Advertisement

Patterns of Initiation of Oral Anticoagulants in Patients with Atrial Fibrillation— Quality and Cost Implications

      Abstract

      Background

      Dabigatran, rivaroxaban, and apixaban have been approved for use in patients with atrial fibrillation based upon randomized trials demonstrating their comparable or superior efficacy and safety relative to warfarin. Little is known about their adoption into clinical practice, whether utilization is consistent with the controlled trials on which their approval was based, and how their use has affected health spending for patients and insurers.

      Methods

      We used medical and prescription claims data from a large insurer to identify patients with nonvalvular atrial fibrillation who were prescribed an oral anticoagulant in 2010-2013. We plotted trends in medication initiation over time, assessed corresponding insurer and patient out-of-pocket spending, and evaluated the cumulative number and cost of anticoagulants. We identified predictors of novel anticoagulant initiation using multivariable logistic models. Finally, we estimated the difference in total drug expenditures over 6 months for patients initiating warfarin versus a novel anticoagulant.

      Results

      There were 6893 patients with atrial fibrillation that initiated an oral anticoagulant during the study period. By the end of the study period, novel anticoagulants accounted for 62% of new prescriptions and 98% of anticoagulant-related drug costs. Female sex, lower household income, and higher CHADS2, CHA2DS2-VASC, and HAS-BLED scores were significantly associated with lower odds of receiving a novel anticoagulant (P <.001 for each). Average combined patient and insurer anticoagulant spending in the first 6 months after initiation was more than $900 greater for patients initiating a novel anticoagulant.

      Conclusions

      This study demonstrates rapid adoption of novel anticoagulants into clinical practice, particularly among patients with lower CHADS2 and HAS-BLED scores, and high health care cost consequences. These findings provide important directions for future comparative and cost-effectiveness research.

      Keywords

      SEE RELATED EDITORIAL p. 1027
      Clinical Significance
      • By mid-2013, novel anticoagulants accounted for 62% of new prescriptions and 98% of anticoagulant-related medication costs.
      • Females, individuals in lower income areas, and those with higher CHADS2 and HAS-BLED scores have significantly lower odds of novel anticoagulant initiation.
      • Adoption patterns demonstrate divergence from the clinical trials on whose basis novel anticoagulants were approved; surveillance is needed to observe whether selection bias persists in patients initiating these medications.
      Warfarin and other vitamin K antagonists significantly reduce the risk of stroke and death in patients with nonvalvular atrial fibrillation and have long been the cornerstone of therapy for this condition.
      Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
      Although these drugs are inexpensive, they require monitoring, have a narrow therapeutic window, and patients frequently discontinue use.
      • Gomes T.
      • Mamdani M.M.
      • Holbrook A.M.
      • Paterson J.M.
      • Juurlink D.N.
      Persistence with therapy among patients treated with warfarin for atrial fibrillation.
      Novel oral anticoagulants that require no monitoring have been approved for use based upon randomized trials demonstrating their comparable or superior efficacy and safety relative to warfarin.
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      Based on these studies, the US Food and Drug Administration (FDA) approved the direct thrombin inhibitor dabigatran in October 2010, followed by the Factor Xa inhibitors rivaroxaban and apixaban in November 2011 and December 2012, respectively.
      A national audit of ambulatory practices evaluating trends in oral anticoagulant use from 2007 to 2011 found rapid adoption of dabigatran in clinical practice.
      • 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.
      Similarly, a recent registry-based analysis of the use of dabigatran in patients with atrial fibrillation found significant uptake of dabigatran use in 2011.
      • 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.
      However, little is known about how the availability of rivaroxaban and apixaban have affected utilization patterns, whether the adoption of the novel anticoagulants in typical practice is consistent with the controlled trials on which their approval was based, or how their use has affected spending for patients and insurers.

