Direct Thrombin Inhibitors (Part 2 of 2)

Clinical Trials of Direct Thrombin Inhibitors The 2 direct thrombin inhibitors that have been studied most extensively are hirudin and bivalirudin. The earlier trials focussed on hirudin in the setting of acute coronary syndromes, MI and PCI and the recent trials are exploring the role of bivalirudin as a replacement of heparin and/or GP IIb/IIIa antagonists and as an adjunct to GP IIb/IIIa receptor antagonists in acute coronary syndromes and PCI. Hirudin use in acute MI, acute coronary syndromes and PCI. TIMI 9A,⁵⁴ GUSTO 2a⁵⁵ and HIT 356 trials, tested hirudin as an adjunct to fibrinolytic therapy in patients with acute ST-elevation MI. These trials were terminated prematurely due to an increased incidence of bleeding. Thereafter, the doses of both hirudin and unfractionated heparin were reduced and the TIMI 9B,⁶⁴ GUSTO 2b⁶³ and HIT 4 were undertaken. TIMI 9B showed that heparin and hirudin have an equal effect as adjunctive therapy to TPA and streptokinase (SK) in preventing unsatisfactory outcome in patients with acute myocardial infarction. Similar rates of major bleeding were observed for patients in the heparin and hirudin groups. GUSTO IIb,⁶³ showed that after adjustment for baseline differences between thrombolytic groups, the rate of major adverse events was 9.1% for SK with hirudin, 10.3% for TPA with hirudin, 10.5% for TPA with heparin and 14.9% for SK with heparin (p = 0.03), suggesting that the beneficial treatment effect of hirudin is limited to the SK-treated ST-elevation acute MI patients. In this trial, hirudin was shown to interact favorably with SK but not t-PA, highlighting the importance of thrombin activity after SK therapy and the potential for simulating the effects of a more potent fibrinolytic agent through direct antithrombin therapy. Using hirudin, in GUSTO IIb,⁶³ the 72-hour and 30-day relative risk reductions(RR) of death or MI were 0.72 and 0.90, respectively, in patients without ST-segment elevation. Compiling the data from GUSTO IIb, OASIS-267 and the (pilot) OASIS-1 trial,⁶⁸ the RR of events with hirudin at 72 hours was 0.72, whereas by 35 days (30 days in GUSTO IIb) the RR was 0.90 (p = 0.06). These data suggest that, when used in these doses, the direct thrombin inhibitor, hirudin, is more efficacious than unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes, without increasing serious bleeding. HELVETICA⁶⁵ was a study comparing two regimens of recombinant hirudin with heparin in the prevention of restenosis after coronary angioplasty. At 7 months, event-free survival was 67.3% in the group receiving heparin, 63.5% in the group receiving intravenous hirudin, and 68.0% in the group receiving both intravenous and subcutaneous hirudin (p = 0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0%, 7.9%, and 5.6% of patients in the respective groups (combined relative risk with hirudin, 0.61; 95% confidence interval, 0.41 to 0.90; p = 0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at 6 months were 1.54, 1.47, and 1.56 mm (p = 0.08). Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up. Although the hypothesis that potent, direct inhibition of thrombin would improve clinical outcomes appears valid, the extent of the benefit is small and of marginal statistical significance. Among the possibilities are an inadequate dose of hirudin, an insufficient duration of treatment, or the lack of durability of the effects of hirudin. Hirudin was associated with a significant and substantial reduction in the risk of death or myocardial infarction at 24 and 48 hours. The small benefit at 30 days was similar in patients with ST-segment elevation and in those without ST-segment elevation. A longer infusion of hirudin might increase efficacy, but the lack of benefit in the TIMI 9 trial, in which therapy was administered an average of 30% longer than in the GUSTO 2b study, makes this possibility less likely. A lack of durability of the effect of thrombin inhibitors has been noted in trials. Mechanistically, hirudin has the advantage of affecting clot-bound thrombin, not requiring any cofactors, and not being inactivated by plasma proteins or platelet Factor 4. Serial assays of prothrombin fragment (Figures 1 and 2) during hirudin therapy have confirmed the inability of hirudin to block the generation of thrombin. The consequent accumulation of thrombin may have detracted from the ability of hirudin