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.

Cost-Effectiveness of Extended and One-Time Screening Versus No Screening for Non-Valvular Atrial Fibrillation in the USA.

BACKGROUND: There is limited evidence on the clinical and cost benefits of screening for atrial fibrillation (AF) with electrocardiogram (ECG) in asymptomatic adults. METHODS: We adapted a previously published Markov model to evaluate the clinical and economic impact of one-time screening for non-valvular AF (NVAF) with a single 12-lead ECG and a 14-day extended screening with a hand-held ECG device (Zenicor single-lead ECG, Z14) compared with no screening. Clinical events considered included ischemic stroke, systemic embolism, major bleeds, myocardial infarction, and death. Epidemiology and effectiveness data for extended screening were from the STROKESTOP study. Risks of clinical events in NVAF patients were derived from ARISTOTLE. Analyses were conducted from the perspective of a third-party payer, considering a population with undiagnosed NVAF, aged 75 years in the USA. Costs and utilities were discounted at a 3% annual rate. Parameter uncertainty was formally considered via deterministic and probabilistic sensitivity analyses (DSA and PSA). Structural uncertainty was assessed via scenario analyses. RESULTS: In a hypothetical cohort of 10,000 patients followed over their lifetimes, the number of additional AF diagnoses was 54 with 12-lead ECG and 255 with Z14 compared with no screening. Both screening strategies led to better health outcomes (ischemic strokes avoided: ECG 12-lead, 9.8 and Z14, 42.2; quality-adjusted life-years gained: ECG 12-lead, 31 and Z14, 131). Extended screening and one-time screening were cost effective compared with no screening at a willingness-to-pay (WTP) threshold of $100,000 per QALY gained ($58,728/QALY with ECG 12-lead and $47,949/QALY with Z14 in 2016 US dollars). ICERs remained below $100,000 per QALY in all DSA, most PSA runs, and in all scenario analyses except for a scenario assuming low anticoagulation persistence. CONCLUSIONS: Our analysis suggests that, screening the general population at age 75 years for NVAF is cost effective at a WTP threshold of $100,000. Both extended screening and one-time screening for NVAF are expected to provide health benefits at an acceptable cost.

Bleeding and recurrent VTE with apixaban vs warfarin as outpatient treatment: time-course and subgroup analyses.

In the phase 3 trial Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy, apixaban was noninferior to enoxaparin, overlapped and followed by warfarin, in the treatment of venous thromboembolism (VTE) with significantly less bleeding; in a real-world evaluation, risks for bleeding and recurrent VTE were lower with apixaban vs warfarin plus parenteral anticoagulant (PAC) bridge therapy. The present study extends this research by comparing outcomes over time and within selected subgroups. A retrospective observational cohort design and 4 US private health care claims databases were used. Study population included patients who initiated outpatient treatment with apixaban or warfarin (plus PAC bridge therapy) for VTE. Major bleeding, clinically relevant nonmajor (CRNM) bleeding, and recurrent VTE were compared during the 180-day follow-up period, at selected follow-up time points (days 21, 90, 180), and within subgroups (pulmonary embolism [PE] with or without deep vein thrombosis [DVT], DVT only, provoked VTE, unprovoked VTE) using multivariable shared frailty models. Study population consisted of 20 561 apixaban patients and 35 080 warfarin patients; baseline characteristics were comparable. Overall, at selected follow-up time points, and within the aforementioned subgroups, adjusted risks were lower among apixaban vs warfarin patients: major bleeding, by 27% to 39%, CRNM bleeding, by 17% to 28%, and recurrent VTE, by 25% to 39% (all P ≤ .01). In this real-world study of VTE patients, risks of bleeding and recurrent VTE were lower among apixaban (vs warfarin) patients during the 180-day follow-up period, at selected follow-up time points, and within subgroups defined by index VTE episode.

Systematic review of societal costs associated with stroke, bleeding and monitoring in atrial fibrillation.

