A review of global health technology assessments of non-VKA oral anticoagulants in non-valvular atrial fibrillation.

BACKGROUND: This review assessed global health technology assessment (HTA) reports and recommendations of non-vitamin K oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF). METHODS: NHTA agency websites were searched for HTA reports evaluating NOACs versus NOACs or vitamin K antagonists. HTA methods and information on patient involvement/access were collected and empirically analyzed. RESULTS: The review identified 38 unique HTA reports published between 2012 and 2017 in 16 countries including 11 in Europe. NOACs that were cost-effective per local willingness-to-pay (WTP) thresholds were positively recommended for the treatment of NVAF. WTP thresholds ranged from €20,000 to 69,000. Apixaban was recommended in 10/12 (83%) countries, dabigatran in 9/13 (69%) countries, and rivaroxaban in 10/13 (76%) over warfarin. Edoxaban was recommended in 5/7 (71%) countries. Economic evaluations and recommendations comparing NOACs were sparse (two or three countries per NOAC) and generally favored apixaban and edoxaban, followed by dabigatran. Eleven HTA reports from four countries considered the patient voice (Canada [n = 3], Scotland [n = 3], England [n = 4], Brazil [n = 1]); however, only 2/11 (18%) developed recommendations based on this. Among the reports with a positive recommendation, 26/30 (87%) featured a decision that aligned with the approved regulatory label. CONCLUSIONS: Most agencies recommended NOACs over warfarin for patients with NVAF. Few countries made statements recommending one NOAC over another. Given different WTP thresholds, a drug that is cost-effective in one market may not be in another. Therefore, the various NOAC recommendations from HTA agencies cannot be generalized across different countries.

Change in Cardiometabolic Risk Factors Associated With Magnitude of Weight Regain 3 Years After a 1-Year Intensive Lifestyle Intervention in Type 2 Diabetes Mellitus: The Look AHEAD Trial.

Background Weight regain after weight loss is common. The impact on cardiometabolic risk factors is not well established. Methods and Results Publicly available data were analyzed from participants of the Look AHEAD (Action for Health in Diabetes) trial with ≥3% initial weight loss (n=1561) during a 1-year intensive lifestyle intervention and with year 4 follow-up data. Participants who regained (regainers) or maintained (maintainers) weight loss were defined with 5 dichotomized cut points (0%, 25%, 50%, 75%, and 100%) of percentage weight loss regained (weight change from years 1-4 as percentage of first year weight loss). Change in cardiometabolic risk factors after initial weight loss was compared in maintainers and regainers, after controlling for demographics, medications, and baseline and year 1 change in body mass index. The effect was assessed separately in participants with <10% and ≥10% initial weight loss, and women and men. Maintainers exhibited significant improvements to the cardiometabolic risk factors assessed compared with regainers. No weight regain cut point maximized risk difference between maintainers and regainers across risk factors or sex/initial weight loss subgroups. For many risk factors, allowing more regain as part of maintenance (increasing cut point) diminished the cardiometabolic benefit among maintainers. Conclusions Maintaining weight loss was better than regain for all risk factors. No single cut point maximized the risk difference between maintainers and regainers. Maintainers who kept off ≥75% of weight lost had the greatest benefit. These findings emphasize the importance of intervention programs focusing not only on weight loss but weight loss maintenance, given the adverse consequences of the latter. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00017953.

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.

Anticoagulant selection for patients with VTE-Evidence from a systematic literature review of network meta-analyses.

The aim of this study was to systematically review published network meta-analyses (NMAs) that compare venous thromboembolism (VTE) treatments. A systematic literature search (in MEDLINE, Embase, and Cochrane Database of Systematic Reviews through September 2017) was conducted to identify NMAs that compared the safety and efficacy of direct oral anticoagulants (DOACs) for the treatment of VTE in the acute and extended treatment settings. The NMAs included randomized controlled trials comparing multiple DOACs, low-molecular weight heparin, unfractionated heparin, and vitamin K antagonists (VKAs). The quality of the NMA results were evaluated using the Grading of Recommendations and Evaluation (GRADE) assessment. The SLR identified 294 records and nine NMAs (68 trials). Among the NMAs, three evaluated the acute treatment setting, five the extended, and one in both treatment settings. The NMAs showed a significant reduction in major bleeding and clinically relevant bleeding (CRB) with apixaban compared to other DOACs. Major bleeding with apixaban was reduced compared to dabigatran, edoxaban, and fondaparinux-VKA combination in all comparisons in the acute setting (range of effect estimates: 0.30-0.43). CRB was reduced with apixaban compared to dabigatran, edoxaban, and rivaroxaban in the acute and extended settings (range of effect estimates: 0.23-0.72). No significant differences were seen in efficacy outcomes between the DOACs. This SLR of NMAs systematically collected all indirect evidence of the impact of apixaban compared to other anticoagulants in patients with VTE. In the absence of head-to-head trials, well-conducted NMAs provide the best evidence.

