Primary autoimmune haemolytic anaemia (AIHA) causes the destruction of red blood cells and a subsequent pro-thrombotic state, potentially increasing the risk of ischaemic stroke. We investigated the ...risk of ischaemic stroke in patients with AIHA in a binational study. We used prospectively collected data from nationwide registers in Denmark and France to identify cohorts of patients with primary AIHA and age- and sex-matched general population comparators. We followed the patient and comparison cohorts for up to 5 years, with the first hospitalization of a stroke during follow-up as the main outcome. We estimated cumulative incidence, cause-specific hazard ratios (csHR) and adjusted for comorbidity and exposure to selected medications. The combined AIHA cohorts from both countries comprised 5994 patients and the 81 525 comparators. There were 130 ischaemic strokes in the AIHA cohort and 1821 among the comparators. Country-specific estimates were comparable, and the overall adjusted csHR was 1.36 95% CI: 1.13-1.65, p = 0.001; the higher rate was limited to the first year after AIHA diagnosis (csHR 2.29 95% CI: 1.77-2.97, p < 10
) and decreased thereafter (csHR 0.89 95% CI: 0.66-1.20, p = 0.45) (p-interaction < 10
). The findings indicate that patients diagnosed with primary AIHA are at higher risk of ischaemic stroke in the first year after diagnosis.
Aims
Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently ...associated with the development of HF.
Methods
Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long‐term HF‐related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias.
Results
Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person‐years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval CI 1.67‐3.52), dasatinib (aHR = 2.22, 95% CI 1.42‐3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69‐2.64), crizotinib (aHR = 1.71, 95% CI 1.07‐2.72), everolimus (aHR = 1.45, 95% CI 1.26‐1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01‐1.86). Sensitivity analyses were consistent with our primary analysis.
Conclusions
The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses.
Introduction: Eltrombopag has been marketed in Europe in 2010 for the treatment of chronic primary immune thrombocytopenia (ITP) lasting 12 months or longer from diagnosis, refractory to other ...treatments in splenectomized patients or patients who are contraindicated for splenectomy. Based on results of clinical trials, this marketing indication has been modified in 2019 for the treatment of patients aged 1 year and above with primary ITP lasting 6 months or longer from diagnosis and who are refractory to other treatments. However, data are lacking regarding the use, the efficacy and the safety of eltrombopag in the clinical practice in Europe. The ELEXTRA study was aimed at assessing these questions in France.
Methods: Population source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in other French centers since 2016, taking the name of CARMEN-France. ITP was defined by platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia. Study population consisted in all incident ITP adults included in the CARMEN-France registry from June 2013 to December 2018 and exposed to eltrombopag during the disease course. We described the time of exposure to eltrombopag from ITP diagnosis and patients' characteristics. Efficacy was assessed in patients who had a platelet count <30 x 109/L at eltrombopag initiation. Overall response was defined by platelet count ≥30 x 109/L and complete response by platelet count ≥100 x 109/L. Adverse drug reactions (ADRs) that occurred during exposure to eltrombopag were collected and assessed using the World Health Organization causality assessment scale. All ADRs at least “possible” were described.
Results: Out of 552 patients included in the registry, 81 (14.7%) had been exposed to eltrombopag for a median duration of 92 days (range: 1-1523). Mean age was 60.9 years (standard deviation: 20.9) and 45 (55.6%) were males; 36 (44.4%) had at least one comorbidity of the Charlson Comorbidity Index score; 45 (55.6%) had at least one cardiovascular risk factor (not including age and sex) and 4 (4.9%) a history of venous thrombosis. At ITP diagnosis, median platelet count was 7 x 109/L (range: 1-88 x 109/L) and 67 (82.7%) patients had bleeding. Median time from ITP onset to first exposure to eltrombopag was 2.7 months (range: 0.2-72.2): 43 (53.1%) patients were exposed before 3 months of ITP duration, 8 (9.9%) between 3 and 6 months, 18 (22.2%) between 6 and 12 months and 12 (14.8%) after 12 months. Exposures to ITP treatments before eltrombopag initiation were: corticosteroids in 75 (92.6%) patients, intravenous immunoglobulin (IVIg) in 61 (75.3%), dapsone in 15 (18.5%), rituximab in 14 (17.3%), romiplostim in 10 (12.3%), hydroxychloroquine in 9 (11.1%), danazol in 5 (6.2%), vinblastine in 3 (3.7%), azathioprine in 1 (1.2%), ciclosporin in 1 (1.2%) and splenectomy in none. Eltrombopag was used as second-line agent in 24 (28.6%) patients and third-line in 20 (24.7%). Among the 81 patients, 39 (48.1%) had a platelet count <30 x 109/L at eltrombopag initiation; 34 (87.2%) achieved overall response and 31 (79.5%) complete response. These response rates were stable across disease duration phases (<3 months, 3-6 months and >6 months), age groups (<60 vs. ≥60 years), Charlson Comorbidity Index score (0, 1-2 and ≥3). Among the 34 patients who achieved overall response, 29 (85.3%) had a concomitant exposure to ITP treatment at eltrombopag initiation (including steroids, n=12; IVIg during the past month, n=15; rituximab in the past 6 months, n=5). Overall, 17 ADRs were reported: the most frequent were: rash (n=3), thrombosis (n=3: 1 deep vein thrombosis, 1 pulmonary embolism and 1 ischemic stroke), thrombocytosis (n=2), hepatitis (n=2) and bronchitis (n=2).