to inhibit the activity of thrombin and thus reduce ischemia. Current data suggest that there is a narrow therapeutic window for treatment with recombinant hirudin and that the administration of doses higher than those tested in the GUSTO 2b trial may increase the risk of bleeding complications without substantially improving efficacy. Other factors besides the dose or duration of treatment may explain the borderline results. All the beneficial effects of hirudin were evident within the first 24 hours. Beyond that point, the event-rate curves neither diverged nor converged. This failure to prevent events beyond 24 hours may be attributed either to rebound hypercoagulability after the infusion of thrombin inhibitors was stopped or to a lack of “passivation” of the arterial surface that continued to allow the formation of platelet thrombus. Bivalirudin. Acute Myocardial Infarction: In the HERO-I trial,⁵⁹ TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose bivalirudin, and 48% (95% CI, 40% to 57%) with high-dose bivalirudin (heparin versus bivalirudin, p = 0.023; heparin versus high-dose bivalirudin, p = 0.03). At 48 hours, reocclusion occurred in 7% of heparin, 5% of low-dose bivalirudin, and 1% of high-dose bivalirudin patients (p = NS). By 35 days, there was no difference in death, cardiogenic shock, or reinfarction between the heparin, low-dose bivalirudin and 17 high-dose bivalirudin patients. Major bleeding occurred in 28% of heparin, 14% of low-dose bivalirudin, and 19% of high-dose bivalirudin patients (heparin versus low-dose bivalirudin, p 150 seconds, or after 24 hours unless the aPTT was > 120 seconds. The HERO-2 study demonstrated no difference in the primary outcome of death at 30 days in patients treated with bivalirudin compared with heparin. There was, however, an 8% reduction in the composite of death or MI at 30 days and a 30% reduction in the incidence of new MI at 96 hours, a benefit that was maintained to 30 days. Modest excess bleeding occurred with bivalirudin compared with heparin (1.4% versus 1.1%) with a similar trend for severe excess bleeding (0.7% versus 0.5%, p = 0.07). This was somewhat unexpected in view of the reduced risk of bleeding seen in earlier studies performed with this agent, but may be due to the higher aPTT levels at 12 hours (median aPPT, 108 versus 77 seconds; p Bivalirudin in acute coronary syndromes. Lidon, et al⁷⁰ investigated the use of bivalirudin in 55 unstable angina patients and concluded that bivalirudin infusions quickly and reproducibly yield stable, dose dependent anticoagulant and antithrombotic effects with a favorable clinical efficacy profile. TIMI 7 was a randomized, double-blind study in which patients received a constant infusion of one of four doses of bivalirudin for 72 hours The primary efficacy end point “unsatisfactory outcome,” defined as death, nonfatal myocardial infarction (MI), rapid clinical deterioration, or recurrent ischemic pain at rest with ECG changes by 72 hours was not different among the 4 dose groups. After uncontrolled studies that demonstrated the feasibility of bivalirudin, several highly promising heparin-controlled pilot studies were performed with bivalirudin in patients with ACS. A meta-analysis of these trials that included data from patients undergoing PCI confirmed the superiority of bivalirudin over heparin for the prevention of death or MI at 30 to 50 days (OR, 0.73; 95% CI, 0.57 to 0.95) with a reduction in risk of major bleeding (OR, 0.41; 95% CI, 0.32 to 0.52). This meta-analysis also included data from the prematurely terminated phase 3 TIMI-8 trial that compared a 72-hour infusion of bivalirudin with heparin in patients with non-ST-segment elevation ACS (target enrollment 5,320). Although only 133 patients were randomized before study termination, there was already a highly promising reduction in the risk of death or MI with bivalirudin compared with UFH at 14 days (2.9% versus 9.2%). The ACUITY-ACS trial is currently on-going enrolling patients with ACS and randomizing patients to heparins or to bivalirudin. Bivalirudin in percutaneous coronary intervention. Enhanced adjunctive pharmacotherapy for percutaneous coronary revascularization is evolving. New modifications to the original antithrombotic, antiplatelet combination of heparin and aspirin have become part of standard practice. Topol and colleagues⁷¹ conducted a multicenter dose escalation Phase 2 study