Aim: Economic consequences associated with the rise in nonvitamin K antagonist oral anticoagulant use on a societal level remain unclear. Materials & methods: Evidence from the past decade on the societal economic burden associated with stroke, bleeding and international normalized ratio monitoring in atrial fibrillation was collected and summarized through a systematic literature review. Results: There were 14 studies identified that reported indirect costs, which were highest among patients with hemorrhagic stroke and intracranial hemorrhage. The contribution of indirect costs to the total was marginal during acute treatment but substantially increased (30-50%) 2 years after stroke and bleeding events. Conclusion: Limited data were available on societal costs in atrial fibrillation and further research is warranted.

Quality of anticoagulation monitoring in nonvalvular atrial fibrillation patients: comparison of anticoagulation clinic versus usual care.

BACKGROUND: Prior research suggests that receiving specialized anticoagulation services enables patients to achieve better clinical outcomes. OBJECTIVE: To assess the quality of anticoagulation therapy in patients with atrial fibrillation who were enrolled in an anticoagulation clinic (ACC) versus usual care (UC). METHODS: Using Sharp Rees-Stealy physician group claims data, we estimated time spent in therapeutic range and time to first major bleeding episode or stroke for ACC and UC patients. t-Tests were used to compare time in therapeutic range proportions, and Kaplan-Meier survival analysis was performed to compare rates of bleeding and stroke between groups. RESULTS: We identified 1107 patients (351 ACC, 756 UC) treated with anticoagulation therapy for atrial fibrillation with more than one international normalized ratio (INR) reported between March 2001 and March 2004. ACC patients spent a greater proportion (68.14%) of time in therapeutic range compared with UC patients (42.07%; p < 0.001). There was a significant difference between groups in average time between INR tests (ACC = 14.31 days, UC = 18.39 days; p < 0.001). ACC patients were 59% less likely to experience a bleed following the index date than were UC patients (HR = 0.41; 95% CI 0.2444 to 0.6999; p = 0.001), but type of care was not a significant predictor for stroke (HR = 0.95; 95% CI 0.5125 to 1.7777; p value NS). CONCLUSIONS: Results from this observational study reinforce the positive impact that anticoagulation services have on anticoagulation therapy outcomes, emphasizing the importance of providing such services for patients undergoing treatment with warfarin.

Daclatasvir combined with asunaprevir is a cost-effective and cost-saving treatment for hepatitis C infection in China.

Aim: To evaluate the cost-effectiveness of the novel all-oral direct-acting antiviral regimen daclatasvir + asunaprevir (DUAL), versus interferon-based regimens for the treatment of chronic hepatitis C virus genotype 1b infection. Methods: Inputs for a lifetime Markov model were sourced from clinical trials and published literature. Outputs include disease management costs, life expectancy, quality-adjusted life-years and cost-effectiveness. Sensitivity analyses assessed the drivers of cost-effectiveness and sustained virologic response thresholds at which DUAL is cost-saving. Results: DUAL was associated with discounted incremental quality-adjusted life-years of 1.29-3.85 and incremental life-years of 0.85-2.59 per patient, with discounted lifetime cost savings of USD$1415-8525. Associated sustained virologic response rates could fall to 45.1-84.8%, while remaining dominant. Conclusion: Treatment with DUAL provides significant clinical benefit, while accruing lower lifetime costs.

Effectiveness and Safety of Apixaban versus Warfarin as Outpatient Treatment of Venous Thromboembolism in U.S. Clinical Practice.

In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients (n = 17,878) and 152 days among warfarin patients (n = 17,878), incidence proportions for apixaban versus warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for CRNM bleeding and 2.3% versus 2.9% for recurrent VTE. In shared frailty models, risks of major bleeding (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64-0.87), CRNM bleeding (HR = 0.77, 95% CI = 0.71-0.83) and recurrent VTE (HR = 0.80, 95% CI = 0.70-0.91) were lower for apixaban versus warfarin. In this large-scale evaluation of VTE patients receiving outpatient treatment with apixaban or warfarin in U.S. clinical practice, risks of major bleeding, CRNM bleeding and recurrent VTE were significantly lower among patients who received apixaban.

Hospital Resource Utilization and Costs Associated With Warfarin Versus Apixaban Treatment Among Patients Hospitalized for Venous Thromboembolism in the United States.

