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National Trends in Ambulatory Oral Anticoagulant Use

      Abstract

      Background

      Four direct oral anticoagulants (DOACs) have been brought to market for the treatment of nonvalvular atrial fibrillation and venous thromboembolism. Many forces, including numerous positive trial results, emerging safety concerns, marketing, and promotion, may shape DOAC adoption by providers. However, relatively little is known regarding their ambulatory utilization compared with warfarin, as well as the degree to which they have decreased under-treatment of atrial fibrillation.

      Methods

      We used the IMS Health National Disease and Therapeutic Index, a nationally representative audit of outpatient office visits, to estimate the use of warfarin and DOACs between 2009 and 2014.

      Results

      Overall, visits with anticoagulation use increased from 2.05 (95% confidence interval [CI], 1.82-2.27) to 2.83 (95% CI, 2.49-3.17) million (M) quarterly visits (P < .001). Of these, DOAC use has grown to 4.21M (95% CI, 3.63M-4.79M; 38.2% of total) treatment visits in 2014 since their introduction in 2010. Use of all oral anticoagulants in treatment visits for atrial fibrillation has increased from 0.88M (95% CI, 0.74M-1.02M) to 1.72M (95% CI, 1.47M-1.97M; P < .001), with similar DOAC and warfarin use in 2014. Atrial fibrillation visits with anticoagulant use increased from 51.9% (95% CI, 50.4%-53.8%) to 66.9% (95% CI, 65.0%-69.3%) between 2009 and 2014 (P < .001). In 2014, rivaroxaban was the most commonly prescribed DOAC for atrial fibrillation (47.9% of office visits), followed by apixaban (26.5%) and dabigatran (25.5%).

      Conclusions

      Direct oral anticoagulants have been adopted rapidly, matching the use of warfarin, and are associated with increased use of oral anticoagulation for patients with atrial fibrillation.

      Keywords

      Clinical Significance
      • The number of office visits with anticoagulant use is increasing, largely driven by new visits with direct oral anticoagulant use in atrial fibrillation patients.
      • Currently, direct oral anticoagulants and warfarin are used in equal numbers of office visits for atrial fibrillation.
      • Overall, oral anticoagulants are being used in an increasing percentage of office visits for atrial fibrillation.
      Thromboembolic events associated with atrial fibrillation and venous thromboembolism are leading causes of morbidity and mortality worldwide.
      • Patel N.J.
      • Deshmukh A.
      • Pant S.
      • et al.
      Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      • Mahan C.E.
      • Borrego M.E.
      • Woersching A.L.
      • et al.
      Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates.
      Prevention and treatment of thromboembolism is best achieved with oral anticoagulant therapy. Vitamin K antagonists (primarily warfarin) have been the traditional oral anticoagulant for decades. However, 4 direct oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—were introduced sequentially into clinical practice beginning in 2010.
      • Barnes G.D.
      • Ageno W.
      • Ansell J.
      • Kaatz S.
      Subcommittee on the Control of A Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH.
      Despite their costs, these agents have achieved popularity among both patients and providers because of their efficacy, ease of use, and favorable safety profile. As such, they are often first-line therapy for stroke prophylaxis in the context of atrial fibrillation, as well as the treatment and prevention of venous thromboembolism.
      Despite the clear benefit of anticoagulation for atrial fibrillation and venous thromboembolism and the growing enthusiasm for DOACs, clinicians and public health officials remain concerned about potential underutilization of oral anticoagulants for these conditions.
      • Ogilvie I.M.
      • Newton N.
      • Welner S.A.
      • Cowell W.
      • Lip G.Y.
      Underuse of oral anticoagulants in atrial fibrillation: a systematic review.
      This has important clinical implications for the estimated 3 million patients with atrial fibrillation and approximately 75,000 patients diagnosed annually with venous thromboembolism.
      • Mozaffarian D.
      • Benjamin E.J.
      • Go A.S.
      • et al.
      Heart disease and stroke statistics–2015 update: a report from the American Heart Association.
      To date, longitudinal nationwide analyses of oral anticoagulation utilization have not demonstrated any meaningful change in the underutilization of anticoagulant therapy for atrial fibrillation patients.
      • Patel N.J.
      • Deshmukh A.
      • Pant S.
      • et al.
      Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning.
      • Chugh S.S.
      • Havmoeller R.
      • Narayanan K.
      • et al.
      Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
      • Mahan C.E.
      • Borrego M.E.
      • Woersching A.L.
      • et al.
      Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates.
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      To establish the utilization of anticoagulants and its impact on treatment for atrial fibrillation and venous thromboembolism, we examined a nationally representative, contemporary audit of commercially available oral anticoagulants between 2009 and 2014. In addition to extending prior work that was limited to examining the early market experience after dabigatran's US Food and Drug Administration (FDA) approval,
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      we explored the impact of 2 additional DOACs on anticoagulant use. We also examined the change in percentage of office visits for atrial fibrillation where an anticoagulant was prescribed. We hypothesized that DOAC use would replace warfarin use for the treatment of atrial fibrillation and venous thromboembolism and that the total number of atrial fibrillation patients receiving oral anticoagulants would increase.

