Therapies for acute myeloid leukemia in patients ineligible for standard induction chemotherapy: a systematic review.

Aim: To review clinical evidence for current and emerging treatments for patients with acute myeloid leukemia (AML) who are ineligible for first-line induction chemotherapy. Methods: A systematic literature review was performed (28 October 2021) to identify clinical outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and adverse events (AEs). Results: Of 233 references that met prespecified criteria, 26 studies were included. Adding targeted therapies (venetoclax/ivosidenib) to hypomethylating agents (HMAs) yielded better OS hazard ratios (HRs) (0.44-0.66) and EFS HRs (0.33-0.63) compared with other agents. AEs were more frequent with combination therapies than control arms, except with ivosidenib plus azacitidine. Conclusion: Targeted therapy combined with a HMA shows the most promising results in this difficult-to-treat population.

Acute myeloid leukemia (AML) is a type of cancer of the bone marrow and blood that leads to overproduction of immature white blood cells. High-dose (intensive) chemotherapy is usually the first treatment option for AML. However, more than half of people newly diagnosed with AML cannot receive the recommended initial intensive chemotherapy due to older age or poor health. Treatment with low-dose cytarabine (LDAC) and hypomethylating agents (HMAs), such as azacitidine, is key for such people. We reviewed 26 clinical trials looking into available and developing treatment options for people who cannot have the recommended initial chemotherapy. The review found evidence that combining LDAC or HMA with a targeted therapy can improve survival. In AML, new therapies (such as ivosidenib, venetoclax and glasdegib) 'target' specific changes in the genes of cancer cells to slow or stop their division and growth. The greatest improvement in survival was seen in clinical trials where targeted therapies were added to azacitidine or LDAC. Targeted therapies may result in certain side effects that require regular monitoring. To provide patients with the benefits of targeted therapies they need to undergo genetic testing at the time of diagnosis. Tests to determine an individual's specific gene changes allows clinicians to develop personalised treatment plans with available targeted therapies. This shows promise in improving survival for people with AML who cannot receive initial intensive chemotherapy.

A UK cost-effectiveness analysis of trifluridine/tipiracil for heavily pretreated metastatic gastroesophageal cancers.

Background: The current work was designed to estimate the cost-effectiveness of trifluridine/tipiracil (T/T) versus best supportive care (BSC) for patients with advanced stage or metastatic gastroesophageal cancer (mGC) from a UK perspective. Materials & methods: A partitioned survival analysis was undertaken using data from the phase III TAGS trial. A jointly fitted lognormal model was selected for overall survival and individual generalized gamma models were chosen for progression-free survival and time-to-treatment-discontinuation. The primary outcome was the cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were undertaken to investigate uncertainty. Results: Compared with BSC, T/T was associated with a cost per QALY gained of £37,907. Conclusion: T/T provides a cost-effective treatment option for mGC in the UK setting.

Cost-effectiveness of treating acute coronary syndrome patients with ticagrelor for 12 months: results from the PLATO study.

AIMS: The efficacy and safety of ticagrelor vs. clopidogrel in patients with acute coronary syndromes (ACS) are well documented in the PLATelet inhibition and patient Outcomes trial (PLATO). The aim of this study was to assess the long-term cost-effectiveness of treating ACS patients for 12 months with ticagrelor compared with generic clopidogrel. METHODS AND RESULTS: Event rates, health-care costs, and health-related quality of life during 12 months of therapy with either ticagrelor or generic clopidogrel were estimated from PLATO. Beyond 12 months, quality-adjusted survival and costs were estimated conditional on whether a non-fatal myocardial infarction (MI), a non-fatal stroke, or no MI or stroke occurred during the 12 months of therapy. Lifetime costs, life expectancy, and quality-adjusted life years (QALYs) were estimated for both treatment strategies. Incremental cost-effectiveness ratios were presented from a health-care perspective in 2010 Euros (€) applying unit costs and life tables from a Swedish setting in the base-case analysis. Treatment with ticagrelor was associated with increased health-care costs of €362 and a QALY gain of 0.13 compared with generic clopidogrel, yielding a cost per QALY gained with ticagrelor of €2753. The cost per life year gained was €2372. The results were consistent in major subgroups. Sensitivity analyses showed a cost per QALY gained with ticagrelor of ∼€7300 under certain scenarios. CONCLUSION: Based on clinical and health-economic evidence from the PLATO study, treating ACS patients with ticagrelor for 12 months is associated with a cost per QALY below generally accepted thresholds for cost-effectiveness. ClinicalTrials.gov Identifier: NCT00391872.

Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial.

PURPOSE: We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients. PATIENTS AND METHODS: Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated. RESULTS: Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm. CONCLUSION: Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.

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.

A Validation Study of the Rank-Preserving Structural Failure Time Model: Confidence Intervals and Unique, Multiple, and Erroneous Solutions.

BACKGROUND: The rank-preserving structural failure time model (RPSFTM) is used for health technology assessment submissions to adjust for switching patients from reference to investigational treatment in cancer trials. It uses counterfactual survival (survival when only reference treatment would have been used) and assumes that, at randomization, the counterfactual survival distribution for the investigational and reference arms is identical. Previous validation reports have assumed that patients in the investigational treatment arm stay on therapy throughout the study period. OBJECTIVES: To evaluate the validity of the RPSFTM at various levels of crossover in situations in which patients are taken off the investigational drug in the investigational arm. METHODS: The RPSFTM was applied to simulated datasets differing in percentage of patients switching, time of switching, underlying acceleration factor, and number of patients, using exponential distributions for the time on investigational and reference treatment. RESULTS: There were multiple scenarios in which two solutions were found: one corresponding to identical counterfactual distributions, and the other to two different crossing counterfactual distributions. The same was found for the hazard ratio (HR). Unique solutions were observed only when switching patients were on investigational treatment for <40% of the time that patients in the investigational arm were on treatment. LIMITATIONS: Distributions other than exponential could have been used for time on treatment. CONCLUSIONS: An HR equal to 1 is a necessary but not always sufficient condition to indicate acceleration factors associated with equal counterfactual survival. Further assessment to distinguish crossing counterfactual curves from equal counterfactual curves is especially needed when the time that switchers stay on investigational treatment is relatively long compared to the time direct starters stay on investigational treatment.

Letter--Prudent Formulary Management or Underutilization of the Novel P2Y12 Receptor Inhibitors in Patients with Acute Coronary Syndrome Who Received Percutaneous Coronary Intervention?

DISCLOSURES: The author is a former employee of AstraZeneca and owns stock in AstraZeneca. The author reports no conflicts of interest related to the subject of this letter.

Treatment patterns and real-world effectiveness of warfarin in nonvalvular atrial fibrillation within a managed care system.

OBJECTIVE: To examine warfarin utilization and clinical effectiveness among patients with nonvalvular atrial fibrillation within usual clinical care in a managed care system. RESEARCH DESIGN AND METHODS: A retrospective analysis of health care claims for an approximately four million member managed care organization was performed. Health plan members with a diagnosis of nonvalvular atrial fibrillation in calendar year 2000 were identified and stratified into two cohorts: Warfarin Therapy (newly initiating warfarin) or Warfarin Candidates (eligible for warfarin therapy according to the ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation, but did not receive warfarin). MEASUREMENTS: The occurrence of thromboembolism, ischemic stroke, and hemorrhage during a maximum 720-day follow-up were compared between cohorts, adjusting for age, gender, and other risk factors, using Cox regression. RESULTS: Among 12 539 subjects (mean age 78.0 +/- 8.8 years) with nonvalvular atrial fibrillation, 4895 (39.0%) initiated Warfarin Therapy and 7644 (61.0%) were Warfarin Candidates. Event occurrences among Warfarin Therapy vs. Warfarin Candidates were: ischemic stroke, 3.7% vs. 4.5%; any thromboembolism, 7.8% vs. 10.8%; and hemorrhage, 4.4% vs. 4.9%, respectively. Warfarin therapy was not associated with an increased risk for hemorrhage (hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.82-1.15), while risks for ischemic stroke and any thromboembolism were significantly reduced, by 22% (HR = 0.78, 95% CI = 0.65-0.93) and 34% (HR = 0.66, 95% CI = 0.59-0.75), respectively. CONCLUSIONS: Within usual clinical care for the managed care population examined, warfarin remains underused despite current guidelines recommending its use in nearly all patients with nonvalvular atrial fibrillation. Although utilization of anticoagulation clinics and INR values attained were unknown in this study, the observed risk reductions for ischemic stroke and thromboembolism were lower than those achieved in clinical trials, while no increased risk for hemorrhage was observed. These findings suggest that warfarin is used conservatively, and dosed cautiously, diminishing the full potential benefit of anticoagulant therapy in patients with nonvalvular atrial fibrillation.