A real-world US database analysis was conducted to evaluate the hospital resource utilization and costs of patients hospitalized for venous thromboembolism (VTE) treated with warfarin versus apixaban. Additionally, 1-month readmissions were evaluated. Of 28 612 patients with VTE identified from the Premier Hospital database (August 2014-May 2016), 91% (N = 26 088) received warfarin and 9% (N = 2524) received apixaban. Outcomes were assessed after controlling for key patient/hospital characteristics. For index hospitalizations, the average length of stay (LOS) was longer (3.8 vs 3.1 days, P < .001; difference: 0.7 days) and mean hospitalization cost higher (US$3224 vs US$2,740, P < .001; difference: US$484) for warfarin versus apixaban-treated patients. During the 1-month follow-up period, warfarin treatment was associated with a greater risk of all-cause readmission (odds ratio [OR]: 1.27; 95% confidence interval [CI]: 1.09-1.48, P = .003), major bleeding (MB)-related readmission (OR: 2.10; 95% CI: 1.03-4.27, P = .04), and any bleeding-related readmission (OR: 1.67; 95% CI: 1.09-2.56, P = .02) versus apixaban. The results of this real-world analysis show that compared to warfarin, apixaban treatment was associated with shorter index hospital stays, lower index hospitalization costs, and reduced risk of MB-related readmissions among hospitalized patients with VTE.

Quality of clinical documentation and anticoagulation control in patients with chronic nonvalvular atrial fibrillation in routine medical care.

OBJECTIVE: Anticoagulation quality and record documentation were retrospectively assessed in patients with chronic nonvalvular atrial fibrillation (CNVAF) managed in a routine care setting. METHODS: Medical record data extraction from physician practices in 4 regions of the United States. RESULTS: Of 686 patients, 59% had an electrocardiogram confirming CNVAF, 84% listed at least 1 stroke risk factor, and 60% indicated the goal target international normalized ratio (INR). Two thirds of INRs>3.0 or <2.0 had no recorded dose change, nor did 45% of INRs>5.0. Vitamin K was given (3%) or anticoagulation was temporarily discontinued (9%) for INRs>5.0. The median interval of INR testing was 21 days, which decreased to 7 days for INRs> 4.60. Patients spent 58% of the time in therapeutic range. CONCLUSION: Serious deficiencies in quality and documentation of routine medical care of anticoagulation for patients with CNVAF continue to exist.

Assessing the Budget Impact and Economic Outcomes of the Introduction of Daclatasvir + Asunaprevir and Sofosbuvir/Ledipasvir for the Treatment of Chronic Hepatitis C Virus Infection in Japan.

BACKGROUND: The advent of highly efficacious, well-tolerated, all-oral direct-acting antiviral regimens has revolutionized the standard of care for patients chronically infected with hepatitis C virus. As efficacy and safety rates converge, prescribers and payers need to consider value for money. OBJECTIVES: To evaluate the health economic value of daclatasvir + asunaprevir versus sofosbuvir/ledipasvir via a cost-effectiveness analysis, and determine the optimal treatment considering both costs and health outcomes in Japan. METHODS: A previously published Markov model was used to estimate the cost-effectiveness of daclatasvir + asunaprevir compared with sofosbuvir/ledipasvir on the basis of a matching-adjusted indirect comparison of pivotal trials and modeling inputs specific to the Japanese setting. A de novo budget impact model was developed and used to predict the cost implications of differing treatment sequences. RESULTS: Cost-effectiveness results demonstrated minimal difference in terms of benefit (0.037 fewer QALYs and 0.014 fewer life-years with daclatasvir + asunaprevir); nevertheless, a significant difference in cost was predicted (estimated ¥2,299,700 [US $21,695] reduction with daclatasvir + asunaprevir). The budget impact analysis estimated that treatment with daclatasvir + asunaprevir is expected to be less expensive than treatment with sofosbuvir/ledipasvir (as the proportion of patients initially treated with sofosbuvir/ledipasvir increased from 0% to 100%, total costs increased from ¥206 to ¥403 billion [US $1.94 billion to US $3.80 billion]). CONCLUSIONS: On the basis of results from an established cost-effectiveness model and a conventional budget impact analysis, treatment with daclatasvir + asunaprevir is expected to be cost-saving compared with treatment with sofosbuvir/ledipasvir in Japan with similar health outcomes, regardless of treatment sequence.

