Corticosteroids and Myocardial Injury in CAP (COLOSSEUM TRIAL) (COLOSSEUM)

Effect of Corticosteroids On MyocardiaL Injury Among Patients Hospitalized for Community-AcquirEd PneUMonia - COLOSSEUM TRIAL

Community-acquired pneumonia (CAP) is often complicated by elevation of cardiac troponin, a marker of myocardial injury, that can be isolated or associated to myocardial infarction (MI). A retrospective study showed that corticosteroid treatment lowers incidence of MI during the hospital-stay. The aim of this clinical trial is to examine whether in-hospital treatment with iv methylprednisolone (20 mg b.i.d) may reduce myocardial injury, as assessed by serum high-sensitivity cardiac T Troponin) and eventually cardiovascular events during a short- and long-term follow-up in patients hospitalized CAP.

Background. Community-acquired pneumonia (CAP) is often complicated by elevation of cardiac troponin, a marker of myocardial injury, that can be isolated or associated to myocardial infarction (MI). A retrospective study showed that corticosteroid treatment lowers incidence of MI during the hospital-stay. No data exist so far on the effect of corticosteroids on myocardial injury in CAP patients. Study design. Double-blind randomized placebo-controlled trial. One hundred twenty-two eligible patients will be randomized to a week treatment with iv methylprednisolone (20 mg b.i.d) or placebo from hospital admission. Serum hs-cTnT will be measured at admission and every day until up 3 days from admission. ECG will be monitored every day until discharge. After dismission, all patients will be followed-up 2 years. Aims of the study. Primary objective of the study is to evaluate if methylprednisolone is able to reduce myocardial injury, as assessed by serum high-sensitivity cardiac T Troponin (hs-cTnT), in a cohort of patients hospitalized for CAP. Secondary aims are to evaluate the potential effect of methylprednisolone on cardiovascular events during hospitalization, at 30 day from hospital admission and during 2 years' follow-up. The trial will also examine whether the potential protective effects of methylprednisolone might be due to platelet activation down-regulation.

Doctors, staff and any primary care provider/s involved in the participant's non-trial management will be blinded to the group allocations. Individual participants will be not told their group allocation until the end of their involvement in the trial and after the completion of the trial

Methylprednisolone Sodium Succinate (20mg/ml) will be given at the dose of 40 mg/day (20 mg x 2/day). The treatment will last 7 days (or the time of hospitalization if the patient is discharged in a period less or more than 7 days).

Saline Solution for Injection will be given ath the dose of 2 ml/day. The treatment placebo will last 7 days (or the time of hospitalization if the patient is discharged in a period less or more than 7 days).

During hospitalization, 40 mg of methylprednisolone (20 mg/ml) will be given intravenously twice a day (20 mg every 12 hours).

During hospitalization, 2 ml of Saline Solution for Injection will be given intravenously twice a day (2 ml every 12 hours).

Primary endpoint of the study will be a significant reduction of hs-cTnT increase. Hs-cTnT will be measured . Hs-cTnT levels will be measured by the Elecsys 2010 (Roche Diagnostics, Indianapolis, IN) in a dedicated core laboratory.

Serum Thromboxane (Tx) B2 will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days).

Plasma sP-selectin will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days).

Plasma sCD40L will be measured on blood sample obtained at admission, after 72 hours and at hospital discharge (within 7 days).

Serum high-sensitivity C-Reactive Protein will be measured in blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days).

Serum sNOX2-dp will be measured on blood samples obtained at admission, after 72 hours and at hospital discharge (within 7 days). Blood levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of NADPH oxidase activation, will be detected by ELISA as previously described (Pignatelli P et al Arterioscler Thromb Vasc Biol 2010;30:360-7).

Serum F2-isoprostane (8-iso-PGF2α -III) will be measured by the enzyme immunoassay method in blood samples obtained at admission, after 72 horus and at hospital discharge (within 7 days).

F2-isoprostanes will be measured in urine samples collected at admission, after 72 horus and at hospital discharge (within 7 days).

This composite outcome will consist in any of the following events during hospitalization: acute myocardial infarction, new or worsening heart failure, new onset atrial fibrillation, stroke, cardiovascular death.

This composite outcome will consist in any of the following events during a 30-days follow-up: cardiovascular death, myocardial infarction and stroke.

This composite outcome will consist in any of the following events during a 2-years f follow-up: cardiovascular death, myocardial infarction and stroke.

Inclusion Criteria: Hospitalization for community-acquired pneumonia Exclusion Criteria: Use of corticosteroids in the previous 30 days Health Care-Associated Pneumonia Reported severe immunosuppression (human immunodeficiency virus infection, immunosuppressive conditions or medications) Preexisting medical condition with a life expectancy of less than 3 months Uncontrolled diabetes mellitus Gastritis with or without major gastrointestinal bleeding within 3 months Any condition requiring acute treatment with glucocorticoids

Cangemi R, Casciaro M, Rossi E, Calvieri C, Bucci T, Calabrese CM, Taliani G, Falcone M, Palange P, Bertazzoni G, Farcomeni A, Grieco S, Pignatelli P, Violi F; SIXTUS Study Group; SIXTUS Study Group. Platelet activation is associated with myocardial infarction in patients with pneumonia. J Am Coll Cardiol. 2014 Nov 4;64(18):1917-25. doi: 10.1016/j.jacc.2014.07.985. Epub 2014 Oct 27.

Cangemi R, Falcone M, Taliani G, Calvieri C, Tiseo G, Romiti GF, Bertazzoni G, Farcomeni A, Violi F; SIXTUS Study Group. Corticosteroid Use and Incident Myocardial Infarction in Adults Hospitalized for Community-acquired Pneumonia. Ann Am Thorac Soc. 2019 Jan;16(1):91-98. doi: 10.1513/AnnalsATS.201806-419OC.

Cangemi R, Carnevale R, Nocella C, Calvieri C, Cammisotto V, Novo M, Castellani V, D'Amico A, Zerbinati C, Stefanini L, Violi F; SIXTUS Study Group. Glucocorticoids impair platelet thromboxane biosynthesis in community-acquired pneumonia. Pharmacol Res. 2018 May;131:66-74. doi: 10.1016/j.phrs.2018.03.014. Epub 2018 Mar 22. Erratum In: Pharmacol Res. 2018 Sep;135:268.

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