a b s t r a c t

Objective: To evaluate the impact of a rivaroxaban discharge initiative on the efficacy and safety of acute venous thromboembolism treatment in emergency department patients.

Practice innovation: Patients discharged on rivaroxaban from the emergency department were provided exten- sive counseling along with a commercially-available medication dose pack by the ED pharmacist. Patients were contacted by phone until they had obtained outpatient follow-up and remained adherent to anticoagulation beyond the initial first month of treatment.

Methods: In this retrospective chart review over a thirteen month period, efficacy and Safety outcomes were com- pared between patients with intervention versus those who received usual care. Efficacy was defined by reduced 90-day readmission rates due to nonadherence or treatment failure, and improved medication adherence be- yond the first month from discharge. Safety was determined by comparing 90-day Readmission rates due to bleeding or adverse event.

Results: 41 patients received intervention with rivaroxaban, and 34 patients received usual care, with 76% pre- scribed rivaroxaban and remaining patients started on enoxaparin alone (6%) or enoxaparin plus warfarin (18%). Improved treatment efficacy in the intervention group was not found to be statistically significant. Safety outcomes were similar between the two groups.

Conclusion: Home treatment of Acute VTE, facilitated by medication dose pack, is a promising tactic to ensure both immediate and Long-term treatment efficacy and safety. Further studies are warranted to demonstrate clinical superiority of this intervention.

(C) 2017

Background

Initial home treatment of venous thromboembolism has be- come increasingly common since it was demonstrated to be safe and ef- fective over two decades ago for Deep vein thrombosis [1,2], and more recently for low-risk pulmonary embolism (PE) [3,4]. Avoidance of hospitalization is more feasible today due to the availability of direct oral anticoagulants (DOAC), which require less frequent lab monitoring and dose titration when compared to warfarin. Two of these agents, apixaban and rivaroxaban, allow patients to forgo parenteral treatment entirely.

Rivaroxaban (Xarelto(TM); Janssen Pharmaceuticals, Titusville, NJ, USA), a factor-Xa inhibitor, is approved for monotherapy treatment of acute VTE. Guidelines by the American College of Chest Physicians

? Disclosures: none.

* Corresponding author at: Emergency Department Pharmacist, Sharp Grossmont Hospital, 5555 Grossmont Center Drive, La Mesa, CA 91942, USA.

E-mail addresses: [email protected] (A. Chu), [email protected] (J. Limberg).

recommend DOACs over warfarin for treatment of lower-extremity DVT or PE in patients without cancer. Rivaroxaban is also a guideline- preferred agent for patients seeking to avoid parenteral anticoagulation and take once-daily therapy [5]. In low-risk VTE patients treated at home, rivaroxaban achieved higher rates of patient and prescriber satis- faction while demonstrating safety and efficacy [6,7]. Rivaroxaban has also been associated with lower cost of medical care compared to LMWH-warfarin and heparin-warfarin [8,9]. For acute low-risk PE pa- tients, studies are ongoing to determine clinical efficacy, safety, and Cost benefits of home treatment with rivaroxaban [10,11].

However, the initial dosing regimen - 15 mg by mouth twice daily for three weeks, followed by 20 mg once daily - has been prone to con- fusion and adverse events due to the combination of two tablet strengths, frequencies, and prescriptions. In an error reported to the In- stitute for Safe Medication Practice (ISMP) in November 2014, a patient took two 15 mg tablets and one 20 mg tablet concomitantly for the first ten days [12]. Anecdotally, there have also been cases of patients taking the rivaroxaban 20 mg tablet twice-daily after the initial three weeks. The Xarelto Starter Pack(TM) (Image 1), a blister pack with dose

http://dx.doi.org/10.1016/j.ajem.2017.08.001

0735-6757/(C) 2017

Image 1. Xarelto Starter Pack(TM), a blister pack with dose instructions for each of the first thirty days of VTE treatment.

instructions for each of the first thirty days of treatment, became avail- able on the market in October 2014 with the intent to minimize such er- rors; its utility was endorsed by ISMP following the reported error [12]. A similar tactic, using an individualized medication box with dividers, has been employed by pharmacists to ensure Patient adherence and proper dose transition [13].

Despite the clinical appropriateness of VTE treatment with DOACs, proper patient selection is imperative and oftentimes challenging. Ther- apeutic convenience of these medications must be weighed against bar- riers to access, as newer oral anticoagulants may carry substantial costs to patients with limited prescription drug coverage [5]. There is also concern for medication nonadherence due to fewer requirements for laboratory monitoring; this is inherently less problematic and easily measured with warfarin due to frequent INR monitoring and provider follow-up, particularly during the initial dose-finding period [14]. Therefore, prior to discharge with a DOAC, it is essential to ensure med- ication adherence through extensive patient counseling and follow-up.

