Joshua N. Goldstein

Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on Vitamin K Antagonists Presenting With Major Bleeding A Randomized, Plasma-Controlled, Phase IIIb Study

Background— Patients experiencing major bleeding while taking vitamin K antagonists require rapid vitamin K antagonist reversal. We performed a prospective clinical trial to compare nonactivated 4-factor prothrombin complex concentrate (4F-PCC) with plasma for urgent vitamin K antagonist reversal. Methods and Results— In this phase IIIb, multicenter, open-label, noninferiority trial, nonsurgical patients were randomized to 4F-PCC (containing coagulation factors II, VII, IX, and X and proteins C and S) or plasma. Primary analyses examined whether 4F-PCC was noninferior to plasma for the coprimary end points of 24-hour hemostatic efficacy from start of infusion and international normalized ratio correction (⩽1.3) at 0.5 hour after end of infusion. The intention-to-treat efficacy population comprised 202 patients (4F-PCC, n=98; plasma, n=104). Median (range) baseline international normalized ratio was 3.90 (1.8–20.0) for the 4F-PCC group and 3.60 (1.9–38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, –5.8 to 19.9]). Rapid international normalized ratio reduction was achieved in 62.2% of patients receiving 4F-PCC versus 9.6% receiving plasma, demonstrating 4F-PCC superiority (difference, 52.6% [95% confidence interval, 39.4 to 65.9]). Assessed coagulation factors were higher in the 4F-PCC group than in the plasma group from 0.5 to 3 hours after infusion start (P<0.02). The safety profile (adverse events, serious adverse events, thromboembolic events, and deaths) was similar between groups; 66 of 103 (4F-PCC group) and 71 of 109 (plasma group) patients experienced ≥1 adverse event. Conclusions— 4F-PCC is an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events, as demonstrated by clinical assessments of bleeding and laboratory measurements of international normalized ratio and factor levels. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708435.

CONTRAST EXTRAVASATION ON CT ANGIOGRAPHY PREDICTS HEMATOMA EXPANSION IN INTRACEREBRAL HEMORRHAGE

Background: Patients with acute intracerebral hemorrhage (ICH) presenting within 3 hours of symptom onset are known to be at increased risk of expansion. However, only a minority arrive within this time frame. Therefore, alternative markers for expansion risk are needed. Objective: To examine whether contrast extravasation on CT angiography (CTA) at presentation predicts subsequent hematoma expansion. Methods: Consecutive patients with primary ICH presenting to an urban tertiary care hospital were prospectively captured in a database. We retrospectively reviewed images for all patients receiving a CTA and at least one further CT scan within 48 hours. Results: Complete data were available for 104 patients. Contrast extravasation at the time of CTA was present in 56% of patients, and associated with an increased risk of hematoma expansion (22% vs 2%, p = 0.003). Patients who received a baseline CTA within 3 hours were more likely to have subsequent expansion (27%, vs 13% for those presenting later, p = 0.1). However, after multivariable analysis, contrast extravasation was the only significant predictor of hematoma expansion (OR 18, 95% CI 2.1 to 162). This effect was independent of time to presentation. Conclusions: Contrast extravasation is independently associated with hematoma expansion. Patients presenting within the first few hours after symptom onset have traditionally been considered those at highest risk of expansion. However, for those presenting later, the presence of contrast may be a useful marker to guide therapies aimed at decreasing this risk.

Prediction of Functional Outcome in Patients With Primary Intracerebral Hemorrhage The FUNC Score

Background and Purpose— Intracerebral hemorrhage (ICH) is the most fatal and disabling stroke subtype. Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not designed to predict functional recovery. We developed an acute clinical score to predict likelihood of functional independence. Methods— We prospectively characterized 629 consecutive patients with ICH at hospital presentation. Predictors of functional independence (Glasgow Outcome Score ≥4) at 90 days were used to develop a logistic regression-based risk stratification scale in a random subset of two thirds and validated in the remaining one third of the cohort. Results— At 90 days, 162 (26%) patients achieved independence. Age, Glasgow Coma Scale, ICH location, volume (all P<0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score ≥4. The FUNC score was developed as a sum of individual points (0–11) based on strength of association with outcome. In both the development and validation cohorts, the proportion of patients who achieved Glasgow Outcome Score ≥4 increased steadily with FUNC score. No patient assigned a FUNC score ≤4 achieved functional independence, whereas >80% with a score of 11 did. The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only, consistent with absence of confounding by early withdrawal of care. Conclusions— FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus, can provide guidance in clinical decision-making and patient selection for clinical trials.

