Posterior Probability Of Superiority Research Articles

Abstract 14153: P2Y12 Inhibitors and Quality of Life Outcomes in Critically Ill Patients Hospitalized for COVID-19: A Pre-Specified Secondary Analysis of the ACTIV4a Randomized Clinical Trial

Background: Post-acute sequela of COVID-19 (PASC) is a complication of SARS-CoV-2 causing persistent symptoms and impaired functional status. We studied the effect of P2Y12 inhibitors on health-related Quality of Life (QoL) at 90 days in critically ill patients hospitalized for COVID-19. Methods: Adults hospitalized for COVID-19 who were randomized in the P2Y12 inhibitor domain of ACTIV-4a platform trial between February 2021 and June 2022. Participants were to receive usual care and either P2Y12 inhibitor (ticagrelor preferred) or no P2Y12 inhibitor for 14-days or until hospital discharge, whichever was sooner. The QoL primary outcome was determined by the EQ-5D-5L utility and visual analog scores, standardized and validated instruments. A Bayesian model estimated difference in health related QoL by randomization status adjusting for risk factors. Results: Among 1,502 participants, 860 critically ill patients were administered English and Spanish translations of EQ-5D-5L at 90-days. Median age was 57 years (IQR: 47, 65), 37% were female, 49% were under-represented minorities, and 10% resided in Spain. In those assigned to P2Y12 inhibitor, the mean EQ-5D-5L utility score was better in those assigned to usual care (adjusted difference: 0.08, 95% CrI: 0.03, 0.13; posterior probability of superiority [defined as a mean difference > 0] was 99.9%). Better health related QoL was also observed with assignment to P2Y12 inhibitors; EQ-5D-5L visual analog score adjusted difference: 5.30 (95% Crl: -0.49, 10.84), probability of superiority: 96.4% (table 1). Conclusion: In secondary analysis of an international randomized trial of critically ill participants with COVID-19, treatment with a P2Y12 inhibitor vs usual care was associated with improved quality of life at 90-days and may decrease symptoms of PASC following hospital discharge.

Rehabilitation Interventions for Physical Capacity and Quality of Life in Adults With Post–COVID-19 Condition

Current rehabilitation guidelines for patients with post-COVID-19 condition (PCC) are primarily based on expert opinions and observational data, and there is an urgent need for evidence-based rehabilitation interventions to support patients with PCC. To synthesize the findings of existing studies that report on physical capacity (including functional exercise capacity, muscle function, dyspnea, and respiratory function) and quality of life outcomes following rehabilitation interventions in patients with PCC. A systematic electronic search was performed from January 2020 until February 2023, in MEDLINE, Scopus, CINAHL, and the Clinical Trials Registry. Key terms that were used to identify potentially relevant studies included long-covid, post-covid, sequelae, exercise therapy, rehabilitation, physical activity, physical therapy, and randomized controlled trial. This study included randomized clinical trials that compared respiratory training and exercise-based rehabilitation interventions with either placebo, usual care, waiting list, or control in patients with PCC. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A pairwise bayesian random-effects meta-analysis was performed using vague prior distributions. Risk of bias was assessed using the Cochrane risk of bias tool version 2, and the certainty of evidence was evaluated using the GRADE system by 2 independent researchers. The primary outcome was functional exercise capacity, measured at the closest postintervention time point by the 6-minute walking test. Secondary outcomes were fatigue, lower limb muscle function, dyspnea, respiratory function, and quality of life. All outcomes were defined a priori. Continuous outcomes were reported as standardized mean differences (SMDs) with 95% credible intervals (CrIs) and binary outcomes were summarized as odds ratios with 95% CrIs. The between-trial heterogeneity was quantified using the between-study variance, τ2, and 95% CrIs. Of 1834 identified records, 1193 were screened, and 14 trials (1244 patients; 45% female participants; median [IQR] age, 50 [47 to 56] years) were included in the analyses. Rehabilitation interventions were associated with improvements in functional exercise capacity (SMD, -0.56; 95% CrI, -0.87 to -0.22) with moderate certainty in 7 trials (389 participants). These improvements had a 99% posterior probability of superiority when compared with current standard care. The value of τ2 (0.04; 95% CrI, 0.00 to 0.60) indicated low statistical heterogeneity. However, there was significant uncertainty and imprecision regarding the probability of experiencing exercise-induced adverse events (odds ratio, 1.68; 95% CrI, 0.32 to 9.94). The findings of this systematic review and meta-analysis suggest that rehabilitation interventions are associated with improvements in functional exercise capacity, dyspnea, and quality of life, with a high probability of improvement compared with the current standard care; the certainty of evidence was moderate for functional exercise capacity and quality of life and low for other outcomes. Given the uncertainty surrounding the safety outcomes, additional trials with enhanced monitoring of adverse events are necessary.

