A brief discussion of the epidemiology of Peripheral Arterial Disease and its global implications on health will be made. This will set the scene for a description of the etiology of the disease, as most patients will have Peripheral Artery Disease as a result of atherosclerosis, and only a minority of cases are related to inflammation, hypercoagulability states, or arterial dissection. The atherosclerosis is a systemic process with the risk factors well documented, for instance, the Framingham Heart Study, which will lead to an important point that PAD should not be regarded as a local disease. This is something pharmaceutical and endovascular device companies often overlook in their product design.
Importance of Antiplatelet Therapy in Peripheral Arterial Disease
Antiplatelet therapy, especially with aspirin, has become the cornerstone of medical therapy for patients with PAD. The absence of palpable pedal pulses, previous revascularization, or a history of lower extremity revascularization, or a history of claudication or previous limb amputation are all independent predictors of increased cardiovascular morbidity and mortality. Thus, patients with PAD are at especially high risk for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality is increased two to three fold in patients with PAD and predictors of risk include age and the presence of atherosclerosis in other vascular beds. Because the risks associated with PAD are related to systemic atherosclerosis and the prognosis of the limb is similar to the prognosis of the patient, the emphasis with respect to medical therapy has shifted away from intermittent claudication and toward global cardiovascular risk reduction. This is especially true for patients with PAD and coexisting coronary or cerebrovascular disease. Antiplatelet agents are effective in reducing the risk of cardiovascular events in patients with and without symptomatic PAD. Subgroup analysis of patients with PAD in the Antithrombotic Trialists’ Collaboration demonstrated a 22% reduction in serious vascular events with antiplatelet therapy. This was similar to the overall risk reduction seen in patients with previous myocardial infarction or stroke. The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial that compared clopidogrel with aspirin in patients with recent myocardial infarction, stroke, or symptomatic PAD, showed an overall 8.7% reduction in risk of myocardial infarction, stroke, or vascular death with clopidogrel. Although the relative risk reduction was only 23.8% for the comparison of clopidogrel with aspirin in patients with PAD, there was a 2.2% absolute reduction in severe cardiovascular events at 28 months, indicating that patients with PAD were at especially high risk for the composite outcome measured in this trial. Given these findings, the American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines have given a class 1 recommendation for antiplatelet therapy in all patients with PAD and the most recent guidelines have given a class IIa recommendation for use of clopidogrel in patients with PAD.
Benefits of Antiplatelet Therapy
Low-dose aspirin (75-325 mg/day) reduces the combined end-point of non-fatal MI, non-fatal stroke, and vascular death in patients with established symptomatic PAD, with an absolute risk reduction of 2.3% at 5 years and a number needed to treat of 44. Aspirin is effective in all patients with PAD, including those with intermittent claudication, and is the cornerstone of antiplatelet therapy. Ticlopidine (250 mg twice daily) reduces the rate of the primary end-point of vascular death, MI, or stroke by 23% compared with placebo in patients with a history of recent stroke or TIA. In patients with PAD, ticlopidine reduces the rate of the combined end-point of vascular death, MI, or stroke by 31%. Clopidogrel has a similar efficacy to ticlopidine in stroke prevention and is currently being compared with aspirin in patients with PAD in the CAPRIE study. Dipyridamole given as 200 mg twice daily is no more effective than aspirin in the secondary prevention of stroke or vascular events, except in ischemic stroke, where the combination of dipyridamole and aspirin is more effective than aspirin alone. Chronic use of triflusal (300-600 mg/day), an inhibitor of thromboxane A2 synthesis, reduces the rate of fatal and non-fatal stroke by 25% compared with aspirin in patients with a recent ischemic stroke. Despite these findings, triflusal is not available in many countries, including the USA. The above-mentioned agents are more effective than pentoxifylline or cilostazol, which have not been shown to be superior to placebo in the secondary prevention of vascular events in patients with PAD.