Practice description

The authors report on an initiative that was started in late 2014 to fa- cilitate management of patients diagnosed with acute VTE and

discharged directly from the ED on rivaroxaban. Specific steps were taken to minimize errors that could potentially occur at various stages throughout the treatment process (Fig. 1).

The practice setting was an urban, community hospital with over 100,000 emergency department visits annually. Of the patients discharged from the ED, over half are either uninsured or underfunded. Therefore, adherence and affordability frequently drive decision-mak- ing for anticoagulation selection; occasionally, lack of out-of-hospital re- sources may result in overnight hospital admission of an otherwise uncomplicated VTE patient.

Patients discharged for home management with rivaroxaban during hours of ED pharmacist coverage - daily from 1300 to midnight - were counseled extensively and provided with a Starter Pack(TM) filled through the on-site outpatient pharmacy. ED pharmacists contacted patients by phone in the weeks following discharge until it was confirmed that they had obtained follow-up and remained adherent to anticoagulation be- yond the initial first month of treatment.

Methods

In this single-center retrospective chart review, the investigators identified ED patients with discharge diagnosis of VTE based on ICD

Fig. 1. Error minimization at each stage of the initial VTE treatment process in intervention group.

coding between January 1, 2015 and January 31, 2016; a thirteen- month period. Patients were excluded from the study if they required any length of hospitalization on their initial visit. Eligibility for home treatment was determined by the physician based on general guidance for VTE treatment; the institution did not enforce use of any specific treatment guideline or clinical prediction model. A 90-day period of

Table 1

Baseline patient demographics.

	Pharmacist intervention (n = 41)	Usual care (n = 34)
Age	53 +- 17	60 +- 16
Sex (M)	25 (59%)	16 (47%)
ED length of stay (hours) Diagnosis	5.9 +- 2.3	6.2 +- 3.9

review was selected to be inclusive of the periods with highest recur- rence rates and to reflect the minimum guideline-recommended dura- tion of treatment for acute VTE.

The primary goal was to evaluate this program’s impact on treat- ment efficacy, defined by 1) improved medication adherence beyond the first month from discharge, and 2) reduced 90-day readmissions for recurrent VTE due to nonadherence or treatment failure. Adherence was presumed if the patient was switched to another DOAC, or had established care with a warfarin clinic. A secondary goal was to evaluate the impact on safety of acute VTE outpatient management, defined by reduced 90-day readmission rates due to bleeding or adverse event. Fisher’s exact test was utilized to determine statistical significance of the primary efficacy and secondary safety outcomes with a predetermined significance level of 0.05.

DVT	39 (95%)	30 (88%)
PE	2 (5%)	3 (9%)	4. Results
DVT & PE	0	1 (3%)

Risk factors for VTE

A total of 75 patient encounters during the study period met criteria for study inclusion (Table 1). 41 patients received intervention at the

Table 2

None	12 (29%)	14 (41%)
Prior DVT/PE	12 (29%)	7 (21%)
Malignancy	1 (2%)	5 (15%)
Immobility due to travel	3 (7%)	3 (9%)
Recent surgery	6 (15%)	4 (12%)
Trauma	4 (10%)	1 (3%)
Other immobility	2 (5%)	1 (3%)
Smoker	2 (5%)	10 (29%)
Other	4 (10%)	1 (3%)
Greater than 1 risk factor for VTE present	3 (7%)	2 (6%)

Outcomes on efficacy and safety.

Pharmacist intervention (n = 41)

Usual care (n = 34)

p value

Anticoagulant prescribed on ED discharge			Overall 90-day readmissions	3 (7%)	6 (18%)	0.66
Rivaroxaban (all)	42 (100%)	26 (76%)	Efficacy
Rivaroxaban Starter Pack(TM)	42 (100%)	17 (50%)	Confirmed medication adherence	29 (71%)	18 (53%)	0.15
Enoxaparin alone	0 (0%)	2 (6%)	90-Day readmissions for treatment failure	1 (2%)	4 (12%)	0.17
Enoxaparin & warfarin	0 (0%)	6 (18%)	or nonadherence
Medication supplied to patient prior to	41 (100%)	9 (26%)	Safety
discharge			90-Day readmissions due to adverse event	2 (5%)	2 (6%)	1

time of discharge, slightly more than the 34 patients who received usual care.

