Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Performance of a Qualitative Point-of-Care Strip Test to Detect DOAC Exposure at the Emergency Department: A Cohort-Type Cross-Sectional Diagnostic Accuracy Study.

An accurate point-of-care test for detecting effective anticoagulation by direct oral anticoagulants (DOACs) in emergencies is an unmet need. We investigated the accuracy of a urinary qualitative strip test (DOAC Dipstick) to detect relevant DOAC exposure in patients who presented to an emergency department. In this prospective single-center cohort-type cross-sectional study, adults on DOAC treatment were enrolled. We assessed clinical sensitivity and specificity of DOAC Dipstick factor Xa and thrombin inhibitor pads to detect DOAC plasma levels ≥30 ng/mL using urine samples as the testing matrix. Liquid chromatography coupled with tandem-mass spectrometry was used as the reference standard method for plasma and urine measurement of DOAC concentrations. Of 293 patients enrolled, 265 patients were included in the analysis, of whom 92 were treated with rivaroxaban, 65 with apixaban, 77 with edoxaban, and 31 with dabigatran. The clinical sensitivity and specificity of the dipstick on urine samples to detect ≥30 ng/mL dabigatran plasma levels were 100% (95% confidence interval [CI]: 87-100%) and 98% (95% CI: 95-99%), respectively. The sensitivity and specificity of the dipstick to detect ≥30 ng/mL factor Xa inhibitor plasma levels were 97% (95% CI: 94-99%) and 69% (95% CI: 56-79%), respectively. The DOAC Dipstick sensitively identified effective thrombin and factor Xa inhibition in a real-world cohort of patients presenting at an emergency department. Therefore, the dipstick might provide a valuable test to detect relevant DOAC exposure in emergencies, although further studies will be needed to confirm these findings.

Out-of-Sample Validity of the PROLOGUE Score to Predict Neurologic Function after Cardiac Arrest.

BACKGROUND: The clinical value of a prognostic score depends on its out-of-sample validity because inaccurate outcome prediction can be not only useless but potentially fatal. We aimed to evaluate the out-of-sample validity of a recently developed and highly accurate Korean prognostic score for predicting neurologic outcome after cardiac arrest in an independent, plausibly related sample of European cardiac arrest survivors. METHODS: Analysis of data from a European cardiac arrest center, certified in compliance with the specifications of the German Council for Resuscitation. The study sample included adults with nontraumatic out-of-hospital cardiac arrest admitted between 2013 and 2018. Exposure was the PROgnostication using LOGistic regression model for Unselected adult cardiac arrest patients in the Early stages (PROLOGUE) score, including 12 clinical variables readily available at hospital admission. The outcome was poor 30-day neurologic function, as assessed using the cerebral performance category scale. The risk of a poor outcome was calculated using the PROLOGUE score regression equation. Predicted risk deciles were compared to observed outcome estimates in a complete-case analysis, a best-case analysis, and a multiple-data-imputation analysis using the Markov chain Monte Carlo method. RESULTS: A total of 1051 patients (median 61 years, IQR 50-71; 29% female) were analyzed. A total of 808 patients (77%) were included in the complete-case analysis. The PROLOGUE score overestimated the risk of poor neurologic outcomes in the range of 40% to 100% predicted risk, involving 63% of patients. The model fit did not improve after missing data imputation. CONCLUSIONS: In a plausibly related sample of European cardiac arrest survivors, risk prediction by the PROLOGUE score was largely too pessimistic and failed to replicate the high accuracy found in the original study. Using the PROLOGUE score as an example, this study highlights the compelling need for independent validation of a proposed prognostic score to prevent potentially fatal mispredictions.

