Dabigatran Adherence Pilot Intervention for Patients With Atrial Fibrillation

Hypotheses and Specific Aims: Atrial fibrillation is common and increases the risk of
thromboembolic events. Current national guidelines recommend long-term treatment with
warfarin, an oral anti-coagulant, for patients with atrial fibrillation and multiple
thromboembolic risk factors. Adherence to warfarin is important because of its narrow
therapeutic window, which requires frequent lab monitoring (i.e., INR) and dose adjustment.
The majority of veterans on warfarin are managed in anti-coagulation clinics staffed by
pharmacists who routinely contact patients to remind them to get blood draws, to re-enforce
medication adherence, and to adjust warfarin dose based on INR values. Sub-therapeutic
anti-coagulation increases the risk of thromboembolic events and is most commonly due to poor
medication adherence.

Dabigatran is a newly approved oral factor X inhibitor medication that is more efficacious
than warfarin for lowering the risk of stroke and systemic embolism in patients with atrial
fibrillation. Additional advantages of dabigatran include fewer drug-drug interactions and
standard dosing, eliminating the need for dose titration or lab monitoring. However,
adherence is an important consideration with dabigatran because it is a twice a day
medication and requires monthly refills due to its formulation, both of which are strong risk
factors for non-adherence. In addition, patients taking dabigatran will not be followed in
anti-coagulation clinics because there is no lab value to monitor, and therefore, they will
no longer benefit from the adherence support provided by these clinics. Non-adherence to
chronic cardiovascular medications is common and non-adherence to dabigatran may potentially
limit its effectiveness in routine clinical use.

Rivaroxaban is a newly approved, Factor Xa inhibitor, oral medication prescribed to reduce
the risk of stroke and systemic embolism among patients with atrial fibrillation. Rivaroxaban
is a once daily medication that is recommended to be taken during an evening meal to reduce
the potential risk of decreased efficacy of therapy. In a randomized, double-blind study
comparing warfarin to Rivaroxaban, Rivaroxaban was found non-inferior to warfarin for the
prevention of stroke and systemic embolism in patients with atrial fibrillation, and the risk
of major and critically relevant non-major bleeding were similar between the two
anticoagulants. In addition, patients taking Rivaroxaban will not be followed in
anti-coagulation clinics because there is no lab value to monitor, and therefore, they will
no longer benefit from the adherence support provided by these clinics. Non-adherence to
chronic cardiovascular medications is common and non-adherence to Rivaroxaban may potentially
limit its effectiveness in routine clinical use.

Apixaban is a FDA approved anticoagulant, Factor Xa inhibitor, oral medication prescribed to
reduce the risk of stroke and blood clots among patients with atrial fibrillation. Apixaban
is taken twice daily. In a double-blind, double-dummy, randomized, non-inferior and superior
controlled trial, apixaban was found to be superior to warfarin in reducing stroke, systemic
embolism, and death. In addition, patients taking apixaban will not be followed in
anti-coagulation clinics because there is no lab value to monitor, and therefore, they will
no longer benefit from the adherence support provided by these clinics. Non-adherence to
chronic cardiovascular medications is common and non-adherence to apixaban may potentially
limit its effectiveness in routine clinical use.

It is anticipated that many patients will be switched to dabigatran following recent
publication of criteria for dabigatran use from the VA National Pharmacy Benefits Management
Program. This provides an opportune time to conduct the proposed study focusing on adherence
to dabigatran, rivaroxaban, and apixaban. We will first perform qualitative interviews with
patients (n~30) and pharmacists (n~20) to better understand barriers and facilitators to
dabigatran adherence. Informed by the qualitative findings and the literature on
interventions to improve cardiovascular medication adherence, we will develop and pilot test
a multi-faceted intervention to improve adherence among patients recently started on
dabigatran, rivaroxaban, and apixaban.

The proposal is innovative because it proactively addresses dabigatran adherence. This pilot
will provide preliminary data for an eventual implementation study to assess the
effectiveness of the intervention to improve adherence to dabigatran and patient outcomes, as
well as its cost-effectiveness.

Specific aims

1. Conduct in-depth, key informant interviews with a sample of patients (n=30) recently
started on dabigatran for atrial fibrillation to determine barriers and facilitators to
dabigatran adherence.

2. Conduct in-depth, key informant interviews with a sample of pharmacists (n=20) in
anti-coagulation clinics in order to understand their perspectives on barriers and
facilitators to patients' maintaining adherence to dabigatran.

