Comparative Safety and Effectiveness of Oral Anticoagulants in Nonvalvular Atrial Fibrillation: The NAXOS Study.

BACKGROUND AND PURPOSE: The effects of direct oral anticoagulants in nonvalvular atrial fibrillation should be assessed in actual conditions of use. France has near-universal healthcare coverage with a unified healthcare information system, allowing large population-based analyses. NAXOS (Evaluation of Apixaban in Stroke and Systemic Embolism Prevention in Patients With Nonvalvular Atrial Fibrillation) aimed to compare the safety, effectiveness, and mortality of apixaban with vitamin K antagonists (VKAs), rivaroxaban, and dabigatran, in oral anticoagulant-naive patients with nonvalvular atrial fibrillation. METHODS: This was an observational study using French National Health System claims data and including all adults with nonvalvular atrial fibrillation who initiated oral anticoagulant between 2014 and 2016. Outcomes of interest were major bleeding events leading to hospitalization (safety), stroke and systemic thromboembolic events (effectiveness), and all-cause mortality. Four approaches were used for comparative analyses: matching on propensity score (PS; 1:n); as a sensitivity analysis, matching on high-dimensional PS; adjustment on PS; and adjustment on known confounders. For each outcome, cumulative incidence rates accounting for competing risks of death were estimated. RESULTS: Overall, 321 501 patients were analyzed, of whom 35.0%, 27.2%, 31.1%, and 6.6% initiated VKAs, apixaban, rivaroxaban, and dabigatran, respectively. Apixaban was associated with a lower PS-matched risk of major bleeding compared with VKAs (hazard ratio [HR], 0.43 [95% CI, 0.40-0.46]) and rivaroxaban (HR, 0.67 [95% CI, 0.63-0.72]), but not dabigatran (HR, 0.93 [95% CI, 0.81-1.08]). Apixaban was associated with a lower risk of stroke and systemic thromboembolic event compared with VKAs (HR, 0.60 [95% CI, 0.56-0.65]), but not rivaroxaban (HR, 1.05 [95% CI, 0.97-1.15]) or dabigatran (HR, 0.93 [95% CI, 0.78-1.11]). All-cause mortality was lower with apixaban than with VKAs, but not lower than with rivaroxaban or dabigatran. CONCLUSIONS: Apixaban was associated with superior safety, effectiveness, and lower mortality than VKAs; with superior safety than rivaroxaban and similar safety to dabigatran; and with similar effectiveness when compared with rivaroxaban or dabigatran. These observational data suggest potentially important differences in outcomes between direct oral anticoagulants, which should be explored in randomized trials.

Risk of Recurrent Bleeding Events in Nonvalvular Atrial Fibrillation Treated with Vitamin K Antagonists: A Clinical Practice Research Datalink Study.

Background There is little evidence on how the occurrence of a bleed in individuals on vitamin K antagonists (VKAs) impacts the risk of subsequent bleeds, and thromboembolic and ischemic events. Such information would help to inform treatment decisions following bleeds. Objective To estimate the impact of bleeding events on the risk of subsequent bleeds, venous thromboembolism (VTE), stroke, and myocardial infarction (MI) among patients initiating VKA treatment for new-onset nonvalvular atrial fibrillation (NVAF). Methods We conducted an observational cohort study using a linked Clinical Practice Research Datalink-Hospital Episode Statistics dataset. Among a cohort of individuals with NVAF, the risk of clinically relevant bleeding, VTE, stroke, and MI was compared between the period prior to the first bleed and the periods following each subsequent bleed. The rate and cost of general practitioner (GP) consultations, prescriptions, and hospitalizations were also compared across these periods. Results The risk of clinically relevant bleeding events was observed to be elevated at least twofold in all periods following the first bleeding event. The risk of VTE, stroke, and MI was not found to differ according to the number of clinically relevant bleeding events. The rate and cost of GP consultations, GP prescriptions, and hospitalizations were increased in all periods relative to the period prior to the first bleed. Conclusions The doubling in the risk of bleeding following the first bleed, taken alongside the stable risk of MI, VTE, and stroke, suggests that the risk-benefit balance for VKA treatment should be reconsidered following the first clinically relevant bleed.

