Epilogue

During the last two decades, interest in low-molecular-weight heparin (LMWH)-related drugs has grown dramatically, as evidenced by a continual increase in the number of indications for these drugs. The developments are occurring so fast that an update on the additional information on these agents warrants continual review. The outstanding scientific research and development activities in the academic centers and pharmaceutical industry have resulted in a steady flow of these products. Third-party validation of developed products and extensive clinical trials have been performed globally to validate the claims on the safety and efficacy of several LMWHs. The results of these studies constitute a significant portion of the progress reported at scientific forums. Through their fast track and revised policies, the regulatory bodies such as the European Medicine Evaluation Agency (EMEA), US Food and Drug Administration (FDA), and other regional agencies have continually contributed to the timely evaluation and approval of the newer indications by providing input at various stages of drug development. The concept of polytherapy, including combination with LMWHs and different drugs, has been introduced.

Owing to these rapid developments, several important issues related to current practices in the clinical use of LMWH therapy have been recognized. These issues include:

The replacement of unfractionated heparin (UFH) by LMWHs in all indications. The potential replacement of heparins by newly developed anti-thrombin and anti-Xa agents. The development of synthetic heparinomimetics representing specific actions of heparins and their relative bioequivalence to heparin. The introduction of generic equivalents of the branded LMWHs to reduce the cost.

Despite several limitations, UFH is still the most widely used anticoagulant in the United States. Several oral formulations of heparin have been developed and tested in clinical trials. Although effective, the oral formulations of heparin failed to exhibit comparable efficacy to LMWHs in the management of deep venous thrombosis (DVT). In addition, several other chemically modified forms of heparin did not exhibit the expected pharmacologic effects in both preclinical and clinical settings. The LMWHs represent an optimal approach of using heparin components. It may be that the oral formulations exhibit efficacy in other indications and additional studies are needed to validate the use of LMWHs in oral formulations.

Although UFH remains the sole anticoagulant used for cardiovascular surgical procedures, the continual expansion of the newer applications of LMWHs has added a new dimension to the overall management of thrombotic and cardiovascular disorders. Evidently, the LMWHs have achieved gold standard status in the management of thromboembolic disorders and now challenges other treatments, such as oral anticoagulants, for various indications. Several recent clinical trials have provided supportive data for the polytherapeutic use of LMWHs in the management of coronary syndromes, thrombotic stroke, malignancy-associated thrombotic events, and cerebrovascular indications. LMWHs have also shown efficacy as surgical and interventional anticoagulants. However, only very limited data are available on the use of these agents in cardiopulmonary bypass surgery. This may be due to the nonavailability of a specific antagonist for these drugs. Unlike UFH, LMWHs exhibit a better therapeutic index in these indications. LMWHs also have recently been evaluated in atrial fibrillation and cardiac transplantation. These drugs represent a refined use of heparins. Being polypharmacologic in nature, the LMWHs have multiple sites of action. Their actions are limited to not only the inhibition of coagulation enzymes, but they also exhibit profound actions on endothelial sites and blood cells. This has led to the development of the non-anticoagulant forms of LMWHs. Anti-thrombin agents such as hirudin and hirulog also have been compared with LMWHs for postsurgical prophylaxis of thromboembolism. Initial reports indicate favorable results with the use of recombinant hirudin for treatment of coronary syndromes. However, safety issues such as bleeding remain a concern.

Understanding the mechanisms of antithrombotic actions and the relevance of structural components of LMWHs has led to the development of synthetic analogs of heparin fragments. One remarkable approach based on the elucidation of the structure of heparin has led to the synthesis of oligosaccharides with high affinity for antithrombin. A synthetic pentasaccharide has undergone extensive clinical trials for both thromboembolic and coronary indications. It is expected that this pentasaccharide and related drugs may be used in additional indications in monotherapeutic and polytherapeutic approaches.

Although the development of the synthetic pentasaccharide represents a major advance in producing heparin-like drugs using synthetic organic methods, this agent produces only a single pharmacologic action of heparin. Furthermore, the pharmacologic actions of these oligosaccharides are dependent on endogenous antithrombin. The FDA and EMEA have recently approved the use of the synthetic heparin pentasaccharide, Arixtra, for the management of post-orthopedic surgical thrombosis. However, the bleeding risk was unexpectedly higher with this drug, and its use is not recommended in underweight patients. The pentasaccharide is likely to be equivalent to other modalities in the management of DVT prophylaxis; however, its use in other indications for which LMWHs are approved may not provide equivalence or superiority. Several additional clinical trials are being performed on the pentasaccharide in multiple indications including treatment of thrombosis. In addition to the lack of a clear clinical response, bleeding issues, nonavailability of an antidote, drug interactions, product accumulation, and thrombocytopenia are some of the issues that will require clarification. The current clinical trials may provide some of the answers for these issues.