      Methods

      Study Population and Data Source

      We used nationwide medical and prescription claims data from commercial patients covered by Aetna, a large health care benefits company, to create a cohort of patients with newly diagnosed nonvalvular atrial fibrillation who were prescribed an oral anticoagulant between October 1, 2010 and June 30, 2013.
      These data contained complete paid claims data for all procedures, physician encounters, hospitalizations, and filled prescriptions (including dose dispensed and amounts paid by the insurer and the patient). These data were linked to eligibility data that included patient age, sex, and zip code of residence. Aggregate data on socioeconomic status, race, and educational attainment were obtained by linking zip code of residence with data from the 2000 United States Census, which specified the median income as well as the distribution of race and educational achievement of the geographic population for each zip code. The Institutional Review Board of Brigham and Women’s Hospital approved the study.

      Study Cohort

      Patients were included in the study if they filled a prescription for warfarin, dabigatran, rivaroxaban, or apixaban during the study period. All patients were required to have maintained continuous insurance eligibility for 6 months before their index date, during which time they must have had a diagnosis of atrial fibrillation (International Classification of Diseases, Ninth Revision [ICD-9]: 427.31) and no filled prescriptions for any anticoagulant agent (ie, they were new initiators). Patients with concomitant valvular heart disease (ICD-9: 394.x-397.x, 398.9, 42.4x, V42.2, V43.3, 35.1x, 35.2x) were excluded. Any subsequent re-initiation of therapy by a patient that met cohort entry criteria was excluded (ie, a patient could only appear in the cohort once). The date of the patient's first eligible prescription was defined as his or her index date.
      We assessed differences in proportions and means with 95% confidence intervals for demographic, clinical, and health care utilization characteristics of initiators of warfarin, dabigatran, and rivaroxaban; apixaban was excluded from these statistical comparisons due to small sample size. Clinical and health care utilization characteristics were based on medical and pharmacy claims in the 6 months before initiation. The Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke (CHADS2) score,
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • Boechler M.
      • Rich M.W.
      • Radford M.J.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      the Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category (CHA2DS2-VASc) score,
      • 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.
      and the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (Age >65 years), Drugs/alcohol concomitantly (HAS-BLED) score
      • Pisters R.
      • Lane D.A.
      • Nieuwlaat R.
      • de Vos C.B.
      • Crijns H.J.
      • Lip G.Y.
      A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
      was calculated for each subject (note: one element of this score, labile international normalized ratio values, was not available in our claims dataset and therefore was not used in the HAS-BLED score calculation). Individuals of unknown sex were excluded.

      Patterns and Predictors of Initiation

      We categorized patients based on calendar month of their drug initiation and the oral anticoagulant they started, and plotted trends over time. We then assessed insurer drug spending (ie, plan-paid amount) and patient out-of-pocket drug spending (ie, copayments, coinsurance, deductible) based on the index prescription, and plotted the share of costs associated with each anticoagulant. Finally, we plotted the cumulative total monthly number of prescriptions of each anticoagulant after the index prescription, regardless of any switching that might have occurred, and computed the monthly costs associated with these prescriptions. Patients who lost eligibility were censored at loss of eligibility. We repeated our plots of trends in anticoagulant initiation stratified on CHADS2 score,
      • Gage B.F.
      • Waterman A.D.
      • Shannon W.
      • Boechler M.
      • Rich M.W.
      • Radford M.J.
      Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
      a stroke prediction score.
      We constructed 3 multivariable logistic models to identify predictors of initiation on a novel oral anticoagulant compared with warfarin. Potential predictors in all models included age, sex, race, income, geographic region, and calendar time. Comorbidity was adjusted for in several ways: 1) investigator-selected diagnoses; 2) CHADS2 score; and 3) HAS-BLED score.

      Economic Analysis

      To evaluate patient and insurer costs associated with anticoagulant use over the 6-month period after treatment initiation, we restricted our cohort to those individuals with 180 days or more of continuous eligibility after their first prescription. For each patient, we calculated total patient out-of-pocket and insurer spending for all anticoagulant medication during the 180 days after treatment initiation, including anticoagulant medications the patients may have switched to during this period. We then subdivided these estimates into patient out-of-pocket and insurer spending for the index medication and for other anticoagulants. From this, we estimated the difference in total expenditures over 6 months for patients initiating warfarin compared with a novel anticoagulant.

