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Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study.

Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, Husted SE, Cannon CP, Becker RC, Steg PG, Åsenblad N, Wallentin L - Platelets (2013)

Bottom Line: Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001).We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy.Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Science, University of Sheffield , Sheffield , UK .

ABSTRACT
In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

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Cumulative Kaplan–Meier estimates of (A) time to pulmonary AE on-treatment and (B) the time to death following pulmonary AE on-treatment, out of all randomized patients who received at least one dose of study medication, comparing treatment with ticagrelor (“T”, N = 9235) and clopidogrel (“C”, N = 9186). p Values and odds ratio (OR) are from multivariable logistic regression for modelling the probability of the event using treatment group and baseline factors (gender, age, weight, asthma, chronic obstructive pulmonary disease, diabetes, smoker, congestive heart failure, chronic renal disease, peripheral arterial disease and clopidogrel pre-randomization) as independent variables. CI = confidence intervals.
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f1: Cumulative Kaplan–Meier estimates of (A) time to pulmonary AE on-treatment and (B) the time to death following pulmonary AE on-treatment, out of all randomized patients who received at least one dose of study medication, comparing treatment with ticagrelor (“T”, N = 9235) and clopidogrel (“C”, N = 9186). p Values and odds ratio (OR) are from multivariable logistic regression for modelling the probability of the event using treatment group and baseline factors (gender, age, weight, asthma, chronic obstructive pulmonary disease, diabetes, smoker, congestive heart failure, chronic renal disease, peripheral arterial disease and clopidogrel pre-randomization) as independent variables. CI = confidence intervals.

Mentions: Pulmonary and sepsis AEs were determined in 9235 patients receiving at least one dose of ticagrelor and 9186 patients receiving at least one dose of clopidogrel (Table I and Supplement Table IA). Fewer pulmonary AEs were seen within 7 days of study medication (“on-treatment”) in the ticagrelor group compared to the clopidogrel group and there were fewer deaths following pulmonary AEs in the ticagrelor group, with all of the difference accounted for by deaths following on-treatment pulmonary AEs (Table I and Figure 1). There were also fewer deaths attributed to sepsis in the ticagrelor group, including fewer deaths attributed to sepsis following a pulmonary AE (Table I). Approximately one-third of pulmonary and sepsis AEs occurred in patients who underwent CABG surgery at any time in the study and similar trends in AE rates and associated mortality were seen in those who either did not or did have CABG surgery (Supplement Table IB). Deaths following pulmonary or sepsis AEs that were adjudicated as both “cardiovascular” and “non-cardiovascular” contributed to the differences between the treatment groups (Supplement Table IC). There were fewer subsequent pulmonary or sepsis AEs following a pulmonary AE with “continuing medication,” and fewer deaths following these recurrent AE, in the ticagrelor group (Table I). There were no significant differences between the treatment groups in the numbers of sepsis AEs that did not follow a pulmonary AE (Supplement Table ID).Figure 1.


Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study.

Storey RF, James SK, Siegbahn A, Varenhorst C, Held C, Ycas J, Husted SE, Cannon CP, Becker RC, Steg PG, Åsenblad N, Wallentin L - Platelets (2013)

Cumulative Kaplan–Meier estimates of (A) time to pulmonary AE on-treatment and (B) the time to death following pulmonary AE on-treatment, out of all randomized patients who received at least one dose of study medication, comparing treatment with ticagrelor (“T”, N = 9235) and clopidogrel (“C”, N = 9186). p Values and odds ratio (OR) are from multivariable logistic regression for modelling the probability of the event using treatment group and baseline factors (gender, age, weight, asthma, chronic obstructive pulmonary disease, diabetes, smoker, congestive heart failure, chronic renal disease, peripheral arterial disease and clopidogrel pre-randomization) as independent variables. CI = confidence intervals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4220996&req=5

f1: Cumulative Kaplan–Meier estimates of (A) time to pulmonary AE on-treatment and (B) the time to death following pulmonary AE on-treatment, out of all randomized patients who received at least one dose of study medication, comparing treatment with ticagrelor (“T”, N = 9235) and clopidogrel (“C”, N = 9186). p Values and odds ratio (OR) are from multivariable logistic regression for modelling the probability of the event using treatment group and baseline factors (gender, age, weight, asthma, chronic obstructive pulmonary disease, diabetes, smoker, congestive heart failure, chronic renal disease, peripheral arterial disease and clopidogrel pre-randomization) as independent variables. CI = confidence intervals.
Mentions: Pulmonary and sepsis AEs were determined in 9235 patients receiving at least one dose of ticagrelor and 9186 patients receiving at least one dose of clopidogrel (Table I and Supplement Table IA). Fewer pulmonary AEs were seen within 7 days of study medication (“on-treatment”) in the ticagrelor group compared to the clopidogrel group and there were fewer deaths following pulmonary AEs in the ticagrelor group, with all of the difference accounted for by deaths following on-treatment pulmonary AEs (Table I and Figure 1). There were also fewer deaths attributed to sepsis in the ticagrelor group, including fewer deaths attributed to sepsis following a pulmonary AE (Table I). Approximately one-third of pulmonary and sepsis AEs occurred in patients who underwent CABG surgery at any time in the study and similar trends in AE rates and associated mortality were seen in those who either did not or did have CABG surgery (Supplement Table IB). Deaths following pulmonary or sepsis AEs that were adjudicated as both “cardiovascular” and “non-cardiovascular” contributed to the differences between the treatment groups (Supplement Table IC). There were fewer subsequent pulmonary or sepsis AEs following a pulmonary AE with “continuing medication,” and fewer deaths following these recurrent AE, in the ticagrelor group (Table I). There were no significant differences between the treatment groups in the numbers of sepsis AEs that did not follow a pulmonary AE (Supplement Table ID).Figure 1.

Bottom Line: Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001).We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy.Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Science, University of Sheffield , Sheffield , UK .

ABSTRACT
In the PLATelet inhibition and patient Outcomes (PLATO) study of patients with acute coronary syndromes, ticagrelor reduced mortality compared to clopidogrel but the mechanisms for this mortality reduction remain uncertain. We analysed adverse events (AEs) consistent with either pulmonary infection or sepsis, and subsequent mortality, in 18,421 PLATO patients treated with ticagrelor or clopidogrel. AEs occurring within 7 days of last dose of study medication were defined as "on-treatment". Serial measurements of blood leukocyte counts, C-reactive protein and interleukin-6 were performed. Fewer on-treatment pulmonary AEs occurred in the ticagrelor compared to the clopidogrel group (275 vs. 331 respectively; p = 0.019), with fewer deaths following these AEs (33 vs. 71; p < 0.001), particularly in those who remained on study medication three days after AE onset (10 vs. 43; p < 0.001). There were fewer deaths attributed to sepsis in the ticagrelor group (7 vs. 23; p = 0.003). Leukocyte counts were lower in the clopidogrel group during treatment (p < 0.0001 at 1, 3 and 6 months) but not at 1 month post-discontinuation. C-reactive protein increased more at discharge in the ticagrelor group (28.0 ± 38.0 vs. 26.1 ± 36.6 mg/l; p < 0.001) and interleukin-6 remained higher during the first month of treatment with ticagrelor. We conclude that the mortality risk following pulmonary AEs and sepsis in acute coronary syndrome patients appears to be lower during ticagrelor compared to clopidogrel therapy. Further work should assess whether ticagrelor and clopidogrel have differential effects on immune signalling.

Show MeSH
Related in: MedlinePlus