Transcatheter or Surgical Treatment of Aortic-Valve Stenosis.

BACKGROUND: Among low-risk patients with severe, symptomatic aortic stenosis who are eligible for both transcatheter aortic-valve implantation (TAVI) and surgical aortic-valve replacement (SAVR), data are lacking on the appropriate treatment strategy in routine clinical practice. METHODS: In this randomized noninferiority trial conducted at 38 sites in Germany, we assigned patients with severe aortic stenosis who were at low or intermediate surgical risk to undergo either TAVI or SAVR. Percutaneous- and surgical-valve prostheses were selected according to operator discretion. The primary outcome was a composite of death from any cause or fatal or nonfatal stroke at 1 year. RESULTS: A total of 1414 patients underwent randomization (701 to the TAVI group and 713 to the SAVR group). The mean (±SD) age of the patients was 74±4 years; 57% were men, and the median Society of Thoracic Surgeons risk score was 1.8% (low surgical risk). The Kaplan-Meier estimate of the primary outcome at 1 year was 5.4% in the TAVI group and 10.0% in the SAVR group (hazard ratio for death or stroke, 0.53; 95% confidence interval [CI], 0.35 to 0.79; P<0.001 for noninferiority). The incidence of death from any cause was 2.6% in the TAVI group and 6.2% in the SAVR group (hazard ratio, 0.43; 95% CI, 0.24 to 0.73); the incidence of stroke was 2.9% and 4.7%, respectively (hazard ratio, 0.61; 95% CI, 0.35 to 1.06). Procedural complications occurred in 1.5% and 1.0% of patients in the TAVI and SAVR groups, respectively. CONCLUSIONS: Among patients with severe aortic stenosis at low or intermediate surgical risk, TAVI was noninferior to SAVR with respect to death from any cause or stroke at 1 year. (Funded by the German Center for Cardiovascular Research and the German Heart Foundation; DEDICATE-DZHK6 ClinicalTrials.gov number, NCT03112980.).

Robotic stereotactic body radiotherapy for localized prostate cancer: final analysis of the German HYPOSTAT trial.

PURPOSE: We report results of the first German prospective multicenter single-arm phase II trial (ARO 2013-06; NCT02635256) of hypofractionated robotic stereotactic body radiotherapy (SBRT) for patients with localized prostate cancer (HYPOSTAT). METHODS: Patients eligible for the HYPOSTAT study had localized prostate cancer (cT1­3 cN0 cM0), Gleason score ≤ 7, prostate-specific antigen (PSA) ≤ 15 ng/ml, prostate volume ≤ 80 cm3, and an International Prostate Symptom Score (IPSS) ≤ 12. Initially, inclusion was limited to patients ≥ 75 years or patients 70-74 years with additional risk factors. The trial protocol was later amended to allow for enrolment of patients aged ≥ 60 years. The treatment consisted of 35 Gy delivered in 5 fractions to the prostate and for intermediate- or high-risk patients, also to the proximal seminal vesicles using the CyberKnife system (Accuray Inc., Sunnyvale, CA, USA). Primary endpoint was the rate of treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity based on the RTOG scale 12-15 months after treatment. Secondary endpoints were acute toxicity, late toxicity, urinary function, quality of life, and PSA response. RESULTS: From July 2016 through December 2018, 85 eligible patients were enrolled and received treatment, of whom 83 could be evaluated regarding the primary endpoint. Patients mostly had intermediate-risk disease with a median PSA value of 7.97 ng/ml and Gleason score of 7a and 7b in 43.5% and 25.9% of patients, respectively. At the final follow-up 12-15 months after treatment, no patient suffered from treatment-related gastrointestinal or genitourinary grade ≥ 2 toxicity. Acute toxicity was mostly mild, with three grade 3 events, and the cumulative rate of grade ≥ 2 genitourinary toxicity was 8.4% (95% CI 4.1-16.4%). There were no major changes in urinary function or quality of life. The median PSA value dropped to 1.18 ng/ml 12-15 months after treatment. There was one patient who developed distant metastases. CONCLUSION: Robotic SBRT with 35 Gy in 5 fractions was associated with a favorable short-term toxicity profile. Recruitment for the HYPOSTAT­2 trial (ARO-2018­4; NCT03795337), which further analyses the late toxicity of this regimen with a planned sample size of 500 patients, is ongoing.

Radiosurgery for ventricular tachycardia (RAVENTA): interim analysis of a multicenter multiplatform feasibility trial.

