Combined Glycoprotein IIb/IIIa and Direct Thrombin Inhibition with Eptifibatide and Bivalirudin in the Interventional Treatment
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Introduction
It has been suggested that treatment strategies for acute and chronic critical limb ischemia (CLI) can be tailored, analogous to treating chronic, and especially, acute coronary syndromes (ACS).1,2 Mechanical thrombectomy devices, distal protection devices, excimer laser and drug-eluting stents are just a few examples of device technologies first applied in coronary artery disease and ACS that are now increasingly being utilized in the treatment of CLI. Substantial clinical evidence showing improved outcomes exists, supporting the use of novel antiplatelet and antithrombin strategies utilizing glycoprotein (GP) IIb/IIIa inhibition and direct thrombin inhibition (DTI) in treating ACS and during percutaneous coronary intervention (PCI).3–6 These results prompted the ACC/AHA 2002 guidelines to recommend the use of GP IIb/IIIa inhibition in diabetes mellitus (DM) patients with ACS undergoing PCI.7 Unfortunately, sparse data exist detailing similar “endopharmacotherapies” in treating peripheral arterial disease (PAD) patients, especially in those requiring percutaneous peripheral interventional (PPI) treatment of CLI.
It is estimated that one out of every four patients with DM will face CLI in their lifetime, and that a diabetic patient is 7 to 40 times more likely to suffer an amputation than the nondiabetic patient.8,9 Similarly, patients with chronic renal insufficiency (CRI) are at higher risk of CLI and amputations, and the incidence of both DM and CRI is significantly higher (2 to 3 times) in the CLI versus the PCI population.1,4,5,10–12 It is now known that PAD, DM and CRI are individually and cumulatively associated with hypercoagulability, inflammation, prothrombotic states, increased thrombin generation, platelet dysfunction, and even unfractionated heparin (UFH) and aspirin (ASA) resistance.13–19 These factors are likely responsible for the higher level of ischemic and hemorrhagic complications during PPI versus PCI, underscoring the need for optimization of antiplatelet and antithrombin strategies in treating CLI.13–15
GP IIb/IIIa and DTI agents, when used individually or in combination, have demonstrated ischemic and hemorrhagic outcomes benefits in PCI.3–6,20 Multiple large PCI trials have shown GP IIb/IIIa inhibition to have improved outcomes in patients with ACS, DM, CRI, small vessels, complex anatomy, visible thrombus and acute and subacute stent outcomes, with the DM subsets deriving the greatest benefits.20–24 The potential for GP IIb/IIIa inhibition to decrease platelet aggregation, therefore minimizing the impact and the role of distal microembolization in CLI patients, is particularly attractive in this clinical setting with already-established, severe, outflow infrapopliteal disease and critically low pedal blood flow.1 Three recent reports describing macroembolization, retrieved by distal protection devices during lower extremity PPI, further suggest that an “upstream” GP IIb/IIIa platelet inhibition strategy has the potential to improve ischemic or thrombotic outcomes.25–27 Similarly, DTI with bivalirudin (Angiomax, The Medicines Company, Parsippany, New Jersey) has shown hemorrhagic outcome benefit in PCI. The safety and feasibility in PPI was reported in the multicenter Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE) trial, further strengthening the evidence that a simultaneous combination of DTI and GP IIb/IIIa inhibition may hold promise to improve overall outcomes in CLI patients undergoing PPI.28
It is estimated that CLI is responsible for 220,000–240,000 amputations yearly in the United States and Europe, with an annual cost of $10–20 billion in the United States alone.6,8,9 The 30-day periprocedural mortality and morbidity rates after an amputation are 4–30% and 20–37%, respectively, with less than 50% ever achieving full mobility.29–39 The overall 1-year mortality rate after an amputation is 20–30%, with a 3-year mortality rate of >50–60%.32–38 Any treatment strategy designed to improve the clinical outcomes of CLI would potentially offer significant clinical and economic benefits. It is estimated that just a 25% reduction of amputations could save $2.9–3.0 billion yearly in U.S. healthcare costs alone.8,32 Therefore, the staggering clinical and economic impact of CLI must be taken into consideration when criticizing the incremental costs of adding new “endopharmaceutical” treatment strategies in managing the challenging clinical scenario of CLI.
Significant data exist that implicate a major role for inflammation in cardiovascular diseases and now PAD.16,39–41 Recent data suggest that GP IIb/IIIa inhibitors also possess significant anti-inflammatory properties and may have potential clinical benefits during PPI.42,43 Shammas et al recently published similar results, investigating the role of GP IIb/IIIa inhibition and inflammation in decreasing the vascular inflammation response during PPI in the Integrilin (Schering-Plough Corporation, Kenilworth, New Jersey) reduces inflammatory responses in patients undergoing peripheral vascular interventions (INFLAME) trial.16 This small, randomized trial (total N = 42) concluded that at low-dose, the UFH inflammatory response was equivalent, as compared with high-dose UFH alone in PPI.16 There is a paucity of data on the use of combination eptifibatide and bivalirudin in the treatment of CLI. Therefore, this retrospective analysis was performed to assess the safety and feasibility of utilizing a combination of eptifibatide and bivalirudin, compared to a matched historical UFH control group in treating CLI with PPI.
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