Conclusion: In the French real-life practice, eltrombopag is used early in ITP course. Efficacy is similar to efficacy in clinical trials, and is stable by subgroups of patients. The profile of ADRs identified in clinical trials is also confirmed. Introduction: Eltrombopag has been marketed in Europe in 2010 for the treatment of chronic primary immune thrombocytopenia (ITP) lasting 12 months or longer from diagnosis, refractory to other treatments in splenectomized patients or patients who are contraindicated for splenectomy. Based on results of clinical trials, this marketing indication has been modified in 2019 for the treatment of patients aged 1 year and above with primary ITP lasting 6 months or longer from diagnosis and who are refractory to other treatments. However, data are lacking regarding the use, the efficacy and the safety of eltrombopag in the clinical practice in Europe. The ELEXTRA study was aimed at assessing these questions in France.
Methods: Population source was the CARMEN-France registry. The CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants) since June 2013. Each investigator follows all adult patients (aged ≥18 years) newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are prospectively recorded. This registry has been implemented in other French centers since 2016, taking the name of CARMEN-France. ITP was defined by platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia. Study population consisted in all incident ITP adults included in the CARMEN-France registry from June 2013 to December 2018 and exposed to eltrombopag during the disease course. We described the time of exposure to eltrombopag from ITP diagnosis and patients' characteristics. Efficacy was assessed in patients who had a platelet count <30 x 109/L at eltrombopag initiation. Overall response was defined by platelet count ≥30 x 109/L and complete response by platelet count ≥100 x 109/L. Adverse drug reactions (ADRs) that occurred during exposure to eltrombopag were collected and assessed using the World Health Organization causality assessment scale. All ADRs at least “possible” were described.
Results: Out of 552 patients included in the registry, 81 (14.7%) had been exposed to eltrombopag for a median duration of 92 days (range: 1-1523). Mean age was 60.9 years (standard deviation: 20.9) and 45 (55.6%) were males; 36 (44.4%) had at least one comorbidity of the Charlson Comorbidity Index score; 45 (55.6%) had at least one cardiovascular risk factor (not including age and sex) and 4 (4.9%) a history of venous thrombosis. At ITP diagnosis, median platelet count was 7 x 109/L (range: 1-88 x 109/L) and 67 (82.7%) patients had bleeding. Median time from ITP onset to first exposure to eltrombopag was 2.7 months (range: 0.2-72.2): 43 (53.1%) patients were exposed before 3 months of ITP duration, 8 (9.9%) between 3 and 6 months, 18 (22.2%) between 6 and 12 months and 12 (14.8%) after 12 months. Exposures to ITP treatments before eltrombopag initiation were: corticosteroids in 75 (92.6%) patients, intravenous immunoglobulin (IVIg) in 61 (75.3%), dapsone in 15 (18.5%), rituximab in 14 (17.3%), romiplostim in 10 (12.3%), hydroxychloroquine in 9 (11.1%), danazol in 5 (6.2%), vinblastine in 3 (3.7%), azathioprine in 1 (1.2%), ciclosporin in 1 (1.2%) and splenectomy in none. Eltrombopag was used as second-line agent in 24 (28.6%) patients and third-line in 20 (24.7%). Among the 81 patients, 39 (48.1%) had a platelet count <30 x 109/L at eltrombopag initiation; 34 (87.2%) achieved overall response and 31 (79.5%) complete response. These response rates were stable across disease duration phases (<3 months, 3-6 months and >6 months), age groups (<60 vs. ≥60 years), Charlson Comorbidity Index score (0, 1-2 and ≥3). Among the 34 patients who achieved overall response, 29 (85.3%) had a concomitant exposure to ITP treatment at eltrombopag initiation (including steroids, n=12; IVIg during the past month, n=15; rituximab in the past 6 months, n=5). Overall, 17 ADRs were reported: the most frequent were: rash (n=3), thrombosis (n=3: 1 deep vein thrombosis, 1 pulmonary embolism and 1 ischemic stroke), thrombocytosis (n=2), hepatitis (n=2) and bronchitis (n=2).
