Aspirine, statines et réduction du risque embolique dans l’endocardite infectieuse

Introduction 

Embolic events (EE) are a major complication of Infective Endocarditis (IE) (1-2) with a high mortality and morbidity since death is the result in a quarter of patients (3-4). The incidence of systemic embolism in endocarditis ranges from 13% to 49% and remains high despite improvement in medical and surgical treatment (5-6). Early antibiotic and surgical therapy in specific subgroups are effective in preventing embolism (7). The embolic risk is correlated to the presence and the length of vegetations. (8-9) Since vegetation is made up of an aggregation of fibrin and platelets (10-12), it has been suggested that aspirin used early in the disease have a beneficial effect in reducing embolic events (13). Animal models have demonstrated the benefit of aspirin (ASA) in this indication. (14-15) However clinical studies have given conflicting results (16-23). Statin (ST) therapy has pleiotropic effects, including inhibition of platelet activation and anti-inflammatory properties (24-28) and may theoretically be useful to reduce embolic risk, but data on their use in IE are very scarce. (22) In addition, the risk of embolism may differ according to the pathogen (5), but the effect of ASA or ST according to different microorganisms has never been studied. To evaluate the benefit of prior ASA and/or ST therapy on embolic risk, we undertook a retrospective study of a large cohort of patients with a diagnosis of IE 4 Methods Data sources This retrospective observational study was performed at La Timone Hospital, Marseille, France, in our endocarditis reference center database of IE, including adult patients hospitalized from 01/01/2010 to 31/12/2106 with a diagnosis of IE according to the modified Duke criteria (29). Diagnosis of IE was based on clinical assessment, blood cultures, causative pathogen serology, transthoracic and transesophageal echocardiography, nuclear imaging and cerebrothoracoabdominal CT scans or magnetic resonance. Antibiotic therapy was started as soon as the diagnosis of IE was suspected. The choice of antibiotic treatments (ATB) was made at the judgement of the infectious disease specialists. From the medical records, demographic information, data on pre-existing comorbidities, risk factors for IE (prosthetic valves, other cardiac abnormalities, use of injection drugs), pathogens, clinical, laboratory and echocardiographic findings, treatment (medical, surgical), chronic ASA and ST therapy, cardiac and extracardiac complications and mortality were recorded in the database by research engineers. In this study, patients with left-sided, right-sided, prosthetic valve or intracardiac device-associated IE were included but only if they were due to Staphylococcus aureus, Staphylococcus coagulase negative (S. co-neg), Streptococci or Enterococcus in the idea to carry out the bacterial analysis on sufficient size samples. 

Variables 

ASA therapy and ST therapy were defined as daily use of aspirin and statin, respectively, prior to admission. From this database, no information on the dosage or duration of ASA and ST therapy was available. ST therapy included atorvastatin, pravastatin, simvastatin, fluvastatin or rosuvastatin. Embolism was defined as one or more of coronary, cerebral, splenic, renal, mesenteric, peripheral and pulmonary embolism, either symptomatic or not. A stroke consisted of a neurological deficit lasting more than 24 hours and presumed of vascular origin. (30) Hemorrhagic complications involved intracranial hemorrhages only. In-hospital mortality was defined as death occurring during the 30 first days from the start of antibiotic therapy. 

End points

 The Primary end point was embolic events (EE) occurring before or during hospitalization for EI. Secondary end points were cerebral emboli, the occurrence of a hemorrhagic event, 30 days mortality among the global population, and EE according to the pathogen. 

Outcomes 

During hospitalization all patients were observed daily in the cardiology unit by cardiologists, infectious disease specialists and had additional consultations when indicated. CT scan, systematically performed during the first week of hospitalization, was subsequently repeated if clinically indicated. Patients were systematically reviewed at one month after discharge for a follow-up consultation. 

Statistical analyses 

First a descriptive analysis of clinical, echocardiographic, therapeutic and biological characteristics of the included patients was performed. Quantitative variables were described as means ± standard deviations. Qualitative variables were described as numbers and percentages. These characteristics were also described and compared according to treatment groups. Quantitative variables were compared using Student t test (or Mann-Whitney test depending on the conditions of application) and qualitative variables were compared using chi-square test (or Fisher test depending on the conditions of application). Then a bivariate analysis between these clinical and biological characteristics and the various endpoints was performed using bivariate logistic regression. Crude odds ratios were estimated with their 95% confidence intervals. Firth’s (31-32) correction was applied by performing penalized-likelihood logistic regression to take into account small numbers when necessary. Finally, a multivariate analysis was performed to assess the independent associations of clinical and biological characteristics and the various endpoints. Multivariate logistic regression models were built using prognostic factors identified according to literature, and therapeutic regimen which was systematically forced in the models. Adjusted odds ratios were estimated with their 95% confidence intervals. An exploratory analysis was performed according to the type of germ identified, by estimating crude odds ratios between therapeutic regimen and the endpoint. All statistical analyses were performed using R software. All tests were two-sided. A value of p<0.05 was considered as significant.