Mechanism of Action
Overall, the antiplatelet drugs which have proved efficacy in preventing serious vascular events in a variety of vascular diseases are almost exclusively those which inhibit platelet activation or aggregation. This strongly implies a crucial role for platelets in the genesis of thrombotic complications in patients with PAD.
Clopidogrel acts by irreversibly inhibiting the ADP receptor P2Y12, preventing amplification of platelet activation signals and ischemic events. High on-treatment platelet reactivity in patients receiving clopidogrel is only partly modified by doubling of the maintenance dose, whilst other affected patients have an inadequate drug-induced antiplatelet effect due to genetic variability in hepatic conversion of clopidogrel to its active metabolite. This has led to the recommendation of routine platelet function testing and use of newer, more potent ADP receptor inhibitors. An intravenous platelet GP IIb/IIIa inhibitor is not recommended for routine management of patients with PAD due to no effect on ischemic events and increased risk of major bleeding.
Aspirin irreversibly inhibits platelet cyclo-oxygenase 1, thus preventing the production of thromboxane A2, a potent promoter of platelet activation and aggregation. In vitro studies have shown aspirin to have a particularly strong inhibitory effect on platelet activation by prothrombotic plaque material or cytokine-stimulated endothelial cells compared with other stimuli. This effect on platelets interacting with the abnormal vascular wall component may be particularly relevant to the prevention of thrombotic complications in patients with PAD. High doses of aspirin have been demonstrated in randomized controlled trials to improve patency of venous and artificial bypass grafts. This is thought to be due to an effect on anastomotic and graft lesion myofibroblastic cells, which are inhibited from expressing cyclo-oxygenase and synthesizing prostanoids.
Platelet involvement in atherosclerosis is complex; it underlies the thrombotic events that precipitate much clinical vascular disease. The numerous roles of platelets in the process include the promotion of lipid deposition into macrophages, release of cytokines that promote monocyte adhesion, and the generation of procoagulant membrane surfaces. However, the critical role is platelet involvement in the formation of the atherosclerotic plaque and the precipitation of acute thrombotic events. The latter occurs when a fissure or rupture of an atherosclerotic plaque exposes subendothelial extracellular matrix and leads to platelet adhesion, activation, and aggregation accompanied by secretion of a variety of platelet granule contents.
Section “2.2 Mechanism of Action”
Types of Antiplatelet Agents
There are several different types of APAs, all of which prevent the aggregation of platelets and may be used in the treatment of PAD. The first class, aspirin and other nonsteroidal anti-inflammatory agents, is widely used to prevent platelet aggregation in patients with PAD or those with risk factors for developing cardiovascular or cerebrovascular events. Aspirin acts by inhibiting the cyclooxygenase pathway of the arachidonic acid cascade, preventing the formation of prostaglandin endoperoxides and thromboxane A2. Because thromboxane A2 is a potent platelet aggregator and vasoconstrictor, it is beneficially inhibited by aspirin therapy. Aspirin reduces cardiovascular events, particularly myocardial infarction, and the risks of revascularization in patients with PAD. Much of the pivotal data supporting the use of aspirin in the secondary prevention of cardiovascular events comes from patients with coronary artery disease, and is equally valid for those with other manifestations of systemic atherothrombotic disease, including PAD. The Antiplatelet Trialists Collaboration demonstrated a 25% reduction in serious vascular events (nonfatal myocardial infarction, nonfatal stroke and vascular death) and a similar reduction in the need for bypass surgery or angioplasty in patients with PAD taking low dose aspirin compared to control groups. High dose aspirin therapy does not appear to confer additional benefit and is associated with increased risk of bleeding complications, making low dose aspirin (75 to 81mg/day) the standard of care for antiplatelet therapy. Nonetheless, while the benefits of aspirin therapy in the secondary prevention of cardiovascular events are clearly established, questions exist about its cost-effectiveness relative to other antiplatelet agents, its effect on intermittent claudication or measures of functional status, and its long-term safety in those with PAD. Given the preliminary aggregate data that antiplatelet agents other than aspirin may be more efficacious at reducing intermittent claudication and/or improving walking distance, some have suggested that aspirin should be the entry-level treatment for most patients with PAD, reserving more expensive agents for those with more advanced disease.