Effect of P2Y12 Inhibitors on Organ Support–Free Survival in Critically Ill Patients Hospitalized for COVID-19

Platelet activation is a potential therapeutic target in patients with COVID-19. To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. ClinicalTrials.gov Identifier: NCT04505774.

Abstract 14850: Effect of Therapeutic-Dose Heparin on Acute Kidney Injury in Non-Critically Ill Hospitalized Patients With Covid-19: The Activ4a and Attac Randomized Trial

Background: Acute kidney injury (AKI) is common in patients with COVID-19 and mediated, in part, by thromboinflammation. In non-critically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support. We investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in non-critically ill patients hospitalized for COVID-19. Methods: Non-critically ill patients hospitalized for COVID-19 were enrolled in an open-label, multiplatform randomized trial of therapeutic-dose heparin versus usual-care pharmacologic thromboprophylaxis. The primary endpoint of this analysis was in-hospital diagnosis of AKI or death. AKI was defined as Kidney Disease Improving Global Outcomes stage 2 or 3 AKI (≥2-fold increase in serum creatinine or initiation of renal replacement therapy). A Bayesian statistical model estimated the risk of AKI or death between those randomized to therapeutic-dose anticoagulation versus usual-care thromboprophylaxis, adjusted for age, sex, D-dimer, time epoch, country, site, and platform. Results: Among 1922 enrolled from ACTIV4a and ATTACC, 23 were excluded due to ESRD at enrollment. Baseline or follow-up creatinine was missing for 205 individuals. Among 1694 participants analyzed, median age was 60, 58% were men, and median baseline creatinine was 0.9 mg/dL. The primary endpoint occurred in 83 participants (4.9%); 4.4% assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR] 0.72, 95% CrI 0.47-1.10; posterior probability of superiority [defined as relative risk < 1.0] was 93.6%). Therapeutic-dose anticoagulation was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs. 4.6%; aRR 0.64, 95% CrI 0.40-0.99) compared to usual-care thromboprophylaxis. Conclusions: Therapeutic-dose anticoagulation with heparin was associated with a high probability of superiority to reduce the incidence of in-hospital stage 3 AKI or death in non-critically ill patients hospitalized for COVID-19, compared with usual-care thromboprophylaxis.

Biodegradable- Versus Durable-Polymer Drug-Eluting Stents for STEMI: Final2-YearOutcomes of the BIOSTEMI Trial.

