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Research in context panel: 445Identifying people at highest risk of ICH may facilitate timely and accurate prognostication to allow mitigation of reversible risk factors for bleeding (e.g. intensive blood pressure control), and selection of participants for clinical trials. While more complex combinations of clinical, biochemical, and radiological markers might further improve stroke risk prediction, balancing accuracy with simplicity will remain important.

Background: Regional citrate anticoagulation (RCA) is not recommended in patients with shock or severe liver failure. We designed a protocol with personalized pre-calculated flow settings for patients with absent citrate metabolism that abrogates risk of citrate toxicity, maintains neutral CKRT circuit calcium mass balance and normal systemic ionized calcium levels. Methods: Single center prospective cohort study of patients in five Adult Intensive Care Units triaged to the CVVHDF-RCA "Shock" protocol. Results: Of 31 patients included in the study, 30 (97%) had acute kidney injury, 16 (52%) had acute liver failure, and 5 (16%) had cirrhosis at the start of CKRT. The median (interquartile range (IQR)) lactate was 5 (3.2 to 10.7), AST 822 (122 to 2950), ALT 352 (41 to 2238), total bilirubin 2.7 (1.0 to 5.1), INR 2 (1.5 to 2.6). The median first hemofilter life censored for causes other than clotting exceeded 70 hours. The cumulative incidence of hypernatremia (Na >148 mM), metabolic alkalosis (HCO3- >30 mM) and hypophosphatemia (P< 2 mg/dL) were 1/26 (4%), 0/30 (0%), 1/30 (3%) respectively and were not clinically significant. Mild hypocalcemia occurred in the first 4 hours in 2/31 patients and corrected by hour 6 with no additional Ca-supplementation beyond the per-protocol administered Ca-infusion. The maximum systemic total Ca (tCa; mM)/ionized Ca (iCa; mM) ratio never exceeded 2.5. Conclusions: The "Shock" protocol can be used without contra-indications and is effective in maintaining circuit patency with a high, fixed ACDA infusion rate to blood flow ratio. Keeping single-pass citrate extraction on the dialyzer >0.75 minimizes the risk of citrate toxicity even in patients with absent citrate metabolism. Pre-calculated, personalized dosing of the initial Ca-infusion rate from a table based on the patient's albumin level and the filter effluent flow rate maintains neutral CKRT circuit calcium mass balance and a normal systemic iCa level.

Background and Purpose: Data on the effectiveness and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in patients with stroke attributable to atrial fibrillation (AF) who were dependent on the daily help of others at hospital discharge are scarce. Methods: Based on prospectively obtained data from the observational Novel-Oral-Anticoagulants-in-Ischemic-Stroke-Patients-longterm registry from Basel, Switzerland, we compared the occurrence of the primary outcome—the composite of recurrent ischemic stroke, major bleeding, and all-cause death—among consecutive patients with AF-stroke treated with either VKAs or DOACs between patients dependent (defined as modified Rankin Scale score, 3–5) and patients independent at discharge. We used simple, adjusted, and weighted Cox proportional hazards regression to account for potential confounders. Results: We analyzed 801 patients (median age 80 years, 46% female), of whom 391 (49%) were dependent at discharge and 680 (85%) received DOACs. Over a total follow-up of 1216 patient-years, DOAC- compared to VKA-treated patients had a lower hazard for the composite outcome (hazard ratio [HR], 0.58 [95% CI, 0.42–0.81]), as did independent compared to dependent patients (HR, 0.54 [95% CI, 0.40–0.71]). There was no evidence that the effect of anticoagulant type (DOAC versus VKA) on the hazard for the composite outcome differed between dependent (HR dependent , 0.68 [95% CI, 0.45–1.01]) and independent patients (HR independent , 0.44 [95% CI, 0.26–0.75]) in the simple model ( P interaction =0.212). Adjusted (HR dependent , 0.74 [95% CI, 0.49–1.11] and HR independent , 0.51 [95% CI, 0.30–0.87]; P interaction =0.284) and weighted models (HR dependent , 0.79 [95% CI, 0.48–1.31] and HR independent , 0.46 [95% CI, 0.26–0.81]; P interaction =0.163) yielded concordant results. Secondary analyses focusing on the individual components of the composite outcome were consistent to the primary analyses. Conclusions: The benefits of DOACs in patients with atrial fibrillation with a recent stroke were maintained among patients who were dependent on the help of others at discharge. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03826927.

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non–vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76–86]; 40% women; median hematoma volume, 11.5 [4.8–27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22–1.82]; P =0.40). There was a signal for interaction with onset-to-treatment time ( P interaction =0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37–3.04]; P =0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37–9.50]; P =0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov ; Unique identifier: NCT02866838.

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Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background Regional citrate anticoagulation (RCA) for the prevention of clotting of the extracorporeal blood circuit during continuous kidney replacement therapy (CKRT) has been employed in limited fashion because of the complexity and complications associated with certain protocols. Hypertonic citrate infusion to achieve circuit anticoagulation results in variable systemic citrate- and sodium load and increases the risk of citrate accumulation and hypernatremia. The practice of “single starting calcium infusion rate for all patients” puts patients at risk for clinically significant hypocalcemia if filter effluent calcium losses exceed replacement. A fixed citrate to blood flow ratio, personalized effluent and pre-calculated calcium infusion dosing based on tables derived through kinetic analysis enable providers to use continuous veno-venous hemo-diafiltration (CVVHDF)-RCA in patients with liver citrate clearance of at least 6 L/h. Methods This was a single-center prospective observational study conducted in intensive care unit patients triaged to be treated with the novel pre-calculated CVVHDF-RCA “Non-shock” protocol. RCA efficacy outcomes were time to first hemofilter loss and circuit ionized calcium (iCa) levels. Safety outcomes were surrogate of citrate accumulation (TCa/iCa ratio) and the incidence of acid-base and electrolyte complications. Results Of 53 patients included in the study, 31 (59%) had acute kidney injury and 12 (22.6%) had the diagnosis of cirrhosis at the start of CVVHDF-RCA. The median first hemofilter life censored for causes other than clotting exceeded 70 h. The cumulative incidence of hypernatremia (Na > 148 mM), metabolic alkalosis (HCO3- > 30 mM), hypocalcemia (iCa < 0.9 mM) and hypercalcemia (iCa > 1.5 mM) were 1/47 (1%), 0/50 (0%), 1/53 (2%), 1/53 (2%) respectively and were not clinically significant. The median (25th–75th percentile) of the highest TCa/iCa ratio for every 24-h interval on CKRT was 1.99 (1.91–2.13). Conclusions The fixed citrate to blood flow ratio, as opposed to a titration approach, achieves adequate circuit iCa (< 0.4 mm/L) for any hematocrit level and plasma flow. The personalized dosing approach for calcium supplementation based on pre-calculated effluent calcium losses as opposed to the practice of “one starting dose for all” reduces the risk of clinically significant hypocalcemia. The fixed flow settings achieve clinically desirable steady state systemic electrolyte levels.