Cardiovascular risk factors in immune thrombocytopenia adults: Results from the CARMEN registry
Authors: Guillaume Moulis, Johanne Germain, Thibault Comont, Amélie Arrouy, Maryse Lapeyre‐Mestre, Daniel Adoue
Journal: American Journal of Hematology (2018)

Immune thrombocytopenia (ITP) is associated to an increased risk of thrombotic events in adults as compared with the general population. If the risk of venous events is demonstrated, the risk of arterial events is still debated.1 Thanks to a new population-based study conducted in the THIN database in UK, Chandan et al. provided recently new evidence for an increased risk of myocardial infarction and stroke in ITP adults as compared with the general population.2 Causal studies are still needed to determine the risk factors of thrombosis in ITP, including the exposure to drugs used for ITP treatment. Among these potential risk factors, a retrospective multicenter Italian study raised the impact of cardiovascular risk factors.3 The study by Chandan et al. presents the high interest of providing original data regarding the prevalence of cardiovascular risk factors in ITP patients, found as frequent as in the general population controls. However, the patients with previous cardiovascular diseases at index date were excluded.2 Consequently, the prevalence of cardiovascular risk factors might be lower in this study as compared with the whole population of ITP patients. Moreover, like every study based on electronic medical records, it presents a risk of missing data,4 miscoding, and incomplete clinical data leading to the use of proxies to identify some covariables (e.g., lipid-lowering drugs to address dyslipidemia). Consequently, we aimed at assessing the prevalence of cardiovascular risk factors at ITP diagnosis in a prospective clinical cohort of ITP adults. The source of data was the CARMEN (Cytopénies Auto-immunes Registre Midi-PyrénéEN) registry. It is a multicenter prospective registry aimed at following all newly diagnosed ITP adults in the Midi-Pyrénées region, southwest of France (3 million inhabitants) since June 2013. Inclusion criteria in the registry are: (1) age ≥18 years, (2) incident ITP (diagnosis < 3 months) defined according to 2009 French guidelines as a platelet count < 150 x 109/L and the exclusion of other causes of thrombocytopenia, (3) and follow-up in the region.5 Known cardiovascular risk factors (except the body mass index) are recorded at ITP diagnosis. They are defined according to international standards: arterial hypertension, ≥140/90 mmHg; diabetes mellitus, glycemia ≥126 mg/dL; hypercholesterolemia, LDL-cholesterol ≥160 mg/dL; hypertriglyceridemia, ≥150 mg/dL; chronic kidney disease, estimated glomerular filtration rate using the CKD-EPI formula <60 ml/min/1.73m2 for ≥3 months. All drug exposures at ITP onset are recorded as well. For the present study, we selected all ITP patients included in the CARMEN registry from June 1st 2013 to December 31st 2017. Patients with a platelet count ≥100 × 109/L were excluded to fit international guidelines on ITP definition.6 Out of 357 incident ITP patients included during the study period, 8 were excluded because of refusal to data collection and 1 because of follow-up out of the region. Thirty patients were further excluded due to a platelet count between 100–149 × 109/L. Median age was 66 years and 162 patients (50.9%) were men. The median platelet count at ITP diagnosis was 19 × 109/L and 145 patients (46.3%) had bleeding symptoms at ITP diagnosis. The frequency of patients with a Charlson Comorbidity Index score equal to 0, 1, 2, and ≥3 were, respectively: 55.1%, 19.7%, 15.9%, and 11.1%. Forty-six patients (14.5%) had secondary ITP (mostly another autoimmune disease, n = 16, and hematological malignancy/myelodysplastic syndrome, n = 10). Overall, 256 patients (80.5%) were treated for ITP. The prevalence of cardiovascular risk factors at ITP diagnosis are presented in Table 1. Missing values are indicated in footnotes, and ranged from 0 to 11 (3.5%). Percentages were computed in complete-case analysis. Overall, 75.3% of the patients had at least one cardiovascular risk factor (frequency increasing with age, Supporting Information Figure S1). The frequency of history of coronary disease was 8.0%. It was 6.6% for ischemic stroke. Diabetes mellitus was observed in 13.9% of the patients, a finding consistent with the exposure to antidiabetic drugs (10.8%), a small proportion of type 2 diabetes patients being treated by diet and physical activity only. An exposure to tobacco in the 3 previous years was observed in 13.4% of the patients, arterial hypertension in 37.0%, chronic kidney disease in 1.6%, hypercholesterolemia in 13.5% and hypertriglyceridemia in 2.9%. This is consistent with the exposure to lipid-lowering drugs (18.7%), the difference being explained by the indication of statins for cardiovascular disease prophylaxis. Overall, 39.2% of the patients were exposed to drugs against arterial hypertension and/or heart failure, 18.0% to antiplatelet agents and 9.2% to anticoagulant drugs. Sensitivity analysis restricted to primary ITP patients and to patients with at least one hospital stay due to ITP (i.e., those captured in most medico-administrative databases) led do similar results (data not shown). The most detailed and recent data regarding the prevalence cardiovascular risk factors in the French general population are from the MONA-LISA cross-sectional study. The population of this study is younger than in the CARMEN registry, explaining an overall higher prevalence of cardiovascular risk factors in our ITP population (Supporting Information Table S1).7 Regarding previous ITP cohorts, we found a higher prevalence of cardiovascular risk factors than in the study by Chandan et al.2 Our population was older than in this study (66 vs 48 years old) and with a balanced men/women repartition, with no female predominance (males: 50.9% vs. 41.3%).2 This may be due, at least in part, by the exclusion of the patients with a previous cardiovascular disease in the study by Chandan et al. In contrast, our results are close to those of the multicenter Italian study by Ruggeri et al.3 and to those of the study conducted in the Clinical Practice Research Database by Sarpatwari et al., that also found a higher prevalence of diabetes and of chronic kidney disease in ITP patients in comparison with the general population.8 The prevalence of chronic kidney disease was lower in our study (1.6% vs. 2.8%), but might be underreported. In conclusion, cardiovascular risk factors are frequent in ITP patients and the use of drug exposures as proxies reflects the underlying conditions. The CARMEN registry setting up has been supported by a grant from the Délégation Régionale à la Recherche Clinique des Hôpitaux de Toulouse 2012 and was also granted by the French National Society of Internal Medicine (Société Nationale Française de Médecine Interne). It is supported by the French referral center for autoimmune cytopenia and the French national center for rare diseases in immunohematology (MaRIH). CSL Behring and Novartis also support the CARMEN registry since 2016. The sponsors had no role in the study (see Conflict of interest section). GM received meeting attendance grants from Novartis and Amgen, as well as research grants from CSL Behring and Novartis for the CARMEN registry. These sponsors have no role in data collection and have not the property of data; they have no role in the conception, the methodology, the analyses, the interpretation of the studies conducted in the registry; manuscripts of research studies conducted in the CARMEN registry are not submitted to the sponsors before publication. Daniel Adoue participated to boards for Novartis and Amgen. All other authors declare having no conflict of interest. Additional Supporting Information may be found online in the supporting information tab for this article. 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