Comparison with Low-Molecular-Weight Heparin

Three studies compared ximelagatran with LMWH. METHRO III (9) and EXPRESS (8) are similarly designed European clinical trials that enrolled patients undergoing THR or TKR. Participants were randomized to receive subcutaneous LMWH enoxaparin 40 mg daily (started 12 hours before surgery) or one dose of subcutaneous melagatran 3 mg after surgery, then oral ximelagatran 24 mg twice daily started the day after surgery. Participants in the EXPRESS trial also received subcutaneous melagatran 2 mg immediately before surgery (8). In METHRO III, the only statistically significant difference was a lower rate of total VTE (proximal or distal DVT, PE, or all-cause death) with enoxaparin in THR subjects (Table 1). In EXPRESS, ximelagatran significantly reduced the rate of total VTE and major VTE (proximal DVT, PE, or all-cause death) in all groups, relative to enoxaparin (Table 1). A double-dummy randomized controlled North American trial compared oral ximelagatran 24 mg twice daily with subcutaneous enoxaparin 30 mg twice daily in patients undergoing THR (5). Treatment was initiated the morning after surgery and continued for 7–12 days. Ximelagatran was associated with a higher rate of VTE (total and major) compared with enoxaparin (Table 1). Differences in efficacy between the trials may be explained by differences in dosing strategies between Europe and North America (20).

Comparison with Warfarin

Three North American trials (6;12;13) compared oral ximelagatran (24 or 36 mg twice daily) with warfarin (target international normalized ratio [INR] of 2.5) in patients undergoing TKR. Ximelagatran 36 mg significantly reduced the rate of total VTE compared with warfarin (6;12) (Table 1). No significant difference was seen with ximelagatran 24 mg (12;13). There was no between-group difference in rates of major VTE for either 24- or 36-mg regimens (Table 1).

Treatment of Patients with Venous Thromboembolism

THRIVE was a randomized, double-blind, noninferiority trial involving 2,489 patients with acute DVT, with or without PE (11). Oral ximelagatran 36 mg twice daily was compared with subcutaneous enoxaparin 1 mg/kg twice daily for 5 to 20 days followed by 6 months of warfarin therapy (target INR: 2–3). There was no statistically significant difference between ximelagatran and enoxaparin/warfarin for the primary end point of VTE recurrence (2.1 percent versus 2 percent; risk difference (RD): 0.2 percent; 95 percent confidence interval [CI]:–1, 1.3).

Secondary Prevention of Venous Thromboembolism

The THRIVE III trial evaluated ximelagatran for the secondary prevention of VTE in DVT/PE patients treated with anticoagulants for 6 months (25). In this multicenter, double-blind trial, patients were randomized to oral ximelagatran 24 mg twice daily (n = 612) or placebo (n = 611) for 18 months. Ximelagatran significantly lowered the overall rate of symptomatic recurrent VTE compared with placebo (2.8 percent versus 12.6 percent; hazard ratio [HR]: 0.16; 95 percent CI: 0.09, 0.3).

Atrial fibrillation

AF is the most common sustained cardiac arrhythmia (2). It is a major risk factor for stroke (7); the rate of ischemic stroke among patients with nonvalvular AF averages 5 percent per year (2;7) and can reach 12– 15 percent in high-risk groups (7). High-risk factors for stroke in AF patients include prior thromboembolism, age >75 years, mitral valve disease, prosthetic heart valve, hypertension, and heart failure (2;14). Several studies show that oral anticoagulant therapy decreases the risk of stroke in patients with AF and is more effective than daily acetylsalicylic acid (ASA) alone in high-risk patients (2;22). However, bleeding risks are more frequent with anticoagulants than with ASA (2). In selecting anticoagulation for AF patients, patients' individual risks of stroke and bleeding must be considered (2;22).

