Effectiveness and Safety of Apixaban, Low-Molecular-Weight Heparin, and Warfarin among Venous Thromboembolism Patients with Active Cancer: A U.S. Claims Data Analysis.

BACKGROUND: This study primarily evaluates the risk of recurrent venous thromboembolism (VTE) and major bleeding (MB) among patients with VTE and active cancer prescribed apixaban, low-molecular-weight heparin (LMWH), or warfarin, with claims data. METHODS: Four U.S. commercial insurance claims databases were used to identify patients with VTE and active cancer who initiated apixaban, LMWH, or warfarin within 30 days following the first VTE event. Stabilized inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Cox proportional hazard models were used to evaluate risk of recurrent VTE and MB. RESULTS: All eligibility criteria were fulfilled by 3,393 apixaban, 6,108 LMWH, and 4,585 warfarin patients. After IPTW, all patient characteristics were balanced. When the follow-up was censored at 6 months, apixaban patients had a lower risk of recurrent VTE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.47-0.81) and MB (HR: 0.63; 95% CI: 0.47-0.86) versus LMWH. Apixaban patients had a lower risk of recurrent VTE (HR: 0.68; 95% CI: 0.52-0.90) and similar risk of MB (HR: 0.73; 95% CI: 0.53-1.00) versus warfarin. Warfarin patients had a similar risk of recurrent VTE (HR: 0.91; 95% CI: 0.72-1.15) and MB (HR: 0.87; 95% CI: 0.68-1.12) versus LMWH. The trends were similar for the entire follow-up; however, apixaban patients had a lower risk of MB versus warfarin patients. CONCLUSION: Patients with VTE and active cancer who initiated apixaban had a lower risk of recurrent VTE and MB compared with LMWH patients. Apixaban patients also had a lower risk of recurrent VTE compared with warfarin patients.

Estimated prevalence of undiagnosed atrial fibrillation in the United States.

INTRODUCTION: As atrial fibrillation (AF) is often asymptomatic, it may remain undiagnosed until or even after development of complications, such as stroke. Consequently the observed prevalence of AF may underestimate total disease burden. METHODS: To estimate the prevalence of undiagnosed AF in the United States, we performed a retrospective cohort modeling study in working age (18-64) and elderly (≥65) people using commercial and Medicare administrative claims databases. We identified patients in years 2004-2010 with incident AF following an ischemic stroke. Using a back-calculation methodology, we estimated the prevalence of undiagnosed AF as the ratio of the number of post-stroke AF patients and the CHADS2-specific stroke probability for each patient, adjusting for age and gender composition based on United States census data. RESULTS: The estimated prevalence of AF (diagnosed and undiagnosed) was 3,873,900 (95%CI: 3,675,200-4,702,600) elderly and 1,457,100 (95%CI: 1,218,500-1,695,800) working age adults, representing 10.0% and 0.92% of the respective populations. Of these, 698,900 were undiagnosed: 535,400 (95%CI: 331,900-804,400) elderly and 163,500 (95%CI: 17,700-400,000) working age adults, representing 1.3% and 0.09% of the respective populations. Among all undiagnosed cases, 77% had a CHADS2 score ≥1, and 56% had CHADS2 score ≥2. CONCLUSIONS: Using a back-calculation approach, we estimate that the total AF prevalence in 2009 was 5.3 million of which 0.7 million (13.1% of AF cases) were undiagnosed. Over half of the modeled population with undiagnosed AF was at moderate to high risk of stroke.

Payer and Pharmaceutical Manufacturer Considerations for Outcomes-Based Agreements in the United States.

BACKGROUND: Considerable interest exists among health care payers and pharmaceutical manufacturers in designing outcomes-based agreements (OBAs) for medications for which evidence on real-world effectiveness is limited at product launch. OBJECTIVES: To build hypothetical OBA models in which both payer and manufacturer can benefit. METHODS: Models were developed for a hypothetical hypercholesterolemia OBA, in which the OBA was assumed to increase market access for a newly marketed medication. Fixed inputs were drug and outcome event costs from the literature over a 1-year OBA period. Model estimates were developed using a range of inputs for medication effectiveness, medical cost offsets, and the treated population size. Positive or negative feedback to the manufacturer was incorporated on the basis of expectations of drug performance through changes in the reimbursement level. Model simulations demonstrated that parameters had the greatest impact on payer cost and manufacturer reimbursement. RESULTS: Models suggested that changes in the size of the population treated and drug effectiveness had the largest influence on reimbursement and costs. Despite sharing risk for potential product underperformance, manufacturer reimbursement increased relative to having no OBA, if the OBA improved market access for the new product. Although reduction in medical costs did not fully offset the cost of the medication, the payer could still save on net costs per patient relative to having no OBA by tying reimbursement to drug effectiveness. CONCLUSIONS: Pharmaceutical manufacturers and health care payers have demonstrated interest in OBAs, and under a certain set of assumptions both may benefit.