      Methods

      Data Source

      The IMS Health National Disease and Therapeutic Index (NDTI) is an ongoing survey of office-based physicians in the United States that provides nationally representative data on the patterns and treatment of disease. The database has been described in detail in previous studies.
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      • Alexander G.C.
      • Sehgal N.L.
      • Moloney R.M.
      • Stafford R.S.
      National trends in treatment of type 2 diabetes mellitus, 1994-2007.
      • Stafford R.S.
      • Furberg C.D.
      • Finkelstein S.N.
      • Cockburn I.M.
      • Alehegn T.
      • Ma J.
      Impact of clinical trial results on national trends in alpha-blocker prescribing, 1996-2002.
      • Stafford R.S.
      • Radley D.C.
      The underutilization of cardiac medications of proven benefit, 1990 to 2002.
      Briefly, the NDTI prospectively collects office-based clinical information from approximately 4800 physicians identified through a random audit of the American Medical Association and American Osteopathic Association databases. The NDTI data include diagnosis, physician specialty, geographic region, patient age, and gender. The NDTI survey captures information on all clinic visits during 2 consecutive working business days per quarter, generating approximately 350,000 annual contract records. The NDTI also includes physician–patient interactions via phone call and in skilled nursing facilities (approximately 15% of all visits), which were excluded from our analysis. For each office-based encounter, all diagnosed conditions and the specific medications used or documented for each diagnosis are recorded. Each medication record within the NDTI is linked to a 6-digit taxonomic code, similar to the International Classification of Diseases, Tenth Revision, Clinical Modification, that captures diagnostic information. Using the sampling frame and weights, national estimates of office-based practice patterns can be extrapolated from NDTI data.
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      • Alexander G.C.
      • Sehgal N.L.
      • Moloney R.M.
      • Stafford R.S.
      National trends in treatment of type 2 diabetes mellitus, 1994-2007.
      • Stafford R.S.
      • Furberg C.D.
      • Finkelstein S.N.
      • Cockburn I.M.
      • Alehegn T.
      • Ma J.
      Impact of clinical trial results on national trends in alpha-blocker prescribing, 1996-2002.
      • Stafford R.S.
      • Radley D.C.
      The underutilization of cardiac medications of proven benefit, 1990 to 2002.

      Analyses

      Our primary unit of analysis was a treatment visit, defined as an office visit in which an oral anticoagulant was used. A single medication can produce more than 1 treatment visit during a single clinical encounter if that medication is used for multiple indications. We limited our analysis to treatment visits for warfarin and the 3 DOACs available during the study period (dabigatran, rivaroxaban, and apixaban) for atrial fibrillation and venous thromboembolism in patients aged ≥18 years. Analysis was performed on aggregated quarterly office visit estimates, because individual patient-level data were not available. Because we are interested in outpatient treatments, we excluded injectable anticoagulants from our analyses. The institutional review board of the University of Michigan Medical School assessed this study as not regulated and waived the requirement for informed consent.
      When assessing indications for oral anticoagulant use, we explored common cardiovascular conditions, specifically atrial fibrillation (including atrial flutter) and venous thromboembolism, as were coded in the visit diagnosis and linked to the use of a specific medication. Although the DOACs are FDA-approved only for nonvalvular atrial fibrillation, the NDTI does not allow for reliable distinction between valvular atrial fibrillation and nonvalvular atrial fibrillation.
      We used descriptive statistics to examine national estimates of treatment visits and dispensed medications between April 2009 and December 2014. We also conducted analyses of treatment visits after stratifying visits by the indication for anticoagulation and for age ≥65 years. Reported data include market share analysis, defined by the proportion of observed visits associated with a specific oral anticoagulant (or class) divided by the total observed visits associated with any oral anticoagulant. We also stratified the market share data by clinical indication. To estimate the percentage of office visits for atrial fibrillation with and without anticoagulant use, we examined all office visits with a diagnosis of atrial fibrillation (or atrial flutter) and stratified according to the use of any oral anticoagulant (warfarin, dabigatran, rivaroxaban, or apixaban) and by age ≥65 years between April 2009 and December 2014. Confidence intervals (CIs) for quarterly estimates were generated using a standardized 2-stage stratified cluster methodology.
      We used weighted least squares linear regression with linear spline analysis to assess the quarterly trend in the estimated office visits with anticoagulant prescription use. Unlike standard linear regression, weighted least squares linear regression corrects the unequal variance in estimates by inversely weighting the estimates according to their precision. The 95% CIs for estimates of office visits, as well as the 95% CIs for the calculated rates, provided the measure of precision. Quarterly trends were statistically significant if likelihood-ratio tests yielded P values <.05. Statistical analysis was performed using Stata Version 13 (StataCorp, College Station, Tex).

