Role of Antithrombotic Drugs in Maintaining Graft Patency

Cilostazol

Cilostazol is a weak platelet inhibitor used in the medical management of patients with intermittent claudication. It functions by inhibiting phosphodiesterase III. However, the more important effects of cilostazol are likely from its non–platelet-inhibiting effects, which include vasodilation and inhibition of smooth muscle cell (SMC) migration and proliferation, thereby reducing neointimal fibroplasia. Neointimal hyperplasia plays a critical role in eventual graft occlusion by causing stenosis not only at anastomotic sites but also within vein grafts, particularly at valve sites. The pathway for inhibition of neointimal hyperplasia is not fully understood, but several aspects have been studied.

Cilostazol has been shown to suppress the tenascin-C (TN-C) mRNA expression induced by platelet-derived growth factor (PDGF)-BB. TN-C blocks adhesion of SMCs to fibronectin and mediates SMC migration. Blocking TN-C suppresses neointimal hyperplasia. Cilostazol also increases intracellular cyclic adenosine monophosphate (cAMP), which inhibits proliferation of vascular SMC (VSMC) by inducing apoptosis through p53 and p21 pathways. Increased cAMP also inhibits phosphorylation of retinoblastoma protein (pRB), which regulates nuclear protein E2F, causing arrest in the cell cycle of VSMC.

The inhibitor effect of cilostazol on neointimal hyperplasia was demonstrated in rat models by inducing carotid artery injury with balloon angioplasty and locally applying cilostazol topically. At 14 days the rats that had local application were found to have significantly less intimal thickness. Similar studies have been done with rat aortic and free artery graft models and anastomotic models in dogs with comparable results. The DECLARE-DIABETES trial showed a reduction of in-stent stenosis and in-segment late loss with patients on cilostazol, aspirin, and clopidogrel after placement of coronary drug-eluting stents compared to those only on aspirin and clopidogrel.

Aspirin

Aspirin (acetylsalicylic acid [ASA]) is the most common platelet inhibitor administered to patients with atherosclerotic disease. Aspirin irreversibly inhibits COX-1 and COX-2. COX-1 is the enzyme responsible for the conversion of arachidonic acid to prostaglandin H2, which is a precursor for thromboxane A ₂ , which promotes platelet binding to thrombin and collagen.

Numerous studies have shown increased graft patency with ASA plus dipyridamole and with ASA alone. The Dutch Bypass Oral Anticoagulants or Aspirin (BOA) Study Group found that patients with venous bypass conduits received less benefit from ASA than those with nonvenous bypass conduits (odds ratio [OR], 1.26). This is likely secondary to the fact that autogenous bypasses have very little platelet deposition compared to prosthetic grafts. In fact, Goldman and colleagues noted that there is early aggressive platelet deposition on prosthetic grafts, and pretreatment with platelet inhibitors significantly reduced platelet deposition.

In a Cochrane meta-analysis, Brown and coworkers found that at 1 year, patients who underwent infrainguinal bypass surgery with both vein and prosthetic conduit benefited from the use of ASA or ASA plus dipyridamole compared with those not receiving platelet inhibition (OR, 0.59; 95% confidence interval [CI], 0.45–0.79). Other meta-analyses in the past have shown a 22% to 38% reduction in occlusion rate in patients receiving ASA therapy. The Veterans Affairs Cooperative Trial randomized 831 patients to receive warfarin plus ASA (international normalized ratio [INR] target, 1.4–2.8) or ASA alone following bypass with either vein or prosthetic grafts. Analysis of outcomes in the prosthetic group demonstrated that the 6-mm bypass subgroup of patients receiving warfarin plus ASA had improved patency at 1 year (71.4% vs. 57.9%, p = .02). The same benefit was not shown in the 8-mm graft or in the vein graft groups.

Thienopyridines

The thienopyridines are ticlopidine, clopidogrel, and prasugrel. Their mechanism of action is irreversible blockade of the P2Y12 ADP receptor on platelet membranes. This prevents activation of the GP IIb/IIIa complex, thereby reducing platelet activation and aggregation. Ticlopidine has been shown to improve primary graft patency rate at 24 months versus placebo from 63% to 82% ( p = .002). However, it is no longer used secondary to its hematologic toxicity, including aplastic anemia, agranulocytosis, neutropenia, and thrombocytopenia purpura. Prasugrel is the newest of the thienopyridines; it is currently approved only for patients with acute myocardial infarction after a coronary intervention.