Efficacy and Safety of Antiplatelet Therapy
Clinical trials have shown antiplatelet therapy to be effective in the secondary prevention of cardiovascular events in patients with PAD. Antiplatelet agents prevent the initiation of atherosclerotic plaque formation and retard the progression of atherosclerosis. In addition, the meta-analysis provided clear quantification of the benefits of antiplatelet therapy compared to placebo or control in reducing the risk of major vascular events in a range of high-risk patients, including those with PAD. For the risk of a non-hemorrhagic stroke, among 6,587 patients with intermittent claudication, the relative risk reduction was 23%, and 37% among 1,442 patients with a previous TIA or stroke. These findings led to the inclusion of PAD as an indication for antiplatelet therapy in various evidence-based guidelines, and it is now considered the standard of care for all patients with PAD. Aspirin is the most commonly prescribed antiplatelet agent and has shown to reduce the incidence of major cardiovascular events in patients with PAD by 22%, though the dose effect was unclear. Clopidogrel has shown to be more effective than aspirin in reducing cardiovascular events and is therefore an alternative treatment for patients with PAD, particularly those that cannot tolerate aspirin. There are no medications that do not have adverse effects, and antiplatelet agents are no exception. The benefits of antiplatelet therapy in patients with PAD must be weighed against the potential complications of therapy, which include an increased risk of bleeding, both into the skin and bruising, and into the gastrointestinal tract or into the brain. Minor bleeding affects 10-100 patients per 1,000 treated, and compared to a 4.1% rate among those treated with placebo, antiplatelet therapy increases the risk of a hemorrhagic stroke to 1% per year to 1.8%. The risk of bleeding with aspirin is dose-dependent, with higher doses of aspirin increasing the bleeding risk without additional benefit on vascular event reduction. Gastrointestinal bleeding can be reduced with the use of proton pump inhibitors (PPI), which has been shown to have no adverse interaction with the benefits of antiplatelet therapy. In addition, PPI use has been shown to reduce the incidence of ulcer complications that include bleeding, perforation, and obstruction, without increasing the risk of cardiovascular events. A recent update on the guidelines for the investigation and management of antiphospholipid syndrome states that the combination of aspirin and clopidogrel may increase the risk of bleeding into critical organs, and therefore the duration of this combination therapy should be carefully reviewed in patients with PAD who have this common comorbidity.
Clinical Trials and Evidence
The evidence has also been conflicting regarding the use of cilostazol. The initial PEDIS trial demonstrated that it was effective in reducing intermittent claudication and the prevention of the progression from subclinical to overt claudication in diabetics. However, the use of cilostazol did not show a significant reduction in the incidence of cardiovascular events, and the recent cessation of the PERTAIN trial due to safety concerns of prolonged cilostazol use has led to questions about its future role in cardioprotective treatment in PAD.
In 2002, the use of clopidogrel gained more attention as the results of the CAPRIE trial demonstrated that it was more effective than aspirin in the reduction of the combined endpoint of MI, stroke, or vascular death in patients with recent ischemic stroke, MI, or symptomatic PAD. The use of clopidogrel was then further tested in the CHARISMA trial, which included a large PAD cohort. The results of this trial failed to identify a benefit of adding clopidogrel to aspirin in reducing major cardiovascular events and, in fact, demonstrated an increased risk of moderate and severely disabling extracranial bleeding.
The use of antiplatelet therapy has gained wide acceptance in the management of PAD for the potential to reduce adverse cardiovascular events, stroke, and MI. Aspirin has remained the primary form of antiplatelet therapy in part due to the low cost and ability to reduce the combined endpoint of MI, stroke, or vascular death. The Antithrombotic Trialists’ Collaboration performed a meta-analysis of 6 trials (n=95,000) in which aspirin was used for the prevention of serious vascular events and found a 25% reduction in the combined events compared to control without a significant increase in major extracranial bleeding. As a result, this has helped to establish the efficacy of aspirin in both secondary prevention of cardiovascular events and primary prevention of cardiovascular events in high-risk patients.