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.

Factors influencing physicians' reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey.

BACKGROUND: Some elderly patients with nonvalvular atrial fibrillation (NVAF) who might benefit from warfarin therapy do not receive it. OBJECTIVE: The goal of this cross-sectional study was to identify physicians' attitudes and beliefs that are associated with their reported use of warfarin in case scenarios. METHODS: A self-administered survey was mailed to a cross-section of general internists randomly selected from a national pool of physicians in the American Medical Association Masterfile. Fourteen clinical vignettes were used, incorporating various comorbid conditions and risk factors for either major bleeding episode or embolic cerebrovascular accident (CVA). The outcome measure was the number of case vignettes for which warfarin was recommended. RESULTS: A total of 142 completed surveys (33% of 426 eligible respondents; 109 men, and 32 women [1 respondent did not provide gender]; mean [SD] age, 45 [10] years) were received. The median number of case vignettes for which warfarin was recommended was 10 (interquartile range, 8-12). We found no relationship between the perceived benefits of warfarin and its use in the case vignettes. However, the perceived risk for warfarin associated hemorrhage was strongly associated with reported warfarin use (P < 0.001). The physicians in our sample provided estimates of the annual rate of warfarin-associated intracerebral hemorrhage that were >10-fold higher than literature-based estimates, and physicians providing higher risk estimates tended to use warfarin less often. On multivariate logistic regression, physicians who recommended warfarin use in more vignettes were less likely to report anticipated regret of committing an error of omission (ischemic CVA in an untreated NVAF patient) (P < 0.001) or a loss-aversive risk preference (P = 0.027), and had a lower perceived annual risk for hemorrhage with warfarin (P < 0.001). Physician age, sex, primary mechanism of reimbursement, academic appointment, and the NVAF patient volume all were unrelated to warfarin use. CONCLUSIONS: Although the decision to use warfarin in NVAF was not driven by the perceived benefit, the perceived risks strongly affected warfarin use. Response bias is a potential limitation, but our data strongly suggest that physicians' attitudes toward anticipated regret and risk aversion can impact on their treatment recommendations.

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.

Incidence of death and recurring acute coronary syndrome after stopping clopidogrel therapy in a large commercially-insured population in the US.

BACKGROUND/OBJECTIVE: Guidelines support clopidogrel therapy in medically-treated or percutaneous coronary intervention (PCI) patients after hospitalization for acute coronary syndrome (ACS). However, clopidogrel discontinuation has been associated with increased short-term risks. This study evaluated the risk of adverse outcomes (AOs), defined as death or recurrent ACS, after clopidogrel discontinuation in a managed-care population. METHODS: ACS patients (n = 7625) with ≥1 clopidogrel pharmacy claim from 2001 to 2006 and no AO before discontinuing clopidogrel were identified from administrative claims data. AO occurrences were recorded at 90-day intervals following clopidogrel discontinuation. RESULTS: The mean (SD) duration of clopidogrel therapy for medically-treated, bare metal stent (BMS) and drug eluting stent (DES) patients was 349.2 (393.1) days, 235.6 (383.0) days, and 280.2 (227.1) days, respectively. Among medically-treated patients, Poisson regression analysis showed a 2.19 times higher AO risk (p < 0.01), a 1.63 times greater risk among BMS patients (p < 0.01), and a 1.56 times greater risk for DES patients (p ≥ 0.05) during days 0-90 versus days 91-180 after clopidogrel discontinuation. Sensitivity analysis showed that medically-treated, BMS and DES patients with ≤90 days of clopidogrel therapy had 2.13, 1.68 and 2.40 times higher AO risk, respectively, during days 0-90 versus 91-180 after discontinuation. No significant elevated AO risk was observed after discontinuation in patients on clopidogrel for 91-270 days. Limitations included those associated with the use of administration claims date, the absence of clinical data and lack of knowledge of aspirin use. CONCLUSIONS: Patients who discontinued clopidogrel therapy were at high risk of death or recurrent ACS during the first 90 days. AO risks following discontinuation appeared elevated in patients with ≤90 days of clopidogrel therapy versus those with >90 days of treatment.

