4—5.6 mmol/L.&#x0D; Non-inferiority of glargine 300 U/mL in the HbA1C reduction vs glargine 100 U/mL was confirmed in EDITION 1, EDITION 2, and EDITION 3 studies. According to the results of a pool analysis of these three trials, annualized rates of confirmed (≤3.9 mmol/L) or severe hypoglycemia were lower with glargine 300 U/mL than with glargine 100 U/mL during the night (31% difference in the rate ratio over 6 months, p=0.0002) and at any time (24 h, 14% difference, p=0.0116). Severe hypoglycemia at any time was rare (glargine 300 U/mL: 2.3%; glargine 100 U/mL: 2.6%). Weight gain was low (&lt;1 kg) in both groups, with the gain being less with glargine 300 U/ml [LS mean difference —0.28 kg (95% CI –0.55 to –0.01); p=0.039]. Both treatments were well tolerated, having similar rates of adverse events.&#x0D; In conclusion, glargine 300 U/mL was characterized by the non-inferior efficacy compared to glargine 100 U/mL, a better safety profile (reduced hypoglycemia), and lower weight gain. These advantages may allow for more active insulin dose titration in real clinical practice, contribute to better-sustained glycemic control and patient compliance, and, consequently, improve the prognosis and clinical outcome.

Lingual Tonsillectomy for Pediatric Persistent Obstructive Sleep Apnea: A Systematic Review and Meta-analysis.

Objective To determine the role of lingual tonsillectomy (LT) in pediatric patients with persistent obstructive sleep apnea (OSA) after tonsillectomy and adenoidectomy (T&A). Data Sources PubMed, OVID-MEDLINE, and Cochrane Central from 2006 to 2017. Review Methods Inclusion criteria included English-language studies containing original data on LT in pediatric patients with persistent OSA. Exclusion criteria included case reports and studies without outcome measures. Two investigators independently reviewed all manuscripts and performed quality assessment using validated tools. Meta-analysis was performed. Results Of the 866 abstracts identified, 5 studies met inclusion criteria. All studies were case series (level of evidence 4). Outcome measures included apnea-hypopnea index (AHI), minimum oxygen saturation (minSaO2), comorbidity status, and adverse events. Qualitatively, all studies demonstrated reduction in AHI and increase in minSaO2 after LT. Comorbidities may not affect the success of LT for lingual tonsil hypertrophy (LTH). LT had similar adverse event rates as T&A. Meta-analysis was performed on 4 studies. LT showed a mean change in reduction of AHI and increase of minSaO2 of -6.64 (95% CI, -8.63 to -4.65) and 4.17 (95% CI, 1.25-7.08), respectively. The overall success rate, defined as postoperative AHI <5, was 52%. Conclusion LT for LTH can be a safe and effective adjunct surgery for persistent OSA in patients after T&A. LT may reduce AHI and increase minSaO2, though complete resolution of OSA is rare. Given the limited number of patients studied, no formal recommendations can be made for the routine use of LT for LTH in persistent pediatric OSA.

Comparison of Adalimumab and Etanercept for the Treatment of Moderate to Severe Psoriasis: An Indirect Comparison Using Individual Patient Data from Randomized Trials

ObjectivesTo compare outcomes between adalimumab and etanercept in the treatment of moderate to severe plaque psoriasis. MethodsStudy groups included patients randomized to adalimumab or placebo (REVEAL and CHAMPION trials) and those randomized to etanercept or placebo (M10-114 and M10-315 trials). Week 12 outcomes were compared between patients receiving adalimumab and those receiving etanercept after adjusting for cross-trial differences in patient characteristics using propensity score weighting and after subtracting effects of placebo. Outcomes included proportion of patients achieving 75% or more, 90% or more, and 100% reductions from baseline in the Psoriasis Area and Severity Index (PASI75, PASI90, PASI100, respectively), symptom resolution (pruritus = 0; psoriatic pain = 0), lesion resolution (minimal scores for plaque signs erythema, desquamation, and induration, and by body regions head, upper limbs, trunk, and lower limbs), absence of skin-related quality-of-life impact (Dermatology Life Quality Index [DLQI] = 0), “complete disease control” (patient’s global assessment [PtGA] = 0), and adverse events. ResultsAfter adjustment, baseline characteristics were balanced among study groups (adalimumab = 875 vs. placebo = 427; etanercept = 260 vs. placebo = 130). Compared with etanercept, adalimumab was associated with significantly better placebo-adjusted outcomes (PASI75: 62.3% vs. 42.6%; PASI90: 35.9% vs. 12.1%; PASI100: 13.1% vs. 4.9%; pruritus: 24.7% vs. 13.0%; psoriatic pain: 27.4% vs. 8.7%; DLQI: 27.7% vs. 11.7%; and PtGA: 16.4% vs. 10.6%; all P < 0.05), except for similar rates of adverse events and head-specific lesion resolution. ConclusionsCompared with etanercept, adalimumab treatment for moderate to severe plaque psoriasis was associated with greater PASI reduction, higher rates of resolution of skin signs and symptoms, and greater improvements in dermatological life quality.