There is much discussion about how LMWHs and related drugs mediate their effects. In addition to potentiation of antithrombin, several other mechanisms have been identified, including the release of tissue factor pathway inhibitor (TFPI), vascular effects, profibrinolytic effects involving the mediation by thrombin activatable fibrinolytic inhibitor (TAFI), platelet selectin modulation, and growth factor modulation. Recently published data also suggest that LMWHs may regulate cellular function.

Clinical trials in Europe have shown that subcutaneous LMWH, given once or twice daily, is at least as safe and effective as continuous intravenous UFH in the prevention of recurrent venous thromboembolism and is associated with reduced bleeding and lower mortality rates. Several recent studies have shown that home administration of LMWHs is as safe and effective as hospital administration of intravenous UFH in patients with proximal vein thrombosis. Initial evidence clearly suggests that the LMWHs may be a useful alternative to UFH in patients with pulmonary embolism. LMWHs also may be useful alternatives to UFH for arterial indications, such as treatment of unstable angina, stroke, and the maintenance of peripheral arterial grafts.

Recognizing the usefulness of LMWHs, the pharmaceutical industry has focused its attention on their use in the management of ischemic and thrombotic strokes. The success of early clinical trials also suggests that LMWHs may be useful in the management of primary and secondary ischemic or thrombotic strokes. Although in several clinical trials the LMWHs did not show any improvement in the outcome of strokes, these drugs showed a clear reduction in the incidence of thrombotic complications in stroke patients. Thus, in the near future, the use of LMWHs for prevention of thrombotic or ischemic strokes will be an important goal. LMWHs have also shown efficacy in vascular senile dementia, Alzheimer's type (SDAT). Thus, these drugs may become useful in neurologic disorders.

There are several studies on the administration of LMWHs during pregnancy. The pharmacokinetic and pharmacodynamic behavior of different LMWHs is product specific. However, on the whole these drugs have been useful in the management of thrombotic complications during pregnancy. Optimized dosing studies are needed and monitoring issues require resolution. With additional well-designed studies and some specific data on safety, the LMWHs may be useful in the management of pregnancy-associated thrombosis. Similarly, in pediatric populations there is a need for specific studies because the pharmacokinetic and pharmacodynamic behavior of these drugs is markedly different in children.

Although LMWHs are proving to be as effective as or safer than UFH for various indications, it is important to realize that the differences in the manufacturing of various LMWHs lead to differences in their pharmacological profile. Although these differences have not been clinically validated, each LMWH is expected to exhibit its own therapeutic index in a given clinical setting. Thus, the interchanging of LMWHs on the basis of equivalent gravimetric or biologic potency of standardized dosages may not be valid as recognized by the FDA, World Health Organization (WHO), and many professional societies. Optimized dosages of various LMWHs have been established for prophylaxis and treatment of DVT. Thus, each agent is given at a specified dosage. The optimized dosage of different LMWHs also differs for the management of acute coronary syndromes. The most notable differences are observed at higher dosages. When these agents are given intravenously for interventional cardiovascular procedures, each one of the LMWHs produces a different anticoagulant response, regardless of the dosage equivalence at the gravimetric or bioassay adjusted potency.

Because of the newer indications and length of therapy, some additional issues related to the optimal use of LMWHs remain to be addressed. Examples include monitoring, control of bleeding and drug interactions. In addition, the use of high-dose subcutaneous LMWHs may require pharmacologic antagonism. Several clinical trials have been designed to obtain information related to these issues. The differential clinical efficacy of various LMWHs was evident in the trials performed with dalteparin (Fragmin during Instability in Coronary Artery Disease [FRISC] and Fragmin in Unstable Coronary Artery Disease [FRIC]), enoxaparin (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events [ESSENCE]), and nadroparin (Fraxiparin versus Unfractionated Heparin in Acute Coronary Syndromes [FRAXIS]) for acute coronary syndrome. Similarly, in percutaneous intervention the dosing of enoxaparin and dalteparin is different for optimal anticoagulation.