EvaluatioN of ApiXaban in strOke and systemic embolism prevention in patients with non-valvular atrial fibrillation in clinical practice Setting in France, rationale and design of the NAXOS: SNIIRAM study.

Non-vitamin K antagonists oral anticoagulants (NOACs) have recently challenged vitamin-K antagonists (VKAs) for stroke and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation (NVAF). Nevertheless, little information is available in routine clinical practice for France. The aim of this study is to describe the effectiveness and safety of apixaban, rivaroxaban, dabigatran or VKAs in routine clinical practice in adult NVAF patients for the prevention of stroke and systemic embolism in France. The NAXOS study is a nationwide observational retrospective cohort generated from the French national healthcare insurance database (SNIIRAM-a comprehensive in- and outpatient healthcare consumption database), consisting of eight distinct sub-cohorts of anticoagulant-naive or anticoagulant-experienced patients diagnosed with NVAF, newly initiated with either NOACs (dabigatran, rivaroxaban or apixaban) or VKAs. Patients will be included if initiating a new anticoagulant treatment for AF during the study period from 1 January 2014 to 31 December 2016. Primary effectiveness outcome will be the incidence of stroke or systemic thromboembolic events; primary safety outcome will be the incidence of major bleeding during the exposure period. The NAXOS study will provide routine clinical practice data on the effectiveness and safety profiles of apixaban vs other NOACs and VKAs in the prevention of stroke and systemic embolism in adult patients with NVAF in clinical practice conditions in France.

Real-world treatment patterns, resource use and cost burden of multiple myeloma in Portugal.

OBJECTIVE: We provide a real-world overview of multiple myeloma (MM) treatment patterns, outcomes and healthcare resource use (HRU) in Portugal. METHODS: Data were collected retrospectively from consecutive patients diagnosed/treated at the Portuguese Oncology Institute of Porto (IPO-Porto) between 2012 and 2015. Primary objectives were progression-free survival (PFS) and overall survival (OS), with treatment patterns and HRU secondary. Analysis was by line of therapy (LOT), and post hoc by age (<65/≥65 years). RESULTS: 165, 73 and 32 patients received first, second and third LOTs respectively (N = 187). OS probabilities were 91.5%, 83.2% (<65 years) and 86.6%, 65.3% (≥65 years) at 12, 24 months respectively. PFS decreased from the start of each LOT for both age groups and was less for patients ≥65 years. Younger patients received more combination treatment (immunomodulatory drugs + proteasome inhibitors) and stem cell transplants, and had higher mean costs than older patients (€81,213 vs. €36,864 where three LOTs were received). Cost drivers were medications, transplantations and hospitalisations. CONCLUSION: Our results suggest divergence between younger and older MM patients. Older patients had lower OS and PFS probabilities, HRU costs and fewer stem cell transplantations. The treatment patterns in each LOT may differ from other countries' findings, suggesting treatment heterogeneity.

Initiation and continuation of oral anticoagulant prescriptions for stroke prevention in non-valvular atrial fibrillation: A cohort study in primary care in France.

BACKGROUND: Oral anticoagulants are prescribed in non-valvular atrial fibrillation for stroke prevention; however, little is known about the current management of anticoagulation in France, particularly given the availability of non-vitamin K antagonist oral anticoagulants in recent years. AIMS: To describe the characteristics of patients prescribed oral anticoagulants, and assess treatment persistence in French primary care. METHODS: We conducted a cohort study of patients with non-valvular atrial fibrillation, who were newly prescribed oral anticoagulants between 1 January 2014 and 31 January 2016, using French primary care data (IMS Longitudinal Patient Database). Adjusting for baseline characteristics, risk of non-persistence (switch or discontinuation) was compared using Cox regression. RESULTS: Of 4111 patients, 1710 were newly prescribed vitamin K antagonists, 1257 rivaroxaban, 744 apixaban and 400 dabigatran. The median age was 76 years, and 57.5% were male. History of hypertension was the most common co-morbidity (68.1%). Compared with vitamin K antagonists, non-persistence was higher with rivaroxaban (hazard ratio: 1.28; 95% confidence interval: 1.13-1.45) and dabigatran (hazard ratio: 1.42; 95% confidence interval: 1.20-1.69) and similar with apixaban (hazard ratio: 1.12; 95% confidence interval: 0.96-1.32). CONCLUSIONS: Non-persistence (treatment discontinuation or switch) with vitamin K antagonists was lower than with rivaroxaban and dabigatran in French primary care; however, non-persistence with the newest drug, apixaban, was similar to vitamin K antagonists. Larger studies with longer follow-up are needed to support these findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Epidemiology, patient profile, and health care resource use for hepatitis C in Italy.

OBJECTIVE: The objectives of this study were to estimate the prevalence of Hepatitis C among six Italian Local Health Units (LHUs), to describe patient and antiviral drug characteristics, and to estimate the health care consumption rates and related costs for the management of patients affected by hepatitis C virus (HCV) infection by using data from routine clinical practice. METHODS: We conducted a retrospective study using administrative databases of six Italian LHUs. All patients who had a record related to HCV during the enrollment period (July 1, 2009, to December 31, 2014) and who had at least 6 months of data available prior to the first HCV record were included. The date of the first record related to HCV during the enrollment period was considered as a proxy of diagnosis and used as the index date. Patients were followed from the index date up to 1 year, death, or exiting the database. Using the overall cohort of HCV adult patients as the numerator, we estimated the prevalence of HCV among six LHUs. The denominators were obtained from the National Institute of Statistics (N=1,665,682). We also evaluated descriptive patient's characteristics and treatment patterns, and estimated health care consumption rates and related costs for the management of the HCV patients. RESULTS: A total of 7,550 patients were analyzed, of whom 57% were male with a mean age of 57.6±16.4 years. The prevalence of HCV was estimated to be 0.45% (95% confidence interval 0.44-0.46). During the follow-up period, 78.6% of HCV patients had received no antiviral treatment. The annual health care cost associated with HCV infection was €6,022.7 (±7,922.6) while the cost specific to HCV care was €3,154.6 (±4,972.0). CONCLUSION: Our findings showed that, in the Italian real-world setting, only a small proportion of HCV-infected patients received an antiviral treatment. Despite the current low prevalence of HCV, the economic impact of such disease remains high.

Oral anticoagulant persistence in patients with non-valvular atrial fibrillation: A cohort study using primary care data in Germany.

This study examined characteristics and treatment persistence among patients prescribed oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). We identified 15,244 patients (51.8% male, 72.7% aged ≥70) with NVAF and no prior OAC therapy who were prescribed apixaban (n = 1,303), rivaroxaban (n = 5,742), dabigatran (n = 1,622) or vitamin-K antagonists (VKAs, n = 6,577) between 1-Dec-2012 and 31-Oct-2014 in German primary care (IMS® Disease Analyzer). We compared OAC persistence using Cox regression over patients' entire follow-up and using a data-driven time-partitioned approach (before/after 100 days) to handle non-proportional hazards. History of stroke risk factors (stroke/transient ischaemic attack [TIA] 15.2%; thromboembolism 14.1%; hypertension 84.3%) and high bleeding risk (HAS-BLED score≥3 68.4%) was common. Apixaban-prescribed patients had more frequent history of stroke/TIA (19.7%) and high bleeding risk (72.6%) than other OACs. 12-month persistence rates were: VKA 57.5% (95% confidence interval (CI) 56.0-59.0%), rivaroxaban 56.6% (54.9-58.2%), dabigatran 50.1% (47.2-53.1%), apixaban 62.9% (58.8-67.0%). Over entire follow-up, compared to VKA, non-persistence was similar with apixaban (adjusted hazard ratio 1.08, 95% CI 0.95-1.24) but higher with rivaroxaban (1.21, 1.14-1.29) and dabigatran (1.53, 1.40-1.68). Using post-hoc time-partitioned approach: in first 100 days, non-persistence was higher with apixaban (1.37, 1.17-1.59), rivaroxaban (1.41, 1.30-1.53) and dabigatran (1.91, 1.70-2.14) compared to VKA. Compared to apixaban, rivaroxaban non-persistence was similar (1.03, 0.89-1.20), dabigatran was higher (1.39, 1.17-1.66). After 100 days, apixaban non-persistence was lower than VKA (0.66, 0.52-0.85); rivaroxaban (0.97, 0.87-1.07) and dabigatran (1.10, 0.95-1.28) were similar to VKA. Furthermore, rivaroxaban (1.46, 1.13-1.88) and dabigatran (1.67, 1.26-2.19) non-persistence was higher than apixaban. This study describes real-world observations on OAC use, particularly early apixaban use following approval for NVAF, in Germany. We identified potential differential OAC prescribing and higher persistence with apixaban than other OACs after 100 days' treatment. Larger studies are needed with longer follow-up to establish long-term patterns.

Evolving landscape of stroke prevention in atrial fibrillation within the UK between 2012 and 2016: a cross-sectional analysis study using CPRD.

OBJECTIVE: To describe the changes in prescribing of oral anticoagulant (AC) and antiplatelet (AP) agents in patients with non-valvular atrial fibrillation (NVAF) in the UK and to identify the characteristics associated with deviation from guideline-based recommendations. DESIGN: Five cross-sectional analyses in a large retrospective population-based cohort study. SETTING: General practices contributing data to the UK Clinical Practice Research Datalink. PARTICIPANTS: The study included patients with a diagnosis of NVAF and eligible for anticoagulation (CHA2DS2-VASc score ≥2) on 1 April of 2012, 2013, 2014, 2015 and 1st January 2016. RESULTS: The proportion of patients being treated with AC increased at each index date, showing an absolute rise of 16.7% over the study period. At the same time, the proportion of patients treated with an AP alone was reduced by half, showing an absolute decrease of 16.8%. The proportion of patients not receiving any antithrombotic (AT) treatment remained the same across the study period. A number of predictors were identified for AP alone or no treatment compared with AC treatment. CONCLUSION: Major improvements in the AT management of patients with NVAF for stroke prevention in the UK were observed between April 2012 and January 2016. Despite this, nearly 20% of at-risk patients still received AP alone and over 15% were on no AT agents in January 2016.

Major Bleeding Complications and Persistence With Oral Anticoagulation in Non-Valvular Atrial Fibrillation: Contemporary Findings in Real-Life Danish Patients.

BACKGROUND: The nonvitamin K antagonist oral anticoagulants have recently become available as an alternative to warfarin as stroke prophylaxis in atrial fibrillation, but data on real-life patient experience, including bleeding risk, are lacking. Our objective was to compare major bleeding events and nonpersistence between the nonvitamin K antagonist oral anticoagulant apixaban and other nonvitamin K antagonist oral anticoagulants (dabigatran and rivaroxaban) and warfarin in a contemporary, nation-wide cohort of patients with nonvalvular atrial fibrillation. METHODS AND RESULTS: Of 54 321 patients (median age, 73 years; 56% male; mean CHA2DS2-VASc score, 2.9), 7963, 6715, 15 413, and 24 230 patients initiated apixaban, rivaroxaban, dabigatran, and warfarin, respectively. Apixaban and rivaroxaban initiators were older, less often male, with higher HAS-BLED and CHA2DS2-VASc scores compared with dabigatran and warfarin initiators. A total of 2418 patients (4.5%) experienced a major bleeding event over all available follow-up. In this period, rivaroxaban (hazard ratio [HR] [95% CI], 1.49 [1.27-1.77]), dabigatran (HR, 1.17 [1.00-1.38]), and warfarin (HR, 1.23 [1.05-1.43]) users were significantly more likely to bleed than apixaban users. Findings were similar when restricted to the first 30 days after OAC initiation. Risk of nonpersistence was higher for dabigatran (HR, 1.45 [1.33-1.59]) and warfarin initiators (HR, 1.22 [1.12-1.33]), but not for rivaroxaban initiators (HR, 1.07 [0.96-1.20]) compared with apixaban initiators. CONCLUSIONS: In a real-world cohort of nonvalvular atrial fibrillation patients, apixaban had a lower adjusted major bleeding risk compared with rivaroxaban, dabigatran, and warfarin. Apixaban had a lower risk of nonpersistence compared with dabigatran and warfarin and similar risk compared with rivaroxaban.

The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease.

BACKGROUND: There is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options. METHODS: A retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling. RESULTS: The 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis. CONCLUSIONS: Daclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.