BACKGROUND: Single-session cardiac stereotactic radiation therapy (SBRT) has demonstrated promising results for patients with refractory ventricular tachycardia (VT). However, the full safety profile of this novel treatment remains unknown and very limited data from prospective clinical multicenter trials are available. METHODS: The prospective multicenter multiplatform RAVENTA (radiosurgery for ventricular tachycardia) study assesses high-precision image-guided cardiac SBRT with 25 Gy delivered to the VT substrate determined by high-definition endocardial and/or epicardial electrophysiological mapping in patients with refractory VT ineligible for catheter ablation and an implanted cardioverter defibrillator (ICD). Primary endpoint is the feasibility of full-dose application and procedural safety (defined as an incidence of serious [grade ≥ 3] treatment-related complications ≤ 5% within 30 days after therapy). Secondary endpoints comprise VT burden, ICD interventions, treatment-related toxicity, and quality of life. We present the results of a protocol-defined interim analysis. RESULTS: Between 10/2019 and 12/2021, a total of five patients were included at three university medical centers. In all cases, the treatment was carried out without complications. There were no serious potentially treatment-related adverse events and no deterioration of left ventricular ejection fraction upon echocardiography. Three patients had a decrease in VT episodes during follow-up. One patient underwent subsequent catheter ablation for a new VT with different morphology. One patient with local VT recurrence died 6 weeks after treatment in cardiogenic shock. CONCLUSION: The interim analysis of the RAVENTA trial demonstrates early initial feasibility of this new treatment without serious complications within 30 days after treatment in five patients. Recruitment will continue as planned and the study has been expanded to further university medical centers. TRIAL REGISTRATION NUMBER: NCT03867747 (clinicaltrials.gov). Registered March 8, 2019. Study start: October 1, 2019.

Use of a taurolidine containing antimicrobial wash to reduce cardiac implantable electronic device infection.

AIMS: TauroPace (Tauropharm, Bavaria Germany), a taurolidine solution for combating cardiac implantable electronic device (CIED) infection, was compared with a historical control of 3% hydrogen peroxide (H2O2) in a prospective observational study. METHODS AND RESULTS: The device pocket was irrigated, and all hardware accessible within (leads, suture sleeves, pulse generator) was wiped with H2O2, TauroPace, or taurolidine in a galenic formulation during any invasive CIED procedure at the study centre. Only CIED procedures covered by TauroPace or H2O2 from 1 January 2017 to 28 February 2022 were included for analysis. Patients who underwent >1 procedure were censored for the last treatment group and reassigned at the next procedure. The primary endpoint was major CIED infection within 3 months. The secondary endpoints were CIED infection beyond 3 months, adverse events potentially related to the antimicrobial solutions, CIED system, procedure, and death, till the end of follow-up. TauroPace covered 654 procedures on 631 patients, and H2O2 covered 551 procedures on 532 patients. The TauroPace group had more patient risk factors for infection than the H2O2 group (P = 0.0058) but similar device and procedure-specific risk factors (P = 0.17). Cardiac implantable electronic device infection occurred in 0/654 (0%) of the TauroPace group and 6/551 (1.1%) of the H2O2 group (P = 0.0075). Death occurred in 23/654 (3.5%) of the TauroPace group and 14/551 (2.5%) of the H2O2 group (P = 0.33). Non-infection related adverse events were rarer in the TauroPace (3.8%) than the H2O2 (6.0%) group (P = 0.0802). CONCLUSION: TauroPace is safe but more effective than H2O2 in reducing CIED infection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05576194.

Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study.

