The emerging role of low-molecular-weight heparin in cardiovascular medicine

doi:10.1053/pcad.2000.0420235

Progress in Cardiovascular Diseases

Volume 42, Issue 4, February 2000, Pages 235-246

https://doi.org/10.1053/pcad.2000.0420235 Get rights and content

Abstract

Although unfractionated heparin is widely used in the treatment of acute coronary syndromes, it has several pharmacokinetic, biophysical, and biological limitations. The practical advantages and success of low-molecular-weight heparin administered subcutaneously without laboratory monitoring for the treatment of venous thromboembolism have prompted a number of randomized studies investigating the efficacy and safety of these agents in patients with acute coronary syndromes. This article will review the limitations of unfractionated heparin and the mechanisms by which low-molecular-weight heparin overcomes these limitations, as well as the results of recent trials involving low-molecular-weight heparin in the management of patients with acute coronary syndromes. Copyright © 2000 by W.B. Saunders Company

Progress in Cardiovascular Diseases, Vol. 42, No. 4 (January/February), 2000: pp 235-246

Section snippets

Limitations of unfractionated heparin

UFH has a number of pharmacokinetic, biophysical, and biological limitations.¹⁰ Although LMWH overcomes the pharmacokinetic and some of the biological limitations of UFH (Table 1), both classes of heparin share the same biophysical limitations.

Low-molecular-weight heparins

LMWHs are fragments of UFH produced by chemical or enzymatic depolymerization processes that yield fragments approximately one-third the size of heparin.⁹ Like UFH, LMWHs are heterogeneous with respect to molecular size and anticoagulant activity. Because LMWHs are prepared by different methods of depolymerization and have different molecular weight profiles, they differ to some extent in their pharmacokinetic properties and anticoagulant profiles and, therefore, may not be clinically

Clinical experience with low-molecular-weight heparin preparations in cardiovascular disease

LMWHs have been evaluated in patients with unstable angina, acute myocardial infarction (MI), and after percutaneous coronary interventions.

Unresolved issues in low-molecular-weight heparin therapy

The unresolved issues related to the use of LMWH include (1) the need for laboratory monitoring in certain subgroups, (2) cost-benefit relative to UFH, (3) the interchangeability of the different LMWH preparations, and (4) reversal of anticoagulant effect with protamine sulfate.

One of the most appealing features of LMWHs is their more predictable dose response, which has been translated clinically into treatment with weight-adjusted dosing without laboratory monitoring. The only study that

Conclusion

Platelet deposition and thrombin generation at sites of plaque rupture lead to the formation of platelet-rich thrombi. Aspirin and UFH are limited in their ability to attenuate this process. LMWH has been evaluated in patients with acute coronary syndromes and in those undergoing percutaneous coronary interventions. This new class of anticoagulants has pharmacokinetic and biological advantages over UFH. These advantages have resulted in (1) greater convenience afforded by the ability to