Direct comparison of tadalafil with sildenafil for the treatment of erectile dysfunction: a systematic review and meta-analysis

AimsErectile dysfunction (ED) is a major care problem worldwide. Tadalafil and sildenafil are the two most common phosphodiesterase 5 inhibitors used to treat ED. This systematic review and meta-analysis were conducted to directly compare tadalafil with sildenafil for the treatment of ED.MethodsWe designed a strategy for searching the PubMed, Embase, EBSCO, Web of Science and Cochrane library databases; the reference lists of the retrieved studies were also investigated. A literature review was performed to identify all published randomized or non-randomized controlled trials that compared tadalafil with sildenafil for the treatment of ED and to assess the quality of the studies. Two investigators independently and blindly screened the studies for inclusion. The meta-analysis was performed using RevMan 5.0.ResultsA total of 16 trials that compared tadalafil with sildenafil for the treatment of ED were included in the meta-analysis. In the meta-analysis, tadalafil and sildenafil appeared to have similar efficacies and overall adverse event rates. However, compared with sildenafil, tadalafil significantly improved psychological outcomes. Furthermore, the patients and their partners preferred tadalafil over sildenafil, and no significant difference was found in the adherence and persistence rates between tadalafil and sildenafil. Additionally, the myalgia and back pain rates were higher and the flushing rate was lower with tadalafil than with sildenafil.ConclusionTadalafil shares a similar efficacy and safety with sildenafil and significantly improves patients’ sexual confidence. Furthermore, patients and their partners prefer tadalafil to sildenafil. Hence, tadalafil may be a better choice for ED treatment.

Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome

BackgroundCurrent pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication.MethodsIn this single-site, double-blind, double-dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of treatment for symptoms of neonatal opioid withdrawal. Secondary clinical end points were the length of hospital stay, the percentage of infants who required supplemental treatment with phenobarbital, and safety.ResultsThe median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P<0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P=0.36). Rates of adverse events were similar in the two groups.ConclusionsAmong infants with the neonatal abstinence syndrome, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. (Funded by the National Institute on Drug Abuse; BBORN ClinicalTrials.gov number, NCT01452789.)

Are outcomes of thoracoabdominal aortic aneurysm repair different in men versus women? A propensity-matched comparison

ObjectiveWomen fare worse than men after many cardiovascular operations, including coronary artery bypass grafting and valve surgery. We sought to determine whether sex affects outcomes after open thoracoabdominal aortic aneurysm repair. MethodsWe evaluated data on 3353 consecutive patients (1281 women, 38.2%) who underwent open thoracoabdominal aortic aneurysm repair between October 1986 and July 2015. We compared preoperative characteristics, surgical variables, and outcomes between men and women in the overall group. A propensity-matching analysis was performed to adjust for preoperative and intraoperative differences. A multivariable analysis was conducted to identify predictors of poor outcomes using relevant preoperative and intraoperative factors. ResultsMen had a significantly higher prevalence of comorbid conditions, including coronary artery disease, and presented more often with dissection; women were slightly older than men (median age, 69 [62-74] years vs 67 [57-73] years; P < .001) and more often symptomatic. Men underwent extent II and IV repairs more often, whereas women more often had extent I and III repairs. The propensity analysis resulted in 958 matched pairs. Overall, women and men had similar early mortality (7.9% vs 7.2%, P = .5) and adverse event rates (14.8% vs 14.1%, P = .6), which were similar in propensity-matched groups. Multivariable analysis showed that predictors of operative death and adverse event differed between the sexes. Survival and freedom from repair failure were similar between the overall and matched groups. ConclusionsMen and women who undergo thoracoabdominal aortic aneurysm repair have similar outcomes, but there are important differences in several perioperative factors and predictors of poor outcomes.