Real-World Data: Policy Issues Regarding their Access and Use.

As real-world data (RWD) in health care begin to cross over to the Big Data realms, a panel of health economists was gathered to establish how well the current US policy environment further the goals of RWD and, if not, what can be done to improve matters. This report summarizes these discussions spanning the current US landscape of RWD availability and usefulness, private versus public development of RWD assets, the current inherent bias in terms of access to RWD, and guiding principles in providing quality assessments of new RWD studies. Three main conclusions emerge: (1) a business case is often required to incentivize investments in RWD assets. However, access restrictions for public data assets have failed to generate a proper market for these data and hence may have led to an underinvestment of public RWDs; (2) Very weak empirical evidence exist on for-profit entities misusing public RWD data entities to further their own agendas, which is the basis for supporting access restrictions of public RWD data; and (3) perhaps developing standardized metrics that could flag misuse of RWDs in an efficient way could help quell some of the fear of sharing public RWD assets with for-profit entities. It is hoped that these discussions and conclusions would pave the way for more rigorous and timely debates on the greater availability and accessibility of RWD assets.

Primary Nonadherence, Associated Clinical Outcomes, and Health Care Resource Use Among Patients with Rheumatoid Arthritis Prescribed Treatment with Injectable Biologic Disease-Modifying Antirheumatic Drugs.

BACKGROUND: Adherence to biologic disease-modifying antirheumatic drugs (bDMARDs) among patients with rheumatoid arthritis (RA) is often suboptimal in routine clinical practice. Low or nonadherence can reduce the effectiveness of bDMARD therapies. OBJECTIVE: To evaluate filling of newly prescribed initial bDMARDs for the treatment of RA and evaluate potential for characterizing treatment decisions and patient outcomes. METHODS: In this retrospective cohort analysis, patients aged ≥ 18 years with an RA diagnosis (ICD-9-CM code 714.xx) were selected from a de-identified database of clinical information from the Electronic Health Record (EHR; Humedica) database linked to health care claims (Optum) from commercial and Medicare Advantage health plans (2007-2013). The first biologic prescription date in EHR was the index date. Patients were categorized as filling the prescription within 30 days (early fillers), 31-180 days (late fillers), or not at all within 180 days (nonfillers) of index date. RESULTS: Of 373 patients meeting inclusion criteria, 170 (45.6%), 59 (15.8%), and 144 (38.6%) were categorized as early fillers, late fillers, and nonfillers, respectively. Most prescriptions were written or ordered for tumor necrosis factor inhibitors (88.7%). Compared with late and nonfillers, early fillers were younger and more likely to be female, with higher pain scores (among those reporting pain scores) and RA severity scores pre-index, and filled more prescriptions for any reason pre-index. More nonfillers (66.0%) were Medicare patients than early (17.7%) and late (35.6%) fillers. During days 0-30 post-index, conventional synthetic DMARD use was greatest for early fillers (45.9%) and lowest among nonfillers (24.3%); however, during days 31-180 post-index, the proportion was highest for late fillers (61.0%) and lowest for nonfillers (35.4%). Of early fillers, 12.9% did not fill/receive a bDMARD after 30 days. Only 23 patients had pre/post-index pain scores, and 47 patients had a rationale for stopping or not filling a bDMARD. In patients with pharmacy and medical coverage for 180 days post-index, early fillers had greater RA-related pharmacy and medical resource use and costs than late and nonfillers combined. CONCLUSIONS: These findings confirm a high rate of primary nonadherence to bDMARDs among patients with RA.

Relationship of hospital-associated bleeding with length of stay and total hospitalization costs in patients hospitalized for atrial fibrillation.