Daclatasvir + asunaprevir versus sofosbuvir/ledipasvir for hepatitis C genotype 1 in Japanese patients: an indirect comparison.

AIM: To compare daclatasvir + asunaprevir (DCV + ASV) versus sofosbuvir/ledipasvir (SOF/LDV) for hepatitis C virus genotype 1b in Japanese patients without NS5A polymorphisms at L31 and Y93H. PATIENTS & METHODS: All Phase III trials of SOF/LDV and DCV + ASV conducted in Japan were included. To adjust for cross-trial differences, DCV + ASV patients were weighted to match reported SOF/LDV summary baseline characteristics. RESULTS: After adjustment, the rate of SVR12 (99.3 vs 100%; p = 0.398) and discontinuation due to adverse events (1.3 vs 0.0%; p = 0.327) were similar between patients treated with DCV + ASV (n = 252) and SOF/LDV (n = 171). CONCLUSION: After adjusting for cross-trial differences in baseline characteristics, DCV + ASV and SOF/LDV were associated with similar efficacy and discontinuation due to adverse events in the treatment of hepatitis C virus genotype 1b in Japanese patients without NS5A polymorphisms.

Longitudinal evaluation of health plan cost per venous thromboembolism or bleed event in patients with a prior venous thromboembolism event during hospitalization.

OBJECTIVE: To measure the per-event health plan costs for acute and follow-up treatment not directed by a clinical study protocol in a group of commercially insured patients in 2 managed care organizations following an incident hospitalization that included a diagnosis for a venous thromboembolism (VTE) event. METHODS: A cohort of patients with an incident in-hospital VTE event, consisting of deep vein thrombosis (DVT), or pulmonary embolism (PE), or both DVT + PE, was retrospectively identified from the administrative claims databases of 2 large U.S. health care plans. Inclusion criteria were (a) an inpatient VTE event between January 1, 1998, and December 31, 2000, (b) no VTE diagnosis or anticoagulation therapy 3 months prior to the incident VTE in-hospital event, (c) at least 1 anticoagulation pharmacy fill following the incident hospital VTE, and (d) continuous health plan enrollment 3 months prior to and 6 months following the incident hospital VTE event. Total costs were reported on a per-event basis and consisted of the aggregated amount paid by the health plan to the provider after subtraction of member cost-share. Costs were collected separately, first for the incident VTE event for all patients identified and second for patients who had at least 1 of the following events in the follow-up period: bleed requiring or not requiring hospitalization, a recurrent VTE event requiring hospitalization, or a recurrent VTE and bleed (VTE + bleed) event requiring hospitalization. Costs were compared between incident diagnosis groups using multivariate generalized linear model techniques. RESULTS: A total of 2,147 patients (DVT=1,499 [69.8%], PE=373 [17.4%], DVT+PE= 275 [12.8%]) were identified (mean age=61.6standard deviation [SD] 16 years; 46.3% male) and were followed for an average of 21.3 (median, 19.2) months. Disease severity was high in these patients, including 59.2% with a history of or active malignancy. The prevalence of VTE was 2.04 per 100,000 study-eligible health plan members. For the incident VTE events, average costs were 7,712+/-18,339 US dollars (median, 3,131 US dollars) per incident DVT event; 9,566+/-13,512 US dollars (median, 6,424 US dollars) per PE incident event; and 12,200+/-24,038 US dollars (median, 6,678 US dollars) per incident DVT+PE event. Warfarin treatment following the incident VTE event was administered to 97.3% of patients for an average of 6.7 (median, 5.0) months at an average cost of 19.40 US dollars per patient per month. During the average period of 21.3 months, 534 patients (24.9%) experienced an average of 1.24 bleed or recurrent VTE events per patient that required hospitalization at a mean cost of 14,975 US dollars per event or 2,101 US dollars per patient per year. For patients with a bleed in the follow-up period that required hospitalization, average costs were 12,326+/-24,448 US dollars (median, 5,736 US dollars) per recurrent VTE; 15,339+/-52,029 US dollars (median, 4,999 US dollars) per bleed; or 24,085+/-65,411 US dollars (median, 10,185 US dollars) per recurrent VTE + bleed event. During the follow-up period, a total of 612 patients (28.5%) experienced 1,489 recurrent bleed events that did not require hospitalization, at an average cost of 239+/-386 US dollars (median, 95 US dollars) per event. There were no significant differences in mean total costs for all pair-wise comparisons between the 3 incident diagnosis groups. CONCLUSIONS: Of patients who experienced a VTE event during the incident hospital stay for any diagnosis, 1 in 4 experienced an average of 1.24 bleed or recurrent VTE events that required hospitalization in the 21 months of follow-up and incurred an average health plan cost of 14,957 US dollars per event. These data may be of interest to managed care decision makers when evaluating the cost impact of new therapies or providing more comprehensive anticoagulation management services for existing therapies.

Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis.

OBJECTIVE: To examine the relationship between international normalized ratio (INR) and outcomes (major bleeding events and strokes) in patients with atrial fibrillation (AF) receiving anticoagulation with warfarin. METHODS: A systematic review and metaanalysis of studies published in the English language between January 1, 1985, and October 30, 2002, was performed. MEDLINE (PubMed), Current Contents, and relevant reference lists were searched. Studies enrolling patients with nonvalvular AF receiving warfarin anticoagulation were eligible for inclusion if they reported stroke and/or major bleeding events in relation to INR, or time spent in therapeutic range. The risk of bleeds in overanticoagulated patients (INR > 3) and the risk of strokes in underanticoagulated patients (INR < 2) were assessed. RESULTS: Twenty-one studies (6,248 patients) met all inclusion criteria. Of the 21 studies, a target conventional INR of 2 to 3 was used in 9 studies. An INR < 2, compared with an INR > or = 2, was associated with an odds ratio (OR) for ischemic events of 5.07 (95% confidence interval [CI], 2.92 to 8.80). An INR > 3, compared with an INR < or = 3, was associated with an OR for bleeding events of 3.21 (95% CI, 1.24 to 8.28). On average, in the four studies with a target INR range of 2 to 3, patients with AF receiving warfarin spent 61% of time within, 13% of time above, and 26% below the therapeutic range. CONCLUSION: Available evidence indicates that in patients with nonvalvular AF, the risk of ischemic stroke with insufficient warfarin anticoagulation (INR < 2), and the risk of bleeding events with overanticoagulation (INR > 3) are significantly higher relative to patients with AF maintained within the recommended INR of 2 to 3. However, the published data are sparse, heterogeneous, and primarily reported from clinical trials. More studies evaluating clinical outcomes in relation to INR are needed, especially in a real-world setting.

Management patterns and outcomes of patients with venous thromboembolism in the usual community practice setting.

OBJECTIVE: The objectives of this study were to observe a commercially insured sample diagnosed with a venous thromboembolism (VTE) event and treated postevent with warfarin and to detail the thromboembolic and bleeding outcomes in the time periods during warfarin therapy and after discontinuation of such therapy. METHODS: This retrospective, observational cohort study used medical, pharmacy, and eligibility data from 2 US health plans. Study inclusion required an inpatient diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) between January 1, 1998, and December 31, 2000; warfarin, heparin, or low-molecular-weight heparin within 30 days after diagnosis; no VTE diagnosis; and no anticoagulant use for 3 months preceding diagnosis. A random sample of medical charts was abstracted to validate VTE events and collect prothrombin time/international normalized ratio (INR) result data. Recurrent VTE events, bleeding events, and proportion of time within INR range were captured in the postindex VTE event time period. Univariate and multivariate statistical techniques were used to assess outcomes. RESULTS: A total of 2,090 patients were identified with a newly diagnosed VTE event (DVT only, 1450; PE with or without DVT, 640). Mean (SD) age was 61.7 (16) years; mean (SD) follow-up time after the index diagnosis was 21.3 (10) months. Overall mean (SD) length of warfarin therapy was 6.6 (6) months. During the follow-up period, 224 patients (10.7%) experienced a recurrent VTE event and 122 patients (5.8%) experienced a bleeding event requiring hospitalization. The cumulative incidence of recurrent VTE events over 3 and 6 months was 9.0% and 10.9%, respectively. Using the chart abstraction subset, patients were within the appropriate INR range 37.7% of the time while receiving warfarin. CONCLUSIONS: Negative outcomes associated with warfarin therapy-recurrent VTE events and bleeding requiring hospitalization-were experienced by 10.7% and 5.8% of patients, respectively. These data suggest that negative outcomes may be more prevalent in usual community medical practice compared with rates observed in the controlled environment of the clinical trial or specialized anticoagulation clinic.