STUDY QUESTION: What are the plasma concentrations of dydrogesterone (DYD) and its metabolite, 20α-dihydrodydrogesterone (DHD), measured on day of embryo transfer (ET) in programmed anovulatory frozen embryo transfer (FET) cycles using 10 mg per os ter-in-die (tid) oral DYD, and what is the association of DYD and DHD levels with ongoing pregnancy rate? SUMMARY ANSWER: DYD and DHD plasma levels reach steady state by Day 3 of intake, are strongly correlated and vary considerably between and within individual subjects, women in the lowest quarter of DYD or DHD levels on day of FET have a reduced chance of an ongoing pregnancy. WHAT IS KNOWN ALREADY: DYD is an oral, systemic alternative to vaginal progesterone for luteal phase support. The DYD and DHD level necessary to sustain implantation, when no endogenous progesterone is present, remains unknown. While DYD is widely used in fresh IVF cycles, circulating concentrations of DYD and DHD and inter- and intraindividual variation of plasma levels versus successful treatment have never been explored as measurement of DYD and DHD is currently only feasible by high-sensitivity chromatographic techniques such as liquid chromatography/tandem mass spectroscopy (LC-MS/MS). STUDY DESIGN, SIZE, DURATION: Prospective, clinical cohort study (May 2018-November 2020) (NCT03507673); university IVF-center; women (n = 217) undergoing a programmed FET cycle with 2 mg oral estradiol (tid) and, for luteal support, 10 mg oral DYD (tid); main inclusion criteria: absence of ovulatory follicle and low serum progesterone on Days 12-15 of estradiol intake; serum and plasma samples were taken on day of FET and stored at -80°C for later analysis by LC-MS/MS; in 56 patients, two or more FET cycles in the same protocol were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women undergoing FET on Day 2 or Day 3 (D2, D3, cleavage) or Day 5 (D5, blastocyst) of embryonic development had blood sampling on the 3rd, 4th or 6th day of 10 mg (tid) DYD oral intake, respectively. The patient population was stratified by DYD and DHD plasma levels by percentiles (≤25th versus >25th) separately by day of ET. Ongoing pregnancy rates (a viable pregnancy at >10th gestational week) were compared between ≤25th percentile versus >25th percentile for DYD and DHD levels (adjusted for day of ET). Known predictors of outcome were screened for their effects in addition to DYD, while DYD was considered as log-concentration or dichotomized at the lower quartile. Repeated cycles were analyzed assuming some correlation between them for a given individual, namely by generalized estimating equations for prediction and generalized mixed models for an estimate of the variance component. MAIN RESULTS AND THE ROLE OF CHANCE: After exclusion of patients with 'escape ovulation' (n = 14, 6%), detected by the presence of progesterone in serum on day of ET, and patients with no results from LC-MS/MS analysis (n = 5), n = 41 observations for cleavage stage ETs and n = 157 for blastocyst transfers were analyzed. Median (quartiles) of plasma levels of DYD and DHD were 1.36 ng/ml (0.738 to 2.17 ng/ml) and 34.0 ng/ml (19.85 to 51.65 ng/ml) on Day 2 or 3 and 1.04 ng/ml (0.707 to 1.62 ng/ml) and 30.0 ng/ml (20.8 to 43.3 ng/ml) on Day 5, respectively, suggesting that steady-state is reached already on Day 3 of intake. DHD plasma levels very weakly associated with body weight and BMI (R2 < 0.05), DYD levels with body weight, but not BMI. Levels of DYD and DHD were strongly correlated (correlation coefficients 0.936 for D2/3 and 0.892 for D5, respectively). The 25th percentile of DYD and DHD levels were 0.71 ng/ml and 20.675 ng/ml on day of ET. The ongoing pregnancy rate was significantly reduced in patients in the lower quarter of DYD or DHD levels: ≤25th percentile DYD or DHD 3/49 (6%) and 4/49 (8%) versus >25th percentile DYD or DHD 42/149 (28%) and 41/149 (27%) (unadjusted difference -22% (CI: -31% to -10%) and -19% (CI: -29% to -7%), adjusted difference -22%, 95% CI: -32 to -12, P < 0.0001). LIMITATIONS, REASONS FOR CAUTION: Some inter- and intraindividual variations in DYD levels could be attributed to differences in time between last 10 mg DYD intake and blood sampling, as well as concomitant food intake, neither of which were registered in this study. Ninety percent of subjects were European-Caucasian and DYD/DHD blood concentrations should be replicated in other and larger populations. WIDER IMPLICATIONS OF THE FINDINGS: Daily 10 mg DYD (tid) in an artificial FET cycle is potentially a suboptimal dose for a proportion of the population. Measurement of DYD or DHD levels could be used interchangeably for future studies. The pharmacokinetics of oral DYD and associated reproductive pharmacodynamics need further study. STUDY FUNDING/COMPETING INTEREST(S): The trial was financed by university funds, except for the cost for plasma and serum sample handling, storage and shipment, as well as the liquid chromatography-mass spectrometry (LC-MS/MS) analysis of DYD, DHD and progesterone, which was financially supported by Abbott Products Operations AG (Allschwil, Switzerland). Abbott Products Operations AG had no influence on the study protocol, study conduct, data analysis or data interpretation. K.N. has received honoraria and/or non-financial support (e.g. travel cost compensation) from Ferring, Gedeon-Richter, Merck and MSD. A.M. has no competing interests. R.V. has no competing interests. M.D. has received honoraria and/or non-financial support from Ferring and Merck. A.S.-M. has no competing interests. T.K.E. has received honoraria and/or non-financial support from Roche, Novartis, Pfizer, Aristo Pharma, Merck. G.G. has received honoraria and/or non-financial support (e.g. travel cost compensation) from Abbott, Ferring, Gedeon Richter, Guerbet, Merck, Organon, MSD, ObsEva, PregLem, ReprodWissen GmbH, Vifor and Cooper. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03507673.