Investigation of the C-3-epi-25(OH)D3 of 25-hydroxyvitamin D3 in urban schoolchildren.

The physiological relevance C-3 epimer of 25-hydroxyvitamin D (3-epi-25(OH)D) is not well understood among youth. The objective of this study was to assess whether demographic/physiologic characteristics were associated with 3-epi-25(OH)D3 concentrations in youth. Associations between 3-epi-25(OH)D3 and demographics and between 3-epi-25(OH)D3, total 25-hydroxyvitamin (25(OH)D) (25(OH)D2 + 25(OH)D3), total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides were examined in racially/ethnically diverse schoolchildren (n = 682; age, 8-15 years) at Boston-area urban schools. Approximately 50% of participants had detectable 3-epi-25(OH)D3 (range 0.95-3.95 ng/mL). The percentage of 3-epi-25(OH)D3 of total 25(OH)D ranged from 2.5% to 17.0% (median 5.5%). Males were 38% more likely than females to have detectable 3-epi-25(OH)D3 concentrations. Both Asian and black race/ethnicity were associated with lower odds of having detectable 3-epi-25(OH)D3 compared with non-Hispanic white children (Asian vs. white, odds ratio (OR) 0.28, 95% confidence interval (CI) 0.14-0.53; black vs. white, OR 0.38, 95%CI 0.23-0.63, p < 0.001). Having an adequate (20-29 ng/mL) or optimal (>30 ng/mL) 25(OH)D concentration was associated with higher odds of having detectable 3-epi-25(OH)D3 than having an inadequate (<20 ng/mL) concentration (OR 4.78, 95%CI 3.23-6.94 or OR 14.10, 95%CI 7.10-28.0, respectively). There was no association between 3-epi-25(OH)D3 and blood lipids. However, when considering 3-epi-25(OH)D3 as a percentage of total 25(OH)D, total cholesterol was lower in children with percent 3-epi-25(OH)D3 above the median (mean difference -7.1 mg/dL, p = 0.01). In conclusion, among schoolchildren, sex, race/ethnicity, and total serum 25(OH)D concentration is differentially associated with 3-epi-25(OH)D. The physiological relevance of 3-epi-25(OH)D3 may be related to the 3-epi-25(OH)D3 as a percentage of total 25(OH)D and should be considered in future investigations.

Comparison among criteria to define successful weight-loss maintainers and regainers in the Action for Health in Diabetes (Look AHEAD) and Diabetes Prevention Program trials.

Background: Given the low rates of successful weight maintenance after lifestyle-induced weight loss, it is critical to develop approaches that distinguish successful weight-loss maintainers from regainers.Objective: The aim of this study was to compare published categorization criteria that differentiate maintainers and regainers via quantitative agreement.Design: The study used publicly available data from Look AHEAD (Action for Health in Diabetes; n = 1791) and Diabetes Prevention Program (DPP; n = 613) participants with ≥3% initial weight loss after lifestyle interventions and 4-y follow-up data. Eight previously published criteria defining maintainers and regainers were compared with respect to number of participants and concordance via agreement statistics. Criteria were assessed separately among those with 3-9% and ≥10% initial weight loss.Results: Regainers had higher body weight at year 4 than did maintainers (mean difference range: 6.6-11.9 kg in Look AHEAD; 11.5-14.6 kg in DPP; P < 0.0001). Assessing concordance among criteria, agreement was dependent on initial weight loss. Among those with 3-9% initial weight loss in both cohorts, 9 of 28 comparisons were concordant (agreement ≥80%). Among those with ≥10% initial weight loss, 7 of 28 comparisons in Look AHEAD and 13 of 28 in the DPP were in high agreement. The definition of successful weight-loss maintenance "regaining ≤25% of initial weight loss during maintenance" showed high agreement with the most commonly used definition of "staying ≥10% below initial weight" among those with ≥10% initial weight loss (agreement: 85.0% in Look AHEAD; 87.4% in DPP). The same definition of ≤25% regain showed high agreement with the definition of staying ≥5% below initial weight among those with 3-9% initial weight loss (agreement: 91.6% in Look AHEAD; 90.5% in DPP).Conclusions: Although all of the criteria discriminated on the basis of weight loss, many showed low agreement, which limited cross-study comparisons. Among criteria with high agreement, the definition of successful weight maintenance "regaining ≤25% of initial weight loss during maintenance" is a preferred definition of success, given the realistic challenges of maintaining 100% weight loss and flexible application in populations with high initial weight-loss variations. This trial was registered at clinicaltrials.gov as NCT00017953 (Look AHEAD) and NCT00004992 (DPP).