      Results

      The study cohort consisted of 6893 patients with nonvalvular atrial fibrillation newly initiated on an oral anticoagulant between October 1, 2010 and June 30, 2013 (Appendix, available online). Patients had a mean age of 61.3 years, were predominantly male (72.8%), and had mean CHADS2 and HAS-BLED scores of 1.7 and 2.0, respectively (Table 1). Approximately one third of patients had a history of coronary artery disease, and one quarter had diabetes. Heart failure, renal dysfunction, or history of stroke or transient ischemic attack was present in 17%, 12%, and 9% of patients, respectively, while 4% had a history of gastrointestinal bleeding. On average, patients had filled more than 8 medications in the 6 months before treatment initiation; 13% had received a nonsteroidal anti-inflammatory medication and 8% had received clopidogrel in the 6 months before initiation.
      Table 1Baseline Demographic Characteristics, Clinical Characteristics, and Health Care Utilization of the Study Cohort
      AllWarfarinDabigatranRivaroxabanApixabanP-Value
      P-value for warfarin versus dabigatran or rivaroxaban.
      Demographics
       Members68934070198282120
       Sex (female)27.2%30.0%23.0%23.5%5.0%<.0001
       Age, years
      Average age61.361.860.760.558.4<.0001
      Age 18-5422.3%21.5%23.6%23.4%20.0%
      Age 55-6444.8%44.1%44.4%48.4%60.0%
      Age 65-7423.1%22.8%24.8%20.6%15.0%
      Age 75+9.8%11.6%7.2%7.7%5.0%
       Region
      Northeast32.7%33.8%31.9%29.4%40.0%.04
      South38.2%36.0%41.0%42.1%35.0%<.0001
      Midwest8.3%8.2%9.1%7.2%10.0%.24
      West19.9%21.2%17.4%20.1%10.0%.002
      Comorbidity: Mean (SD)
       CHADS2 score1.67 (1.10)1.79 (1.18)1.50 (0.94)1.53 (0.97)1.40 (0.68)<.0001
       CHA2DS2-VASC score2.57 (1.62)2.83 (1.71)2.19 (1.37)2.23 (1.43)2.05 (0.94)<.0001
       HAS-BLED1.96 (1.16)2.08 (1.22)1.77 (1.01)1.81 (1.08)1.60 (0.82)<.0001
       %
      Coronary artery disease31%33%28%30%30%<.0001
      Congestive heart failure17%20%12%12%5%<.0001
      Hypertension91%91%91%92%95%.68
      Diabetes mellitus24%26%21%20%25%<.0001
      Deep vein thrombosis or pulmonary embolism10%15%2%3%5%<.0001
      Liver disease5%6%4%3%5%.001
      Renal dysfunction12%16%7%8%5%<.0001
      Previous ischemic stroke or transient ischemic attack9%10%6%8%5%<.0001
      Hemorrhagic stroke1%1%0%0.1%0%.003
      Gastrointestinal bleeding4%4%3%3%0%.001
      Urogenital bleeding12%15%6%9%10%<.0001
      Other major bleeding4%5%2%2%0%<.0001
      Bleeding history or predisposition18%22%12%14%10%<.0001
      Healthcare utilization: Mean (SD)
       Number of medications8.25 (4.92)8.63 (5.15)7.56 (4.48)8.05 (4.61)7.15 (3.60)<.0001
       Hospitalizations0.51 (0.72)0.59 (0.80)0.40 (0.58)0.40 (0.57)0.20 (0.41)<.0001
       Hospital days4.52 (13.64)6.28 (16.86)2.07 (6.36)1.82 (4.18)0.65 (1.42)<.0001
       Office visits9.59 (9.99)10.25 (11.18)8.71 (7.81)8.45 (8.04)8.75 (8.75)<.0001
       Cardiologist visits2.07 (2.65)1.92 (2.77)2.35 (2.54)2.14 (2.21)2.40 (2.72)<.0001
       Neurologist visits0.11 (0.53)0.12 (0.57)0.08 (0.46)0.11 (0.53)0.00 (0.00).08
       %
      Hospitalization in 30 days before treatment initiation30%34%26%25%15%<.0001
      CHADS2 = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke; CHA2DS2-VASC = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex category; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (age >65 years), drugs/alcohol concomitantly.
      P-value for warfarin versus dabigatran or rivaroxaban.