The aim of this study was to investigate the safety and efficacy of biodegradable-polymer sirolimus-eluting stents (BP-SES) compared with durable-polymer everolimus-eluting stents (DP-EES) in patients with ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI) is an effective treatment for patients with STEMI, and long-term outcomes are determined by the safety and efficacy profile of the newest generation drug-eluting stents. BIOSTEMI (A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent for Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention) was an investigator-initiated, multicenter, assessor-blind, randomized superiority trial using Bayesian methods. Patients with STEMI undergoing primary PCI within 24h of symptom onset were randomized in a 1:1 ratio to receive BP-SES (n=649) or DP-EES (n=651). The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target vessel myocardial reinfarction, and clinically indicated target lesion revascularization (TLR) at 2 years. Between April 2016 and March 2018, 1,300 patients were included. Baseline characteristics were comparable between the 2 treatment groups. Follow-up through 2 years was complete in 1,221 patients (94%). At 2 years, TLF occurred in 33 patients (5.1%) treated with BP-SES and in 53 patients (8.1%) treated with DP-EES (rate ratio: 0.58; 95% Bayesian credible interval: 0.40 to 0.84; posterior probability of superiority=0.998). The difference was driven by a lower incidence of clinically indicated TLR in patients treated with BP-SES compared with DP-EES (2.5% vs. 5.1%; rate ratio: 0.52; 95% Bayesian credible interval: 0.30 to 0.87; posterior probability of superiority=0.993). There were no significant differences in rates of cardiac death, target vessel myocardial reinfarction, and definite stent thrombosis between the 2 treatment arms. In patients with STEMI undergoing primary PCI, BP-SES were superior to DP-EES with respect to TLF at 2 years. The difference was driven by lower rates of ischemia-driven TLR. (A Comparison of an Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent for Patients With AcuteST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention [BIOSTEMI];NCT02579031).

Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial

Newer-generation drug-eluting stents that combine ultrathin strut metallic platforms with biodegradable polymers might facilitate vascular healing and improve clinical outcomes in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention (PCI) compared with contemporary thin strut second-generation drug-eluting stents. We did a randomised clinical trial to investigate the safety and efficacy of ultrathin strut biodegradable polymer sirolimus-eluting stents versus thin strut durable polymer everolimus-eluting stents in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI. The BIOSTEMI trial was an investigator-initiated, multicentre, prospective, single-blind, randomised superiority trial at ten hospitals in Switzerland. Patients aged 18 years or older with acute STEMI who were referred for primary PCI were eligible to participate. Patients were randomly allocated (1:1) to either biodegradable polymer sirolimus-eluting stents or durable polymer everolimus-eluting stents. Central randomisation was done based on a computer-generated allocation sequence with variable block sizes of 2, 4, and 6, which was stratified by centre, diabetes status, and presence or absence of multivessel coronary artery disease, and concealed using a secure web-based system. Patients and treating physicians were aware of group allocations, whereas outcome assessors were masked to the allocated stent. The experimental stent (Orsiro; Biotronik; Bülach, Switzerland) consisted of an ultrathin strut cobalt-chromium metallic stent platform releasing sirolimus from a biodegradable polymer. The control stent (Xience Xpedition/Alpine; Abbott Vascular, Abbott Park, IL, USA) consisted of a thin strut cobalt-chromium stent platform that releases everolimus from a durable polymer. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial reinfarction (Q-wave and non-Q-wave), and clinically-indicated target lesion revascularisation, within 12 months of the index procedure. All analyses were done with the individual participant as the unit of analysis and according to the intention-to-treat principle. The trial was registered with ClinicalTrials.gov, number NCT02579031. Between April 26, 2016, and March 9, 2018, we randomly assigned 1300 patients (1623 lesions) with acute myocardial infarction to treatment with biodegradable polymer sirolimus-eluting stents (649 patients and 816 lesions) or durable polymer everolimus-eluting stents (651 patients and 806 lesions). At 12 months, follow-up data were available for 614 (95%) patients treated with biodegradable polymer sirolimus-eluting stents and 626 (96%) patients treated with durable polymer everolimus-eluting stents. The primary composite endpoint of target lesion failure occurred in 25 (4%) of 649 patients treated with biodegradable polymer sirolimus-eluting stents and 36 (6%) of 651 patients treated with durable polymer everolimus-eluting stents (difference -1·6 percentage points; rate ratio 0·59, 95% Bayesian credibility interval 0·37-0·94; posterior probability of superiority 0·986). Cardiac death, target vessel myocardial reinfarction, clinically-indicated target lesion revascularisation, and definite stent thrombosis were similar between the two treatment groups in the 12 months of follow-up. In patients with acute STEMI undergoing primary PCI, biodegradable polymer sirolimus-eluting stents were superior to durable polymer everolimus-eluting stents with respect to target lesion failure at 1 year. This difference was driven by reduced ischaemia-driven target lesion revascularisation in patients treated with biodegradable polymer sirolimus-eluting stents compared with durable polymer everolimus-eluting stents. Biotronik.

