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Surgical Bypass Summit — Session 4:
Drug therapy and the impact it has on surgical bypass — Co-Chair Russell H. Samson, MD

  • Video

Russell H. Samson, MD

Infrainguinal arterial bypass grafts are prone to early and late failure. This is irrespective of whether they are constructed from autologous vein or prosthetic, nonautogenous material such as expanded polytetrafluoroethylene (ePTFE). Early graft failures (< 30 days) are typically technical failures, so most adjuvant medications will not be effective during the first 30 days. Failures after 30 days are likely due to a confluence of factors that may differ depending upon the conduit used. These factors include intimal hyperplasia, spontaneous graft thrombosis, and the development of proximal or distal atherosclerosis. Further, atherosclerotic disease can also occur within vein grafts. These factors are all interrelated and reflect ongoing disease processes. Although graft thrombosis is often idiopathic, it can also be associated with hypercoagulable states or external compression.

Adjuvant agents prescribed to help prevent graft failure may target intimal hyperplasia, graft thrombosis, atherosclerosis, or all factors concurrently. For the most part, current adjuvant medications include antiplatelet agents, antithrombotics, and statins. Beta-blockers, cilostazol, and the transcription factor decoy edifoligide have also been explored as adjuvants. Currently, there is no ongoing trial to compare the efficacy of these drugs in preventing graft failure. The largest study to evaluate any of these adjuvant agents was the PREVENT III trial of edifoligide.1 Edifoligide targets E2F, which is a transcription factor that plays a critical role in coordinating the expression of several genes that regulate cell-cycle progression, thus potentially preventing the development of hyperplastic intimal thickening. However, ex vivo treatment of lower extremity vein grafts with edifoligide was unable to protect graft failure.1

ANTIPLATELET AGENTS

Antiplatelet agents are typically prescribed to help prevent platelet aggregation that leads to hyperplastic intimal thickening. They may also prevent platelet agglutination and subsequent spontaneous thrombosis. Activated platelets aggregate on injured endothelial cells in denuded areas and fibrin is deposited. The deposited fibrin acts with platelets to form an adhesive surface that binds circulating leukocytes. The leukocytes then become the central modulators in the development of hyperplastic intimal thickening.

There are multiple antiplatelet agents including ASPIRIN® (acetylsalicylic acid) (ASA), clopidogrel bisulfate, and ticagrelor. The field becomes even more complex with the addition of a new drug (eg, vorapaxar). Vorapaxar is unique in that it is the first antiplatelet agent approved by the US Food and Drug Administration (FDA) specifically for the treatment of peripheral artery disease. However, there are no current data to support its use in preventing graft failure.

In 1994, the Antiplatelet Trialists’ Collaboration studied approximately 3,000 patients who underwent peripheral artery procedures.2 The procedures included vein grafts and nonautologous grafts. The study found that antiplatelet therapy (primarily ASA) resulted in 38% fewer graft occlusions when compared with placebo. This study was seminal in the consideration of adjuvant therapy for improving vascular graft failure rates.

In 1999, Tangelder et al3 reviewed trials comparing ASA versus anticoagulation versus placebo. The investigators found a 22% relative reduction (RR) with ASA, a 44% RR with warfarin, and a 62% RR with combined ASA and warfarin. However, patients who received ASA combined with warfarin had a higher incidence of bleeding.

A subgroup analysis of the CASPAR trial suggested a benefit for dual-antiplatelet agents (eg, ASA, clopidogrel) in prosthetic grafts (not vein grafts) without an increase in bleeding risk.4 However, as a post hoc analysis this result may be suspect. Furthermore, the CASCADE trial failed to show any benefit for clopidogrel over ASA in the prevention of coronary artery graft intimal hyperplasia.5-6

ANTICOAGULANTS

Although there are many new novel anticoagulants, the only anticoagulants currently studied to prevent graft thrombosis have been heparin, low-molecular-weight heparin, and warfarin.

The Cochrane Review examined the effectiveness of low-molecular-weight heparin compared to unfractionated heparin and found no difference in graft patency between the two therapies.7

In 1998, Sarac et al examined the effects of warfarin and other vitamin K antagonists in a randomized trial.8 The investigators reported a patency of 74% at 3 years in the high-risk group randomized to warfarin and ASA. Patency was significantly higher in the patients who received warfarin and ASA when compared to the patients who received only ASA. However, bleeding was more common in the group receiving warfarin.