Conclusion: In the French real-life practice, eltrombopag is used early in ITP course. Efficacy is similar to efficacy in clinical trials, and is stable by subgroups of patients. The profile of ADRs identified in clinical trials is also confirmed.
Moulis:Novartis pharma: Research Funding, Speakers Bureau; Amgen pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding.
Eltrombopag was used off-label in some patients in this real-life study
Introduction: Epidemiological studies suggest a risk of immune thrombocytopenia (ITP) following viral infections, particularly influenza. Conversely, an increased risk of ITP following vaccination ...has been proven for some vaccines like Measles-Mumps-Rubella vaccine. However, the risk of ITP induced by influenza vaccine is debated. Two case-controls studies has been conducted, with contradictory results: in the Berlin Case-Control Surveillance Study, an increased risk has been found (odds ratio - OR: 3.8 95% confidence interval - CI: 1.5- 9.1. Conversely, the French PGRx study suggested the absence of risk of ITP after influenza vaccination OR: 0.9; 95% CI: 0.4-2.1. These studies were limited by the number of ITP patients included (169 and 198, respectively) and other limitations. Therefore, we aimed to assess the risk of ITP induced by influenza vaccine in a nationwide cohort in France.
Methods: We conducted a population-based study in France within the FAITH cohort (NCT03429660). This cohort is built within the National Health Database that links sociodemographic, hospital and out-hospital data. The FAITH cohort includes all adult patients with incident ITP in France since 2009. Patients are identified using a validated algorithm combining diagnosis codes and drug exposures (with very high positive predictive values). We included in the present study all patients with incident primary ITP aged ≥65 years at ITP diagnosis (indication of influenza vaccination in the general population in France) between July 2009 and June 2015. We assessed the link between influenza vaccine and ITP onset using two designs: a case-control and a self-controlled case series designs. In the case-control design, ITP cases were matched with four controls from the general population for age, sex and place of residency. Index dates for controls were similar to index dates of their matched cases. Cases and controls were compared for exposure to influenza vaccine in the 6 weeks before the index date using conditional logistic regression models adjusted for exposure to other drugs known as inducers of ITP. In the self-controlled case series study, only vaccinated ITP cases were included. The analysis compared the incidence of ITP within periods of risk (6 weeks following vaccination) to the incidence of ITP within other periods of time. We further excluded the 2 weeks prior to vaccine dispensing from the analysis to address selective survival bias (healthy vaccinee effect). Incidence rate ratios (IRRs) adjusted for seasonality were calculated.
Results: We included 3,142 incident primary ITP patients aged ≥65 years matched with 12,528 controls in the case-control study. Overall, 147 cases (4.7%) and 579 controls (4.6%) were vaccinated with influenza vaccine during the 6 weeks prior to the index date (adjusted OR: 0.99; 95% CI: 0.80-1.23). In the self-controlled case series study, 1,875 vaccinated ITP cases were included. Among them, 146 (7.8%) patients were diagnosed for ITP during one of the risk periods following vaccination. The adjusted IRR was 0.96 95 CI%: 0.80-1.17.
Conclusion: This nationwide population-based study using two different designs showed no increased risk of ITP after influenza vaccination.
Moulis:Novartis pharma: Research Funding, Speakers Bureau; Amgen pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding.
The worldwide coronavirus disease 2019 (COVID-19) vaccination campaign triggered several autoimmune diseases. We hereby aimed to describe IgA vasculitis (IgAV) following COVID-19 vaccination.