250. Interspinous process distraction compared to nonoperative care for moderate lumbar degenerative disc disease: results of the FDA IDE clinical trial

BACKGROUND CONTEXT Interspinous process distraction (IPD) devices aim to alleviate back and leg pain by limiting extension and unloading the 3-joint complex at the affected lumbar level. IPDs may offer a treatment option for painful degenerative disc disease (DDD) that is not yet indicated for fusion or disc replacement. PURPOSE To compare the safety and effectiveness of IPD and nonoperative treatment after 2 years for the treatment of moderate lumbar DDD. STUDY DESIGN/SETTING A prospective, randomized, controlled FDA IDE clinical trial at 23 US centers (ClinicalTrials.gov: NCT00456378). PATIENT SAMPLE A total of 278 patients with moderate low back pain for less than 1 year and radiographic evidence of single-level DDD between L2 and L5 who failed at least 6 weeks but less than 6 months of conservative management were randomized and treated with investigational IPD (n=181) or control nonoperative treatment (n=97). OUTCOME MEASURES The primary endpoint was Overall Success, a composite variable that included: 1) Oswestry Disability Index (ODI) score improvement of ≥ 15 points; and 2) no serious adverse event (AE) caused by the implant or by both the implant and surgical procedure (IPD) or caused by the nonoperative treatment (control); and 3) no secondary surgery (IPD) or treatment surgery (control) at the involved level. Additional safety and effectiveness endpoints included back and leg pain numerical (0-20) rating scales, SF-36 PCS/MCS, AEs and secondary surgeries. METHODS Investigational treatment consisted of the IPD implantation (without decompression) and nonoperative treatments, as necessary. Control treatment consisted of information/ education on low back pain, medication, physical therapy, and epidural and/or facet joint steroidal injections. Clinical and radiographic assessments were performed preoperatively, intra-operatively, and postoperatively up to 2 years. Statistical analyses used Bayesian methods with non-informative priors. Last observation was carried forward (LOCF) for patients lost to follow-up including patients receiving surgery (control crossovers) or additional surgery (IPD investigational) at the involved level. RESULTS Baseline demographic characteristics and outcomes scores were not statistically different between the two groups, except back pain (16.8 for investigational vs 16.1 for control, p=0.033). The IPD rate of Overall Success at 24-months was statistically superior to control (observed rate of 63.0% vs 13.4%, respectively; posterior probability of superiority (pps) > 99.9%). The improvement in outcomes for IPD was statistically superior to control (pps > 99.9%) for: ODI (26.4 vs 1.1), back pain (8.4 vs 1.2), leg pain (4.9 vs -1.1, PCS (12.6 vs.1.4), and MCS (4.4 vs -0.8). Spinous process bony erosion increased slowly to 33.7% (61/181) of patients but was not related to clinical outcomes. Treatment-related serious AEs in the control group were associated with increasing low back pain. Fifteen (8.3%) IPD and 34 (35.1%) control patients experienced a treatment-related serious AE. Twenty (11.0%) IPD patients had secondary surgery and 10 (10.3%) control patients had treatment surgery at the index level. After 6 months of nonoperative treatment, control patients had the option to crossover to IPD: 57 (58.8%) control patients had crossed over by 24 months. CONCLUSIONS These analyses support the superiority of this IPD over conservative care for moderate back pain in appropriately selected patients. FDA DEVICE/DRUG STATUS DIAM™ Spinal Stabilization System (Investigational/Not approved)

Two-level cervical disc arthroplasty versus anterior cervical discectomy and fusion: 10-year outcomes of a prospective, randomized investigational device exemption clinical trial.

