Journal of Clinical Pharmacy and Therapeutics, 2015, 40, 525–530

doi: 10.1111/jcpt.12296

Evaluation of prescribing and patient use of target-specific oral anticoagulants in the outpatient setting J. Simon* PharmD BCACP, E. Hawes†‡ PharmD BCPS CPP, Z. Deyo† PharmD BCPS CPP and B. Bryant Shilliday§ PharmD CPP BCACP *Department of Pharmacy Practice, University of Charleston School of Pharmacy, Charleston, WV, †Department of Pharmacy, UNC Medical Center, UNC Eshelman School of Pharmacy, Chapel Hill, NC, ‡Department of Family Medicine, UNC School of Medicine, Chapel Hill, NC, and §UNC General Internal Medicine, UNC School of Medicine, UNC Eshelman School of Pharmacy, Advanced Practice Provider Center, UNC Health Care, Chapel Hill, NC, USA

Received 5 January 2015, Accepted 7 May 2015

Keywords: ambulatory care, anticoagulants, apixaban, dabigatran, factor Xa, rivaroxaban

inappropriate storage of dabigatran. Ten patients (6%) reported missing at least one TSOAC dose per week, and 25 (16%) described minor bleeding with their TSOAC. What is new and conclusion: Inappropriate prescribing, monitoring and administration of TSOACs occurred frequently in patients not formally enrolled in an anticoagulation monitoring programme. These results indicate a need for more thorough patient education at the time of TSOAC initiation, as well as improved prescriber education regarding recommended TSOAC dosing and monitoring.

SUMMARY What is known and objective: Pharmacist-managed anticoagulation programmes have been shown to improve appropriate use of warfarin, but few programmes have included the new targetspecific oral anticoagulants (TSOACs) in their protocols. A greater understanding of TSOAC prescribing, monitoring and administration is needed to identify common errors in the current outpatient practice. The objective of this study is to assess the rate of errors related to prescribing, baseline monitoring and patient administration of TSOACs. Methods: A retrospective chart review was conducted to identify patients on TSOAC therapy in each of four outpatient practice sites. Data were abstracted to include TSOAC indication, dosage and frequency prescribed, pertinent past medical history, and laboratory monitoring obtained at the time of TSOAC initiation. In addition, patients were contacted by telephone to assess TSOAC adherence, storage, administration and incidence of adverse events. Results and discussion: A total of 395 patients were included in the evaluation. Prescribers did not obtain baseline laboratory values within 1 week before or after the time of TSOAC initiation for a majority of study patients. At the time of TSOAC initiation, two patients had abnormally elevated alanine aminotransferase, six had elevated total bilirubin, and 43 had low haemoglobin. A majority (61%) of study patients were prescribed an appropriate TSOAC dose based upon their indication and renal function; however, dosing accuracy could not be determined for all patients as baseline serum creatinine was not obtained by prescribers for 148 patients (37%) at the time of prescribing. TSOACs were dosed inappropriately according to baseline serum creatinine in six patients, and two patients receiving treatment for venous thromboembolism were maintained on a high dose of rivaroxaban for an inappropriate duration. A total of 157 (40%) patients were available by phone and agreed to answer questions regarding their current TSOAC use. Twenty-four patients (23%) reported taking rivaroxaban inappropriately without food, and six patients (14%) endorsed

WHAT IS KNOWN AND OBJECTIVE Since the approval of the target-specific oral anticoagulants (TSOACs), dabigatran, rivaroxaban and apixaban, patients requiring anticoagulation therapy for venous thromboembolism (VTE) or non-valvular atrial fibrillation (NVAF) now have additional options for treatment. Clinical trials vs. warfarin demonstrated comparable or superior efficacy of TSOACs leading to their inclusion in current anticoagulation guidelines.1,2 Patients and physicians may find TSOACs desirable because they do not require dietary restrictions, frequent dose adjustments or significant laboratory monitoring as is required with warfarin. Despite these benefits, TSOACs possess properties that prevent their use in some patient populations, require limited laboratory monitoring and necessitate specific patient counselling regarding storage and administration to ensure their safe and effective use. Dabigatran (Pradaxa®), a direct thrombin inhibitor, was approved by the Food and Drug Administration (FDA) in 2010 for the prevention of stroke and systemic embolism in patients with NVAF and was later approved for treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE) in 2014.3 Dabigatran is an oral capsule that must be taken twice daily and stored in the original manufacturer’s container to minimize product breakdown from exposure to moisture.4 Breaking, chewing or opening the capsule and ingesting its contents can increase bioavailability by 75%; therefore, dabigatran must be swallowed whole.3 The recommended dose of dabigatran varies according to indication, creatinine clearance (CrCl), and concomitant use with dronedarone, ketoconazole or permeability glycoprotein (P-gp) inhibitors (see Table 1).3 In 2011, the first factor Xa inhibitor, rivaroxaban (Xarelto®), was approved by the FDA for DVT prophylaxis in patients undergoing knee or hip replacement surgery and was approved the following year for the prevention of stroke and systemic embolism in patients with NVAF as well as treatment and prevention of DVT

Correspondence: J. Simon, Assistant Professor, Department of Pharmacy Practice, University of Charleston School of Pharmacy, 2300 MacCorkle Ave SE, Charleston, WV 25304, USA. Tel.: +304 357 4850; fax: +304 357 4868; e-mail: [email protected] Data from this study were presented in the abstract and poster format at the Thrombosis and Hemostasis Summit of North America on 10 April 2014 in Chicago, IL.

