P666Anti-platelet therapy in the primary prevention of cardiovascular disease in patients with chronic obstructive pulmonary disease: randomised controlled proof of concept trial (APPLE COPD-ICON 2)

Abstract

Abstract The APPLE COPD-ICON2 trial is a prospective 2x2 factorial, double blinded proof of concept randomised controlled trial targeting patients with chronic obstructive pulmonary disease (COPD) at high risk of cardiovascular disease. The primary goal was to investigate if antiplatelet therapy (APT) will produce the predefined cut-off of platelet inhibition measured using the Multiplate test. We also assessed inflammatory biomarkers in serum. Patients were randomised to Aspirin plus placebo, ticagrelor plus placebo, Aspirin plus ticagrelor or placebo only for 6 months. The primary outcome is inhibition of arachidonic acid (ASPI-test, cut-off <40) and adenosine diphosphate (ADP-test, cut-off <46) induced platelet aggregation at 6 months based on intention to treat (ITT) and sensitivity per protocol (PP) analyses. Safety outcomes included rates of major/minor bleeding. Of 543 patients screened, 120 were recruited (mean age of 67.5 years). The ITT response rate to Aspirin was 48.3% (95% confidence interval [CI] 35.8–61.0%) according to ASPI-test and the response rate to ticagrelor was 41.4% (95% CI 29.3–54.6%) according to ADP-test. The PP ASPI-test response rate to Aspirin was 68.3% (95% CI 52.3–80.9%) and the PP ADP-test response rate to ticagrelor was 68.8% (95% CI 50.4–82.6%). There were no differences between the groups in the changes in Quality of Life using questionnaires (EQ5D 5L, St. George's COPD-C), inflammatory markers, carotid intima media thickness and vascular stiffness from baseline to 6-months. There were 5 type 1 bleeds according to the BARC criteria recorded in this study; 2 in the placebo arm, 2 in the Aspirin arm, and 1 in the ticagrelor arm. The MRC Dyspnoea score, FEV1 and FVC was similar across the groups. Primary outcome measures Aspirin No Aspirin Ticagrelor No Ticagrelor ITT analysis set* n 60 60 58 62 Baseline No. of responders 1 6 4 1 % (95% CI) 1.7 (0.2, 11.3) 10 (4.5, 20.8) 6.9 (2.6, 17.3) 1.6 (0.2, 10.9) 6 months No. of responders 29 7 24 2 % (95% CI) 48.3 (35.8, 61) 11.7 (5.6, 22.8) 41.4 (29.3, 54.6) 3.2 (0.8, 12.3) PP analysis set** n 41 45 32 54 6 months No. of responders 28 7 22 2 % (95% CI) 68.3 (52.3, 80.9) 15.6 (7.5, 29.6) 68.8 (50.4, 82.6) 3.7 (0.9, 14.0) *Descriptive statistics for the primary outcome of response for the comparative groups at baseline and 6 months for the ITT analysis set and **PP analysis set. Note that response is ASPI response in the Aspirin and No Aspirin columns and ADP response in the ticagrelor and No ticagrelor columns. Primary outcome measure Nearly one third of COPD patients did not have a platelet response to antiplatelet therapy with Aspirin and ticagrelor. These findings support the high pro-thrombotic milieu and the need for further research in COPD patients. Acknowledgement/Funding Astra Zeneca (Funder reference number ISSBRIL0303)