Current Development in Antithrombotic Therapy

The last few years have seen the development of several new anticoagulant and antiplatelet drugs that are designed to replace the traditional unfractionated heparin and warfarin. Some of these compounds have been approved for specific clinical diseases; others are still being tested in extensive clinical trials. At the same time, generic equivalents are being developed to compete with approved low-molecular-weight heparins and with warfarin. All of these developments raise serious questions about safety, efficacy, and monitoring. To provide readers with a better understanding of these complex problems, this issue of Seminars in Thrombosis and Hemostasis presents selected works from experts who originally spoke at the 4th annual Antithrombotic Therapy Symposium in 2003 in Dearborn, Michigan.

In the first article, Andersen provides a brief review of anticoagulants presently in use and gives an overview of newly developed compounds that were recently approved for use in special clinical conditions or are being tested for new indications. Emphasis is placed on direct thrombin inhibitors, such as hirudin, desirudin, bivalirudin, argatroban, and ximalagatran. In addition, the synthetic factor Xa inhibitor fondaparinux is discussed. Dr. Andersen then reviews the use of these compounds for thromboprophylaxis in major orthopedic surgeries and weighs advantages against disadvantages. Specific licensed indications and dosing schemes are presented. This article provides the reader with a comprehensive perspective on anticoagulant therapy with special emphasis on orthopedic procedures.

Bongiorno and Nutescu report the results of a survey they conducted on the use of generic warfarins. There are presently three generic versions marketed, and many health care providers seem to be concerned about their true equivalency, recognizing the relatively narrow window between overcoagulation and undercoagulation that exists with warfarin. Concern appears to exist that the Food and Drug Administration regulations for the marketing of generic drugs are too broad for generic warfarins. The survey, composed of 39 questions, was sent to 570 anticoagulation clinics. Of these, 32.8% responded. Interestingly, 66.7% of the respondents preferred the innovator drug (Coumadin^®); some (28.8%) use both forms and only 4.5% use exclusively generic versions. All of the latter belong to managed-care organizations. In contrast to this perception, only few adverse events have been reported when patients were switched from the innovator drug to the generic versions, and several studies are reviewed that appear to suggest that the generic compounds are indeed equivalent and safe.

In the next contribution Mukherjee and Bates review the use of anticoagulants in patients with acute coronary syndromes (ACS). Several large studies have been conducted in which low-molecular-weight heparins (LMWHs) were compared with unfractionated heparin (UFH). LMWHs were combined with antiplatelet agents and with fibrinolytic drugs, and in several trials improved outcomes were reported when LMWHs were added to the treatment regimen. More recently direct thrombin inhibitors, especially hirudin and bivalirudin, were used instead of heparins. Hirudin and its analogues have the advantage of not requiring antithrombin for their action. They can thus neutralize clot-bound thrombin. Bivalirudin is generally preferred because of its shorter in vivo half-life. The combination of direct thrombin inhibitors with antiplatelet agents demonstrated superior outcome when compared with heparins. However, the bleeding risk appeared to be higher. Although great progress is reported in managing patients with ACS, the optimal treatment regimen is still undefined, and further studies are required to come closer to this goal.

Bauer addresses the issue of duration of anticoagulation following venous thromboembolism in patients with acquired and congenital thrombophilic states. Presently, standard treatment for patients with deep vein thrombosis (DVT) or pulmonary embolism (PE), or both, is heparinization followed by oral anticoagulants for 6 months at a target International Normalized Ratio (INR) between 2 and 3. The risk of recurrence is low when the risk factors are transient but higher in patients with persistent risk factors (acquired or congenital). Because factor V Leiden and the prothrombin G20210A gene mutation are the most common congenital thrombophilic states, concern about the duration of anticoagulation exists in these patients. Several studies have suggested that the risk of mortality due to chronic anticoagulation is greater in these patients than the risk of recurrences of DVT and PE. In general, the decisions should be made individually and several criteria that enter the decision-making process are listed. The issue of low-intensity oral anticoagulation (INR 1.5 to 1.9) is at this time still a matter of debate, and studies for and against this approach have been reported. Bauer suggests that the introduction of new long-term anticoagulants may change the present recommendations.

In the next contribution, Harrington addresses the issue of use of platelet glycoprotein (GP)IIb/IIIa inhibitors in percutaneous coronary intervention (PCI) and in ACS. These more recently introduced drugs play a key role in cardiology because the complications associated with PCI and ACS is platelet-driven and platelet-dependent thrombosis. The work presented by the Antithrombotic Trialist Collaboration, published in 2002, conclusively established that virtually all groups of patients with acute coronary vascular diseases benefit from the use of antiplatelet compounds. Especially, the GPIIb/IIIa antagonists have received great attention in a multitude of clinical trials. The author reviews the studies performed on patients requiring PCI and patients with ACS. Despite these impressive improvements in patient outcome, there still may be further improvements possible once the ideal combination of antiplatelet agents and anticoagulants, most notably the newly developed direct thrombin inhibitors and factor Xa antagonists, have been fully evaluated.