      Results

      Overall anticoagulation treatment visits increased from 2.05 million (M) (95% CI, 1.82M- 2.27M) in the second quarter of 2009 (2009/Q2) to 2.83M (95% CI, 2.49M-3.17M) in 2014/Q4, driven by an increase of 83,000 (83K) (95% CI, 58K-109K) visits per quarter since 2012/Q2 (P < .001; Figure 1 and Supplementary Table 1, available online). Between 2009/Q2 and 2012/Q1, there was no significant increase in treatment visits with anticoagulant use. Although warfarin treatment visits declined between 2009 and 2014, DOAC treatment visits have risen to more than 1 million per quarter since their introduction in 2010/Q4. Among DOAC treatment visits, dabigatran accounted for the majority of prescriptions between 2010/Q4 and 2012/Q4. However, since 2013/Q1, use of rivaroxaban is most common among the DOACs (Figure 1).
      Figure thumbnail gr1
      Figure 1Quarterly use of oral anticoagulant during office visits. DOAC = direct oral anticoagulant.
      Source: IMS Health National Disease and Therapeutic Index, 2009-2014.

      Warfarin and DOAC Use by Clinical Indication

      Use of all oral anticoagulants in treatment visits for atrial fibrillation has increased from 0.88M (95% CI, 0.74M-1.02M) in 2009/Q2 to 1.72M (95% CI, 1.47M-1.97M) in 2014/Q4, driven by an increase of 154K (95% CI, 119K-188K) visits per quarter since 2013/Q2 (P < .001; Figure 2 and Supplementary Table 2, available online). The increase in total anticoagulant use for atrial fibrillation visits has been largely driven by a more than 3-fold increase in DOAC use between 2013/Q2 (0.22M; 95% CI, 0.15M-0.28M) and 2014/Q4 (0.74M; 95% CI, 0.60M-0.88M). In 2014, use of DOACs was similar to warfarin use in atrial fibrillation treatment visits (Figure 2). As of 2014, rivaroxaban is the most commonly prescribed DOAC during atrial fibrillation office visits (48.2%), followed by apixaban (26.4%) and dabigatran (25.4%; Supplementary Table 2, available online). Use of dabigatran has been relatively stable since 2011/Q4, whereas use of rivaroxaban and apixaban continue to increase (Supplementary Table 2, available online).
      Figure thumbnail gr2
      Figure 2Quarterly visits for atrial fibrillation by anticoagulant type. DOAC = direct oral anticoagulant.
      Source: IMS Health National Disease and Therapeutic Index, 2009-2014.
      Use of all oral anticoagulants in patients with venous thromboembolism has increased from 367K (95% CI, 280K-453K) visits in 2009/Q2 to 583K (95% CI, 458K-707K) in 2014/Q4, an increase of 9K (95% CI, 4K-14K) visits per quarter (P = .001; Supplementary Table 2, available online). Use of DOACs has increased since 2012 and accounts for 36% of all venous thromboembolism visits in 2014.
      The majority of atrial fibrillation treatment visits with oral anticoagulant use occurred in patients aged ≥65 years (82.5%). Patients aged <65 years represent a minority of treatment visits for atrial fibrillation with both DOAC use (23.8%) and warfarin use (15.3%). The majority of venous thromboembolism treatment visits with oral anticoagulant use occurred in patients aged <65 years (55.7%). Patients aged <65 years were common among venous thromboembolism treatment visits with DOAC use (49.3%) but represented the majority of venous thromboembolism treatment visits with warfarin use (56.5%).

