Sphincterotomy for Biliary Sphincter of Oddi Disorder and idiopathic Acute Recurrent Pancreatitis: THE RESPOND LONGITUDINAL COHORT.

Objective: Sphincter of Oddi Disorders (SOD) are contentious conditions in patients whose abdominal pain, idiopathic acute pancreatitis (iAP) might arise from pressurization at the sphincter of Oddi. The present study aimed to measure the benefit of sphincterotomy for suspected SOD. Design: Prospective cohort conducted at 14 U.S. centers with 12 months follow-up. Patients undergoing first-time ERCP with sphincterotomy for suspected SOD were eligible: pancreatobiliary-type pain with or without iAP. The primary outcome was defined as the composite of improvement by Patient Global Impression of Change (PGIC), no new or increased opioids, and no repeat intervention. Missing data were addressed by hierarchal, multiple imputation scheme. Results: Of 316 screened, 213 were enrolled with 190 (89.2%) of these having a dilated bile duct, abnormal labs, iAP, or some combination. By imputation, an average of 122/213 (57.4% [95%CI 50.4-64.4]) improved; response rate was similar for those with complete follow-up (99/161, 61.5%, [54.0-69.0]); of these, 118 (73.3%) improved by PGIC alone. Duct size, elevated labs, and patient characteristics were not associated with response. AP occurred in 37/213 (17.4%) at a median of 6 months post-ERCP and was more likely in those with a history of AP (30.9 vs. 2.9%, p<0.0001). Conclusion: Nearly 60% of patients undergoing ERCP for suspected SOD improve, although the contribution of a placebo response is unknown. Contrary to prevailing belief, duct size and labs are poor response predictors. AP recurrence was common and like observations from prior non-intervention cohorts, suggesting no benefit of sphincterotomy in mitigating future AP episodes.Key Messages: WHAT IS ALREADY KNOWN ON THIS TOPIC: It is not clear if the sphincter of Oddi can cause abdominal pain (Functional Biliary Sphincter of Oddi Disorder) and idiopathic acute pancreatitis (Functional Pancreatic Sphincter of Oddi Disorder), and whether ERCP with sphincterotomy can ameliorate abdominal pain or pancreatitis.WHAT THIS STUDY ADDS: Using multiple patient-reported outcome measures, most patients with suspected sphincter of Oddi disorder improve after ERCP with sphincterotomy.Duct size, elevated pancreatobiliary labs, and baseline patient characteristics are not independently associated with response.There is a high rate of recurrent acute pancreatitis within 12 months of sphincterotomy in those with a history of idiopathic acute pancreatitis.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY: Since a discrete population with a high (> 80-90%) response rate to sphincterotomy for suspected pancreatobiliary pain could not be identified, there is a need for additional observational and interventional studies that include phenotyping of patients using novel imaging or biochemical biomarkers.There remains a pressing need for quantitative nociceptive biomarkers to distinguish pancreatobiliary pain from other causes of abdominal pain or central sensitization.Discovery of blood-, bile-, or imaging-based biomarkers for occult microlithiasis and pancreatitis may be helpful in predicting who is likely to benefit from sphincterotomy.

Cognitive Outcome after Acute Spontaneous Intracerebral Hemorrhage: Analysis of the iDEF Randomized Trial.