Timing of Fresh Frozen Plasma Administration and Rapid Correction of Coagulopathy in Warfarin-Related Intracerebral Hemorrhage

Background and Purpose— Anticoagulation-related intracerebral hemorrhage (ICH) is often fatal, and rapid reversal of anticoagulation is the most appealing strategy currently available for treatment. We sought to determine whether particular emergency department (ED) interventions are effective in reversing coagulopathy and improving outcome. Methods— Consecutive patients with warfarin-related ICH presenting to an urban tertiary care hospital from 1998 to 2004 were prospectively captured in a database. ED records were retrospectively reviewed for dose and timing of fresh-frozen plasma (FFP) and vitamin K, as well as serial coagulation measures. After excluding patients with incomplete ED records, do-not-resuscitate orders established in the ED, initial international normalized ratio (INR) ≤1.4, and for whom no repeat INR was performed, 69 patients were available for analysis. The primary outcome was a documented INR ≤1.4 within 24 hours of ED presentation. Results— Patients whose INR was successfully reversed within 24 hours had a shorter median time from diagnosis to first dose of FFP (90 minutes versus 210 minutes; P=0.02). In multivariable analysis, shorter time to vitamin K, as well as FFP, predicted INR correction. Every 30 minutes of delay in the first dose of FFP was associated with a 20% decreased odds of INR reversal within 24 hours (odds ratio, 0.8; 95% CI, 0.63 to 0.99). Dosing of FFP and vitamin K had no effect. No ED intervention was associated with improved clinical outcome. Conclusions— Time to treatment is the most important determinant of 24-hour anticoagulation reversal. Although additional study is required to determine the clinical benefit of rapid reversal of anticoagulation, minimizing delays in FFP administration is a prudent first step in emergency management of warfarin-related ICH.

Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial

BACKGROUND Rapid reversal of vitamin K antagonist (VKA)-induced anticoagulation is often necessary for patients needing urgent surgical or invasive procedures. The optimum means of VKA reversal has not been established in comparative clinical trials. We compared the efficacy and safety of four-factor prothrombin complex concentrate (4F-PCC) with that of plasma in VKA-treated patients needing urgent surgical or invasive procedures. METHODS In a multicentre, open-label, phase 3b randomised trial we enrolled patients aged 18 years or older needing rapid VKA reversal before an urgent surgical or invasive procedure. We randomly assigned patients in a 1:1 ratio to receive vitamin K concomitant with a single dose of either 4F-PCC (Beriplex/Kcentra/Confidex; CSL Behring, Marburg, Germany) or plasma, with dosing based on international normalised ratio (INR) and weight. The primary endpoint was effective haemostasis, and the co-primary endpoint was rapid INR reduction (≤1·3 at 0·5 h after infusion end). The analyses were intended to evaluate, in a hierarchical fashion, first non-inferiority (lower limit 95% CI greater than -10% for group difference) for both endpoints, then superiority (lower limit 95% CI >0%) if non-inferiority was achieved. Adverse events and serious adverse events were reported to days 10 and 45, respectively. This trial is registered at ClinicalTrials.gov, number NCT00803101. FINDINGS 181 patients were randomised (4F-PCC n=90; plasma n=91). The intention-to-treat efficacy population comprised 168 patients (4F-PCC, n=87; plasma, n=81). Effective haemostasis was achieved in 78 (90%) patients in the 4F-PCC group compared with 61 (75%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 14·3%, 95% CI 2·8-25·8). Rapid INR reduction was achieved in 48 (55%) patients in the 4F-PCC group compared with eight (10%) patients in the plasma group, demonstrating both non-inferiority and superiority of 4F-PCC over plasma (difference 45·3%, 95% CI 31·9-56·4). The safety profile of 4F-PCC was generally similar to that of plasma; 49 (56%) patients receiving 4F-PCC had adverse events compared with 53 (60%) patients receiving plasma. Adverse events of interest were thromboembolic adverse events (six [7%] patients receiving 4F-PCC vs seven [8%] patients receiving plasma), fluid overload or similar cardiac events (three [3%] patients vs 11 [13%] patients), and late bleeding events (three [3%] patients vs four [5%] patients). INTERPRETATION 4F-PCC is non-inferior and superior to plasma for rapid INR reversal and effective haemostasis in patients needing VKA reversal for urgent surgical or invasive procedures. FUNDING CSL Behring.