Frequency of concurrent use of warfarin with potentially interacting drugs.

STUDY OBJECTIVE: To determine the rates of concomitant use of drugs known to interact with warfarin by increasing the prothrombin time expressed as the international normalized ratio (INR), decreasing the INR, or increasing bleeding risk without apparent changes in INR in a cohort of patients receiving long-term warfarin therapy. DESIGN: Retrospective, longitudinal cohort study. SETTING: Large pharmacy benefits manager database. PATIENTS: A total of 134,833 patients who were prescribed long-term warfarin from June 1, 1999-May 31, 2000. MEASUREMENTS AND MAIN RESULTS: Longitudinal pharmacy claims from the pharmacy benefits manager database were reviewed to identify coprescription of warfarin and drugs associated with significant interactions with warfarin. Of the 134,833 patients receiving long-term warfarin therapy, 109,998 (81.6%) were prescribed a concurrent prescription for at least one potentially interacting drug, including 87,346 (64.8%) who were prescribed one or more concomitant drugs associated with interactions known to increase the INR. Acetaminophen-containing products, prescribed for 22.7% of patients receiving concomitant prescriptions, and thyroid hormones, prescribed for 17.5%, were the most commonly prescribed concurrent drugs associated with an increased INR response. The most frequently prescribed interacting agents associated with a decreased INR response were trazodone (2.2%) and carbamazepine (1.1%). The most commonly prescribed agents independently associated with increased bleeding risk were cyclooxygenase-2 inhibitors. CONCLUSION: Many patients receiving warfarin therapy are treated with concomitant drugs that may interact with the warfarin. The high percentage of patients taking drugs that may increase INR or bleeding risk is a reminder that bleeding events are a likely adverse outcome of combining drugs that interact with warfarin. Careful warfarin management is necessary to avoid adverse events associated with drug interactions.

A new instrument for measuring anticoagulation-related quality of life: development and preliminary validation.

BACKGROUND: Anticoagulation can reduce quality of life, and different models of anticoagulation management might have different impacts on satisfaction with this component of medical care. Yet, to our knowledge, there are no scales measuring quality of life and satisfaction with anticoagulation that can be generalized across different models of anticoagulation management. We describe the development and preliminary validation of such an instrument - the Duke Anticoagulation Satisfaction Scale (DASS). METHODS: The DASS is a 25-item scale addressing the (a) negative impacts of anticoagulation (limitations, hassles and burdens); and (b) positive impacts of anticoagulation (confidence, reassurance, satisfaction). Each item has 7 possible responses. The DASS was administered to 262 patients currently receiving oral anticoagulation. Scales measuring generic quality of life, satisfaction with medical care, and tendency to provide socially desirable responses were also administered. Statistical analysis included assessment of item variability, internal consistency (Cronbach's alpha), scale structure (factor analysis), and correlations between the DASS and demographic variables, clinical characteristics, and scores on the above scales. A follow-up study of 105 additional patients assessed test-retest reliability. RESULTS: 220 subjects answered all items. Ceiling and floor effects were modest, and 25 of the 27 proposed items grouped into 2 factors (positive impacts, negative impacts, this latter factor being potentially subdivided into limitations versus hassles and burdens). Each factor had a high degree of internal consistency (Cronbach's alpha 0.78-0.91). The limitations and hassles factors consistently correlated with the SF-36 scales measuring generic quality of life, while the positive psychological impact scale correlated with age and time on anticoagulation. The intra-class correlation coefficient for test-retest reliability was 0.80. CONCLUSIONS: The DASS has demonstrated reasonable psychometric properties to date. Further validation is ongoing. To the degree that dissatisfaction with anticoagulation leads to decreased adherence, poorer INR control, and poor clinical outcomes, the DASS has the potential to help identify reasons for dissatisfaction (and positive satisfaction), and thus help to develop interventions to break this cycle. As an instrument designed to be applicable across multiple models of anticoagulation management, the DASS could be crucial in the scientific comparison between those models of care.

