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Published in final edited form as: Am J Med. 2015 Jul 2;128(12):1300–1305.e2. doi: 10.1016/j.amjmed.2015.05.044

National Trends in Ambulatory Oral Anticoagulant Use

Geoffrey D Barnes 1, Eleanor Lucas 2, G Caleb Alexander 2, Zachary D Goldberger 3
PMCID: PMC4658248  NIHMSID: NIHMS707484  PMID: 26144101

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 undertreatment of atrial fibrillation.

Method

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% CI 1.82-2.27) to 2.83 (95% CI 2.49-3.17) million (M) quarterly visits (p<0.001). 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<0.001), 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<0.001). 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

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

Keywords: Anticoagulants, Warfarin, Atrial Fibrillation, Venous Thromboembolism

Background

Thromboembolic events associated with atrial fibrillation and venous thromboembolism are leading causes of morbidity and mortality worldwide.1-3 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, four direct oral anticoagulants (DOACs)—dabigatran, rivaroxaban, apixaban, and edoxaban—were sequentially introduced into clinical practice beginning in 2010.4 Despite their costs, these agents have achieved popularity among both patients and providers due to 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.5 This has important clinical implications for the estimated 3 million patients with atrial fibrillation and approximately 75,000 patients diagnosed annually with venous thromboembolism.6 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.1-3, 7

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 food and drug administration (FDA) approval, 7 we explored the impact of two additional DOACs on anticoagulant use. We also examined the change in percent 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 U.S. that provides nationally representative data on the patterns and treatment of disease. The database has been described in detail in previous studies.7-10 Briefly, the NDTI prospectively collects office-based clinical information from approximately 4,800 physicians identified through a random audit of the American Medical Association and American Osteopathic Association databases. NDTI data includes diagnosis, physician specialty, geographic region, patient age, and gender. The NDTI survey captures information on all clinic visits during two consecutive working business days per quarter, generating approximately 350,000 annual contract records. NDTI also includes physician-patient interactions via phone call and in skilled nursing facilities (∼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 (ICD 10-CM), that captures diagnostic information. Using the sampling frame and weights, national estimates of office-based practice patterns can be extrapolated from NDTI data.7-10

Analyses

Our primary unit of analysis was a treatment visit, defined as an office visit where an oral anticoagulant was used. A single medication can produce more than one 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 three DOACs available during the study period (dabigatran, rivaroxaban and apixaban) for atrial fibrillation and venous thromboembolism in patients 18 years of age and older. Analysis was performed on aggregated quarterly office visit estimates, as individual patient-level data was 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 non-valvular 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. Reported data includes 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 percent 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 based on the use of any oral anticoagulant (warfarin, dabigatran, rivaroxaban or apixaban) and by age ≥ 65 between April 2009 and December 2014. Confidence intervals for quarterly estimates were generated using a standardized two-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% confidence intervals (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 <0.05. Statistical analysis was performed using Stata Version 13 (StataCorp, College Station, Texas).

Results

Overall anticoagulation treatment visits increased from 2.05 million (M) (95% CI 1.82M-2.27M) in the 2nd quarter of 2009 (2009/Q2) to 2.83M (95% CI 2.49M -3.17M) in 2014/Q4, driven by an increase of 83K (95% CI 58K-109K) visits per quarter since 2012/Q2 (p<0.001; Figure 1 and Online Appendix). Between 2009/Q2 and 2012/Q1, there was no significant increase in treatment visits with anticoagulant use. While warfarin treatment visits declined between 2009 and 2014, DOAC treatment visits have risen to over 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 1. Quarterly Visits with Oral Anticoagulant Use.

Figure 1

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Quarterly 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<0.001; Figure 2 and Online Appendix). The increase in total anticoagulant use for atrial fibrillation visits has been largely driven by a more than three-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%; Online Appendix). Use of dabigatran has been relatively stable since 2011/Q4 while use of rivaroxaban and apixaban continue to increase (Online Appendix).

Figure 2. Quarterly Visits for Atrial Fibrillation by Anticoagulant Type.