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m2; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications.

2 Sacubitril/valsartan: real world experience of delivery and tolerability

Background Based on the PARADIGM-HF study trial, sacubitril/valsartan (SV) was approved by NICE in April 2016 (TA388) for patients with symptomatic heart failure. SV is recommended in patients with a left ventricular ejection fraction (LVEF) 35% despite a stable dose of ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB), and large numbers are potentially eligible for this first-in-class drug. However, there is a lack of real world experience of both drug tolerability and systems for initiation and monitoring in overstretched heart failure services. Methods Suitable patients were identified and started on SV by heart failure specialists. Dedicated, registrar-delivered monitoring and up titration clinics were established. Patients were reviewed 2–4 weekly. Symptoms, vital signs, biochemistry and hospital admissions were recorded at each visit. Once stable on optimal doses, patients were discharged to primary care, as pre-arranged with the District Prescribing Committee. Our initial 6 month experience has been analysed. Results 69 patients (mean age 63.2±11.6 years) were commenced on SV. Mean LVEF 27.5±6.7%; mean baseline eGFR 66.1±21.9 ml/min/1.73m2. Prior to initiation of SV, mean baseline ACEi/ARB dose was equivalent to 16.3±6.7 mg enalapril daily. Overall 68/69 (98.6%) prescriptions of SV were NICE TA388 compliant (1 patient ACEi/ARB intolerant). 9 patients (13.0%) stopped the medication due to adverse effects (PARADIGM-HF 17.8%), whilst another 3 patients (4.3%) were down titrated to a tolerable lower dose. 15.9% of all patients experienced symptomatic hypotension (PARADIGM-HF 14.0%). No episodes of angioedema, nor significant deterioration in renal function (50% reduction in eGFR) were observed. Only 1 (1.4%) patient was hospitalised with decompensated heart failure symptoms, but 3 (4.3%) patients were admitted with syncope secondary to orthostatic hypotension. A total of 36 patients were discharged, with a median ?follow up time of 39 days (IQR 23) from commencement to?stable discharge dose each requiring 1 initiation consultation and a mean of 2.4±1.0 follow up consultations. The majority of patients 25 (69.4%) were discharged at the highest ?dose?–?97/?103 mg BD. 23 (63.9%) of those discharged reported a subjective improvement in symptoms and quality of life. Conclusions Initiation of SV and dose optimisation in clinical practice represents a significant burden of additional work for heart failure teams. Dedicated, registrar-led outpatient clinics to monitor patients commenced on SV by heart failure specialists can successfully address this. Prescribing within NICE TA388 guidelines in real world patients, there were similar drug tolerance and adverse event rates to those reported in PARADIGM-HF. However, the lower mean age within this particular population, who were carefully selected, may indicate that such findings are not representative of the entire heart failure population.

Response Tailored Protocol Versus the Fixed 12 Weeks Course of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial

BackgroundThe most recent European Association for the Study of the Liver (EASL) 2016 Guidelines on treatment of hepatitis C (HCV), allowed for shortening the course of treatment for some subsets of patients with sofosbuvir/ledipasvir and with grazoprevir/elbasvir based on cutoff baseline HCV RNA values. We hypothesized that it would be prudent to also consider an objectively assuring very rapid, on-treatment, virologic response to therapy at week 2 (vRVR) before taking the decision of shortening the treatment duration. So we planned this study to test whether a dual sofosbuvir/daclatasvir (SOF/DCV) treatment duration tailored according to achieving vRVR to 8 or 12weeks is non-inferior to the recommended fixed 12weeks course in non-cirrhotic Egyptian chronic HCV genotype-4 patients. MethodsThe study was conducted in an outpatient setting according to a prospective, randomized, open-label, comparative, non-inferiority study design. A hundred twenty eligible, non-cirrhotic, chronic HCV patients were randomly assigned (1:1) to receive daily doses in the form of one Gratisovir 400mg table (generic sofosbuvir produced by Pharco Pharmaceuticals, Alexandria, Egypt) plus one Daktavira 60mg tablet (generic daclatasvir produced by Dawood Pharm, Egypt) for either a fixed 12weeks duration (reference group) or a response tailored duration (test group). In the test group the treatment duration was tailored according to the virus load tested by real time PCR into 8weeks for patients who had undetectable HCV RNA level in their serum by the end of the second week of treatment (vRVR)), or 12weeks for those who did not show vRVR. The primary outcome of the trial was the proportions of patients achieving SVR12 (HCV RNA below lower level of quantification at week 12 after end of treatment). The comparison between groups was based on testing the null hypothesis of inferiority of the response-tailored group with a pre-specified margin of non-inferiority (NI-m) of 0.1 (10%).The protocol was registered with a WHO Clinical Trial Registration ID: ACTRN12617000263392. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372041 FindingsStarting from Jun, 5 2016, a hundred twenty eligible patients from 4 outpatient clinics in Alexandria, Egypt were randomized to either a fixed duration group (reference group: n=60 patients) or a response tailored duration group (test group: n=60 patients). During the whole period of the study, only 1 patient dropped-out from each group. Both were lost to follow-up after the 4th week's visit. Baseline characteristics in both groups were almost matching. Fifty eight out of the total 60 intention-to-treat (ITT) patients in the reference group achieved SVR12 (96.67% (95% confidence interval (CI): 88.64–99%). Whereas, 59 out of the total 60 (ITT) patients in the test group achieved SVR12 (98.33% (CI: 91.14–99.71%). The per-protocol (PP) analysis, excluding patients who dropped-out before collecting their final result, showed that 58/59 (98.31% (CI: 91–99.7%)) of patients in the reference group and 59/59 (100% (CI: 93.89–100%) of the test group achieved SVR12. Non-inferiority was declared since the upper bound of the two-sided 95% CI for the difference in proportions of SVR12 between groups (P(reference)−P(test)) did not exceed the specified non-inferiority margin of +0.1 (10%), both in ITT population (−1.67%, CI: −9.8%–+5.9%), and in the PP population (−1.69%, CI: −9%–+4.58%). No fatalities or serious adverse events were reported during the period of the study. Similar rates of non-serious adverse events were reported in both groups with a trend of higher incidence rate in the fixed 12weeks group; all were mild in severity. InterpretationShortening the duration of therapy based on observed vRVR could provide a prudent basis to avoid unnecessary long treatment courses. This could not only reduce the drug exposure and the risk of adverse drug reactions, but also cut the cost of full treatment course with such expensive medications by one third. This could economize the treatment budget at the individual out-of-pocket level as well as the public health services and insurance levels and allow for better utilization of public health resources.

A meta-analysis of the use of rifaximin to prevent travellers' diarrhoea.

Travellers' diarrhoea affects tens of millions of people travelling to less developed countries or regions annually. There are positive reports of the use of rifaximin, a non-absorbed, gut-selective antibiotic to prevent travellers' diarrhoea. This study will critically review and analyse clinical trials on the subject. Using the keywords [diarrhoea OR diarrhoea OR travel*] AND [rifaximin OR xifaxan OR xifaxanta OR normix OR rifagut], a preliminary search on the PubMed and Ovid databases yielded 411 papers published in English between 1 January 1988 and 1 July 2016. Of these, there were only five relevant clinical trials. The clinical trials were double-blind, placebo-controlled, randomized trials with a total of 879 subjects. The meta-analysis found significant reduction in risk of travellers' diarrhoea with rifaximin use compared to placebo (pooled RR 0.478, 95% CI: 0.375-0.610, and P < 0.001). For the entire travel and follow-up period, the risk of developing travellers' diarrhoea was significantly greater in individuals receiving the placebo than those receiving rifaximin (daily doses of 400-600 mg). Overall, rifaximin offered significant protection rates of 48-72%, with lower protection rates for Asian than Latin American countries. In terms of tolerability, similar rates of adverse events were reported for the rifaximin and placebo group ( P > 0.05), with no clinically significant or serious adverse events related to rifaximin use. There is good evidence supporting the use of rifaximin as a chemoprophylactic agent against travellers' diarrhoea, especially in individuals who are at high risk of severe complications from acute infectious diarrhoea. Rifaximin has an excellent tolerability/safety profile and demonstrated efficacy against diarrhoeagenic Escherichia coli and even enteroinvasive bacteria such Campylobacter species. Future studies should study the most effective dosing regimen for rifaximin chemoprophylaxis, as well as profile local antimicrobial resistance/susceptibility data in less developed regions to further guide rifaximin use.