A systematic review and mixed-treatment comparison of dapagliflozin with existing anti-diabetes treatments for those with type 2 diabetes mellitus inadequately controlled by sulfonylurea monotherapy.

BACKGROUND: To compare the first-in-class sodium glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, with existing type 2 diabetes mellitus (T2DM) treatment options available within the European Union (EU) for add-on therapy to sulfonylureas (SUs). METHODS: A systematic review was conducted to identify randomised controlled trials (RCTs) in T2DM patients inadequately controlled by SU monotherapy. Direct meta-analysis, Bucher indirect comparisons and Bayesian network meta-analysis (NMA) were conducted on studies meeting predefined inclusion criteria. Sufficient data were available to assess three clinical endpoints at 24 (+/- 6) weeks follow-up: mean change in HbA1c from baseline, mean change in weight from baseline, and the proportion of patients experiencing at least one episode of hypoglycaemia. The effect of confounding baseline factors was explored through covariate analyses. RESULTS: The search identified 1,901 unique citations, with 1,870 excluded based on title/abstract. From reviewing full-texts of the remaining 31 articles, 5 studies were considered eligible for analysis. All studies were comparable in terms of baseline characteristics, including: HbA1c, age and body mass index (BMI). In addition to dapagliflozin, sufficient data for meta-analysis was available for three dipeptidyl peptidase-4 (DPP-4) inhibitors and one glucagon-like peptide-1 (GLP-1) analogue. Based on fixed-effect NMA, all treatment classes resulted in statistically significant decreases in HbA1c at follow-up compared to placebo. Dapagliflozin treatment resulted in significantly decreased weight at follow-up compared to placebo (-1.54 kg; 95% CrI -2.16, -0.92), in contrast to treatment with GLP-1 analogues (-0.65 kg; 95% CrI -1.37, 0.07) and DPP-4 inhibitors (0.57 kg; 95% CrI 0.09, 1.06). The odds of hypoglycaemia were similar to placebo for dapagliflozin and DPP-4 inhibitor add-on treatment, but significantly greater than placebo for GLP-1 analogue add-on treatment (10.89; 95% CrI 4.24, 38.28). Assessment of NMA model heterogeneity was hindered by the small size of the network. CONCLUSIONS: Dapagliflozin, DPP-4 inhibitors and GLP-1 analogues, in combination with SU, all provided better short-term glycaemic control compared to SU monotherapy. Dapagliflozin was the only add-on therapy that had both a favourable weight and hypoglycaemia profile compared to the other classes of treatment evaluated.

Risk factors for cardiovascular events and bleeding complications following non-cardiac surgery or procedure in patients with drug eluting stent placement.

OBJECTIVES: Previous studies suggest an increased incidence of cardiovascular (CV) events after P2Y12 receptor blocker cessation. The aim of this study was to examine the effect of P2Y12 receptor blocker cessation and other risk factors on the risk of CV events and bleeding events after non-cardiac surgery/procedure in patients with drug-eluting stents (DES). DESIGN: Retrospective cohort study. SETTING: Single large healthcare system in the northeast of the USA. PATIENTS: All adult patients who had a coronary drug eluting stent (DES) placed between 2002 and 2007 in our institution. INTERVENTIONS: No randomised intervention. The principal exposure was cessation of P2Y12 receptor blocker. METHODS: This was a retrospective study of all adult patients who had a coronary DES placed between 2002 and 2007 in our institution. We considered all non-cardiac procedures up to 1 year after DES placement. Generalised estimating equations were used to identify the independent risk factors. Multiple imputations were used to replace missing values. MAIN OUTCOME MEASURES: The outcomes were CV events including death from any cause and bleeding, occurring within 30 days after the procedure. RESULTS: From 2002 to 2007, 6397 patients had DES, 873 (13.6%) had at least one non-cardiac procedure. A total of 3.6% (33/927) of the admissions were complicated by at least one cardiovascular event and 6.9% (55/795) were complicated by bleeding. Urgent procedure (versus elective) was the only independent risk factor for CV events (OR=4.82, 95% CI 1.95 to 11.89). Older age, diabetes, urgent procedures, orthopaedic and vascular surgery compared to unclassified surgery were independent risk factors for bleeding. CONCLUSIONS: Non-cardiac procedures are common within 1 year after DES placement. Urgent nature of procedure is a risk factor for CV events and bleeding complications. Older age, diabetes, type of surgery, are risk factors associated only with bleeding events.

