Revised Pathway Speeds Anticoagulation Reversal in Stroke

Daniel M. Keller, PhD

June 07, 2012

June 7, 2012 (Lisbon, Portugal) — British researchers have reduced by more than half the door-to-needle time to reverse oral anticoagulant therapy (OAT) for patients with intracerebral hemorrhage (ICH).

Speaking here at the XXI European Stroke Conference (ESC), Adrian Parry-Jones, MBChB, PhD, honorary specialist registrar in neurology in the Brain Injury Research Group at the Salford Royal NHS Foundation Trust in Salford, United Kingdom (UK), said that by eliminating several barriers to faster therapy, they have streamlined the treatment pathway.

Dr. Parry-Jones estimated that 5%-12% of ICH cases are associated with concomitant anticoagulant use, which can lead to hematoma expansion and poor prognosis. UK national guidelines recommend rapid reversal of anticoagulation using prothrombin complex concentrate (PCC) and vitamin K.

For this study, the investigators set out to identify barriers to treatment at their comprehensive stroke center at Salford Royal Hospital and to survey practice in the UK.

Recording the timing of key steps in treatment derived from the hospital records, they analyzed the treatment pathway for 26 patients with ICH receiving OAT by retrospectively reviewing records for cases between December 2008 and November 2010 and a prospective study from December 2010 to April 2012.

The protocol at the hospital had involved urgent clotting and computed tomography (CT) of the brain. If the international normalized ratio (INR) was 1.2 or greater and ICH was evident on CT, intravenous vitamin K, 10 mg, was administered; with hematologist approval, PCC, 20 IU/kg (30 IU/kg if the INR was > 2.5) was given via blood transfusion..

Patients had a median age of 78 years (interquartile range [IQR], 73 - 83 years), 62% were male, the median Glasgow Coma Scale score was 15 (IQR, 5 - 15) at presentation, and the median ICH volume was 23.6 mL (IQR, 7.4 - 48.7 mL). They had a median INR of 2.9 (IQR, 1.7 - 3.9) at presentation and of 1.3 (IQR, 1.1 - 1.5) after treatment. Survival rates were 62% at 7 days and 58% at 30 days.

Intravenous vitamin K and PCC were administered to 21 patients, vitamin K alone to 2, and no treatment to 3.

Key components of the door-to-needle time for the administration of PCC were the door-to-decision, decision-to-order, order-to-collection of PCC, and collection-to-administration times.

During the study conducted from March 2009 to March 2012, the door-to-needle time steadily decreased as barriers were identified and eliminated (r = 0.67; P < .001). In 2009 (n = 6), the median time was just under 240 minutes. Mainly by reducing the door-to-decision and collection-to administration times, the door-to-needle time was just under 150 minutes in 2010 (n = 6).

Dr. Parry-Jones said that in late 2010 the stroke physicians "reached an agreement with the hematologists" that they did not need the hematologists' permission to use PCC, and PCC was then stocked in the clinical area. In conjunction with other improvements, the 2011 door-to-needle time was reduced to just over 120 minutes.

Finally, point-of-care INR testing was introduced in late 2011, and the 2012 (n = 6) door-to-needle time was reduced to about 100 minutes.

UK Stroke Practice

The survey of UK practice was performed online between December 2010 and January 2011 among members of the British Association of Stroke Physicians, of whom 139 (23%) responded. Eighty percent of respondents were senior physicians, and all regions of the UK were represented.

Four percent reported using point-of-care INR testing, 10% administering fresh frozen plasma, and 77% using PCC, with 76% consulting a hematologist before using PCC. PCC was reportedly kept in the blood bank or hematology area by 67% and in the clinical area by 5% of respondents.

Dr. Parry-Jones concluded that important barriers to reversing OAT after ICH were requiring hematologist approval for PCC, sending blood to the laboratory for INR determination, not stocking PCC in the clinic area, and infrequent situations and staff unfamiliarity with protocol and procedures. He said these factors probably reflected practice in many centers in the UK.

Modifying the treatment pathway can overcome these barriers and significantly reduce the time to definitive treatment, he said. Pathway modification includes agreeing with hematologists on the treatment protocol, point-of-care INR testing, keeping PCC in the clinic area, regular staff training, and continuing prospective audits and team discussions.

Common Barriers

Session moderator Turgut Tatlisumak, MD, PhD, vice chairman of the Department of Neurology and Director of the Acute Stroke Unit at Helsinki University Central Hospital in Helsinki, Finland, commented to Medscape Medical News that the barriers were probably common to many centers beyond the UK and that identifying and eliminating them should be an ongoing process. He noted that the therapies to reverse OAT used in this study really apply specifically to warfarin.

PCC has recently been shown to reverse the effects of factor Xa inhibitors, such as rivaroxaban, but does not affect the anticoagulant effect of a direct thrombin inhibitor, such as dabigatran. Dr. Tatlisumak speculated that the methods developed by the British researchers can serve as a good model for eliminating barriers to reversing OAT whenever effective antidotes are found or developed for these new anticoagulants.

Michael Hennerici, MD, professor and head of the Department of Neurology at the University of Heidelberg and Mannheim Hospital in Mannheim, Germany, and chairman of the European Stoke Conference, told Medscape Medical News that a problem with the newer anticoagulants is that there is no standard test to detect whether people are taking them. Their INR is completely normal.

"The only test that is not normal is the thromboplastin time – not the aPTT [activated partial thromboplastin time]... which is produced regularly for coagulation checking — but the thrombin time, which is a special test," he said. This test has not been used for many years because there was no need for it, he added, and the results are far more variable than an INR.

Dr. Hennerici said the companies producing the new anticoagulants rivaroxaban, apixaban, and dabigatran are developing tests to determine whether patients are taking the treatment and whether they are in a therapeutic range.

The lack of tests "has caused already some problems," he said. "The other thing is that we cannot block it like with vitamin K," as occurs with warfarin. "Probably the question of a diagnosis is easier than how to block a [factor] Xa inhibitor or thrombin inhibitor," he said.

Dr. Parry-Jones, Dr. Tatlisumak, and Dr. Hennerici have disclosed no relevant financial relationships. Dr. Tatlisumak and Dr. Hennerici were not involved in the study.

XXI European Stroke Conference (ESC). Presented May 23, 2012.

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