Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients with Severe Renal Insufficiency

Context The risks of low-molecular-weight heparin (LMWH) in patients with severe renal insufficiency are not clear. Contribution In this review of 12 studies, patients with severe renal insufficiency receiving LMWH had an increased risk for major bleeding events. Four studies found that fixed-dose enoxaparin had greater anticoagulant effects in these patients. Three studies suggested that empirically dose-adjusted enoxaparin might not increase anticoagulant effects. Cautions Evidence relating to LMWHs other than enoxaparin was scant. Implications Patients with severe renal insufficiency receiving standard fixed-dose enoxaparin have greater anticoagulant effects and a higher risk for major bleeding. Empirical dose adjustment may reduce the risk for such events. The Editors One of the most important advantages of low-molecular-weight heparin (LMWH) compared with unfractionated heparin (UFH) is its predictable anticoagulant response, which allows it to be administered in fixed, weight-based doses without laboratory monitoring. When used to treat patients with acute venous thromboembolism, LMWH is associated with lower rates of recurrent thrombosis, bleeding, and death than is weight-adjusted, monitored UFH (1, 2). These advantages have revolutionized management of acute venous thromboembolism by allowing most patients to be treated out of hospital. Low-molecular-weight heparin has also greatly simplified in-hospital management of selected patients with venous thromboembolism and those with acute coronary syndromes. However, uncertainty still surrounds use of LMWH in patients with severe renal insufficiency because it is excreted by the kidneys (3) and, unlike UFH, its anticoagulant effect cannot be completely reversed. Although most randomized trials of LMWH excluded patients with renal insufficiency (4), pharmacokinetic studies suggest an association between creatinine clearance and levels of anti-factor Xa heparin (which measures the anticoagulant effect of LMWH), and increased bleeding complications have been reported when LMWH is used in patients with chronic renal insufficiency (5, 6). Because of concerns about the risk for accumulation and bleeding in patients with renal impairment, the American College of Chest Physicians and the College of American Pathologists recommend UFH instead of LMWH in patients with a creatinine clearance of 30 mL/min or less, or monitoring of anti-Xa activity if LMWH is used (4, 7). However, the evidence for this recommendation is conflicting (8) and there are no reliable data to guide the interpretation of anti-Xa levels to monitor treatment or to adjust LMWH doses (7). Despite this limitation, anti-Xa levels are the only available method to monitor LMWH activity and their use in clinical practice is based on consensus recommendations. Peak anti-Xa levels occur 4 hours after a therapeutic dose of subcutaneous LMWH is administered. Peak levels above the upper limit of the recommended therapeutic range (0.6 to 1.0 IU/mL) may be associated with an increased risk for bleeding (4). To further clarify the relationship between LMWH anti-Xa levels and creatinine clearance and the risk for bleeding in patients with a creatinine clearance of 30 mL/min or less, we performed a systematic review of all studies of LMWH in nondialysis-dependent patients with varying degrees of renal function that reported creatinine clearance and anti-Xa levels or major bleeding events. Methods This study was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (9). Study Identification We attempted to identify all published and unpublished studies of LMWH in nondialysis-dependent patients with renal insufficiency using the MEDLINE (1966 to week 3 of November 2005), EMBASE (1980 to 2005, week 51), and Cochrane Library (2005, Issue 4) electronic databases. The search was completed on 19 December 2005. The search strategy, which had no language restrictions, was developed in collaboration with a professional librarian (Appendix). We manually reviewed the reference lists of all retrieved articles and contacted content experts for additional published or unpublished trials. Study Selection Study selection was performed independently and in duplicate; disagreements were resolved through discussion. Studies were included if they 1) had at least 10 patients; 2) involved patients with varying degrees of renal function, including those with a creatinine clearance of 30 mL/min or less; 3) administered at least 1 dose of a commercially available LMWH; and 4) reported at least 1 of the following outcomes: anti-Xa levels or major bleeding. Studies were excluded if patients were dialysis-dependent, if LMWH was administered intravenously, if more than 1 LMWH preparation or dose (for example, prophylactic and therapeutic doses) were used, and if the data for anti-Xa or bleeding for individual LMWH preparations or doses could not be