      Patterns of Medication Initiation Over Time

      Over the 36-month study period, there were a total of 45,472 prescriptions filled for anticoagulants, among which 26,253 (57.7%) were for warfarin, 14,922 (32.8%) for dabigatran, 4241 (9.3%) for rivaroxaban, and 56 (0.1%) for apixaban.
      Dabigatran rapidly gained market share after entering the market in November 2010 (Figure 1A). By October 2011, patients were as likely to start on this drug as they were to initiate warfarin. After its introduction, rivaroxaban use increased rapidly, overtaking both warfarin and dabigatran in June 2013. Apixaban, FDA-approved as of December 2012, saw only modest uptake, accounting for only 2% of new anticoagulant prescriptions as of June 2013.
      Figure thumbnail gr1
      Figure 1Monthly trends in oral anticoagulant initiation (panel A) and total spending (panel B).

      Predictors of Initiating Treatment with a Novel Oral Anticoagulant

      As compared with patients initiating warfarin, those starting a novel oral anticoagulant had significantly fewer concomitant medications, office visits, hospital days, and hospitalizations within 30 days of initiation, but higher number of visits to a cardiologist (P <.001) (Table 1). Novel anticoagulant initiators tended to be younger and healthier, and with significantly lower CHADS2, CHA2DS2-VASC, and HAS-BLED scores. As seen in Figure 2, 46% of patients with CHADS2 scores of 0 or 1 initiated a novel anticoagulant, compared with just 39% and 26% for CHADS2 scores of 2 and 3, respectively (P <.0001 for test of trend).
      Figure thumbnail gr2
      Figure 2Number of warfarin and novel anticoagulant initiators by CHADS2 score during study period. CHADS2 = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke.
      In multivariable models, increasing CHADS2 and HAS-BLED scores were significantly associated with lower odds of novel anticoagulant initiation (Table 2). For every 1-point increase in CHADS2, patients were 20% less likely to receive a novel anticoagulant (odds ratio [OR] 0.80; 95% confidence interval [CI], 0.76-0.84). Similarly, for every 1-point increase in HAS-BLED, patients were 18% less likely to receive a novel anticoagulant (OR 0.82; 95% CI, 0.78-0.87). In addition, women were 24% less likely to be initiated on a novel oral anticoagulant as compared with men (OR 0.76; 95% CI, 0.67-0.86). There was a significant, step-wise increase in the likelihood of receiving a novel agent with progressively increasing neighborhood household income, compared with median household income of $50,000 or less.
      Table 2Multivariable Analysis Predicting Initiation with a Novel Anticoagulant versus Warfarin Among Patients with Atrial Fibrillation
      PredictorOdds Ratio (95% CI) of Initiating Therapy With a Novel Anticoagulant vs Warfarin
      Model 1
      Model 1 includes age, sex, race, income, geographic region, calendar time, and investigator-selected clinical diagnoses.
      Model 2
      Model 2 includes age, sex, race, income, geographic region, calendar time, and CHADS2 score.
      Model 3
      Model 3 includes age, sex, race, income, geographic region, calendar time and HAS-BLED score.
      Age, years (vs under 50)
       50-650.98 (0.82-1.16)
       65+0.92 (0.76-1.12)
      Calendar month from October 20101.06 (1.05-1.06)1.06 (1.05-1.06)1.06 (1.05-1.06)
      Sex (female)0.76 (0.67-0.86)0.76 (0.67-0.86)0.76 (0.67-0.86)
      Region (vs Northeast)
       Midwest1.18 (0.96-1.44)1.17 (0.95-1.43)1.15 (0.94-1.41)
       South1.36 (1.20-1.55)1.37 (1.21-1.56)1.37 (1.21-1.56)
       West0.87 (0.74-1.01)0.85 (0.73-0.99)0.86 (0.74-1.00)
      Median household income in zip code (vs <$50,000)
       $50,000-$99,9991.20 (1.05-1.38)1.21 (1.06-1.38)1.21 (1.06-1.38)
       $100,000-$149,9991.69 (1.21-2.36)1.69 (1.22-2.35)1.74 (1.25-2.43)
       $150,000-$200,0001.90 (0.62-5.79)1.98 (0.65-6.07)2.03 (0.66-6.23)
      Percent black in zip code1.06 (0.75-1.50)0.98 (0.70-1.38)0.98 (0.70-1.37)
      Percent graduated college or high school in zip code1.01 (1.01-1.02)1.01 (1.01-1.02)1.02 (1.01-1.02)
      Comorbidity
       Coronary artery disease1.00 (0.88-1.14)0.92 (0.81-1.04)0.92 (0.81-1.04)
       Deep vein thrombosis or pulmonary embolism0.17 (0.13-0.23)0.15 (0.11-0.19)0.16 (0.12-0.20)
       Congestive heart failure0.72 (0.61-0.84)
       Previous myocardial infarction0.82 (0.60-1.11)
       Diabetes mellitus0.86 (0.75-0.98)
       Alcohol use1.12 (0.80-1.57)
       NSAID, aspirin, clopidogrel, prasugrel, or ticagrelor use1.00 (0.88-1.15)
       Stroke0.71 (0.60-0.84)
       Bleeding history or predisposition0.64 (0.55-0.75)
       Abnormal liver function0.92 (0.70-1.20)
       Hypertension1.20 (0.99-1.45)
       Renal dysfunction0.64 (0.52-0.77)
      CHADS2 score (per 1-point increase)0.80 (0.76-0.84)
      HAS-BLED score (per 1-point increase)0.82 (0.78-0.87)
      CHADS = congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke; CI = confidence interval; HAS-BLED = hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (age >65 years), drugs/alcohol concomitantly; NSAID = nonsteroidal anti-inflammatory drug.
      Model 1 includes age, sex, race, income, geographic region, calendar time, and investigator-selected clinical diagnoses.
      Model 2 includes age, sex, race, income, geographic region, calendar time, and CHADS2 score.
      Model 3 includes age, sex, race, income, geographic region, calendar time and HAS-BLED score.