Figure 2

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Quarterly office 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=0.001; Online Appendix). Use of DOACs has increased since 2012 and account for 36% of all venous thromboembolism visits in 2014.

The majority of atrial fibrillation treatment visits with oral anticoagulant use occurred in patients ≥ 65 years of age (82.5%). Patients < 65 years of age 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 <65 years of age (55.7%). Patients < 65 years of age 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<0.001; Online Appendix). The percent 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<0.001; Figure 3).

Figure 3. Quarterly Atrial Fibrillation Visits and Percent with Anticoagulation.

Figure 3

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The percent 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 appears 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 percent 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 undertreatment of atrial fibrillation patients has been a long-standing concern.11-13 This is highlighted by recent studies supporting the use of longer-term monitoring to detect occult atrial fibrillation.14-17 Prior studies have identified patient characteristics associated with use of warfarin vs DOACs in atrial fibrillation patients.18, 19 However, it was not previously known if 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 undertreatment of atrial fibrillation, our findings of increased treatment of atrial fibrillation since the advent of DOAC therapy are noteworthy.13 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.20 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 2014.21 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.22 Our population demonstrated relatively steady rates of office visits with oral anticoagulant use in the three 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 Anti- coagulation Therapy (RE-LY)23 and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)24 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 Antago- nism 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.25-27 Other potential contributors to its market share include differential marketing and promotion, 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 if the favorable trial results with apixaban will be linked to greater use over time or if 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.28-31 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 prior to 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 undertreated 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. DOAC use during office visits for venous thromboembolism patients is almost exclusively rivaroxaban, likely due 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.7, 18, 32-35 Initial data from a Danish national registry of atrial fibrillation patients in 2011 showed minimal use (2-3%) of dabigatran.35 Subsequent to that report, two 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 US and 20% of oral anticoagulant prescriptions in Canada.7, 32-34 Most recently, Desai et al. described higher rates of DOAC use (62%) within a single health insurer database, but without any trends over time.18 Additionally, none have been able to demonstrate a meaningful increase in the total atrial fibrillation population receiving anticoagulant therapy. Confirming the findings from Desai and colleagues, 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.18

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.10, 36, 37 Second, estimates are based on sampling data and do not represent exact number of office visits or number of patients as 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 non-prescription 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 does not include patient-level factors and therefore limits 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. DOAC use 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 if 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.38

Supplementary Material

Table 1. Office Visits with Oral Anticoagulant Use

Table 2. Office Visits with Oral Anticoagulant Use by Diagnosis

Take Home/Clinical Significance Points.

  • The number of office visits with anticoagulant use is increasing, largely driven by new visits with direct oral anticoagulant use in atrial fibrillation patients

  • Direct oral anticoagulants and warfarin are currently 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

Acknowledgments

Funding Source: Dr. Barnes is supported by the National Heart, Lung and Blood Institute (T32 HL007853-16). Dr. Alexander is also supported by the National Heart, Lung and Blood Institute (R01 HL107345).

Footnotes

All authors had access to the data and a role in writing the manuscript.

Conflict of Interest Disclosures: Dr. Barnes has received research funding from Bristol-Myers-Squibb/Pfizer and Blue Cross-Blue Shield of Michigan as well as consulting fees from Portola Pharmaceutical, none of which supported this analysis. Dr. Alexander is Chair of the FDA's Peripheral and Central Nervous System Advisory Committee, serves as a paid consultant to IMS Health, and serves on an IMS Health scientific advisory board. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

Additional Disclosures: The statements, findings, conclusions, views, and opinions contained and expressed in this article are based in part on data obtained under license from the following IMS Health Incorporated information service(s): National Disease and Therapeutic Index (2009– 2014), IMS Health Incorporated. All Rights Reserved. The statements, findings, conclusions, views, and opinions contained and expressed herein are not necessarily those of IMS Health Incorporated or any of its affiliated or subsidiary entities.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table 1. Office Visits with Oral Anticoagulant Use

Table 2. Office Visits with Oral Anticoagulant Use by Diagnosis

NIHMS707484-supplement-supplement_1.pdf (69.7KB, pdf)

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