Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

Efficacy of Dabigatran for Dissolving Deep Vein Thromboses in Outpatients With a Deteriorated General Condition.

Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for the prevention of ischemic strokes in patients with nonvalvular atrial fibrillation (AF). At present, NOACs have been evaluated for the treatment of deep vein thrombosis (DVT). We examined the efficacy of dabigatran, the first NOAC for anticoagulation of AF in Japan, in outpatients who suffered from DVTs under a deteriorated general condition.Thirty-six consecutive outpatients diagnosed with DVT at our institute were enrolled. Not all patients could be hospitalized due to other clinical problems; 15 (42%) had malignant tumors, 9 (25%) psychological disorders, and 6 (17%) postoperative orthopedic disease. Dabigatran was administered at a dose of 110-150 mg once or twice daily, depending on the renal function and age. The mean dosage of dabigatran was 211.7 ± 36.6 mg per day. In 18 (50%) patients, the DVTs were completely dissolved and disappeared over a treatment term of 4.3 ± 4.3 months. In 9 patients (25%), the DVTs partly dissolved, but in the remaining 9 (25%) patients, dabigatran was totally ineffective. During a follow-up of 30.5 ± 5.3 months, DVTs did not recur with dabigatran in 18 patients with an effective efficacy. In a multivariate analysis, patients with small sized thromboses and those without malignant tumors were significantly associated with the DVTs dissolving (P = 0.003 and P = 0.006, respectively).Dabigatran was effective for dissolving DVTs in outpatients with a poor condition, particularly when the size of the DVT was small and malignant tumors were absent.

Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study.

OBJECTIVE: To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin. DESIGN: Retrospective, propensity matched cohort study. SETTING: Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees. PARTICIPANTS: New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013. MAIN OUTCOME MEASURES: Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model. RESULTS: The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively). CONCLUSIONS: The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.

Economic process to co-produce poly(ε-l-lysine) and poly(l-diaminopropionic acid) by a pH and dissolved oxygen control strategy.

This study tended to apply biorefinery of indigenous microbes to the fermentation of target-product generation through a novel control strategy. A novel strategy for co-producing two valuable homopoly(amino acid)s, poly(ε-l-lysine) (ε-PL) and poly(l-diaminopropionic acid) (PDAP), was developed by controlling pH and dissolved oxygen concentrations in Streptomyces albulus PD-1 fermentation. The production of ε-PL and PDAP got 29.4 and 9.6gL(-1), respectively, via fed-batch cultivation in a 5L bioreactor. What is more, the highest production yield (21.8%) of similar production systems was achieved by using this novel strategy. To consider the economic-feasibility, large-scale production in a 1t fermentor was also implemented, which would increase the gross profit of 54,243.5USD from one fed-batch bioprocess. This type of fermentation, which produces multiple commercial products from a unified process is attractive, because it will improve the utilization rate of raw materials, enhance production value and enrich product variety.

Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation.

BACKGROUND: The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established. METHODS AND RESULTS: We formed new-user cohorts of propensity score-matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67-0.96); intracranial hemorrhage, 0.34 (0.26-0.46); major gastrointestinal bleeding, 1.28 (1.14-1.44); acute myocardial infarction, 0.92 (0.78-1.08); and death, 0.86 (0.77-0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis. CONCLUSIONS: In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily, whereas the association of 75 mg twice daily with study outcomes was indistinguishable from warfarin except for a lower risk of intracranial hemorrhage with dabigatran.

Risk of bleeding with dabigatran in atrial fibrillation.

IMPORTANCE: It remains unclear whether dabigatran etexilate mesylate is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice. OBJECTIVE: To compare the risk of bleeding associated with dabigatran and warfarin using Medicare data. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011. EXPOSURES: Dabigatran users (n = 1302) and warfarin users (n = 8102). MAIN OUTCOMES AND MEASURES: We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities. RESULTS: Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. CONCLUSIONS AND RELEVANCE: Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.

