Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

Cardiovascular and renal diseases in type 2 diabetes patients: 5-year cumulative incidence of the first occurred manifestation and hospitalization cost: a cohort within the French SNDS nationwide claims database.

BACKGROUND: Myocardial infarction (MI), stroke, peripheral arterial disease (PAD), heart failure (HF) and chronic kidney disease (CKD) are common cardiovascular renal diseases (CVRD) manifestations for type 2 diabetes. The objective was to estimate the incidence of the first occurring CVRD manifestation and cumulative hospitalization costs of each CVRD manifestation for type 2 diabetes without CVRD history. METHODS: A cohort study of all type 2 diabetes free of CVRD as of January 1st 2014, was identified and followed-up for 5 years within the French SNDS nationwide claims database. The cumulative incidence of the first occurring CVRD manifestation was estimated using the cumulative incidence function, with death as a competing risk. Cumulative hospitalization costs of each CVRD manifestations were estimated from the perspective of all payers. RESULTS: From 2,079,089 type 2 diabetes without cancer or transplantation, 76.5% were free of CVRD at baseline with a mean age of 65 years, 52% of women and 7% with microvascular complications history. The cumulative incidence of a first CVRD manifestation was 15.3% after 5 years of follow-up with a constant linear increase over time for all CVRD manifestations: The most frequent was CKD representing 40.6% of first occurred CVRD manifestation, followed by HF (23.0%), then PAD (13.5%), stroke (13.2%) and MI (9.7%). HF and CKD together reached about one patient out of ten after 5 years and represented 63.6% of first CVRD manifestations. The 5-year global cost of all CVRD hospitalizations was 3.9 billion euros (B€), i.e. 2,450€ per patient of the whole cohort, with an exponential increase over time for each specific CVRD manifestation. The costliest was CKD (2.0 B€), followed by HF (1.2 B€), then PAD (0.7 B€), stroke (0.6 B€) and MI (0.3 B€). CONCLUSIONS/INTERPRETATION: While MI, stroke and PAD remain classic major risks of complications for CVRD-free type 2 diabetes, HF and CKD nowadays represent individually a higher risk and cost than each of these classic manifestations, and jointly represents a risk and a cost twice as high as these three classic manifestations all together. This should encourage the development of specific HF and CKD preventive strategies.

Cohort Event Monitoring of Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose.

INTRODUCTION: COVID-19 vaccines were rapidly authorised, thus requiring intense post-marketing re-evaluation of their benefit-risk profile. A multi-national European collaboration was established with the aim to prospectively monitor safety of the COVID-19 vaccines through web-based survey of vaccinees. METHODS: A prospective cohort event monitoring study was conducted with primary consented data collection in seven European countries. Through the web applications, participants received and completed baseline and up to six follow-up questionnaires on self-reported adverse reactions for at least 6 months following the first dose of COVID-19 vaccine (Netherlands, France, Belgium, UK, Italy) and baseline and up to ten follow-up questionnaires for one year in Germany and Croatia. Rates of adverse reactions have been described by type (solicited, non-solicited; serious/non-serious; and adverse events of special interest) and stratified by vaccine brand. We calculated the frequency of adverse reaction after dose 1 and prior to dose 2 among all vaccinees who completed at least one follow-up questionnaire. RESULTS: Overall, 117,791 participants were included and completed the first questionnaire in addition to the baseline: 88,196 (74.9%) from Germany, 27,588 (23.4%) from Netherlands, 984 (0.8%) from France, 570 (0.5%) from Italy, 326 (0.3%) from Croatia, 89 (0.1%) from the UK and 38 (0.03%) from Belgium. There were 89,377 (75.9%) respondents who had received AstraZeneca vaccines, 14,658 (12.4%) BioNTech/Pfizer, 11,266 (9.6%) Moderna and 2490 (2.1%) Janssen vaccines as a first dose. Median age category was 40-49 years for all vaccines except for Pfizer where median age was 70-79 years. Most vaccinees were female with a female-to-male ratio of 1.34, 1.96 and 2.50 for AstraZeneca, Moderna and Janssen, respectively. BioNtech/Pfizer had slightly more men with a ratio of 0.82. Fatigue and headache were the most commonly reported solicited systemic adverse reactions and injection-site pain was the most common solicited local reaction. The rates of adverse events of special interest (AESIs) were 0.1-0.2% across all vaccine brands. CONCLUSION: This large-scale prospective study of COVID-19 vaccine recipients showed, for all the studied vaccines, a high frequency of systemic reactions, related to the immunogenic response, and local reactions at the injection site, while serious reactions or AESIs were uncommon, consistent with those reported on product labels. This study demonstrated the feasibility of setting up and conducting cohort event monitoring across multiple European countries to collect safety data on novel vaccines that are rolled out at scale in populations which may not have been included in pivotal trials.

