Effect of Ticagrelor on Reducing the Risk of Gram-Positive Infections in Patients With Acute Coronary Syndrome

Abstract

•Patients treated with dual antiplatelet therapy that includes ticagrelor have a 64% lower risk of gram-positive infection during the first year following hospitalization compared with patients treated with dual antiplatelet therapy treatment that includes clopidogrel.•This observed association is bolstered by the fact that gram-positive infection risk is comparable between ticagrelor and clopidogrel treated patients after discontinuation of dual antiplatelet therapy.•Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections during the first year following acute coronary syndrome hospitalization, a finding compatible with previous in vitro studies. In light of recent studies describing the antibacterial properties of ticagrelor, the association between treatment with ticagrelor and subsequent risk for infection following acute coronary syndrome (ACS) is taking on increased importance. A single center, retrospective, matched cohort analysis was performed. All patients older than 30 years of age admitted between January 1, 2013 and November 1, 2019 for an ACS and discharged with dual antiplatelet therapy (DAPT) were included. The primary outcome was defined as hospital admissions due to infections likely caused by gram-positive bacteria up to 1 year following the ACS hospitalization. The base cohort included 3,909 patients. About 2,035 (52.1%) were treated with ticagrelor and 1,874 (47.9%) with clopidogrel. Patients treated with ticagrelor had a 64% lower risk of gram-positive infection during the first year following hospitalization after adjusting for demographic and co-morbidity factors compared with those treated with clopidogrel (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21 to 0.61; p <0.001). In a cohort starting from 1 year (conclusion of DAPT period) and up to 3 years following ACS hospitalization, the risk of gram-positive infection was comparable in both groups (HR, 0.70; 95% CI, 0.41 to 1.19; p = 0.182). Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections (HR, 0.48; 95% CI, 0.21 to 1.06; p = 0.07). In conclusion, DAPT regimen that includes aspirin and ticagrelor is associated with reduced risk of gram-positive infection compared with the combination of aspirin and clopidogrel. In light of recent studies describing the antibacterial properties of ticagrelor, the association between treatment with ticagrelor and subsequent risk for infection following acute coronary syndrome (ACS) is taking on increased importance. A single center, retrospective, matched cohort analysis was performed. All patients older than 30 years of age admitted between January 1, 2013 and November 1, 2019 for an ACS and discharged with dual antiplatelet therapy (DAPT) were included. The primary outcome was defined as hospital admissions due to infections likely caused by gram-positive bacteria up to 1 year following the ACS hospitalization. The base cohort included 3,909 patients. About 2,035 (52.1%) were treated with ticagrelor and 1,874 (47.9%) with clopidogrel. Patients treated with ticagrelor had a 64% lower risk of gram-positive infection during the first year following hospitalization after adjusting for demographic and co-morbidity factors compared with those treated with clopidogrel (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21 to 0.61; p <0.001). In a cohort starting from 1 year (conclusion of DAPT period) and up to 3 years following ACS hospitalization, the risk of gram-positive infection was comparable in both groups (HR, 0.70; 95% CI, 0.41 to 1.19; p = 0.182). Treatment with ticagrelor was not associated with a reduced risk of gram-negative infections (HR, 0.48; 95% CI, 0.21 to 1.06; p = 0.07). In conclusion, DAPT regimen that includes aspirin and ticagrelor is associated with reduced risk of gram-positive infection compared with the combination of aspirin and clopidogrel. Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor antagonist is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes (ACS).1Ibanez B James S Agewall S Antunes MJ Bucciarelli-Ducci C Bueno H Caforio ALP Crea F Goudevenos JA Halvorsen S Hindricks G Kastrati A Lenzen MJ Prescott E Roffi M Valgimigli M Varenhorst C Vranckx P Widimský P ESC Scientific Document Group2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2018; 39: 119-177Crossref PubMed Scopus (5421) Google Scholar, 2Roffi M Patrono C Collet J-P Mueller C Valgimigli M Andreotti F Bax JJ Borger MA Brotons C Chew DP Gencer B Hasenfuss G Kjeldsen K Lancellotti P Landmesser U Mehilli J Mukherjee D Storey RF Windecker S 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2016; 37: 267-315Crossref PubMed Scopus (4344) Google Scholar, 3Levine GN Bates ER Bittl JA Brindis RG Fihn SD Fleisher LA Granger CB Lange RA Mack MJ Mauri L Mehran R Mukherjee D Newby LK O'Gara PT Sabatine MS Smith PK Smith SC Halperin JL Levine GN Al-Khatib SM Birtcher KK Bozkurt B Brindis RG Cigarroa JE Curtis LH Fleisher LA Gentile F Gidding S Hlatky MA Ikonomidis JS Joglar JA Pressler SJ Wijeysundera DN 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Thorac Cardiovasc Surg. 2016; 152: 1243-1275Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar The choice of P2Y12 inhibitor for individual patients is currently guided by a multiparameter assessment that includes the risk of additional thrombotic events balanced by the risk for acute bleeding and comprise a number of individual patient factors that affects 1 or both risks.4Berger JS. Oral antiplatelet therapy for secondary prevention of acute coronary syndrome.Am J Cardiovasc Drugs. 2018; 18: 457-472Crossref PubMed Scopus (13) Google Scholar, 5Schiele F Ecarnot F Chopard R Coronary artery disease: risk stratification and patient selection for more aggressive secondary prevention.Eur J Prev Cardiol. 2017; 24: 88-100Crossref PubMed Scopus (44) Google Scholar, 6Valgimigli M Bueno H Byrne RA Collet J-P Costa F Jeppsson A Jüni P Kastrati A Kolh P Mauri L Montalescot G Neumann F-J Petricevic M Roffi M Steg PG Windecker S Zamorano JL Levine GN Badimon L Vranckx P Agewall S Andreotti F Antman E Barbato E Bassand J-P Bugiardini R Cikirikcioglu M Cuisset T De Bonis M Delgado V Fitzsimons D Gaemperli O Galiè N Gilard M Hamm CW Ibanez B Iung B James S Knuuti J Landmesser U Leclercq C Lettino M Lip G Piepoli MF Pierard L Schwerzmann M Sechtem U Simpson IA Uva MS Stabile E et al.2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTSThe Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS).Eur Heart J. 2018; 39: 213-260Crossref PubMed Scopus (1840) Google Scholar Patients hospitalized with ACS, especially those with co-morbid conditions, are at a considerable risk for infectious complications.7Truffa AAM Granger CB White KR Newby LK Mehta RH Hochman JS Patel MR Pieper KS Al-Khalidi HR Armstrong PW Lopes RD Serious infection after acute myocardial infarction: incidence, clinical features, and outcomes.JACC Cardiovasc Interv. 2012; 5: 769-776Crossref PubMed Scopus (29) Google Scholar Previous studies have suggested ticagrelor might have antibacterial activity. A post hoc analysis of the Platelet Inhibition and Patient Outcome trial showed lower mortality associated with pulmonary infections in patients treated with ticagrelor compared with those on clopidogrel (33 cases (0.4%) vs 71 cases (0.8%); p <0.001).8Storey RF James SK Siegbahn A Varenhorst C Held C Ycas J Husted SE Cannon CP Becker RC Steg PG Åsenblad N Wallentin L Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study.Platelets. 2014; 25: 517-525Crossref PubMed Scopus (123) Google Scholar A recently published study showed that ticagrelor has in vitro dose-dependent bactericidal activity against antibiotic-resistant gram-positive bacteria, but not against gram-negative strains.9Lancellotti P Musumeci L Jacques N Servais L Goffin E Pirotte B Oury C Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant gram-positive bacteria.JAMA Cardiol. 2019; 4: 596-599Crossref PubMed Scopus (61) Google Scholar In this study, we investigated the association between treatment with ticagrelor and subsequent risk for gram-positive infection in the first year following hospitalization for ACS. We hypothesized that treatment with ticagrelor would be associated with a lower rate of gram-positive infections. This is a single center, retrospective analysis. Patient information was retrieved from the database of the Tel Aviv Medical Center (TLVMC), a 1,500-bed academic medical center and a tertiary reference center. The study was approved by the institutional review board. Under local law, informed consent is not required for retrospective analyses of anonymized data. All patients older than 30 years of age admitted to the TLVMC between January 1, 2013 and November 1, 2019 for an ACS [ICD9 codes 410.X, 411.1] were included. The index date for calculating the prevalence of infections was set as per discharge date. The primary outcome was defined as hospital admissions due to infections likely caused by gram-positive bacteria (pneumonia, cellulitis, endocarditis, and bacteremia with gram-positive bacteria) up to 1 year following