Commentary
Heparin in Peripheral Vascular Intervention — Time for a Change?
May 2003
Throughout the history of interventional procedures, unfractionated heparin has been the standard anticoagulant.1 More recently, in coronary intervention, agents have been found to provide better efficacy and/or safety than sole therapy with unfractionated heparin.2–5 While the need to improve upon the results obtained with unfractionated heparin has been acknowledged in coronary intervention, peripheral intervention has lagged in this regard. In this issue of the Journal, Shammas et al. have elegantly described the incidence of in-hospital complications in patients undergoing non-carotid peripheral arterial intervention while receiving unfractionated heparin during the procedure.
See Shammas et al.
Several important observations are made in this paper. There was a 4.6% rate of major bleeding seen in this study. Patients with peripheral arterial disease requiring intervention are in general a higher risk cohort than those requiring isolated coronary intervention. They have a higher risk of bleeding, vascular, and ischemic complications. Angiographic thrombus is more often present, and given the size of peripheral arteries, the actual thrombus burden is larger than typically found in coronaries. In their series, Shammas et al. report a 15.3% rate of intraprocedural thrombus. Also observed in this analysis, patients with peripheral arterial disease were more likely to have renal dysfunction, a marker of increased risk of bleeding, as well as of ischemic complications, especially with standard-dose heparin.6 Based on a recent meta-analysis, it appears that alternative modes of anticoagulation, such as with bivalirudin, are particularly efficacious in those with renal failure.7 The benefit of bivalirudin over heparin appears most pronounced in groups at high risk for bleeding, such as women.8 Thus, optimizing anticoagulation by simultaneously striving for greater efficacy and less bleeding may be even more crucial during peripheral intervention. An interesting finding in the analysis by Shammas et al. is the link between higher activated clotting time (ACT) levels and increasing risk of bleeding complications in the context of peripheral intervention. While there did not appear to be linkage between ACT and efficacy, a much larger number of patients would need to be studied to either prove or disprove that connection. A large meta-analysis of coronary interventional trials has described such a relationship, with an ACT of ~375 as optimal for minimizing ischemic outcomes when unfractionated heparin is used as the sole anticoagulant; unfortunately, this degree of anticoagulation was also associated with a large increase in the rate of major bleeding in this meta-analysis.9 While the heparin-ACT relationship may be less evident in straightforward cases of coronary stenting in the modern era,10 in more prolonged and complex peripheral arterial procedures, likely the data from the above meta-analysis are relevant. In patients receiving both unfractionated heparin and glycoprotein (GP) IIb/IIIa inhibitors, there does not appear to be any benefit in an ACT greater than 250 seconds, though the degree of bleeding increases quite steeply.9 Indeed, in patients receiving both unfractionated heparin and intravenous GP IIb/IIIa inhibitors, the degree of anticoagulation as assessed by the ACT is a more powerful determinant of bleeding complications than is the degree of antiplatelet activity as assessed by platelet activation units (PAU).11 Thus, much like the situation with coronary intervention, higher levels of heparin lead to increased rates of bleeding in peripheral intervention. Problems with dosing of unfractionated heparin, including with weight-based dosing, make it difficult to titrate doses to a target ACT precisely. This conundrum leads to the need for better anticoagulant and/or adjunctive antiplatelet therapy. The potential for closure devices to decrease complications during peripheral intervention deserves further exploration. Closure devices, predominantly suture-mediated closure, were used in 84.7% of patients in this series. In cardiac procedures, closure devices certainly increase patient comfort and decrease time to ambulation,12 and may also decrease groin complications. The relative benefits of closure devices may be amplified in peripheral arterial intervention, where larger sheath sizes are still utilized. Another point raised by this paper, and worth reflecting upon, is the cross-fertilization of ideas generated from the coronary literature into the peripheral literature by interventional cardiologists who are pan-vascular interventionalists. Much effort has been invested in the study of antithrombotic therapy in coronary intervention and perhaps many of these lessons can be adapted and applied to the peripheral arteries. The report by Shammas et al. highlights one such area of future investigation — development of superior antithrombotic strategies than use of unfractionated heparin alone during endovascular intervention. Potential refinements include clopidogrel pretreatment, potentially with even larger loading doses than currently employed, prolonged clopidogrel post-procedurally, substitution of bivalirudin for unfractionated heparin, and the addition of GP IIb/IIIa blockade.13,141. Gruentzig A. Transluminal dilatation of coronary-artery stenosis. Lancet 1978;1:263.
2. Bittl JA, Chaitman BR, Feit F, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001;142:952–959.
3. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.
4. Topol EJ, Mark DB, Lincoff AM, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: Results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999;354:2019–2024.
5. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2000;284:1549–1558.
6. Jeremias A, Bhatt DL, Chew DP, et al. Safety of abciximab during percutaneous coronary intervention in patients with chronic renal insufficiency. Am J Cardiol 2002;89:1209–1211.
7. Chew DP, Bhatt DL, Berger PB, et al. Bivalirudin provides increasing benefit with declining renal function in percutaneous coronary intervention: a meta-analysis of 5,035 patients enrolled in three randomized trials. J Am Coll Cardiol 2003;41:83A.
8. Bhatt DL, Cho L, Lincoff AM, et al. Reduction in PCI-related bleeding with bivalirudin is particularly striking in women. J Am Coll Cardiol 2002;39:17A.
9. Chew DP, Bhatt DL, Lincoff AM, et al. Defining the optimal activated clotting time during percutaneous coronary intervention: Aggregate results from 6 randomized, controlled trials. Circulation 2001;103:961–966.
10. Tolleson TR, O’Shea JC, Bittl JA, et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. J Am Coll Cardiol 2003;41:386–393.
11. Tamberella MR, Bhatt DL, Chew DP, et al. Relation of platelet inactivation with intravenous glycoprotein IIb/IIIa antagonists to major bleeding (from the GOLD study). Am J Cardiol 2002;89:1429–1431.
12. Bhatt DL, Raymond RE, Feldman T, et al. Successful “pre-closure” of 7Fr and 8Fr femoral arteriotomies with a 6Fr suture-based device (the Multicenter Interventional Closer Registry). Am J Cardiol 2002;89:777–779.
13. Bhatt DL, Kapadia SR, Bajzer CT, et al. Dual antiplatelet therapy with clopidogrel and aspirin after carotid artery stenting. J Invas Cardiol 2001;13:767–771.
14. Ansel GM, George BS, Botti CF, et al. Use of glycoprotein IIb/IIIa platelet inhibitors in peripheral vascular interventions. Rev Cardiovasc Med 2002;3:S35–S40.
