Hemorrhagic Complications of Anticoagulant Treatment. part 20

There were no major bleeds in the ximelagatran group and one in the warfarin group. In the SPORTIF III trial, 3,407 patients with nonvalvular atrial fibrillation received ximelagatran, 36 mg bid, or warfarin (INR, 2.0 to 3.0). The rates of major bleeding were 1.3% and 1.8%, respectively. This difference was not statistically significant.

Oral direct thrombin inhibition with ximelagatran at doses of 24 mg, 36 mg, 48 mg, or 60 mg bid plus 160 mg/d of aspirin was compared to 160 mg/d of aspirin alone in a recent multicenter blinded trial for secondary prevention of myocardial infarction. There were 1,883 patients followed up for a 6-month treatment period. The rates of major bleeding did not differ between treatment groups (1% for aspirin alone vs 2% for combined ximelagatran doses), but patients in the combined ximelagatran groups were three times more likely to stop therapy due to bleeding (hazard ratio, 3.35; 95% CI, 1.87 to 6.01). In addition, any bleeding (major and minor) was more frequent in the combined ximelagatran group (22%) compared to the aspirin-alone group (13%) [hazard ratio, 1.76; 95% CI, 1.38 to 2.25].

Ximelagatran has been evaluated for both short-term and long-term treatment of VTE (Thrombin Inhibitors in Venous Thromboembolism studies). In the shortterm treatment study, 2,491 patients with acute DVT were treated for 6 months with ximelagatran, 36 mg bid, or LMWH followed by vitamin K antagonist therapy (INR, 2.0    to 3.0), using a blinded design. An “on-treatment” analysis suggested less major bleeding with ximelagatran (1.3% vs 2.2%; 95% CI for difference, -2.0 to + 0.2%); intention-to-treat analyses have not been reported for bleeding.

In a long-term treatment study, 18 months of ximel-agatran, 24 mg bid, was compared with placebo in 1,224 patients with DVT or pulmonary embolism who had completed 6 months of initial treatment with vitamin K antagonists. There was no apparent increase of major bleeding with ximelagatran (0.7%/yr; hazard ratio, 1.2; 95% CI, 0.4 to 3.8).

3.0    Heparins

Heparin is usually administered in low doses by subcutaneous injection to prevent venous thrombosis (prophylactic heparin), in higher doses to treat patients with acute VTE or with acute coronary syndromes (therapeutic heparin), and in very high doses in patients during open-heart surgery. In this chapter, we will discuss only bleeding associated with therapeutic heparin (see the chapter by Geerts et al for a discussion of bleeding associated with prophylactic heparin). Heparin has the potential to induce bleeding by inhibiting blood coagulation, by impairing platelet function, and by increasing capillary permeabil-ity. Heparin can also produce thrombocytopenia, but this is rarely an important cause of bleeding.

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