Aspirin, still first-line in secondary prevention of cardiovascular complications in peripheral artery disease

Background

Clinical manifestation of atherosclerosis include myocardial infarction, stroke, aortic aneurysms, renal artery stenosis and peripheral artery disease. Peripheral artery disease is one of the prevalent manifestations with a significant portion of the population over age 60 affected (1).
Peripheral artery disease tends to occlude the carotid, vertebral, upper extremity, mesenteric, renal or more often, the lower extremity vessels. However, due to its association with atherosclerosis in other vascular beds, such as the coronary, aortic arch, or brain vasculature, it is accompanied with increased morbidity and mortality mainly due to myocardial infarction and stroke. For this reason, peripheral artery disease needs to be treated as coronary artery disease is, regardless of the vascular bed.
Thus, management of patients with PAD should not only focus on treating peripheral vessel occlusion and preventing organ damage with local treatment such as peripheral bypass graft surgery or percutaneous endovascular procedures, but on gaining systemic access through identical or similar measures as those taken in coronary artery disease: beyond lifestyle measures, with treatment including drugs, antiplatelets especially as well as antithrombotic and antilipemic drugs (see previous authors' article on statins and thromboembolism).
Patients with PAD manifest platelet hyperaggregability and heightened thrombogenesis such that antithrombotic prophylaxis in patients with PAD is important (2, 3). Aspirin is the oldest anti-platelet drug - Hippocrates, wrote about a bitter powder extracted from the willow tree 400 BC - and since the 1980’s, the precise action of aspirin as inhibitor of the enzyme cyclooxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation has been uncovered. It is also the most frequently investigated antiplatelet drug – aspirin obtains 50,000+ hits on Pubmed and a tripling of the number of publications in the last 30 years. 

As stated in the ESC guidelines on PAD, antiplatelet drugs are one of the basic options for treatment along with drugs such as ticlopidine, dipyridamole and clopidogrel. On top of lifestyle measures, aspirin is recommended as a first line treatment for secondary prevention of coronary events in patients with PAD.

1 - Review of latest meta-analyses and trials

Peripheral artery disease is characterised by artery stenosis and occlusions in the peripheral artery bed; it can be symptomatic or asymptomatic. Symptomatic PAD ranges in severity from intermittent claudication (IC) to critical limb ischemia, while asympomatic PAD also holds the artery stenosis and occlusions in the peripheral artery bed - but without any clinical symptom present. Significant meta-analyses in symptomatic patients have been:

• Antithrombotic Trialists' Collaboration (2002). As reviewed in a previous edition of the e-journal by the same author, the effect of antiplatelet therapy on cardiovascular events was investigated and systematically reviewed in patients with acute or previous vascular disease, by the Antithrombotic Trialists' Collaboration. Although a 23% relative risk reduction of adverse cardiovascular events was found in this meta-analysis comprising 287 studies, it did not address the efficacy of aspirin specifically since of the 135,000 patients reviewed in the meta-analysis, only one third of the 9,214 patients with PAD included were treated with aspirin alone (4).
• A more recent meta-analysis (2009) investigated the effect of aspirin on cardiovascular event rates in patients with PAD only (5). The data from 18 prospective randomised trials of aspirin therapy with or without dipyridamole involving 5,269 individuals was studied. In the subset of 3,019 participants taking aspirin alone, there was no significant decrease in the primary endpoint which was cardiovascular events defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. Only a significant reduction in non-fatal stroke was observed. 

Thus, in symptomatic patients, recent keys studies have been either not designed to examine aspirin specifically, or offered results that were only partially positive. 
On the other hand, the effect of aspirin specifically on cardiovascular events in patients with asymptomatic PAD specifically was studied most recently in:

• The Aspirin for Asymptomatic Atherosclerosis (AAA) trial (2010) (6). This double-blind randomised controlled trial included 3,350 subjects with a low ankle - brachial index - ABI (= 0.95). Mean follow-up was 8.2 years, and the primary end-point was: non-fatal coronary event, stroke, or revascularisation. No statistically significant difference was found between subjects treated with aspirin and the placebo group.

In asymptomatic patients, no positive difference was noted between aspirin and placebo in the setting of asymptomatic PAD.

