Combined Therapy Raises Risks in Peripheral Arterial Disease

For patients with peripheral arterial disease, there is substantial risk and no benefit to combining antiplatelet and anticoagulation therapy, according to the results of a large randomized trial.

“We found that combination therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with a substantial increase in the risk of life-threatening bleeding,” wrote Dr. Sonia Anand of McMaster University, Hamilton, Ont., and her coinvestigators on the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial (N. Engl. J. Med. 2007;357:217–27).

“The totality of evidence shows clearly that the addition of an anticoagulant to an antiplatelet drug results in increased rates of bleeding complications,” wrote Dr. Emile Mohler III of the University of Pennsylvania, Philadelphia, in an editorial appearing in the same issue of the journal (N. Engl. J. Med. 2007;357:293–6).

The trial compared outcomes in 1,081 patients randomized to antiplatelet therapy alone and 1,080 patients randomized to a combination of antiplatelet and oral anticoagulant therapy. The mean age of the patients was 64 years, 74% were male, and the mean follow-up time was 35 months.

There were two coprimary composite outcomes: The first was myocardial infarction, stroke, or death from cardiovascular causes; the second was MI, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular causes. The safety outcomes were life-threatening, moderate, or minor bleeding episodes.

No significant differences were observed between groups for either of the primary outcomes. The first end point occurred in 12.2% of the combination group and 13.3% of the antiplatelet group (relative risk [RR] 0.92), whereas the second end point occurred in 15.9% of the combination group and 17.4% of the antiplatelet group (RR 0.91).

The differences emerged in the safety outcomes. Compared with the antiplatelet group, the combination group showed increases in both life-threatening bleeding (4.0% vs. 1.2%, RR 3.41) and moderate bleeding (2.9% vs. 1.0%, RR 2.82).

“According to our data, treating 1,000 patients with combination therapy as compared with antiplatelet therapy alone for 3 years would lead to 24 fewer cardiovascular events but 28 more episodes of life-threatening bleeding, resulting in a net increase in serious adverse outcomes,” wrote Dr. Anand and her coauthors.

WAVE's findings of increased bleeding associated with combination therapy (as opposed to antiplatelet therapy alone) differ from a similar comparison of treatments in patients with coronary artery disease (N. Engl. J. Med. 2002;347:9609–74) but are consistent with the results of another trial involving patients with peripheral arterial disease (Lancet 2000;355:346–51), the investigators noted.

“Therefore, it appears that patients with peripheral arterial disease who are treated with oral anticoagulation may be more likely to have bleeding complications … than are patients with coronary artery disease.” The reasons for this difference may be that patients with peripheral arterial disease are older, have more systemic atherosclerosis (including cerebrovascular disease), and have more coexisting conditions, they suggested.

The authors noted that the WAVE results are consistent with those of the Department of Veterans Affairs Cooperative Studies Program, the only other large randomized trial comparing these two therapies (J. Vasc. Surg. 2002;35:413–21). However, despite this, their results were not what they had expected.

“On the basis of previous clinical trials, we expected that the rates of minor, and possibly of moderate, bleeding would be significantly increased in the combination-therapy group. However, we also expected that the benefits of treatment would outweigh the risks,” the investigators wrote.

There is a rationale for this hypothesis, noted Dr. Mohler. Antiplatelet treatment has proven benefits for peripheral arterial disease, a common feature of which is atherothrombosis, whereas anticoagulation therapy has proven benefits for venous thrombosis.

“Therefore, the addition of oral anticoagulation to antiplatelet treatment might be presumed to be beneficial for the management of atherothrombosis in patients with peripheral arterial disease as well,” he wrote.

A possible reason that this was not found in the WAVE trial could lie in “the differences in thrombus formation between the arterial and venous systems,” he suggested.

For patients with peripheral arterial disease, there is substantial risk and no benefit to combining antiplatelet and anticoagulation therapy, according to the results of a large randomized trial.

“We found that combination therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with a substantial increase in the risk of life-threatening bleeding,” wrote Dr. Sonia Anand of McMaster University, Hamilton, Ont., and her coinvestigators on the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial (N. Engl. J. Med. 2007;357:217–27).

“The totality of evidence shows clearly that the addition of an anticoagulant to an antiplatelet drug results in increased rates of bleeding complications,” wrote Dr. Emile Mohler III of the University of Pennsylvania, Philadelphia, in an editorial appearing in the same issue of the journal (N. Engl. J. Med. 2007;357:293–6).

The trial compared outcomes in 1,081 patients randomized to antiplatelet therapy alone and 1,080 patients randomized to a combination of antiplatelet and oral anticoagulant therapy. The mean age of the patients was 64 years, 74% were male, and the mean follow-up time was 35 months.

There were two coprimary composite outcomes: The first was myocardial infarction, stroke, or death from cardiovascular causes; the second was MI, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular causes. The safety outcomes were life-threatening, moderate, or minor bleeding episodes.

No significant differences were observed between groups for either of the primary outcomes. The first end point occurred in 12.2% of the combination group and 13.3% of the antiplatelet group (relative risk [RR] 0.92), whereas the second end point occurred in 15.9% of the combination group and 17.4% of the antiplatelet group (RR 0.91).

The differences emerged in the safety outcomes. Compared with the antiplatelet group, the combination group showed increases in both life-threatening bleeding (4.0% vs. 1.2%, RR 3.41) and moderate bleeding (2.9% vs. 1.0%, RR 2.82).