Patients with stable coronary artery disease and type 2 diabetes but without prior myocardial infarction or stroke and THEMIS-like patients: real-world prevalence and risk of major outcomes from the SNDS French nationwide claims database.

AIM AND HYPOTHESES: The THEMIS randomized trial compared ticagrelor plus aspirin versus placebo plus aspirin for patients with stable coronary artery disease and type 2 diabetes mellitus (CAD-T2DM), and without prior myocardial infarction (MI) or stroke. The aim of the study was to quantify the size of the CAD-T2DM population without prior MI or stroke population in a real-world setting, and more specifically populations with similar THEMIS selection criteria (THEMIS-like and THEMIS-PCI-like populations), as well as their risk of major outcomes in current practice. METHODS: A 2-year follow-up cohort study included all CAD-T2DM without MI/stroke prevalent patients on January 1st, 2014 in the SNDS French nationwide claims database. The THEMIS-like population concerned those ≥ 50 years of age with similar THEMIS inclusion and exclusion criteria. Prevalence was standardized to the European population. The cumulative incidence function was used to estimate the incidence of clinical outcomes (MI, ischemic stroke, and major bleeding according to the TIMI classification) with death as competing risk, and the Kaplan-Meier estimate for all-cause death and a composite outcome of MI, stroke and all-cause death. RESULTS: From a population of about 50 million adults, the prevalence of CAD-T2DM without MI/stroke, THEMIS-like and THEMIS-PCI-like populations was respectively at 6.04, 1.50 and 0.27 per 1000 adults, with a mean age of 72.7, 72.3 and 70.9 years and less comorbidities and diabetic complications for the THEMIS-like and THEMIS-PCI-like population. The 2-year cumulative incidence was respectively 1.7%, 1.3% and 1.6% for MI, 1.7%, 1.5% and 1.4% for stroke, 4.8%, 3.1% and 2.9% for major bleeding, 13.6%, 9.7% and 6.8% for all-cause death, and 16.2%, 12.0% and 9.5% for the composite outcome. CONCLUSION: THEMIS-like prevalence was estimated at 1.50 per 1,000 adults, representing about a quarter of CAD-T2DM without MI/stroke patients, and 0.27 per 1000 adults for the THEMIS-PCI-like populations. In current French practice, the median age of both these populations was about 5-6 years older than in the THEMIS trial, with a 2-year incidence of major outcomes between two or four time above the ones of the placebo arm of the THEMIS trial using very close definitions. Registration No. EUPAS27402 ( http://www.ENCEPP.eu ).

Use of Nalmefene in Routine Practice: Results from a French Prospective Cohort Study and a National Database Analysis.

AIMS: Two complementary studies were used to assess the real-life use of nalmefene in alcohol-dependent patients and its impact on alcohol use health status. METHODS: USE-PACT was a prospective cohort study designed to evaluate the real-life effectiveness of nalmefene in the management of alcohol dependence, as assessed by total alcohol consumption (TAC) and number of heavy drinking days (HDD) at 1 year. USE-AM was a cohort study using data from the French nationwide claims database and was used to evaluate the external validity of the population in the prospective study. RESULTS: Overall, 256 of 700 new nalmefene users enrolled in the USE-PACT study had valid data at 1 year. After 1 year, patients treated with nalmefene showed a mean ± SD reduction from baseline in TAC (-41.5 ± 57.4 g/day) and number of HDD (-10.7 ± 11.7 days/4 weeks). Patients took a mean ± SD of 20.0 ± 12.0 tablets/4 weeks (median of 1 tablet/day) for the first 3 months and then reduced the dose. The proportion of patients who no longer took nalmefene gradually increased from 5% at 1 month to 52% at 1 year. The USE-AM study identified 486 patients with a first reimbursement for nalmefene in 2016; baseline characteristics confirmed external validity of the USE-PACT study. Overall, 46.3% of initial USE-AM prescriptions were made by GPs; most (91.8%) patients stopped treatment during follow-up. However, 15.2% of patients resumed treatment after stopping. CONCLUSIONS: In this analysis of French routine practice, patients with alcohol dependence treated with nalmefene showed reduced alcohol consumption, and nalmefene was generally well tolerated.