The LMWHs have also shown remarkable clinical efficacy in the management of cancer-associated thrombosis (Enoxaparin Alone versus Enoxaparin followed by Warfarin in the Secondary Prevention of Venous Thromboembolism in Patients with Malignancy [ONCENOX] and Comparison of Low Molecular Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent VTE in Patients with Cancer [CLOT] trials). In addition, some of these clinical trials have shown that these drugs reduce mortality in cancer patients. Thus, in addition to the anticoagulant effects, there may be additional actions of these agents that warrant further investigation. Another use of these agents in cancer patients is with such chemotherapeutic agents such as thalidomide that produce thrombotic complications. Many other drugs used in cancer patients, such as erythropoietin and other cytokines, also produce thrombotic complications. These drugs can also be coadministered with LMWHs.

Economic analyses of the treatment cost in various clinical settings show that although the cost of LMWHs is higher than the cost of UFH ($150 versus $40), the expected reduction in costs for all treatment-related clinical events is much higher for LMWHs ($350 to $2700) than for UFH. Thus, LMWHs are an attractive alternative in an era of managed health care reform. Individual economic analyses for specific indications may provide additional information about reduced costs with the use of LMWHs for long-term outpatient treatment of such syndromes as unstable angina and ischemic cerebral events. There is also a cost differential for specific LMWHs. In addition, in some countries such as India and Brazil, generic versions of enoxaparin have become available at considerably lower cost. Thus, it is quite conceivable that generic versions of branded products may be introduced at relatively lower costs in different countries.

The pharmaceutical industry has played a key role in providing less expensive equivalents of original branded drugs that would not have been otherwise accessible to a large group of patients. Thus, the generic drugs have a major public health importance. Recognizing this, President Bush has already announced the expansion of the Office of Generic Drugs. Thus, at the federal government level there is endorsement of the development of generic drugs, and an effort is being made to have them accessible to all patients.

Recently, the FDA accepted the application for a generic version of enoxaparin (Lovenox®, Aventis, Bridgewater, NJ) from Amphastar, Inc. (Rancho Cucamonga, CA), who filed a certificate against one of two patents for enoxaparin. However, the FDA cannot approve the generic version before the drug's second patent expires on December 24, 2004. Another generic company, Teva Pharmaceutical (North Wales, PA), submitted an abbreviated new drug application (ANDA) against the same enoxaparin patent on June 30, 2003. Gland Pharma (India) has introduced the Cutenox brand of generic enoxaparin in India. The same generic version of enoxaparin is also available in Brazil. Several other companies throughout the world are considering the development of generic versions of the branded LMWHs.

The regulatory bodies may eventually allow generic versions of LMWHs and apply the same or expanded guidelines as for other biologicals. This may result in generic products that will meet these specifications, but in fact, they may not be the same and may therefore behave differently in clinical settings. It is important, therefore, to have additional requirements to provide supplementary chemical and biological data to support the filing of a generic version of a branded drug. Clinical trials may or may not be required for specific products for approved indications, depending on the filing process to evaluate data for the FDA review.

It is clear that generic versions of branded products will gain regulatory approval in coming years. However, it is important that the generic products should be manufactured in strict compliance with the manufacturing specifications of the branded product. Furthermore, regulatory agencies should require additional data on the chemical, biological, pharmacologic/toxicologic, and dose-response relationship in specific settings.

Additional depolymerization of LMWHs has resulted in the development of ultralow LMWHs. Several of these have recently become available. Bemiparin represents such a product that has been found efficacious in the management of DVT in Europe. Several other agents are being clinically tested in indications such as vascular dementia, inflammatory bowel disease, and acute coronary syndromes.

The coming years will witness dramatic developments in the management of thrombotic and cardiovascular disorders. LMWHs and related drugs will provide cost-effective and clinically useful compounds. LMWHs and synthetic heparin analogs are expected to have significant effects on the overall management of thrombotic and cardiovascular disorders. Factors such as managed care, regulatory issues, polytherapy, and combined pharmacologic and mechanical approaches will redirect the focus in management of venous thromboembolism, myocardial infarction, and thrombotic strokes. Postsurgical control of the thrombotic processes may require combination therapy and heparin-derived agents such as the pentasaccharide and nonheparin glycosaminoglycans such as dermatan sulfate. Biotechnology-derived heparin analogues will also be developed.

Conventional drugs such as UFH and LMWHs will remain the gold standards despite their known limitations. They require further optimization and can be used for various indications in a cost-effective manner. The newer drugs such as the anti-thrombin drugs, however, provide alternatives for heparin-compromised patients such as those suffering from heparin-induced thrombocytopenia. LMWHs will also be used with such non-anticoagulant drugs as cholesterol-lowering agents (statins), specific inhibitors of cyclooxygenase, drugs capable of donating nitric oxide or upregulating its mediators, and drugs modulating endothelial function. The LMWHs in combination therapy will have a major influence on the future management of thrombotic and cardiovascular diseases.