Risk modifiers and mortality in patients with high platelet reactivity to Adenosine-diphosphate (ADP) in the LURIC study

Background Increased platelet reactivity (PR) is an established predictor of cardiovascular (CV) and all-cause mortality. However, therapeutic targeting of PR by tailored antiplatelet therapy (APT) failed to show significant clinical benefit. It remains unclear whether increased PR constitutes a risk-modifier that identifies patients that benefit from risk-factor adjustment. Purpose To identify risk factors that allow modification and/or elimination of increased CV and all-cause mortality in patients with altered PR. Methods ADP- and TRAP-induced PR was measured by CD62P and CD63 expression in 1780 patients who were referred for coronary angiography between 1997 and 2000 and participated in the LURIC study. Statistical analysis was performed by SPSS v25.0 and R v3.6.1 Results ADP-induced PR was an excellent predictor of CV-mortality and risk-equivalent to the presence of coronary artery disease (Figure 1A). Stratification of platelet ADP-response into tertiles demonstrated that patients with high-PR (HPR) and low-PR (LPR) were at increased risk for CV-mortality when compared to the reference group (HPR: HR 1.7 [95% CI: 1.3–2.3]; LPR: HR 1.4 [95% CI: 1.0–1.8]) (Figure 1B). Multivariable-adjustment did not change the association of PR with CV-mortality. Using a relative weight analysis, we identified HbA1c and estimated glomerular filtration rate (eGFR) as potential risk-modifiers. In addition, presence of APT appeared to be an exclusive risk-modifier in the HPR-group. In an multivariable-adjusted risk assessment, we verified that in the HPR group (i) treatment of PR by APT reduced CV-mortality with a HR of 0.5 (95% CI: 0.3–0.7) p=0.0004), (ii) HbA1c of >7.0% in patients with diabetes increased CV-mortality with a HR of 2.0 (95% CI: 1.2–3.2 p=0.004) and (iii) eGFR <60ml/min increased CV-mortality with a HR 1.7 (95% CI: 1.1–2.6 p=0.013). Other risk-factors including blood pressure (<140mmHg), LDL-C (<100mg/dL) and hs-CRP (<2mg/dL) did not alter the mortality risk. None of the risk-modifiers tested affected CV-mortality risk of patients in the LPR group. In the HPR group, risk modification by APT and HbA1c <7.0% in patients with diabetes independently reduced CV-mortality risk to a level that was no longer statistically different to the reference group (p>0.05). Risk modification by an eGFR >60ml/min led to a profound risk reduction in the HPR group but remained statistically different from the reference group (Figure 1C). Conclusion Here, we demonstrate that HPR and LPR are predictors for CV mortality in the LURIC study. Treatment of platelet hyperreactivity by APT, HbA1c of ≤7% in patients with diabetes and an eGFR ≥60ml/min were associated with a reduced CV-mortality in HPR patients and might constitute adjustable risk factors in this group. In addition, we were unable to identify any significant risk factors for patients with LPR underlining a high-risk patient group with insufficient therapeutic options. Figure 1 Funding Acknowledgement Type of funding source: None

Risk modifiers of acute respiratory distress syndrome in patients with non-pulmonary sepsis: a retrospective analysis of the FORECAST study

Background Predisposing conditions and risk modifiers instead of causes and risk factors have recently been used as alternatives to identify patients at a risk of acute respiratory distress syndrome (ARDS). However, data regarding risk modifiers among patients with non-pulmonary sepsis is rare. Methods We conducted a secondary analysis of the multicenter, prospective, Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) cohort study that was conducted in 59 intensive care units (ICUs) in Japan during January 2016–March 2017. Adult patients with severe sepsis caused by non-pulmonary infection were included, and the primary outcome was having ARDS, defined as meeting the Berlin definition on the first or fourth day of screening. Multivariate logistic regression modeling was used to identify risk modifiers associated with ARDS, and odds ratios (ORs) and their 95% confidence intervals were reported. The following explanatory variables were then assessed: age, sex, admission source, body mass index, smoking status, congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, steroid use, statin use, infection site, septic shock, and acute physiology and chronic health evaluation (APACHE) II score. Results After applying inclusion and exclusion criteria, 594 patients with non-pulmonary sepsis were enrolled, among whom 85 (14.3%) had ARDS. Septic shock was diagnosed in 80% of patients with ARDS and 66% of those without ARDS (p = 0.01). APACHE II scores were higher in patients with ARDS [26 (22–33)] than in those without ARDS [21 (16–28), p < 0.01]. In the multivariate logistic regression model, the following were independently associated with ARDS: ICU admission source [OR, 1.89 (1.06–3.40) for emergency department compared with hospital wards], smoking status [OR, 0.18 (0.06–0.59) for current smoking compared with never smoked], infection site [OR, 2.39 (1.04–5.40) for soft tissue infection compared with abdominal infection], and APACHE II score [OR, 1.08 (1.05–1.12) for higher compared with lower score]. Conclusions Soft tissue infection, ICU admission from an emergency department, and a higher APACHE II score appear to be the risk modifiers of ARDS in patients with non-pulmonary sepsis.