Comparison of SARS-CoV-2 Antibody Response 4 Weeks After Homologous vs Heterologous Third Vaccine Dose in Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Fewer than 50% of kidney transplant recipients (KTRs) develop antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine. Preliminary data suggest that a heterologous vaccination, combining mRNA and viral vector vaccines, may increase immunogenicity. Objective: To assess the effectiveness of a third dose of an mRNA vs a vector vaccine in KTRs who did not have antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine. Design, Setting, and Participants: This was a single center, single-blinded, 1:1 randomized clinical trial of a third dose of vaccine against SARS-CoV-2, conducted from June 15 to August 16, 2021, in 201 KTRs who had not developed SARS-CoV-2 spike protein antibodies after 2 doses of an mRNA vaccine. Data analyses were performed from August 17 to August 31, 2021. Interventions: mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as a third dose of a SARS-CoV-2 vaccine. Main Outcomes and Measures: The primary study end point was seroconversion after 4 weeks (29-42 days) following the third vaccine dose. Secondary end points included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). In addition, the association of patient characteristics and vaccine response was assessed using logistic regression, and the reactogenicity of the vaccines was compared. Results: Among the study population of 197 kidney transplant recipients (mean [SD] age, 61.2 [12.4] years; 82 [42%] women), 39% developed SARS-CoV-2 antibodies after the third vaccine. There was no statistically significant difference between groups, with an antibody response rate of 35% and 42% for the mRNA and vector vaccines, respectively. Only 22% of seroconverted patients had neutralizing antibodies. Similarly, T-cell response assessed by IGRA was low with only 17 patients showing a positive response after the third vaccination. Receiving nontriple immunosuppression (odds ratio [OR], 3.59; 95% CI, 1.33-10.75), longer time after kidney transplant (OR, 1.44; 95% CI, 1.15-1.83, per doubling of years), and torque teno virus plasma levels (OR, 0.92; 95% CI, 0.88-0.96, per doubling of levels) were associated with vaccine response. The third dose of an mRNA vaccine was associated with a higher frequency of local pain at the injection site compared with the vector vaccine, while systemic symptoms were comparable between groups. Conclusions and Relevance: This randomized clinical trial found that 39% of KTRs without an immune response against SARS-CoV-2 after 2 doses of an mRNA vaccine developed antibodies against the SARS-CoV-2 spike protein 4 weeks after a third dose of an mRNA or a vector vaccine. The heterologous vaccination strategy with a vector-based vaccine was well tolerated and safe but not significantly better than the homologous mRNA-based strategy. Trial Registration: EudraCT Identifier: 2021-002927-39.

Predicting spontaneous conversion to sinus rhythm in symptomatic atrial fibrillation: The ReSinus score.

BACKGROUND: The optimal management of patients presenting to the Emergency Department with hemodynamically stable symptomatic atrial fibrillation remains unclear. We aimed to develop and validate an easy-to-use score to predict the individual probability of spontaneous conversion to sinus rhythm in these patients METHODS: This retrospective cohort study analyzed 2426 cases of first-detected or recurrent hemodynamically stable non-permanent symptomatic atrial fibrillation documented between January 2011 and January 2019 in an Austrian academic Emergency Department atrial fibrillation registry. Multivariable analysis was used to develop and validate a prediction score for spontaneous conversion to sinus rhythm during Emergency Department visit. Clinical usefulness of the score was assessed using decision curve analysis RESULTS: 1420 cases were included in the derivation cohort (68years, 57-76; 43% female), 1006 cases were included in the validation cohort (69years, 58-76; 47% female). Six variables independently predicted spontaneous conversion. These included: duration of atrial fibrillation symptoms (<24hours), lack of prior cardioversion history, heart rate at admission (>125bpm), potassium replacement at K+ level ≤3.9mmol/l, NT-proBNP (<1300pg/ml) and lactate dehydrogenase level (<200U/l). A risk score weight was assigned to each variable allowing classification into low (0-2), medium (3-5) and moderate (6-8) probability of spontaneous conversion. The final score showed good calibration (p=0.44 and 0.40) and discrimination in both cohorts (c-indices: 0.74 and 0.67) and clinical net benefit CONCLUSION: The ReSinus score, which predicts spontaneous conversion to sinus rhythm, was developed and validated in a large cohort of patients with hemodynamically stable non-permanent symptomatic atrial fibrillation and showed good calibration, discrimination and usefulness REGISTRATION: NCT03272620.

Low PCSK-9 levels Are Associated with Favorable Neurologic Function after Resuscitation from out of Hospital Cardiac Arrest.

Endotoxemia after cardiopulmonary resuscitation (CPR) is associated with unfavorable outcome. Proprotein convertase subtilisin/kexin type-9 (PCSK-9) regulates low-density lipoprotein receptors, which mediate the hepatic uptake of endotoxins. We hypothesized that PCSK-9 concentrations are associated with neurological outcome in patients after CPR. Successfully resuscitated out-of-hospital cardiac arrest patients were included prospectively (n = 79). PCSK-9 levels were measured on admission, 12 h and 24 h thereafter, and after rewarming. The primary outcome was favorable neurologic function at day 30, defined by cerebral performance categories (CPC 1-2 = favorable vs. CPC 3-5 = unfavorable). Receiver operating characteristic curve analysis was used to identify the PCSK-9 level cut-off for optimal discrimination between favorable and unfavorable 30-day neurologic function. Logistic regression models were calculated to estimate the effect of PCSK-9 levels on the primary outcome, given as odds ratio (OR) and 95% confidence interval (95%CI). PCSK-9 levels on admission were significantly lower in patients with favorable 30-day neurologic function (median 158 ng/mL, (quartiles: 124-225) vs. 207 ng/mL (174-259); p = 0.019). The optimally discriminating PCSK-9 level cut-off was 165ng/mL. In patients with PCSK-9 levels ≥ 165 ng/mL, the odds of unfavorable neurological outcome were 4.7-fold higher compared to those with PCSK-9 levels < 165 ng/mL. In conclusion, low PCSK-9 levels were associated with favorable neurologic function.

