Platelet activation subsequent to the adhesion of platelets to the vascular wall results in the release of mediators that promote platelet aggregation, which plays a pivotal role in the development of the polyvascular atherosclerotic disease that can be referred to by the acronym 'ATIS' (
AtheroThrombosIS). The currently available
antiplatelet drugs used to prevent vascular events in patients with
cardiovascular disease, including
peripheral arterial disease (PAD), include
aspirin and
thienopyridines such as
clopidogrel. These drugs decrease platelet aggregability, each of them by inhibiting a different pathway of platelet activation and recruitment.
Aspirin acts by inhibiting
thromboxane A2 (TXA2) formation through the inhibition (acetylation) of
cyclo-oxygenase. On the other hand,
thienopyridines suppress the platelet aggregation
adenosine diphosphate (
ADP) pathway by inhibiting the platelet P2Y12 subtype of the
ADP receptor. The results of the large ATT (Antithrombotic Trialists' Collaboration) meta-analysis of published clinical studies on
aspirin, reported in 2002, confirmed the previous meta-analysis and major trials that treatment with
aspirin (mixed with other
antiplatelet agents in these large meta-analyses) can prevent vascular events in high-risk patients with
cardiovascular disease. However, it must be stressed that specifically in PAD patients no significant effect of
aspirin was demonstrated in a more recent meta-analysis. This was also the case for primary and
secondary prevention in diabetic patients. In keeping with these observations, neither a five-year follow-up study of Japanese diabetic patients in the JPAD (Japanese Primary Prevention of
Atherosclerosis with
Aspirin for Diabetes) study, a seven-year follow-up study of UK diabetic patients with PAD in the POPADAD (Prevention of Progression of Arterial Disease and Diabetes) study, nor a very recent Scottish study in the same population of diabetics with PAD revealed a significant beneficial effect for
aspirin in preventing ischaemic events. This failure may be a consequence of more rapid recovery of platelet aggregability following each dose of
aspirin in these PAD or diabetic populations, with the accelerated platelet turnover resulting in a condition of
aspirin resistance. Results of the large scale CAPRIE (
Clopidogrel versus
Aspirin in Patients at Risk of Ischaemic Events) trial that evaluated
clopidogrel in patients with
cerebral infarction,
myocardial infarction or PAD have found
clopidogrel to be significantly more effective than
aspirin in preventing ischaemic events in patients with PAD. Furthermore, a subgroup analysis of the study has confirmed the efficacy of
clopidogrel in diabetic patients with PAD, showing a significant reduction of events in
clopidogrel-treated, compared with
aspirin-treated, diabetic patients. These results are also likely to be attributable to the greater frequency of
aspirin resistance in
aspirin-treated patients in these populations (diabetics and/or PAD). Platelets, through activation and aggregation, have an important role in ATIS. However, although antiplatelet
therapy with low-dose
aspirin has been reported to prevent vascular events in high-risk patients with
cardiovascular disease, recent studies in patients with PAD or
diabetes mellitus have failed to support the efficacy of
aspirin in preventing vascular events in these patient populations. In contrast,
clopidogrel appears to be a useful
antiplatelet agent in the prevention of vascular events in patients with PAD or diabetes.