INTRODUCTION: The impact of intracerebral hemorrhage (ICH) on cognition and the determinants of cognitive recovery early after ICH remain elusive. In this post hoc analysis of the intracerebral hemorrhage deferoxamine (iDEF) trial, we examined the trajectories of cognitive impairment and the determinants of early cognitive recovery after ICH. METHODS: We examined baseline factors associated with a 90-day cognitive outcome and constructed generalized linear mixed models to examine the trajectory of cognitive function over time among iDEF participants. Cognition was measured by the Montreal Cognitive Assessment (MoCA) scores on days 7, 30, and 90. RESULTS: 291 were available for analysis under the trial's modified intention-to-treat definition (38% female, mean age 60.3 ± 12.0 years, median NIHSS 13, IQR 8-18). The median baseline ICH volume was 12.9 IQR (6.4-26.0) mL; 59 (20%) of the ICH cases were lobar, 120 (41%) had intraventricular extension. There was an overall significant increase in total MOCA score with time (p < 0.0001). Total MOCA score increased by an estimated 3.9 points (95% CI: 3.1, 4.7) between the day 7 and day 30 assessments and by an additional 2.9 points (95% CI: 2.2, 3.6) between the day 30 and day 90 assessments. Despite the overall improvement, 134 of 205 (65%) patients with an available 90-day MoCA score remained cognitively impaired with a score <26 on day 90. Older age, higher NIHSS score, baseline ICH volume, intraventricular hemorrhage, and perihematoma edema had an adjusted negative impact on cognitive recovery. CONCLUSIONS: Although ICH survivors exhibit significant improvement of cognitive status over the first 3 months, cognitive performance remains impaired in the majority of patients. Among factors independently associated with worse cognitive recovery, higher baseline ICH, intraventricular blood and perihematomal edema volumes, are potential therapeutic targets that merit further exploration.

Rationale and Design of the Statins Use in Intracerebral Hemorrhage Patients (SATURN) Trial.

INTRODUCTION: The benefits and risks of HMG-CoA reductase inhibitor (statin) drugs in survivors of intracerebral hemorrhage (ICH) are unclear. Observational studies suggest an association between statin use and increased risk of lobar ICH, particularly in patients with apolipoprotein-E (APOE) ε2 and ε4 genotypes. There are no randomized controlled trials (RCTs) addressing the effects of statins after ICH leading to uncertainty as to whether statins should be used in patients with lobar ICH who are at high risk for ICH recurrence. The SATURN trial aims to evaluate the effects of continuation versus discontinuation of statin on the risk of ICH recurrence and ischemic major adverse cerebro-cardio-vascular events (MACCE) in patients with lobar ICH. Secondary aims include the assessment of whether the APOE genotype modifies the effects of statins on ICH recurrence, functional and cognitive outcomes and quality of life. METHODS: The SATURN trial is a multi-center, pragmatic, prospective, randomized, open-label, Phase III clinical trial with blinded end-point assessment. A planned total of 1456 patients with lobar ICH will be recruited from 140 sites in the United States, Canada and Spain. Patients presenting within seven days of a spontaneous lobar ICH that occurred while taking a statin, will be randomized (1:1) to continuation (control) vs. discontinuation (intervention) of the same statin drug and dose that they were using at ICH onset. The primary outcome is the time to recurrent symptomatic ICH within a two-year follow-up period. The primary safety outcome is the occurrence of ischemic MACCE. CONCLUSION: The results will help to determine the best strategy for statin use in survivors of lobar ICH and may help to identify if there is a subset of patients who would benefit from statins.

Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

BACKGROUND: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. METHODS: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. FINDINGS: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. INTERPRETATION: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. FUNDING: US National Institutes of Health.

Cigarette Smoking as a Risk Factor for Hematoma Expansion in Primary Intracerebral Hemorrhage: Analysis From a Randomized Clinical Trial.