[Doubts about the new oral anticoagulants]. / Vraagtekens bij de nieuwe antistollingsmiddelen: alarmerend signaal over de introductie van NOAC's.

Recently, The British Medical Journal published three articles and an editorial on the RE-LY trial and the admission to the market of dabigatran. In these publications, concerns were raised regarding the data in this key trial and the registration process. Moreover, a lack of transparency was brought to light about the safety of unmonitored dabigatran use. The results of the RE-LY trial were important evidence for an advice of the Health Council of the Netherlands on the introduction of the new oral anticoagulants (NOACs) in the Netherlands, published in 2012. At present, the question arises whether dabigatran use requires monitoring and what the consequences are for the cost-effectiveness of NOACs.

Novel oral anticoagulants in non-valvular atrial fibrillation.

Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥ 2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.

[Laboratory assessment of haemostatic parameters in patients taking a direct thrombin inhibitor].

The problem of prevention and treatment of thromboembolic complications has a significant place in clinical practice for many years. The gold-standard agents in long-term protection from embologenic strokes, secondary prevention of venous thromboses and embolisms still remain vitamin K antagonists (in Russia - warfarin). However, despite high efficacy, administration of warfarin is fraught with dangers and associated with a series of inconveniences. A direct thrombin inhibitor, dabigatran etexilate (hereinafter referred to as dabigatran) was approved in the Russian Federation for prevention of thromboembolic complications in orthopaedic practice (2009), for prevention of ischaemic embologenic stroke in atrial fibrillation (2011) and for treatment of recurrent thrombosis of deep veins and pulmonary artery thromboembolism (2014). A characteristic feature of a therapeutic agent possessing an anticoagulation effect is correlation between intensity of hypocoagulation and haemorrhage. The effect of dabigatran on the laboratory parameters of haemostasis has been studied insufficiently, with no practical guidelines on assessing these alterations for prediction of the risk for haemorrhagic and thromboembolic complications. The present study included a total of 65 patients with non-valvular aetiology atrial fibrillation, taking dabigatran during from 6 to 18 months. All patients underwent laboratory assessment of the coagulation level and measuring blood coagulation activation markers in dynamics 10-14 days, 1, 6, 12 and 18 months after taking the agent. Thromboembolic and haemorrhagic risks were also assessed. It was revealed that administration of dabigatran leads to alterations in the main parameters of coagulogram. Determination of prothrombin (in % according to Quick's method) and activated partial thromboplastin time may be used for qualitative assessment of hypocoagulation. During the follow up period no statistically significant changes in the coagulation activation markers level were observed.

Cost effectiveness of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in two different European healthcare settings.

OBJECTIVES: Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK). METHODS: A decision-analytic Markov model was used to analyse the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives in the Netherlands and the UK over a lifetime horizon. RESULTS: In the Netherlands, the use of rivaroxaban, apixaban, or dabigatran increased health by 0.166, 0.365, and 0.374 quality-adjusted life-years (QALYs) compared with coumarin derivatives, but also increased costs by 5,681, 4,754, and 5,465, respectively. The incremental cost-effectiveness ratios (ICERs) were 34,248, 13,024, and 14,626 per QALY gained. In the UK, health was increased by 0.302, 0.455, and 0.461 QALYs, and the incremental costs were similar for all three new oral anticoagulants (5,118-5,217). The ICERs varied from 11,172 to 16,949 per QALY gained. In the Netherlands, apixaban had the highest chance (37 %) of being cost effective at a threshold of 20,000; in the UK, this chance was 41 % for dabigatran. The quality of care, reflected in time in therapeutic range, had an important influence on the ICER. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran are cost-effective alternatives to coumarin derivatives in the UK, while in the Netherlands, only apixaban and dabigatran could be considered cost effective. The cost effectiveness of the new oral anticoagulants is largely dependent on the setting and quality of local anticoagulant care facilities.

Cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for stroke prevention in patients with atrial fibrillation.

PURPOSE: This study aimed to evaluate the cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for the prevention of stroke in patients with atrial fibrillation (AF) in Singapore. METHODS: A Markov model was constructed to compare the lifetime costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) of dabigatran 110 and 150 mg, rivaroxaban 20 mg and adjusted-dose warfarin from the perspective of the Singapore healthcare system, using clinical data from published studies, utilities from a patient-reported survey and costs from hospital databases. The target population was a hypothetical cohort of 65-year-old AF patients with no contraindications to anticoagulation. RESULTS: In the base-case analysis, the QALYs were 8.75 with warfarin, 8.73 with dabigatran 110 mg, 8.82 with dabigatran 150 mg, and 9.33 with rivaroxaban. The costs were Singapore dollar (SG$) 34,648 for warfarin, SG$54,919 for dabigatran 110 mg, SG$50,484 for dabigatran 150 mg and SG$51,975 for rivaroxaban. The ICER of rivaroxaban versus warfarin was SG$29,697 (US$26,727) per QALY. Rivaroxaban and warfarin had extended dominance over the high-dose dabigatran. The low-dose dabigatran was dominated by warfarin. Deterministic sensitivity analyses showed that the ICER of rivaroxaban versus warfarin was sensitive to cost of rivaroxaban and utilities for rivaroxaban and warfarin. Probability sensitivity analysis demonstrated that the probability of rivaroxaban being the optimal choice was 97.8% and 99.5% at a willingness-to-pay threshold of SG$65,000 (US$58,500) and SG$130,000 (US$117,000) per QALY, respectively. CONCLUSION: Rivaroxaban may be a cost-effective alternative to warfarin for the prevention of stroke in patients with AF in Singapore.

Identifying future research priorities using value of information analyses: left atrial appendage occlusion devices in atrial fibrillation.

BACKGROUND: Left atrial appendage occlusion devices are cost effective for stroke prophylaxis in atrial fibrillation when compared with dabigatran or warfarin. We illustrate the use of value-of-information analyses to quantify the degree and consequences of decisional uncertainty and to identify future research priorities. METHODS AND RESULTS: A microsimulation decision-analytic model compared left atrial appendage occlusion devices to dabigatran or warfarin in atrial fibrillation. Probabilistic sensitivity analysis quantified the degree of parameter uncertainty. Expected value of perfect information analyses showed the consequences of this uncertainty. Expected value of partial perfect information analyses were done on sets of input parameters (cost, utilities, and probabilities) to identify the source of the greatest uncertainty. One-way sensitivity analyses identified individual parameters for expected value of partial perfect information analyses. Population expected value of perfect information and expected value of partial perfect information provided an upper bound on the cost of future research. Substantial uncertainty was identified, with left atrial appendage occlusion devices being preferred in only 47% of simulations. The expected value of perfect information was $8542 per patient and $227.3 million at a population level. The expected value of partial perfect information for the set of probability parameters represented the most important source of uncertainty, at $6875. Identified in 1-way sensitivity analyses, the expected value of partial perfect information for the odds ratio for stroke with left atrial appendage occlusion compared with warfarin was calculated at $7312 per patient or $194.5 million at a population level. CONCLUSION: The relative efficacy of stroke reduction with left atrial appendage occlusion devices in relation to warfarin is an important source of uncertainty. Improving estimates of this parameter should be the priority for future research in this area.

[Cost-effectiveness of apixaban compared to other new oral anticoagulants in patients with non-valvular atrial fibrillation].

