Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs

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Abstract

Background

New oral anticoagulant (NOAC) drugs are known to influence the results of some routine hemostasis tests. Further data are needed to enable routine assessment of the effects of NOAC on clotting parameters in some special circumstances.

Methods

Following administration of rivaroxaban to patients, at the likely peak and trough activity times, we assessed the effects on prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and clotting time using Russell’s viper venom, and in the presence of phospholipids and calcium reagent available as DVVreagent® and DVVconfirm®. The data were used to determine an adequate NOAC plasma level based on anticoagulant activities expressed as a ratio (patients/normal, R-C).

Results

DVVconfirm as R-C could be rapidly performed, and the results were reasonably sensitive for rivaroxaban and probably for other FX inhibitors. This assay is not influenced by lupus anticoagulant and heparin, does not require purified NOAC as control, and will measure whole-plasma clotting activity.

Conclusions

We propose a cut-off R-C value of 4.52 ± 0.33 for safety, but clinical studies are needed to establish whether this cut-off is useful for identifying patients at increased risk of hemorrhage or exhibiting low anticoagulation effect. It also seems possible that normal R-C could indicate an absence of anticoagulant activity when rivaroxaban is discontinued due to episodes of uncontrolled bleeding during anticoagulation or for emergency surgery.

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Most cited references 33

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Adverse impact of bleeding on prognosis in patients with acute coronary syndromes.

John W Eikelboom, Shamir R Mehta, Sonia S. Anand … (2006)

The use of multiple antithrombotic drugs and aggressive invasive strategies has increased the risk of major bleeding in acute coronary syndrome (ACS) patients. It is not known to what extent bleeding determines clinical outcome. Using Cox proportional-hazards modeling, we examined the association between bleeding and death or ischemic events in 34,146 patients with ACS enrolled in the Organization to Assess Ischemic Syndromes and the Clopidogrel in Unstable Angina to Prevent Recurrent Events studies. Patients with major bleeding were older, more often had diabetes or a history of stroke, had a lower blood pressure and higher serum creatinine, more often had ST-segment changes on the presenting ECG, and had a 5-fold-higher incidence of death during the first 30 days (12.8% versus 2.5%; P < 0.0001) and a 1.5-fold-higher incidence of death between 30 days and 6 months (4.6% versus 2.9%; P = 0.002). Major bleeding was independently associated with an increased hazard of death during the first 30 days (hazard ratio, 5.37; 95% CI, 3.97 to 7.26; P < 0.0001), but the hazard was much weaker after 30 days (hazard ratio, 1.54; 95% CI, 1.01 to 2.36; P = 0.047). The association was consistent across subgroups according to cointerventions during hospitalization, and there was an increasing risk of death with increasing severity of bleeding (minor less than major less than life-threatening; P for trend = 0.0009). A similar association was evident between major bleeding and ischemic events, including myocardial infarction and stroke. In ACS patients without persistent ST-segment elevation, there is a strong, consistent, temporal, and dose-related association between bleeding and death. These data should lead to greater awareness of the prognostic importance of bleeding in ACS and should prompt evaluation of strategies to reduce bleeding and thereby improve clinical outcomes.

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Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.

Elaine Hylek, Alan S Go, Yuchiao Chang … (2003)

The incidence of stroke in patients with atrial fibrillation is greatly reduced by oral anticoagulation, with the full effect seen at international normalized ratio (INR) values of 2.0 or greater. The effect of the intensity of oral anticoagulation on the severity of atrial fibrillation-related stroke is not known but is central to the choice of the target INR. We studied incident ischemic strokes in a cohort of 13,559 patients with nonvalvular atrial fibrillation. Strokes were identified through hospitalization data bases and validated on the basis of medical records, which also provided information on the use of warfarin or aspirin, the INR at admission, and coexisting illnesses. The severity of stroke was graded according to a modified Rankin scale. Thirty-day mortality was ascertained from hospitalization and mortality files. Of 596 ischemic strokes, 32 percent occurred during warfarin therapy, 27 percent during aspirin therapy, and 42 percent during neither type of therapy. Among patients who were taking warfarin, an INR of less than 2.0 at admission, as compared with an INR of 2.0 or greater, independently increased the odds of a severe stroke in a proportional-odds logistic-regression model (odds ratio, 1.9; 95 percent confidence interval, 1.1 to 3.4) across three severity categories and the risk of death within 30 days (hazard ratio, 3.4; 95 percent confidence interval, 1.1 to 10.1). An INR of 1.5 to 1.9 at admission was associated with a mortality rate similar to that for an INR of less than 1.5 (18 percent and 15 percent, respectively). The 30-day mortality rate among patients who were taking aspirin at the time of the stroke was similar to that among patients who were taking warfarin and who had an INR of less than 2.0. Among patients with nonvalvular atrial fibrillation, anticoagulation that results in an INR of 2.0 or greater reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke. Our findings provide further evidence against the use of lower INR target levels in patients with atrial fibrillation. Copyright 2003 Massachusetts Medical Society

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Apixaban with antiplatelet therapy after acute coronary syndrome.

John H Alexander, Renato D Lopes, Stefan James … (2011)

Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

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Author and article information

Contributors

Raul Altman

Claudio Daniel Gonzalez

Journal

Journal ID (nlm-ta): Thromb J

Journal ID (iso-abbrev): Thromb J

Title: Thrombosis Journal

Publisher: BioMed Central

ISSN (Electronic): 1477-9560

Publication date Collection: 2014

Publication date (Electronic): 21 March 2014

Volume: 12

Page: 7

Affiliations

[1 ]Centro de Trombosis de Buenos Aires, Viamonte 2008, Buenos Aires 1056, Argentina

[2 ]Catedra de Farmacologia, Facultad de Medicina, Universidad Nacional de Buenos Aires, Viamonte 2008, Buenos Aires 1056, Argentina

Article

Publisher ID: 1477-9560-12-7

DOI: 10.1186/1477-9560-12-7

PMC ID: 3974190

PubMed ID: 24656069

SO-VID: c3bb471e-f49e-4e8b-92f8-3876d097bcbb

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Simple and rapid assay for effect of the new oral anticoagulant (NOAC) rivaroxaban: preliminary results support further tests with all NOACs

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Abstract

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Karger: Cardiovascular System

Most cited references 33

Adverse impact of bleeding on prognosis in patients with acute coronary syndromes.

Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.

Apixaban with antiplatelet therapy after acute coronary syndrome.

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