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Citation Excerpt :
These are the major advantages that can potentially reduce the cost of health care.10,11 Because of the limitations of antithrombotic agents, new agents aimed at improving the safety of these medications have been developed over the last 10 years, but these did not seem to be more effective or safer than heparin.12−15 The strategies that have been used are based on the synthesis of new molecules, use of absorption promoters, intercellular junction modifications, and increases in the paracellular permeability, but these have not been successful due to the high doses needed to reach therapeutic blood concentration.
The aims of this work were preparation and physical–chemical characterization of a microparticulate release system for delivery of enoxaparin sodium (ENX), a low-molecular-weight heparin, as a potential vehicle for optimization of deep venous thrombosis therapy. Microparticles (MPs) containing ENX were prepared from polylactide-co-glycolic acid [PLGA; (50:50)] by a double emulsification/solvent evaporation method. The preparation parameters, such as proportion ENX/PLGA, surfactant concentration, type, time, and speed of stirring, were evaluated. The encapsulation efficiency and yield process were determined and optimized, and the in vitro release profile was analysed at 35 days. The MPs showed a spherical shape with smooth and regular surfaces. The size distribution showed a unimodal profile with an average size of 2.0 ± 0.9 μm. The low encapsulation efficiency (< 30%), characteristic of hydrophilic macromolecules was improved, reaching 50.2% with a procedure yield of 71.3%. The in vitro profile of ENX release from the MPs was evaluated and showed pseudo-zero-order kinetics. This indicated that diffusion was the main drug release mechanism.
Models of blood coagulation
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Our research aims to provide quantitatively transparent, biologically realistic descriptions of the processes involved in hemostasis which will permit predictions of the behavior of the coagulation system in normal and pathologic states. We use four models of coagulation: (1) numerical approximations of the tissue factor (Tf) pathway of thrombin generation based upon mechanism and dynamics; (2) Tf activation of the “blood coagulation proteome” from isolated cells and proteins; (3) Tf activated contact pathway inhibited whole blood in vitro; and (4) blood shed from standardized microvascular wounds in vivo. The results from these models are integrated in interactive assessments aimed at achieving convergence of biochemical rigor and biological authenticity. Microvascular injury is the most biologically secure but least accessible to mechanistic study. Numerical models while quantitatively transparent are biologically limited. By the integrated analyses of all four models, we establish observations which require inclusion or discovery of new parameters to achieve mechanistically interpretable biological reality. Discoveries made in this fashion have included thrombin's role in the initiation phase, TFPI/ATIII/APC synergy interactions, rfVIIa in fVII deficiency, the roles of fVIII and fIX in the Tf reaction, and the cleavage of fIX by fXa membrane. Ideally, our results will provide descriptions which predict the behavior of the biological blood coagulation system under normal and pathologic conditions.
Medical indications and considerations for future clinical decision making
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There are many well-known drawbacks associated with the currently used antithrombotic agents, warfarin, heparin, and low-molecular-weight heparins (LMWHs). Because heparins can be administered only parenterally, their application is limited. Though warfarin can be administered orally, its unpredictable anticoagulant effect means that it must be regularly monitored. Ximelagatran (Exanta™, AstraZeneca) is a novel, oral direct thrombin inhibitor (oral DTI) that is rapidly converted to its active form, melagatran, upon administration. The antithrombotic effects of melagatran have been demonstrated. Following the oral administration of ximelagatran, melagatran has stable and reproducible pharmacokinetic and pharmacodynamic properties that enable ximelagatran to be administered orally, twice daily, according to a fixed-dose regimen, with no need for routine coagulation monitoring. In view of its favourable profile, a clinical trial programme has been designed to evaluate the efficacy and tolerability of ximelagatran compared with standard therapies, for the prophylaxis and treatment of venous thromboembolism (VTE), the prevention of stroke in patients with atrial fibrillation (AF), and the prevention of cardiovascular events in patients with previous acute coronary syndromes. These studies show that oral ximelagatran is well tolerated at doses of up to 60 mg, twice daily (bid), and that it is as effective as standard therapy for the prevention of thromboembolic events in patients undergoing hip or knee replacement surgery, for the treatment of clinically verified acute deep vein thrombosis (DVT), and in patients with nonvalvular AF who have a moderate to high risk of stroke. The protocols and results of some of these studies—and a study that investigates the use of ximelagatran in combination with aspirin for the management of acute coronary artery disease—are described in this paper.
A novel approach to thrombin inhibition
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The inability of the heparin–antithrombin complex to inhibit fibrin-bound thrombin limits the utility of heparin for treatment of arterial thrombosis. In contrast with heparin, melagatran, a direct thrombin inhibitor (DTI), is equally effective at inhibiting fluid-phase thrombin and thrombin bound to fibrin. This reflects the ability of melagatran, a reversible, active site-directed DTI, to access the active site of thrombin even when it is fibrin-bound. Because bivalent DTIs, such as hirudin, compete with fibrin for access to the fibrin-binding site on thrombin, bivalent DTIs produce less inhibition of fibrin-bound thrombin than free thrombin when given in low doses. Consequently, higher doses of hirudin are needed for complete inhibition of fibrin-bound thrombin resulting in a steep dose–response curve. This phenomenon, combined with the fact that hirudin irreversibly inhibits thrombin, may account for hirudin's narrow therapeutic window. In a rabbit arterial thrombosis prevention and ear bleeding model, melagatran produced less bleeding than hirudin when the two agents were given at doses that produced nearly complete inhibition of thrombosis. The more favourable benefit-to-risk profile of melagatran in this model likely reflects better access to fibrin-bound thrombin and the reversible nature of the melagatran/thrombin complex. The theoretical advantages of melagatran may endow it with mechanistic advantages over heparin, and safety advantages over hirudin. Large-scale clinical trials are under way to evaluate the utility of an orally active prodrug form of melagatran for prevention and treatment of venous and arterial thrombosis.
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Heparin and the vitamin K antagonist warfarin have been in clinical use for more than 50 years. However, both are associated with several well-documented drawbacks that limit their use. Warfarin can be administered orally, making it the agent of choice for long-term management of thromboembolic conditions, but frequent coagulation monitoring is necessary because of its unpredictable anticoagulant effect—the result, in part, of food and drug interactions—and its narrow therapeutic window. Heparin and low-molecular-weight heparin (LMWH) can be administered parenterally only. Coagulation monitoring is also required with heparin although not with LMWH, due to reduced levels of plasma protein binding.
In the last 10 years, in the quest to develop new agents that are at least as effective as those currently available, with improved safety and greater ease of use, anticoagulants that target almost every step in the coagulation pathway have been developed. These include inhibitors of the factor VIIa (FVIIa)/tissue factor complex, FIXa inhibitors, direct and antithrombin-dependent FXa inhibitors, agents that enhance the protein C anticoagulant pathway, and direct thrombin inhibitors (DTIs) that inhibit the activity of thrombin. Of the new agents, three DTIs—hirudin, bivalirudin, and argatroban—and the synthetic pentasaccharide (Arixtra) are approved for clinical use. Three other new agents—activated protein C (APC), tissue factor pathway inhibitor (TFPI), and the oral DTI ximelagatran (Exanta™, AstraZeneca)—have been evaluated in Phase III studies. The mechanism of action and properties of these new anticoagulants and their potential to replace those in current use will be reviewed here.
The use of low-molecular-weight heparins in outpatient oral surgery for patients receiving anticoagulation therapy
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Citation Excerpt :
The antidote is protamine sulfate. With unfractionated heparin there is a potential for drug-induced thrombocytopenia and thromboembolic disease.6–12 In cases in which patients receive unfractionated heparin, the patient usually is admitted to the hospital a few days before the surgical procedure, oral anticoagulation therapy is discontinued, and intravenous, or IV, heparin therapy is initiated.
When planning oral surgery, dentists occasionally will have patients who first need to have their anticoagulation regimen altered. To minimize the side effects and not adversely affect the patient’s health, therapeutic anticoagulation should be interrupted for as short a time as possible. Low-molecular-weight heparins, or LMWHs, recently have emerged as an alternative in the management of patients whose anticoagulant status should not be modified for lengthy periods.
A 72-year-old man, who had a history of deep venous thrombosis, needed to have 19 teeth extracted and an alveoloplasty performed. An LMWH was substituted for warfarin a few days before surgery, and it was withheld from the patient for only a few hours the day of the surgery.
LMWHs are administered on an outpatient basis and do not require hospitalization, as does unfractionated heparin. As a result, they are more cost-effective and offer greater convenience than heparin therapy. Depending on the procedure and the degree to which patients are medically compromised, dentists may not feel comfortable treating patients who continuously receive anticoagulation therapy. As a result, patients’ physicians may prescribe LMWH injections to be administered by patients, family members or caregivers to more safely manage the patients’ care during oral surgery. As part of the health care team, dentists must be familiar with LMWH and its use to help guide patients safely through treatment.