The authors assessed the 10-year clinical safety and effectiveness of cervical disc arthroplasty (CDA) to treat degenerative cervical spine disease at 2 adjacent levels compared to anterior cervical discectomy and fusion (ACDF). A prospective, randomized, controlled, multicenter FDA-approved clinical trial was conducted comparing the low-profile titanium ceramic composite-based Prestige LP Cervical Disc (n = 209) at two levels with ACDF (n = 188). Ten-year follow-up data from a postapproval study were available on 148 CDA and 118 ACDF patients and are reported here. Clinical and radiographic evaluations were completed preoperatively, intraoperatively, and at regular postoperative follow-up intervals for up to 10 years. The primary endpoint was overall success, a composite variable that included key safety and efficacy considerations. Ten-year follow-up rates were 86.0% for CDA and 84.9% for ACDF. From 2 to 10 years, CDA demonstrated statistical superiority over ACDF for overall success, with rates at 10 years of 80.4% versus 62.2%, respectively (posterior probability of superiority [PPS] = 99.9%). Neck Disability Index (NDI) success was also superior, with rates at 10 years of 88.4% versus 76.5% (PPS = 99.5%), as was neurological success (92.6% vs 86.1%; PPS = 95.6%). Improvements from preoperative results in NDI and neck pain scores were consistently statistically superior for CDA compared to ACDF. All other study effectiveness measures were at least noninferior for CDA compared to ACDF through the 10-year follow-up period, including disc height. Mean angular ranges of motion at treated levels were maintained in the CDA group for up to 10 years. The rates of grade IV heterotopic ossification (HO) at the superior and inferior levels were 8.2% and 10.3%, respectively. The rate of severe HO (grade III or IV) did not increase significantly from 7 years (42.4%) to 10 years (39.0%). The CDA group had fewer serious (grade 3-4) implant-related or implant/surgical procedure-related adverse events (3.8% vs 8.1%; posterior mean 95% Bayesian credible interval [BCI] of the log hazard ratio [LHR] -0.92 [-1.88, -0.01]). The CDA group also had statistically fewer secondary surgical procedures at the index levels (4.7%) than the ACDF group (17.6%) (LHR [95% BCI] -1.39 [-2.15, -0.61]) as well as at adjacent levels (9.0% vs 17.9%). The Prestige LP Cervical Disc, implanted at two adjacent levels, maintains improved clinical outcomes and segmental motion 10 years after surgery and is a safe and effective alternative to fusion.Clinical trial registration no.: NCT00637156 (clinicaltrials.gov).

Assessing treatment benefits with CDK4/6i+ET for hormone receptor-positive advanced breast cancer: A network meta-analysis.

e12543 Background: Previously, the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (aBC) has relied solely on endocrine therapy (ET). Unfortunately, almost all tumors developed resistance to ET. Although cyclin-dependent kinase inhibitors (CDKi)+ET clearly improve several clinical outcomes, many relevant questions remain unanswered: is there a benefit in (i) overall survival (OS) (ii) progression-free survival (PFS), and (iii) which CDKi is the best. Methods: A systematic review was performed to identify trials that compared CDKi+ET versus ET alone for HR+/HER2-aBC. Pooled meta-estimates were generated to assess CDKi+ET OS benefit and PFS benefit. Bayesian network meta-analysis was performed to compare each CDKi in terms of PFS, clinical benefit rate (CBR), response rate (RR) and toxicity. Results: 2,523 studies were screened and 8 studies satisfied the inclusion criteria. There was a trend for OS benefit with CDKi+ET compared to ET alone with 97% posterior probability that CDKi+ET is better than ET alone and HR 0.81 (95% CrI 0.66-1.00). CDKi+ET also showed > 99% probability of better than ET alone in both first and second-line settings in terms of PFS, RR, and CBR with PFS HR 0.56 (0.47-0.66) first line, 0.49 (0.39-0.60) second-line; RR OR 1.61 (1.29-1.97) first-line, 2.58 (1.71-3.80) second-line; CBR OR 1.75 (1.38-2.25) first-line, 2.38 (1.65-3.37) second-line. Ribociclib and abemaciclib showed weak-moderate evidence of better PFS and RR compared to palbociclib (64% to 81% posterior probability of superiority). There was no evidence of differences between ribociclib and abemaciclib. Palbociclib achieved better CBR compared to ribociclib and abemaciclib, although this difference may be related to the poor performance of placebo arm in studies that used palbociclib. In terms of safety, abemaciclib caused less neutropenia, but more diarrhea than ribociclib and palbociclib. Deep vein thrombosis was less frequent with ribociclib. Conclusions: CDKi+ET was 97% superior in terms of OS and > 99% superior in terms of PFS, RR, and CBR compared to ET alone. Further studies are necessary in order to find the best agent and the best sequencing of CDKi for HR+/HER2- aBC treatment.

Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct

BackgroundThe effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy.MethodsWe enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, which ranges from 0 to 6, with higher scores indicating more severe disability) at 90 days.ResultsA total of 206 patients were enrolled; 107 were assigned to the thrombectomy group and 99 to the control group. At 31 months, enrollment in the trial was stopped because of the results of a prespecified interim analysis. The mean score on the utility-weighted modified Rankin scale at 90 days was 5.5 in the thrombectomy group as compared with 3.4 in the control group (adjusted difference [Bayesian analysis], 2.0 points; 95% credible interval, 1.1 to 3.0; posterior probability of superiority, >0.999), and the rate of functional independence at 90 days was 49% in the thrombectomy group as compared with 13% in the control group (adjusted difference, 33 percentage points; 95% credible interval, 24 to 44; posterior probability of superiority, >0.999). The rate of symptomatic intracranial hemorrhage did not differ significantly between the two groups (6% in the thrombectomy group and 3% in the control group, P=0.50), nor did 90-day mortality (19% and 18%, respectively; P=1.00).ConclusionsAmong patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone. (Funded by Stryker Neurovascular; DAWN ClinicalTrials.gov number, NCT02142283.)

Antimicrobials for the treatment of drug-resistant Acinetobacter baumannii pneumonia in critically ill patients: a systemic review and Bayesian network meta-analysis

BackgroundAn optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis.MethodsSystematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%.ResultsTwenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41–0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04–0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07–0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19–0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32–0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16–0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL.ConclusionsThis Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order.

Long-term clinical and radiographic outcomes of the Prestige LP artificial cervical disc replacement at 2 levels: results from a prospective randomized controlled clinical trial.

OBJECTIVE The aim of this study was to assess long-term clinical safety and effectiveness in patients undergoing anterior cervical surgery using the Prestige LP artificial disc replacement (ADR) prosthesis to treat degenerative cervical spine disease at 2 adjacent levels compared with anterior cervical discectomy and fusion (ACDF). METHODS A prospective, randomized, controlled, multicenter FDA-approved clinical trial was conducted at 30 US centers, comparing the low-profile titanium ceramic composite-based Prestige LP ADR (n = 209) at 2 levels with ACDF (n = 188). Clinical and radiographic evaluations were completed preoperatively, intraoperatively, and at regular postoperative intervals to 84 months. The primary end point was overall success, a composite variable that included key safety and efficacy considerations. RESULTS At 84 months, the Prestige LP ADR demonstrated statistical superiority over fusion for overall success (observed rate 78.6% vs 62.7%; posterior probability of superiority [PPS] = 99.8%), Neck Disability Index success (87.0% vs 75.6%; PPS = 99.3%), and neurological success (91.6% vs 82.1%; PPS = 99.0%). All other study effectiveness measures were at least noninferior for ADR compared with ACDF. There was no statistically significant difference in the overall rate of implant-related or implant/surgical procedure-related adverse events up to 84 months (26.6% and 27.7%, respectively). However, the Prestige LP group had fewer serious (Grade 3 or 4) implant- or implant/surgical procedure-related adverse events (3.2% vs 7.2%, log hazard ratio [LHR] and 95% Bayesian credible interval [95% BCI] -1.19 [-2.29 to -0.15]). Patients in the Prestige LP group also underwent statistically significantly fewer second surgical procedures at the index levels (4.2%) than the fusion group (14.7%) (LHR -1.29 [95% BCI -2.12 to -0.46]). Angular range of motion at superior- and inferior-treated levels on average was maintained in the Prestige LP ADR group to 84 months. CONCLUSIONS The low-profile artificial cervical disc in this study, Prestige LP, implanted at 2 adjacent levels, maintains improved clinical outcomes and segmental motion 84 months after surgery and is a safe and effective alternative to fusion. Clinical trial registration no.: NCT00637156 (clinicaltrials.gov).