Background Cigarette smoking is a well-known risk factor for ischemic and hemorrhagic stroke. We evaluated the impact of smoking status on hematoma expansion and clinical outcome in patients with primary intracerebral hemorrhage. Methods and Results This is a post hoc exploratory analysis of the ATACH (Antihypertensive Treatment at Acute Cerebral Hemorrhage)-2 trial. Patients with intracerebral hemorrhage were randomized into intensive blood pressure lowering (systolic blood pressure, <139 mm Hg) versus standard blood pressure lowering (systolic blood pressure, 140-179 mm Hg) in this study. We compared the demographic characteristics; hematoma size, location, and expansion rate; and clinical outcome based on subjects' smoking status. Of a total of 914 patients in the trial with known smoking status, 439 (48%) patients were ever smokers (264 current smokers and 175 former smokers). Current and former smokers were younger and more likely to be men. Baseline Glasgow Coma Scale score and initial hematoma size did not vary based on smoking status. Ever smokers had higher rates of thalamic hemorrhage (42% versus 34%) and intraventricular hemorrhage (29% versus 23%); this rate was highest among former smokers versus current smokers (49% versus 35%, respectively). Ever smokers had a higher rate of hematoma expansion in 24 hours (adjusted relative risk [RR] [95% CI], 1.46 [1.08-1.96]) compared with nonsmokers on multivariate analysis. There was no significant difference in the rate of death and disability at 90 days between the 2 groups (adjusted RR [95% CI], 1.18 [0.998-1.40]). Conclusions Our analysis demonstrates cigarette smoking as an independent predictor for hematoma expansion. There was no significant difference in death and disability based on smoking status.

An adaptive clinical trial design to identify the target dose of tenecteplase for treatment of acute pulmonary embolism.

BACKGROUND/AIMS: Fibrinolytic therapy with tenecteplase has been proposed for patients with pulmonary embolism but the optimal dose is unknown. Higher-than-necessary dosing is likely to cause excess bleeding. We designed an adaptive clinical trial to identify the minimum and assumed safest dose of tenecteplase that maintains efficacy. METHODS: We propose a Bayesian adaptive, placebo-controlled, group-sequential dose-finding trial using response-adaptive randomization to preferentially allocate subjects to the most promising doses, dual analyses strategies (continuous and dichotomized) using a gatekeeping approach to maximize clinical impact, and interim stopping rules to efficiently address competing trial objectives. The operating characteristics of the proposed design were evaluated using Monte Carlo simulation across multiple hypothetical efficacy scenarios. RESULTS: Simulation demonstrated response-adaptive randomization can preferentially allocate subjects to doses which appear to be performing well based on interim data. Interim decision-making, including the interim evaluation of both analysis strategies with gatekeeping, allows the trial to continue enrollment when success with the dichotomized analysis strategy appears sufficiently likely and to stop enrollment and declare superiority based on the continuous analysis strategy when there is little chance of ultimately declaring superiority with the dichotomized analysis. CONCLUSION: The proposed design allows evaluation of a greater number of dose levels than would be possible with a non-adaptive design and avoids the need to choose either the continuous or the dichotomized analysis strategy for the primary endpoint.

Effect of Deferoxamine on Trajectory of Recovery After Intracerebral Hemorrhage: A Post Hoc Analysis of the i-DEF Trial.

BACKGROUND: There are limited data on the trajectory of recovery and long-term functional outcomes after intracerebral hemorrhage (ICH). Most ICH trials have conventionally assessed outcomes at 3 months following the footsteps of ischemic stroke. The i-DEF trial (Intracerebral Hemorrhage Deferoxamine Trial) assessed modified Rankin Scale (mRS) longitudinally at prespecified time points from day 7 through the end of the 6-month follow-up period. We evaluated the trajectory of mRS among trial participants and examined the effect of deferoxamine on this trajectory. METHODS: We performed a post hoc analysis of the i-DEF trial, a multicenter, randomized, placebo-controlled, double-blind, futility-design, phase 2 clinical trial, based on the actual treatment received. Favorable outcome was defined as mRS score of 0-2. A generalized linear mixed model was used to evaluate the outcome trajectory over time, as well as whether the trajectory was altered by deferoxamine, after adjustments for randomization variables, presence of intraventricular hemorrhage, and ICH location. RESULTS: A total of 291 subjects were included in analysis (145 placebo and 146 deferoxamine). The proportion of patients with mRS score of 0-2 continually increased from day 7 to 180 in both groups (interaction P<0.0001 for time in main effects model), but treatment with deferoxamine favorably altered the trajectory (interaction P=0.0010). Between day 90 and 180, the deferoxamine group improved (P=0.0001), whereas there was not significant improvement in the placebo arm (P=0.3005). CONCLUSIONS: A large proportion of patients continue to improve up to 6 months after ICH. Future ICH trials should assess outcomes past 90 days for a minimum of 6 months. In i-DEF, treatment with deferoxamine seemed to accelerate and alter the trajectory of recovery as assessed by mRS. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02175225.