BACKGROUND: While literature has focused on the impact of bleeding beginning outside the hospital setting among patients with atrial fibrillation (AF), there is little information regarding bleeding that first occurs within a hospital setting. This study was performed to determine the association between hospital-associated bleeding in patients admitted for AF on outcomes of length of stay (LOS) and total hospitalization cost. METHODS AND RESULTS: The Premier research database was queried to identify adult inpatients discharged between 2008-2011 having a primary diagnosis code for AF where a bleeding diagnosis code was not present on admission. Regression was used to adjust for baseline differences in patients to estimate outcomes comparing patients with and without a hospital-associated bleed. There were 143,287 patients that met the study criteria. There were 2991 (2.1%) patients identified with a hospital associated bleed. After adjustment for covariates, the mean estimated LOS was significantly greater in the bleed group, at 6.0 days (95% CI = 5.8-6.1) vs the no bleed group at 3.3 days (95% CI = 3.3-3.3) (p < 0.0001). Similarly, the adjusted mean estimated total hospitalization cost was also significantly greater in the bleed group, $12,069 (95% CI = $11,779-$12,366) vs $6561 (95% CI = $6538-$6583) in the no bleed group (p < 0.0001). CONCLUSIONS: After adjustments for baseline differences the data show that the 2.1% (n = 2991) of patients with hospital associated bleeding accounted for an estimated additional 8106 hospitalization days and $16.4 million dollars in cost over the study period compared to non-bleeders.

Economic Burden of Undiagnosed Nonvalvular Atrial Fibrillation in the United States.

Atrial fibrillation (AF) may be clinically silent and therefore undiagnosed. To date, no estimates of the direct medical cost of undiagnosed AF exist. We estimated the United States (US) incremental cost burden of undiagnosed nonvalvular AF nationally using administrative claims data. To calculate the incremental costs of undiagnosed AF, we compared annual medical costs (in 2014 US Dollars) for patients with AF compared to propensity-matched controls and multiplied this by estimates of undiagnosed AF prevalence derived from the same data sources. The study population included US residents aged ≥18 years with 24 months of continuous enrollment drawn from 2 large administrative claims databases. Mean per capita medical spending for patients with AF aged from 18 to 64 year was $38,861 (95% confidence interval [CI] $35,781 to $41,950) compared to $28,506 (95% CI $28,409 to $28,603) for similar patients without AF (incremental cost difference $10,355, p <0.001); total spending for patients aged ≥65 years with AF was $25,322 (95% CI $25,049 to $25,595) compared to $21,706 (95% CI $21,563 to $21,849) for similar patients without AF (incremental cost difference $3,616, p <0.001). Using estimates of the US prevalence of undiagnosed AF (596,000) drawn from the same data, we estimated that the US incremental cost burden of undiagnosed nonvalvular AF is $3.1 billion (95% CI $2.7 to $3.7 billion). In conclusion, the direct medical costs for patients with undiagnosed AF are greater than patients with similar observable characteristics without AF and strategies to identify and treat patients with undiagnosed AF could lead to sizable reductions in stroke sequelae and associated costs.

Comparison of Medical Costs of Patients With Atrial Fibrillation Unsuitable for Warfarin Treatment With Apixaban or Aspirin Based on AVERROES Trial.

BACKGROUND: The AVERROES trial name is the following: The Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial demonstrated that apixaban reduced the risk of stroke relative to aspirin, without significantly increasing major bleeding risk in patients with atrial fibrillation (AF) considered unsuitable for warfarin therapy. Based on AVERROES trial results, this study compared the medical costs for clinical end points among patients with AF treated with either apixaban or aspirin. METHODS: Medical costs per patient-year for clinical events were determined. Based on clinical event rates for patients in the AVERROES trial, medical costs excluding drug costs were estimated for apixaban- and aspirin-treated patient groups. RESULTS AND CONCLUSIONS: Based on AVERROES trial results, among patients with AF unsuitable for warfarin therapy, apixaban use was estimated to be associated with a mean medical cost avoidance of US$735 in a patient-year relative to aspirin. The primary driver was the significant reduction in ischemic stroke rate. The medical cost reduction associated with apixaban use was consistent in sensitivity analyses.

Estimated medical cost reductions associated with use of novel oral anticoagulants vs warfarin in a real-world non-valvular atrial fibrillation patient population.

