Enoxaparin Dosing in ACS Often Varies From Labeling, Can Raise Bleeding Risk

July 27, 2007 — Almost half of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) who received enoxaparin (Lovenox, Sanofi-Aventis) were given doses that were either higher or lower than what the labeling recommends, in a US registry analysis that also tied "excess" dosing to an increased in-hospital risk of serious bleeding.
Evidence-based guidelines for anticoagulation in acute coronary syndromes (ACS) tend to spend more time on choice of agent than on appropriate dosing, observed lead author Dr Nancy M Allen LaPointe (Duke University Medical Center, Durham, NC). But, she told heartwire, "It's important that we not just look at getting the appropriate drugs into the patients, but also that we try to get the most appropriate dose into the patients so we can maximize both efficacy and safety." The analysis, based on the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) registry, appears in the July 23 Archives of Internal Medicine.
"Lower-than-recommended" enoxaparin dosing didn't significantly affect the adjusted in-hospital risks of bleeding or death in the analysis, but that doesn't mean it was without cost. The analysis, Allen LaPointe observed, didn't look at reinfarction or other endpoints with more relevance to inadequate anticoagulation.
Of the 10,687 CRUSADE patients who received enoxaparin for NSTE-ACS, 47.3% received a dosage that varied from the recommended 2 mg/kg/day (or 1 mg/kg/day if creatinine clearance <30 mL/min) by more than 10 mg; the dosage was excessive in 18.7% and lower-than-recommended in 29.2% of the total.
The increased major-bleeding risk among patients getting excessive enoxaparin was significant at p<0.001 after adjusting for patient history, features, and drug and procedure-based therapies. All-cause mortality was also raised, but the difference fell short of significance at p=0.06. Lower-than-recommended dosing appeared to increase the all-cause mortality risk, but the difference wasn't significant after adjustment for patient characteristics and therapies.
Odds ratios* (95% CI) for major bleeding and death among patients receiving excess and lower-than-recommended enoxaparin dosing in CRUSADE
*Adjusted for age; sex; body-mass index; history of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft (CABG), heart failure, and stroke; smoking status, hematocrit, renal function, acutely received medications; and procedures performed.† Major bleeding defined as intracranial or retroperitoneal bleeding, a >12% reduction in hematocrit, red blood cell transfusion when hematocrit is increased or decreased. Cohort excludes patients transferred to other hospitals or who underwent CABG.‡ Cohort excludes patients transferred to other hospitals.
Although the analysis doesn't address why dosing was often excessive, one possible reason, Allen LaPointe said, may have been that some practitioners failed to appropriately consider creatinine clearance. In the analysis, about 58% patients who received excessive enoxaparin had an initial creatinine clearance <30 mL/min, the threshold for going from a full dose to a half dose. As for the remaining 42%, she speculated, perhaps the practitioners didn't have an accurate weight for the patient, or they didn't adjust the dosage in response to changes in creatinine clearance over time.
The analysis was partially supported by Millennium Pharmaceuticals. The CRUSADE initiative "is funded by Schering-Plough Corporation and Bristol-Myers Squibb/Sanofi-Aventis Pharmaceuticals partnership." Allen LaPointe reports receiving a research funding or support from Pfizer and Merck and an honorarium from Sanofi-Aventis for speaking. Disclosures for other coauthors appear in the report.
Arch Intern Med. 2007;167:1539-1544.

Enoxaparin Outdoes Heparin for Post-Stroke Venous Thromboembolism

SAN ANTONIO, Tex., April 20 -- Enoxaparin (Lovenox), a low molecular-weight heparin, proved more effective than unfractionated heparin for preventing potentially fatal leg and lung clots after acute ischemic stroke, researchers reported.
In a head-to-head study of 1,762 stroke patients unable to walk unassisted, enoxaparin was 43% more effective at preventing venous thromboembolism than unfractionated heparin, David G. Sherman, M.D., of the University of Texas here, and colleagues reported in the Apil 21 issue of The Lancet.
The results of this study, Dr. Sherman concluded, suggest that for patients with acute ischemic stroke, enoxaparin is preferable to unfractionated heparin for venous thromboembolism prophylaxis in view of its better clinical benefits-to-risk ratio and convenience of once daily administration.
Venous thrombembolism with either low-molecular-weight heparin or unfractionated heparin is recommended for acute ischemic stroke, but because large studies are lacking, it has been uncertain which is the better regimen, Dr. Sherman said.
To compare the efficacy and safety of the drugs, the researchers undertook a large, 15-nation multinational randomized study (PREVAIL), sponsored by Sanofi-Aventis, maker of enoxaparin.
Within 48 hours of symptoms, 666 patients were given enoxaparin (40 mg subcutaneously) once daily for 10 days, while 669 got unfractionated heparin (5,000 U subcutaneously) every 12 hours, for 10 days (range for all, six to 14 days).
The patients were stratified by the National Institutes of Health Stroke Scale (NIHSS) (severe stroke ≥14, less severe stroke <14).
Enoxaparin reduced the risk of venous thromboembolism by 43% compared with unfractionated heparin (68 [10%] versus 121 [18%]; relative risk 0.57, 95% CI 0.44-0.76, P=0.0001; difference -7.9%, -11.6 to -4.2).
The greater reduction with enoxaparin was consistent for patients with an NIHSS score of 14 or more (26 [16%] versus 52 [30%]; P=0.0036) or less than 14 (42 [8%] versus 69 [14%]; P=0.0044).