We ...conducted a national, multicenter, retrospective study in France of new-onset adult IgAV diagnosis following COVID-19 vaccination.
In total, 12 patients with new-onset IgAV were included. Of these, 5 (41.7%) were women, and the median age was 52.5 (IQR 30.75-60.5) years. Of the 12 patients, 10 had received an mRNA vaccine and 2 had received a viral vector vaccine. The median time from vaccination to onset of symptoms was 11.5 (IQR 4.25-21.25) days. Vasculitis occurred after the first vaccine dose in most patients (n = 8). All patients had skin involvement, with skin necrosis in 4 patients. In total, 7 patients had joint involvement and 2 had arthritis. A total of 4 patients had nonsevere gastrointestinal involvement and 2 had nonsevere renal involvement. The median C-reactive protein level was 26 (IQR 10-66.75) mg/L, the median creatininemia level was 72 (IQR 65-81) μmol/L, and 1 patient had an estimated glomerular filtration rate of less than 60 mL/min at management. All patients received treatment, including 9 patients (75%) who received glucocorticoids. In total, 5 patients received a vaccine dose after developing IgAV, 1 of whom experienced a minor cutaneous relapse.
The baseline presentation of IgAV following COVID-19 vaccination was mild to moderate, and outcomes were favorable. Thus, a complete COVID-19 vaccination regimen should be completed in this population. Of note, a fortuitous link cannot be ruled out, requiring a worldwide pharmacovigilance search to confirm these findings.
Previous studies have found that patients with Immune thrombocytopenia (ITP) have an increased risk of arterial thrombosis (AT) and venous thromboembolism (VTE). However, risk factors for thrombosis ...in adults with primary ITP remain unassessed in large cohorts.
Aim
To assess the occurrence and impact of risk factors for AT and VTE in patients with primary ITP in France and Sweden.
Both countries have national health databases, including hospital diagnoses and drug dispensing data. Adults with incident primary ITP identified using algorithms between the years 2009–2015 in France, and 2009–2016 in Sweden were included. Cumulative incidence rates (IR) of AT and VTE were calculated by risk factors and multivariable Cox models were used to estimate associations.
The study included 7225 patients from France and 2490 from Sweden. The IR of AT were 15.0 (95% CI: 13.4–16.7) and 14.7 (95% CI: 12.4–17.5) per 1000 person-years, respectively. The incidences of VTE were 6.9 (95% CI: 5.9–8.1) and 6.5 (95% CI: 5.1–8.4), respectively. Increasing age, male sex and a previous AT were associated with AT in both countries and so were exposure to antiplatelet drugs in France and a history of VTE and chronic kidney disease in Sweden. Increasing age and a history of VTE were associated with VTE in both countries, in France also cancer.
The IR of AT and VTE were similar in France. Age and male sex remained the most important risk factors for AT, age for VTE.
•7225 patients from France and 2490 from Sweden with primary ITP have similar incidence rates of AT and VTE.•Comorbidities present at ITP baseline increase the risk of both AT and VTE.•Age, male sex and a previous AT are the most important risk factors for AT in this patient group.•Age and cancer are the strongest risk factors for VTE.
Introduction: The association of measles, mumps and rubella (MMR) vaccination with immune thrombocytopenia (ITP) occurrence has been shown. The risk of ITP with other vaccines is still not known. ...This study was aimed at assessing the association of recommended vaccinations in children with ITP occurrence.
Methods: We conducted a population-based study in France including all children newly diagnosed for primary ITP between July 2009 and June 2015. This cohort was built using a validated algorithm in the nationwide French health insurance database (SNDS). We assessed the risk of ITP with MMR vaccine, all combined vaccines containing diphtheria, tetanus and poliomyelitis (DTP) vaccines, pneumococcal and meningococcal C vaccines. We used two self-controlled designs: a case cross-over and a self-controlled case series. For the case cross-over, we compared the frequency of exposure to vaccines during a 6-week period immediately preceding the event (case period) with the frequency of exposure during a previous time period (control period, having the same duration as the case period). We performed sensitivity analyses using 8- and 12-week periods. Analyses were adjusted for exposure to other drugs known as inducers of ITP and seasonality. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated. For the self-controlled case series, we compared the ITP incidence within periods of risk (following vaccination, named exposure period) with the incidence within the control period of non-exposure. The exposure period was defined by the 6 weeks after the vaccine dispensing in the principal analysis (8 and 12 weeks in sensitivity analyses). We further excluded the 2 weeks prior to vaccine dispensing from the non-exposure period to address selective survival bias (healthy vaccinee effect). The observation period was censored at ITP occurrence, due to variation of vaccination probability after ITP diagnosis and to the impossibility to distinguish ITP relapses from chronic ITP in the database. Analyses were adjusted for seasonality. Incidence rate ratios (IRRs) and their 95% CI were calculated. We assessed the exposure to each vaccine, and conducted subgroup analyses in patients without any concurrent vaccination during case and control periods for the case cross-over study and exposure periods for the self-controlled case series study. We also calculated the number of ITP cases occurring during the 6 weeks after vaccination divided by the number of vaccine doses dispensed in the French children population during the study period.
