Heparin and Low Molecular Weight Heparins
Heparin has been the established therapy for prevention and treatment of thrombotic disorders for many years and the cornerstone of this therapy has been unfractionated heparin (UFH). Although safe and effective, there are substantial problems with UFH, including the need for regular laboratory monitoring, wide differences in responses between patients and the small risk of heparin-induced thrombocytopenia. Low molecular weight heparins (LMWH) circumvent some of these problems and are increasingly used as substitutes for UFH in clinical practice.
Both UFH and LMWH are polysaccharide structures (glycosaminoglycans); UFH consists of chains of widely varying length (molecular weight (MW) 3000 to 30 000) while LMWH contains shorter chains with a mean MW between 4000 and 6000 (for review see ref. 1). Antithrombin is the molecular target of heparin and when it is activated it binds either thrombin (activated factor II; factor IIa) or activated factor X (factor Xa). Any heparin chain that contains a specific pentasaccharide sequence (about 1/3 of UFH and 15-25% of LMWH chains) can bind and activate antithrombin and no further action is required to bind and inhibit factor Xa. In contrast, inhibition of factor IIa requires long heparin chains which are more prevalent in UFH than in LMWH. Hence, the ratio of anti-Xa:anti-IIa activity is higher for LMWH (1.9 to 3.8) than for UFH (about 1).
Other features of LMWH, which differ from those of UFH, include greater bioavailability after subcutaneous administration (about 100%), longer half-life, dose-independent clearance and more predictable anticoagulant response due to these factors as well as less binding to plasma proteins and vascular cells. Thus for the vast majority of patients laboratory monitoring (of anti-factor Xa activity) is not required, even with therapeutic doses of LMWH.
Low molecular weight heparins are safe and effective for the prevention and treatment of venous thrombosis in patients with medical and surgical conditions and have largely replaced UFH in this regard (for review see ref. 1). Recent studies have suggested that they may also replace UFH in the treatment of acute coronary syndromes.
Although intravenous unfractionated heparin has been standard therapy for unstable angina for many years, doubts about its superiority to aspirin alone led to a placebo-controlled trial of LMWH (high-dose subcutaneous dalteparin for 6 days followed by a moderate dose for 35-45 days) versus placebo (FRISC) 2. The primary end-point, the rate of death and new myocardial infarction at 6 days, was lower in the dalteparin group than in the placebo group (13 [1.8%] vs. 36 [4.8%]) and differences persisted to 40 days. The FRIC study 3 showed that a similar dalteparin regime was as effective as, but not more effective than, UFH. During the first 6 days, the rate of death, myocardial infarction, or recurrence of angina was 7.6% in the UFH-treated patients and 9.3% in the dalteparin-treated patients; the corresponding rates in the two treatment groups for the composite of death or myocardial infarction were 3.6% and 3.9%, respectively. In contrast, in the ESSENCE study4 the rate of death, MI or recurrent angina at 30 days was significantly lower following treatment with enoxaparin for a mean of 2.6 days, compared with UFH (19.8% vs. 23.3%). The differences in clinical efficacy in the treatment of acute coronary syndromes between dalteparin and enoxaparin may at least in part be expained by their antiXa:IIa ratios, which is higher with enoxaparin.
Current studies are investigating the efficacy and safety of LMWH compared with UFH following fibrinolytic therapy for acute MI. Preliminary evidence suggests that LMWHs are as safe and probably as effective as UFH 5. There is still some debate as to whether heparin and aspirin are more effective than aspirin alone after fibrinolytic therapy.
References
1. Weitz JI. Low molecular weight heparins. N Engl J Med 1997; 337: 688-98
2. The FRISC Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561–8
3. Klein W, Buchwald A, Hillis SE et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Circulation 1997; 96: 61–8
4. Cohen M, Demers C, Gurfinkel EP et al. Low molecular weight heparin versus unfractionated heparin for unstable angina and non-Q wave myocardial infarction. N Engl J Med 1997; 337: 447–52
5. Baird SH, McBride SJ, Trouton TG, Wilson C. Low molecular weight heparin versus unfractionated heparin following thrombolysis in myocardial infarction (abstract). J Am Coll Cardiol 1997; 31 (suppl. A): 191A.
Niall Herity, M.D.