Characteristics of Patients Undergoing Endoscopic Retrograde Cholangiopancreatography for Sphincter of Oddi Disorders.

The concept that sphincter of Oddi dysfunction (SOD) can cause attacks of biliary-type pain in postcholecystectomy patients and those with unexplained recurrent acute pancreatitis, and that endoscopic sphincterotomy can ameliorate symptoms, remains unproven. The Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction (EPISOD) study of patients without objective evidence for biliary obstruction showed no difference in outcomes between those who underwent sphincterotomy or sham treatment.1 To date, there have been no studies examining the characteristics of patients who still are being offered endoscopic retrograde cholangiopancreatography (ERCP) for SOD since the EPISOD publication, although the absolute number appears to have declined.2.

Effect of Deferoxamine on Outcome According to Baseline Hematoma Volume: A Post Hoc Analysis of the i-DEF Trial.

BACKGROUND: Hematoma volume (HV) is a powerful determinant of outcome after intracerebral hemorrhage. We examined whether the effect of the iron chelator, deferoxamine, on functional outcome varied depending on HV in the i-DEF trial (Intracerebral Hemorrhage Deferoxamine). METHODS: A post hoc analysis of the i-DEF trial; participants were classified according to baseline HV (small <10 mL, moderate 10-30 mL, and large >30 mL). Favorable outcome was defined as a modified Rankin Scale score of 0-2 at day-180; secondarily at day-90. Logistic regression was used to evaluate the differential treatment effect according to HV. RESULTS: Two hundred ninety-one subjects were included in the as-treated analysis; 121 with small, 114 moderate, and 56 large HV. Day-180 modified Rankin Scale scores were available for 270/291 subjects (111 with small, 105 moderate, and 54 large HV). There was a differential effect of treatment according to HV on day-180 outcomes (P-for-interaction =0.0077); 50% (27/54) of deferoxamine-treated patients with moderate HV had favorable outcome compared with 25.5% (13/51) of placebo-treated subjects (adjusted odds ratio, 2.7 [95% CI, 1.13-6.27]; P=0.0258). Treatment effect was not significant for small (adjusted odds ratio, 1.37 [95% CI, 0.62-3.02]) or large (adjusted odds ratio, 0.12 [95% CI, 0.01-1.05]) HV. Results for day-90 outcomes were comparable (P-for-interaction =0.0617). Sensitivity analyses yielded similar results. CONCLUSIONS: Among patients with moderate HV, a greater proportion of deferoxamine- than placebo-treated patients achieved modified Rankin Scale score 0-2. The treatment effect was not significant for small or large HVs. These findings have important trial design and therapeutic implications. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02175225.

Early Convalescent Plasma for High-Risk Outpatients with Covid-19.

BACKGROUND: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19. METHODS: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause. RESULTS: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups. CONCLUSIONS: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).

Why Are Women Less Represented in Intracerebral Hemorrhage Trials?