      Anticoagulant Use with Atrial Fibrillation Visits

      Total visits for atrial fibrillation increased from 1.67M (95% CI, 1.46M-1.87M) in 2009/Q2 to 2.52M (95% CI, 2.21M-2.83M) in 2014/Q4, an increase of 170K (95% CI, 114K-225K) per quarter since 2013/Q2 (P < .001; Supplementary Table 2, available online). The percentage of atrial fibrillation visits with anticoagulant use increased from 51.9% (95% CI, 50.4%-53.8%) in 2009/Q2 to 66.9% (95% CI, 65.0%-69.3%) in 2014/Q4, an increase of 2.3% (95% CI, 1.2%-3.4%) per quarter since 2013/Q2 (P < .001; Figure 3).
      Figure thumbnail gr3
      Figure 3Percentage of quarterly office visits for atrial fibrillation with anticoagulant use.
      Source: IMS Health National Disease and Therapeutic Index, 2009-2014.

      Discussion

      Using data from a large, nationally representative audit of ambulatory practice in the United States, we found continued brisk adoption of DOAC use in place of vitamin K antagonists. In particular, the use of DOACs for atrial fibrillation patients seems to be accelerating, largely driven by increasing use of rivaroxaban and apixaban alongside consistent use of dabigatran. In fact, use of DOACs is now similar to the use of warfarin for atrial fibrillation patients. Most importantly, the percentage of atrial fibrillation visits with anticoagulant use has been increasing since 2013/Q2, suggesting that more atrial fibrillation patients are receiving anticoagulation therapy.
      Our findings are particularly timely given that under-treatment of atrial fibrillation patients has been a long-standing concern.
      • Lang K.
      • Bozkaya D.
      • Patel A.A.
      • et al.
      Anticoagulant use for the prevention of stroke in patients with atrial fibrillation: findings from a multi-payer analysis.
      • Robson J.
      • Dostal I.
      • Mathur R.
      • et al.
      Improving anticoagulation in atrial fibrillation: observational study in three primary care trusts.
      • Gorin L.
      • Fauchier L.
      • Nonin E.
      • Charbonnier B.
      • Babuty D.
      • Lip G.Y.
      Prognosis and guideline-adherent antithrombotic treatment in patients with atrial fibrillation and atrial flutter: implications of undertreatment and overtreatment in real-life clinical practice; the Loire Valley Atrial Fibrillation Project.
      This is highlighted by recent studies supporting the use of longer-term monitoring to detect occult atrial fibrillation.
      • Wang S.H.
      • Kang Y.C.
      • Wang C.C.
      • et al.
      Annual atrial tachyarrhythmia burden determined by device interrogation in patients with cardiac implanted electronic devices is associated with a risk of ischaemic stroke independent of known risk factors.
      • Sanna T.
      • Diener H.C.
      • Passman R.S.
      • et al.
      Cryptogenic stroke and underlying atrial fibrillation.
      • Ritter M.A.
      • Kochhauser S.
      • Duning T.
      • et al.
      Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors.
      • Flint A.C.
      • Banki N.M.
      • Ren X.
      • Rao V.A.
      • Go A.S.
      Detection of paroxysmal atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke: the Stroke and Monitoring for PAF in Real Time (SMART) Registry.
      Prior studies have identified patient characteristics associated with use of warfarin vs DOACs in atrial fibrillation patients.
      • Desai N.R.
      • Krumme A.A.
      • Schneeweiss S.
      • et al.
      Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications.
      • Lauffenburger J.C.
      • Farley J.F.
      • Gehi A.K.
      • Rhoney D.H.
      • Brookhart M.A.
      • Fang G.
      Factors driving anticoagulant selection in patients with atrial fibrillation in the United States.
      However, it was not previously known whether the introduction of DOAC agents would help to increase the proportion of atrial fibrillation patients receiving anticoagulant therapy. Given the morbidity and mortality associated with the under-treatment of atrial fibrillation, our findings of increased treatment of atrial fibrillation since the advent of DOAC therapy are noteworthy.
      • Gorin L.
      • Fauchier L.
      • Nonin E.
      • Charbonnier B.
      • Babuty D.
      • Lip G.Y.
      Prognosis and guideline-adherent antithrombotic treatment in patients with atrial fibrillation and atrial flutter: implications of undertreatment and overtreatment in real-life clinical practice; the Loire Valley Atrial Fibrillation Project.
      The use of the Congestive heart failure, Hypertension, Age 75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [female] (CHA2DS2-VASc) score to estimate the annual risk of stroke in atrial fibrillation patients should lead to additional patients eligible for anticoagulant therapy.
      • Lip G.Y.
      • Nieuwlaat R.
      • Pisters R.
      • Lane D.A.
      • Crijns H.J.
      Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