Secondary prevention of acute coronary syndrome with antiplatelet agents in real life: A high-dimensional propensity score matched cohort study in the French National claims database.

Users of newly marketed drugs often differ from the patients included in randomized clinical trials, and from patients prescribed similar drugs. Cohorts of such users may be compared using propensity score adjustment, or similar user cohorts may be built using high-dimensional propensity score matching in large population databases. One such database is SNDS, the French nationwide claims and hospitalization database, which covers 99 % of the French population. It has yet been rarely used. To study the comparative effectiveness and safety in secondary coronary prevention of ticagrelor, compared to clopidogrel or prasugrel, we identified in SNDS patients who were dispensed any of the three antiplatelet agents of interest (± aspirin) within a month after discharge from hospital for acute coronary syndrome (ACS) and followed them one year for recurrence of ACS, stroke, acute bleeding, or death. High-dimensional propensity scores were developed to identify matched cohorts. Drug performances were also compared in the whole population using adjustment on the same parameters. Here we describe the database that was used, and the methods developed for the high-dimensional propensity score matching, resulting in standardized mean differences between the matched populations of less than 2 % for all of the 500+ variables included in the model. •This study was done in a newly available large-scale claims database, which may differ from other population databases, by it size and exhaustiveness•The methods elaborate on standard high-dimensional propensity scores as adapted to this claims database.

Comparative Real-Life Effectiveness and Safety of Dabigatran or Rivaroxaban vs. Vitamin K Antagonists: A High-Dimensional Propensity Score Matched New Users Cohort Study in the French National Healthcare Data System SNDS.

BACKGROUND: Clinical trials have indicated that the direct-acting oral anticoagulants dabigatran and rivaroxaban have better risk/benefit profiles than do vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (NVAF). OBJECTIVE: Our objective was to compare the 1-year real-life risk of major clinical events with dabigatran or rivaroxaban versus VKAs for NVAF. METHODS: This was a high-dimensional propensity score (hdPS)-matched cohort study of new users of dabigatran, rivaroxaban or VKAs for NVAF in the French national healthcare systems database in 2013 followed-up for 1 year [22]. Hazard ratios (HRs) with 95% confidence intervals (CIs) for clinical events and death were determined during exposure. RESULTS: In 2013, a total of 103,101 new anticoagulant users had definite NVAF: 44,653 VKA, 27,060 dabigatran, and 31,388 rivaroxaban. In matched populations, HRs were as follows for dabigatran versus VKAs (20,489 per group): stroke and systemic embolism (SSE) 0.75 (95% CI 0.63-0.88), clinically relevant bleeding (CRB) 0.58 (95% CI 0.51-0.66), hemorrhagic stroke (HS) 0.22 (95% CI 0.14-0.36), gastrointestinal bleeding (GIB) 0.98 (95% CI 0.80-1.19), acute coronary syndrome (ACS) 0.79 (95% CI 0.65-0.95), death 0.74 (95% CI 0.67-0.82), composite (any of the above) 0.71 (95% CI 0.66-0.76). For matched rivaroxaban versus VKA (23,053 per group) HRs were as follows: SSE 0.98 (95% CI 0.85-1.14), CRB 0.83 (95% CI 0.75-0.92), HS 0.65 (95% CI 0.49-0.87), GIB 1.08 (95% CI 0.90-1.30), ACS 0.84 (95% CI 0.71-1.00), death 0.77 (95% CI 0.71-0.84), composite 0.84 (95% CI 0.79-0.89). Numbers needed to treat to observe one fewer death were 49 ± 0.05 with dabigatran or rivaroxaban versus VKAs. CONCLUSION: Consistent with results from clinical trials and other observational studies, dabigatran and rivaroxaban were at least as effective and safer than VKAs for the prevention of thromboembolic events in NVAF over 1 year in the French population. STUDY REGISTRATION: European Medicines Agency EUPAS 13017 (www.encepp.eu) Clinicaltrials.gov id NCT02785354.