Adverse Effects
Antiplatelet agents have substantial adverse effects in terms of both bleeding and compliance. In the overall meta-analysis, the odds ratio for major extracranial bleeds was 1.66 (95% CI 1.45-1.89; p<0.001). For aspirin, the odds ratio for major extracranial bleeds was 1.54 (95% CI 1.27-1.87; p<0.001). There were greater absolute reductions in serious vascular events than in hemorrhagic strokes across all levels of baseline risk. This means that the overall balance of cautions and benefits from antiplatelet therapy will usually be less favorable in those at low risk of both IHD and ischemic stroke. The most important predictable, dose-related adverse effect of aspirin is gastric irritation which may cause dyspepsia or, at a more serious level, ulcers and even gastric hemorrhage. By and large, these adverse effects are not severe and can be avoided by a simple expedient – taking the aspirin with food. More serious GI side effects include the formation of asymptomatic gastric ulcers and, less frequently, GI bleeding, obstruction, and perforation. In a meta-analysis of randomized trials by the Antiplatelet Trialists’ Collaboration, the pooled estimate of the annual risk of a major GI bleed with long-term aspirin was 0.10% for an elderly patient with previous IHD or stroke, but less for those with just coronary risk factors (0.05%) and higher for patients with a history of a previous GI ulcer or bleed. Such patients are at special risk of upper GI damage from aspirin, which is defined as damage above the duodenum, as this occurs in 3-37% of healthy volunteers given 1200mg aspirin per day for one week. This is due to the fact that aspirin is absorbed in its active form all along the GI tract and so can cause damage at any site. The above evidence for increased risk of consequence of serious or fatal GI bleeds should be factored into decisions regarding whether to use aspirin in a particular patient and at what dose. The risk is moveable, varying with the underlying risk of vascular events and other risk factors for bleeding. For example, in a healthy middle-aged man with just one or two coronary risk factors and no previous GI ulcer or bleed, the annual risk of a serious or fatal GI bleed is likely to be less than his 0.12% reduction in serious vascular events from aspirin. By contrast, in a patient with known peripheral vascular disease and a history of a previous GI ulcer, the risk of a serious or fatal GI bleed may well outweigh the benefit of aspirin.
Considerations for Antiplatelet Therapy in Management
Patient selection is more or less confined to the decision of whether to treat with monotherapy or dual antiplatelet therapy with aspirin and clopidogrel. Subsequently this decision may be influenced by future stenting or surgical management a patient plans to undergo, discussed further in the respective sections. Patient selection for treatment with dual antiplatelet therapy may be influenced by the risk of the individual for significant gastrointestinal complications due to higher dose regimens of aspirin postulated to enhance antiplatelet effects discussed in the dose and duration section. A small subset of patients may have a history of symptomatic PAD and recent minor ischemic stroke postulated to benefit from the combination of aspirin and clopidogrel shown to decrease incidence of stroke compared to aspirin alone in these patients.
So despite the stated inherent limitations with this drug, it should also be considered an option in patients with symptomatic PAD. The combination of aspirin and dipyridamole demonstrated a statistically significant reduction in the incidence of myocardial infarction or fatal, non-fatal stroke in comparison to clopidogrel alone in the management of patients with a history of TIA or stroke. The benefit in patients with PAD has been suggested in a post-hoc analysis of the same trial. Though the role of dipyridamole in PAD treatment is vague, this data could suggest a benefit in using a combination of aspirin and dipyridamole in patients with symptomatic PAD. An increased incidence of major bleeding was seen in the combination therapy group, but was not associated with hemorrhagic stroke or fatality and was less than the background bleeding rate.