BACKGROUND: Atrial fibrillation is associated with development of thromboembolic events. New oral anticoagulants (apixaban, rivaroxaban and dabigatran) are recommended for antithrombotic therapy in patients with non-valvular atrial fibrillation (NVAF) with moderate and high risk of stroke. OBJECTIVES: The objective of this study was to evaluate the cost-effectiveness ratio of apixaban compared to dabigatran and rivaroxaban in patients with NVAF from the Russian Federation national health care system perspective. METHODS: This analysis used a Markov model that allowed estimation of the incremental cost-effectiveness ratio (ICER) for apixaban compared to rivaroxaban and dabigatran 110 mg and 150 mg over lifetime horizon for patients with NVAF. The model enclosed cardiovascular event rates based on the results of the indirect treatment comparison that combined data from the randomized clinical trials comparing clinical effectiveness and safety of apixaban, rivaroxaban and dabigatran with warfarin (ARISTOTLE, ROCKET-AF, RE-LY). The following cardiovascular events were considered: ischemic and hemorrhagic stroke, systemic embolism, intracranial hemorrhage, other major bleeds, clinically relevant non-major bleeds and myocardial infarction. Direct medical costs were determined based on the rates of the compulsory national medical insurance system. The price of the new oral anticoagulants was taken as a weighted average tender price for the year 2013. In the model both costs and benefits (quality-adjusted life years and life-years) were discounted at 3.5%. Cost-effectiveness threshold was set at 1.4 million rubles per quality-adjusted life year (QALY) gained and corresponded to the three times GDP per capita in 2013 in the Russian Federation. RESULTS: In the base case analysis it was demonstrated that apixaban compared to dabigatran 110 mg and 150 mg and rivaroxaban provided additional 0.101, 0.060 and 0.072 life years as well as additional 0.063; 0.038 and 0.041 QALYs respectively. Over lifetime horizon apixaban compared to dabigatran 110 mg and 150 mg and rivaroxaban required additional treatment costs equal to 22.78; 31.18 and 6.70 thousands rubles, respectively. With that estimated incremental cost-effectiveness ratio for apixaban compared to dabigatran 110 mg and 150 mg and rivaroxaban was 362.60, 805.54 and 162.45 thousands rubles per QALY correspondingly. CONCLUSION: Apixaban provided increased life expectancy compared to other new anticoagulants and may be considered as a cost-effective alternative to dabigatran 110 mg and 150 mg and rivaroxaban from the Russian Federation national health care system perspective.

Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients.

OBJECTIVE: This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE). RESEARCH DESIGN AND METHODS: Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEIN-Pooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out. RESULTS: A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were -$146, -$482, -$918, and -$344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy. CONCLUSIONS: When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.

Efficacy and cost-effectiveness of dabigatran etexilate versus warfarin in atrial fibrillation in different age subgroups.

This study aims to estimate the cost-effectiveness of dabigatran 150 mg twice daily versus warfarin for stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation initiating treatment before age 75 (<75), at or after age 75 (≥ 75), and the overall population (All) from a US Medicare payer perspective. Clinical event rates by age cohort with dabigatran or warfarin for safety-on-treatment and intent-to-treat populations were estimated from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY). An economic model was adapted using these data to evaluate the impact of starting age on clinical and economic outcomes. Costs were obtained from Medicare payment schedules and utilities from publications. Model outputs included event rates, costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. The RE-LY analysis shows that the <75 cohort has lower rates of all events than the ≥ 75 cohort; versus warfarin, dabigatran performed better in main efficacy and safety in all age cohorts with the exception of extracranial hemorrhage in the ≥ 75 cohort. The clinical event costs avoided per patient for dabigatran were $1,100, $135, and $713 for cohorts <75, ≥ 75, and All, respectively. Extrapolating over a lifetime horizon, the model found that dabigatran resulted in lower rates of stroke and intracranial hemorrhage and higher rates for extracranial hemorrhage versus warfarin for all age cohorts. Lifetime quality-adjusted life-years and costs were higher for dabigatran than warfarin, resulting in incremental cost-effectiveness ratios of $52,773, $65,946, and $56,131 for cohorts <75, ≥ 75, and All, respectively. In conclusion, dabigatran was cost-effective versus warfarin in US patients with atrial fibrillation regardless of age of treatment initiation.

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.