Reduced dose of rivaroxaban and dabigatran vs. vitamin K antagonists in very elderly patients with atrial fibrillation in a nationwide cohort study.

AIMS: The real-life benefits and risks of the non-vitamin K antagonist oral anticoagulants for stroke prevention in very elderly patients with atrial fibrillation (AF) are still debated. METHODS AND RESULTS: Cohorts of new users of rivaroxaban 15 mg, dabigatran 110 mg, or vitamin K antagonists (VKA) for AF ≥85 years old in 2013 or 2014 were identified in the nationwide French claims database and followed-up for 1 year. Cohorts were compared after 1:1 matching using high-dimensional propensity score. Compared to VKA use and considering 1-year cumulative incidences, risk of stroke, and systemic embolism was not different with rivaroxaban use [hazard ratio 1.14, 95% confidence interval (CI): 0.93-1.40] and lower with dabigatran use (0.77, 95% CI: 0.60-0.99), risk of major bleeding was not different with rivaroxaban use (0.91, 95% CI: 0.74-1.11) and with dabigatran use (0.81, 95% CI: 0.64-1.03), risk of all-cause death was borderline to significance lower with rivaroxaban use (0.91, 95% CI: 0.83-1.00), and lower with dabigatran use (0.87, 95% CI: 0.78-0.97). The risk for a composite of all events above was not different with rivaroxaban use (0.96, 95% CI: 0.88-1.04) and lower with dabigatran use (0.87, 95% CI: 0.79-0.96) as compared with VKA use. The risk for the composite of all events was not different with rivaroxaban use as compared with dabigatran use (1.09, 95% CI: 0.97-1.23). CONCLUSION: This study shows for the first time in more than 25 000 new real-life anticoagulant users for AF aged ≥85 years a neutral overall benefit-risk of rivaroxaban 15 mg vs. VKA and a favourable overall benefit-risk of dabigatran 110 mg vs. VKA on relevant clinical events. STUDY REGISTRATION: European Medicines Agency EUPAS14567 (www.encepp.eu) and Clinicaltrials.gov id NCT02864758.

Use of benzodiazepines and z-drugs not compliant with guidelines and associated factors: a population-based study.

Benzodiazepines and z-drugs are primarily indicated for the treatment of sleep disorders and anxiety symptoms. Their frequent long-term use contrasts with the international guidelines that limit treatment duration to a maximum of 4 weeks. The objective of this study was to assess the frequency of their use that was not in accordance with guidelines in the French general population between 2007 and 2012 and associated characteristics. A cohort of 67,550 benzodiazepine new users was set up in an exhaustive database for health-care reimbursements and representative of the French population. Benzodiazepine use not in accordance with guidelines was defined as the concomitant dispensation of several benzodiazepines, the dispensation of treatment over a period longer than recommended, or a new dispensing within the 2 months following the end of a previous treatment of maximum recommended duration, considering that French recommendations distinguish between hypnotic (4 weeks) and anxiolytic benzodiazepines (12 weeks). Benzodiazepine use not in accordance with guidelines was high, in about 30% of new hypnotic users and 20% of new anxiolytic users. Its frequency was stable over the study period. Associated characteristics were similar for new hypnotic or anxiolytic users, i.e.. older age, treatment initiation by a psychiatrist, presence of a chronic disease, hospitalization, or another psychotropic treatment. These findings provide a solid basis for establishing a public health policy to reduce benzodiazepine use not compliant with guidelines. They should be further explored in patients most at risk in the present study, e.g., patients treated by a psychiatrist.

Effectiveness and Safety of Rivaroxaban 15 or 20 mg Versus Vitamin K Antagonists in Nonvalvular Atrial Fibrillation.