Results: We included 2,549 newly diagnosed primary ITP children. Among them, median age was 5.1 years and 46.5 % were females; 41.4% had been exposed to at least one studied vaccine before ITP onset. The results of the principal analysis are detailed in the Table. There was an increased occurrence of ITP following MMR vaccination (OR: 1.60, 95% CI: 1.09-2.34; IRR: 1.30, 95% CI: 0.95-1.80). Analyses excluding the patients with concurrent vaccination, notably meningococcal vaccination, led to similar results (OR: 1.66, 95% CI: 1.02-2.71; IRR: 1.39, 95% CI: 0.80-2.42). There was also an increased occurrence of ITP with the meningococcal C vaccine (OR: 1.92, 95% CI: 0.95-3.86; IRR: 1.40, 95% CI: 0.86-2.29). Analyses conducted in patients without any concurrent vaccination, notably MMR vaccination, confirmed these results with wide 95% CI because of fewer patients included (OR: 1.64, 95% CI: 0.57-4.71; IRR: 1.64, 95% CI: 0.69-3.86). No association was observed between other vaccines and ITP occurrence. The numbers of ITP cases occurring in the 6 weeks following vaccination per million doses dispensed were 8.2 for pneumococcal, 9.2 for DTP, 9.6 for meningococcal and 11.5 for MMR vaccines. Of note, these numbers overestimate the probability of vaccine-induced ITP. Indeed, they are ITP cases chronologically compatible with vaccine adverse reaction without any individual causality assessment (a worst-case scenario considering that all cases were triggered by vaccines).
Conclusion: This study showed an increased occurrence of ITP after MMR and meningococcal C vaccines. It is reassuring for other vaccines. We cannot exclude temporal association with MMR and meningococcal C vaccines due to the peak of ITP incidence at 12 months of age in the general population. However, vaccine-induced ITP is a very rare event, which does not cast doubt on the interest of vaccination.
No relevant conflicts of interest to declare.
Data are lacking on the impact of ACEI/ARB exposure on unfavorable outcome in the population of patients hospitalized for COVID‐19 with hypertension/cardiovascular disease, particularly in Europe. ...The ACE‐CoV study was designed to assess this question. The study was conducted in the Covid‐Clinic‐Toul cohort, which contains data about all patients hospitalized at Toulouse University hospital, France with a SARS‐CoV‐2 infection since March, 2020. We selected the patients with a history of cardiovascular disease (heart failure or coronary disease) and/or arterial hypertension. We conducted a subgroup analysis in patients with arterial hypertension. ACEI/ARB exposures at admission were assessed. The outcome was composite: admission to intensive care unit, need of mechanical ventilation or death during the 14 days after admission to hospital. We used logistic regression models with propensity scores (PS) weighted by overlap weighting (OW) and inverse probability of treatment weighting (IPTW). Between March 2020 and April 20, 2020, the Covid‐Clinic‐Toul included 263 patients. Among them, 111 were included in the ACE‐CoV study population. In OW‐PS‐adjusted analyses, the association of exposure to ACEIs or ARBs with outcome occurrence was OR: 1.56 (95% CI: 0.73–3.33). It was 0.99 (95% CI: 0.68–1.45) for ACEIs and 1.64 (95% CI: 0.77–3.50) for ARBs. Analyses with weighting by the IPTW‐PS method gave similar results. Results were similar when considering the subgroup of patients with arterial hypertension. The ACE‐CoV study found no association between exposure to ACEIs or ARBs and unfavorable outcome in hospitalized patients for COVID‐19 with a history of cardiovascular disease/arterial hypertension.
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