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The emerging role of low-molecular-weight heparin in cardiovascular medicine

Abstract

Section snippets

Limitations of unfractionated heparin

Low-molecular-weight heparins

Clinical experience with low-molecular-weight heparin preparations in cardiovascular disease

Unresolved issues in low-molecular-weight heparin therapy

Conclusion

Biochem Biophys Acta

J Biol Chem

J Biol Chem

J Biol Chem

Blood

Thromb Res

Chest

Chest

Blood

Blood

Am J Obstet Gynecol

Am J Obstet Gynecol

Blood

Blood

Thromb Res

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Thromb Res

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

Coronary plaque disruption

Circulation

The pathogenesis of coronary artery disease and the acute coronary syndromes

N Engl J Med

Pathogenesis of thrombosis

Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home

N Engl J Med

A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis

N Engl J Med

Low-molecular-weight heparin in the treatment of patients with venous thromboembolism

N Engl J Med

A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism

N Engl J Med

Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis

N Engl J Med

Low-molecular-weight heparins

N Engl J Med

Heparin

N Engl J Med

Heparin binding to plasma proteins, an important mechanism for heparin resistance

Thromb Haemost

Histidine-rich glycoprotein modulation of the anticoagulant activity of heparin

J Biol Chem

Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo

J Clin Invest

A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin

Arch Intern Med

The elimination from plasma of intravenous heparin. An experimental study on dogs and humans

Acta Med Scand

Heparin kinetics determined by three assay methods

Clin Pharmacol Ther

Studies on the heparin sulphamidase activity from rat spleen. Intracellular distribution and characteristics of the enzyme

Biochem J

Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis

N Engl J Med

Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction

N Engl J Med