separately analyzed. Study Quality Assessment Two unmasked investigators independently assessed study quality according to the following criteria: 1) method of patient enrollmentstudies with consecutive patient enrollment were considered to be of higher quality than those with nonconsecutive enrollment; 2) duration and completeness of patient follow-up for major bleeding studies with longer and more thorough follow-up were considered to be of higher quality because major bleeding outcomes are more accurately reported; and 3) method of outcome ascertainmentstudies in which bleeding was objectively and reproducibly assessed by using a priori definitions were rated higher than those that did not use bleeding definitions or those that had unclear or nonobjective methods of measurement. Data Extraction Two unmasked investigators independently extracted data on study design, patient characteristics, renal function, type and dose of LMWH, anti-Xa levels, and number of major bleeding episodes. Data were extracted in duplicate, and disagreements were resolved through discussion. We defined a creatinine clearance of 30 mL/min or less as severe renal insufficiency, calculated by using the CockcroftGault (10) or Modification of Diet in Renal Disease (MDRD) (11) equation. For studies that adopted other thresholds to define severe renal failure or those that reported only mean creatinine clearance, we contacted the authors to obtain the data corresponding to a creatinine clearance threshold of 30 mL/min. We extracted peak anti-Xa levels 4 hours after subcutaneous injection of LMWH because peak levels correlate more strongly with efficacy and safety than do trough levels (12). Because maximum LMWH activity (Amax) is observed at 4 hours, Amax data were considered equivalent to 4-hour anti-Xa levels. A meta-analysis of anti-Xa levels at 4 hours was not performed because measures of variance were not reported in most studies, thereby precluding pooling of the data. We report the anti-Xa data according to LMWH type because differences in molecular weight and charge density of LMWH may result in differences in renal clearance and anti-Xa levels (13, 14). The LMWHs, such as tinzaparin, that are structurally similar to UFH may be less prone to accumulate in patients with renal insufficiency than smaller, less negatively charged LMWHs, such as enoxaparin. We accepted the definitions of major bleeding reported by authors and did not reclassify events. Therapeutic doses of LMWH (enoxaparin, 1.5 mg/kg of body weight once daily or 1 mg/kg twice daily; tinzaparin, 175 IU/kg once daily; dalteparin, 200 IU/kg once daily or 100 IU/kg twice daily) and prophylactic doses (enoxaparin, 40 mg once daily or 30 mg twice daily) were defined according to the product monographs. Adjusted-dose LMWH was defined as any dose that was modified empirically or according to renal function or measured anti-Xa levels. If the required data could not be extracted from the published report, we contacted the corresponding author by e-mail to request additional data. If a response was not received after 15 days, we sent a second e-mail; if we still received no response, we contacted secondary authors. Statistical Analysis To assess the agreement between reviewers for study selection, we used the k statistic, which measures chance-corrected agreement (15). The odds ratio for major bleeding in patients with and without severe renal insufficiency treated with LMWH was calculated for each study and pooled with the Peto method (fixed-effects) by using Review Manager, version 4.2 (RevMan, Oxford, United Kingdom; the Cochrane Collaboration, 2003). Statistical heterogeneity was evaluated by using the I2 statistic, which measures the extent of inconsistency among study results and describes the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error. We preferred the Peto method to other statistical approaches for combining odds ratios because it provides relatively unbiased estimates of treatment effects when the event rates are low. We also calculated a pooled risk difference and 95% CIs by using exact statistical methods for stratified 2 2 tables. Two a priori secondary analyses were performed. The first compared major bleeding according to LMWH type because accumulation may vary among different preparations in patients with renal insufficiency (13, 14). The second compared major bleeding according to LMWH dose. Because bleeding is correlated with the intensity of anticoagulation, studies using therapeutic doses reported higher bleeding rates than those using prophylactic doses. A sensitivity analysis that included only high-quality studies was performed to assess the robustness of our primary results. A funnel plot of effect size versus standard error was used to assess possible publication bias (16). Role of the Funding Source No funding was received for this study. Results Study Identification and Selection Our search identified 875 published studies (219 from