Dabigatran Adherence Pilot Intervention for Patients With Atrial Fibrillation
Condition: Atrial Fibrillation
MeSH terms: Atrial Fibrillation
Study type: Interventional

Summary: 
      Atrial fibrillation is common and increases the risk of clotting especially in patients with
      multiple clotting risk factors. Patients treated with warfarin, an oral anti-coagulant,
      require frequent lab monitoring and dose adjustments and are managed in pharmacy staffed
      anti-coagulation clinics that routinely contact them to remind them about blood draws,
      re-enforce medication adherence, and adjust dosing based on labs.

      Dabigatran, a newly approved medication that may be better for some with atrial fibrillation
      to lower risk of stroke and clotting, has been found to have fewer drug problems and
      eliminates lab monitoring need. Following instructions for taking dabigatran is important
      because it is a twice daily medication requiring monthly refills. Rivaroxaban is a once
      daily, newly approved Factor Xa inhibitor oral medication, prescribed to reduce risk of
      stroke and systemic embolism among patients with atrial fibrillation. Apixaban is a twice
      daily, FDA approved Factor Xa inhibitor oral anticoagulant, prescribed to reduce the risk of
      stroke and blood clots among patients with atrial fibrillation. In a double-blind RCT,
      apixaban was found to be superior to warfarin in reducing stroke, systemic embolism, and
      death. Patients on dabigatran, rivaroxaban, and apixaban will not be followed in
      anti-coagulation clinics, therefore will not benefit from the support provided by these
      clinics.

      It's anticipated many patients will be switched to dabigatran, rivaroxaban, or apixaban
      following recent publication of criteria for dabigatran use from the VA National Pharmacy
      Benefits Management Program, providing an opportune time to conduct the proposed adherence
      study. We will conduct qualitative interviews with patients(n~30) and pharmacists(n~20) to
      understand barriers/facilitators to oral anticoagulant adherence. Informed by the findings,
      we will develop and pilot test a multi faceted intervention to improve adherence among
      patients recently started on dabigatran/rivaroxaban/apixaban.

      Specific study aims:

        1. Conduct interviews with a sample of patients (n=30) recently started on dabigatran for
           atrial fibrillation to determine why patients do or don't take medications

        2. Conduct interviews with pharmacists (n=20) in anti-coagulation clinics in order to
           understand their opinions why patients do or don't take medications

        3. Informed by interviews, develop and test an intervention targeting patients/pharmacists
           to improve adherence to dabigatran/rivaroxaban/apixaban
    

Detailed description: 
      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.
    

Intervention name(s): Intervention; Control
Intervention type(s): Behavioral; Other
Intervention description(s): Patient education: Patients will receive information on dabigatran, including risks, benefits and potential side effects. This information will be re-enforced during the study on a monthly basis during the IVR calls and during the pharmacy service calls to patients.
Tele-monitoring: We will use IVR technology to send patients an automated reminder to refill their dabigatran, rivaroxaban, and apixaban prescriptions. This call will be delivered on day 20 following each dabigatran, rivaroxaban, and apixaban prescriptions.
Pharmacists follow-up: If dabigatran, rivaroxaban, and apixaban have not been refilled, the pharmacy staff will contact the patient to assess reasons that the patient has not refilled the medication.; Usual care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Health Services Research
Keywords: Anti-coagulation