3. Informed by the qualitative interviews, develop and pilot test a multi-faceted
intervention targeting patients and pharmacists to improve adherence to dabigatran,
rivaroxaban, and apixaban.

II. Background and Significance:

Atrial fibrillation is common, affecting 2.2 million Americans and is likely to increase with
the aging of the US population. The most devastating sequelae of atrial fibrillation is
stroke. National guidelines recommend warfarin, an oral anticoagulant for patients with
atrial fibrillation and multiple risk factors (e.g., hypertension, diabetes, older age,
stroke or TIA, heart failure) to reduce the stroke risk. Veterans prescribed warfarin are
usually managed closely in anti-coagulation clinics. Pharmacists staff these clinics,
coordinating blood draws, titrating warfarin dose to maintain therapeutic INR levels, and
re-enforcing adherence to therapy. Prior meta-analysis suggests that patients on warfarin
managed in these clinics have better anticoagulation control compared to patients followed in
non-specialized clinics.

Dabigatran is a newly approved oral direct thrombin inhibitor that was demonstrated to be
more efficacious than warfarin for patients with atrial fibrillation. In the RE-LY trial,
dabigatran reduced stroke and systemic embolism (Relative risk 0.66; 95% CI, 0.53 to 0.82;
P<0.001) with a similar risk of major bleeding (3.36% vs. 3.11% per year; for warfarin vs.
dabigatran p=0.31). There are several potential advantages of dabigatran over warfarin,
including: 1) standard dosing without need for dose adjustment; 2) no need for lab
monitoring; and 3) fewer drug-drug interactions. For these reasons, dabigatran may be
preferred by patients requiring chronic anti-coagulation therapy for atrial fibrillation.

Non-adherence to cardiovascular medications is common and limits the effectiveness of
medications in routine clinical practice. For most chronic cardiovascular medications,
adherence rates begin to decline following the initial prescription, particularly for
medications that need to be taken more than once daily, treat asymptomatic conditions and
require frequent refills. A prior study found that only ~25% of patient prescribed statins
for primary prevention were still adherent at 2 years from the index prescription. The
benefits of dabigatran seen in the clinical trial may be significantly lessened if adherence
to dabigatran is similar to other chronic cardiovascular medications. This issue of
non-adherence is particularly germane to dabigatran because it is a twice a day medication,
requires monthly refills due to the formulation of the medication and is used generally as a
primary prevention medication for an asymptomatic condition.

In the ROCKET AF Study, Rivaroxaban was found to be non-inferior to warfarin for the
prevention of stoke and systemic embolism in patients with atrial fibrillation. Rivaroxaban
was non-inferior to warfarin and significantly reduced the risk of stroke or systemic
embolism by 21% (hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.66 to 0.96; p less
than 0.001). The risk of major and clinically relevant non-major bleeding was similar between
both anticoagulant drugs.

In the ARISTOTLE trial, apixaban had a greater reduction of hemorrhagic stroke compared to
the warfarin group (HR 0.51; 95% CI 0.35 to 0.75; p less than 0.001). For the secondary
outcome of death from any cause, apixaban was superior to warfarin (HR 0.89; 95% CL 0.8 to
0.998; p=0.047).

Pharmacists have helped patients to improve adherence to cardiovascular medications and
intermediate outcomes such as BP and LDL control. For anticoagulation therapy, pharmacists
have helped patients maintain better INR control via anti-coagulation clinics compared to
patients not managed in these clinics. Specific components of anti-coagulation clinics that
have been found to be particularly helpful for improving adherence include computerized
patient monitoring that identifies delinquent patients (i.e., for lab monitoring) and
frequent contacts with the patient. An intervention focusing on adherence involving
pharmacists can have the potential to improve dabigatran, rivaroxaban, and apixaban use so
that the benefits demonstrated in the clinical trials for dabigatran can be realized in
routine clinical practice.

Inclusion Criteria:

- Patients who have transitioned from warfarin to dabigatran, rivaroxaban, or apixaban
or are recently started on anti-coagulation for atrial fibrillation with dabigatran,
rivaroxaban, or apixaban will be eligible to be interviewed and partake in the
intervention.

- Pharmacists from the Denver VA Medical Center and who work in the anti-coagulation
clinics will be eligible to be interviewed.

Exclusion Criteria:

- Patients who prefer a telephone interview but do not have a telephone or cell phone
will be excluded.

- Patients for whom the VA is not the primary source of care will also be excluded.

- Pregnant patients will be excluded.