Application of the Statistical Method to Convert Published PASI 50/75/90/100 into Absolute PASI Response Rate in Patients with Moderate-to-Severe Plaque Psoriasis Treated with Tildrakizumab Based on Data from the Two Pivotal Phase 3 Studies reSURFACE 1 and reSURFACE 2.

BACKGROUND: Absolute Psoriasis Area and Severity Index (PASI) is a key endpoint in psoriasis management. Petto et al. [Pharm Stat. 2019;18(1):4-21] developed a statistical method to estimate the proportion of patients reaching absolute PASI response given baseline PASI score and proportion of patients achieving relative improvements at predefined time points. OBJECTIVES: To test this method on clinical data from two phase 3 tildrakizumab trials (reSURFACE 1/2) comparing estimated absolute PASI ≤1/≤2/≤3/≤5 responses with reference responses from clinical databases. METHODS: Reference PASI responses of ≤1/≤2/≤3/≤5 were extracted from clinical databases. Estimation of absolute PASI ≤1/≤2/≤3/≤5 response rates at week (W) 12 and W28 by treatment and trial were performed. Differences between estimated and reference responses were analysed. Bland-Atman limits of agreement and Passing-Bablok regression to assess variations between estimated and reference responses were performed. RESULTS: Differences between estimated and reference absolute PASI ≤1/≤2/≤3/≤5 responses at W12 and W28 by treatment and trial were of little clinical relevance with an overall mean difference in PASI response proportion of -2.2% (e.g., for the tildrakizumab 100-mg arm, original proportions of patients achieving PASI of ≤1/≤2/≤3/≤5 at W28 were 38.5%/52.2%/63.5%/73.9% and 39.8%/54.8%/63.6%/76.9% [reSURFACE 1 and 2, respectively] vs. estimated proportions of 33.2%/49.8%/62.5%/78.3% and 34.3%/51.6%/64.5%/79.9%). Limits of agreement were -7.1% to 1.4% at W12 and -6.8% to 4.3% at W28. Scatterplots revealed linearity that stood the cusum test in Passing-Bablok regression with slope 1.14 (95% confidence intervals: 1.06 to 1.20). CONCLUSION: Good estimates of absolute PASI response rates were achieved with the application of the statistical method to tildrakizumab data reported in the phase 3 studies, in particular in the verum study arms. Our data support the method provided by Petto et al. [2019] to estimate proportions of psoriasis patients reaching absolute PASI value thresholds using relative PASI improvements.

General Versus Local Anesthesia With Conscious Sedation in Transcatheter Aortic Valve Implantation: The Randomized SOLVE-TAVI Trial.

BACKGROUND: In clinical practice, local anesthesia with conscious sedation (CS) is performed in roughly 50% of patients undergoing transcatheter aortic valve replacement. However, no randomized data assessing the safety and efficacy of CS versus general anesthesia (GA) are available. METHODS: The SOLVE-TAVI (Comparison of Second-Generation Self-Expandable Versus Balloon-Expandable Valves and General Versus Local Anesthesia in Transcatheter Aortic Valve Implantation) trial is a multicenter, open-label, 2×2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement comparing CS versus GA. The primary efficacy end point was powered for equivalence (equivalence margin 10% with significance level 0.05) and consisted of the composite of all-cause mortality, stroke, myocardial infarction, infection requiring antibiotic treatment, and acute kidney injury at 30 days. RESULTS: The primary composite end point occurred in 27.2% of CS and 26.4% of GA patients (rate difference, 0.8 [90% CI, -6.2 to 7.8]; Pequivalence=0.015). Event rates for the individual components were as follows: all-cause mortality, 3.2% versus 2.3% (rate difference, 1.0 [90% CI, -2.9 to 4.8]; Pequivalence<0.001); stroke, 2.4% versus 2.8% (rate difference, -0.4 [90% CI, -3.8 to 3.8]; Pequivalence<0.001); myocardial infarction, 0.5% versus 0.0% (rate difference, 0.5 [90% CI, -3.0 to 3.9]; Pequivalence<0.001), infection requiring antibiotics 21.1% versus 22.0% (rate difference, -0.9 [90% CI, -7.5 to 5.7]; Pequivalence=0.011); acute kidney injury, 9.0% versus 9.2% (rate difference, -0.2 [90% CI, -5.2 to 4.8]; Pequivalence=0.0005). There was a lower need for inotropes or vasopressors with CS (62.8%) versus GA (97.3%; rate difference, -34.4 [90% CI, -41.0 to -27.8]). CONCLUSIONS: Among patients with aortic stenosis undergoing transfemoral transcatheter aortic valve replacement, use of CS compared with GA resulted in similar outcomes for the primary efficacy end point. These findings suggest that CS can be safely applied for transcatheter aortic valve replacement. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02737150.

