An Overview of Antithrombins in Peripheral Vascular Interventions

Of approximately ten million people in the United States that live with peripheral vascular disease, only a small percentage are being treated (25%).1 The presence of peripheral vascular disease is an indicator of a higher mortality risk. A considerable overlap between atherosclerotic disease in the periphery, the heart, and the cerebral circulation exists. In fact, patients who have documented peripheral vascular disease (PVD) are at four times greater risk of heart attacks and two to three times greater risk of strokes.2 Percutaneous transluminal angioplasty (PTA) of PVD has become widely accepted and the number of peripheral vascular procedures has significantly increased over the past few years. The rapid growth in techniques and devices utilized in the angiographic laboratory has shifted the focus of therapy from a surgical one to a percutaneous one. Despite all these advances, unfractionated heparin (UFH) has remained, until recently, the mostly widely utilized and unchallenged antithrombin during PTA. New antithrombins are now being tested as an alternative to UFH during peripheral vascular interventions and appear to have promising results. An overview of UFH and other antithrombins in the periphery is presented below. Unfractionated Heparin and Peripheral Vascular Interventions. UFH is the currently utilized antithrombotic agent in peripheral vascular interventions. UFH has an unpredictable anticoagulation response, is an indirect thrombin inhibitor, does not inhibit bound thrombin and activates platelets. In-hospital complication rate following PTA has been reported in the literature and ranged from 3.5% to as high as 32.7%.3–10 At our center, major in-hospital complications occurred in 9.2% of 131 consecutive patients who underwent PTA (all included except carotid angioplasty).10 We defined major adverse events as follows: 1. Major bleed: defined as requiring > 2 Units of PRBC transfusion, retroperitoneal bleed, or a drop of hemoglobin (Hb) after the procedure by more than 3 g/dL. 2. Vascular complications: defined as an AV fistula or pseudoaneurysm after the procedure when suspected clinically and confirmed by duplex ultrasound 3. Death due to procedural complications 4. Limb loss 5. Need for in-hospital salvage revascularization (angioplasty or surgery) of the same treated vessel 6. Embolic stroke. The most frequent major complication was the need for a salvage revascularization in 10 (7.6%) followed by major bleed in 6 (4.6%). When the relationship between heparin and the occurrence of any adverse endpoint was evaluated there was a non-significant trend toward higher event rates with higher dosing of heparin administered (Figure 1). Exact logistic regression modeling showed that cigarette smoking within the past year (odds-ratio = 13.51; p-value = 0.0118), recent onset of claudication and PTA treatment below the knee were predictors of in-hospital complications. Matsi and Manninen3 have shown total and major complication rates of 10.5% and 5% respectively in 295 consecutive patients undergoing lower-limb PTA. In this prospective study females and patients with total occlusions had a higher rate of complications than males or patients with stenoses, respectively. Morse et al.6 have shown an 8.8% significant complications rate in 370 patients treated with lower limb angioplasty. Elderly patients were at significantly increased risk of complications. In 202 PTA procedures, Hasson et al.7 have shown 32.7% total complications rate. In this series there were 1.4% amputations and 2.2% deaths. In multivariate analysis, the most important predictor of the occurrence of a complication, amputation or procedural-related death was the premorbid clinical status of the limb (claudication versus limb threat). Greenfield9 reported 11.4% (8 of 70 patients) major complications in the treatment of femoral, popliteal and tibial arteries. Amputation rate ranged from 0.6% to approximately 3% in published literature with the use of UFH. In a retrospective study of 71 consecutive patients undergoing infrapopliteal PTAs for limb salvage, Boyer et al.8 reported a global morbidity rate of 16%, including 2 amputations (2.8%), 5 major vascular complications (7%) and one death (1.4%). In a prospective audit of 988 peripheral angioplasties, Axisa et al.5 described a 0.6% incidence of amputation rate. The amputation rate following angioplasty for critical limb ischemia was 2.2%. In this study, the overall risk of death and/or major complications was 3.5%. Gutteridge et al.4 reported in a non-randomized observational study of 212 patients that amputations were more common in patients undergoing below the inguinal ligament procedures and were more likely to occur in diabetic compared to non-diabetic. In our series,10 diabetics had less complication rates than non-diabetics. Although, this could reflect a selection bias, the diabetics also have received significantly less heparin than non-diabetics. In contrast smokers received more heparin than non-smokers and had a higher rate of complications. The optimal activated clotting time (ACT) or heparin dosing during peripheral vascular interventions has not been defined. In the coronary literature, and prior to the use of GP IIb/IIIa inhibitors, Narins and colleagues11 have shown a significant inverse relation between the degree of anticoagulation during angioplasty and the risk of abrupt vessel closure. Ferguson and colleagues12 have also shown that a diminished activated coagulation