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Evaluation of TSOAC prescribing and use Table 1. Criteria for target-specific oral anticoagulant dosing according to the manufacturer’s package inserta Drug

Indication

CrCl (mL/min)

Recommended dose

Dabigatran1

Reduction in risk of stroke and systemic embolism in NVAF Treatment of DVT or PE or reduction in the risk of recurrence of DVT or PE Reduction in risk of stroke in NVAF

>30 15–30 30 >50 15–50 ≥30

150 mg orally twice dailyb 75 mg orally twice daily Avoid coadministration with P-gp inhibitors 150 mg orally twice daily 20 mg orally once daily 15 mg orally once daily 15 mg orally twice daily for 21 days then 20 mg orally once daily for the remaining treatment duration 20 mg orally once daily 10 mg orally once daily for 35 days 10 mg orally once daily for 12 days Use reduced dose in patients with any 2 of the following: Age ≥80 years, weight ≤60 kg, SCr ≥1
5 mg/dLc Usual dose: 5 mg orally twice dailyd Reduced dose: 2
5 mg orally twice dailye 2
5 mg orally twice daily for 35 dayse 2
5 mg orally twice daily for 12 dayse 10 mg orally twice daily for 7 days, then 5 mg orally twice dailyd 2
5 mg orally twice daily after at least 6 months of treatment for DVT or PEe

Rivaroxaban5

Treatment of DVT or PE

Apixaban6

Reduction in the risk of recurrence of DVT or PE Prophylaxis of DVT following hip replacement surgery Prophylaxis of DVT following knee replacement surgery Reduction in the risk of stroke and systemic embolism in patients with NVAF

Prophylaxis of DVT following hip replacement surgery Prophylaxis of DVT following knee replacement surgery Treatment of DVT or PE

No criteria for CrCl

No criteria for CrCl

Reduction in the risk of recurrence of DVT or PE

a DVT, deep vein thrombosis; NVAF, non-valvular atrial fibrillation; PE, pulmonary embolism; P-gp, P-glycoprotein; SCr, serum creatinine; TSOAC, targetspecific oral anticoagulant. b For patients with CrCl of 30–50 mL/min and concomitant use of dronedarone and ketoconazole, consider reducing dose to 75 mg orally twice daily. c NVAF patients with end-stage renal disease (ESRD) on haemodialysis may use the usual dose of apixaban. The reduced dose must be used if the patient has one of the following characteristics, in addition to ESRD on haemodialysis: age ≥80 years or body weight ≤60 kg. d Reduce dose by 50% if coadministered with a strong dual inhibitor of CYP3A4 and P-gp. e Avoid coadministration with a strong dual inhibitor of CYP3A4 and P-gp.

and PE.5 The recommended dose of rivaroxaban varies according to indication and CrCl (see Table 1). Rivaroxaban should be avoided in patients with moderate (Child–Pugh B) and severe (Child–Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy due to an increased risk of haemorrhage.5 In addition, rivaroxaban 15 mg and 20 mg doses must be administered with food as bioavailability of these doses is significantly reduced in the fasting state. For example, the mean area under the curve (AUC) and maximum concentration (Cmax) of rivaroxaban 20 mg increase by 39% and 76%, respectively, when taken with food.5 The bioavailability of the 10 mg dose is not affected by food. Apixaban (Eliquis®) was the second factor Xa inhibitor to be approved by the FDA. In 2012, it was approved for the prevention of stroke and systemic embolism in patients with NVAF, and later, labelling was expanded to include DVT prophylaxis following hip or knee replacement surgery, treatment of DVT and PE, and reduction of the risk of recurrence of DVT and PE.6 Apixaban is administered twice daily, and the recommended dose is determined by patient weight, age and serum creatinine (SCr) as well as coadministration with strong dual inhibitors of P-gp and CYP3A46 (see Table 1). Due to its limited use in patients with hepatic impairment and the risk of intrinsic coagulation abnormalities in this population, apixaban is not recommended for use in patients with severe hepatic impairment.6 For NVAF patients with ESRD maintained on haemodialysis, pharmacokinetic and pharmacodynamic data support maintaining the usual dose of apixaban unless the patient is 80 years of age or older or has a body weight of 60 kg or less.6