Ganglioneuromas across age groups: Systematic review of individual patient data.

BACKGROUND: Ganglioneuromas are very rare tumours of the sympathetic nervous system. Clinical and pathological knowledge is currently based on largely incomparable registries and case series that focus on paediatric or adrenal cases. To comprehensively characterize the full clinical spectrum across ages and locations, a meta-analysis was performed where amenable and complemented by systematic literature review of individual patient data (IPD). DESIGN: Articles containing "ganglioneuroma" in English on humans, published from 1/1/1995-6/27/2018, were identified from PubMed. Aggregate data from 10 eligible patient series on 19 variables were considerably inhomogeneous, restricting meta-analysis to age and gender distribution. To determine basic disease characteristics across ages and locations, IPD were retrieved from case reports and small case series (PROSPERO CRD42018010247). RESULTS: Individual patient data representing 364 cases revealed that 65.7% (60.6%-70.4%) were diagnosed in adults, more frequently in females (62%, 56.9%-66.9%). 24.5% (20.3%-39.1%) were discovered incidentally. Most often, ganglioneuromas developed in abdomen/pelvis (66.2, 32.1% adrenal). With age, the proportion of ganglioneuroma localizations with high post-surgical complication rate (35.6% head/neck and 16.3% thorax) decreased. Contrarily, the diagnosis of adrenal ganglioneuromas (<1% post-surgical complications) increased with age. Hormone production, hypertension or coincidence with another non-neuroblastic neural-crest-derived tumour component was more common for adrenal location. Recurrence and metastatic spread have not been reported for ganglioneuromas without secondary tumour component. CONCLUSIONS: This work summarizes characteristics of the currently largest number of international GN patients across all ages. The data confirm a benign nature of GN, independent of age. Age-related differences in predominant tumour location, associated post-surgical complications and hormone production suggest case-centred management strategies.

Adjuvant hypofractionated radiotherapy with simultaneous integrated boost after breast-conserving surgery: results of a prospective trial.

PURPOSE: We report results of a multicenter prospective single-arm phase II trial (ARO-2013-04, NCT01948726) of moderately accelerated hypofractionated radiotherapy with a simultaneous integrated boost (SIB) in patients with breast cancer receiving adjuvant radiotherapy after breast-conserving surgery. METHODS: The eligibility criteria included unifocal breast cancer with an indication for adjuvant radiotherapy to the whole breast and boost radiotherapy to the tumor bed. The whole breast received a dose of 40 Gy and the tumor bed a total dose of 48 Gy in 16 fractions of 2.5 and 3 Gy, respectively. Radiotherapy could be given either as 3D conformal RT (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The study was designed as a prospective single-arm trial to evaluate the acute toxicity of the treatment regimen. The study hypothesis was that the frequency of acute skin reaction grade ≥2 would be 20% or less. RESULTS: From November 2013 through July 2014, 149 patients were recruited from 12 participating centers. Six patients were excluded, leaving 143 patients for analysis. Eighty-four patients (58.7%) were treated with 3D-CRT and 59 (41.3%) with IMRT. Adherence to the treatment protocol was high. The rate of grade ≥2 skin toxicity was 14.7% (95% confidence interval 9.8-21.4%). The most frequent grade 3 toxicity (11%) was hot flashes. CONCLUSION: This study demonstrated low toxicity of and high treatment adherence to hypofractionated adjuvant radiotherapy with SIB in a multicenter prospective trial, although the primary hypothesis was not met.

Impact of guideline changes on adoption of hypofractionation and breast cancer patient characteristics in the randomized controlled HYPOSIB trial.

PURPOSE: Hypofractionated radiotherapy is the standard of care for adjuvant whole breast radiotherapy (RT). However, adoption has been slow. The indication for regional nodal irradiation has been expanded to include patients with 0-3 involved lymph nodes. We investigated the impact of the publication of the updated German S3 guidelines in 2017 on adoption of hypofractionation and enrollment of patients with lymph node involvement within a randomized controlled phase III trial. METHODS: In the experimental arm of the HYPOSIB trial (NCT02474641), hypofractionated RT with simultaneous integrated boost (SIB) was used. In the standard arm, RT could be given as hypofractionated RT with sequential boost (HFseq), normofractionated RT with sequential boost (NFseq), or normofractionated RT with SIB (NFSIB). The cutoff date for the updated German S3 guidelines was December 17, 2017. Temporal trends were analyzed by generalized linear regression models. Multiple logistic regression models were used to investigate the influence of time (prior to/after guideline) and setting (university hospital/other institutions) on the fractionation patterns. RESULTS: Enrollment of patients with involved lymph nodes was low throughout the trial. Adoption of HFseq increased over time and when using the guideline publication date as cutoff. Results of the multiple logistic regressions showed an interaction between time and setting. Furthermore, the use of HFseq was significantly more common in university hospitals. CONCLUSION: The use of HFseq in the standard arm increased over the course of the HYPOSIB trial and after publication of the S3 guideline update. This was primarily driven by patients treated in university hospitals. Enrolment of patients with lymph node involvement was low throughout the trial.

Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: the randomized SOLVE-TAVI trial.

AIMS: Transcatheter aortic valve implantation (TAVI) has emerged as established treatment option in patients with symptomatic aortic stenosis. Technical developments in valve design have addressed previous limitations such as suboptimal deployment, conduction disturbances, and paravalvular leakage. However, there are only limited data available for the comparison of newer generation self-expandable valve (SEV) and balloon-expandable valve (BEV). METHODS AND RESULTS: SOLVE-TAVI is a multicentre, open-label, 2 × 2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVI comparing SEV (Evolut R, Medtronic Inc., Minneapolis, MN, USA) with BEV (Sapien 3, Edwards Lifesciences, Irvine, CA, USA). The primary efficacy composite endpoint of all-cause mortality, stroke, moderate/severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30 days was powered for equivalence (equivalence margin 10% with significance level 0.05). The primary composite endpoint occurred in 28.4% of SEV patients and 26.1% of BEV patients meeting the prespecified criteria of equivalence [rate difference -2.39 (90% confidence interval, CI -9.45 to 4.66); Pequivalence = 0.04]. Event rates for the individual components were as follows: all-cause mortality 3.2% vs. 2.3% [rate difference -0.93 (90% CI -4.78 to 2.92); Pequivalence < 0.001], stroke 0.5% vs. 4.7% [rate difference 4.20 (90% CI 0.12 to 8.27); Pequivalence = 0.003], moderate/severe paravalvular leak 3.4% vs. 1.5% [rate difference -1.89 (90% CI -5.86 to 2.08); Pequivalence = 0.0001], and permanent pacemaker implantation 23.0% vs. 19.2% [rate difference -3.85 (90% CI -10.41 to 2.72) in SEV vs. BEV patients; Pequivalence = 0.06]. CONCLUSION: In patients with aortic stenosis undergoing transfemoral TAVI, newer generation SEV and BEV are equivalent for the primary valve-related efficacy endpoint. These findings support the safe application of these newer generation percutaneous valves in the majority of patients with some specific preferences based on individual valve anatomy.

Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction.

BACKGROUND: Experimental trials suggest improved outcome by mild therapeutic hypothermia for cardiogenic shock after acute myocardial infarction. The objective of this study was to investigate the hemodynamic effects of mild therapeutic hypothermia in patients with cardiogenic shock complicating acute myocardial infarction. METHODS: Patients (n=40) with cardiogenic shock undergoing primary percutaneous coronary intervention without classic indications for mild therapeutic hypothermia underwent randomization in a 1:1 fashion to mild therapeutic hypothermia for 24 hours or control. The primary end point was cardiac power index at 24 hours; secondary end points included other hemodynamic parameters and serial measurements of arterial lactate. RESULTS: No relevant differences were observed for the primary end point of cardiac power index at 24 hours (mild therapeutic hypothermia versus control: 0.41 [interquartile range, 0.31-0.52] versus 0.36 [interquartile range, 0.31-0.48] W/m2; P=0.50; median difference, -0.025 W/m2; 95% CI, -0.12 to 0.06). Similarly, all other hemodynamic measurements were not statistically different. Arterial lactate levels at 6, 8, and 10 hours were significantly higher in patients in the mild therapeutic hypothermia group with a slower decline ( P for interaction=0.03). There were no differences in 30-day mortality (60% versus 50%; hazard ratio, 1.27; 95% CI, 0.55-2.94; P=0.55). CONCLUSIONS: In this randomized trial, mild therapeutic hypothermia failed to show a substantial beneficial effect on cardiac power index at 24 hours in patients with cardiogenic shock after acute myocardial infarction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01890317.

Angiotensin II-mediated nondipping during sleep in healthy humans: effects on baroreflex function at subsequent daytime.

