Changing Trends in Anti-Coagulant Therapies. Are Heparins and Oral Anti-Coagulants Challenged?
By Fareed, J Iqbal, O; Cunanan, J; Demir, M; Wahi, R; Clarke, M; Adiguzel, C; Bick, R
The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant targets, such as tissue factor, individual clotting factors, recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral anticoagulants. Both the anti-factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active antithrombin agent Ximelagatran for several indications. The synthetic pentasaccharide (Fondaparinux) has undergone clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y^sub 12^ receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y^sub 12^ antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come. [Int Angiol 2008;27:176- 92]
Key words: Heparin – Warfarin – Aspirin – Antithrombins.
Over the past decade, interest in anticoagulant drugs has grown, as evidenced by the increase in the number of drugs introduced for both preclinical and clinical development.1,2 These drugs include the new heparins, synthetic heparinomimetic agents, anti-IIa agents, anti-Xa agents, biotechnology derived antithrombotic proteins, and newer antiplatelet drugs. The newer drugs represent a wide spectrum of chemicals and biologics with both structural and functional diversity (Figure 1). These drugs represent proteins, carbohydrates, synthetic organo-mimetics and biotechnology derived agents. The scientific research and development activities in the academic centers and pharmaceutical industry have resulted in a steady flow of many of the new products including the following:
1) ultra low molecular weight heparins (LMWHs) (Bemiparin, Deligoparin and Octaparin);
2) Heparinomimetics, such as the Fondaparinux and Idraparinux;
3) Synthetic direct antithrombin agents (parenteral and oral);
4) Synthetic direct anti-Xa agents (parenteral and oral).
Of these agents, Fondaparinux is in advanced clinical development in various indications including postsurgical deep vein thrombosis (DVT) and acute coronary syndrome (ACS). The parenteral anti-IIa agents are primarily used for substitute anticoagulation for heparin- cornpromised patients (i.e. heparin-induced thrombocytopenia syndrome [HITS]). The oral agents are currently developed for the potential replacement of warfarin and heparins. However, safety considerations and rebound thrombosis are major concerns. Thrombosis is a polypathologic syndrome, where blood and endothelial cells, plasmatic components, inflammatory responses and hemodynamic abnormalities contribute to its pathogenesis (Figure 2). Single target drugs, such as the newly developed anti-protease agents, may have a limited value in the management of thrombosis. These agents may mimic polytherapeutic actions of conventional drugs when used in combined modalities.
Extensive clinical trials have been carried out globally to support the claims on the safety and efficacy of the newer drugs. Several reports on the possible replacement of warfarin by newly developed oral antithrombin agents have become available.3,4 Through their fast track and revised policies, the regulatory bodies such as the European Medicine Evaluation Agency (EMEA), US Food and Drug Administration (US FDA), and other regional agencies have continually contributed to the timely evaluation and approval of new drugs by providing input at various stages of drug development. Such interactions have accelerated the approval process of many new drugs, such as LMWHs, synthetic heparin pentasaccharide (Fondaparinux), and activated protein C (APC) (Xigris).
It is now widely perceived that the conventional anticoagulants, such as the heparins, warfarin and aspirin, will eventually be replaced by newer drugs.4 This is partly due to several reported problems with their use and associated adverse reactions. Table I lists the conventional drugs and their potential substitute for various indications. Unfractionated heparin (UFH) has been in use for nearly 50 years and it is the only anticoagulant drug with an antidote. In many countries, this anticoagulant still remains the main drug for the anticoagulant management of thrombosis and cardiovascular disorders. Warfarin still remains the drug of choice for the outpatient management of thrombosis, whereas aspirin has been used for multiple indications for a long period of time.