the index date. Hospitalizations due to infection up to 30 days following the index date were excluded, likely representing hospital acquired infectious complications. Additional exclusion criteria included death within 30 days of the index date and patients discharged ≤30 days before the end of the study period. The base study cohort consisted of patients that were discharged with a recommendation for continued DAPT of either aspirin and clopidogrel, aspirin and ticagrelor or aspirin and prasugrel. Data retrieved from the medical center's database included age at the index date, gender, ever-smoking status, history of atrial fibrillation and diagnosis of anemia (hemoglobin concentration <13 mg/dl in men and <12 mg/dl in women). The Charlson co-morbidity index score, commonly used as a measure of multimorbidity, was calculated for each patient.10Charlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.J Chronic Dis. 1987; 40: 373-383Abstract Full Text PDF PubMed Scopus (34492) Google Scholar Patient characteristics were compared using the chi-square test or Fisher's exact test for categorical variables and the t test for continuous variables. The probability of DAPT combination with aspirin and clopidogrel versus aspirin and ticagrelor or prasugrel was estimated using a logistic regression model. The independent variables included patients’ age, gender, admission year, and Charlson scores. Patients with similar model-based probabilities (maximum caliper ±0.05) were then matched using the nearest neighbors method.11Ho DE Imai K King G Stuart EA Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference.Polit Anal. 2007; 15: 199-236Crossref Scopus (2367) Google Scholar Since the outcome (eg, hospitalization due to infection) incidence in the original cohort was low, the matching process was performed 5 times and the matched cohort retaining the maximum number of infections was selected as the final matched cohort. Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for the association between antiplatelet agent treatment and the 1-year risk of gram-positive infections were estimated using a Cox proportional-hazards model. The model included the following potential confounders: age, gender, Charlson co-morbidity index score and year of ACS diagnosis. Data were censored at death, following 1 year after the index date or at the end of the study period. Kaplan-Meier survival curves were compared using the log-rank test. Following the primary analysis, several preplanned secondary analyses were performed to evaluate the robustness of our results: first, the primary analysis was repeated with an extended model including all aforementioned confounders with the addition of confounders that were significantly different between treatment groups after matching: anemia, ever-smoking status, atrial fibrillation, cerebrovascular accident (CVA), congestive heart failure (CHF), chronic kidney disease (CKD), and the presence of any malignancy. Second, in order to minimize treatment group disparity caused by unmeasured variables, the analysis was repeated on a subcohort consisting only of patients admitted to the cardiology ward. Third, in order to in patient we the prevalence of gram-positive infections after ticagrelor between 1 and 3 years after the index date. to the association between ticagrelor treatment and gram-negative the analysis was repeated for admissions due to and infections during the first year after the index date. to the in our medical center, the group of patients discharged with a DAPT combination of aspirin and prasugrel was to be and association with infection was as an analysis. All analyses were performed using R R for A of patients were admitted to the TLVMC for ACS during the study period. Patient is in The base cohort included 3,909 patients. About 2,035 (52.1%) were treated with ticagrelor and 1,874 (47.9%) with clopidogrel. with patients treated with clopidogrel, patients treated with ticagrelor had a of men vs p were years vs p and had a lower Charlson co-morbidity index score vs p <0.001). score patients treated with ticagrelor were matched with patients treated with clopidogrel. The group characteristics after matching are in and clinical characteristics of patients admitted with an ACS and discharged with DAPT including either clopidogrel or ticagrelor, before and after score = = = = year heart comorbidity index = = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in in a new SD = = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in patients admitted with a diagnosis of ACS, of patients were admitted with