Randomized Controlled Trial of Minimally Invasive Sacroiliac Joint Fusion Using Triangular Titanium Implants vs. NonSurgical Management for Sacroiliac Joint Dysfunction

IntroductionSacroiliac (SI) joint dysfunction is a prevalent cause of unremitting low back pain. Does minimally invasive SIJ fusion provide superior outcomes compared with nonsurgical treatment? Methods148 subjects with SI joint dysfunction were randomly assigned at 19 US centers to minimally invasive SI joint fusion with triangular titanium implants (N = 102) or nonsurgical management (NSM, n = 46). Pain, disability and quality of life scores were collected at baseline and at 1, 3, 6 and 12 months. Success rates were compared using Bayesian methods. Crossover from nonsurgical to surgical care was allowed after the 6month study visit was complete. ResultsSixmonth success rates were higher in the surgical group (81.4% versus 26.1%, posterior probability of superiority > 0.9999). Clinically important (≥15 point) ODI improvement at 6 months occurred in 73.3% of the SIJ fusion group versus 13.6% of the NSM group (p < 0.0001). Improvements in SIJ pain and ODI were sustained at 12 months in the surgical group. Subjects who crossed over had improvements in pain, disability and quality of life similar to those in the original surgical group. Adverse events were slightly more common in the surgical group (1.3 versus 1.1 events per subject, p = 0.3063). One patient underwent immediate revision surgery for neuropathic pain related to implant malposition. 77 and 78% of subjects assigned to SIJ fusion were “very satisfied” with SIJ fusion at 6 and 12 months, respectively. ConclusionsIn this study, minimally invasive SI joint fusion using triangular titanium implants was more effective than nonsurgical management at one year in relieving pain, improving function and improving quality of life in patients with SI joint dysfunction.

Sacroiliac Joint Fusion Using Triangular Titanium Implants vs. Non-Surgical Management: Six-Month Outcomes from a Prospective Randomized Controlled Trial.

BackgroundSacroiliac (SI) joint pain is a prevalent, underdiagnosed cause of lower back pain. SI joint fusion can relieve pain and improve quality of life in patients who have failed nonoperative care. To date, no study has concurrently compared surgical and non-surgical treatments for chronic SI joint dysfunction.MethodsWe conducted a prospective randomized controlled trial of 148 subjects with SI joint dysfunction due to degenerative sacroiliitis or sacroiliac joint disruptions who were assigned to either minimally invasive SI joint fusion with triangular titanium implants (N=102) or non-surgical management (NSM, n=46). SI joint pain scores, Oswestry Disability Index (ODI), Short-Form 36 (SF-36) and EuroQol-5D (EQ-5D) were collected at baseline and at 1, 3 and 6 months after treatment commencement. Six-month success rates, defined as the proportion of treated subjects with a 20-mm improvement in SI joint pain in the absence of severe device-related or neurologic SI joint-related adverse events or surgical revision, were compared using Bayesian methods.ResultsSubjects (mean age 51, 70% women) were highly debilitated at baseline (mean SI joint VAS pain score 82, mean ODI score 62). Six-month follow-up was obtained in 97.3%. By 6 months, success rates were 81.4% in the surgical group vs. 23.9% in the NSM group (difference of 56.6%, 95% posterior credible interval 41.4-70.0%, posterior probability of superiority >0.999). Clinically important (≥15 point) ODI improvement at 6 months occurred in 75% of surgery subjects vs. 27.3% of NSM subjects. At six months, quality of life improved more in the surgery group and satisfaction rates were high. The mean number of adverse events in the first six months was slightly higher in the surgical group compared to the non-surgical group (1.3 vs. 1.0 events per subject, p=0.1857).ConclusionsSix-month follow-up from this level 1 study showed that minimally invasive SI joint fusion using triangular titanium implants was more effective than non-surgical management in relieving pain, improving function and improving quality of life in patients with SI joint dysfunction due to degenerative sacroiliitis or SI joint disruptions.Clinical relevanceMinimally invasive SI joint fusion is an acceptable option for patients with chronic SI joint dysfunction due to degenerative sacroiliitis and sacroiliac joint disruptions unresponsive to non-surgical treatments.

Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.Objectives: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting β2-agonists.Methods: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%).Measurements and Main Results: The improvement from baseline in the integrated AQLQ score was...

Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma

Rationale: Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle.Objectives: To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting β2-agonists.Methods: A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%).Measurements and Main Results: The improvement from baseline in the integrated AQLQ score was...

Effectiveness and Safety of Bronchial Thermoplasty in the Treatment of Severe Asthma

Bronchial thermoplasty (BT) is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. To evaluate the effectiveness and safety of BT versus a sham procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose inhaled corticosteroids and long-acting beta(2)-agonists. A total of 288 adult subjects (Intent-to-Treat [ITT]) randomized to BT or sham control underwent three bronchoscopy procedures. Primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). Adverse events and health care use were collected to assess safety. Statistical design and analysis of the primary endpoint was Bayesian. Target posterior probability of superiority (PPS) of BT over sham was 95%, except for the primary endpoint (96.4%). The improvement from baseline in the integrated AQLQ score was superior in the BT group compared with sham (BT, 1.35 +/- 1.10; sham, 1.16 +/- 1.23 [PPS, 96.0% ITT and 97.9% per protocol]). Seventy-nine percent of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater (PPS, 99.6%). Six percent more BT subjects were hospitalized in the treatment period (up to 6 wk after BT). In the posttreatment period (6-52 wk after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work/school compared with the sham group (PPS, 95.5, 99.9, and 99.3%, respectively). BT in subjects with severe asthma improves asthma-specific quality of life with a reduction in severe exacerbations and healthcare use in the posttreatment period. Clinical trial registered with www.clinialtrials.gov (NCT00231114).

Bayesian Monitoring and Bootstrap Trial Simulation: A New Paradigm to Implement Adaptive Trial Design for Testing Antidepressant Drugs

A novel methodology is proposed for continuous monitoring of efficacy data in ongoing antidepressant clinical trials and for decision making to support progression or discontinuation of the trial or one of the treatment arms. The Posterior Probability of Superiority (PPS) resulting from the application of Monte Carlo Markov Chain approach to a longitudinal model describing the time course of placebo and antidepressant drugs was used to estimate criteria to discontinue a treatment arm or the trial for futility, and to predict the treatment effect at study-end while the trial was still ongoing. The decision to stop the study was based on PPS, Predictive Power and on risk analysis based on a non-parametric bootstrap trial simulation. The performance of the Bayesian monitoring was evaluated by the retrospective analysis of 3 clinical trials. The Bootstrap-based methodology was compared to the Conditional Power and the Predictive Probability approaches. The application of the proposed methodology showed the possibility to stop a trial for futility when about 50% of total information was available and to detect signal of a treatment effect when limited information (<40%) was available. The comparisons with the Condition Power and the Predictive Probability approaches indicated that the Bayesian Bootstrap method, based on data-driven assumptions for priors, provided a better control for the risk of inappropriate decisions. The results suggest that the proposed methodology to monitor the accumulating information and to provide a scenario- based risk analysis could constitute a valuable approach to re-engineer the development process of novel drugs.