Two phase III trials investigated ximelagatran for stroke prevention in patients with AF. The SPORTIF III and V trials were designed to test the noninferiority of ximelagatran relative to warfarin based on a less than 2 percent difference in event rates (3;10). SPORTIF III enrolled 3,407 participants in 259 sites located in 23 countries in Europe, Asia, and Australasia (10). It was a randomized, open-label, parallel group trial, with blinded end point assessment (10). SPORTIF V was a North American, multicenter, randomized, double-blind, double dummy trial with 3,922 participants (3). In both studies, patients with nonvalvular AF and one or more risk factors for stroke were randomized to either a fixed dose of ximelagatran 36 mg twice daily or to adjusted-dose warfarin (target INR: 2 to 3) (3;10). ASA, up to 100 mg daily, was allowed in both trials (3;10). The primary end point in both SPORTIF studies was the incidence of all strokes (ischemic or hemorrhagic) and systemic embolic events, based on an intention-to-treat analysis. Secondary end points included all cause mortality, transient ischemic attack, myocardial infarction (MI), and composites of these outcomes (3;10). There was no statistically significant between-group difference in event rates in both SPORTIF studies. Based on this evidence, ximelagatran may be considered at least as effective as warfarin for the prevention of stroke in high-risk AF patients (Table 2). However, the use of a noninferiority margin of 2 percent was considered too liberal by the FDA. Indeed, a margin of that size could leave open the possibility that ximelagatran is only half as effective as warfarin and still be considered “noninferior” (4).

Myocardial Infarction

Currently, the mortality rate during hospitalization for acute MI varies between 5 percent and 15 percent, depending on the age (26). Antiplatelet and anticoagulant agents are usually part of the acute MI treatment; however, patients still remain at high risk for subsequent events, especially when anticoagulant therapy is stopped (16). Controversy exists regarding whether or not to continue anticoagulants after an MI to prevent recurrent cardiac ischemia (26). Limited evidence shows that combined moderate-intensity (target INR: 2 to 3) warfarin and ASA may be better than ASA alone with a marginal increase in major bleeding (19).

The ESTEEM trial evaluated ximelagatran for secondary prevention in post-MI patients. It was a phase II, randomized, placebo-controlled, double-blind, dose-guiding study of 1,883 patients in eighteen countries (27). Patients who experienced an acute MI within the past 14 days received either oral ximelagatran at doses of 24, 36, 48, or 60 mg twice daily, or placebo, for 6 months. Study drug was initiated within 6 to 12 hours of heparin cessation. All patients received ASA 160 mg once daily. The combined four ximelagatran groups significantly reduced the risk for the primary end points (all-cause mortality, nonfatal MI, and severe recurrent ischemia) compared with placebo (16.3 percent vs. 12.7 percent; HR: 0.76; 95 percent CI: 0.59, 0.98). There was no difference in efficacy among ximelagatran dose groups (27).

Bleeding Complications

The overall rates of bleeding complications between ximelagatran and comparators were similar in the VTE treatment or prevention studies, except in the EXPRESS trial (Table 3). In the SPORTIF trials, rates of major bleeding (bleeding causing death, involving critical anatomical sites, causing significant reduction in hemoglobin, or requiring blood transfusion) were similar between treatment groups. However, rates of combined bleeding (major and minor) were significantly lower in patients randomized to ximelagatran. In the ESTEEM trial, the frequency of major bleeding did not differ between ximelagatran and placebo groups (HR: 1.97; 95 percent CI: 0.80, 4.84) (Table 3). However, the combined bleeding rates were higher in the ximelagatran group (HR: 1.76; 95 percent CI: 1.38, 2.25), and the risk increased in a dose-related manner (27). In SPORTIF III and V, 15 to 18 percent of the study population was taking concurrent ASA and had higher rates of combined bleeding compared with those not on ASA (3;10). The concurrent use of ASA and a higher dose of ximelagatran may increase the risk of bleeding.

Liver Enzymes

Ximelagatran was associated with a greater than three times the upper limit of normal elevation of the liver enzyme alanine aminotransferase (ALT) in longer-term (6–18 months) VTE trials (11;25) (Table 4). Enzyme levels normalized in most patients (25). Long-term use (6– 26 months) of ximelagatran was also associated with elevated ALT levels in stroke prevention (3;10) and post-MI trials (27) (Table 4). ALT increases were typically asymptomatic, detected after 2–6 months of treatment, and returned toward baseline levels, even with those who continued the drug (27). ALT elevations were generally not associated with any serious clinical adverse events (10;27), although at least two suspected fatal cases of drug-induced hepatitis occurred in patients treated with ximelagatran (3;11). The FDA review identified three deaths associated with severe liver injury in patients using ximelagatran for more than 35 days. Although there does not appear to be an elevated risk of severe liver injury during short-term use (less than 12 days), it is unknown whether delayed onset of severe liver injury after short-term ximelagatran use could occur (4).

Others

In the THRIVE study, a retrospective analysis of adverse events found a higher rate of serious coronary events (including MI) with ximelagatran (10/1,240 patients) relative to enoxaparin/warfarin (1/1,249 patients; p = .006) (11).