      Economic Impact of Initial Medication Choice

      Trends in monthly spending are shown in Figure 1B. Since the introduction of dabigatran in late 2010, novel anticoagulant spending has accounted for 98% of total spending. This corresponds to insurer spending of $5.82 million, of which warfarin accounted for $0.43 million (Figure 3A); and patient out-of-pocket spending of $1.3 million, of which warfarin accounted for $0.28 million (Figure 3B).
      Figure thumbnail gr3
      Figure 3Accumulated insurer amount (panel A) and patient out-of-pocket amount (panel B) by anticoagulant.
      Considering only the first 6 months postinitiation, total out-of-pocket and insurer costs for patients initiating a novel anticoagulant were considerably higher than those for patients initiating warfarin (Figure 4). On average, patients initiating warfarin paid $54 for 6 months of medication, while those initiating dabigatran or rivaroxaban paid $205 and $221, respectively. Insurer spending for patients initiated on warfarin during this period was $68 for warfarin, compared with $852 and $865 for dabigatran and rivaroxaban, respectively. The average combined patient and insurer spending for anticoagulants over 6 months for patients initiating warfarin was $122, dabigatran $1053, and rivaroxaban $1084. This represents a difference over 6 months of more than $900 per patient.
      Figure thumbnail gr4
      Figure 4Total patient and insurer spending during 6 months after initiation stratified by anticoagulant on which patients were started.

      Discussion

      This study of a contemporary cohort of patients with atrial fibrillation starting oral anticoagulant therapy demonstrates rapid adoption of novel anticoagulants into clinical practice, utilization associated with lower CHADS2 and HAS-BLED scores, and significant health care cost implications. This study is the first, to our knowledge, to evaluate real-world use of all novel anticoagulants currently on the market.
      • 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 observed a significant decline in the proportion of patients with atrial fibrillation starting warfarin concurrent with the availability of novel anticoagulants beginning in October 2010. By June 2013, more than 60% of patients newly initiating an oral anticoagulant were being prescribed dabigatran, rivaroxaban, or apixaban. Before the introduction of rivaroxaban in November 2011, dabigatran accounted for 44% of anticoagulant initiation, but this dropped to approximately 15% of starts in the subsequent 12 months, a reversal that may have been related to reports beginning in late 2011 of increased risk of myocardial infarction and serious and fatal bleeding events in dabigatran users.