a gram-positive infection during the first year after the index date. were patients admitted with with with gram-positive and with treatment was associated with a reduced risk of gram-positive infections with an incidence of in the clopidogrel group and in the ticagrelor group HR for the aspirin and ticagrelor 95% CI, to p This association on analysis, adjusting to age, gender, admission year and Charlson co-morbidity index (HR, 0.36; 95% CI, 0.21 to 0.61; p model were with to confounders that significantly different between treatment groups after including a medical history of anemia, atrial fibrillation, and the presence of any of (HR, 95% CI, to p model association between dual antiplatelet therapy with either ticagrelor or clopidogrel and the risk of gram-positive infection during the first year following acute coronary syndrome admission to either the or cardiology comorbidity kidney heart = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in for age, admission year and Charlson co-morbidity for age, admission year, Charlson co-morbidity congestive heart chronic kidney cerebrovascular atrial fibrillation, anemia, and in a new SD = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in for age, admission year and Charlson co-morbidity for age, admission year, Charlson co-morbidity congestive heart chronic kidney cerebrovascular atrial fibrillation, anemia, and In a analysis that included only patients admitted to the Cardiology ticagrelor treatment was associated with a reduced risk of gram-positive infection with an incidence of in the clopidogrel group and in the ticagrelor group 95% CI, to 0.70; p = were after to age, gender, admission year and Charlson co-morbidity index (HR, 95% CI, to p = and the aforementioned medical history that significantly different between treatment groups after matching (HR, 0.36; 95% CI, to p = association between dual antiplatelet therapy with either ticagrelor or clopidogrel and the risk of gram-positive infection during the first year following acute coronary syndrome admission to the cardiology comorbidity kidney heart = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in for age, admission year and Charlson co-morbidity for age, admission year, Charlson co-morbidity congestive heart chronic kidney cerebrovascular atrial fibrillation, anemia and in a new SD = = 1 = was defined as concentration <13 mg/dl in men and <12 mg/dl in for age, admission year and Charlson co-morbidity for age, admission year, Charlson co-morbidity congestive heart chronic kidney cerebrovascular atrial fibrillation, anemia and In a analysis of the patient cohort starting from 1 year (conclusion of DAPT period) and up to 3 years after the index date, the risk of gram-positive infection was comparable in both with an incidence of in the clopidogrel group and in the ticagrelor group (HR, 0.70; 95% CI, 0.41 to 1.19; p = 0.182). treatment with ticagrelor was not associated with a reduced risk of gram-negative infections during the first year following the index date (HR, 0.48; 95% CI, 0.21 to 1.06; p = In a analysis of a matched cohort = patients in each prasugrel was associated with a reduced risk of gram-positive with an incidence of in the clopidogrel group and in the ticagrelor group 95% CI, to p = In this study, patients treated with DAPT that included ticagrelor had a 64% lower risk of gram-positive infection during the first year following hospitalization for ACS after adjusting for age, gender, admission year, and Charlson co-morbidity index score compared with those treated with clopidogrel. This after for including anemia, atrial fibrillation, and malignancy. our this is the first study that this association using data. are bolstered by preplanned including the comparable prevalence between both study groups after discontinuation of DAPT is in thrombotic events and in patients with L Becker RC A Cannon CP H Held C J Husted S James S H A Steg PG Storey RF RA versus clopidogrel in patients with acute coronary J PubMed Scopus Google Scholar, SD E versus clopidogrel in patients with acute coronary J 2007; PubMed Scopus Google Scholar, S F Mehta S G KK in to events trial of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment J PubMed Scopus Google Scholar ticagrelor is currently as the of choice following ACS admissions B James S Agewall S Antunes MJ Bucciarelli-Ducci C Bueno H Caforio ALP Crea F Goudevenos JA Halvorsen S Hindricks G Kastrati A Lenzen MJ Prescott E Roffi M Valgimigli M Varenhorst C Vranckx P Widimský P ESC Scientific Document Group2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2018; 