High Platelet Reactivity after Transition from Cangrelor to Ticagrelor in Hypothermic Cardiac Arrest Survivors with ST-Segment Elevation Myocardial Infarction.

Transition from cangrelor to oral P2Y12 inhibitors after PCI carries the risk of platelet function recovery and acute stent thrombosis. Whether the recommended transition regimen is appropriate for hypothermic cardiac arrest survivors is unknown. We assessed the rate of high platelet reactivity (HPR) after transition from cangrelor to ticagrelor in hypothermic cardiac arrest survivors. Adult survivors of out-of-hospital cardiac arrest with ST-segment elevation myocardial infarction (STEMI), who were treated for hypothermia (33 °C ± 1) and received intravenous cangrelor during PCI and subsequent oral loading with 180mg ticagrelor were enrolled in this prospective observational cohort study. Platelet function was assessed using whole blood aggregometry. HPR was defined as AUC > 46U. The primary endpoint was the rate of HPR (%) at predefined time points during the first 24 h after cangrelor cessation. Poisson regression was used to estimate the relationship between the overlap time of cangrelor and ticagrelor co-administration and the number of subsequent HPR episodes, expressed as incidence rate ratio (IRR) with 95% confidence interval (95%CI). Between December 2017 and October 2019 16 patients (81% male, 58 years) were enrolled. On average, ticagrelor was administered 39 min (IQR 5-50) before the end of cangrelor infusion. The rate of HPR was highest 90 min after cangrelor cessation and was present in 44% (7/16) of patients. The number of HPR episodes increased significantly with decreasing overlap time of cangrelor and ticagrelor co-administration (IRR 1.03, 95%CI 1.01-1.05; p = 0.005). In this selected cohort of hypothermic cardiac arrest survivors who received cangrelor during PCI, ticagrelor loading within the recommended time frame before cangrelor cessation resulted in a substantial amount of patients with HPR.

Increased Citrullinated Histone H3 Levels in the Early Post-Resuscitative Period Are Associated with Poor Neurologic Function in Cardiac Arrest Survivors-A Prospective Observational Study.

The exact contribution of neutrophils to post-resuscitative brain damage is unknown. We aimed to investigate whether neutrophil extracellular trap (NET) formation in the early phase after return of spontaneous circulation (ROSC) may be associated with poor 30 day neurologic function in cardiac arrest survivors. This study prospectively included adult (≥18 years) out-of-hospital cardiac arrest (OHCA) survivors with cardiac origin, who were subjected to targeted temperature management. Plasma levels of specific (citrullinated histone H3, H3Cit) and putative (cell-free DNA (cfDNA) and nucleosomes) biomarkers of NET formation were assessed at 0 and 12 h after admission. The primary outcome was neurologic function on day 30 after admission, which was assessed using the five-point cerebral performance category (CPC) score, classifying patients into good (CPC 1-2) or poor (CPC 3-5) neurologic function. The main variable of interest was the effect of H3Cit level quintiles at 12 h on 30 day neurologic function, assessed by logistic regression. The first quintile was used as a baseline reference. Results are given as crude odds ratio (OR) with 95% confidence interval (95% CI). Sixty-two patients (79% male, median age: 57 years) were enrolled. The odds of poor neurologic function increased linearly, with 0 h levels of cfNDA (crude OR 1.8, 95% CI: 1.2-2.7, p = 0.007) and nucleosomes (crude OR 1.7, 95% CI: 1.0-2.2, p = 0.049), as well as with 12 h levels of cfDNA (crude OR 1.6, 95% CI: 1.1-2.4, p = 0.024), nucleosomes (crude OR 1.7, 95% CI: 1.1-2.5, p = 0.020), and H3Cit (crude OR 1.6, 95% CI: 1.1-2.3, p = 0.029). Patients in the fourth (7.9, 95% CI: 1.1-56, p = 0.039) and fifth (9.0, 95% CI: 1.3-63, p = 0.027) H3Cit quintile had significantly higher odds of poor 30 day neurologic function compared to patients in the first quintile. Increased plasma levels of H3Cit, 12 h after admission, are associated with poor 30 day neurologic function in adult OHCA survivors, which may suggest a contribution of NET formation to post-resuscitative brain damage and therefore provide a therapeutic target in the future.