time response to an initial bolus of heparin is associated with major in-hospital complications after coronary angioplasty. An “optimal” ACT during coronary interventions, using heparin alone, has been generally considered to be between 350–375 seconds.13 UFH leads to an unpredictable ACT ranges at the same dosing in different patients. Twenty-nine percent (29.0%) of our patients10 had a suboptimal ACT ( 400 sec) than desired illustrating the difficulty in dosing heparin for the presumed desired ACT range of 300–400 seconds14–15 (Figure 2). In summary, UFH provides unpredictable anticoagulation with a trend toward higher complications with higher dosing. Major adverse events continue to occur at a significantly higher rates ranging from 3.5% to 32.7%. Given the need for a better anticoagulant than UFH during PTA, other antithrombins such as bivalirudin or the adjunctive use of GPIIb/IIIa inhibitors are currently being evaluated. Bivalirudin and Peripheral Vascular Interventions. Bivalirudin, a direct thrombin inhibitor, has been recently shown to reduce both ischemic and bleeding complications during coronary interventions when compared to UFH.16-18 In contrast to UFH, bivalirudin has a short half-life, provides predictable anticoagulation response, and inhibits free and bound thrombin.19 These properties might provide potential benefits over UFH during PTA where thrombin activation is expected to be significant given the extent of atherosclerotic burden and large vessel size dilated with balloon angioplasty. The short half-life of bivalirudin might also allow early sheath removal, less bleeding complications than UFH, and a more reliable anticoagulation with no need for frequent ACT measurements during long procedures. Early experience with bivalirudin in the periphery has been recently published or presented at scientific meetings.20–23 The data appear favorable showing low major bleeding rate and adverse events compared to historic data with UFH. None of these studies, however, are randomized and double-blinded. In our experience,23 in-hospital complication rate during PTA in 48 consecutive patients who received bivalirudin was 4.2%. Previously we have reported that peripheral vascular complications are not trivial with UFH as the base anticoagulant (9.2%).10 Our in-hospital outcomes with bivalirudin during PTA compare favorably with UFH. The complication rate appeared doubled with UFH when compared to bivalirudin (9.2% vs. 4.2% respectively). This is also in concordance with data recently reported in scientific meetings.20–22 Grubbs and colleagues20 reported their experience with 69 PTA patients receiving bivalirudin as a primary anticoagulant. In their series, there were no adverse events reported including no major bleeding, acute thrombosis, or death. Knopf et al.21 also reported on 72 patients receiving bivalirudin during PTA. There were no deaths, major bleeding, strokes, or distal embolization in their series. Furthermore, Allie et al.22 have used bivalirudin in 180 renals and 75 iliac interventions with no major complications reported. In contrast, complication rates with UFH have ranged from 3.5% to 32.7% in several published series.3–10 The safer profile of bivalirudin over UFH use during percutaneous coronary procedures has been shown in several studies. In the Bivalirudin Angioplasty Trial (BAT),16 bivalirudin reduced the risk of bleeding by 62% when compared to UFH (p Low-molecular weight heparins (LMWH) and Peripheral Vascular Interventions. Enoxaparin, like bivalirudin, has a predictable anticoagulation profile, does not require routine monitoring of ACT, and have little effect on platelet reactivity when compared to unfractionated heparin.24,25 Enoxaparin, however, at clinically relevant concentrations (0.4 to 1 U/ml) inhibits only 33-55% of clot bound thrombin (factor IIa) and 43–70% of clot- or platelet-associated thrombin or factor Xa (Weitz J, Unpublished data on file). In unstable angina pectoris and non-ST-segment elevation acute myocardial infarction, enoxaparin reduced the release of von Willebrand factor (vWF) compared with UFH and had a more favorable effect on glycoprotein Ib/IX complexes.26 Although LMWH was more superior to UFH in reducing the combined end point of death, myocardial infarction and recurrent angina in the ESSENCE study,27,28 only 43% of the UFH patients were at therapeutic level. Also, the soft endpoint of recurrent angina accounted for about 70% of the events in this study. In a metaanalysis by Eikelboom et al.,29 short-term UFH or LMWH halves the risk of myocardial infarction or death in aspirin-treated patients with acute coronary syndrome without ST elevation. There was no convincing difference in efficacy or safety between LMWH and UFH. In the recently presented SYNERGY study at the American College of Cardiology scientific sessions meeting (2004), UFH and LMWH had the same reduction in death or myocardial infarction or the combined endpoint of death and myocardial infarction (14.0% enoxaparin versus 14.5% UFH, p = 0.396). More hemoglobin drop was noted in the enoxaparin group compared to UFH. The latter also had less major bleeding (9.1% enoxaparin versus 7.6% UFH, p = 0.008). Data on LMWH in peripheral vascular interventions is very limited. Norgren30 recently reported the data on a randomized trial between intravenous LMWH (40 mg enoxaparin) and UFH (5000 units) on the rate of occlusion and bleeding during peripheral vascular surgery. LMWH was comparable to UFH during peripheral vascular reconstruction in terms of 1-day