39: 119-177Crossref PubMed Scopus (5421) Google Scholar, 2Roffi M Patrono C Collet J-P Mueller C Valgimigli M Andreotti F Bax JJ Borger MA Brotons C Chew DP Gencer B Hasenfuss G Kjeldsen K Lancellotti P Landmesser U Mehilli J Mukherjee D Storey RF Windecker S 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).Eur Heart J. 2016; 37: 267-315Crossref PubMed Scopus (4344) Google Scholar, 3Levine GN Bates ER Bittl JA Brindis RG Fihn SD Fleisher LA Granger CB Lange RA Mack MJ Mauri L Mehran R Mukherjee D Newby LK O'Gara PT Sabatine MS Smith PK Smith SC Halperin JL Levine GN Al-Khatib SM Birtcher KK Bozkurt B Brindis RG Cigarroa JE Curtis LH Fleisher LA Gentile F Gidding S Hlatky MA Ikonomidis JS Joglar JA Pressler SJ Wijeysundera DN 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.J Thorac Cardiovasc Surg. 2016; 152: 1243-1275Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar the to aspirin with either clopidogrel or ticagrelor is especially for patients with In our patients with a co-morbidity and a risk of infections and D V V A A K M K M an process by the of with the Dis. 2018; 18: PubMed Scopus Google Scholar were more likely to be treated with clopidogrel that infectious to the atherothrombotic and bleeding as end might the ratio of ticagrelor versus clopidogrel in patients. might have similar for the choice between prasugrel and clopidogrel. In order to prasugrel treatment is associated with the risk of gram-positive a analysis was performed and a reduced risk of gram-positive infections in patients treated with prasugrel was to the number of patients treated with prasugrel in our additional analysis be performed. that the of P2Y12 a in the observed The lower risk for gram-positive infections associated with ticagrelor be an bactericidal or The P2Y12 receptor a in the of and the and of the P2Y12 receptor and of the are for might be to patients with gram-positive SC JJ a in failure patients with sepsis due to gram-positive 2019; PubMed Scopus Google M R S of and potential clinical Cardiol. 2014; PubMed Scopus Google Scholar The in study showed that ticagrelor (eg, in patients with G LA R S in patients with 2018; Scholar The study showed ticagrelor, but not clopidogrel, to be associated with a reduced and survival in with Additional studies ticagrelor with clopidogrel have a in and and in and in patients treated with ticagrelor following J R F J P of the of ticagrelor and clopidogrel on and in patients with acute ST-segment elevation myocardial infarction coronary a 2018; Google R M S H J B of clopidogrel vs ticagrelor on and after coronary for myocardial J Cardiol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar might be to on D C L S JE of the of Inhibition of Cardiovasc 2014; January PubMed Scopus Google Scholar or the and P2Y12 of ticagrelor compared to S H S M G and of the P2Y12 antagonist with aspirin in patients with a to clopidogrel with Heart J. PubMed Scopus Google Scholar In addition to potential a recent study bactericidal activity of ticagrelor against gram-positive bacteria including and against and in a dose-dependent P Musumeci L Jacques N Servais L Goffin E Pirotte B Oury C Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant gram-positive bacteria.JAMA Cardiol. 2019; 4: 596-599Crossref PubMed Scopus (61) Google Scholar on gram-negative bacteria was compatible with our study has several is a retrospective database study without review of individual patient the risk for information and Second, the study groups might not be due to selection patients might be more likely to be treated with a DAPT regimen that includes clopidogrel, and not This was by score matching and with a subcohort analysis only on patients admitted to the cardiology but be Third, we used the index hospitalization treatment for group might be we patients not hospitalized for gram-positive those hospitalized in and might have from infections before medical are likely to both groups in the but the of the risk for gram-positive infections. due to the number of patients treated with we not the risk of infections between patients treated with prasugrel and those treated with between the index date and the date of gram-positive infection were not be a risk for In conclusion, DAPT regimen that includes aspirin and ticagrelor for the treatment of ACS is associated with reduced risk of gram-positive infection compared with the combination of aspirin and clopidogrel. are in or in the choice of P2Y12 inhibitor for ACS to individual patient and review review review analysis, The of

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