      Pradaxa (dabigatran etexilate mesylate): Drug safety communication – safety review of post-market reports of serious bleeding events; 2011. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm282820.htm. Accessed December 23, 2013.

      • Artang R.
      • Rome E.
      • Nielsen J.D.
      • Vidaillet H.J.
      Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.
      • Mak K.H.
      Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials.
      The once-daily dosing of rivaroxaban as compared with twice daily for dabigatran may also be a factor in the substitution away from dabigatran.
      With only 2% of market share 6 months after approval, it remains to be seen whether the adoption of apixaban will follow the same trajectory as dabigatran and rivaroxaban. The impending FDA approval of new factor Xa inhibitors such as edoxaban

      Daiichi Sankyo Company. Daiichi Sankyo submits SAVAYSA(TM) (edoxaban) tablets new drug application to the U.S. FDA for once-daily use for stroke risk reduction in atrial fibrillation and for the treatment and prevention of recurrence of venous thromboembolism [press release]. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006065.html. Accessed January 13, 2014.

      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      and betrixaban
      • Palladino M.
      • Merli G.
      • Thomson L.
      Evaluation of the oral direct factor Xa inhibitor – betrixaban.
      may also influence an increasingly crowded market for therapeutic alternatives to warfarin. It remains unclear whether the market for novel anticoagulants has been fully saturated and whether uptake of one drug will generally occur at the expense of other novel agents, or whether aggressive promotion of this class will result in an overall increase in the use of anticoagulants in patients with atrial fibrillation and market expansion for all therapies.
      We found similar use of warfarin and novel anticoagulants among patients with CHADS2 score of 0 or 1, with progressively higher use of warfarin among patients with CHADS2 of 2 and then predominant use of warfarin among patients with CHADS2 of 3 or greater. In a multivariate model, higher CHADS2 and HAS-BLED scores were associated with a significantly lower odds of initiating therapy with a novel agent, results corroborated by a recent registry-based analysis of the adoption of dabigatran.
      • 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.
      These patterns of adoption demonstrate some divergence from the clinical trials on whose basis the novel anticoagulants were approved. Notably, the mean CHADS2 scores for the Randomized Evaluation of Long-Term Anticoagulation therapy
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      (RE-LY), 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),
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular 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 were 2.1, 3.5, and 2.1, respectively, and eligibility criteria for the ROCKET-AF trial was based on a CHADS2 score of at least 2 (in fact, enrollment for patients with CHADS2 of 2 was limited to 10%).
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      The greatest absolute benefit from novel anticoagulants has been shown to be among patients at highest baseline risk for stroke or systemic embolization, which is at odds with our observation of selection of seemingly lower-risk patients for these drugs. Such a finding may reflect provider conservatism for new drug adoption, particularly given longitudinal experience with warfarin. Nonetheless, given this finding as well as the potential disparities in the use of novel anticoagulants based on geography, sex, and income, it will be important to conduct ongoing surveillance of the penetration of novel anticoagulants and whether this initial phase with dominant use among lower-risk patients is followed by use in more high-risk patients or whether a significant selection bias persists in the patients for whom they are prescribed.
      Our observation that users of the newer anticoagulants were generally healthier and had a lower stroke risk than warfarin users has important implications for surveillance data concerning their propensity to cause bleeding, as well as likely future observational comparative effectiveness studies. An early population-based assessment performed by the FDA documented substantially lower rates of intracerebral and gastrointestinal hemorrhage in atrial fibrillation patients taking dabigatran versus warfarin,
      • Southworth M.R.
      • Reichman M.E.
      • Unger E.F.
      Dabigatran and postmarketing reports of bleeding.
      but did not adjust for any differences in risk among the 2 patient groups, nor for age or sex.
      • Avorn J.
      The promise of pharmacoepidemiology in helping clinicians assess drug risk.
      The differences we have documented in the levels of comorbidity among users of these agents will need to be taken into account in any future observational studies of the drugs' outcomes.