BACKGROUND AND PURPOSE: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage. It is unclear whether this reflects lower prevalence of intracerebral hemorrhage in women, selection bias, or poor recruitment efforts. We undertook this study to examine differences between men and women in the reasons for exclusion from the iDEF trial (Intracerebral Hemorrhage Deferoxamine). METHODS: The screen failure log included 29 different reasons for exclusion. Chi-square statistics were used to evaluate the differences in reasons for exclusion between men and women. RESULTS: A total of 38.2% of participants in iDEF were women. Three thousand nine hundred eighty-two women (45.7%) and 4736 men (54.3%) were screen failures (P<0.0001). Similar proportions of women (1.28%) and men (1.73%) were excluded due to inability to obtain consent (P=0.1). Patients or families declined participation in 1.26% of women versus 1.31% of men (P=0.9). More women than men failed screening because of age>80 (22.40% versus 12.61%; adjusted P=0.0007) and preexisting do-not-resuscitate/do-not-intubate (3.69% versus 2.83%; adjusted P=0.067). CONCLUSIONS: Lower rates of women enrollment in the iDEF trial may be attributed to older age. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other intracerebral hemorrhage trials to determine best strategies to improve women's representation in future trials.

An Unsuccessful Randomized Trial of Percutaneous vs Endoscopic Drainage of Suspected Malignant Hilar Obstruction.

Percutaneous transhepatic biliary drainage (PTBD) and endoscopic retrograde cholangiopancreatography (ERCP) are widely accepted but competing approaches for the management of malignant obstruction at the hilum of the liver. ERCP is favored in the United States on the basis of high success rates for non-hilar indications, the perceived safety and superior tissue sampling capability of ERCP relative to PTBD, and the avoidance of external drains that are undesirable to patients. A recent randomized controlled trial (RCT) comparing the 2 modalities in patients with resectable hilar cholangiocarcinoma was terminated prematurely because of higher mortality in the PTBD group.1 In contrast, most observational data suggest that PTBD is superior for achieving complete drainage.2-6 Because the preferred procedure remains uncertain, we aimed to compare PTBD and ERCP as the primary intervention in patients with cholestasis due to malignant hilar obstruction (MHO).

Regional Differences in the Response to Acute Blood Pressure Lowering After Cerebral Hemorrhage.

OBJECTIVE: To compare the impact of intensive blood pressure (BP) lowering right after intracerebral hemorrhage (ICH) on clinical and hematoma outcomes among patients from different geographic locations, we performed a prespecified subanalysis of a randomized, multinational, 2-group, open-label trial to determine the efficacy of rapidly lowering BP in hyperacute ICH (Antihypertensive Treatment of Acute Cerebral Hemorrhage [ATACH]-2), involving 537 patients from East Asia and 463 recruited outside of Asia. METHODS: Eligible patients were randomly assigned to a systolic BP target of 110 to 139 mm Hg (intensive treatment) or 140 to 179 mm Hg (standard treatment). Predefined outcomes were poor functional outcome (modified Rankin Scale score 4-6 at 90 days), death within 90 days, hematoma expansion at 24 hours, and cardiorenal adverse events within 7 days. RESULTS: Poor functional outcomes (32.0% vs 45.9%), death (1.9% vs 13.3%), and cardiorenal adverse events (3.9% vs 11.2%) occurred significantly less frequently in patients from Asia than those outside of Asia. The treatment-by-cohort interaction was not significant for any outcomes. Only patients from Asia showed a lower incidence of hematoma expansion with intensive treatment (adjusted relative risk [RR] 0.56, 95% confidence interval [CI] 0.38-0.83). Both Asian (RR 3.53, 95% CI 1.28-9.64) and non-Asian (RR 1.71, 95% CI 1.00-2.93) cohorts showed a higher incidence of cardiorenal adverse events with intensive treatment. CONCLUSIONS: Poor functional outcomes and death 90 days after ICH were less common in patients from East Asia than those outside of Asia. Hematoma expansion, a potential predictor for poor clinical outcome, was attenuated by intensive BP lowering only in the Asian cohort. CLINICALTRIALSGOV IDENTIFIER: NCT01176565. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients from East Asia with ICH, intensive blood pressure lowering significantly reduces the risk of hematoma expansion.

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

Correction to: Rectal indomethacin alone versus indomethacin and prophylactic pancreatic stent placement for preventing pancreatitis after ERCP: study protocol for a randomized controlled trial.