      However, the rise in anticoagulant therapy in our US-based cohort began before the American College of Cardiology/American Heart Association-based guidelines endorsed the use of the CHA2DS2-VASc score in 2014.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Additionally, the national expansion of health insurance coverage associated with the Affordable Care Act did not occur until 2014, after the rise in use of anticoagulants for atrial fibrillation visits was seen in our population.
      • Collins S.R.
      • Rasmussen P.W.
      • Doty M.M.
      • Beutel S.
      The rise in health care coverage and affordability since health reform took effect: findings from the Commonwealth Fund Biennial Health Insurance Survey, 2014.
      Our population demonstrated relatively steady rates of office visits with oral anticoagulant use in the 3 years between 2009 and mid-2012. Starting in mid-2012, the number of office visits with anticoagulant use began to rise, and a similar rise in the proportion of atrial fibrillation visits with oral anticoagulant use was seen beginning in mid-2013.
      Of note, rivaroxaban now accounts for half of all DOAC use in atrial fibrillation patients among this population. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      trials demonstrated the superiority of dabigatran and apixaban, respectively, over warfarin. Conversely, in the The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, rivaroxaban was not able to demonstrate superiority for either stroke prevention or major bleeding in the intention-to-treat analysis. However, once-daily dosing and its association with improved medication adherence is a potentially strong motivator for both patients and providers to adopt rivaroxaban use and may contribute to its dominant market share in our analysis.
      • Laliberte F.
      • Nelson W.W.
      • Lefebvre P.
      • Schein J.R.
      • Rondeau-Leclaire J.
      • Duh M.S.
      Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients.
      • Laliberte F.
      • Bookhart B.K.
      • Nelson W.W.
      • et al.
      Impact of once-daily versus twice-daily dosing frequency on adherence to chronic medications among patients with venous thromboembolism.
      • Caldeira D.
      • Vaz-Carneiro A.
      • Costa J.
      The impact of dosing frequency on medication adherence in chronic cardiovascular disease: systematic review and meta-analysis.
      Other potential contributors to its market share include differential marketing and promotion, and early FDA approval for both venous thromboembolism and atrial fibrillation patients, as well as its formulary placement across different health plans. It remains to be seen whether the favorable trial results with apixaban will be linked to greater use over time or whether the convenience of once-daily dosing of rivaroxaban will maintain it as the most frequently used DOAC for stroke prevention in atrial fibrillation. Furthermore, despite dabigatran being the first DOAC approved for use in the United States, there have been recent concerns about myocardial infarction and bleeding risk that may impact its current and future use.
      • Harper P.
      • Young L.
      • Merriman E.
      Bleeding risk with dabigatran in the frail elderly.
      • Eikelboom J.W.
      • Wallentin L.
      • Connolly S.J.
      • et al.
      Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
      • Uchino K.
      • Hernandez A.V.
      Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.
      • Hohnloser S.H.
      • Oldgren J.
      • Yang S.
      • et al.
      Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial.
      Apixaban was recently approved (December 2012) and has had little time to gain market share, yet its use outnumbers dabigatran for office visits in the latter half of 2014. Edoxaban was approved after the completion of data analysis and therefore is not included in this study.
      Unlike visits for atrial fibrillation, we did not identify increases in anticoagulant treatment visits for venous thromboembolism after DOAC introduction. Instead, there was a small, steady increase in anticoagulant venous thromboembolism office visits throughout the study period, including before introduction of DOACs. We believe that this finding is consistent with clinical practice because nearly all patients with newly diagnosed venous thromboembolism are treated with anticoagulants. Therefore, there is not a large under-treated population of acute venous thromboembolism patients for whom the introduction of DOAC agents offers a new rationale to prescribe anticoagulation. However, use of warfarin has declined as use of DOAC agents have increased for venous thromboembolism. The DOAC use during office visits for venous thromboembolism patients is almost exclusively rivaroxaban, likely owing to the once-daily dosing and its early FDA approval for venous thromboembolism treatment.
      Other recent reports have described the use of DOACs in specific patient populations.
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      • Desai N.R.
      • Krumme A.A.
      • Schneeweiss S.
      • et al.
      Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications.
      • Schoof N.
      • Schnee J.
      • Schneider G.
      • et al.
      Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.
      • Xu Y.
      • Holbrook A.M.
      • Simpson C.S.
      • Dowlatshahi D.
      • Johnson A.P.
      Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis.
      • Steinberg B.A.
      • Holmes D.N.
      • Piccini J.P.
      • et al.
      Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.
      • Sorensen R.
      • Gislason G.
      • Torp-Pedersen C.
      • et al.
      Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study.
      Initial data from a Danish national registry of atrial fibrillation patients in 2011 showed minimal use (2%-3%) of dabigatran.
      • Sorensen R.
      • Gislason G.
      • Torp-Pedersen C.
      • et al.
      Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study.
      Subsequent to that report, 2 studies described a rapid rise in adoption of dabigatran for atrial fibrillation patients in North America, 12%-19% of all atrial fibrillation outpatient visits in the United States and 20% of oral anticoagulant prescriptions in Canada.
      • Kirley K.
      • Qato D.M.
      • Kornfield R.
      • Stafford R.S.
      • Alexander G.C.
      National trends in oral anticoagulant use in the United States, 2007 to 2011.
      • Schoof N.
      • Schnee J.
      • Schneider G.
      • et al.
      Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.
      • Xu Y.
      • Holbrook A.M.
      • Simpson C.S.
      • Dowlatshahi D.
      • Johnson A.P.
      Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis.
      • Steinberg B.A.
      • Holmes D.N.
      • Piccini J.P.
      • et al.
      Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.
      Most recently, Desai et al
      • Desai N.R.
      • Krumme A.A.
      • Schneeweiss S.
      • et al.
      Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications.
      described higher rates of DOAC use (62%) within a single health insurer database, but without any trends over time. Additionally, none have been able to demonstrate a meaningful increase in the total atrial fibrillation population receiving anticoagulant therapy. Confirming the findings from Desai et al,
      • Desai N.R.
      • Krumme A.A.
      • Schneeweiss S.
      • et al.
      Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications.
      our report finds similarly prevalent DOAC and warfarin use in atrial fibrillation patients, but in a large, nationally representative sample of patients with multiple payers, including Medicare, Medicaid, and the commercially insured.
      Our results must be taken in the context of several limitations. First, although these data are derived from a nationally representative sample, they exclude care provided in emergency departments and outpatient anticoagulation clinics and may not be generalizable to all office-based practices. Despite this, a number of prior reports have demonstrated similar estimates between NDTI and the National Ambulatory Medical Care Survey.
      • Stafford R.S.
      • Radley D.C.
      The underutilization of cardiac medications of proven benefit, 1990 to 2002.
      • Zell E.R.
      • McCaig L.F.
      • Kupronis B.A.
      • Besser R.E.
      • Schuchat A.
      A comparison of the National Disease and Therapeutic Index and the National Ambulatory Medical Care Survey to evaluate antibiotic usage.
      • Higashi A.
      • Zhu S.
      • Stafford R.S.
      • Alexander G.C.
      National trends in ambulatory asthma treatment, 1997-2009.
      Second, estimates are based on sampling data and do not represent exact number of office visits or number of patients because a single patient may have been observed more than once. However we are unaware of any secular trends beginning in 2013 that would influence the frequency of office visits for atrial fibrillation patients. Third, use of nonprescription aspirin is not reliably captured in the NDTI dataset and therefore was not included in this analysis. Finally, although the NDTI is based on clinical information provided by clinicians or office staff, the data do not include patient-level factors and therefore limit the ability to judge the appropriateness of treatments received, such as information about individuals' renal function, history of valve replacement surgery, comorbidity burden, and decisions about switching anticoagulant therapies.
      In conclusion, use of DOACs is rising rapidly and accounts for half of all anticoagulant use during atrial fibrillation office visits. Use of DOACs is rising among venous thromboembolism office visits, largely replacing the use of warfarin. Our findings suggest that DOAC adoption is associated with an increase in the number of atrial fibrillation patients treated with anticoagulant therapy. It remains to be seen whether these trends will continue or change once a DOAC reversal agent becomes available. Additionally, determining the economic impact of the shifting anticoagulant use at both a societal level and an individual level merits further investigation.
      • Avorn J.
      The relative cost-effectiveness of anticoagulants: obvious, except for the cost and the effectiveness.