“According to our data, treating 1,000 patients with combination therapy as compared with antiplatelet therapy alone for 3 years would lead to 24 fewer cardiovascular events but 28 more episodes of life-threatening bleeding, resulting in a net increase in serious adverse outcomes,” wrote Dr. Anand and her coauthors.

WAVE's findings of increased bleeding associated with combination therapy (as opposed to antiplatelet therapy alone) differ from a similar comparison of treatments in patients with coronary artery disease (N. Engl. J. Med. 2002;347:9609–74) but are consistent with the results of another trial involving patients with peripheral arterial disease (Lancet 2000;355:346–51), the investigators noted.

“Therefore, it appears that patients with peripheral arterial disease who are treated with oral anticoagulation may be more likely to have bleeding complications … than are patients with coronary artery disease.” The reasons for this difference may be that patients with peripheral arterial disease are older, have more systemic atherosclerosis (including cerebrovascular disease), and have more coexisting conditions, they suggested.

The authors noted that the WAVE results are consistent with those of the Department of Veterans Affairs Cooperative Studies Program, the only other large randomized trial comparing these two therapies (J. Vasc. Surg. 2002;35:413–21). However, despite this, their results were not what they had expected.

“On the basis of previous clinical trials, we expected that the rates of minor, and possibly of moderate, bleeding would be significantly increased in the combination-therapy group. However, we also expected that the benefits of treatment would outweigh the risks,” the investigators wrote.

There is a rationale for this hypothesis, noted Dr. Mohler. Antiplatelet treatment has proven benefits for peripheral arterial disease, a common feature of which is atherothrombosis, whereas anticoagulation therapy has proven benefits for venous thrombosis.

“Therefore, the addition of oral anticoagulation to antiplatelet treatment might be presumed to be beneficial for the management of atherothrombosis in patients with peripheral arterial disease as well,” he wrote.

A possible reason that this was not found in the WAVE trial could lie in “the differences in thrombus formation between the arterial and venous systems,” he suggested.

For patients with peripheral arterial disease, there is substantial risk and no benefit to combining antiplatelet and anticoagulation therapy, according to the results of a large randomized trial.

“We found that combination therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with a substantial increase in the risk of life-threatening bleeding,” wrote Dr. Sonia Anand of McMaster University, Hamilton, Ont., and her coinvestigators on the Warfarin Antiplatelet Vascular Evaluation (WAVE) trial (N. Engl. J. Med. 2007;357:217–27).

“The totality of evidence shows clearly that the addition of an anticoagulant to an antiplatelet drug results in increased rates of bleeding complications,” wrote Dr. Emile Mohler III of the University of Pennsylvania, Philadelphia, in an editorial appearing in the same issue of the journal (N. Engl. J. Med. 2007;357:293–6).

The trial compared outcomes in 1,081 patients randomized to antiplatelet therapy alone and 1,080 patients randomized to a combination of antiplatelet and oral anticoagulant therapy. The mean age of the patients was 64 years, 74% were male, and the mean follow-up time was 35 months.

There were two coprimary composite outcomes: The first was myocardial infarction, stroke, or death from cardiovascular causes; the second was MI, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular causes. The safety outcomes were life-threatening, moderate, or minor bleeding episodes.

No significant differences were observed between groups for either of the primary outcomes. The first end point occurred in 12.2% of the combination group and 13.3% of the antiplatelet group (relative risk [RR] 0.92), whereas the second end point occurred in 15.9% of the combination group and 17.4% of the antiplatelet group (RR 0.91).

The differences emerged in the safety outcomes. Compared with the antiplatelet group, the combination group showed increases in both life-threatening bleeding (4.0% vs. 1.2%, RR 3.41) and moderate bleeding (2.9% vs. 1.0%, RR 2.82).

“According to our data, treating 1,000 patients with combination therapy as compared with antiplatelet therapy alone for 3 years would lead to 24 fewer cardiovascular events but 28 more episodes of life-threatening bleeding, resulting in a net increase in serious adverse outcomes,” wrote Dr. Anand and her coauthors.

WAVE's findings of increased bleeding associated with combination therapy (as opposed to antiplatelet therapy alone) differ from a similar comparison of treatments in patients with coronary artery disease (N. Engl. J. Med. 2002;347:9609–74) but are consistent with the results of another trial involving patients with peripheral arterial disease (Lancet 2000;355:346–51), the investigators noted.

“Therefore, it appears that patients with peripheral arterial disease who are treated with oral anticoagulation may be more likely to have bleeding complications … than are patients with coronary artery disease.” The reasons for this difference may be that patients with peripheral arterial disease are older, have more systemic atherosclerosis (including cerebrovascular disease), and have more coexisting conditions, they suggested.

The authors noted that the WAVE results are consistent with those of the Department of Veterans Affairs Cooperative Studies Program, the only other large randomized trial comparing these two therapies (J. Vasc. Surg. 2002;35:413–21). However, despite this, their results were not what they had expected.

“On the basis of previous clinical trials, we expected that the rates of minor, and possibly of moderate, bleeding would be significantly increased in the combination-therapy group. However, we also expected that the benefits of treatment would outweigh the risks,” the investigators wrote.

There is a rationale for this hypothesis, noted Dr. Mohler. Antiplatelet treatment has proven benefits for peripheral arterial disease, a common feature of which is atherothrombosis, whereas anticoagulation therapy has proven benefits for venous thrombosis.

“Therefore, the addition of oral anticoagulation to antiplatelet treatment might be presumed to be beneficial for the management of atherothrombosis in patients with peripheral arterial disease as well,” he wrote.

A possible reason that this was not found in the WAVE trial could lie in “the differences in thrombus formation between the arterial and venous systems,” he suggested.