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Prof. Mateja Kaja Jezovnik
Prof. Pavel Poredos,
Aspirin may be less effective in secondary prevention of peripheral artery disease than in that of coronary artery disease. Also, new anti-platelet drugs may in the future stand superior to aspirin with perhaps some definite advantages. That however, is not yet the case. In this short review of key trials, the reader can find the reasons why aspirin may not be revealing its full efficacy.
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.
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:
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:
In asymptomatic patients, no positive difference was noted between aspirin and placebo in the setting of asymptomatic PAD.
In the trial setting, non-efficacy of aspirin in PAD may be due to:
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.
New anti-platelet drugs have shown only marginal superiority over aspirin without definite advantages.
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.
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.
1. The prevalence of peripheral arterial disease in a defined populationCriqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D.Circulation 1985;71(3):510-5.2. Platelet activation is increased in peripheral arterial diseaseCassar K, Bachoo P, Ford I, Greaves M, Brittenden J. J Vasc Surg 2003;38(1):99-103.3. Coagulation, fibrinolysis and platelet P-selectin expression in peripheral vascular diseaseKoksch M, Zeiger F, Wittig K, Siegemund A, Reininger CB, Pfeiffer D, Ruehlmann C. Eur J Vasc Endovasc Surg 2001;21(2):147-54.4. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patientsBMJ 2002;324(7329):71-86.5.Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trialsBerger JS, Krantz MJ, Kittelson JM, Hiatt WR. JAMA 2009;301(18):1909-19.6. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trialFowkes FG, Price JF, Stewart MC, Butcher I, Leng GC, Pell AC, Sandercock PA, Fox KA, Lowe GD, Murray GD. JAMA 2010;303(9):841-8.7. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery diseaseBiondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, Testa L, Sheiban I, Sangiorgi G. Eur Heart J 2006;27(22):2667-74.8. Does the preventive effect of different drugs depend on location of the atherosclerotic process?Poredos P, Jezovnik MK. Int Angiol 2008;27(4):274-80.9. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial diseaseTran H, Anand SS. JAMA 2004;292(15):1867-74.10. Clinical aspects of platelet inhibitors and thrombus formationMeadows TA, Bhatt DL. Circ Res 2007;100(9):1261-75.11. COX-1 sensitivity and thromboxane A2 production in type 1 and type 2 diabetic patients under chronic aspirin treatmentPulcinelli FM, Biasucci LM, Riondino S, Giubilato S, Leo A, Di Renzo L, Trifirò E, Mattiello T, Pitocco D, Liuzzo G, Ghirlanda G, Crea F. Eur Heart J 2009;30(10):1279-86.12. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetesRocca B. et al. J Thromb Haemost. 2012 Jul;10(7):1220-30.13. Cardiovascular Events in Acute Coronary Syndrome Patients With Peripheral Arterial Disease Treated With Ticagrelor Compared to Clopidogrel: Data From the PLATO TrialM. Patel et al. Circulation 2013 Meeting abstract. Session title: Anti-Platelet Research: Unique Populations and Outcomes. Latest updates in ACS research. 14. Vorapaxar in the Secondary Prevention of Atherothrombotic EventsDavid A. Morrow et al. N Engl J Med 2012; 366:1404-1413 April 12, 2012
Volume Number: Vol11 N°14
Prof. Pavel Poredoš, MD, PhD, Assoc. Prof. Mateja Kaja Jezovnik, dr. med.University Medical Centre Ljubljana, Department of vascular disease, Zaloška 7, 1000 Ljubljana, SloveniaE-mail: email@example.com@kclj.siAuthors' disclosures: None declared.