OBJECTIVE: RESULTS of randomized clinical trials (RCT) demonstrate that novel oral anticoagulants (NOAC) are effective therapies for reducing the risk of stroke in non-valvular atrial fibrillation (NVAF). Prior medical cost avoidance studies have used warfarin event rates from RCTs, which may differ from patients receiving treatment in a real-world (RW) setting, where the quality of care may not be the same as in a RCT. The purpose of this study was to estimate the change in medical costs related to stroke and major bleeding for each NOAC (apixaban, dabigatran, and rivoraxaban) relative to warfarin in a RW NVAF population. METHODS: Patients (n = 23,525) with a diagnosis of NVAF during 2007-2010 were selected from a Medco population of US health plans. Stroke and major bleeding excluding intracranial hemorrhage (MBEIH) events were identified using diagnosis codes on medical claims. RW reference event rates were calculated during periods of warfarin exposure. RW event rates for NOACs were estimated by multiplying the corresponding relative risk (RR) from the RCTs by each reference rate. Absolute risk reductions (ARR) or number of events avoided per patient year were then estimated. Changes in medical costs associated with each NOAC were calculated by applying the ARR to the 1-year cost for each event. Costs for stroke and MBEIH were obtained from the literature. Drug and international normalized ratio monitoring costs were not considered in this analysis. RESULTS: Compared to RW warfarin, use of apixaban and dabigatran resulted in total (stroke plus MBEIH) medical cost reductions of $1245 and $555, respectively, during a patient year. Rivaroxaban resulted in a medical cost increase of $144. CONCLUSIONS: If relative risk reductions demonstrated in RCTs persist in a RW setting, apixaban would confer the greatest medical cost savings vs warfarin, resulting from significantly lower rates of both stroke and MBEIH.

Health care burden of dyspepsia among nonvalvular atrial fibrillation patients.

BACKGROUND: Although dyspepsia is common among nonvalvular atrial fibrillation (NVAF) patients, its impact on patient health and cost has not been adequately studied. OBJECTIVE: To evaluate the incremental health care burden associated with dyspepsia among NVAF patients and its impact on warfarin treatment. METHODS: NVAF patients ≥ 18 years of age with continuous insurance coverage were identified (January 1, 2007, to December 31, 2009) from the MarketScan Commercial and Medicare Research databases. Patients with 1 inpatient or 2 outpatient dyspepsia diagnoses within 12 months following any NVAF diagnosis were grouped into the dyspeptic cohort, and patients without any dyspepsia diagnosis were grouped into the nondyspeptic cohort. Of the overall cohorts, patients were matched by key patient characteristics. Dyspepsia was further categorized as having a prior history of dyspepsia (chronic) or no dyspepsia (nonchronic) during the baseline period. Health care resource utilization, associated costs, and warfarin use were evaluated during a 12-month follow-up period. RESULTS: Of NVAF patients included in the study (N = 142,322), 10.4% were diagnosed with dyspepsia. After matching for key characteristics, NVAF patients with dyspepsia had significantly greater inpatient, outpatient, and prescription claims per patient year than those without dyspepsia (1.24 ± 1.21 vs. 0.36 ± 0.68, P < 0.0001; 110.18 ± 101.03 vs. 66.98 ± 72.43, P < 0.0001; and 52.13 ± 35.30 vs. 44.29 ± 32.41, P < 0.0001, respectively). This greater number of claims was reflected in higher annual inpatient, outpatient, and prescription payments ($23,610 ± $54,748 vs. $5,509 ± $19,142, P < 0.0001; $18,182 ± $28,790 vs. $9,765 ± $22,009, P < 0.0001; and $4,661 ± $5,628 vs. $3,897 ± $4,586, P < 0.0001, respectively). NVAF patients with chronic dyspepsia were the least likely to take warfarin for stroke prevention. CONCLUSIONS: NVAF patients with dyspepsia experienced more all-cause hospitalizations and required more outpatient medical services, all associated with greater expenditures than NVAF patients without dyspepsia. Additionally, dyspepsia may be a barrier to warfarin use among NVAF patients.

Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials.

Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET-AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant (-0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin.

Bleeding as an outcome among patients with nonvalvular atrial fibrillation in a large managed care population.