Retrospective study of total healthcare costs associated with chronic nonvalvular atrial fibrillation and the occurrence of a first transient ischemic attack, stroke or major bleed.

OBJECTIVE: To determine the direct healthcare costs associated with the onset of chronic nonvalvular atrial fibrillation (CNVAF), warfarin utilization and the occurrence of cerebrovascular events in a commercially-insured population. RESEARCH DESIGN AND METHODS: This retrospective, observational cohort study utilized medical and pharmacy claims from a large, geographically diverse managed-care organization (N = 18.5 million) to identify continuously benefit-eligible CNVAF patients > or =45 years of age without prior valvular disease or warfarin use between January 1, 2001 and June 1, 2002. All patients were followed at least 6 months, until plan termination or the end of study follow-up. Stroke risk was assessed using the CHADS(2) (stroke-risk) index; warfarin use was defined as having filled at least one pharmacy claim. Inpatient and outpatient cost benchmarks were utilized to estimate total direct healthcare costs (pre- and post-AF index claim). For patients with transient ischemic attacks (TIA), ischemic stroke (IS) and major bleed (MB) total direct healthcare costs were also assessed. The limitations of this study included a descriptive retrospective study design without a comparison group or adjustment for baseline disease severity and drug exposure, as well as, the reliance upon administrative claims data and use of a standardized reference costing methodology. RESULTS: The pre- and post-AF onset total direct healthcare costs (pmpm) for 3891 incidence CNVAF patients were $412 and $1235, respectively, a 200% increase. Of the 448 (12%) patients with a cerebrovascular event, pmpm costs post-AF ranged from $2235 to $3135 correlating with CHADS(2) stroke-risk status and exposure to warfarin. Total cohort pmpm costs pre and post event increased 24% from $3446.91 to $4262.12. Approximately 20% of all events occurred <2 days and 46% within 1 month after the index AF claim. Any warfarin exposure, regardless of CHADS(2) risk had an 18% to 29 % decrease in pmpm costs. CONCLUSIONS: Post-AF total direct healthcare costs were 3 times greater than pre-AF costs. For those with a TIA, IS or MB, post-AF total direct healthcare costs increased 4.5 times from pre-AF costs; overall post-event costs in this cohort increased approximately 25% over pre-event costs. Nearly half of the events occurred within 1 month of a claim associated with an AF diagnosis. Warfarin exposure appeared to be associated with lower pmpm costs in this population.

One-year costs of ischemic heart disease among patients with acute coronary syndromes: findings from a multi-employer claims database.

OBJECTIVE: Acute coronary syndromes (ACS) are life-threatening disorders requiring intensive medical management or invasive cardiovascular procedures. Limited data exist on the costs and resource utilization associated with ACS. METHODS: This retrospective single-cohort study analyzed administrative claims data from employer-sponsored plans for patients with an ACS hospitalization in 2001-2002. A 1-year follow-up period was used, and patients who were under age 35 or had an ACS diagnosis in the 12 months before the hospitalization were excluded. Costs were reported in 2005 US dollars. RESULTS: We identified 16,321 patients hospitalized for ACS during the study period. Mean (+/- SD) age was 55.6 (+/- 6.7) years, 66.7% were male, and 46.3% underwent a revascularization procedure during their initial hospitalization. Mean length of stay for the initial hospitalization was 4.6 days (median: 3.0; IQR: 2.0-5.0), and per-patient expenditures averaged $22,921 (median: $13,960; IQR: $6839-28 588). During the follow-up period, 21% of patients were rehospitalized for ischemic heart disease (IHD), and the cost of rehospitalization averaged $28,637. Additionally, in the year following the inpatient admission, 50% of patients were prescribed antiplatelet or anticoagulant medications, and 90% of patients were prescribed lipid-lowering, antihypertensive, or antiarrhythmic medications. IHD-related expenditures after the initial inpatient stay averaged $9425 (median: $2800; IQR: $899-7577); 61% of these costs were due to rehospitalization. Total first-year costs averaged $32,345 (median: $21,653; IQR: $10,642-41,106). LIMITATIONS: Diagnoses could not be verified through medical charts. Payments for Medicare patients were not assessed given our focus on the working-age population. CONCLUSIONS: In this employer-sponsored health plan population, the costs of inpatient and outpatient IHD-related care were high. Future studies should evaluate the impact of improved patient management on post-discharge costs.

