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Abstract & Commentary
Source: Bijsterveld NR, et al. The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular weight heparin in the initial treatment of acute coronary syndromes. J Am Coll Cardiol 2003; 42:424-427.
Low molecular-weight heparins (LMWH) now are used routinely in the emergency department treatment of patients presenting with acute coronary syndromes (ACS). However, clinical trials investigating the efficacy of LMWH in ACS used either subcutaneous (SQ) LMWH alone or an intravenous (IV) loading dose followed by subcutaneous administration of LMWH. It is unclear which regimen is superior in the treatment of ACS.
The authors of this study sought to quantify the impact of adding an IV loading dose to a SQ regimen of enoxaparin among patients with ACS by examining several in vivo and ex vivo measures of anti-coagulation among patients randomized to one of these two regimens. The measures of anti-coagulation used included anti-factor Xa levels (anti-Xa), prothrombin fragment plasma concentrations (PFC), thrombin generation time (TGT), and tissue factor pathway inhibitor activity (TFPI), a natural anti-coagulant.
Patients admitted to the coronary care unit at this Amsterdam hospital with a diagnosis of unstable angina or non-Q-wave myocardial infarction were eligible. Patients were excluded if they were using any anticoagulant or anti-platelet agent other than aspirin. Enrolled patients were randomized to 40 mg IV enoxaparin initially combined with 1 mg/kg of SQ enoxaparin twice daily (IV+SQ) or to 1 mg/kg of SQ enoxaparin twice daily (SQ). The maximum dose of enoxaparin used was 100 mg. Blood samples were obtained before the initial dose of enoxaparin and at eight other time points throughout the first 24 hours of hospitalization.
Twenty-five patients were randomized, with 14 in the IV+SQ enoxaparin group, and 11 in the SQ enoxaparin-only group. In the group receiving IV LMWH, anti-Xa levels rose within five minutes and remained significantly higher than the SQ group until six hours later. Anti-Xa levels at steady state (> 24 hours) were comparable between the groups. The highest anti-Xa levels achieved in the IV+SQ group were 1.25 U/mL (therapeutic range of enoxaparin, 0.5-1.0 U/mL). In-vitro TGT measurement showed an immediate increase in TGT in the IV+SQ group, which remained significantly higher than the SQ alone group until six hours.
Measuring in-vivo thrombin generation using PFC, the IV+SQ group had significantly lower PFC until two hours after administration. In-vivo natural anti-coagulant levels, as measured by TFPI, were significantly higher among the IV+SQ group for the first two hours, with both groups returning to baseline by six hours after administration.
The authors conclude that IV+SQ enoxaparin results in more rapid inhibition of the coagulation system than SQ enoxaparin alone during the initial phase of treatment for ACS patients. They also conclude that IV+SQ enoxaparin at these doses does not result in unacceptably high anti-coagulation levels.
Commentary by Jacob W. Ufberg, MD
This small study demonstrates a period (approximately six hours) during which superior anti-coagulation levels are achieved using a 40 mg IV bolus of enoxaparin when initiating a SQ regimen for ACS. What cannot possibly be answered by this small study is whether this earlier anti-coagulation results in any clinical benefit. Even if benefit is demonstrated by further study, we also must quantify any possible increased bleeding risks, and whether they are outweighed by the clinical benefit. While this study is a step in the right direction, far too many questions remain unanswered to know whether IV+SQ LWMH is clinically superior to SQ LMWH alone in treating patients with ACS.
Dr. Ufberg, Assistant Professor of Emergency Medicine, Assistant Residency Director, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA, is on the editorial board of Emergency Medicine Alert.