2 - Potential reasons for non-efficacy of aspirin in PAD patients

In the trial setting, non-efficacy of aspirin in PAD may be due to:

• Non compliance: medication noncompliance is one of the most frequent and important contributors to non-responsiveness to aspirin (7). For example, over the course of the eight-year Aspirin for Asymptomatic Atherosclerosis (AAA) study, compliance was only 60%.
• Lack of evidence: in contrast to the abundance of randomised trials evaluating aspirin and other antiplatelet drugs in primary and secondary prevention of coronary heart disease, patients with PAD have been under-represented in randomised trials such that aspirin efficacy in patients with PAD has not had many opportunities to be established.
• The type of atherosclerotic disease: experience with anti-platelet agents supports the presumption that the efficacy of anti-platelet drugs is variable in distinct patient populations and is dependent on the type and location of atherosclerotic disease (8). 
• Non-responsiveness caused by pharmacogenetics: in the last decade, the concept of aspirin resistance as one of the most important reasons for aspirin non-responsiveness has been put forward. Genetic variability of COX-1 is responsible for persistent production of thromboxane A2, which is normally suppressed by aspirin - in patients chronically treated with it (10). 
• Clinical conditions: certain clinical conditions may influence aspirin metabolism and cause a high platelet turnover. They are acute coronary syndrome, coronary artery by-pass grafting, poor glucose control, and obesity. A diminished responsiveness to the antiplatelet effect of aspirin has also been reported in patients with type 2 diabetes mellitus (11).
• Incomplete thromboxane inhibition: faster recovery of platelet cyclooxygenase-1 activity may explain incomplete thromboxane inhibition during a 24 hour dosing interval, which may limit the duration of the antiplatelet effect of low-dose aspirin. Inadequate thromboxane inhibition by low-dose aspirin can be corrected with a twice-daily regimen (12).
• Advanced atherosclerosis: non-responsiveness of PAD patients to aspirin could also be due to advanced atherosclerosis and a higher atherosclerotic burden in this group of patients.

3 - Comparing with coronary patients

In patients with coronary heart disease, some studies have shown that the combination of aspirin with dipyridamole reduced the risk of ischaemic stroke, but this combination is no more effective than aspirin alone (9). In the Anti-platelet Trialists’ Collaboration (4), the greatest benefit was found in coronary patients: acute MI – RR 30%, stable angina pectoris – RR 33%, and unstable angina pectoris – RR 46%. The anti-platelet treatment also significantly - less however than for coronary events-, reduced recurrent ischaemic stroke (RR – 22%). Among patients with peripheral artery disease, there was a 23% reduction of serious vascular events. These results show that aspirin is effective in the prevention of atherosclerotic cardiovascular events in all three of the most frequently affected vascular beds coronary, aortic or femoral, but the highest efficacy of aspirin (with the limitation that aspirin alone was only given to a third of the PAD patients in the study) - was indicated in the coronary bed. 

4 - New anti-platelet drugs 

New anti-platelet drugs have shown only marginal superiority over aspirin without definite advantages.

• Ticagrelor: in PLATO, a post hoc analysis of patients with PAD (n=1,144) at baseline compared to those without PAD was performed for clinical characteristics and outcomes with approved ticagrelor in ACS and clopidogrel at 12 months. Ticagrelor use compared to clopidogrel in the PAD patients resulted in similar reductions in clinical events without an increase in major bleeding. (13)
• Vorapaxar: inhibition of PAR-1 with expiermental vorapaxar, which produces inhibition of thrombin-mediated platelet activation, reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial haemorrhage (14). 

The trial EUCLID has results due in 2016 and will compare ticagrelor with clopidogrel treatment on the risk of cardiovascular death, myocardial infarction and ischemic stroke in patients with established Peripheral Artery Disease.

Conclusion

Aspirin is effective in the prevention of cardiovascular events in various vascular beds such as the coronary, aortic arch, or brain vasculature but is are also effective, albeit slightly less in PAD that usually affects the lower limbs. Ticagrelor and Vorapaxar have shown only marginal superiority over aspirin without other definite advantages. Therefore, aspirin remains the first line of antiplatelet drug for secondary prevention of cardiovascular events in PAD patients. 
Ways to improve aspirin response are to improve patient compliance, to focus on PAD use and to target atherosclerotic disease. Also, it is very important to gain knowledge of patient genetic variability in the clinical conditions and using a twice-daily regimen. Nevertheless, additional randomised controlled trials of aspirin therapy are needed to establish the net benefit and bleeding risks in PAD.