Background and Purpose- We compared the 1-year safety and effectiveness of rivaroxaban 15 mg (R15) or rivaroxaban 20 mg (R20) to vitamin K antagonists (VKAs) in patients with nonvalvular atrial fibrillation. Methods- New user cohort study of patients dispensed R15 or R20 versus VKA in 2013 or 2014 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million people). R15 and R20 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing, and high-dimensional propensity score. Hazard ratios (95% CIs) for stroke and systemic embolism, major bleeding, and death were computed using Cox proportional hazards or models by Fine and Gray during exposure. Results- In 31 171 matched R20 and VKA, mean age, 71; 62% men; 76% with CHA2DS2-VASc ≥2; 5% HAS-BLED >3 (hypertension, abnormal renal and liver function, stroke, bleeding, labile INR, elderly, drugs or alcohol); incidence rates for stroke and systemic embolism were 1.5% and 1.9% (hazard ratio, 0.79 [0.69-0.90]); major bleeding, 1.5% and 2.2% (0.67 [0.59-0.77]); death, 3.9% and 5.8% (0.67 [0.61-0.73]). In 23 314 matched R15 and VKA patients, mean age, 80; 47% men; 93% with CHA2DS2-VASc ≥2 and 9% with HAS-BLED >3; incidence rates of stroke and systemic embolism were 2.3% and 2.1% (1.05 [0.92-1.21]); major bleeding, 2.4% and 2.9% (0.84 [0.74-0.96]); death, 9.1% and 10.8% (0.85 [0.79-0.90]). Numbers needed to treat to observe one fewer death (NNT) were 46 for R15 and 61 for R20. Conclusions- In real life in France over 2013 to 2015, R15 and R20 were at least as effective and safer than VKA. Clinical Trial Registration- URL: http://www.encepp.eu. Unique identifier: EUPAS14567.

Monitoring of drug misuse or potential misuse in a nationwide healthcare insurance database: A cross-sectional study in France.

AIM OF THE STUDY: To provide a tool for drug misuse or potential misuse monitoring by using a healthcare insurance database. METHODS: A cross-sectional study repeated quarterly from 2007 to 2014 was conducted using data from a 1/97th random sample of the French national healthcare reimbursement system. For each drug studied, ad hoc indicators were designed to assess drug misuse, defined as prescriptions that did not comply with the label stipulated in the summary of product characteristics, in terms of the drug (e.g., interactions) or the patient (age, medical history). We focused on specifically identified situations of drug misuse involving non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics in patients with Parkinson's disease and antipsychotics in pediatrics; we also focused on direct anticoagulants, asthma and oral antidiabetic drugs but results for these latter are only shown in supplementary materials. RESULTS: At-risk prescribing of NSAIDs in patients treated by diuretics or renin-angiotensin system inhibitors always remained higher than 14% over the study (maximum: 19%; 2014 quarter 4: 15.4%). Off-label prescribing of contraindicated anti-dopaminergic antiemetics with dopaminergic antiparkinson drugs was marginal (maximum: 2.2%; 2014 quarter 4: 0.5%) but represented at least 5.5% of antiemetic prescriptions. Despite the rise in antipsychotic prescriptions in pediatrics, no dramatic increase in misuse related to age was observed during the study period (2007 quarter 1: 16.1%; 2014 quarter 4: 11.1%). The highest degree of misuse was observed for aripiprazole and for second-generation antipsychotics other than risperidone and aripiprazole. CONCLUSION: This study provides a simple tool to monitor drug misuse or potential misuse using information from a health insurance database. The results highlight the need for the Regulator to rethink risk management information campaigns and to modify the official information on products.

Six-year survival study after myocardial infarction: The EOLE prospective cohort study. Long-term survival after MI.

