What's New in Coagulation - May 2017

Want to be in the know? Check out our monthly compilation of the latest studies, guidelines, and discussions in coagulation.

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Is Fibrinogen Useful in High-Risk Cardiac Surgery?

Thigh risk cardiac surgery also can be accompanied by bleeding. This would include valve replacements, reconstruction of the aortic root, ascending aorta or aortic arch and combined coronary artery bypass graft surgery. In a study conducted in the Netherlands, 203 patients were enrolled. Bleeding was measured by packing the thoracic cavity with surgical gauze and wringing out the blood after 5 minutes. Patients were excluded if the total bleeding was <60 mls.

Eighty-three patients were excluded due to insufficient bleeding.

The remaining 120 patients had a >250ml blood loss were randomly assigned to receive either fibrinogen concentrate or a placebo. The dose of fibrinogen was variable and was based on fibrinogen levels post cardiopulmonary bypass. The lower the fibrinogen value the higher dose of fibrinogen received. Target concentration was 2.5g/L.

Primary outcome was blood loss in milliliters between intervention with a shorter duration (4.2 minutes) in the fibrinogen group versus (8.7 minutes) in the control group. After controlling for confounding variables median blood loss was 50mls in the fibrinogen group versus 70mls in the control group. Cumulative blood loss was less in the first 24 hours after surgery was lower for the fibrinogen group (570mls) versus the control group of 690 mls. The conclusion is that fibrinogen concentration did not reduce intraoperative blood loss. Postoperatively fibrinogen concentrations increased and at 24 hours levels were nearly equal.

Silent Cerebral Microbleeds Common After TAVR, Says Study

Subclinical cerebral microbleeds that are associated with transcatheter aortic-valve replacement (TAVR) can be high. This can impact neurological outcomes. In an observation study of 84 patients, it was noted that 26% had one or more CMBs before undergoing TAVR, as measured by cerebral MRI. But 23% of the total participants had at least one new CMB 3 days after the procedure. All resulting in worse neurological scores at baseline and 6 months. Significant predictors for a new CMB occurrence during TAVR included a prolonged fluoroscopy time and persistence of acquired von Willebrand disease. This study enhances the importance of pre and post assessment on both MRI and neurologic tests. Having guidelines on procedural issues and a team approach will improve outcomes on these patients.

Apixaban Cost-effective vs Warfarin in Nonvalvular Atrial Fibrillation: ARISTOTLE

Lifetime oral anticoagulation was previously only available with warfarin, however patients have options. One of the advantages of warfarin is that it is an inexpensive drug. This study revealed that apixaban appears to be as cost effective in patients with atrial fibrillation as warfarin. In the ARISTOTLE trial data from18,000 patients with nonvalvular AF and 3500 US patients for stroke prevention was reviewed. Patients were followed 1.8 years between 2006-2011. In primary outcomes apixaban showed a significant advantage over warfarin in prevention of stroke, systemic embolism while also resulting in significantly fewer major bleed. Risk of hospitalization did not differ significantly between treatment.

The cost of hospitalizations for apixaban therapy was $4757 versus $5122 for warfarin. Life expectancy was also 0.5 years longer when compared with warfarin (9.83 vs. 9.33 yrs.)

The "most influential" determinant of costs in their analysis was the cost of the drug. Warfarin, including INR monitoring, is a tiny fraction of the DOAC's annual cost. Apixaban was pegged at $9.87 per day and warfarin at $0.09 per day. If apixaban were hypothetically to be priced lower, and found them to be $40,426 per QALY with apixaban at 75% of current price, $26,927 with the drug priced at 50%, and $13,427 with it at 25% of current price.

Suggestions are that cost savings with apixaban are based due to reduced monitoring, decreased risk for bleeding and stroke, and also if healthcare systems could purchase the drug cheaper.

Negative Data Piling Up on Absorb Bioresorbable Scaffold

The risk of thrombosis is significantly higher in patients on the bioresorbable vascular scaffold (BVS) versus an everolimus-eluting metallic stent based on results from the AIDA trial. There was no significant difference in the risk of target vessel failure, rates were similar for cardiac death and target vessel revascularization. However there was a significantly higher risk of target vessel MI for absorb BVS.

There was an FDA alert to clinicians investigating a significantly higher risk of adverse events. The risk of thrombosis was 3.5 times higher in the BVS group versus the stent group. Definite/probable device thrombosis was higher with the BVS than the everolimus-eluting stent for all postimplantation periods: acute (<24 hours; 13 vs five patients), subacute (>24 hours to 30 days; eight patients vs one patient), and very late (>1 to 3 years; 10 vs two patients). Thrombosis occurs regardless of implantation technique.

Based on the finding, dual anti-platelet therapy was recommended to extending it to 3 years in this group since the no issues of late thrombosis were seen in patients who were treated for this length of time.

Cheap Drug Cuts Maternal Deaths Due to Postpartum Hemorrhage

A randomized controlled trial (WOMAN) in which women with postpartum hemorrhage were administered tranexamic acid reduced death from bleeding by one third. No side effects were noted for either the mothers or babies. This is the leading cause of maternal death with 99% occurring in lower income countries. Since fibrinolysis is activated soon after childbirth, the WHO recommends the administration of an antifibrinolytic drug tranexamic acid based on the outcomes in surgery and trauma. The WOMEN study investigated using it as a treatment of postpartum hemorrhage. Data was accumulated from 20,021 women between 2010-2016 who received 1 g IV tranexamic acid versus a placebo.