An amendment to this paper has been published and can be accessed via the original article.

Intensive Blood Pressure Lowering in Patients with Moderate to Severe Grade Acute Cerebral Hemorrhage: Post Hoc Analysis of Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH)-2 Trial.

OBJECTIVE: To study the effect of intensive blood pressure reduction in patients with moderate to severe intracerebral hemorrhage (ICH) within the subjects recruited in Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial. DESIGN: Randomized, multicenter, 2 group, open-label clinical trial. SETTING: A total of 110 sites in the USA, Japan, China, Taiwan, South Korea, and Germany. PATIENTS: A total of 1,000 patients underwent randomization from May 2011 till September 2015. INTERVENTIONS: We analyzed the effect of intensive (goal 110-139 mm Hg) over standard (goal 140-179 mm Hg) systolic blood pressure (SBP) reduction using intravenous nicardipine within 4.5 h of symptom onset in moderate to severe grade subjects with ICH in a non-prespecified analysis. Moderate to severe grade was defined by Glasgow Coma Scale score <13 or baseline National Institutes of Health Stroke Scale score ≥10 or baseline intraparenchymal hemorrhage volume ≥30 mL or presence of intraventricular hemorrhage. The primary outcome was death or disability (score 4-6 on the modified Rankin scale) at 3 months after randomization ascertained by a blinded investigator. MEASUREMENTS AND MAIN RESULTS: Of a total of 682 subjects who met the definition of moderate to severe grade (mean age 61.9 ± 13.1 years, 62.5% men) with a mean baseline SBP of 174.7 ± 24.8 mm Hg, the frequency of hematoma expansion was significantly lower among subjects randomized to intensive SBP reduction than among subjects randomized to standard SBP reduction (20.4 vs. 27.9%, relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.55-0.96). The primary endpoint of death or disability was observed in 52.5% (170/324) of subjects receiving intensive SBP reduction and 48.9% (163/333) of subjects receiving standard SBP reduction (RR: 1.1; 95% CI: 0.9-1.2). CONCLUSIONS: Intensive SBP lowering reduced the frequency of hematoma expansion but did not reduce the rate of death or disability in patients with moderate to severe grade ICH.

Late Neurological Deterioration after Acute Intracerebral Hemorrhage: A post hoc Analysis of the ATACH-2 Trial.

BACKGROUND: Neurological deterioration (ND) has a major influence on the prognosis of intracerebral hemorrhage (ICH); however, factors associated with ND occurring after 24 h of ICH onset are unknown. METHODS: We performed exploratory analyses of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial, which compared intensive and standard blood pressure lowering treatment in ICH. NDs were captured on the adverse event case report form. Logistic regression analysis was performed to examine the independent predictors of late ND. RESULTS: Among 1,000 participants with acute ICH, 82 patients (8.2%) developed early ND (≤24 h), and 64 (6.4%) had late ND. Baseline hematoma volume (adjusted OR [aOR] per 1-cm3 increase 1.04, 95% CI 1.02-1.06, p < 0.0001), hematoma volume increase in 24 h (aOR 2.24, 95% CI 1.23-4.07, p = 0.008), and the presence of intraventricular hemorrhage (IVH; aOR 2.38, 95% CI 1.32-4.29, p = 0.004) were independent predictors of late ND (vs. no late ND). Late ND was a significant risk factor for poor 90-day outcome (OR 3.46, 95% CI 1.82-6.56). No statistically significant difference in the incidence of late ND was noted between the 2 treatment groups. CONCLUSIONS: Initial hematoma volume, early hematoma volume expansion, and IVH are independent predictors of late ND after ICH. Intensive reduction in the systolic blood pressure level does not prevent the development of late ND.

Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial.

BACKGROUND: Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial. METHODS: We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed. FINDINGS: We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related. INTERPRETATION: Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile. FUNDING: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Clinical Outcomes Depending on Acute Blood Pressure After Cerebral Hemorrhage.