of bivalirudin to determine its appropriate dose and feasibility as the sole anticoagulant during coronary angioplasty. The study documented for the first time that it is possible to perform coronary angioplasty with an anticoagulant other than heparin in aspirin-pretreated patients. Bivalirudin was associated with a rapid onset, dose-dependent anticoagulant effect, minimal bleeding complications, and at doses of 1.8–2.2 mg/kg, a rate of 3.9% for abrupt vessel closure. The Bivalirudin Angioplasty Study (Phase 3)⁵⁸ (Figure 4) compared the efficacy and safety of bivalirudin with weight-adjusted heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) for unstable or post-infarction angina. In the total study group, bivalirudin did not significantly reduce the incidence of the primary end point (11.4%, versus 12.2% for heparin) but did result in a lower incidence of bleeding (3.8% versus 9.8%, p Bivalirudin as an adjunct to glycoprotein IIb/IIIa antagonists. Bivalirudin may be better than heparin as an adjunct to GP IIb/IIIa antagonists. It causes less bleeding than heparin^55,56 and produces a more predictable anticoagulant response.⁵¹ Consequently, laboratory monitoring may not be necessary with bivalirudin. In addition, the ability of bivalirudin to inactivate fibrin-bound thrombin^5,15 may give it an efficacy advantage over heparin in the setting of arterial thrombosis. The superior safety profile of bivalirudin over hirudin makes bivalirudin a better choice for adjunctive therapy with GP IIb/IIIa antagonists. Well designed clinical trials are needed to test the possibility that bivalirudin is better than heparin as an adjunct to GP IIb/IIIa antagonists. The CACHET⁷² trial (Figure 5) aimed to evaluate improved anticoagulation with bivalirudin and pre-procedural oral antiplatelet protection and the use of ad hoc abciximab as a basis for a practical, acceptable antithrombotic, antiplatelet strategy to improve outcomes in percutaneous coronary revascularization. It therefore compared primary abciximab plus aspirin and heparin with aspirin plus intraprocedural bivalirudin and ad hoc abciximab in patients who are candidates for stenting. This study showed that bivalirudin provides predictable anticoagulation without altering platelet aggregation in patients receiving abciximab, and appears generally safe in patients receiving abciximab during coronary intervention. The combined incidence of MI , revascularization and major hemorrhage reported within 7 days was 3.55% (5/144) in bivalirudin patients and 14.1% (9/64) in heparin/abciximab patients (p-value) revascularization was 2.1% (3/144) and 3.1% (2/64) in bivalirudin and heparin/abciximab patients respectively. Non-Q-wave MI was detected following PCI in 2.1% (3/144) and 1.6% (1/64) patients treated with bivalirudin and heparin/abciximab respectively. Revascularization procedures were more frequent in the heparin/abciximab group. All revascularizations were percutaneous procedures; no patients in either group underwent CABG. Major bleeding occurred in 2/144 (1.4%) of the bivalirudin treated patients compared to 4/64 (6.3%) heparin/abciximab–treated patients. Similarly, the composite incidence of major bleeding and transfusion was less frequent in the bivalirudin group (3/144, 2.2%) than in the heparin/abciximab group (4/64, 6.3%). Bivalirudin versus heparin and Gp IIb/IIIa antagonists. The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary PCI. The purpose of REPLACE 273 was to determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned GP IIb/IIIa blockade with regard to protection from peri-procedural ischemic and hemorrhagic complications. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6,010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002. Patientswere randomly assigned to receive intravenous bivalirudin (0.75 mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional GP IIb/IIIa inhibition (n = 2999), or heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3,011). Provisional GP IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group versus 10.0% of patients in the heparin-plus-GP IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77–1.09; p = 0.