Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products

Abstract To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

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Prothrombin Complex Concentrate Use in Intracranial Hemorrhage Patients With Cirrhosis Not on Prior Anticoagulation

Journal of Intensive Care Medicine ◽

10.1177/08850666211012650 ◽

2021 ◽

pp. 088506662110126

Author(s):

Clay Small ◽

Rebecca L. Attridge ◽

Crystal Franco-Martinez ◽

Jonathan Donnelly ◽

Colleen Barthol

Keyword(s):

Intracranial Hemorrhage ◽

Randomized Clinical Trials ◽

Anticoagulation Therapy ◽

Standard Of Care ◽

Hematoma Expansion ◽

Multivariate Logistic Regression Model ◽

Head Ct ◽

Number Of Patients ◽

History Of

Background/Objective: Patients with intracranial hemorrhage (ICH) have a 30-day mortality rate up to 52%, and the risk of mortality is increased in patients with disease-induced coagulopathy such as cirrhosis. The objective of this study was to evaluate whether 4F-PCC administration mitigates hematoma expansion in ICH patients with cirrhosis not currently receiving anticoagulation therapy compared to standard of care therapies. Methods: This was a single-center, retrospective study comparing adult patients with ICH and history of cirrhosis who received 4F-PCC versus standard of care therapies. The primary outcome was rate of ICH expansion within 24 hours after admission. Results: A total of 58 patients were included with 21 who received 4FPCC vs 37 who received standard of care therapies. The 4F-PCC group had a significantly higher number of patients with Child Pugh Class C cirrhosis (85.7% vs. 48.6%, P = 0.006), higher baseline INR (1.7 vs. 1.4, P = 0.001) and more patients with a spontaneous cause of hemorrhage (61.9% vs. 29.7%, P = 0.01). Stable follow-up head CT was achieved in 68.4% of patients who received 4F-PCC versus 72.7% of patients treated with standard of care therapies ( P = 0.11). Patients who received 4F-PCC had a significantly greater change in INR within 24 hours (-0.2 vs. 0, P = 0.02) and higher rate of mortality (61.9% vs. 18.9%, P = 0.001). Baseline INR > 2 and surgical evacuation for ICH were associated with decreased odds of stable follow-up head CT in the multivariate logistic regression model. Conclusions: A single dose of 4F-PCC did not significantly improve the rate of stable head CT at 24 hours in patients with ICH and cirrhosis. Randomized clinical trials with larger patient populations are warranted to fully determine the role of 4F-PCC in this unique population.

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Abstract P26: Association of Tranexamic Acid Use With Outcomes in Alteplase-Associated Intracranial Hemorrhage

Stroke ◽

10.1161/str.52.suppl_1.p26 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Leana Mahmoud ◽

Andrew Zullo ◽

Liqi Shu ◽

Shadi Yaghi ◽

Ava L Liberman ◽

...

Keyword(s):

Tranexamic Acid ◽

Functional Outcome ◽

Intracranial Hemorrhage ◽

Standard Of Care ◽

Outcome Data ◽

Hematoma Expansion ◽

Study Cohort ◽

Poor Functional Outcome ◽

Chi Square ◽

Increased Risk

Background: Alteplase (tPA) is the standard of care in acute ischemic stroke (AIS) treatment, but it is associated with increased risk of symptomatic intracranial hemorrhage (sICH). Cryoprecipitate (Cryo) is recommended for tPA-associated sICH reversal. Tranexamic acid (TXA), an antifibrinolytic, is of interest as an adjunct therapy, but data in AIS is limited. We aim to assess the relationship of TXA and sICH reversal. Methods: We conducted a multicenter retrospective cohort study of AIS patients admitted between April 2015 and July 2020 who were treated for tPA-associated sICH. Patients with extracranial bleeds, who were not reversed, or who died within 24 hours were excluded. Demographics, clinical characteristics, imaging, and outcome data were collected from electronic health records. Outcomes included hematoma expansion, a poor functional outcome at 90 days (modified Rankin Score 3-6), and thrombotic events. We used Pearson chi-square, Fisher’s exact, and Wilcoxon rank-sum tests to compare outcomes between adjunct TXA treatment (TXA+Cryo) vs. Cryo only groups. Results: The study cohort included 30 patients with tPA-related sICH (mean age 80 ±12.4 years; 60% female). Overall median (IQR) hematoma size was 4.4 ml (1.1-20). Multifocal bleeds were present in 39% of patients. TXA+Cryo was administered in 16 (53%) patients. Initial hematoma size was smaller in the TXA+Cryo group than the Cryo only group, median (IQR) of 2.4 ml (0.5-14.3) vs 24.1 ml (2.5-56.5), p=0.043. However, there were no marked differences between TXA+Cryo and the Cryo only groups for hematoma expansion (5 [33%] vs. 6 [50%] patients, p=0.38), poor functional outcome (15 [94%] vs. 11 [79%] patients, p=0.32), or thrombotic events (1 [6%] vs. 0, p=1.00). Conclusion: Among patients treated for tPA-related sICH, there was no difference in hematoma expansion, poor functional outcome, or thrombotic events in patients treated with adjunct TXA compared to Cryo alone.