      The observed patterns of anticoagulant initiation among patients with atrial fibrillation additionally have important economic implications for patients, payers, and the health care system. Average patient out-of-pocket and insurance spending was more than 5-fold and 15-fold higher, respectively, for novel anticoagulants as compared with warfarin. Novel anticoagulants have only recently attained >50% of market share, yet have accounted for more than 90% of insurer spending on anticoagulants since the introduction of dabigatran in 2010. A 6-month difference in total costs of $900 in our cohort translates into billions of dollars at a national level.
      Whereas registration trials for these agents have demonstrated clinical superiority and at least equal safety to warfarin,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      the cost effectiveness of these drugs in routine care has not been evaluated conclusively. Early analyses were limited by uncertainty or error concerning the pricing of both warfarin and its newer competitors.
      • Camm A.J.
      • Lip G.Y.
      • De Caterina R.
      • et al.
      2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      Canestaro et al
      • Canestaro W.J.
      • Patrick A.R.
      • Avorn J.
      • et al.
      Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation.
      found that apixaban appears to be cost-effective at a willingness-to-pay threshold of $100,000, but noted substantial uncertainty in this estimate in probabilistic sensitivity analyses. Limone et al’s
      • Limone B.L.
      • Baker W.L.
      • Kluger J.
      • Coleman C.I.
      Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models.
      meta-analysis of cost-effectiveness models for novel anticoagulants showed high model heterogeneity, including incremental cost-effectiveness ratios for dabigatran as compared with warfarin ranging from $3547 to $86,000. An analysis based on the RE-LY clinical trial concluded that, contrary to the patterns of anticoagulant use we observed, warfarin is the optimal strategy among patients with lower CHADS2 scores.
      • Shah S.V.
      • Gage B.F.
      Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation.
      There are several limitations to our analysis. First, our study relied on administrative claims data for study inclusion as well as clinical characteristics. Although misclassification of patients with nonvalvular atrial fibrillation could have occurred, we used well-standardized methods and approaches.
      • Norberg J.
      • Backstrom S.
      • Jansson J.H.
      • Johansson L.
      Estimating the prevalence of atrial fibrillation in a general population using validated electronic health data.
      • Winkelmayer W.C.
      • Liu J.
      • Patrick A.R.
      • Setoguchi S.
      • Choudhry N.K.
      Prevalence of atrial fibrillation and warfarin use in older patients receiving hemodialysis.
      While we lacked detailed clinical information, we did integrate medical claims data with prescription claims data to more fully examine patterns of novel anticoagulant utilization. Second, several demographic factors, including race, income level, and educational attainment were derived from census data, assessed at the zip-code level. Third, our analysis of anticoagulant use among privately insured patients might not be representative of treatment patterns among patients with Medicare, Medicaid, or uninsured patients. However, to the extent that claims data reflect the full spectrum of patient exposure and outcomes, we believe our results are generalizable to the US insured population. Finally, our economic analysis did not include international normalized ratio testing for patients taking warfarin. Eliminating the need for these tests would reduce the relative expenditure for the novel anticoagulants compared with warfarin, but only modestly.
      Current European Society of Cardiology and Canadian Cardiovascular Society guidelines
      • Camm A.J.
      • Lip G.Y.
      • De Caterina R.
      • et al.
      2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      recommend use of one of the 3 novel agents over warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation. In contrast, the American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines offer no such preference.
      • Wann L.S.
      • Curtis A.B.
      • Ellenbogen K.A.
      • et al.
      2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
      Our results demonstrate rapid adoption of novel anticoagulants, particularly among lower-risk patients with atrial fibrillation, and correspondingly high health care cost burden. These findings point to the need to conduct ongoing surveillance of the adoption of new agents into clinical practice, as well as the need for robust, real-world comparative-effectiveness analyses of these medications, to enable patients and providers to make informed decisions about their relative benefit, safety, and cost-effectiveness.