When starting a TSOAC therapy, prescribers need to be aware of the various dosing and monitoring requirements for each agent, and patients need to be counselled regarding appropriate use of their medication to prevent treatment failure and adverse effects. The European Heart Rhythm Association (EHRA) suggests obtaining a baseline assessment of haemoglobin, renal function and hepatic function for each patient prior to initiating a TSOAC therapy.7 In addition, the EHRA suggests providing thorough patient counselling including information regarding appropriate administration and the need for strict adherence.7 Given that the criteria for dosing vary among agents according to several factors including indication, renal function, age and weight (apixaban), and the use of concomitant interacting medications (dabigatran and apixaban), the potential for prescribing errors exists. Among four outpatient clinics associated with an academic medical centre, patients requiring anticoagulation with warfarin have been enrolled in anticoagulation monitoring programmes that provide dosing adjustments, baseline and ongoing laboratory monitoring, and disease state and medication counselling. Patients requiring anticoagulation with a TSOAC, however, are not enrolled in anticoagulation monitoring programmes. Currently, it is unknown whether patients starting a TSOAC therapy are receiving the appropriate initial dose, baseline monitoring and counselling on appropriate use that is typically provided for patients taking warfarin. The purpose of this study was to determine the rate of errors associated with TSOAC prescribing, baseline laboratory monitoring and administration among patients seen in four outpatient clinics affiliated with an academic medical centre. The incidence of

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patient-reported adverse effects related to TSOAC use was also assessed.

RESULTS AND DISCUSSION Study population

METHODS

A total of 406 patients were identified as having an active TSOAC on the EHR medication list. Eleven patients were identified as having never started TSOAC treatment and were excluded from the analysis. Baseline characteristics for the remaining 395 patients are listed in Table 2. All patients taking dabigatran and apixaban and 84% of patients taking rivaroxaban had an indication of NVAF. Thirty-seven patients (9
4%) were taking rivaroxaban for the treatment or prevention of VTE, and one patient (0
25%) was taking rivaroxaban for post-operative thromboprophylaxis following hip replacement surgery. A majority of the patients were male (61%), and the mean patient age was 66 years. Approximately 25% of patients were aged 75 years or older. Other characteristic differences among patients are listed in Table 2.

A medication-use evaluation was completed in four outpatient clinics affiliated with an academic medical centre to assess the rate of errors related to prescribing, baseline monitoring and patient administration of TSOACs. A search of the electronic health record (EHR) was conducted to identify all patients with a TSOAC listed as an active medication in the EHR medication list as of 13 September 2013. Patients included in the study were receiving care from a provider at one of four outpatient clinics within the academic medical centre. Study patients were not enrolled in a formal anticoagulation programme at the time of data collection; however, physicians at each clinic had access to drug information resources and TSOAC dosing algorithms as well as consultation from a clinical pharmacist at the time of prescribing. A retrospective chart review was conducted between 1 December 2013 and 31 March 2014. Data obtained included patient demographics, primary indication for anticoagulation, TSOAC start date, dose and frequency of TSOAC prescribed, patient weight at the time of TSOAC initiation, and laboratory test results obtained within 1 week before or after the date of TSOAC initiation. If patients started a TSOAC therapy prior to establishing care at one of the clinics, the date they established care was considered the date of TSOAC initiation. Laboratory test results obtained during data collection included serum haemoglobin, SCr, aspartate transaminase (AST), alanine transaminase (ALT) and serum total bilirubin. The current medication list for each patient was evaluated for the presence of concomitant interacting medications, including dual strong CYP3A4 and P-gp Inhibitors; however, the medication list at the time of TSOAC prescribing was not available in the EHR. Therefore, a retrospective evaluation for appropriate prescribing in relation to drug interactions could not be conducted. A minimum of one attempt was made to contact each patient by telephone to obtain information pertaining to TSOAC adherence, storage, administration, and incidence of adverse events attributable to a TSOAC including incidence of bleeding and gastrointestinal (GI) upset. Patients were contacted by one of two investigators and were asked to answer a series of questions from a scripted survey. Patients were excluded from data analysis if they were identified as not starting a TSOAC therapy according to the EHR or if the patient confirmed by telephone that they never initiated treatment. If a patient was switched to a different anticoagulant or the TSOAC was discontinued prior to data collection, information obtained from chart review at the time of TSOAC initiation was included in data analysis; however, patientreported data related to their past TSOAC use were not included due to the risk of inaccuracy. The primary outcomes of the study include the number of TSOACs dosed inappropriately, the percentage of patients without baseline laboratory data, the percentage of patients inappropriately storing or administering their medication, the number of patients reporting missed doses, and the number of patientreported adverse events related to TSOAC use. CrCl was calculated for each patient with the Cockroft–Gault equation using the patient’s actual body weight at the time of TSOAC initiation. TSOAC dose was considered to be appropriate if the dose prescribed matched the recommended dose in the package insert.

Outcomes Laboratory values for AST/ALT, total bilirubin, haemoglobin and serum creatinine are summarized in Table 3. Baseline laboratory values were not obtained within 1 week before or after the time of TSOAC initiation for a majority of study patients. Specifically, total bilirubin, AST or ALT, haemoglobin and SCr were not obtained at baseline for 82%, 74%, 46% and 37% of study patients, respectively. Among those patients with laboratory data collected at baseline, a majority of the results were normal. AST or ALT was >3 times the upper limit of normal in two patients (0
51%) at baseline, and six patients (1
5%) had total bilirubin above 1
2 mg/dL at baseline. Forty-three patients (11%) had baseline haemoglobin 1
2 mg/dL, and haemoglobin