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High-Dose 4-Factor Prothrombin Complex Concentrate for Warfarin-Induced Intracranial Hemorrhage

The Neurohospitalist ◽

10.1177/1941874419844343 ◽

2019 ◽

Vol 10 (1) ◽

pp. 16-21 ◽

Cited By ~ 1

Author(s):

Cristian Merchan ◽

Tania Ahuja ◽

Veronica Raco ◽

Ariane Lewis

Keyword(s):

Intracranial Hemorrhage ◽

Prothrombin Complex Concentrate ◽

Standard Dose ◽

Package Insert ◽

International Normalized Ratio ◽

Hematoma Expansion ◽

High Dose ◽

Vein Thrombosis ◽

Dosing Strategy ◽

Deep Vein

Background and Purpose: The ideal dosing regimen of 4-factor prothrombin complex concentrate (4FPCC) after warfarin-induced intracranial hemorrhage (WICH) remains unclear. We sought to compare the safety and efficacy of the 4FPCC package insert dosing strategy (standard dose [SD]) with our institutional guideline for high-dose (HD) 4FPCC for patients with WICH. Methods: We compared the percentage of SD and HD patients who achieved an international normalized ratio (INR) ≤1.3 at a single institution between January 2014 and July 2017. Additionally, we assessed hematoma expansion, recurrence of INR > 1.3, and occurrence of thrombotic events within 7 days of 4FPCC administration. Results: Of 48 patients with WICH, 30 received SD and 18 received HD. The median baseline INR was 2.5 (2.0-3.8) for SD patients and 3.3 (2.5-5) for HD patients ( P = .147). Successful achievement of an INR ≤ 1.3 after the initial 4FPCC dose was obtained in 70% of patients in the SD group and 94% of patients in the HD group ( P = .124). A higher percentage of patients in the SD group had an INR > 1.3 at some point after admission (30% vs 6%; P = .053). There was a trend toward more hematoma expansion in the SD group, but this was not statistically significant (17% in the SD group vs 0% in HD group; P = .056). There were 2 thrombotic events: one deep vein thrombosis in each group ( P = .243). Conclusions: High-dose 4FPCC appears to be more effective at lowering INR and preventing bleed expansion in patients with WICH, while maintaining a similar safety profile.

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Acute Rejection Following Kidney Transplantation: State-of-the-Art and Future Perspectives

Current Pharmaceutical Design ◽

10.2174/1381612826666200610184433 ◽

2020 ◽

Vol 26 (28) ◽

pp. 3468-3496

Author(s):

Emilio Rodrigo ◽

Marcio F. Chedid ◽

David San Segundo ◽

Juan C.R. San Millán ◽

Marcos López-Hoyos

Keyword(s):

Kidney Transplantation ◽

Acute Rejection ◽

Rescue Therapy ◽

Standard Of Care ◽

Rejection Rate ◽

New Drugs ◽

High Dose ◽

Current Standard ◽

Antibody Mediated Rejection ◽

Cellular Rejection

: Although acute renal graft rejection rate has declined in the last years, and because an adequate therapy can improve graft outcome, its therapy remains as one of the most significant challenges for pharmacists and physicians taking care of transplant patients. Due to the lack of evidence highlighted by the available metaanalyses, we performed a narrative review focused on the basic mechanisms and current and future therapies of acute rejection in kidney transplantation. : According to Kidney Disease/Improving Global Outcomes (KDIGO) guidelines, both clinical and subclinical acute rejection episodes should be treated. Usually, high dose steroids and basal immunosuppression optimization are the first line of therapy in treating acute cellular rejection. Rabbit antithymocytic polyclonal globulins are used as rescue therapy for recurrent or steroid-resistant cellular rejection episodes. Current standard-of-care (SOC) therapy for acute antibody-mediated rejection (AbMR) is the combination of plasma exchange with intravenous immunoglobulin (IVIG). Since a significant rate of AbMR does not respond to SOC, different studies have analyzed the role of new drugs such as Rituximab, Bortezomib, Eculizumab and C1 inhibitors. Lack of randomized controlled trials and heterogenicity among performed studies limit obtaining definite conclusions. Data about new direct and indirect B cell and plasma cell depleting agents, proximal and terminal complement blockers, IL-6/IL-6R pathway inhibitors and antibody removal agents, among other promising drugs, are reviewed.

