Several pharmacologic agents have been used to help increase lower extremity arterial reconstruction patency. Antithrombotic therapy can be defined as any form of antithrombotic treatment including antiplatelet or anticoagulant, with the focus on antiplatelet therapy. Anticoagulant therapy was not in the scope of this article. A recent meta-analysis demonstrated that anti-platelet agent use results in improved autologous and prosthetic graft patency at both 1 and 2 years [7]. Acetylsalicylic acid (ASA) is the most commonly used anti-platelet agent in the world due to its safety profile and low cost. Aspirin inhibits platelet cyclooxygenase-1 in an irreversible manner. This subsequently blocks the production of thromboxane A2 and prevents further platelet recruitment and activation. In higher doses, aspirin can inhibit COX 2 as well. Patients with vascular disease benefit from aspirin with a 25 % reduction in risk for cardiovascular death, stroke, or myocardial infarction [9, 10]. Low dose aspirin (75–150 mg) is proven to be as effective as higher doses with lower risk of side effects. Gastric ulcer disease is the most common side effect and is dose dependent. Major bleeding risk for patients taking aspirin is 1–3 % annually. ASA allergy causing bronchospasm has been reported in up to 0.3 % of patients and should be avoided in this population. There is both a clinical and biochemical phenomenon known as aspirin resistance but the clinical applications are not useful as testing for the biochemical condition is not standardized. ASA may be continued up until the time of surgery in patients who are at high risk for cardiovascular events as are most patients requiring vascular surgery [10].

Clopidogrel is the most commonly used of the P2Y12 antagonists that selectively block an ADP receptor on platelets. This blocks the effect of platelet recruitment and activation that aspirin produces but through a different mechanism. This group also includes, ticlopidine, and prasurgel and are known collectively as thienopyridines. The effect of thienopyridines on blocking the P2Y12 receptor is also irreversible and lasts for the life of the platelet. These medications are metabolized in the liver by cytochrome p450 enzyme system. As these drugs require metabolic activation, drug-drug interactions and loss of these enzymes may delay or reduce drug activation and reduce the effect of the drug. Prasurgel is converted to active form most efficiently and therefore has the most rapid onset of action. Ticagrelor inhibits P2Y12 but does not require metabolic activation, giving it a more rapid onset of action and is reversible meaning that the effect is lost more rapidly as well. Clopidogrel has been shown to be marginally more effective than aspirin in terms of reducing ischemic cardiovascular events [10]. The delay in onset of action means that loading doses must be given for the thienopyridines. Bleeding comprises the major side effect of clopidogrel, prasurgel, and ticagrelor, which can also cause mild dyspnea and asymptomatic bradycardia. Resistance to clopidogrel is more common and more significant clinically than aspirin resistance. Up to a third of patients may exhibit some form of clopidogrel resistance through loss of CYP2C19 alleles. Proton pump inhibitors, specifically omeprazole may also lead to a decreased effectiveness of clopidogrel in terms of preventing ADP induced platelet aggregation. Patients undergoing surgery should stop clopidogrel or prasurgel 7–10 days prior to surgery and ticagrelor 5 days prior to surgery due to higher risk of bleeding than with aspirin. Elective surgery should be delayed if recent coronary stenting prevents clopidogrel from being discontinued [10].

Dipyridamole has been used in combination with aspirin (aggrenox) due to its relatively weak antiplatelet effect as an independent medication. It is used mostly for patients who are being treated for transient ischemic attacks. Dipyridamole blocks phosphodiesterase which then prevents breakdown of cyclic AMP which reduces platelet activation. Side effects include vasodilatation which can be deleterious in patients with pre-existing cardiac disease. Aggrenox produced similar rates of stroke reduction as clopidogrel but had increased rates of bleeding complication. Onset of action is rapid and half life is short for dipyrimadole alone but aspirin component means that platelet inhibition will last for approximately 7–10 days [10].

The use of antiplatelet therapy in the treatment of patients who have undergone bypass has not been standardized as demonstrated in two large prospective trials. The Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial reported results of an angioplasty or surgery first strategy. Of all patients randomized to the bypass first strategy, 62 % were receiving an antiplatelet agent. The data for this study was accrued in the United Kingdom from 1999 to 2004 [2]. Amputation free survival without secondary intervention at 12 months follow up for the surgery first group was noted to be 56 % during the course of the trial. The study was not designed to test whether anti-platelet therapy alone had an impact on graft patency. The PREVENT III trial was a randomized, double blinded study designed to examine whether the novel agent edifoligide would prevent vein graft failure in patients undergoing infra-inguinal bypass. The study randomized 1404 patients in North America from 2001 to 2003. Sixty seven percent of all patients were noted to be on anti-platelet therapy at the time of the lower extremity bypass (50 % on ASA and 17 % on thienopyridine). At time of discharge, the number of patients on anti-platelet therapy had increased to 80 %. The effect this had on patency is unclear from the trial data. Patients treated in the university hospital setting, those with CAD, and those with hyperlipidemia were more likely to have received anti-platelet therapy at time of discharge [2]. Antiplatelet agent use in patients with peripheral arterial disease continues to increase even prior to lower extremity bypass. Simons, et al. demonstrated that approximately 82–84 % of patients undergoing lower extremity bypass in New England from 2003 to 2009 were on antiplatelet agent at the time of surgery [11].