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin versus 7.1% of patients in the heparin-plus-GP IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90–1.32; p = 0.40). Prespecified statistical criteria for noninferiority to heparin plus GP IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% versus 4.1%; p 75 years old, acute coronary syndrome or unstable patients and patients who had received any heparin pre-treatment derived statistically significant mortality reductions in the bivalirudin group (p 74 Clinical trials of other direct thrombin antagonists. Argatroban is approved for use in patients with HIT or HIT with thrombosis. Patients with HIT who were treated with argatroban experienced more major bleeding (4.9%) than historical controls given oral anticoagulation or no treatment. However, in a study of 1,001 patients given either argatroban or heparin with thrombolytic therapy, the incidence of major bleeding was not significantly different (0.4% versus 1.2%, respectively).⁷⁴ In a study of 160 patients with HIT, the incidence of all-cause death, all-cause amputation, or new-cause thrombosis was significantly reduced compared with control subjects after 37 days (25.6% versus 38.8%, respectively; p = 0.014).⁷⁵ In 144 patients with HIT and thrombosis, the reduction in the composite endpoint did not reach significance compared with control subjects (43.8% versus 56.5%, respectively; p = 0.13); however, the time-to-event analysis favored treatment with argatroban.⁷⁶ Although a small trial (n = 125) suggested that argatroban might have superior efficacy to heparin in acute MI patients treated with thrombolysis, the results of a larger study (n = 1001) did not demonstrate such a difference.⁷⁷ Ximelagatran: DTIs can be structurally modified for oral administration. Approximately 10 oral DTIs are reported to be in development; however, to date, ximelagatran is the only one in Phase III clinical trials (Table 2). Clinical trials to date have shown that bleeding associated with ximelagatran therapy is equivalent to that of placebo in patients receiving extended VTE prophylaxis following initial treatment and similar to that of well-controlled warfarin therapy in patients with atrial fibrillation treated to prevent stroke. In orthopedic surgery patients given ximelagatran for VTE prophylaxis, no difference was found in the bleeding rate compared with well-controlled warfarin.⁷⁸ However, bleeding rates in studies comparing ximelagatran and LMWHs vary depending on the timing of anticoagulation with respect to surgery and the ximelagatran dose. Either similar or greater bleeding rates are observed in patients given ximelagatran. An extensive clinical trials program involving 30,000 patients is in progress to test the effectiveness of ximelagatran for a variety of indications. Several studies have examined the efficacy and safety of ximelagatran for prophylaxis of VTE in patients undergoing total hip or total knee arthroplasty. Several dosing strategies have been employed. In European studies (METHRO II, EXPRESS)^79–84 melagatran up to 3 mg subcutaneously twice daily was given pre-operatively and for several days postoperatively, followed by a fixed dose of oral ximelagatran up to 24 mg twice daily for up to 11 days. Low-molecular weight heparins (LMWH) were used as comparators. In North American studies, including EXULT, a fixed dose of ximelagatran up to 36 mg twice daily was initiated 12 to 24 hours postoperatively and continued for varying periods of time (6 days). A standard dose of enoxaparin or warfarin, with INR maintained at 1.8–3.0, was used as a comparator. Study endpoints included the incidence of VTE determined venographically and the incidence of bleeding complications. Monitoring of anticoagulant effects was performed only in patients given warfarin. Preliminary data are available for METHRO II, METHRO III^80,84–87 North American studies.The METHRO studies show similar efficacy between ximelagatran and LMWHs.The North American studies to date show that unmonitored fixed-dose ximelagatran (24 mg orally twice daily) appears to be as effective as warfarin, whereas a ximelagatran dose of 36 mg twice daily is more effective than warfarin in prevention of VTE after hip or knee replacement surgery. The lower ximelagatran dose is also as effective as or somewhat less effective than enoxaparin. Studies examining the role of ximelagatran in treating acute DVT with or without pulmonary embolism are also ongoing. Results from THRIVE I88 indicate that ximelagatran doses between 24 and 60 mg twice daily reduce thrombus size and symptoms of VTE similarly to warfarin, suggesting that ximelagatran has a