BACKGROUND: Patients with nonvalvular atrial fibrillation (NVAF) are at increased risk for stroke and bleeding events, but bleeding as an outcome has not been extensively studied in this patient population. OBJECTIVES: The goal of this study was to estimate the incidence of bleeding events among patients with NVAF enrolled in managed care, investigate the relationships between bleeding incidence and bleeding and stroke risks, and estimate health care costs for patients who had a major bleeding event. METHODS: Adults with commercial insurance or Medicare Advantage coverage and health care claims related to AF between January 2005 and June 2009 but with no evidence of valvular disease were included in this retrospective claims data analysis. Baseline stroke risk (CHADS2 [Congestive Heart Failure, Hypertension, Age >75 Years, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack]) and bleeding risk (HAS-BLED [Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratios, Elderly, Drugs/Alcohol]) were estimated. Bleeding events were identified during the variable follow-up period, which lasted from the date of the first qualifying AF visit until the earlier of death, disenrollment from the health plan, or June 30, 2010. Bleeding events were classified as major, serious nonmajor, or minor. Health care costs for patients with major bleeding events were calculated. RESULTS: Among 48,260 patients with NVAF (mean age, 67 years), 34% had an incident bleeding event during a mean (SD) follow-up period of 802 (540) days. Incidence rates for bleeding events of any severity and major events were 29.6 and 10.4 per 100 patient-years, respectively. Bleeding incidence rates increased with greater CHADS2 and HAS-BLED risk scores. All-cause health care costs for patients during a major bleeding event averaged $16,830. Average costs per patient with a major event increased from approximately $52 per day in the prebleeding period to approximately $63 per day in the postbleeding period. Costs for patients who did not experience a major bleeding event averaged approximately $38 per day. CONCLUSIONS: Bleeding incidence among patients with NVAF in a real-world setting was high and increased with greater stroke and bleeding risk scores. Health care costs for patients with major bleeding events were elevated. All rights reserved.

Medical costs in the US of clinical events associated with oral anticoagulant (OAC) use compared to warfarin among non-valvular atrial fibrillation patients ≥75 and <75 years of age, based on the ARISTOTLE, RE-LY, and ROCKET-AF trials.

OBJECTIVES: Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared. RESULTS: Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = -$825, rivaroxaban =-$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced -$254, -$367, and -$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin. LIMITATIONS: This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment. CONCLUSIONS: Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.

Estimated medical cost reductions associated with apixaban in real-world patients with non-valvular atrial fibrillation.

OBJECTIVE: The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial demonstrated that apixaban was effective in reducing the risk of stroke and major bleeding in non-valvular atrial fibrillation (NVAF) patients. Medical cost avoidance studies for oral anticoagulants have used warfarin event rates from clinical trials, which may not reflect the real-world (RW) setting. This study aimed to estimate the difference in medical costs associated with apixaban instead of warfarin in RW NVAF patients. METHODS: This study selected patients with NVAF diagnosis during 2007-2010 from a Medco population of US commercial and Medicare health plans. Stroke and major bleeding excluding intracranial hemorrhage (MBEIH) were identified using diagnosis codes. Pharmacy claims were used to define warfarin exposure periods. Rates of stroke and MBEIH were calculated during warfarin exposure. To estimate the absolute risk reduction (ARR) between warfarin and apixaban in RW, the relative risk reductions (RRR) from ARISTOTLE were multiplied by the event rates observed in RW during warfarin exposure. Medical cost reductions associated with apixaban were calculated by applying the ARR to the 1-year incremental cost for each event. Stroke and MBEIH costs were obtained from the literature and adjusted to 2011 levels. RESULTS: During a patient year, the use of apixaban instead of warfarin resulted in medical cost reductions of $493 for stroke and $752 for MBEIH and $1245 for the combined outcome of both events. The medical costs avoided were greater as baseline stroke risk increased. CONCLUSION: If RRRs demonstrated in ARISTOTLE persist in RW, the use of apixaban will be associated with lower medical costs vs warfarin. Main limitations of this study were: identification of clinical events using administrative codes rather than confirmatory clinical data, inability to evaluate the level of international normalized ratio (INR) control, and not including INR monitoring and drug costs.

Warfarin use and stroke risk among patients with nonvalvular atrial fibrillation in a large managed care population.