Impact of adherence and weight loss on glycemic control in patients with type 2 diabetes: cohort analyses of integrated medical record, pharmacy claims, and patient-reported data.

BACKGROUND: Managed care organizations put great effort into managing the population of patients with type 2 diabetes mellitus (T2DM) because of the health and economic burden of this disease. In patients with T2DM, weight loss and glycemic control are primary treatment aims to help improve patient outcomes, but these goals are not easily achieved. While achieving these aims requires a multifaceted approach of drug therapy management and lifestyle modification, truly understanding the role of medication adherence in achieving these outcomes is important for both patient and population management. This study expands on existing evidence that weight loss is associated with improved glycemic control by examining the role of medication adherence in achieving these goals in a managed care setting. This study is unique in that these associations are evaluated using multiple sources of data, including medical records for treatment outcomes, pharmacy claims, and patient-reported data to assess medication adherence. These data sources represent those typically available to payers or providers.  OBJECTIVE: To describe the relationships between medication and adherence, weight change, and glycemic control in patients with T2DM. METHODS: This historical cohort study included adult patients with T2DM in a large integrated health system and was based on electronic health record and pharmacy claims data from November 1, 2010, through October 31, 2011, as well as data from a self-reported adherence survey conducted in March 2012. Included patients received a diabetes medication from a therapeutic class not previously received, between November 1, 2010, and April 30, 2011 (index date), who had blood glucose (HbA1c) and weight values at index date and 6 months follow-up, participated in an adherence survey, and had ≥ 1 prescription claim for the index-date drug. Associations between the dual outcomes of weight loss (≥ 3%) and HbA1c control ( less than 7.0%), while controlling for medication adherence and other demographic, treatment, and clinical variables, were evaluated using structural equation models (SEM). Separate models adjusted for different measures of medication adherence-self-reported using the 5-item Medication Adherence Rating Scale (MARS-5) and a modified medication possession ratio (mMPR) from pharmacy claims data. RESULTS: The study included 166 patients with a mean age of 61.1 (standard deviation = 12.1) years; 56.0% were female. Medication adherence was high, with 72.2% adherent using MARS-5 and 77.1% using mMPR measures. The SEMs found that only self-reported medication adherence is associated with weight loss (MARS-5: OR = 1.70, 95% CI = 1.11-2.60), while both self-reported and claims-based medication adherence were associated with HbA1c less than 7.0% (MARS-5: OR = 1.59, 95% CI = 1.09-2.34; mMPR: OR 2.71, 95% CI = 1.22-5.98). Further, weight loss is significantly associated with HbA1c less than 7.0% (MARS-5: OR = 3.60, 95% CI = 2.39-5.46; mMPR: OR 2.99, 95% CI = 1.45-6.17). CONCLUSIONS: This study has provided additional evidence in a managed, integrated setting that in patients treated for T2DM, weight loss is associated with good glycemic control. Adherence is associated with weight loss according to self-report, but not claims-based adherence measures. Adherence is also associated with glycemic control as measured by the 2 different methods. This study adds to the body of literature highlighting the importance of adherence as well as weight loss in achieving good glycemic control. The fact that the association of weight loss and adherence on glycemic control outcomes was significant regardless of medication adherence method is important in payer-provider collaborations, where access to data sources to evaluate adherence may vary. This study also supports continued investment in weight loss and adherence programs in the management of patients with T2DM.