OBJECTIVE: To determine the association between clinical outcomes and acute systolic blood pressure (SBP) levels achieved after intracerebral hemorrhage (ICH). METHODS: Eligible patients who were randomized to the ATACH-2 (Antihypertensive Treatment in Intracerebral Hemorrhage 2) trial (ClinicalTrials.gov: NCT01176565) were divided into 5 groups by 10-mmHg strata of average hourly minimum SBP (<120, 120-130, 130-140, 140-150, and ≥ 150 mmHg) during 2 to 24 hours after randomization. Outcomes included: 90-day modified Rankin Scale (mRS) 4 to 6; hematoma expansion, defined as an increase ≥6 ml from baseline to 24-hour computed tomography; and cardiorenal adverse events within 7 days. RESULTS: Of the 1,000 subjects in ATACH-2, 995 with available SBP data were included in the analyses. The proportion of mRS 4 to 6 was 37.5, 36.0, 42.8, 38.6, and 38.0%, respectively. For the "140 to 150" group relative to the "120 to 130," the odds ratio (OR), adjusting for sex, race, age, onset-to-randomization time, baseline National Institutes of Health Stroke Scale score, hematoma volume, and hematoma location, was 1.62 (95% confidence interval [CI], 1.02-2.58). Hematoma expansion was identified in 16.9, 13.7, 21.4, 18.5, and 26.4%, respectively. The 140 to 150 (OR, 1.80; 95% CI, 1.05-3.09) and "≥150" (1.98; 1.12-3.51) showed a higher frequency of expansion than the 120 to 130 group. Cardiorenal events occurred in 13.6, 16.6, 11.5, 8.1, and 8.2%, respectively. The 140 to 150 (0.43; 0.19-0.88) and ≥ 150 (0.44; 0.18-0.96) showed a lower frequency of the events than the 120 to 130. INTERPRETATION: Beneficial effects of lowering and maintaining SBP at 120 to 130 mmHg during the first 24 hours on clinical outcomes by suppressing hematoma expansion was somewhat offset by cardiorenal complications. ANN NEUROL 2019;85:105-113.

Blood Pressure-Attained Analysis of ATACH 2 Trial.

BACKGROUND AND PURPOSE: We compared the rates of death or disability, defined by modified Rankin Scale score of 4 to 6, at 3 months in patients with intracerebral hemorrhage according to post-treatment systolic blood pressure (SBP)-attained status. METHODS: We divided 1000 subjects with SBP ≥180 mm Hg who were randomized within 4.5 hours of symptom onset as follows: SBP <140 mm Hg achieved or not achieved within 2 hours; subjects in whom SBP <140 mm Hg was achieved within 2 hours were further divided: SBP <140 mm Hg for 21 to 22 hours (reduced and maintained) or SBP was ≥140 mm Hg for at least 2 hours during the period between 2 and 24 hours (reduced but not maintained). RESULTS: Compared with subjects without reduction of SBP <140 mm Hg within 2 hours, subjects with reduction and maintenance of SBP <140 mm Hg within 2 hours had a similar rate of death or disability (relative risk of 0.98; 95% confidence interval, 0.74-1.29). The rates of neurological deterioration within 24 hours were significantly higher in reduced and maintained group (10.4%; relative risk, 1.98; 95% confidence interval, 1.08-3.62) and in reduced but not maintained group (11.5%; relative risk, 2.08; 95% confidence interval, 1.15-3.75) compared with reference group. The rates of cardiac-related adverse events within 7 days were higher among subjects with reduction and maintenance of SBP <140 mmHg compared to subjects without reduction (11.2% versus 6.4%). CONCLUSIONS: No decline in death or disability but higher rates of neurological deterioration and cardiac-related adverse events were observed among intracerebral hemorrhage subjects with reduction with and without maintenance of intensive SBP goals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01176565.