Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial.

OBJECTIVES: To investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA). METHODS: This multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry. RESULTS: In the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier. CONCLUSION: Biomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients. TRIAL REGISTRATION NUMBER: ISRCTN69963079.

Effect of Intraoperative Handovers of Anesthesia Care on Mortality, Readmission, or Postoperative Complications Among Adults: The HandiCAP Randomized Clinical Trial.

Importance: Intraoperative handovers of anesthesia care are common. Handovers might improve care by reducing physician fatigue, but there is also an inherent risk of losing critical information. Large observational analyses report associations between handover of anesthesia care and adverse events, including higher mortality. Objective: To determine the effect of handovers of anesthesia care on postoperative morbidity and mortality. Design, Setting, and Participants: This was a parallel-group, randomized clinical trial conducted in 12 German centers with patients enrolled between June 2019 and June 2021 (final follow-up, July 31, 2021). Eligible participants had an American Society of Anesthesiologists physical status 3 or 4 and were scheduled for major inpatient surgery expected to last at least 2 hours. Interventions: A total of 1817 participants were randomized to receive either a complete handover to receive anesthesia care by another clinician (n = 908) or no handover of anesthesia care (n = 909). None of the participating institutions used a standardized handover protocol. Main Outcomes and Measures: The primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. There were 19 secondary outcomes, including the components of the primary composite, along with intensive care unit and hospital lengths of stay. Results: Among 1817 randomized patients, 1772 (98%; mean age, 66 [SD, 12] years; 997 men [56%]; and 1717 [97%] with an American Society of Anesthesiologists physical status of 3) completed the trial. The median total duration of anesthesia was 267 minutes (IQR, 206-351 minutes), and the median time from start of anesthesia to first handover was 144 minutes in the handover group (IQR, 105-213 minutes). The composite primary outcome occurred in 268 of 891 patients (30%) in the handover group and in 284 of 881 (33%) in the no handover group (absolute risk difference [RD], -2.5%; 95% CI, -6.8% to 1.9%; odds ratio [OR], 0.89; 95% CI, 0.72 to 1.10; P = .27). Nineteen of 889 patients (2.1%) in the handover group and 30 of 873 (3.4%) in the no handover group experienced all-cause 30-day mortality (absolute RD, -1.3%; 95% CI, -2.8% to 0.2%; OR, 0.61; 95% CI, 0.34 to 1.10; P = .11); 115 of 888 (13%) vs 136 of 872 (16%) were readmitted to the hospital (absolute RD, -2.7%; 95% CI, -5.9% to 0.6%; OR, 0.80; 95% CI, 0.61 to 1.05; P = .12); and 195 of 890 (22%) vs 189 of 874 (22%) experienced serious postoperative complications (absolute RD, 0.3%; 95% CI, -3.6% to 4.1%; odds ratio, 1.02; 95% CI, 0.81 to 1.28; P = .91). None of the 19 prespecified secondary end points differed significantly. Conclusions and Relevance: Among adults undergoing extended surgical procedures, there was no significant difference between the patients randomized to receive handover of anesthesia care from one clinician to another, compared with the no handover group, in the composite primary outcome of mortality, readmission, or serious postoperative complications within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04016454.

Mortality after use of paclitaxel-based devices in peripheral arteries: a real-world safety analysis.

AIMS: Drug-eluting devices (DED) represent a well-established therapy being widely used for endovascular revascularization (EVR) of peripheral vessels. Recent data indicate a two-fold increased long-term mortality in patients treated with paclitaxel-based DED. The subsequent safety concerns affected international regulatory authorities to enunciate several alerts for further application of DED. METHODS AND RESULTS: In 9.2 million insurants of the German BARMER Health Insurance, data on the application of paclitaxel-based drug-eluting stents (DES) and drug-coated balloons (DCB) were retrieved from their introduction on the market in 2007 until present. All patients with first EVR between 2007 and 2015 were indexed and followed until 31 December 2017. Each subsequently applied DES, DCB, bare-metal stent, and uncoated balloon was included in further analyses. Multivariable Cox regression analysis considered potential non-linear time-dependent hazard ratios (HRs) of DES and DCB over 11 years. We identified 64 771 patients who underwent 107 112 EVR procedures using 23 137 DED. Multivariable Cox regression analysis showed paclitaxel-based DES not to be associated with increased long-term mortality for over 11 years past application (all P > 0.057). DCB was associated with decreased long-term mortality for the first year past application (HR 0.92; P < 0.001), and indifferent correlation in the years thereafter (all P > 0.202). CONCLUSION: Our real-world analysis showed no evidence for increased mortality associated with paclitaxel-based DED for over 11 years.

Physical activity and health-related quality of life in pediatric cancer patients following a 4-week inpatient rehabilitation program.

