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Background Apixaban pharmacokinetic properties and some clinical reports suggest cessation 48 hours prior to surgery is safe, but this has not been demonstrated in a naturalistic setting. We sought to measure the residual apixaban exposure in patients who had apixaban held as part of standard of care peri-operative management. Methods This was a prospective, observational study of patients in whom apixaban plasma concentration and anti-Xa activity were measured while at steady state apixaban dosing and again immediately prior to surgery. Clinical management of cessation and resumption of apixaban was at the discretion of the treating physician. Results One hundred and eleven patients provided paired blood samples. Ninety four percent (104/111) patients had measured apixaban concentrations of < 30 ng/mL. Only one patient had a value > 50 ng/mL. The median time between the self-reported last dose and pre-surgery blood sampling was 76 hours (range 32 – 158) for those who achieved concentrations < 30 ng/mL and 59 hours (range 49 – 86) for those > 30 ng/mL. Measured anti-Xa activity correlated well with apixaban exposure. Clinically significant non-major bleeding was reported in one patient at 1-week post-surgery. There was one venous thromboembolic event and one stroke in the peri-operative period. Conclusion In a naturalistic setting with a heterogeneous patient population, apixaban discontinuation for at least 48 hours before a procedure resulted in a clinically insignificant degree of anticoagulation prior to a surgical procedure. (NCT02935751)

It was hypothesized that the four-factor prothrombin complex concentrate (4F-PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, two-period crossover, assessor-blinded trial, 12 healthy subjects received 5 mg apixaban every 12 h. Three h after the fifth dose, four-factor prothrombin complex concentrate (4F-PCC) 25 unit/kg or saline were infused. Serial blood samples were assessed for thrombin generation using PPP-reagent and PPP-reagent low, anti-Xa, PT, and PTT assays. Geometric mean ratio was calculated at 30 min postinfusion, and at 24, 48, and 72 h. Peak thrombin generation was 76% higher at 30 min postinfusion with 4F-PCC (p = 0.025). The difference declined to 24% at 24 h and resolved by 48 h. Other thrombin generation parameters were also partially normalized. There was no difference between 4F-PCC and saline in anti-Xa assessment at 30 min or later time points.

Warfarin has been a mainstay of therapy for treatment and prevention of venous thromboembolic disease (VTED) and prevention of stroke and systemic embolism for over 50 years. Recent FDA approval of several novel oral anticoagulants has offered more extensive treatment options for management of these disease states. The availability of the novel anticoagulants offers an attractive alternative to warfarin therapy for patients due to their convenience of use. In comparison to warfarin, dabigatran, rivaroxaban and apixaban offer: - a fixed dosage regimen - a relatively small potential drug interaction profile - minimal laboratory monitoring - little to no dietary restrictions. Although these agents offer a relatively fixed dose regimen, dosage adjustment is required in moderate renal dysfunction, and use is contraindicated in severe renal dysfunction. Currently there are no specific reversal agents in the event of a nov- el anticoagulant associated bleed. These concerns led to the development of an anticoagulation stewardship program at our institution to monitor and guide the usage of these agents.

Dabigatran, an alternative to warfarin for prevention of stroke with non-valvular atrial fibrillation (AF), offers advantages of a fixed dosage, minimal laboratory monitoring and limited medication interactions. Dabigatran requires dosage adjustment in renal dysfunction and is contraindicated if severe dysfunction. No identified dabigatran reversal agent exists. Methods: As part of an ongoing quality initiative, novel anticoagulant associated adverse events (AE) are monitored at a dedicated neuroscience hospital. Results: 5 cases of intracranial bleeding associated with dabigatran occurred from 12/2011-4/2012. All patients were on anticoagulation for AF, the most common dose of dabigatran was 150 mg BID. Mean admission values were as follows: age 83.2 yrs (range 79-90), serum creatinine 1.48 mg/dL (range 0.9- 3.5), creatinine clearance 45.6 mL/min (18-59) and aPTT 49 seconds (range 32- 60). Strategies for the management of bleeding included withholding dabigatran, supportive care, administration of blood products and hemodialysis, when required. Dialysis was initiated on 3 patients. One patient had 3 dialysis sessions in an effort to normalize coagulation assays and had transfusions with 10 units of platelets and 4 units of fresh frozen plasma in an effort to stabilize bleeding. One patient died. Mean time for aPTT to normalize when abnormal on admission was 30.8 hours (range 21-37). Conclusions: Appropriate patient selection is required to prevent dabigatran associated AE, especially in the setting of advanced age and kidney dysfunction. aPTT values may remain prolonged for extended periods, despite efforts to normalize. Hospitals need a defined management plan for major bleeding associated with novel anticoagulants.

The optimal method of thromboprophylaxis and the value of screening ultrasonography for detection of deep venous thrombosis (DVT) in neurosurgery patients remains unclear. The goal of this study was to determine the incidence of DVT in neurosurgical patients who, by hospital protocol, receive surveillance ultrasonography of the lower extremities twice weekly, in addition to prophylaxis with unfractionated heparin and external pneumatic compression sleeves. A retrospective review of 7,298 ultrasound studies carried out on 2,593 patients over 4 years at a university neurosurgical hospital was conducted. There was a 7.4% incidence of proximal lower extremity DVT and a 9.7% total incidence including distal DVT. A greater number of distal DVTs were detected with the implementation of whole-leg ultrasonography in the last 2 years of observation. Chart review of 237 patients diagnosed with DVT demonstrated an admitting diagnosis of subarachnoid hemorrhage in nearly half of the patients. The median hospital length of stay for DVT patients was 18 days. Institutional control data demonstrated non-ruptured aneurysm and cerebrovascular anomalies to be the leading reason for admission, followed closely by subarachnoid hemorrhage. The hospital protocol of biweekly screening ultrasound and dual modality prophylaxis for neurosurgery patients resulted in a proximal DVT incidence consistent with that demonstrated by previous studies of standardized dual modality prophylaxis, and higher than that demonstrated in previous studies that employed ultrasound screening protocols.