      Supplementary Data

      Supplementary Table 1Office Visits with Oral Anticoagulant Use
      Source: IMS Health National Disease and Therapeutic Index, 2009-2014.
      Parameter200920102011201220132014
      Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4
      Total visits, n (thousands)21882123198320362119212821082119200221202118198319242394226125262143294924942544272729172831
       Warfarin visits, %1001001001001001009793908881847980847976756963606368
       DOAC visits, %00000037101219162120162124253137403738
       Dabigatran visits, %10010010010089776360524543243033232613
       Rivaroxaban visits, %000011233740485352675651615060
       Apixaban visits, %0000000002591416162427
      DOAC = direct oral anticoagulant.
      Supplementary Table 2Office Visits with Oral Anticoagulant Use by Diagnosis
      Source: IMS Health National Disease and Therapeutic Index, 2009-2014.
      Parameter200920102011201220132014
      Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4Q1Q2Q3Q4
      Atrial fibrillation visits, n (thousands)88090886382382390895091385688092075875591797287664910419431151139417631724
       Warfarin visits, %1001001001001001009488827973766470766866675348465357
       DOAC visits, %000000612182127243630243234334752524743
       Dabigatran visits, %10010010010095846567594941203032272518
       Rivaroxaban visits, %00005163533414950675444534748
       Apixaban visits, %00000000029131624202834
      Venous thromboembolism visits, n (thousands)367387255321414442325423404456349422316452446653434552476505512368583
       Warfarin visits, %1001001001001001001009998999510010097989086837762647260
       DOAC visits, %0000000121500321014172338362840
       Dabigatran visits, %10010010010000010000060
       Rivaroxaban visits, %000010010010090100100100968792
       Apixaban visits, %00000000000478
      DOAC = direct oral anticoagulant.