PURPOSE: Chronic health conditions and impaired quality of life are commonly experienced in childhood cancer survivors. While rehabilitation clinics support patients in coping with the disease, studies evaluating an inpatient rehabilitation program on promoting physical activity (PA) and health-related quality of life (HRQoL) are missing. METHODS: A 4-week inpatient rehabilitation program was prospectively evaluated. One hundred fifty patients with leukemia or lymphoma (N = 86), brain tumors (N = 38), and sarcomas (N = 26) were enrolled on average 17 months after cessation of acute medical treatment. PA amount and cadence (indicating the intensity of walking activity) using the StepWatch™ 3 Activity Monitor and HRQoL global and physical well-being scores using the KINDL(®) questionnaire were assessed before, immediately after, and 6 and 12 months following the program and analyzed using multiple linear mixed models. RESULTS: Significant effects on PA were only found at 12-month follow-up for amount and cadence variables (all p < 0.05). While leukemia and lymphoma patients revealed the highest PA level throughout the study, rehabilitation effects were more pronounced for cadence variables in brain tumor and sarcoma patients. The rehabilitation program had immediate (t = 4.56, p < 0.001) and sustainable effects on HRQoL global scores (6-month follow-up, t = 4.08, p < 0.001; 12-month follow-up, t = 3.13, p < 0.006). CONCLUSIONS: Immediate and sustainable increases in HRQoL indicate that a 4-week rehabilitation program is beneficial for improving psychosocial well-being, while the significant increase in PA levels could be related to general recovery as well. The lack of a control group hampers the evaluation of the rehabilitation program on promoting PA levels in pediatric cancer patients.

Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study.

INTRODUCTION: Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. METHODS AND ANALYSIS: A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5 mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598 f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. TRIAL REGISTRATION NUMBERS: NCT02933697,Pre-results.

Anticoagulation with rivaroxaban for livedoid vasculopathy (RILIVA): a multicentre, single-arm, open-label, phase 2a, proof-of-concept trial.

BACKGROUND: Livedoid vasculopathy is a thrombotic skin disease characterised by recurrent occlusion of the cutaneous microcirculation in lower extremities, which results in skin infarctions with painful ulcerations and irreversible scar formation. Rivaroxaban is a direct factor Xa inhibitor that prevents thrombus formation. We investigated whether rivaroxaban is effective for the treatment of livedoid vasculopathy. METHODS: We did this single-arm, open-label, multicenter, phase 2a, proof-of concept trial at three university hospitals in Germany. Patients with livedoid vasculopathy and a minimum pain score of 40 on the visual analogue scale were eligible to participate. Patients received oral rivaroxaban tablets for 12 weeks at an initial dose of 10 mg twice per day, which was reduced to once per day if a reduction of pain by 50% on the visual analogue scale was achieved. Subcutaneous enoxaparin at 1 mg per kg bodyweight once or twice per day was allowed as a backup treatment in case of insufficient efficacy and increased pain. The primary endpoint was change in pain on the visual analogue scale from baseline to 12 weeks. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. This trial is registered with the EU Clinical Trials Register, EudraCT number 2012-000108-13-DE, and is closed to new participants. FINDINGS: Between Dec 28, 2012, and April 24, 2014, 36 patients were screened, 28 patients were recruited for the study, and 25 patients received treatment. During treatment, five patients dropped out of the study because of withdrawal of consent (one patient), lack of compliance (one patient), violation of inclusion criteria (two patients), and a serious adverse event (one patient). Median pain on the visual analogue scale decreased from 65·0 (IQR 52·0-78·0) at baseline to 6·0 (1·0-14·0) after 12 weeks of treatment (p<0·0001). Six of the 20 patients required additional treatment with enoxaparin. Eight treatment-related adverse events were recorded in six (24%) of the 25 patients: five cases of menorrhagia including one classified as both menorrhagia and dysmenorrhoea, one case of dyspnoea, and one case of gingival bleeding. The only serious adverse reaction to rivaroxaban during the study was one case of menorrhagia in a patient with concomitant endometriosis, which resulted in study discontinuation. INTERPRETATION: Rivaroxaban seems to effectively reduce pain in livedoid vasculopathy. Therefore we suggest that rivaroxaban with enoxaparin as a backup treatment is a suitable treatment option for patients with livedoid vasculopathy. FUNDING: Deutsche Forschungsgemeinschaft and Bayer Vital.

Multistation proprioceptive exercise program prevents ankle injuries in basketball.

PURPOSE: To investigate the effectiveness of a multistation proprioceptive exercise program for the prevention of ankle injuries in basketball players using a prospective randomized controlled trial in combination with biomechanical tests of neuromuscular performance. METHODS: A total of 232 players participated in the study and were randomly assigned to a training or control group following the CONSORT statement. The training group performed a multistation proprioceptive exercise program, and the control group continued with their normal workout routines. During one competitive basketball season, the number of ankle injuries was counted and related to the number of sports participation sessions using logistic regression. Additional biomechanical pre­post tests (angle reproduction and postural sway) were performed in both groups to investigate the effects on neuromuscular performance. RESULTS: In the control group, 21 injuries occurred, whereas in the training group, 7 injuries occurred. The risk for sustaining an ankle injury was significantly reduced in the training group by approximately 65%. [corrected] The corresponding number needed to treat was 7. Additional biomechanical tests revealed significant improvements in joint position sense and single-limb stance in the training group. CONCLUSIONS: The multistation proprioceptive exercise program effectively prevented ankle injuries in basketball players. Analysis of number needed to treat clearly showed the relatively low prevention effort that is necessary to avoid an ankle injury. Additional biomechanical tests confirmed the neuromuscular effect and confirmed a relationship between injury prevention and altered neuromuscular performance. With this knowledge, proprioceptive training may be optimized to specifically address the demands in various athletic activities.