A modified self‐controlled case series method for event‐dependent exposures and high event‐related mortality, with application to COVID‐19 vaccine safety

We propose a modified self‐controlled case series (SCCS) method to handle both event‐dependent exposures and high event‐related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID‐19 vaccines. Event‐dependence of vaccinations, and high event‐related mortality, are likely to arise in other SCCS studies of COVID‐19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death

Profiles of copper intrauterine devices and levonorgestrel intrauterine systems users in France in 2019: A national observational population-based study

International audienceObjective: To assess the user profiles of copper intrauterine devices (Cu-IUD) and levonorgestrel intrauterine systems (LNG-IUS) in France in 2019 and the rates of continuation 1 year later. Methods: A population-based study was conducted of all French women aged 13–49 years for whom an IUD was dispensed in 2019. Information was collected from the French National Health Data System about their characteristics at the time of dispensation and indicators of continued use 1 year later. Associations between these characteristics and the type of IUD were analyzed using multivariate regressions. Results: A total of 477 705 Cu-IUDs and 355 242 LNG-IUSs (mean age 32.5 ± 7.3 and 36.4 ± 7.7 years, respectively) were dispensed in 2019. After adjustment, having a LNG-IUS rather than a Cu-IUD was associated with being aged 35–44 years compared to 25–35 years (odds ratio [OR35–44] 2.03, 95% confidence interval [CI] 2.01–2.05), having a prescription by a gynecologist rather than a general practitioner (OR35–44 1.09, 95% CI 1.08–1.11), and having a gynecological history (OR35–44 2.28, 95% CI 2.20–2.36). The continuation rates 1 year after dispensation were 86.4% for Cu-IUD versus 85.7% for LNG-IUS. A Cu-IUD dispensation rather than a LNG-IUS one was associated with a higher chance of continued use 1 year later. Conclusion: Two different patterns of use of Cu-IUDs and LNG-IUSs in France are highlighted

Reduced risk of severe COVID-19 in more than 1.4 million elderly people aged 75 years and older vaccinated with mRNA-based vaccines

International audienceRandomized clinical trials have shown mRNA-based vaccines to be 92–95% effective to prevent COVID-19 in adults. We aimed to estimate the impact of vaccination on the risk of severe COVID-19 (requiring hospitalization) in elderly people. Each 1,422,461 vaccinated subject aged 75 or older was matched to two unvaccinated subjects of same age, sex, administrative region, and type of residence. They were followed from date of first injection between 27 December 2020 and 24 February 2021 to 20 March 2021 for COVID-19 hospitalization. Mean age was 82.4 years (SD, 5.7) and median follow-up was 38 days [IQR, 17–54]. Adjusted Hazard Ratio for COVID-19 hospitalization from day 7 after the second dose was estimated at 0.14 (95% confidence interval, 0.11–0.17), i.e. an estimated 86% risk reduction in people aged 75 and older, highlighting the major impact of mRNA vaccination on reducing the risk of COVID-19 among elderly people

Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID-19: A Nationwide Matched Population-Based Cohort Study

International audienceBACKGROUND: There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID-19. METHODS AND RESULTS: The French National Healthcare Data System database was used to conduct a matched-cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID-19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long-term medications. Its association with in-hospital death from COVID-19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID-19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81–0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low-and moderate-intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71–0.86] and HR, 0.84 [95% CI, 0.80–0.89], respectively), whereas high-intensity statins did not (HR, 1.01; 95% CI, 0.86–1.18). We found similar results with in-hospital death from COVID-19. CONCLUSIONS: Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID-19 and of in-hospital death from COVID-19

Comment on ‘Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19’ by Konig et al . Long-term exposure to hydroxychloroquine or chloroquine and the risk of hospitalisation with COVID-19: a nationwide, observational cohort study in 54 873 exposed individuals and 155 689 matched unexposed individuals in France

International audienceNo abstract availabl

Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France

Background: The BNT162b2 (Pfizer–BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. Objective: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. Design: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. Setting: France, 27 December 2020 to 20 July 2021. Patients: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). Measurements: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer–BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford–AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). Results: No association was found between the Pfizer–BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford–AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). Limitations: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. Conclusion: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. Primary Funding Source: None

Characteristics associated with the residual risk of severe COVID-19 after a complete vaccination schedule: A cohort study of 28 million people in France

International audienceBackground: Prior to the availability of vaccines, the risk factors for developing severe forms of COVID-19 were mostly older age and various comorbidities such as diabetes, cardiovascular diseases, mental disorders, transplantations, and kidney disease. Although vaccines have been shown to be highly effective in preventing severe forms of COVID-19, a residual risk may persist, despite vaccination, for certain population groups. Methods: The study was based on data from the national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS), which contains comprehensive reimbursement and hospitalisation data for all of France. All people fully vaccinated by July 31, 2021, with a double-injection vaccine, i.e., the mRNA BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 vaccines, or a single dose for people with a previous confirmed SARS-CoV-2 infection were included and followed until August 31, 2021. Cox proportional hazard models were performed to estimate adjusted hazard ratios (aHR) for COVID-19-related hospitalisation or in-hospital death associated with age, gender, deprivation index, comorbidities, and immunosuppressive or oral corticosteroid therapy from day 14 after full-vaccination. Findings: In a population of 28,031,641 fully vaccinated individuals with an average follow-up of 80 days, 5,345 (87 hospitalisations per 100,000 person-years) were hospitalised for COVID-19 and 996 (16 in-hospital death per 100,000 person-years) died in hospital. In multivariable analysis, a higher risk was observed with increasing age, male gender, and social deprivation. Most of the 47 chronic conditions considered were positively associated with an increased risk of COVID-19-related hospitalisation and a slight excess risk of death. The risk of hospitalisation and in-hospital death for COVID-19 also increased with the use of immunosuppressants (aHR 3.3 [2.8-3.8] and 2.4 [1.7-3.5], respectively) and oral corticosteroids (aHR 2.8 [2.5-3.1] and 4.1 [3.3-5.1]). Less than 10% (519/5,345) of hospitalised cases and 2% (24/996) of those who died in hospital had no identified comorbidities. There was a strong association between an increasing number of comorbidities and the risk of hospitalisation and in-hospital death (e.g., 5+ versus none, aHR 10.1 95%CI 9.0-11.5 and 17.8 95%CI 11.5-27.4, respectively). Interpretation: Although vaccination has dramatically reduced the occurrence of severe forms of COVID-19, a residual risk remains for the elderly, immunocompromised, and polypathological populations and warrants complementary preventive measures. Funding: None

Comment on ‘Baseline use of hydroxychloroquine in systemic lupus erythematosus does not preclude SARS-CoV-2 infection and severe COVID-19’ by Konig et al

International audienceNo abstract availabl

Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients

International audienceAfter initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations. We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs). Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020. We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias. The primary end point was time to hospitalization for COVID-19. The secondary end point was time to intubation/death during a hospital stay for COVID-19. In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19. ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65-0.83] and 0.84 [0.76-0.93], respectively) and a lower risk of intubation/death. Risks were slightly lower for ACE inhibitor users than for ARB users. This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs. These results, if confirmed, tend to contradict previous hypotheses and raise new hypothes