Blood pressure dipping at night is mediated by sleep-inherent, active downregulation of sympathetic vascular tone. Concomitantly, activity of the renin-angiotensin system is reduced, which might contribute to the beneficial effect of baroreflex downward resetting on daytime blood pressure homeostasis. To evaluate whether experimental nondipping mediated by angiotensin II during sleep would alter blood pressure and baroreflex function the next day in healthy humans, angiotensin-II or placebo (saline) was infused for a 7-h period at night, preventing blood pressure dipping in 11 sleeping normotensive individuals (5 males, balanced, crossover design). Baroreflex function was assessed about 1 h upon awakening and stop of infusion via microneurographic recordings of muscle sympathetic nerve activity (MSNA), showing that resting MSNA was significantly increased following angiotensin II nondipping compared with placebo (P = 0.029), whereas blood pressure and heart rate remained unchanged. Baroreflex sensitivity in response to vasoactive drug challenge was preserved, and neuroendocrine markers of fluid balance and electrolytes did not differ between conditions. Ambulatory blood pressure during subsequent daytime was not altered. Data were compared with analog experiments previously performed within the same subjects during awake daytime (ANCOVA). We conclude that angiotensin-II mediated nocturnal nondipping did not induce blood pressure elevation at subsequent daytime in healthy humans but was linked to increased vasoconstrictive sympathetic activity. This is in contrast to a prolonged increase in blood pressure in corresponding daytime experiments of the same individuals. Evidently, sleep strongly preserves normotensive blood pressure homeostasis in healthy humans.

[Aspects unique to medical device studies in review and consultation by ethics committees]. / Besonderheiten von Medizinproduktstudien bei der Bewertung und Beratung durch Ethikkommissionen.

The evaluation of the safety and performance of medical devices like implants, measuring devices or software may require clinical investigations sponsored by the manufacturer. Such clinical investigations need to be approved by the national competent authority and need the favourable opinion of the ethics committee.In the ethics committee's view, clinical investigations of medical products are special in several respects: (1) Medical devices may be marketed without authorization; (2) the effect of a device may depend on the user; (3) study designs differ strongly because there are so many different devices; (4) authorities monitor medical devices with different intensity based on risk classes; (5) device regulations are less known to physicians and ethics committees, as device regulations are younger than those for drugs; (6) many small manufacturers are not prepared for clinical investigation; (7) medical devices tend to have short lifecycles and are developed incrementally, while investigations should be product specific; and (8) manufacturers use standards.Because of these peculiarities, ethics committee consultations need to consider some distinct points: the intended use and purpose of the medical device, general requirements, existing and achievable evidence, patient's benefit, ambition of trial objectives, choice of comparator, changes to the clinical investigation plan, measures against bias, instruction of users and their learning curve, traceability of devices and of data, quality and risk management, custom-made devices, validated measuring instruments, standards and state of the art as well as funding. In short, ethics committees often have to refer to the rules and methods of evidence-based medicine.

Optimal timing of an invasive strategy in patients with non-ST-elevation acute coronary syndrome: a meta-analysis of randomised trials.

BACKGROUND: A routine invasive strategy is recommended for patients with non-ST-elevation acute coronary syndromes (NSTE-ACS). However, optimal timing of invasive strategy is less clearly defined. Individual clinical trials were underpowered to detect a mortality benefit; we therefore did a meta-analysis to assess the effect of timing on mortality. METHODS: We identified randomised controlled trials comparing an early versus a delayed invasive strategy in patients presenting with NSTE-ACS by searching MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. We included trials that reported all-cause mortality at least 30 days after in-hospital randomisation and for which the trial investigators agreed to collaborate (ie, providing individual patient data or standardised tabulated data). We pooled hazard ratios (HRs) using random-effects models. This meta-analysis is registered at PROSPERO (CRD42015018988). FINDINGS: We included eight trials (n=5324 patients) with a median follow-up of 180 days (IQR 180-360). Overall, there was no significant mortality reduction in the early invasive group compared with the delayed invasive group HR 0·81, 95% CI 0·64-1·03; p=0·0879). In pre-specified analyses of high-risk patients, we found lower mortality with an early invasive strategy in patients with elevated cardiac biomarkers at baseline (HR 0·761, 95% CI 0·581-0·996), diabetes (0·67, 0·45-0·99), a GRACE risk score more than 140 (0·70, 0·52-0·95), and aged 75 years older (0·65, 0·46-0·93), although tests for interaction were inconclusive. INTERPRETATION: An early invasive strategy does not reduce mortality compared with a delayed invasive strategy in all patients with NSTE-ACS. However, an early invasive strategy might reduce mortality in high-risk patients. FUNDING: None.

Psychosocial benefits of insulin pump therapy in children with diabetes type 1 and their families: The pumpkin multicenter randomized controlled trial.

