Antiplatelet and antithrombotic treatment of patients with PAD

Many studies have suggested that patients with peripheral arterial disease (PAD) manifest platelet hyperaggregability, increased levels of soluble platelet activation markers, enhanced thrombin generation and altered fibrinolytic potential. These data underline the importance of antithrombotic prophylaxis in patients with PAD (1). Therefore, antiplatelet and antithrombotic drugs represent one of the basic options for prevention and treatment of such patients (2). There are no trials including only patients with PAD that would have sufficient power to precisely estimate the preventive effect of these drugs.

I - Antiplatelet therapy

a) Aspirin

The effect of antiplatelet therapy on cardiovascular events has been systematically reviewed by the Antithrombotic Trialists' Collaboration (3). A meta-analysis comprising 287 studies compared the efficacy of antiplatelet therapy in approximately 135.000 high-risk patients with vascular diseases including lower extremity peripheral arterial disease.

Among those patients with PAD treated with antiplatelet therapy, there was a 22 % odds reduction for adverse cardiovascular events, including MI, stroke, or vascular death.

Similar benefit was observed in patients with intermittent claudication, those having peripheral angioplasty, and those having peripheral bypass graft procedures. The most frequently used drug was aspirin and some trials included ticlopidine.

Low dose aspirin (75 - 325 mg daily) is as effective as higher doses, but it already comes at the price ofincreased risk of gastrointestinal bleeding – odds ratio 1.7 (95 % confidence interval, 0.8-3.3) for a major extracranial bleeding.

However there was a significantly smaller (13 %) reduction in cardiovascular events in patients being treated with less than 75 mg of aspirin per day.

b) Clopidogrel

Clopidogrel is thesecond most frequently used drug after aspirin for prevention of cardiovascular events in PAD patients.

• In the subgroup of patients with PAD in the CAPRIE trial clopidogrel (75 mg daily) was found to be 23.8 % more effective than aspirin (325 mg daily) in preventing atherotrombotic events and resulted in less gastrointestinal bleeding (4).

Although clopidogrel is generally recognised as slightly more effective than aspirin in preventing major atherothrombotic events in high risk patients, the magnitude of this benefit is statistically uncertain and, mainly due to its much higher cost, clopidogrel has not been accepted as superior by regulatory authorities. Aspirin thus remains the first-line antiplatelet drug and clopidogrel as its effective alternative (5).

c) Combination treatment

The question arises regarding whether a combination of 2 or more antiplatelet drugs is more effective than a single one. The combination of clopidogrel plus aspirin versus aspirin alone has been examined in patients who had presented with acute coronary syndrome.

In patients with acute coronary syndrome :

• Combination aspirin and clopidogrel therapy was associated with a 20 % relative risk reduction for MI, stroke, or cardiovascular death (6).
• Dual antiplatelet treatment has a proven benefit in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention and is also perceived as beneficial in conjunction with placement of peripheral vascular stents where they are widely used (7).

In patients with vascular disease, high risk or low extremity PAD :

• The CHARISMA trial did not show a benefit of combined aspirin and clopidogrel treatment versus aspirin alone in a combined cohort of subjects with established vascular disease and subjects at high risk, although dual antiplatelet therapy was marginally better in subgroup with already established vascular disease (8).
• Taken together, there is no evidence to support the efficacy of combined aspirin and clopidogrel treatment versus a single antiplatelet agent in patients with lower extremity PAD.

Lower limb ischemia

Another important, but less well-documented issue is whether antiplatelet treatment prevents worsening of lower limb ischemia in patients with PAD. Several studies have suggested that antiplatelet therapy may reduce the risk of progression to arterial occlusion in patients with lower extremity PAD.

• The Antiplatelet Trialists' Collaboration found a 30 % reduction in the rate of lower arterial occlusion by antiplatelet treatment compared with no additional medical intervention (9).
• A meta-analysis of randomised, controlled trials in patients with intermittent claudication showed that aspirin reduced the risk of arterial occlusion and ticlopidine reduced the need for revascularization procedures (10).
• The Physician Health Study confirmed that low dose aspirin impeded the progression to intermittent claudication and reduced the risk of undergoing peripheral arterial surgery: there were 20 procedures in the aspirin group and 36 in the placebo group among a total of 22.071 initially healthy US physicians after 5 years of follow-up. The relative risk of surgical revascularisation in the aspirin group was thus reduced to 0.54 (11).

II - Anticoagulant therapy

a) Oral anticoagulants with coumarin derivates

The efficacy of oral anticoagulants with coumarin derivates such as warfarin, in reducing adverse cardiovascular events was confirmed primarily in studies of patients with coronary artery disease. Meta-analyses comprising 37 trials of anticoagulant therapy (OAC) in more than 20.000 patients with coronary artery disease evaluated the efficacy and safety of oral anticoagulation (warfarin) alone versus the control (12).

In patients with CAD

• High-intensity oral anticoagulant therapy (INR of 2.8 to 4.8) was associated with a 22 % odds reduction in mortality and a 43 % odds reduction in MI, but it was associated with a 4.5-fold increase in major bleeding.
• Moderate-intensity anticoagulation (INR of 2 to 3) was associated with a nonsignificant odds reduction of 26 % for cardiovascular death and stroke and 52 % for MI, but it increased bleeding by 7.7-fold.

Three major trials have shown, that oral anticoagulation (target International Normalised Ratio - INR 2-3) on top of aspirin is effective in reducing cardiovascular death, reinfarction and stroke after myocardial infarction in comparison to aspirin alone (13). 

Thus, among patients with coronary artery disease, moderate and high-intensity oral anticoagulation with coumarin derivatives reduces the risk of MI and death but increases the rate of bleeding.

b) Oral anticoagulation to aspirin in PAD patients

There are only a few studies evaluating the effect of oral anticoagulation to aspirin in PAD patients.

• In one study a direct comparison of aspirin alone against oral anticoagulation alone in peripheral vascular surgery did not show any benefit of oral anticoagulation alone, but increased the bleeding risk (14).

In the WAVE trial over 2.100 patients with peripheral vascular disease were randomised to the combination of oral anticoagulation (target INR 2-3, achieved INR 2.2) plus aspirin, or to aspirin alone and followed for nearly 3 years (15).

• In the combination therapy, no benefit on cardiovascular death, myocardial infarction or stroke was observed, but there was a 3.5 times increase in severe bleeding complications including cerebral haemorrhage. Life-threatening bleeding was seen in 4.0 % on the combination therapy versus 1.2 % with aspirin alone (p < 0.001).

Anand et al recently reported a meta-analysis of nine randomised trials of oral anticoagulants compared with control (no treatment) involving 4889(16). They found that

• The combination of OAC plus aspirin was not more effective than aspirin alone, with higher rates of mortality and major haemorrhage and no reduction in graft loss.
• Moderate intensity warfarin treatment (INR 2.5) would be acceptable in the presence of coexisting indications such as atrial fibrillation or recent venous thrombosis, although it might also be considered for patients with a history of peripheral graft occlusion.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.