The use of UFH has been optimized by the development of the LMWHs. Therefore, the LMWHs actually represent an optimized use of heparin. This is mainly due to our current understanding of the chemistry and biology of heparin. It is more than 40 years since the oral anticoagulant drugs such as warfarin began to be used for the management of thrombotic and cardiovascular disorders. Response variation, need for monitoring and delayed onset/cessation are some of the problems associated with its continued use. Antithrombin drugs, such as Lepirudin, Argatroban and Bivalirudin, have been in development for many years. These drugs are useful as a substitute for heparin in such conditions as heparin induced thrombocytopenia (HIT). However, these drugs do not have any antidote and cannot be used for surgical indications at this time. The anti-Xa drugs and the heparinomimetics do not have any direct effect on thrombin and produce minimal anticoagulant effects. Therefore, these drugs may or may not be useful in the management of patients who are heparin compromised. However, the long-term use of these agents requires further clinical validation. Also, whilst heparin represents a polytherapeutic drug, the newer drugs tend to be monotherapeutic. Thus, their indications will be somewhat limited. Moreover, some of the therapeutic effects observed with heparins may not be seen with the newer drugs.
More recently, the oral antithrombin drugs, such as Ximelagatran have been developed as potential substitutes for warfarin.3 While this agent is shown to be effective and in some cases non-inferior to warfarin, its use has been associated with an increase in liver enzymes and this agent passes the placental and blood brain barriers. For these reasons the US FDA has disapproved the clinical use of Ximelagatran in various indications. This drug was also withdrawn from the European countries by Aster-Zeneca due to safety concerns. It development and clinical use is now completely stopped.
Several oral anti-Xa agents are also in clinical development at this time.5 In contrast to the antiHa agents, these drugs do not compromise the regulatory function of thrombin. In addition, these agents may have a broader therapeutic index than the oral thrombin inhibitors. Because the target is factor Xa, these drugs may mimic oral anticoagulants in pharmacodynamic actions. Initial studies on various factor Xa inhibitors have had promising results; however, additional trials by directly comparing these agents with oral anticoagulants are needed. A direct comparison between the anti-Xa agents and oral anticoagulant drugs is not available at this time. Thus, additional clinical trials are needed to further validate the therapeutic index of these agents in comparison to warfarin. The development of oral heparins and related drugs has been somewhat disappointing as these agents were not as effective as the subcutaneous LMWHs. Aspirin has been in clinical use for over a hundred years and its antiplatelet effects have been well recognized. Aspirin has been a life saving drug for several types of thrombotic indications. Several newer formulations of aspirin have been developed. Aspirin now represents a universal antithrombotic drug in both thrombotic and cardiovascular indications. The newly developed COX inhibitors exhibit some specific effects of aspirin, but may or may not exhibit the potential therapeutic effects in thrombosis. As a matter of fact, due to the specificity of these agents they may exhibit thrombotic complications. Table II shows a comparison between aspirin and adenosine diphosphate (ADP) receptor inhibitors. In comparison to aspirin, the ADP receptor inhibitors are single target drugs. The selective ADP receptors, when combined with aspirin, exhibit superior efficacy in comparison to monotherapy. However, their clinical spectrum without aspirin will be limited. Thus, it is highly unlikely that the newer antiplatelet drug will provide the broad therapeutic index observed with aspirin, including the anti-inflammatory and immunomodulatory actions.
Owing to rapid developments in these potential therapeutics, several important issues related to current practices in anticoagulant therapy should be recognized. These issues include:
1) the replacement of UFH by LMWHs in all indications including medical and surgical anti-coagulation;
2) the potential replacement of heparins by newly developed antithrombin and anti-Xa agents;
3) the feasibility of oral anti-Xa and anti-IIa agents as potential substitutes for oral anticoagulant drugs;
4) the development of synthetic heparinomimetics and their relative bioequivalence to heparin;
5) the development of recombinant antithrombotic agents, such as the APC, tissue factor pathway inhibitor, recombinant equivalent of serpins and thrombomodulin, with reference to their relative applications in specific disorders;
6) the development of newer antiplatelet drugs, such as the ADP receptor inhibitors, glycoprotein Ilb/TIIa receptors, phosphodiesterase inhibitors and specific COX-1 and COX-2 inhibitors and their relevance in the management of vascular disorders. The relevance of on board aspirin for the therapeutic index of each of these agents also requires additional investigations. COX-2 inhibitors have been known to produce hypercoagulable states due to the sparing of COX-1;
7) the recent recognition of the antithrombotic actions of statins, nitric oxide donors and other non-anticoagulant drugs and their impact on overall therapeutic approaches;
8) since the patents for some of the anticoagulant drugs such as the LMWHs are due to expire, it is likely that generic versions of some of these agents, including Enoxaparin and Dalteparin may soon become available.6 However, if the generic drugs are approved based solely on the current specifications/guidelines, many products with similar characteristics, but non-similar biological or clinical equivalence will be introduced. This may result in safety and efficacy compromise. The need for systematic review and newer guidelines therefore exists at all levels.