BACKGROUND: Stroke prevention is a goal of atrial fibrillation (AF) management, but discontinuation of warfarin anticoagulation therapy is common. OBJECTIVE: To investigate the association between warfarin discontinuation and hospitalization for stroke among nonvalvular AF (NVAF) patients enrolled in managed care. METHODS: Patients with NVAF who initiated warfarin therapy from January 2005 through June 2009 were included. Warfarin discontinuation was defined as a supply gap >60 days without evidence of International Normalized Ratio measurements. Follow-up, which was a variable time period from warfarin initiation until the earlier of death, disenrollment from the health plan, or June 30, 2010, was divided into periods of warfarin treatment and discontinuation. Stroke events were identified based on claims for inpatient stays with a primary diagnosis of stroke or transient ischemic attack. Cox proportional hazards models were constructed to assess the relationship between warfarin discontinuation and incident stroke while adjusting for baseline demographics, stroke and bleeding risk, and comorbidities, as well as time-dependent antiplatelet use, stroke, and bleeding events in the previous warfarin treatment period. RESULTS: Among warfarin initiators with NVAF (N = 16,253), 51.4% discontinued warfarin therapy at least once during a mean follow-up of 668 days. Stroke risk was significantly greater during warfarin discontinuation periods compared with therapy periods (hazard ratio = 1.60; 95% CI, 1.35-1.90; P < 0.001). CONCLUSIONS: More than half of patients on warfarin had treatment gaps or discontinued therapy. Therapy gaps were associated with increased stroke risk.

Application of randomized clinical trial data to actual practice: apixaban therapy for reduction of stroke risk in non-valvular atrial fibrillation patients.

BACKGROUND: Clinical event rates may differ among patients treated in the real world (RW) compared to randomized controlled trials (RCTs). When translating the efficacy of new treatments to RW, the relative risk reductions (RRRs) from RCTs may produce different absolute risk reductions in RW. OBJECTIVE: To estimate the absolute effect of apixaban on stroke and major bleeding (MB) rates in a RW non-valvular atrial fibrillation (NVAF) population. METHODS: NVAF patients were selected during 2007-2010 from a population of U.S. commercial and Medicare health plans using the Medco claims database. Pharmacy claims were used to define warfarin exposure periods. Stroke and MB were identified using diagnosis codes. RW event rates were calculated during periods of warfarin exposure. The numbers of stroke and MB events estimated to be avoided in RW with apixaban versus warfarin were calculated by applying RRRs from the ARISTOTLE trial to RW rates from the Medco database. The Medco data did not contain information for patients receiving apixaban as it was not on the market at the time of analysis. RESULTS: Stroke and MB rates among RW NVAF patients during warfarin exposure were higher compared with event rates in patients treated with warfarin in ARISTOTLE (stroke: 5.29 vs. 1.51 per 100 person years (PYs); MB: 10.78 vs. 3.09 per 100 PYs). If RRRs from trials persist in RW, apixaban vs. warfarin would result in greater absolute risk reductions (ARRs) and a lower number needed to treat (NNT) in RW vs. ARISTOTLE (stroke: 91 vs. 313; MB: 30 vs. 105). CONCLUSION: The impact of apixaban, as an alternative to warfarin in RW may be greater than in RCTs. The NNT with apixaban versus warfarin in RW may be lower versus ARISTOTLE if RRRs from the trial persists in RW and if baseline stroke and MB rates among RW patients are higher compared to trial participants.

Rate of deep-vein thrombosis and pulmonary embolism during the care continuum in patients with acute ischemic stroke in the United States.