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High-dose Aprotinin in Cardiac Surgery—A Prospective, Randomized Study

Anaesthesia and Intensive Care ◽

10.1177/0310057x9402200505 ◽

1994 ◽

Vol 22 (5) ◽

pp. 529-533 ◽

Cited By ~ 20

Author(s):

M. J. Swart ◽

P. C. Gordon ◽

P. B. Hayse-Gregson ◽

R. A. Dyer ◽

A. L. Swanepoel ◽

...

Keyword(s):

Cardiac Surgery ◽

Placebo Group ◽

Blood Loss ◽

Artery Bypass ◽

Randomized Study ◽

Postoperative Blood Loss ◽

High Dose ◽

Maintenance Infusion ◽

Transfusion Requirements ◽

High Dose Aprotinin

Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin (2 million units loading dose, 2 million units added to the CPB prime, and 500,000 units/hr maintenance infusion) or placebo. Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group (95% confidence interval (CI) for difference = 95 to 189 ml). Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood. This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery.

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346. Eastern Equine Encephalitis and Use of Intravenous Immunoglobulin Therapy and High-Dose Steroids

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.541 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S242-S243

Author(s):

Sarah I Collens ◽

Douglas R Wilcox ◽

Shibani Mukerji ◽

Farrah J Mateen ◽

Isaac H Solomon

Keyword(s):

Cerebrospinal Fluid ◽

Temporal Lobe ◽

Standard Of Care ◽

High Dose ◽

High Morbidity ◽

Intravenous Immunoglobulin Therapy ◽

Eastern Equine Encephalitis ◽

Neuroanatomical Region ◽

Ivig Administration

Abstract Background Eastern equine encephalitis (EEE) is a mosquito-borne viral infection with significant neurological morbidity and mortality. The clinical presentation and patient outcomes after treatment with IVIG, high-dose steroids, or standard of care alone in EEE remains unclear. Methods A retrospective observational study of patients admitted to two tertiary academic medical centers in Boston, Massachusetts with EEE from 2005 to 2019. Results Of 17 patients (mean [SD] age, 50 [26] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with cerebrospinal fluid (CSF) cell count differential had a neutrophil predominance (mean [SD], 60.6% of white blood cells [22.8]) with an elevated protein level (mean [SD], 112 mg/dL [48.8]). Affected neuroanatomical regions included the basal ganglia (n=9/17), thalamus (n=7/17), and mesial temporal lobe (n=7/17). A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by modified Rankin Score (mRS) (r=0.72, p=0.02); steroid use was not associated with mRS score. The mortality was 12%. Figure 1. Imaging Characteristics: Typical Pattern of MRI Involvement and Affected Neuroanatomical Regions in Patients with Eastern Equine Encephalitis. All images displayed are the T2-FLAIR sequence. (A) Representative images of pattern of typical neuroanatomical region involved in one patient with demonstrated involvement of the temporal lobe and pons, temporal lobe and midbrain, and basal gangial by T2-FLAIR hyperintensity (panels left to right). (B) Representative images of patients with mild (mRS 0–2), moderate (mRS 3–4), and severe (mRS 5–6) disability score at discharge. (C) Representative images of one patient over course of hospitalization at days 1, 4, and 10 after admission. (D) Quantification of neuroanatomical region involvement in initial MRI of patients with EEE as determined by T2-FLAIR hyperintensity. An area was scored as abnormal only once per patient. Figure 2. Outcomes in Patients with Eastern Equine Encephalitis. Patient disability by modified Rankin Score (mRS) of EEE patients at admission to the hospital, discharge from the hospital, and last recorded follow-up (A). Time to IVIG administration compared to mRS at discharge (B), and most recent clinical follow-up (C). Table 1. Demographics, Clinical Characteristics, and Laboratory Data in Patients with Eastern Equine Encephalitis. Abbreviations: CSF = cerebrospinal fluid, WBC = white clood count, EEG = electroencephalogram, ALT = alanine aminotransferase, AST = aspartate transaminase. Demographic data was collected for all patients with confirmed EEE. Altered mental status included any description of encephalopathy, confusion, or difficulty with attention. Seizures were defined as clinical events with a high-degree of suspicion to be true seizures, and were entirely comprised of generalized tonic-clonic seizures. Conclusion Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization. Disclosures All Authors: No reported disclosures

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High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

Clinical Infectious Diseases ◽

10.1093/cid/ciab162 ◽

2021 ◽

Author(s):

Fiona V Cresswell ◽

David B Meya ◽

Enock Kagimu ◽

Daniel Grint ◽

Lindsey te Brake ◽

...

Keyword(s):

Adverse Events ◽

Phase Ii ◽

Tuberculous Meningitis ◽

Geometric Mean ◽

Standard Of Care ◽

Hiv Positive ◽

High Dose ◽

Open Label ◽

Dose Oral ◽

Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

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