BACKGROUND: Studies of survival after myocardial infarction (MI) are often based on intention to treat analyses of controlled trials. OBJECTIVES: Describe long-term survival after MI in France. METHODS: Six-year cohort study of patients recruited within 3 months after MI. Primary outcome was all-cause death. Vital status was verified in the national death registry. Analysis used Cox models with time-dependent variables and propensity scores. RESULTS: Five thousand five hundred and twenty-seven (5527) subjects were included, 62.1±13 years old, 77.6% male, 9.6% smokers, 16.7% diabetic, 13.3% with previous MI. Up to 99% of patients were initially prescribed secondary prevention drugs (aspirin and/or other antiplatelet agents, beta-blockers, statins or other lipid-lowering agents, angiotensin converting enzyme inhibitors or angiotensin receptor blockers); 73% had all four classes. Overall 6-year mortality was 13.1% [95% confidence interval 12.3 to 14.0%], 2.34 per hundred patient-years (% PY); 49% returned all or all but one of the possible questionnaires (compliant [C]), 50.8% did not (non-compliant [NC]). The main predictors for death were non-compliance with study protocol (death rates NC 2.98% PY, C 1.69%PY, hazard ratio (HR) 3.13 [2.63-3.57]); increasing age at inclusion (HR up to 15.7 [10.7-23.2] for age ≥80); diabetes (1.39 [1.17-1.65]); smoking at inclusion (1.76 [1.27-2.44]), previous MI (1.46 [1.22-1.75]). Beta-blockers (0.79 [0.64-0.96]), statins (0.68 [0.51-0.90]), and enrolment in physical rehabilitation programs (0.74 [0.62-0.89]) were associated with a lower death rate. CONCLUSION: Association of mortality with non-compliance to study protocol probably indicates general non-compliance with prevention. Analyses of treatment effects were hindered by paucity of events and of unexposed patients.

Secondary prevention of acute coronary events with antiplatelet agents (SPACE-AA): One-year real-world effectiveness and safety cohort study in the French nationwide claims database.

BACKGROUND AND AIMS: We aimed to compare the effectiveness of ticagrelor vs. clopidogrel or prasugrel on recurrence of acute coronary syndromes (ACS) in real-life conditions, as requested by regulatory authorities at the time of marketing. METHODS: We performed a cohort study in SNDS, the French national healthcare database. All patients with a hospital admission for ACS in 2013 were followed one year. Patients on ticagrelor, clopidogrel or prasugrel were matched 1:1 using age, gender, index ACS type, and high-dimensional propensity scores (hdPS). Outcomes were ACS, stroke, all-cause death, and major bleeding, compared within matched groups using Cox proportional hazards models analysis during treatment. RESULTS: 54,048 ACS were hospitalized in 2013. At discharge, 19,796 were dispensed clopidogrel, 8242 prasugrel, and 13,916 ticagrelor. Per group, 9224 ticagrelor vs. clopidogrel, 6752 ticagrelor vs. prasugrel, and 4676 prasugrel vs. clopidogrel patients were matched. Compared to clopidogrel, ticagrelor was associated with a lower hazard ratio of death 0.73 [0.59-0.90] and composite criterion (0.88, 95% CI [0.79-0.99] but not ACS 0.92 [0.80-1.06], stroke (0.96 [017-5.53]) or major bleeding (1.02 [0.82-1.26]). Prasugrel was not different from ticagrelor or clopidogrel for any outcome, in matched patients. CONCLUSIONS: Ticagrelor in real-life conditions in matched populations was associated with a lower risk of all-cause death than clopidogrel, and a lower risk of composite outcome, as in the main pivotal clinical trial. Ticagrelor and prasugrel were not different, nor were prasugrel and clopidogrel.

Comparative Effectiveness and Safety of Standard or Reduced Dose Dabigatran vs. Rivaroxaban in Nonvalvular Atrial Fibrillation.

Dabigatran and rivaroxaban at standard or reduced doses have been compared to warfarin in nonvalvular atrial fibrillation (NVAF), but not to each other. This was a new user study of standard dose and reduced dose dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high-dimensional propensity score, followed 2 years. Hazard ratios (HRs; 95% confidence intervals (CI)) of stroke or systemic embolism (SSE), major bleeding (MB), or death were computed. In matched standard-dose patients (8,290 per arm), mean age 67 years, HRs for dabigatran vs. rivaroxaban were SSE 0.92 (95% CI = 0.67-1.26), MB 0.59 (95% CI = 0.39-0.90), and death 0.84 (95% CI = 0.65-1.11). In reduced-dose patients (7,639 per arm), mean age 80 years, HRs for dabigatran vs. rivaroxaban were SSE 0.73 (95% CI = 0.59-0.94), MB 0.74 (95% CI = 0.57-0.96), and death 0.95 (95% CI = 0.83-1.09). In conclusion, at either dose, dabigatran had similar or better effectiveness than rivaroxaban but lower bleeding risk. Death rates were not different.

Effectiveness and safety of 110 or 150 mg dabigatran vs. vitamin K antagonists in nonvalvular atrial fibrillation.