Rajagopal and Bhatt review the experiences gained with the use of aspirin, clopidogrel, and ticlopidine in patients with ACS and PCI. For a long time, aspirin has been the most widely used platelet antagonist, but aspirin resistance is a frequent finding that negates the benefits in these patients. Many studies have been conducted on the effects of clopidogrel and ticlopidine, and, generally, positive outcomes were reported in ACS patients. Combinations of aspirin with clopidogrel markedly increase the bleeding tendency. Considerable experience also exists in patients undergoing stenting, and pretreatment as well as long-term treatment with these drugs, especially clopidogrel, affords good protection from restenosis. It is conceivable that therapies with a combination of these agents, including the use of GPIIb/IIIa inhibitors, may even further improve outcome in these patient groups.

Jafri and Metha discuss the issue of “bridging” patients who are on long-term warfarin and need an invasive procedure that requires discontinuation of oral anticoagulant therapy. Simple discontinuation increases the risk of thromboembolic events, and continuation of therapy risks major bleeding. In some instances, as in patients requiring oral dental procedures or minor ophthalmologic surgeries, warfarin can be continued and a decrease of the INR to approximately 1.5 is a safe option. In other cases, such as endoscopic procedures or neurological operations, bleeding could jeopardize the patient if warfarin were to be continued. Patients with mechanical heart valves or atrial fibrillation would be at great risk of thromboembolism if warfarin were to be discontinued. The use of LMWHs has been studied in several clinical trials as a bridging option, and this approach appears to be relatively safe, if certain precautions are taken into consideration. The authors review the use of LMWHs extensively and provide a protocol that will assist clinicians in this difficult task.

Kher and Marsh provide a review of the pathogenesis of atherosclerosis. Endothelial cells and smooth muscle cells participate in this process, and receptors in both layers play a key role. It is hypothesized that atherosclerosis is initiated by injury to endothelial cells, and many injurious factors have been identified. Endothelial disruption brings platelets and macrophages into play, and these interactions propagate the process. Intimately linked is the inflammatory cascade with its many cytokines. Considerable discussion is provided on the instability and vulnerability of the atherosclerotic plaque that leads to the potential occlusion of arteries, most notably coronary and cerebral vessels. New insights into this process provide ways to identify vulnerable plaques that aid potentially in the early diagnosis of imminent vascular events.

Weinstock next discusses the contemporary management of ST elevation myocardial infarction. The article contains a description of the early use of thrombolytic agents, from streptokinase to the present third-generation agents, the successes, and the problems associated with it. Trials are listed in which thrombolytic agents were combined with GPIIb/IIIa inhibitors and epifibatide. Each approach has its advantages, but bleeding and recurrences of myocardial infarction are potential disadvantages. Because the window of opportunity for successful dissolution of clots is rather narrow, prehospital treatment options are discussed. Primary angioplasty was found to have a better outcome than thrombolytic therapy had. The same was found with stent implantation. Primary stenting, combined with GPIIb/IIIa inhibitors is at present the most promising approach to patients with myocardial infarction, depending again on when the patient presents to the appropriate health care facility. Ultimately only individualized, patient-specific and institution-specific approaches will bring optimal treatment outcomes.

Walenga and Hoppensteadt expertly review the laboratory methods presently available to monitor antithrombotic drugs. The introduction of new compounds has necessitated the assessment of the older, most commonly available techniques and the development of new procedures. Some manufacturers indicate that there is no need for monitoring their new compounds, but, as pointed out by the authors, there may be occasionally the necessity for assessment of efficacy, especially in certain groups of patients. The appropriate laboratory methods for each antithrombotic drug are listed and critically discussed. Pitfalls are pointed out and caution is expressed when interpreting laboratory results. Most methods measure a single factor or a single function whereas most antithrombotic drugs have multiple points of action.

In the next contribution, Nutescu reviews the status of point of care devices that are presently used to monitor anticoagulant therapy. These hand-held instruments are measuring the prothrombin time/International Normalized Ratio (PT/INR) in patients from a droplet of blood obtained from a finger prick. They are widely used in physician offices, in anticoagulant clinics, and by patients themselves. Several generations of instruments have been developed, and numerous studies have performed comparison testing with the traditional, laboratory performed PT/INR in plasma. Generally, good results are reported. In addition, these instrument performances depend on the sensitivity of the thromboplastin reagents, and differences in results were noted between institutions. These differences are, however, not large enough to negate the use of these devices. The great advantages of the systems are the fast turnaround times, the ease of handling, lack for venipuncture, and self-testing by certain patients.

In the last article, Fareed and colleagues discuss the development of generic forms of anticoagulants, especially LMWHs. It is pointed out that each product is unique and different. This has prompted several regulatory and professional organizations to state firmly that the different LMWHs are not interchangeable. Although generic products have been produced, and in some countries they are already marketed, they may not be identical or equivalent. The regulations that govern the production of generic compounds are relatively easy to follow and are probably valid for many chemicals but may not be sufficient to guarantee equivalency for LMWHs. Although generic forms may have the same biological activity (anti-Xa U/mg), they are chemically different. Like UFH, LMWHs are polycomponent drugs that serve more functions than just anticoagulant properties. The authors argue that generic forms of LMWHs should be subjected to the same clinical studies as their original compound was, to ensure full biological equivalence.

Thanks are due to the organizers of the symposium, who serve as guest editors for this issue, and great appreciation is expressed to all authors for their superb contributions.