The benefits of antiplatelet agents, specifically aspirin, in patients with PAD are well documented. A decrease in MI, stroke, and vascular death may occur with aspirin use. Due to the well-defined benefit and low cost of aspirin, it should be considered in all patients unless contraindicated. Clopidogrel demonstrated benefit albeit modest in comparison to aspirin. A subgroup analysis of the CAPRIE trial revealed patients with symptomatic PAD had a reduction in the combined endpoint of ischemic stroke, MI, or vascular death with clopidogrel compared to aspirin.
Patient Selection
Antiplatelet therapy is relatively contraindicated in patients with advanced disease due to an increased risk of bleeding from revascularization procedures and the need for surgical intervention. Again, a careful assessment of the potential benefits and risks in any individual patient is required.
The risk of bleeding with any therapy must be weighed against the potential benefits. An increased risk of bleeding is the result of increased age and concurrent use of NSAIDs, oral anticoagulants, or dual antiplatelet therapy. In these patients, the case for antiplatelet therapy becomes less clear, and individual patient circumstances need to be taken into account in the decision to treat. Current guidelines do not recommend the use of antiplatelet therapy in patients with PAD without other concomitant risk factors or cardiovascular disease due to a lower absolute risk of cardiovascular events. However, given the aforementioned benefit of antiplatelets on atherosclerotic disease, it is likely that many patients may still be treated.
Antiplatelets are useful in reducing cardiovascular events in patients with PAD. There is evidence of benefit for any history of cardiovascular event, either symptomatic or asymptomatic. Patients with intermittent claudication alone without other risk factors have a lower risk of cardiovascular events but still potentially benefit from antiplatelet therapy. The presence of other risk factors such as diabetes, hypertension, and hypercholesterolemia greatly increases the cardiovascular risk and justifies the use of antiplatelets.
Dose and Duration
It remains unsettled whether higher doses of aspirin provide greater benefit in reducing vascular events. In the Physician’s Health Study, those randomized to aspirin 325 mg every other day had a 44% reduction in the risk of a first MI compared with placebo, while those on 325 mg/d had a 22% reduction in the risk of a stroke. Caution should be exercised in interpreting these findings, as subgroup analyses of patients with diabetes in the HOT Study found no benefit for aspirin doses above 160 mg/d in reducing vascular events, and a post-hoc analysis of the CAPRIE study found the benefit of clopidogrel over aspirin to be independent of the aspirin dose taken. Dose-response studies for any agent used for secondary prevention in PAD have not been performed. Ideally, the optimal antiplatelet dose for reducing the occurrence of limb events would be identified. A study directly comparing different doses of aspirin in PAD is needed to determine the potential benefit for reducing the incidence of intermittent claudication and critical limb ischemia, where the morbidity is high and the economic impact substantial. With regard to duration of therapy, the CAPRIE and CHARISMA studies have shown the benefit of clopidogrel, added to aspirin, to be sustained over long-term follow-up. However, specific data on the duration of antiplatelet therapy in PAD are lacking.
Monitoring and Follow-up
Analysis of any future trials which compare different antiplatelet regimens in PAD should include monitoring of adverse events and attempt to define the optimal method of monitoring whether the treatment is having its intended effect.
Testing for platelet function, specifically to see if a particular drug has achieved its intended pharmacodynamic effect, is more difficult due to a lack of standardized and readily available tests to measure it.
Global hemostasis will generally not be tested, as it is not specific enough to answer the question of whether a change of antiplatelet regimen would be beneficial and has not been shown to help guide treatment.
Monitoring in this case takes two forms: assessing the patient for the occurrence of cardiovascular ischemic events or bleeding, and testing of the platelet function or global hemostasis. The first form of monitoring is relatively simple in that the occurrence of a major or minor ischemic event while on treatment suggests that the regimen should be re-evaluated. Long term, this will probably be the clinical outcome of antiplatelet treatment, as the occurrence of an ischemic event or bleeding may cause the physician to stop or alter the regimen. For example, elderly patients may need to forego more potent antiplatelet therapy due to a high risk of bleeding.
Antiplatelet agents are approved for the prevention of thrombotic events in patients with PAD. However, data is limited on methods to monitor the effects of the drugs or when it might be appropriate to adjust the regimen.