AIMS: We compared the 1-year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) twice daily to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation. METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing and high-dimensional propensity score. Hazard ratios [HR (95% confidence intervals)] for stroke and systemic embolism (SSE), major bleeding (MB) and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14 442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA2 DS2 -VASc ≥2 and 8% with HAS-BLED score >3, incidence rates of SSE were 1.9% and 2.6% person-years [HR 0.69 (0.56-0.84)], MB 1.8% and 2.9% [0.62 (0.51-0.76)], death 7.2% and 8.6% [0.84 (0.76-0.94)]. In 8389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA2 DS2 -VASC ≥2; < 5% HAS-BLED >3, incidence rates were for SSE 1.4% and 1.9% [0.76 (0.56-1.04)], MB 0.6% and 1.9% [0.30 (0.20-0.46)], death 1.6% and 3.6% [0.46 (0.35-0.59)]. Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150. CONCLUSION: In real life D110 and D150 were at least as effective, and safer than VKA.

Medications Recommended for Secondary Prevention After First Acute Coronary Syndrome: Effectiveness of Treatment Combinations in a Real-Life Setting.

Long-term effectiveness of evidence-based cardiovascular medications (EBCMs) indicated after acute coronary syndrome (ACS) needs to be assessed considering the combination effects for these drugs recommended in association. Using a nationwide database, we conducted a cohort study to evaluate the effectiveness of all possible incomplete EBCMs-based combinations as compared to that associating the four recommended EBCMs over up to 5 years of follow-up. Among the 31,668 patients included, 22.9% had ACS recurrence or died during follow-up. The risks associated with the use of 3-EBCM based combinations were 1.46 (95% confidence interval: 1.33-1.60) for the combinations without statins, 1.30 (1.17-1.43) for the combinations without angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 1.11 (0.98-1.25) for the combinations without antiplatelet agents, and 0.99 (0.89-1.10) for the combination without beta-blockers. These findings question the interest of maintaining long-term treatment with beta-blockers in addition to the other EBCMs for post-ACS secondary prevention.

Outcomes in patients after myocardial infarction similar to those of the PEGASUS-TIMI 54 trial: A cohort study in the French national claims database.

AIMS: The present study aims to describe real-life outcomes in stable patients after-myocardial infarction (MI) similar to those in the PEGASUS-TIMI 54 trial (PEGASUS), which found long-term benefits of ticagrelor in patients with a history of MI. METHODS: One-year event-free post-MI patients were identified in the French claims database representative 1/97 sample (2005-2010) and followed for up to 3 years. A PEGASUS-like (PL) population included patients with age ≥ 65 years, or age ≥ 50 and diabetes, renal dysfunction or prior MI, without stroke, end-stage renal failure or oral anticoagulation. Outcomes were: a composite of all-cause death or hospital admission for MI or stroke; individual events; major bleeding. RESULTS: There were 1585 post-MI patients totalling 3926 person-years including 865 PL patients (2114 PY); 68% were male; mean age was 66 (standard deviation 15) in post-MI, 74 (10) in PL. Outcomes per 100 person-years [95% confidence interval] were, respectively, in post-MI and PL 6.3 [5.6-7.1] and 7.8 [6.7-8.9] for the composite outcome; 5.1 [4.4-5.8] and 6.5 [5.5-7.6] for death; 1.0 [0.7-1.3] and 1.0 [0.6-1.4] for MI; 0.6 [0.4-0.9] and 0.9 [0.5-1.2] for stroke; 1.3 [0.9-1.6] and 1.4 [0.9-1.9] for major bleeding. Event rates were stable over the 3 study years. Placebo patients in the PEGASUS-TIMI54 Study were younger, more often male and had lower event rates, especially for all-cause death and major bleeding. CONCLUSIONS: Patients selected using the criteria described in PEGASUS were older with more comorbidities, resulting in higher all-cause death and bleeding rates, but similar MI recurrence rates.

A population database study of outcomes associated with vitamin K antagonists in atrial fibrillation before DOAC.

AIMS: This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF). METHODS: This was a cohort study in Echantillon Généraliste de Bénéficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome). RESULTS: Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2 DS2 -VASc score ≥ 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient-years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events. CONCLUSIONS: Real-life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials.