Overcoming Heparin Limitations in High-Risk Percutaneous Coronary Intervention: The Alternative Strategy — Replacing Heparin wit

Continued from previous page Overcoming heparin limitations in PCI with direct thrombin inhibitors Direct thrombin inhibitors, i.e., univalent agents such as argatroban, and bivalent agents such as lepirudin (Refludan®), desirudin (Revasc®) and bivalirudin (Angiomax®), are able to overcome the limitations of heparin and therefore offer potential improvements in patient outcome after PCI — particularly among patients at high risk for ischemic complications. With one exception, direct thrombin inhibitors bind specifically to the protease thrombin and not to other proteases or cells. Notably, the small molecule direct thrombin inhibitor argatroban binds 54% to human serum proteins (albumin, alpha 1 glycoprotein and others). Direct thrombin inhibitors are not inhibited by platelet factor-IV and do not cause platelet aggregation. In fact, bivalirudin has been demonstrated to inactivate platelets at concentrations equivalent to 1/500th the clinical plasma concentration used in PCI.⁹² Crucially, direct thrombin inhibitors are able to inhibit both fluid phase and fibrin-bound fibrin with similar affinity and effect.^93,94 Direct thrombin inhibitors are superior to heparin for the prevention of death or MI in patients with ACS. In a recent meta-analysis of 11 randomized trials, a total of 35,970 patients were assigned up to 7 days of treatment with a direct thrombin inhibitor or heparin and followed up for at least 30 days. Compared with heparin, direct thrombin inhibitors were associated with a lower risk of death or MI (4.3% versus 5.1%; odds ratio, 0.85; 95% CI, 0.77–0.94; p = 0.001). This was due primarily to a reduction in MIs. Subgroup analyses suggested a benefit of direct thrombin inhibitors on death or MI in trials of both ACS and PCI, but the benefit was restricted to bivalent inhibitors. Among the agents superior to heparin for effectiveness, only bivalirudin also demonstrated a reduced risk of bleeding.⁹⁵Argatroban. Argatroban is a small molecule thrombin inhibitor that attacks the active binding site of thrombin with moderate affinity.⁹⁶ While argatroban has been approved by the Food and Drug Administration (FDA) for treatment of patients with heparin-induced thrombocytopenia (HIT)/thrombosis syndrome (HITTS),⁹⁷ and may shortly be approved by the FDA for patients with heparin-induced thrombocytopenia undergoing PCI, this agent has not been studied in randomized trials in interventional cardiology. Therefore, the relative performance of argatroban and heparin in PCI is unknown. Randomized trials of argatroban versus heparin in other coronary artery disease settings such as MI have proven disappointing with no evidence of improved effectiveness, but with evidence of significant rebound effects after discontinuation of argatroban.^95,97,98 Argatroban is effectively metabolized and excreted in patients with renal impairment, but must be used with caution in patients with hepatic disease due to liver metabolism.⁹⁷ As a univalent thrombin inhibitor, argatroban does not displace fibrin or fibrinogen from thrombin. Hirudin analogues. Lepirudin (Refludan) is an analogue of hirudin — the 65-amino acid protein originally discovered in the saliva of the medicinal leech.⁹⁹ Like argatroban, lepirudin is approved for treatment of patients with HIT/HITTS only. Randomized trials of lepirudin have not been reported in PCI. In ACS patients — both with and without ST-elevation on electrocardiogram but not undergoing PCI — lepirudin reduced the incidence of thrombotic complications, but increased the incidence of bleeding compared to heparin.100–103 In the OASIS 2 trial, a total of 10,141 patients with non-ST elevation ACS were randomized to 72 hours of intravenous lepirudin or unfractionated heparin. Analysis of 117 patients undergoing PCI within the first 72 hours was recently reported.¹⁰⁴ Among these high-risk patients, lepirudin reduced the incidence of death or MI by 70% at 96 hours and by 75% at 35 days (Table 4). The apparent treatment benefit was evident both before and after early PCI and persisted after adjustment for the propensity for undergoing intervention (which was higher among patients randomized to heparin than lepirudin). However, as found in the overall study population, the improved effects of lepirudin were achieved at a cost of increased bleeding. Major bleeds were reported in 3/47 patients (6.4%) treated with lepirudin and in none of the patients treated to heparin. Desirudin (Revasc) is another analogue of hirudin, but is not available in the United States. Desirudin has been studied in arterial and venous thrombosis and approved by European regulators for use in deep vein thrombosis as Revasc®. Desirudin was studied in PCI in the HELVETICA randomized double-blind study of patients undergoing angioplasty and in a subset of patients with ACS undergoing early PCI in the GUSTO-IIb trial.106 Both studies demonstrated improved effectiveness of the direct thrombin inhibitor desirudin over the indirect thrombin inhibitor heparin — particularly among high-risk patients. In HELVETICA, a total of 1,141 patients with UA were randomly assigned to heparin (n = 382), to desirudin bolus (n = 381), or to desirudin bolus followed by subcutaneous dosing for 3 days (n = 378). Administration of desirudin was associated with a significant reduction in the incidence of death, MI, or revascularization from 11.0% on heparin to 7.9% on bolus hirudin and 5.6% on bolus plus subcutaneous desirudin — an overall risk reduction of 39% among all patients treated with desirudin (p = 0.023) (Table 5). Benefits of desirudin were most evident in unstable patients, in whom event rates increased on heparin but not desirudin. For example, analysis of 236 patients who had Braunwald Class III UA revealed an event rate of 21.6% on heparin compared with 8.8% on desirudin (combined odds ratio on desirudin, 0.41; 95% CI, 0.21–0.78; p = 0.006). Furthermore, among patients pre-treated with heparin, the combined odds ratio for ischemic complications on desirudin was 0.37 (95% CI, 0.19–0.70; p = 0.007). Bleeding was slightly more frequent among desirudin than heparin patients. Intracranial bleeding and overt bleeding with a decrease in hemoglobin concentration by > 2 g/dl, associated with transfusion of > 2 units of blood were reported in 6.6% of patients treated with desirudin compared to 6.3% treated with heparin. Minor bleeding was also more frequent among desirudin patients (14.1%) than heparin patients (11.3%). The GUSTO-IIb trial compared desirudin with heparin for the treatment of ACS.¹⁰⁷ Patients with ischemic chest pain 106 Among these high-risk patients, desirudin reduced the incidence of death or MI by 31% at 30 days and by 26% at 6 months (Table 6). Desirudin effects relative to heparin were similar both before and after PCI, but overall these patients had increased bleeding. Moderate and major bleeding episodes defined by the GUSTO score were slightly higher on desirudin in association with PCI (2.8% versus 2.3%) and clearly higher throughout the period of hospitalization (9.7% versus 7.5%). Bivalirudin. Bivalirudin is the most extensively studied direct thrombin inhibitor in PCI. A series of comparative studies have been performed and reported in a total of 6,134 patients undergoing PCI.^{40,47,108–110} Results have shown a consistent reduction in clinical ischemic and bleeding complications following PCI compared to heparin, irrespective of background therapy with aspirin, thienopyridines, GP IIb/IIIa inhibitors, stents and closure devices. Integrated results from all trials completed up to the end of 2001 are summarized in Table 7. Final results from the largest individual trial of bivalirudin were recently reported.⁴⁰ The results reported data on 4,312 patients randomized to heparin or bivalirudin as antithrombin treatment during angioplasty for new onset of severe, accelerating or rest angina. The protocol specified two high-risk groups that in total comprised 1,506 patients. The first group of 741 patients underwent intervention within 14 days of MI. The second group of 1,006 patients underwent PCI within 1 hour of heparin pre-treatment. Two hundred and forty-one of the 1,506 patients had both risk factors. The remaining 2,806 patients had stabilized clinically after diagnosis of UA in the last month. Patients were randomized to treatment with either heparin administered to achieve an ACT of 350 seconds or bivalirudin during the PTCA procedure. All patients received aspirin; stents were not used for the primary interventions. Clinical events were adjudicated by independent experts blinded to therapy. Among all 1,506 high-risk patients assessed at 7 days, the composite endpoint of death, MI or revascularization was reported in 40/761 bivalirudin patients (5.3%) and 65/745 heparin patients (8.7%; p = 0.005) (Figure 3). The composite incidence of death, MI or revascularization among patients without risk factors and treated with heparin during PCI was 7.0%, and reduced to 6.1% with bivalirudin. In these and all other patients (including high-risk), the incidence of bleeding (TIMI major or minor bleeding or transfusion of > 2 units of blood products) was also significantly lower among patients randomized to bivalirudin (p 47 Summary. Multiple factors predict the risk of ischemic complications following percutaneous coronary intervention (PCI). Many of these high-risk characteristics are related to intracoronary thrombus formation. The indirect thrombin inhibitor heparin does not inhibit fibrin-bound thrombin due to stereochemical constraints. Consequently, heparin is relatively ineffective in the presence of intracoronary thrombus. Patients with acute coronary syndrome (ACS) may also experience heparin resistance due to the drug’s inhibition by platelet factor-IV, or non-specific heparin binding to other acute phase reactants. The effectiveness of heparin may also be reduced among specific patient groups (elderly, females, extreme body mass) and disease states (diabetes, chronic kidney disease), which are associated with hypercoagulability and arterial dysfunction — also linked to an increased incidence of intracoronary thrombosis. In recent years, the pharmacological and clinical limitations of heparin have been addressed by adding potent antiplatelet inhibitors [thienopyridines and glycoprotein (GP) IIb/IIIa inhibitors] to heparin and aspirin. This increases the risk of bleeding and results in the need to reduce the dose of heparin, potentially compounding its relative lack of effectiveness in high-risk PCI. An alternative strategy to overcome heparin resistance is to replace heparin with more effective and safer antithrombin agents. Direct thrombin inhibitors are superior to heparin for the prevention of death or myocardial infarction (MI) in patients with ACS.^95,111 In a recent meta-analysis of 35,970 patients, direct thrombin inhibitors were associated with a lower risk of death or MI (4.3% versus 5.1%; odds ratio, 0.85; 95% CI, 0.77–0.94; p = 0.001). Subgroup analyses suggested a benefit of direct thrombin inhibitors in trials of both ACS and PCI, but the benefit was restricted to bivalent inhibitors. Among the agents that were more effective than heparin, only bivalirudin also demonstrated a reduced risk of bleeding.⁹⁵ Three direct thrombin inhibitors have been studied in PCI trials: argatroban, desirudin (Revasc) and bivalirudin (Angiomax). Argatroban is available for use in patients with heparin-induced thrombocytopenia, but has not shown improvements in clinical outcome compared to heparin in randomized trials. Lepirudin is also available for HITS patients, but with no available data in PCI and evidence of increased bleeding risk compared to heparin. Desirudin has shown improved effectiveness compared to heparin in high-risk patients undergoing PCI, but with no reduction in the risk of bleeding. Desirudin is not currently available for clinical use in the United States. Bivalirudin is a reversible direct thrombin inhibitor that has been tested in a series of randomized PCI trials. Data from these trials demonstrate substantial improvements in therapeutic ratio compared to heparin. In particular, analysis of high-risk subgroups, including patients who are elderly, female, abnormally heavy or light in weight, diabetic, renally impaired or ACS including post-infarction and refractory unstable angina, demonstrates an improved therapeutic ratio with both reduced ischemic complications and reduced bleeding complications of PCI. Bivalirudin appears to be an excellent agent to improve the antithrombotic foundation in these high-risk patients.