Direct oral anticoagulants (DOACs) have been utilized in clinical practice over the past decade. These include the direct factor Xa inhibitors apixaban, betrixaban, edoxaban, and rivaroxaban, and the direct thrombin inhibitor dabigatran. The Food and Drug Administration (FDA) has approved DOACs for the prevention of stroke and thromboembolic events in patients with non-valvular atrial fibrillation (AF), deep vein thrombosis (DVT), pulmonary embolism (PE), and the prevention of DVT/PE following total hip/knee replacement.^1,2 Published retrospective cohorts show that more than 56% of DOAC prescriptions are inappropriately dosed.^3-6 DOACs may be under-dosed for fear of increased risk of bleeding. Changes in patient specific factors and lack of provider education may lead to inappropriate dosing which compromises efficacy and safety, putting patients at increased thrombotic or bleeding risk. This is particularly true for patients with AF who are anticoagulated with DOACs.⁶ A multicenter, prospective outpatient disease registry known as the ORBIT-AF II, evaluated over 5,000 DOAC doses among AF patients. Results demonstrated that both under- and over-dosing of DOACs increased rates of hospitalization, all-cause mortality, major bleeding, systemic embolism or stroke, and myocardial infarctions. 

The purpose of this study was to assess the effectiveness of a guideline to standardize the dose and duration of hospital formulary DOACs and to ensure compliance with prescribing information. In this study, a pharmacist-led DOAC guideline was implemented at a 312-bed community teaching hospital in the Midwest. Prescribing practices were evaluated by chart review pre- and post- guideline implementation (Figure 1). The study included education of healthcare professionals, adjustment of doses led by pharmacists, review of inappropriate prescription origins, and evaluation of prescribing practices.

Methods
Creation of a hospital formulary-specific DOAC guideline standardizing rivaroxaban and apixaban doses per anticoagulation indication and duration was approved by the Pharmacy & Therapeutics Committee and the project was reviewed by an Institutional Review Board. Outpatient prescriptions were not evaluated.  Patients were eligible for inclusion in this study if they were treated with apixaban or rivaroxaban, were at least 18 years of age, and were not pregnant. The primary outcome measured the rate of appropriate inpatient prescriptions concordant with package insert labeling. Inappropriate prescriptions were classified as either an overdose or under-dose to determine where healthcare provider education was needed. Secondary outcomes included number of thrombotic or bleeding events during hospitalization, readmissions for bleeds/thromboembolisms, and patients with end stage renal disease.

Data were collected through a comprehensive chart review. Prescriptions ordered, evaluated, and verified in this study came from medical and pharmacy residents in addition to clinical pharmacists, physicians, nurse practitioners, and physician assistants. Pharmacist-led renal dose adjustments allowed for both the increase and decrease of apixaban and rivaroxaban inpatient dosages based on daily laboratory results, without the need to contact the prescriber.

Each pre- and post-guideline period was 45 days which included a set number of orders not to exceed 200, which was chosen to meet a predefined scope and timeline for the residency research project (Figure 1). The pre-guideline time period was July 1- August 15, 2018.  The post-guideline time period was November-December 2018.  Data collected included:  patient characteristics such as age, sex, and weight, corrected Cockcroft-Gault creatinine clearance, prescribed DOAC dose, number of bleeding or thrombosis events, thrombosis, readmission rates, and anticoagulation indication.

Results
A total of 383 orders were included with 200 prescriptions in the pre-guideline arm and 183 prescriptions in the post-guideline arm. Baseline characteristics were similar in age, anticoagulation indication, and about half of all patients in each group had a creatinine clearance of 15 to 50 mL/min. Overall there were more males in the pre-guideline arm (64% versus 46%) and approximately 24% of all patients were above100 kg. No p-values were calculated for baseline characteristics (See Table 1). DOACs were appropriately dosed in 87% (175/200) versus 93% (171/183) of prescriptions pre- and post-guideline implementation, respectively. Evaluation of inappropriate apixaban prescriptions alone identified 16 (10%) pre-guideline compared with 10 (7%) post-guideline. Assessment of rivaroxaban dosing alone identified nine (27%) inappropriate pre-guideline doses compared to two (5%) post-guideline doses. After investigating the 37 inappropriate hospital DOAC prescriptions, it was determined that more than half were due to continuation of a patient’s original home dose upon hospital admission. Missed opportunities were due to both pharmacist and provider hesitation to change established home dosages and from providers denying auto substitutions.  (See Table 2.) 

Bleeding events decreased post-guideline implementation, with no patients being readmitted for bleeds, and one pre-guideline rivaroxaban patient was readmitted for venous thromboembolism. No contraindicated drug-drug interactions were found. There were 23 patients with end stage renal disease on apixaban and none on rivaroxaban.  Numbers of pharmacist-driven renal interventions were similar between the two arms with the majority being associated with apixaban. Pharmacist interventions decreased overall, pre-guideline (n=21) compared to post-guideline (n=18). Most to least documented pharmacist interventions were as follows: renal dose adjustments including pharmacist-led dose adjustments 6 (33%), patient-specific factors for age and weight in apixaban 5 (28%), transitions of anticoagulation 3 (16.5%), dosing frequency 3 (16.5%), and allergies 1 (6%).  (See Table 3.)

Discussion
Study strengths included use of an electronic medical record (EMR) system which contains medication detail, including patients’ external fill history, patient specific information, prescriber documentation, and laboratory results.  This allowed for more accurate assessment of dosing appropriateness and potential for drug-drug interactions. Implementation of pharmacist-led renal dose adjustments allowed for timely administration of appropriate doses based on daily hospital laboratory results. Study limitations include a small sample size and timeframe compared to previously published DOAC studies.^4-6 Some patient information was missing at time of inpatient order verification, which was later discovered during the visit. For instance, anticoagulation indication and appropriateness were unclear for AF patients hospitalized for another indication such as DVT. These occurrences were not excluded, but rather the newest diagnosis was evaluated as the primary anticoagulation indication in the retrospective data collection. Another limitation is that CHA2DS2-VASc scores were not calculated and therefore not used to determine anticoagulation appropriateness in AF patients. Discharge prescriptions were not evaluated in this study. Other barriers include potential drug-drug interactions due to unavailable external medication fill histories and incomplete medication histories. Future studies should evaluate the home DOAC regimen and appropriateness of continuing this on hospital admission as well as upon discharge.

Conclusion
Results suggest underdosing in apixaban patients, especially continuation of home doses upon admission, may require further provider education.  As evidenced by this study, implementation of a pharmacist-led DOAC guideline allowing for renal dose adjustments may improve both FDA-approved concordant prescribing of these medications and decrease rates of bleeding.

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2. Xarelto (rivaroxaban) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2012.
3. Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non-vitamin k antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol. 2017;69(23):2779-2790.
4. Ruiz OM, Muniz J, Rana M, et al. Inappropriate doses of direct oral anticoagulants in real-world clinical practice: prevalence and associated factors. A subanalysis of the FANTASSIA Registry. Europace. 2018;20(10):1577-1583.
5. McAlister FA, Garrison S, Kosowan L, Ezekowitz JA, Singer A. Use of direct oral anticoagulants in Canadian primary care practice 2010–2015: A cohort study from the Canadian primary care sentinel surveillance network. J Am Heart Assoc. 2018;7(3): e007603. https://www.ahajournals.org/doi/full/10.1161/JAHA.117.007603. (accessed 2018 May 27). 
6. Steinberg BA, Shrader P, Thomas L, et al. Off-label dosing of non-vitamin k antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol. 2016;68(24):2597-2604.