Abstract
Background: Aspirin (and its precursors) have been used for centuries. More recently, we have realised its effect in preventing atherothrombosis. Evidence suggests that aspirin is not as effective in Peripheral Arterial Disease (PAD) as in Coronary Artery Disease (CAD). Millions of people today are affected with PAD with 5% of those on aspirin +/- a thienopyridine still having a thrombotic complication yearly. The risk continues post event with a 2-3-fold increased risk of stroke, myocardial infarction and cardiovascular death. This thesis assesses if the reduced effect of aspirin in PAD vs CAD is due to increased platelet turnover such that once daily aspirin is unable to adequately suppress thromboxane production.
Methods: 1. A systematic review and meta-analysis was completed assessing the time-dependent pharmacodynamic effect of aspirin after taking/finishing aspirin. Bleeding Time (BT), Platelet Aggregation (PA) and Serum Thromboxane B2 (sTXB2) were used. Percentage above baseline (for BT) and percent inhibition (for PA and sTXB2) were calculated. 2. These data were then analysed and compared to sTXB2 testing in healthy volunteers using the ALPCO kit. sTXB2 was tested at five timepoints (4- to 96-hours) post taking five days of aspirin 81 mg to determine an absolute ng/ml value above which represents aspirin resistance. 3. Finally, a cohort of PAD patients underwent sTXB2 testing at 4- and 24-hours to determine the difference from normal and rates of resistance to aspirin in this population.
Results: 26 studies were identified from the systematic review. The meta-analysis demonstrated a return to normal at 96 hours for BT, 120 hours for PA and 336 hours for sTXB2. All measures significantly returned towards normal at 72 hours therefore this timepoint was chosen for analysis. 20 healthy volunteers had sTXB2 tested and percent inhibition was comparable with the metaanalysis data. From the 72-hour data sTXB2 levels of 50, 64 and 78 ng/ml were chosen for further evaluation. Between November 2018 and January 2020, 107 PAD patients were enrolled. However, due to COVID restrictions, only 43 had both 4- and 24- hour sTXB2 levels. Those with PAD (predominantly Fontaine stage II) had no difference in mean sTXB2 compared to healthy volunteers 7 (mean sTXB2 10.7 ng/ml; 95% CI 4.2 – 17.2 and 10.7; 5.1 – 16.3 respectively). Aspirin resistance was low. Only 5% of the healthy volunteers and 4.1% of the PAD cohort had a sTXB2 >50 ng/ml at 24 hours.
Conclusion: Aspirin’s effect lasts for 72-96 hours. Aspirin resistance should be considered a sTXB2 level >50 ng/ml at 24 hours when tested with the ALPCO kit. There is no difference in mean sTXB2 between healthy volunteers and low-grade PAD patients with only 4.1% having evidence of resistance to aspirin which is similar to the 5% observed in healthy volunteers. The preliminary findings from this thesis suggest there is no evidence of increased platelet turnover in low grade PAD patients. Future directions include testing sTXB2 in those with more severe PAD and those with acute atherothrombosis. This may show a significant difference which in turn would imply a randomised trial of once vs. twice daily aspirin might provide insight into a new treatment paradigm.