Results showed that treatment versus placebo significantly reduced the risk for death from bleeding, with better outcomes in women who received treatment within 3 hours of delivery. Results when give later than 3 hours did not significantly reduce the risk for hysterectomy. This supports the WHO recommendation with the suggestion it be administered as soon as possible after onset of bleeding.

However IV administration in lower income countries may be difficult due to births being outside of healthcare facilities.


Continued Use of Warfarin in Veterans With Atrial Fibrillation After Dementia Diagnosis

Ariela R. Orkaby, MD; Al Ozonoff, PhD; Joel I. Reisman, AB; Donald R. Miller, ScD; Shibei Zhao, MPH; Adam J. Rose, MD, MSc

J Am Geriatr Soc. 2017;65(2):249-256.

Abstract and Introduction

Objective: To determine the effectiveness of warfarin in older adults with dementia.

Design: Retrospective cohort study.

Setting: Department of Veterans Affairs national healthcare system.

Participants: Veterans aged 65 and older (73% aged ≥75, 99% male, 91% white) who had been receiving warfarin for nonvalvular atrial fibrillation for at least 6 months, were newly diagnosed with dementia in fiscal year 2007 or 2008, and were not enrolled in Medicare Advantage (n = 2,572).

Measurements: The onset of dementia was defined according to International Classification of Diseases, Ninth Revision, code. Participants were followed for up to 4 years for persistence of warfarin therapy, anticoagulation control, major hemorrhage, ischemic stroke, and all-cause mortality.

Results: The average CHADS2 score was 3.3 ± 1.3. After a diagnosis of dementia, 405 individuals (16%) persisted on warfarin therapy. Unadjusted Cox proportional hazards analysis demonstrated a protective effect of warfarin in prevention of ischemic stroke (hazard ratio (HR) = 0.64, 95% confidence interval (CI) = 0.46-0.89, P = .008), major bleeding (HR = 0.72, 95% CI = 0.55-0.94, P = .02), and all-cause mortality (HR = 0.66, 95% CI = 0.55-0.79, P < .001). Using propensity score matching, the protective effect of continuing warfarin persisted in prevention of stroke (HR = 0.74, 95% CI = 0.54-0.996, P = .047) and mortality (HR = 0.72, 95% CI = 0.60–0.87, P < .001), with no statistically significant decrease in risk of major bleeding (HR = 0.78, 95% CI = 0.61-1.01, P = .06).

Conclusion: Discontinuing warfarin after a diagnosis of dementia is associated with a significant increase in stroke and mortality.

Predicting Early Death in Patients With Traumatic Bleeding: Development and Validation of Prognostic Model

Pablo Perel; David Prieto-Merino; Haleema Shakur; Tim Clayton; Fiona Lecky; Omar Bouamra; Rob Russell; Mark Faulkner; Ewout W Steyerberg; Ian Roberts


Abstract and Introduction

Objective: To develop and validate a prognostic model for early death in patients with traumatic bleeding.

Design: Multivariable logistic regression of a large international cohort of trauma patients.

Setting: 274 hospitals in 40 high, medium, and low income countries.

Participants: Prognostic model development: 20,127 trauma patients with, or at risk of, significant bleeding, within 8 hours of injury in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial. External validation: 14,220 selected trauma patients from the Trauma Audit and Research Network (TARN), which included mainly patients from the UK.

Outcomes: In-hospital death within 4 weeks of injury.

Results: 3076 (15%) patients died in the CRASH-2 trial and 1765 (12%) in the TARN dataset. Glasgow coma score, age, and systolic blood pressure were the strongest predictors of mortality. Other predictors included in the final model were geographical region (low, middle, or high income country), heart rate, time since injury, and type of injury. Discrimination and calibration were satisfactory, with C statistics above 0.80 in both CRASH-2 and TARN. A simple chart was constructed to readily provide the probability of death at the point of care, and a web based calculator is available for a more detailed risk assessment (

Conclusion: This prognostic model can be used to obtain valid predictions of mortality in patients with traumatic bleeding, assisting in triage and potentially shortening the time to diagnostic and lifesaving procedures (such as imaging, surgery, and tranexamic acid). Age is an important prognostic factor, and this is of particular relevance in high income countries with an aging trauma population.

Potent P2Y12 Inhibitors in Men Versus Women

A Collaborative Meta-Analysis of Randomized Trial

Emily S. Lau, MD; Eugene Braunwald, MD; Sabina A. Murphy, MPH; Stephen D. Wiviott, MD; Marc P. Bonaca, MD, MPH; Steen Husted, MD; Stefan K. James, MD, PHD; Lars Wallentin, MD, PHD; Peter Clemmensen, MD, PHD; Matthew T. Roe, MD, MHS; E. Magnus Ohman, MD; Robert A. Harrington, MD; Jessica L. Mega, MD, MPH; Deepak L. Bhatt, MD, MPH; Marc S. Sabatine, MD, MPH; Michelle L. O'Donoghue, MD, MPH

J Am Coll Cardiol. 2017;69(12):1549-1559.

Abstract and Introduction

Background: Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.

Objectives: The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease.

Methods: A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.

Results: Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).

Conclusion: In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.