wide dose range. Results from THRIVE III82 ^{demonstrated that treatment with oral ximelagatran 24 mg twice daily for 18 months after 6 months of standard treatment with warfarin (INR 2.0–3.0) reduced the risk of recurrent VTE by 84% compared with placebo. The efficacy and safety of ximelagatran in preventing recurrent ACS are being assessed in the Phase II ESTEEM}90,91trial. Doses of ximelagatran between 24 and 60 mg twice daily combined with aspirin 160 mg/day will be studied. Clinical trials on the long-term prevention of stroke resulting from atrial fibrillation are also in progress. Patients chosen for these studies have atrial fibrillation and at least 1 additional risk factor for stroke. SPORTIF II⁹² was a 12-week dose-finding study of 257 patients that was extended to treatment (SPORTIF IV)⁸³ with ximelagatran 36 mg twice daily or warfarin for 5 years. SPORTIF III has randomized 3,400 patients for a 12- to 26-month open-label study of the stroke event rate in participants taking ximelagatran 36 mg twice daily versus warfarin (INR 2.0–3.0). SPORTIF V⁸⁴ has randomized 4,000 patients for a similar, but double-blind, study. The latter 2 studies will confirm efficacy and determine the incidence of any adverse events in long-term treatment, as well as prospectively examine efficacy in patients > 75 years old versus younger patients. Preliminary results from SPORTIF II and IV are positive, with similar low numbers of strokes in both the ximelagatran and warfarin-treated groups. Preliminary results from SPORTIF III also showed that ximelagatran is not inferior to warfarin (INR 2.0–3.0) in preventing all strokes and systemic thrombotic events. A secondary analysis demonstrated a significant decrease in the combined endpoint of all strokes, systemic thrombotic events, major bleeding, and death compared with warfarin (INR 2.0–3.0). All bleeding was also significantly reduced in the ximelagatran group. Few adverse events have been noted with ximelagatran therapy. Asymptomatic A-alanine aminotransferase elevation was observed in a few long-term studies. Increases of > 3 times normal were observed in 6.4% of patients receiving ximelagatran and 1.2% of patients receiving placebo in THRIVE III. In SPORTIF III, 6.5% of patients receiving ximelagatran and 0.7% of patients receiving warfarin had A-alanine aminotransferase levels > 3 times normal. However, these levels decreased spontaneously during continued treatment or after discontinuation of treatment. Taken together, these data suggest that ximelagatran is promising as a potential alternative to anticoagulants given intravenously or subcutaneously. Its exact role in clinical practice remains to be determined pending the results of ongoing clinical studies. Conclusions. Decades of research have been devoted to developing effective, safe, and convenient anticoagulant agents. Elucidation of the central role of thrombin in the coagulation cascade directed the development of medications that prevent thrombin generation or activity by affecting various enzymes within the coagulation system. Structural analysis of key proteins, such as factor Xa and thrombin, has allowed the development of specifically targeted anticoagulants. Review of the clinical data indicates that most new anticoagulants are at least as effective as traditional anticoagulants, and some are more effective (ie, fondaparinux in orthopedic surgery, hirudin in ACS). DTIs also have the potential to decrease bleeding risk compared with traditional anticoagulants in some circumstances (ie, bivalirudin in patients given percutaneous intervention). Furthermore, DTIs eliminate the risk of HIT, exhibit fewer drug interactions than warfarin, and sometimes do not require routine dose adjustments and monitoring, making their use more convenient in the clinical setting. Oral formulations of DTIs and other drug classes are in development. To date, the attributes of ximelagatran appear promising: oral administration, predictable pharmacokinetics and pharmacodynamics, a broad therapeutic window, no routine monitoring, no significant drug interactions, and fixed-dose administration. A well-developed clinical trial program will determine the benefits offered by ximelagatran. The availability of ximelagatran or another oral agent may revolutionize antithrombotic therapy, allowing for safer and more convenient administration.

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