A review of baseline demographics revealed similar characteristics between the two groups. Average ED length of stay, approximately 6 h, was inclusive of time in the waiting room, observation, and if avail- able, reception of pharmacist intervention and medication supply. With respect to VTE risk factors, there were more patients with pulmonary embolism and malignancy in the usual-care group. No patients in the study met criteria that, per CHEST guidelines, made them unsuitable for home treatment. In the usual-care group, 76% of patients received rivaroxaban with the remaining receiving either enoxaparin alone (6%) or enoxaparin plus warfarin (18%).

For the efficacy endpoints (Table 2), confirmed medication adher- ence was numerically higher in the intervention group (67% vs 53%, p

= 0.2) and 90-day readmissions were numerically lower (3% vs 12%, p = 0.16). For the safety endpoint, 90-day readmissions for medication related adverse events were similar between the two groups and were all due to mild bleeding. No statistical significance was found amongst results for these endpoints.

Discussion

The primary purpose of this initiative was to ensure appropriate and thorough outpatient management of VTE patients upon ED discharge. Though 29% of patients in the intervention group were lost to follow- up, compared to patients with usual care, a higher percentage had con- firmed medication adherence beyond one month from ED discharge; however this result was not statistically significant. The usual-care group was assessed by subsequent visit notes in the healthcare system’s electronic medical record, thus adherence was undetermined for an un- known percentage of these patients. This could have accounted for the slight increase in confirmed medication adherence in the intervention group. Future studies would benefit from prescription Claims data to more appropriately measure adherence.

Use of this discharge program did not demonstrate a statistically sig- nificant reduction in efficacy-related 90-day readmissions. One patient with DVT in the intervention group was readmitted with a pulmonary embolism within a week, despite reported adherence with rivaroxaban. For four patients in the usual-care group, causes of readmission were predominantly related to lack of continued access to medication. Yet an- other major limitation of this review was that investigators had access only to encounters within the hospital system. Despite the large geo- graphic area served by this system, it is possible that some patients may have presented to another facility for treatment failure or adverse event.

Further studies with larger sample sizes may be considered to vali- date these findings, as well as determine if discharge from inpatient hospitalization may benefit from pharmacist provision of medication, counseling, and follow-up. Thus far, patient and prescriber satisfaction as well as recognized cost-saving potential with this program has result- ed in expansion to a system-wide protocol integrating follow-up by out- patient warfarin clinic services.

Additional findings

An incidental finding was the identification of four patients who were prescribed rivaroxaban on hospital discharge following VTE diag- nosis, then presented to the ED during the study period due to lack of immediate insurance coverage for the medication. These patient experi- ences exemplify the very gaps in transitions of care that our service was intended to prevent. It is well established that recurrence rates are highest immediately following the initial VTE event, most notably with- in the first two to three weeks [15]. As such, anticoagulant adherence during this time period is especially crucial. Increased awareness about affordability and insurance limitations is highly recommended,

and translatable to other high-risk medication regimens and underfunded patient populations.

Logistical considerations

For the intervention group, cost limitations for initial fill were a non- issue due to availability of manufacturer trial coupon covering the initial 30-day supply. However, it was heavily emphasized to all patients that adequate follow-up is necessary and to ensure refill supply in a timely fashion. Failure to ensure follow-up or continued access may result in readmission at the conclusion of the first month, as has also been ob- served at our institution, particularly in patients with limited insurance coverage or requiring prior-authorization.

It is important to note that this hospital benefits from having an on- site outpatient pharmacy that stocks the Starter Pack(TM) and is always ac- cessible to its ED pharmacists. As such, it was uniquely feasible to supply all patients with up to one month’s worth of medication prior to dis- charge, even outside of normal business hours. In the absence of an on-site outpatient pharmacy, we recommend that facilities maintain references of local outpatient pharmacies willing to carry the Starter Pack product. We recommend against its prescription if the Starter Pack is difficult for patients to locate in their community.

The CHEST guidelines recommend all DOACs over warfarin in VTE not associated with cancer. However, the findings of this study may have limited applicability to the other agents (apixaban, edoxaban, and dabigatran) due to highly varied dosing, current lack of other dose packets to facilitate adherence, and for dabigatran and edoxaban, initial need for parenteral therapy.

Conclusion

Home treatment of acute VTE, facilitated by commercially-available dose pack combined with extensive counseling and follow-up, is a promising tactic to ensure both immediate and long-term efficacy and safety. Further studies with larger sample sizes are warranted to dem- onstrate superiority of this intervention over usual care.

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