The Dutch Bypass Oral Anticoagulants or ASPIRIN study compared oral anticoagulants to ASA in a large randomized trial that included vein grafts and prosthetic grafts.9 The investigators found that ASA at a dose of 80 mg significantly reduced occlusion in prosthetic grafts when compared with warfarin. Patients who received ASA also experienced fewer bleeding episodes. This study from 2000 likely has had the largest influence on subsequent guidelines.

The Veteran Affairs Cooperative trial in 2002 included 665 patients undergoing femoropopliteal bypass.10 Patients were randomized to 325 mg ASA and warfarin, or ASA alone. The investigators found no significant difference in patency rates between the treatment groups in the 8-mm bypass subgroup; however, they did find a difference in the 6-mm bypass subgroups (71.4% in the warfarin-plus-ASA group vs 57.9% in the ASA-only group; P = .02). However, again, warfarin nearly doubled the risk of major bleeding episodes when compared to patients who received ASA alone.

Guidelines published in 2004 recommend ASA for all patients undergoing prosthetic infrainguinal bypass.11 Warfarin was not recommended due to an increased risk of bleeding. The guidelines suggest that patients who are at a high risk for occlusion should receive combination therapy with warfarin and ASA. However, these guidelines changed in 2008 with only ASA being recommended for all grafts (unless a patient has the rare ASA allergy).

Despite these published findings, the Vascular Study Group of New England reported that patients receiving prosthetic conduit were more likely to be treated with warfarin than those receiving a saphenous vein conduit (57% vs 24%; P < .001).12

STATINS

Although statins are primarily prescribed to prevent atherosclerotic disease, they are also effective in reducing inflammation.

In vitro studies have demonstrated that statins increase endothelial progenitor cells and promote smooth muscle apoptosis.13 This suggests that statins may be helpful in bypass surgery through a mechanism of action that is distinct from lowering low-density lipoprotein (LDL) cholesterol.14 A 2004 study found that the risk of graft failure was 3.2-fold higher in a control group when compared to patients who received statins.15 The investigators reported that the levels of cholesterol were not statistically different between the two groups, suggesting that the mechanism behind the protective effect was distinct from the LDL-lowering effect of the statins. Statin therapy in the CASCADE trial16 achieved an LDL level < 100 mg, which was associated with improved graft patency. On the other hand, PREVENT III1 found that statins had no effect on patency at 1 year and no effect on perioperative mortality. However, patients who received statins did have decreased mortality at 1 year. Similarly, the Vascular Study Group of New England found that statin therapy was not associated with 1-year rates of major amputation or graft occlusion.17

Summary

Current treatment guidelines are controversial. The American College of Chest Physicians recommends only ASA for prosthetic and vein grafts.18 In 2011, the Cochrane Review suggested that all patients receiving a prosthetic graft benefit would benefit from platelet inhibitors, whereas vein grafts would more likely benefit from a vitamin K antagonist.7 The consensus is that statins should be prescribed because even if they do not improve patency, they do appear to prolong life. Patients who receive high-risk prosthetic grafts may benefit from a vitamin K antagonist or dual-antiplatelet agents.

Russell H. Samson, MD, FACS, RVT, is Clinical Professor of Surgery at Florida State University Medical School and is an attending surgeon with Sarasota Vascular Specialists in Sarasota, Florida. He has disclosed that he has received compensation from Gore for participating in the Summit and has received honoraria from Gore for writing this article. Dr. Samson may be reached at [email protected]

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  2. Collaborative overview of randomised trials of antiplatelet therapy--II: maintenance of vascular graft or arterial patency by antiplatelet therapy. Antiplatelet Trialists’ Collaboration. Br Med J. 1994;308:159-168.
  3. Tangelder MJ, Lawson JA, Algra A, et al. Systematic review of randomized controlled trials of ASPIRIN and oral anticoagulants in the prevention of graft occlusion and ischemic events after infrainguinal bypass surgery. J Vasc Surg. 1999;30:701-709.
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