      References

        • Patel N.J.
        • Deshmukh A.
        • Pant S.
        • et al.
        Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: implications for healthcare planning.
        Circulation. 2014; 129: 2371-2379
        • Chugh S.S.
        • Havmoeller R.
        • Narayanan K.
        • et al.
        Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study.
        Circulation. 2014; 129: 837-847
        • Mahan C.E.
        • Borrego M.E.
        • Woersching A.L.
        • et al.
        Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates.
        Thromb Haemost. 2012; 108: 291-302
        • Barnes G.D.
        • Ageno W.
        • Ansell J.
        • Kaatz S.
        Subcommittee on the Control of A Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH.
        J Thromb Haemost. 2015;
        • Ogilvie I.M.
        • Newton N.
        • Welner S.A.
        • Cowell W.
        • Lip G.Y.
        Underuse of oral anticoagulants in atrial fibrillation: a systematic review.
        Am J Med. 2010; 123: 638-645.e4
        • Mozaffarian D.
        • Benjamin E.J.
        • Go A.S.
        • et al.
        Heart disease and stroke statistics–2015 update: a report from the American Heart Association.
        Circulation. 2015; 131: e29-322
        • Kirley K.
        • Qato D.M.
        • Kornfield R.
        • Stafford R.S.
        • Alexander G.C.
        National trends in oral anticoagulant use in the United States, 2007 to 2011.
        Circ Cardiovasc Qual Outcomes. 2012; 5: 615-621
        • Alexander G.C.
        • Sehgal N.L.
        • Moloney R.M.
        • Stafford R.S.
        National trends in treatment of type 2 diabetes mellitus, 1994-2007.
        Arch Intern Med. 2008; 168: 2088-2094
        • Stafford R.S.
        • Furberg C.D.
        • Finkelstein S.N.
        • Cockburn I.M.
        • Alehegn T.
        • Ma J.
        Impact of clinical trial results on national trends in alpha-blocker prescribing, 1996-2002.
        JAMA. 2004; 291: 54-62
        • Stafford R.S.
        • Radley D.C.
        The underutilization of cardiac medications of proven benefit, 1990 to 2002.
        J Am Coll Cardiol. 2003; 41: 56-61
        • Lang K.
        • Bozkaya D.
        • Patel A.A.
        • et al.
        Anticoagulant use for the prevention of stroke in patients with atrial fibrillation: findings from a multi-payer analysis.
        BMC Health Serv Res. 2014; 14: 329
        • Robson J.
        • Dostal I.
        • Mathur R.
        • et al.
        Improving anticoagulation in atrial fibrillation: observational study in three primary care trusts.
        Br J Gen Pract. 2014; 64: e275-e281
        • Gorin L.
        • Fauchier L.
        • Nonin E.
        • Charbonnier B.
        • Babuty D.
        • Lip G.Y.
        Prognosis and guideline-adherent antithrombotic treatment in patients with atrial fibrillation and atrial flutter: implications of undertreatment and overtreatment in real-life clinical practice; the Loire Valley Atrial Fibrillation Project.
        Chest. 2011; 140: 911-917
        • Wang S.H.
        • Kang Y.C.
        • Wang C.C.
        • et al.
        Annual atrial tachyarrhythmia burden determined by device interrogation in patients with cardiac implanted electronic devices is associated with a risk of ischaemic stroke independent of known risk factors.
        Eur J Cardiothorac Surg. 2015; 47: 840-846
        • Sanna T.
        • Diener H.C.
        • Passman R.S.
        • et al.
        Cryptogenic stroke and underlying atrial fibrillation.
        N Engl J Med. 2014; 370: 2478-2486
        • Ritter M.A.
        • Kochhauser S.
        • Duning T.
        • et al.
        Occult atrial fibrillation in cryptogenic stroke: detection by 7-day electrocardiogram versus implantable cardiac monitors.
        Stroke. 2013; 44: 1449-1452
        • Flint A.C.
        • Banki N.M.
        • Ren X.
        • Rao V.A.
        • Go A.S.
        Detection of paroxysmal atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke: the Stroke and Monitoring for PAF in Real Time (SMART) Registry.
        Stroke. 2012; 43: 2788-2790
        • Desai N.R.
        • Krumme A.A.
        • Schneeweiss S.
        • et al.
        Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications.
        Am J Med. 2014; 127: 1075-1082.e1
        • Lauffenburger J.C.
        • Farley J.F.
        • Gehi A.K.
        • Rhoney D.H.
        • Brookhart M.A.
        • Fang G.
        Factors driving anticoagulant selection in patients with atrial fibrillation in the United States.
        Am J Cardiol. 2015; 115: 1095-1101
        • Lip G.Y.
        • Nieuwlaat R.
        • Pisters R.
        • Lane D.A.
        • Crijns H.J.
        Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation.
        Chest. 2010; 137: 263-272
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • et al.
        2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
        Circulation. 2014; 130: e199-e267
        • Collins S.R.
        • Rasmussen P.W.
        • Doty M.M.
        • Beutel S.
        The rise in health care coverage and affordability since health reform took effect: findings from the Commonwealth Fund Biennial Health Insurance Survey, 2014.
        Issue Brief (Commonw Fund). 2015; 2: 1-16
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • Laliberte F.
        • Nelson W.W.
        • Lefebvre P.
        • Schein J.R.
        • Rondeau-Leclaire J.
        • Duh M.S.
        Impact of daily dosing frequency on adherence to chronic medications among nonvalvular atrial fibrillation patients.
        Adv Ther. 2012; 29: 675-690
        • Laliberte F.
        • Bookhart B.K.
        • Nelson W.W.
        • et al.
        Impact of once-daily versus twice-daily dosing frequency on adherence to chronic medications among patients with venous thromboembolism.
        Patient. 2013; 6: 213-224
        • Caldeira D.
        • Vaz-Carneiro A.
        • Costa J.
        The impact of dosing frequency on medication adherence in chronic cardiovascular disease: systematic review and meta-analysis.
        Rev Port Cardiol. 2014; 33: 431-437
        • Harper P.
        • Young L.
        • Merriman E.
        Bleeding risk with dabigatran in the frail elderly.
        N Engl J Med. 2012; 366: 864-866
        • Eikelboom J.W.
        • Wallentin L.
        • Connolly S.J.
        • et al.
        Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial.
        Circulation. 2011; 123: 2363-2372
        • Uchino K.
        • Hernandez A.V.
        Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials.
        Arch Intern Med. 2012; 172: 397-402
        • Hohnloser S.H.
        • Oldgren J.
        • Yang S.
        • et al.
        Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial.
        Circulation. 2012; 125: 669-676
        • Schoof N.
        • Schnee J.
        • Schneider G.
        • et al.
        Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.
        Curr Med Res Opin. 2014; 30: 795-804
        • Xu Y.
        • Holbrook A.M.
        • Simpson C.S.
        • Dowlatshahi D.
        • Johnson A.P.
        Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis.
        CMAJ Open. 2013; 1: E115-E119
        • Steinberg B.A.
        • Holmes D.N.
        • Piccini J.P.
        • et al.
        Early adoption of dabigatran and its dosing in US patients with atrial fibrillation: results from the outcomes registry for better informed treatment of atrial fibrillation.
        J Am Heart Assoc. 2013; 2: e000535
        • Sorensen R.
        • Gislason G.
        • Torp-Pedersen C.
        • et al.
        Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study.
        BMJ Open. 2013; 3: e002758
        • Zell E.R.
        • McCaig L.F.
        • Kupronis B.A.
        • Besser R.E.
        • Schuchat A.
        A comparison of the National Disease and Therapeutic Index and the National Ambulatory Medical Care Survey to evaluate antibiotic usage.
        in: Proceedings of the Survey Research Methods Section, American Statistical Association. American Statistical Association, Alexandria, VA2000
        • Higashi A.
        • Zhu S.
        • Stafford R.S.
        • Alexander G.C.
        National trends in ambulatory asthma treatment, 1997-2009.
        J Gen Intern Med. 2011; 26: 1465-1470
        • Avorn J.
        The relative cost-effectiveness of anticoagulants: obvious, except for the cost and the effectiveness.
        Circulation. 2011; 123: 2519-2521