Despite its limitations, heparin is still the most widely used anticoagulant. The clinical experience with heparin and the fundamental understanding of its biologic actions have provided additional insights for optimizing the use of this drug. These include the development of heparin fractions, improved production methods understanding of the structure of heparin and development of heparin derivatives, and better understanding of the direct and indirect mechanisms of action. This has led to improved clinical outcomes and reduction of adverse event incidence, such as bleeding and HIT.
Low molecular weight heparins and related drugs
While heparin remains the sole anticoagulant used for interventional 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 challenge 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, and malignancy associated thrombotic events. LMWHs have also shown efficacy as surgical and interventional anticoagulants.7 Unlike heparin, these drugs exhibit a better therapeutic index in these indications. LMWHs have also recently been evaluated in atrial fibrillation and cardiac transplantation. Being polypharmacologic in nature, the LMWHs have multiple sites of action. Their actions are not only limited to the inhibition of coagulation enzymes, but these drugs also exhibit profound actions on endothelial sites and blood cells. This has led to the development of the newer forms of LMWHs with structural and functional modifications.
Antithrombin agents such as Lepirudin and Bivalirudin also have been compared with LMWHs for postsurgical prophylaxis of thromboembolism. Initial reports indicate favorable results with the use of recombinant Lepirudin 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 approach, based on the elucidation of the structure of heparin, has led to the synthesis of oligosaccharides with high affinity for antithrombin. While synthetic Fondaparinux have undergone extensive clinical trials for both thromboembolic and coronary indications, safety considerations such as bleeding and catheter thrombosis remain.
Clinical trials in Europe have shown that subcutaneous LMWHs, given once or twice daily, are at least as safe and effective as continuous intravenous heparin in the prevention of recurrent venous thromboembolism (VTE) and are 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 heparin in patients with proximal vein thrombosis. Initial evidence clearly suggests the LMWHs may be a useful alternative to heparin in patients with pulmonary embolism. LMWHs also may be useful alternatives to heparin for arterial indications, such as treatment of unstable angina and 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 stroke. The success of early clinical trials also suggests that LMWHs may be useful in the management of primary and secondary ischemic or thrombotic stroke. While in several clinical trials the LMWHs did not show any improvement for the neurovascular deficit in stroke, 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 stroke will be an important goal. LMWHs have also shown efficacy in vascular senile dementia of Alzheimer’s type. Thus, these drugs may become useful in neurologic disorders. There are several studies that are currently ongoing on the effect of LMWHs and related drugs in neurodegenerative diseases.
Although LMWHs are proving to be as effective as, or safer than, heparin for various indications, it is important to realize the differences in the manufacturing of various LMWHs may lead to differences in the pharmacological profile. Each of the LMWHs is expected to exhibit its own therapeutic index in a given clinical setting. Thus, unlike heparin, the interchanging of LMWHs based on equivalent gravimetric or biologic potency of standardized dosages may not be feasible. 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 ACS. The most notable differences are observed at higher dosages. When these agents are given intravenously for interventional cardiovascular procedures, each of the LMWHs produces a different anticoagulant response regardless of the dosage equivalence at the gravimetric or bioassay adjusted potency. Therefore, the US FDA, World health Organization (WHO) and professional organizations consider each drug distinct. 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 carried out with Dalteparin (FRISC and FRIC), Enoxaparin (ESSENCE), and Nadroparin (FRAXIS).8
The LMWHs have also shown remarkable clinical efficacy in the management of cancer-associated thrombosis.9 More recently, the US FDA has approved a LMWH, namely Dalteparin, for the management of cancer-associated thrombosis. Clinical trials have shown that LMWHs reduce the mortality in cancer patients. Several trials, in medical patients for the prophylaxis and treatment of thrombosis, have provided supportive data that cancer-associated mortality can be reduced by using LMWHs. Thus, besides the anticoagulant effects, there may be additional actions of these agents, which warrant further investigation. Additional depolymerization of LMWHs has resulted in the development of ultra-low 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 several possible indications including vascular dementia, inflammatory bowel disease and ACS. Many of the major pharmaceutical companies are currently developing various forms of LMWHs with averaged molecular weight <3 000 Da. These lowered molecular weight heparins may exhibit better safety and efficacy indices.