Effect of Systolic Blood Pressure Reduction on Hematoma Expansion, Perihematomal Edema, and 3-Month Outcome Among Patients With Intracerebral Hemorrhage: Results From the Antihypertensive Treatment of Acute Cerebral Hemorrhage Study

BACKGROUND Evidence indicates that systolic blood pressure (SBP) reduction may reduce hematoma expansion in patients with intracerebral hemorrhage (ICH) who are initially seen with acute hypertensive response. OBJECTIVE To explore the relationship between different variables of SBP reduction and hematoma expansion, perihematomal edema, and 3-month outcome among patients with ICH. DESIGN Post hoc analysis of a traditional phase 1 dose-escalation multicenter prospective study. SETTING Emergency departments and intensive care units. PATIENTS Patients having ICH with an elevated SBP of at least 170 mm Hg who were seen within 6 hours of symptom onset. INTERVENTION Systolic blood pressure reduction using intravenous nicardipine hydrochloride targeting 3 tiers of sequentially escalating SBP reduction goals (170-199, 140-169, or 110-139 mm Hg). MAIN OUTCOME MEASURES We evaluated the effect of SBP reduction (relative to initial SBP) on the following: hematoma expansion (defined as an increased intraparenchymal hemorrhage volume >33% on 24-hour vs baseline computed tomographic [CT] images), higher perihematomal edema ratio (defined as a >40% increased ratio of edema volume to hematoma volume on 24-hour vs baseline CT images), and poor 3-month outcome (defined as a modified Rankin scale score of 4-6). RESULTS Sixty patients (mean [SD] age, 62.0 [15.1] years; 34 men) were recruited (18, 20, and 22 patients in each of the 3 SBP reduction goal tiers). The median area under the curve (AUC) (calculated as the area between the hourly SBP measurements over 24 hours and the baseline SBP) was 1360 (minimum, 3643; maximum, 45) U. Comparing patients having less vs more aggressive SBP reduction based on 24-hour AUC analysis, frequencies were 32% vs 17% for hematoma expansion, 61% vs 40% for higher perihematomal edema ratio, and 46% vs 38% for poor 3-month outcome (P > .05 for all). The median SBP reductions were 54 mm Hg at 6 hours and 62 mm Hg at 6 hours from treatment initiation. Comparing patients having equal to or less vs more than the median SBP reduction at 2 hours, frequencies were 21% vs 31% for hematoma expansion, 42% vs 57% for higher perihematomal edema ratio, and 35% vs 48% for poor 3-month outcome (P > .05 for all). CONCLUSIONS We found no significant relationship between SBP reduction and any of the outcomes measured herein; however, the Antihypertensive Treatment of Acute Cerebral Hemorrhage study was primarily a safety study and was not powered for such end points. The consistent favorable direction of these associations supports further studies with an adequately powered randomized controlled design to evaluate the efficacy of aggressive pharmacologic SBP reduction.

Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score.

Background and Purpose— The presence of active contrast extravasation (the spot sign) on computed tomography (CT) angiography has been recognized as a predictor of hematoma expansion in patients with intracerebral hemorrhage. We aim to systematically characterize the spot sign to identify features that are most predictive of hematoma expansion and construct a spot sign scoring system. Methods— We retrospectively reviewed CT angiograms performed in all patients who presented to our emergency department over a 9-year period with primary intracerebral hemorrhage and had a follow-up noncontrast head CT within 48 hours of the baseline CT angiogram. Three neuroradiologists reviewed the CT angiograms and determined the presence and characteristics of spot signs according to strict radiological criteria. Baseline and follow-up intracerebral hemorrhage volumes were determined by computer-assisted volumetric analysis. Results— We identified spot signs in 71 of 367 CT angiograms (19%), 6 of which were delayed spot signs (8%). The presence of any spot sign increased the risk of significant hematoma expansion (69%, OR=92, P<0.0001). Among the spot sign characteristics examined, the presence of ≥3 spot signs, a maximum axial dimension ≥5 mm, and maximum attenuation ≥180 Hounsfield units were independent predictors of significant hematoma expansion, and these were subsequently used to construct the spot sign score. In multivariate analysis, the spot sign score was the strongest predictor of significant hematoma expansion, independent of time from ictus to CT angiogram evaluation. Conclusion— The spot sign score predicts significant hematoma expansion in primary intracerebral hemorrhage. If validated in other data sets, it could be used to select patients for early hemostatic therapy.

