New Data on Bleeding Risk Reduction Strategies in Anticoagulation Therapy

In this session, data were presented from 3 separate trials that focused on potential ways to reduce the risk for bleeding in patients who require anticoagulation therapy, including the use of genetic tests to optimize warfarin dosing and the use of the factor Xa inhibitor edoxaban. Munir Pirmohamed, MD, PhD, from the University of Liverpool, discussed results from the EU-PACT trial; Stephen Kimmel, MD, from the University of Pennsylvania School of Medicine discussed results from the COAG trial; and Robert P. Giugliano, MD, SM, FAHA, FACC, from Brigham and Women's Hospital, discussed results from the ENGAGE TIMI-AF 48 trial.

Data from 3 separate trials presented at an American Heart Association Late-Breaking Session focused on potential ways to reduce the risk for bleeding in patients who require anticoagulation therapy. Newly published data were presented for the EU-PACT and COAG trials, which examined the use of genetic tests to optimize warfarin dosing, and the ENGAGE TIMI-AF 48 study for the factor Xa inhibitor edoxaban versus warfarin.

Approximately 25 million Americans take warfarin. Maintaining patients’ dosing within a narrow therapeutic range is critical to optimizing its safety and effectiveness. Dosing that is too low puts patients at increased risk for clots, but too high dosing creates an increased risk for bleeding.

Genetics-Guided Dosing

“The problem with warfarin is that we can’t determine what the individual dose should be,” said trial investigator Munir Pirmohamed, MD, PhD, lead author of the EU-PACT study and NHS chair of pharmacogenetics, University of Liverpool.

Various factors determine the individual dosing requirements for warfarin. About 50% to 55% of the daily dosing requirement can be explained by 2 genetic factors, CYP2C9 and VKORC1, Dr Pirmohamed said. The US Food and Drug Administration changed the labels in 2010 to include recommendations concerning dosing that are based on these factors, he said; however, current guidelines do not recommend genotyping for warfarin dosing.

EU Pharmacogenetics of Anticoagulant Therapy (EU-PACT)1

The European study compared the use of genetics to guide warfarin dosing with usual dosing methods, which depend on frequent blood testing to measure the therapeutic range. A total of 455 patients were randomized to either the genotype-guided dosing arm or standard dosing and were followed for 3 months. Most patients were males (61%) with a mean age of 67 years. The majority of patients had atrial fibrillation (AF; 72%). Primary end point results showed that genotyping was associated with a 7% increase in the time patients were within therapeutic range (67.4% vs 60.3% for the genotyping and standard arms, respectively; P <.001). Genotyping was also associated with a reduction in over-coagulation, time to reach the therapeutic range, and time to reach a stable dose.

“Our study very much fits in with the concept of personalized medicine, which aims to get the right drug, at the right dose, to the right patient,” Dr Pirmohamed said.

The Clarification of Optimal Anticoagulation Through Genetics (COAG) Trial2

“Warfarin has served as a model for pharmacogenetics,” said lead COAG investigator Stephen Kimmel, MD, professor of medicine and epidemiology, University of Pennsylvania School of Medicine.

In the COAG trial, researchers randomized 1015 patients with histories of stroke, venous thrombosis, and AF to 1 of 2 groups to determine the incremental effect of using genetic information to guide dosing. One group had dosing adjustments based on both genetic information and clinical information (eg, age, weight, and smoking status), while the other group’s dosing decisions were based only on clinical information. Patients were followed for up to 6 months. Patients’ average age was 57 years; 51% were male; 27% were African American; 22% had AF; and 58% had deep vein thrombosis in the legs or lungs.

Results showed no differences in the primary end point of percent time within therapeutic range (approximately 45% for both groups). There were significant differences, however, for African Americans. In this population, those receiving therapy based on genetics didn’t do as well as those who did not use genetics (35.2% vs 34.1%, respectively; P = .01).

“There is huge potential in the cardiovascular field for personalizing therapy on the basis of genetic or non-genetic tests,” Dr Kimmel said. “For genetic testing, in some cases it may be possible to undertake the testing at the bedside or in surgery, so called point-of-care tests as we did in this trial. We need evidence from randomized controlled trials to show the utility of genetic testing.”

Novel Oral Anticoagulant Alternative3

The ENGAGE-TIMI 48 inferiority trial included 21,105 patients with AF who were randomized to 1 of 3 groups: warfarin, the factor Xa inhibitor edoxaban 30 mg/day, or edoxaban at 60 mg/day. The primary end point was a composite of stroke, systemic embolic events (SEEs), and major bleeding, according to lead trial investigator Robert P. Giugliano, MD, SM, FAHA, FACC of Brigham and Women’s Hospital, who presented the results.

The data showed that both doses of edoxaban met the primary end point for noninferiority. The higher dose was associated with a 21% reduction in stroke and SEE (P <.001). With the secondary efficacy end points, both doses were associated with significant reductions in hemorrhagic stroke (P <.001). For the primary safety end point, International Society of Thrombosis and Hemostasis (ISTH) major bleeding, the high dose was associated with a 20% reduction, and the low dose a 53% reduction. Both the high and low doses of edoxaban were also associated with significant reductions in intracranial hemorrhaging (53% and 70%, respectively; P <.001).

“Atrial fibrillation is a common problem among the elderly, and as Americans live longer we need safer, yet effective treatments,” Dr Giugliano said.

Currently, edoxaban is approved only in Japan.

All 3 studies were published online ahead of print in the New England Journal of Medicine to coincide with this late-breaking session.


  1. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1311386.
  2. Kimmel SE, French, B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1310669.
  3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs warfarin in patients with atrial fibrillation [published online November 19, 2013]. N Engl J Med. doi:10.1056/NEJMoa1310907.
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