Monitoring anticoagulation in atrial fibrillation.

BACKGROUND: Randomized control trials and observational studies show high-quality warfarin therapy leads to safe and effective stroke prophylaxis. In usual community practice, patient, physician and health care system factors are barriers to optimal anticoagulation. We examined the predictive relationship between inpatient and outpatient INR values in chronic non-valvular atrial fibrillation (AF) patients hospitalized for ischemic stroke (S), bleed (B) and control events (C) in usual community practice. METHODS: This nested case-control analysis identified AF patients hospitalized for S, B and C using medical and pharmacy claims spanning 4.5 years ('98-'03) and validating diagnosis with chart abstraction. AF was defined as 2 medical claims for AF >or= 42 days apart with a related prescription claim for warfarin. INRs from both outpatient and inpatient settings were used to yield a continuous history of coagulation status. Time-in-therapeutic-range (TTR) was calculated by Rosendaal's linear interpolation method. Correlation of inpatient and prognostic utility of last outpatient INRs was tested with S or B hospitalizations using univariate and multivariate logistic regression. RESULTS: Overall, 614 hospitalizations (means: age 73.9, CHADS(2) = 3.24; 52% male) included S (n = 98), B (n = 101) and C (n = 415) events. Average TTR was 28.6% (49.4% at INR <2.0, 21.9% at INR >3.0). First INR on admission (INR <2.0 or >3.0) was associated with S and B hospitalizations (OR-adjusted [95%CI], 1.68 [1.04-2.73] and 1.72 [1.02-2.90]), respectively. Last outpatient INR <2.0 was not associated with S (OR-adjusted [95%CI], 1.12 [0.77-1.81]), and INR >3.0 was not associated with B (OR-adjusted [95%CI], 1.25 [0.67-2.32]). Last outpatient INR measurement occurred at 28, 22 and 24 days (median; S, B & C, respectively) before hospitalization. CONCLUSION: Patients were observed within therapeutic range less than 30% of their time on warfarin. While inpatient INRs were clearly associated with both ischemic stroke and bleed events, last outpatient INR before event was not predictive.

Warfarin exposure and the risk of thromboembolic and major bleeding events among medicaid patients with atrial fibrillation.

BACKGROUND: Outcomes of anticoagulation have been assessed in commercially insured populations, but similar data do not exist for Medicaid populations. OBJECTIVE: To assess the association between warfarin exposure and rates of thromboembolic and bleeding events among patients with nonvalvular atrial fibrillation (NVAF) enrolled in California Medicaid. METHODS: Using a retrospective cohort design based on administrative claims data, we selected Medicaid enrollees aged 50 years and older based on their first claim with a diagnosis of AF between January 1, 1998, and March 31, 2002. Patients were excluded if they had selected contraindications to warfarin, claims for valve replacement procedures, or evidence that AF resulted from transient or reversible causes. Pharmacy claims and prothrombin time tests were used to define subsequent periods of warfarin use (exposure) and nonuse (nonexposure) by all patients. The relative rates of hospitalization for thromboembolic and bleeding events associated with periods of warfarin exposure versus nonexposure were estimated. RESULTS: The 4355 study patients had a mean age of 74 years, and 65% were female. Fifty-nine percent filled any prescriptions for warfarin following AF diagnosis. Across all patients, warfarin exposure occurred during 37% of days after diagnosis. Thromboembolic events were 27% less frequent during periods of warfarin exposure relative to periods of non-exposure (p < 0.01). Major bleeding events were not significantly more common during periods of warfarin exposure (p = 0.55). CONCLUSIONS: In this Medicaid population with NVAF, warfarin use was low and was associated with a relatively modest reduction in thromboembolic events, with no increase in major bleeding risk.