and 30-day graft patency, operative blood loss, and hemorrhagic complications in this study. Reviparin was also tested during peripheral reconstructive surgery.31 In this study, sixty-five patients were randomly allocated to receive twice-daily subcutaneous injections of reviparin, 3500 (group A, n = 17), 4200 (group B, n = 16), 5950 (group C, n = 16), and 7000 (group D, n = 16) anti-Xa IU per day. Patients included in group C had no major bleeding event and a significant improvement in lower extremity blood flow as assessed by ankle-brachial index measurement. Higher doses were associated with unacceptable bleeding rates. In this study, comparison with UFH was not done. Furthermore, LMWH and UFH were compared in the prevention of early graft thrombosis in patients undergoing femorodistal reconstructive surgery.32 In this open label, multicenter randomized study, intravenous bolus of either enoxaparin {75 anti-Xa IU/kg (n = 100)}, or UFH {50 IU kg (n = 101)} were administered before arterial cross-clamping. Graft thrombosis occurred in 8% in the LMWH group and 22% in the UFH group (p = 0.009) but there were no significant differences between the two groups in terms of major hemorrhages. During the follow-up period five patients in the LMWH group died compared to nine in the UFH group (statistically not significant). The role of GpIIb/IIIa inhibitors in Peripheral Vascular Interventions. Gp IIb/IIIa inhibitors combined with antithrombins have a synergistic effect on platelet aggregation inhibition.33 Also, combining GpIIb/IIIa inhibitors and LMWH, but not UFH, has shown to have an additional inhibitory effect on thrombin generation.33 In a randomized study, Bhatt et al.34 compared the bleeding rates with enoxaparin versus UFH, in addition to background therapy with eptifibatide during percutaneous coronary intervention. The bleeding index (change in hemoglobin corrected for blood transfusions) was 0.8 in the patients randomized to enoxaparin and 1.1 in patients randomized to UFH (p = 0.15). Vascular access site complications were 9.3% in the enoxaparin arm versus 9.8% in the UFH arm (not significant). Current data on the use of GpIIb/IIIa inhibitors during PTA is limited. A report by Ansel et al.35 indicated that these agents are safe during renal intervention. Also, in a small study, abciximab appears to be safe as an adjunct therapy during complex infrainguinal arterial interventions. Stavropoulos et al.36 reported a technical success rate of 94% in sixteen infrainguinal interventions. Only one groin hematoma occurred in a patient that required a blood transfusion. Furthermore, the combined use of GpIIb/IIIa inhibitors with LMWH in a group of 56 consecutive patients (93 procedures) undergoing non-emergent coronary and peripheral vascular interventions yielded a major bleeding rate of 2% and no vascular complications. The procedural success was 99%.37 A theoretical advantage to use these agents might be in elective infrapopliteal interventions37 and in patients undergoing tibial salvage.35 Data suggest that GpIIb/IIIa inhibitors have significant anti-inflammatory properties,38–40 a condition highly prevalent in the peripheral vascular patients.41 One study has indicated that the level of inflammation in a significant percentage of PVD patients is equivalent to that of unstable angina patients and single vessel disease as measured by high-sensitivity-C Reactive Protein (hs-CRP).41 The use of GpIIb/IIIa inhibitors with traditional anticoagulants in PTA procedures might have significant advantage in reducing inflammation and thrombotic complications. A high hs-CRP at baseline42–45 and after coronary angioplasty appears to correlate with an increased event rates following the intervention.46,47 It is yet unclear whether increase in inflammation following angioplasty in the periphery has serious clinical consequences such as influencing long-term restenosis or event rates. Recently, we have initiated a randomized trial integrilin reduces inflammatory responses in patients undergoing peripheral vascular interventions (INFLAME) to study the vascular inflammatory response following PTA. In INFLAME, the combination of a GPIIb/IIIa inhibitor with unfractionated heparin is being studied for its ability to reduce acute inflammation following PTA. A secondary endpoint of the study is to evaluate in-hospital clinical events, and at one-month and 6-month follow-up. Results of INFLAME is expected to be presented later this year. Conclusion. UFH is associated with a high rate of bleeding and thrombotic complications during PTA. More reliable anticoagulants such as bivalirudin might offer significant advantages over UFH. Early data with bivalirudin is promising and currently being tested in a multicenter registry (APPROVE). Data on LMWH in the periphery are still lacking. However, in a recent study in the unstable patient undergoing percutaneous coronary intervention, enoxaparin had an increase in major bleeding. The addition of GPIIb/IIIa inhibitors to conventional anticoagulants might also be one approach to lower thrombotic complications and reduce inflammation acutely during the intervention. Further data are needed to test this hypothesis. The INFLAME trial is currently ongoing and should offer some insight into the role of GPIIb/IIIa inhibition in reducing inflammation acutely in the periphery. It is unclear, however, whether acute reduction in inflammation will lead to a significant reduction in short and long term clinical events.

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