Early real-world evidence of persistence on oral anticoagulants for stroke prevention in non-valvular atrial fibrillation: a cohort study in UK primary care.

OBJECTIVES: To examine the characteristics and persistence in patients newly initiated with oral anticoagulants (OACs) for stroke prevention in non-valvular atrial fibrillation (NVAF). DESIGN: Cohort study in Clinical Practice Research Datalink. SETTING: UK primary care. PARTICIPANTS: 15 242 patients with NVAF newly prescribed apixaban, rivaroxaban, dabigatran or vitamin K antagonists (VKAs) between 1 December 2012 and 31 October 2014. 13 089 patients were OAC naïve. OUTCOME MEASURES: Patient characteristics and risk of non-persistence compared to apixaban using Cox regression models over the entire follow-up and using a time-partitioned approach to handle non-proportional hazards. RESULTS: Among the OAC naïve patients, VKAs were most common (78.1%, n=10 218), followed by rivaroxaban (12.1%, n=1589), dabigatran (5.7%, n=741) and apixaban (4.1%, n=541). High baseline stroke risk (CHA2DS2VASc ≥2) ranged from 80.2% (dabigatran) to 88.4% (apixaban and rivaroxaban). History of stroke and bleeding was the highest among apixaban (23.7% and 31.6%) and lowest among VKA patients (15.9% and 27.5%). Across the entire follow-up period, adjusting for differences in characteristics, there was no evidence of a difference in non-persistence between VKA and apixaban (HR 0.92 (95% CI 0.68 to 1.23)). Non-persistence was higher with dabigatran (HR 1.67 (1.20 to 2.32)) and rivaroxaban (HR 1.41 (1.02 to 1.93)) than apixaban. Using the partitioned approach, non-persistence was lower with VKA (HR 0.33 (0.22 to 0.48)), and higher with dabigatran (HR 1.65 (1.08 to 2.52)) compared to apixaban in the first 2 months of follow-up. After 2 months, non-persistence was higher with VKA (HR 1.70 (1.08 to 2.66)) and dabigatran (HR 2.10 (1.30 to 3.41)). Pooling OAC naïve and experienced patients, non-persistence was also higher with rivaroxaban compared to apixaban after 2 months of follow-up (HR 1.69 (1.19 to 2.39)). CONCLUSIONS: Observed differential prescribing of OACs can result in channelling bias in comparative effectiveness research. Persistence patterns changed over follow-up time, but there are indications of improved persistence rates with apixaban over other OACs in the UK. A larger study with longer follow-up is needed to corroborate findings. This study is registered on ClinicalTrials.gov (NCT02488421).

Literature review of the distribution of hepatitis C virus genotypes across Europe.

Recent advances in hepatitis C virus (HCV) therapies have transformed the treatment landscape for this disease. However, efficacy of current treatments depends on HCV genotype and individual patient characteristics. This review aimed to appraise observational studies reporting epidemiological outcomes to characterize HCV genotype distribution in Europe, in the general HCV population and various subpopulations of interest. MEDLINE and EMBASE entries published between November 2008 and November 2013 were systematically searched. Studies were grouped according to the patient populations of interest: general HCV population, HCV-HIV co-infected patients, patients with advanced fibrosis/cirrhosis, and liver transplant recipients. Thirty publications provided estimates of HCV genotype distribution in four distinct patient groups: general HCV population (n = 21), HCV-HIV co-infected patients (n = 6), liver transplant patients (n = 3), and patients with HCV-compensated cirrhosis (n = 1). Nationwide estimates of genotype distribution in the general HCV population were available for 10 countries, with genotypes 1 and 3 the most commonly reported. Romanian studies were found to have reported genotype 1 infections almost exclusively (98.0-99.8%). Considerable regional variation was reported in some countries (e.g., Italy), but not others (e.g., France). National and multi-national estimates for the HCV-HIV co-infected population suggested a different genotype distribution to that in the general HCV population. No studies reported nationwide genotype distribution in patients with advanced liver disease. Given the clinical importance of genotype in developing optimal HCV eradication strategies, further nationwide European studies are needed to fully characterize genotype distribution in both the general HCV population and in HCV subpopulations. J. Med. Virol. 88:2157-2169, 2016. © 2016 Wiley Periodicals, Inc.