The Spot Sign Score in Primary Intracerebral Hemorrhage Identifies Patients at Highest Risk of In-Hospital Mortality and Poor Outcome among Survivors

Background and Purpose— The spot sign score is a potent predictor of hematoma expansion in patients with primary intracerebral hemorrhage (ICH). We aim to determine the accuracy of this scoring system for the prediction of in-hospital mortality and poor outcome among survivors in patients with primary ICH. Methods— Three neuroradiologists retrospectively reviewed CT angiograms (CTAs) performed in 573 consecutive patients who presented to our Emergency Department with primary ICH over a 9-year period to determine the presence and scoring of spot signs according to strict criteria. Baseline ICH and intraventricular hemorrhage volumes were independently determined by computer-assisted volumetric analysis. Medical records were independently reviewed for baseline clinical characteristics and modified Rankin Scale (mRS) at hospital discharge and 3-month follow-up. Poor outcome among survivors was defined as a mRS ≥4 at 3-month follow-up. Results— We identified spot signs in 133 of 573 CTAs (23.2%), 11 of which were delayed spot signs (8.3%). The presence of any spot sign increased the risk of in-hospital mortality (55.6%, OR 4.0, 95% CI 2.6 to 5.9, P<0.0001) and poor outcome among survivors at 3-month follow-up (50.8%, OR 2.5, 95% CI 1.4 to 4.3, P<0.0014). The spot sign score successfully predicted an escalating risk of both outcome measures. In multivariate analysis, the spot sign score was an independent predictor of in-hospital mortality (OR 1.5, 95% CI 1.2 to 1.9, P<0.0002) and poor outcome among survivors at 3-month follow-up (OR 1.6, 95% CI 1.1 to 2.1, P<0.0065). Conclusion— The spot sign score is an independent predictor of in-hospital mortality and poor outcome among survivors in primary ICH.

Headache in United States emergency departments: demographics, work-up and frequency of pathological diagnoses.

Headache is a common complaint in the emergency department (ED). In order to examine headache work-ups and diagnoses across the USA, we queried a representative sample of adult ED visits (the National Hospital Ambulatory Medical Care Survey) for the years 1992–2001. Headache accounted for 2.1 million ED visits per year (2.2% of visits). Of the 14% of patients who underwent neuroimaging, 5.5% received a pathological diagnosis. Of the 2% of patients who underwent lumbar puncture, 11% received a pathological diagnosis. On multivariable analysis, a decreased rate of imaging was noted for patients without private insurance [odds ratio (OR) 0.61, confidence interval (CI) 0.44, 0.86] and for those presenting off-hours (OR 0.55, CI 0.39, 0.77). Patients over 50 were more likely to receive a pathological diagnosis (OR 3.3, CI 1.2, 9.3). In conclusion, clinicians should ensure that appropriate work-ups are performed regardless of presentation time or insurance status, and be vigilant in the evaluation of older patients.

Effects of morphine analgesia on diagnostic accuracy in emergency department patients with abdominal pain: a prospective, randomized trial ☆

BACKGROUND Because of concerns about masking important physical findings, there is controversy surrounding whether it is safe to provide analgesia to patients with undifferentiated abdominal pain. The purpose of this study was to address the effects of analgesia on the physical examination and diagnostic accuracy for patients with abdominal pain. STUDY DESIGN The study was a prospective, double-blind clinical trial in which adult Emergency Department (ED) patients with undifferentiated abdominal pain were randomized to receive placebo (control group, n = 36) or morphine sulphate (MS group, n = 38). Diagnostic and physical examination assessments were recorded before and after a 60-minute period during which study medication was titrated. Diagnostic accuracy and physical examination changes were compared between groups using univariate statistical analyses. RESULTS There were no differences between control and MS groups with respect to changes in physical or diagnostic accuracy. The overall likelihood of change in severity of tenderness was similar in MS (37.7%) as compared with control (35.3%) patients (risk ratio [RR] 1.07, 95% confidence interval [CI] 0.64-1.78). MS patients were no more likely than controls to have a change in pain location (34.0% versus 41.2%, RR 0.82, 95% CI 0.50-1.36). Diagnostic accuracy did not differ between MS and control groups (64.2% versus 66.7%, RR 0.96, 95% CI 0.73-1.27). There were no differences between groups with respect to likelihood of any change occurring in the diagnostic list (37.7% versus 31.4%, RR 1.20, 95% CI 0.71-2.05). Correlation with clinical course and final diagnosis revealed no instance of masking of physical examination findings. CONCLUSIONS Results of this study support a practice of early provision of analgesia to patients with undifferentiated abdominal pain.