OBJECTIVE: Continuous subcutaneous insulin infusion (CSII) is on the rise among pediatric patients with type 1 diabetes mellitus. Metabolic effects alone cannot explain this rising popularity. From the patient's perspective, the main benefits of CSII may be found in subjective psychosocial health outcomes (patient-reported outcomes [PRO]). SUBJECTS AND METHODS: In a multicenter open randomized controlled trial, children and adolescents aged 6 to16 years currently treated with multiple daily injections (MDI) were randomized 1:1, stratified by center, to either starting with CSII immediately after the baseline interview or to continuing MDI while waiting 6 months for transmission to CSII. The primary outcomes were patient-reported diabetes-specific health-related quality of life (DHRQOL) and diabetes burden of the main caregiver. Secondary outcomes were caregiver stress, fear of hypoglycemia, satisfaction with treatment, and HbA1c. RESULTS: Two-hundred and eleven patients were randomized between February 2011 and October 2014, and 186 caregivers and 170 patients were analyzed using the intention-to-treat principle for primary outcomes. Children 8 to 11 years in the CSII group reported improved DHRQOL at follow-up compared to MDI (median difference [MD] 9.5, 95% confidence interval [CI] 3.6-16.7, P = 0.004). There were no treatment differences in the adolescent age-group 12 to 16 years (MD 2.7; 95% CI -3.2-9.5; P = 0.353). The main caregivers of the CSII group reported a significant decline of overall diabetes burden at follow-up compared to the MDI group (MD 0; 95% CI -1-0; P = 0.029). Secondary PROs also were in favor of CSII. CONCLUSIONS: CSII has substantial psychosocial benefits. PROs demonstrate these benefits. Registered as NCT01338922 at clinicaltrials.gov.

Biomimetic Heparan Sulfate-Like Coated ePTFE Grafts Reduce In-graft Neointimal Hyperplasia in Ovine Carotids.

BACKGROUND: Thrombogenicity and neointimal hyperplasia are major causes for synthetic vascular graft failure. Bioactive coatings like heparin have improved patency by reducing thrombogenicity, but neointimal hyperplasia still remains an unsolved problem. Surface coatings with heparan sulfate (HS), the major component of the glycocalyx of endothelial cells, have shown reduced platelet and cell adhesion in vitro. The aim of the study was to evaluate the in vivo surface properties of expanded ePTFE vascular grafts with a semisynthetic HS-like coating (SSHS). METHODS: ePTFE vascular grafts (n = 16, diameter 3.5 mm) covalently coated with SSHS were compared with uncoated grafts (n = 16) of the same diameter in a carotid interposition model in 16 sheep. The grafts were harvested at 20 wk for histological and morphometric analysis. RESULTS: SSHS-coated grafts showed less neointima formation than uncoated grafts (P < 0.001). There was no evidence for cell or protein adhesion to SSHS-coated grafts, whereas the surface of uncoated ePTFE grafts was covered with a confluent circular layer of neointima. No difference was found concerning reactions at the anastomotic site of the genuine carotid vessel, both groups displayed neointimal hyperplasia. CONCLUSIONS: ePTFE grafts covalently coated with a semisynthetic SSHS-glycosaminoglycan successfully mimicked the endothelial glycocalyx. They displayed excellent antiadhesive properties preventing neointimal formation on the graft surface. The results indicate that a biomimetic SSHS coating may be a useful component of bioengineered grafts and an alternative to synthetic surfaces and endothelial seeding.

Clinical presentation and long-term outcome of 144 patients with microscopic polyangiitis in a monocentric German cohort.

OBJECTIVE: To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. METHODS: We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. RESULTS: Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. CONCLUSION: MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort.

A comparison between an in vitro ureteroscopic stone size estimation and the stone size measurement with the help of a scale on stone baskets.

INTRODUCTION: Endoscopic treatment of ureter stones and renal calculi relies on the surgeon's estimation of the stone size for both lithotripsy and removal of stones or stone fragments. We therefore compared precision and reliability of the endoscopic estimation of stone size by the surgeon with measurements on a scale on a stone basket. MATERIALS AND METHODS: Two surgeons (one high experienced and one low experienced) first estimated, then measured the size of 12 stones differing in size and color using different stone baskets (2.5, 3.0, 4.0 Ch) each via a semirigid renoscope in an artificial ureter under water repeatedly on two different days. All together, we had 288 measurements and 288 estimations. RESULTS: On the whole, the accuracy of the estimation diminished with bigger stones. There is an increasing underestimation with increasing stone size. Factors, which significantly influence the estimation, are the operating surgeon, the color of the stone, the time sequence, and the size of the closed basket, which was held beside the stone. The accuracy of the measurement of the stone baskets is not as good as the estimation. The small 2.5-Ch basket is the most accurate in measuring big stones (>6 mm), the 3.5 Ch in intermediate stones (3-6 mm), the big basket (4.0 Ch) in small stones (<3 mm). CONCLUSION: This first attempt at validation of a scale on stone baskets shows different results for each basket which could be systematically improved. Until now, the estimation of the surgeons is better than the measurement, but it is also influenced by factors like the surgeon or the color of the stone.