Eighteen studies (n=6,081) were included in the review. These comprised two subgroups of patients from RCTs (n=3,934), 12 prospective cohort studies (n=1,320) and 4 retrospective cohort studies (n=827).
Twelve of the 14 prospective studies had consecutive enrolment of the patients. The mean follow-up varied from 5 to 45 days in the prospective studies, but could not be determined for retrospective studies or those measuring only anti-Xa-levels. Ten of the 12 studies reporting bleeding outcomes used a priori definitions of major bleeding.
Ten studies used enoxaparin and assessed anti-Xa levels. Four studies used a therapeutic dose, three used an empirically adjusted dose and three a prophylactic dose. In three of the therapeutic dose studies, levels of anti-Xa were statistically significantly higher in patients with a creatinine clearance of up to 30 mL/min.
Two studies used tinzaparin at therapeutic doses and assessed levels of anti-Xa. Neither study found a correlation between the peak level of anti-Xa and creatinine clearance.
One study used dalteparin and assessed levels of anti-Xa. No difference between patients with renal insufficiency and those with normal renal function was found.
Major bleeding events.
Twelve studies (n=4,971) reported major bleeding events. Ten evaluated enoxaparin (n=4,741) and two evaluated tinzaparin (n=230). For all studies, severe renal insufficiency (a creatinine clearance of up to 30 mL/min) was associated with an increased risk of major bleeding (pooled OR 2.25, 95% CI: 1.19, 4.27). A sensitivity analysis excluded 2 studies that did not meet the quality criterion of using a priori definitions of bleeding. This showed an increased risk of bleeding in patients with renal insufficiency (OR: 2.17, 95% CI: 1.14, 4.16).
The pooled OR for studies using enoxaparin also showed an increased risk of major bleeding for patients with severe renal insufficiency (OR 2.59, 95% CI: 1.34, 5.01).
Studies using a therapeutic dose of enoxaparin also showed an increased risk of major bleeding for patients with severe renal insufficiency (pooled OR 3.88, 95% CI: 1.78, 8.45).
Studies using empirically adjusted doses of enoxaparin did not show any difference between patients with and without severe renal insufficiency (pooled OR 0.58, 95% CI: 0.09, 3.78).