BACKGROUND: Deep-vein thrombosis (DVT) and pulmonary embolism (PE) are frequent and life-threatening complications of ischemic stroke. We evaluated rates of symptomatic DVT/PE, and of in-hospital and post-discharge thromboprophylaxis in patients with acute ischemic stroke (AIS). METHODS: In a retrospective US database analysis, data were extracted from the Premier Perspective™-i3 Pharma Informatics linked database for patients aged ≥18 years who were hospitalized for ischemic stroke from January 2005 to November 2007, and who had ≥6 months' continuous plan enrollment prior to index hospitalization. Patients discharged to an acute-care facility or with atrial fibrillation were excluded. Prophylaxis was evaluated during index hospitalization and for 14 days' post-discharge. DVT/PE rates were calculated during index hospitalization and up to 30 days post-discharge. RESULTS: A total of 1524 patients were included; 46.1% received pharmacological and/or mechanical prophylaxis in-hospital (28.3%, 11.4% and 12.3% received unfractionated heparin, enoxaparin and mechanical prophylaxis, respectively). 6.4% of patients received outpatient pharmacological prophylaxis; warfarin was most frequently prescribed (5.9%). Total mean ± standard deviation length of index hospitalization was 3.0 ± 2.5 days. Mean prophylaxis duration in all patients was 0.9 ± 1.5 days in-hospital and 1.7 ± 6.9 days post-discharge. Symptomatic DVT/PE occurred in 25 patients overall (1.64%), with an inpatient rate of 0.98% and an outpatient rate of 0.66%. CONCLUSIONS: Approximately 1% of patients with AIS experienced symptomatic in-hospital and/or post-discharge DVT/PE. Although 46% received prophylaxis in-hospital, only 6% received prophylaxis in the outpatient setting. This highlights the need for sustained thromboprophylaxis prescribing across the continuum of care.

Medical Costs of Oral Anticoagulants vs Warfarin for Atrial Fibrillation Patients with Different Stroke Risks.

INTRODUCTION: The Apixaban for the Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), and 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) trials demonstrated that the oral anticoagulants (OACs), apixaban, dabigatran, and rivaroxaban, respectively, are efficacious for stroke prevention among nonvalvular atrial fibrillation (NVAF) patients. Based on clinical trial results this study evaluated medical costs of clinical events associated with use of individual OACs relative to those of warfarin in NVAF patients with moderate and high stroke risk. METHODS: Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients with CHADS2 = 2 and ≥3 were determined from the three OAC trials. One-year incremental costs among patients with clinical events from a US payer perspective were obtained from the literature and inflation adjusted to 2010 costs. Medical costs for clinical events associated with each OAC vs. warfarin were estimated and compared. RESULTS: For NVAF patients with moderate stroke risk (CHADS2 = 2) differences in clinical event medical costs vs. warfarin were -$298, -$143, and +$117 per patient year for apixaban, dabigatran (150 mg), and rivaroxaban, respectively (negative numbers indicate cost reduction). For NVAF patients with high stroke risk (CHADS2 ≥ 3) differences in clinical event medical costs vs. warfarin were -$697, +$2, and -$100 for apixaban, dabigatran (150 mg), and rivaroxaban, respectively. CONCLUSIONS: Medical cost differences associated with OACs vs. warfarin vary according to stroke risk. Of the three OACs, apixaban demonstrated consistent medical cost reductions vs. warfarin for NVAF patients with moderate and high stroke risks.

Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records.

OBJECTIVE: Automated electronic queries of structured data fields in electronic medical records (EMR) found no barriers to warfarin in 42% of patients with atrial fibrillation or atrial flutter (AF) with moderate or high risk of stroke and no warfarin. A thorough manual review of records (including text reports) from the same EMR may better identify physicians' reasons for not using warfarin. METHODS: This was a cross-sectional, retrospective, manual EMR review. Patients identified in a previous automated EMR study with a CHADS2 (Chronic heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke) score≥2, no record of warfarin, no barrier to warfarin use, and (in the present study) confirmation of AF diagnosis were included in the manual EMR review. A structured chart abstraction form was used to extract data visible in the clinicians' EMR user interface. Reasons why warfarin had not been prescribed were reported using descriptive statistics. RESULTS: Among 408 patients with 'no barriers' to warfarin in the automated EMR review, AF diagnosis was confirmed in 319 patients (mean age 74.8; 65% female). Forty-one percent (n=132) did not have chart records explaining why they were not on warfarin. Among the 59% (187) with a rationale against warfarin found in the records, the most common category (52%) was indicative of the risk of bleeding, either risk of fall or history of recent bleeding. The second most common category (16%) reflected that the patient was back in sinus rhythm. These findings are subject to inherent limitations of retrospective chart reviews. CONCLUSIONS: Many patients with AF and moderate-to-high risk of stroke are not treated with warfarin, and reasons for not using warfarin could not always be identified in patient records. Among patients with documented reasons, risk of bleeding (risk of fall or recent bleeding) was the most common category.