Improved costs and outcomes with conscious sedation vs general anesthesia in TAVR patients: Time to wake up?

BackgroundTranscatheter aortic valve replacement (TAVR) has become a commonplace procedure for the treatment of aortic stenosis in higher risk surgical patients. With the high cost and steadily increasing number of patients receiving TAVR, emphasis has been placed on optimizing outcomes as well as resource utilization. Recently, studies have demonstrated the feasibility of conscious sedation in lieu of general anesthesia for TAVR. This study aimed to investigate the clinical as well as cost outcomes associated with conscious sedation in comparison to general anesthesia in TAVR.MethodsRecords for all adult patients undergoing TAVR at our institution between August 2012 and June 2016 were included using our institutional Society of Thoracic Surgeons (STS) and American College of Cardiology (ACC) registries. Cost data was gathered using the BIOME database. Patients were stratified into two groups according to whether they received general anesthesia (GA) or conscious sedation (CS) during the procedure. No-replacement propensity score matching was done using the validated STS predicted risk of mortality (PROM) as a propensity score. Primary outcome measure with survival to discharge and several secondary outcome measures were also included in analysis. According to our institution's data reporting guidelines, all cost data is presented as a percentage of the general anesthesia control group cost.ResultsOf the 231 patients initially identified, 225 (157 GA, 68 CS) were included for analysis. After no-replacement propensity score matching, 196 patients (147 GA, 49 CS) remained. Overall mortality was 1.5% in the matched population with a trend towards lower mortality in the CS group. Conscious sedation was associated with significantly fewer ICU hours (30 vs 96 hours, p = <0.001) and total hospital days (4.9 vs 10.4, p<0.001). Additionally, there was a 28% decrease in direct cost (p<0.001) as well as significant decreases in all individual all cost categories associated with the use of conscious sedation. There was no difference in composite major adverse events between groups. These trends remained on all subsequent subgroup analyses.ConclusionConscious sedation is emerging as a safe and viable option for anesthesia in patients undergoing transcatheter aortic valve replacement. The use of conscious sedation was not only associated with similar rates of adverse events, but also shortened ICU and overall hospital stays. Finally, there were significant decreases in all cost categories when compared to a propensity matched cohort receiving general anesthesia.

Su1925 - Long-Term Safety and Tolerability of Oral Tofacitinib in Patients with Crohn’s Disease: Results from a Phase 2 Open-Label 48-Week Extension Study

Background: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. Aims: This 48-week open-label extension study primarily investigated long-term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease. Methods: Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks’ fixed, open-label treatment. Results: Sixty-two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non-responder imputation). Study design prevented between-dose efficacy comparisons. Conclusions: No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.

Meta-Analysis of Drug-Eluting Stents Versus Coronary Artery Bypass Grafting in Unprotected Left Main Coronary Narrowing

Patients with unprotected left main coronary artery (ULMCA) disease are increasingly treated with percutaneous coronary intervention (PCI) using new-generation drug-eluting stents (DES); however, the benefits of DES compared with coronary artery bypass grafting (CABG) in ULMCA remain controversial. This meta-analysis evaluated the effects of PCI with DES compared with CABG for the treatment of ULMCA stenosis. Databases were searched through November 30, 2016. Randomized controlled trials (RCTs) comparing DES with PCI versus CABG for ULMCA stenosis were identified. We calculated summary odds ratios (ORs) and 95% CIs with the random-effects model. The primary outcome was major adverse cardiovascular events, defined as a composite of death from any cause, stroke, or myocardial infarction (MI). The analysis included 4,612 patients from 5 RCTs. Compared with CABG, patients assigned to PCI had a similar rate of major adverse cardiovascular events (OR 1.06, 95% CI 0.79 to 1.43), all-cause mortality (OR 1.03, 95% CI 0.79 to 1.35), cardiovascular death (OR 1.03, 95% CI 0.73 to 1.45), stroke (OR 0.81, 95% CI 0.38 to 1.76), and MI (OR 1.47, 95% CI 0.87 to 2.47). The risk of any repeat revascularization was significantly greater in the PCI group than that in the CABG group (OR 1.85, 95% CI 1.53 to 2.24). In conclusion, our meta-analysis of RCTs suggest that PCI with DESresults in comparable mortality, stroke, and MI compared with CABG for revascularization of ULMCA stenosis, with PCI associated with higher rates of repeat revascularization.