      Appendix A: Study Cohort Construction

      References

      1. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.
        Arch Intern Med. 1994; 154: 1449-1457
        • Gomes T.
        • Mamdani M.M.
        • Holbrook A.M.
        • Paterson J.M.
        • Juurlink D.N.
        Persistence with therapy among patients treated with warfarin for atrial fibrillation.
        Arch Intern Med. 2012; 172: 1687-1689
        • 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
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • 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
        • 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
        • 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
        • Gage B.F.
        • Waterman A.D.
        • Shannon W.
        • Boechler M.
        • Rich M.W.
        • Radford M.J.
        Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
        JAMA. 2001; 285: 2864-2870
        • 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
        • Pisters R.
        • Lane D.A.
        • Nieuwlaat R.
        • de Vos C.B.
        • Crijns H.J.
        • Lip G.Y.
        A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.
        Chest. 2010; 138: 1093-1100
      2. Pradaxa (dabigatran etexilate mesylate): Drug safety communication – safety review of post-market reports of serious bleeding events; 2011. Available at: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm282820.htm. Accessed December 23, 2013.

        • Artang R.
        • Rome E.
        • Nielsen J.D.
        • Vidaillet H.J.
        Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors.
        Am J Cardiol. 2013; 112: 1973-1979
        • Mak K.H.
        Coronary and mortality risk of novel oral antithrombotic agents: a meta-analysis of large randomised trials.
        BMJ Open. 2012; 2: e001592
      3. Daiichi Sankyo Company. Daiichi Sankyo submits SAVAYSA(TM) (edoxaban) tablets new drug application to the U.S. FDA for once-daily use for stroke risk reduction in atrial fibrillation and for the treatment and prevention of recurrence of venous thromboembolism [press release]. Available at: http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006065.html. Accessed January 13, 2014.

        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Palladino M.
        • Merli G.
        • Thomson L.
        Evaluation of the oral direct factor Xa inhibitor – betrixaban.
        Expert Opin Investig Drugs. 2013; 22: 1465-1472
        • Southworth M.R.
        • Reichman M.E.
        • Unger E.F.
        Dabigatran and postmarketing reports of bleeding.
        N Engl J Med. 2013; 368: 1272-1274
        • Avorn J.
        The promise of pharmacoepidemiology in helping clinicians assess drug risk.
        Circulation. 2013; 128: 745-748
        • Camm A.J.
        • Lip G.Y.
        • De Caterina R.
        • et al.
        2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
        Eur Heart J. 2012; 33: 2719-2747
        • Canestaro W.J.
        • Patrick A.R.
        • Avorn J.
        • et al.
        Cost-effectiveness of oral anticoagulants for treatment of atrial fibrillation.
        Circ Cardiovasc Qual Outcomes. 2013; 6: 724-731
        • Limone B.L.
        • Baker W.L.
        • Kluger J.
        • Coleman C.I.
        Novel anticoagulants for stroke prevention in atrial fibrillation: a systematic review of cost-effectiveness models.
        PLoS One. 2013; 8: e62183
        • Shah S.V.
        • Gage B.F.
        Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation.
        Circulation. 2011; 123: 2562-2570
        • Norberg J.
        • Backstrom S.
        • Jansson J.H.
        • Johansson L.
        Estimating the prevalence of atrial fibrillation in a general population using validated electronic health data.
        Clin Epidemiol. 2013; 5: 475-481
        • Winkelmayer W.C.
        • Liu J.
        • Patrick A.R.
        • Setoguchi S.
        • Choudhry N.K.
        Prevalence of atrial fibrillation and warfarin use in older patients receiving hemodialysis.
        J Nephrol. 2012; 25: 341-353
        • Wann L.S.
        • Curtis A.B.
        • Ellenbogen K.A.
        • et al.
        2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        Circulation. 2011; 123: 1144-1150

      Linked Article

      • The NOACs (Novel Oral Anticoagulants) Have Landed!
        The American Journal of MedicineVol. 127Issue 11
        • Preview
          Unless you are practicing medicine on Mars, you have already realized that there is a revolution going on in the United States and throughout the world in terms of anticoagulant therapy. For many decades, the only anticoagulant available was warfarin, with all of its attendant requirements and prohibitions. I am fond of telling my trainees that I never had a patient thank me for putting them on warfarin!
        • Full-Text
        • PDF