Generic low molecular weight heparin
The branded LMWHs are now challenged with the insurgence of the generic, apparently equivalent products. At the present time, there are no clear guidelines for the acceptance of the generic LMWHs. The available guidelines are insufficient to address the complex issues related to the functional and structural characteristics of these drugs. Many countries around the world have already allowed generic versions of Enoxaparin, Dalteparin, and Fraxiparin. It is important to track the clinical performance of these generic products and to recognize any potential differences between the generic and the innovative product. Such data may be helpful for the proper validation and potential acceptance of generic LMWHs. Warfarin has remained the sole oral anticoagulant for the extended management for thrombotic conditions. The generic versions of warfarin have been successfully introduced throughout the world including the USA. The use of INR for the monitoring of this oral anticoagulant has greatly facilitated harmonization in the dosing and has helped in eliminating reagent-based variations. Additionally, point-of-care testing devices and selfmonitoring programs with guided dose adjustments have resolved many problems associated with monitoring.
Direct thrombin inhibitors
The understanding of the hemostatic process has led to the identification of thrombin as a key enzyme in the thrombogenic processes. Several direct thrombin inhibitors (DTIs) have been developed over the past few years.10 Argatroban, Bivalirudin and Lepirudin have become available for alternative management of patients who are heparin compromised. The recognition of HIT as the most catastrophic adverse effect of heparin has led to the use of alternate anticoagulants. The antithrombin agents are most useful in this indication and have been specifically developed for HIT. Lepirudin, the leech-derived protein, has been compared with heparin for the treatment and prophylaxis of venous and arterial thrombotic disorders. The use of Lepirudin has been reported to be associated with increased risk of bleeding, indicating that better monitoring and dose-adjustment protocols are needed as well as antidotes. To date, clinical trials comparing Lepirudin and heparin as adjuncts in thrombolytic therapy in myocardial infarction (TIMI 9B) and ACSs (GUSTO IIb) have shown Lepirudin to be marginally superior to heparin.11,12 Recently, several reports comparing the effects of heparin and Lepirudin have become available. A study comparing heparin and recombinant Lepirudin for the prophylaxis of DVT provided impressive data in favor of Lepirudin.13 In a second study, LMWHs also was compared with Lepirudin for postsurgical prophylaxis of DVT.14 The results favored Lepirudin. Both studies emphasize an important point about the validity of well-designed clinical trials. It is important to understand that the efficacy and safety of a new drug may not be determined by trials for a single indication. The use of Lepirudin is associated with the generation of antibodies, which can impair the pharmacokinetics and pharmacodynamics of this drug. Severe anaphylactic reactions have also been reported with the use of Lepirudin. Therefore, additional clinical trials are needed to demonstrate the safety of Lepirudin and related drugs.
Bivalirudin represents a designer antithrombin drug that combines the features of Lepirudin and other anticoagulant peptides. It is a reversible antithrombin agent and offers several advantages over Lepirudin. This agent has undergone several clinical trials for interventional and surgical anticoagulation.1518 The FDA has approved this agent for anticoagulation during percutaneous coronary angioplasty (PTCA). Currently, Bivalirudin is undergoing clinical trials for cardiovascular bypass surgery. Furthermore, antithrombin agents such as argatroban and Bivalirudin may be useful in off pump bypass surgery. Antibody generation to Bivalirudin has also been reported.19 This can also influence the dosing and the relative responses of this drug.
Argatroban, a small peptidomimetic thrombin inhibitor is also approved by the US FDA as an alternate anticoagulant for patients with HIT. It has been used successfully in Japan for over a decade in the treatment of thrombotic disorders. Several clinical trials in both Europe and the United States have been designed to investigate its use as an alternative to heparin in heparin-compromised patients and as a prophylactic agent to reduce late restenosis after PTCA and coronary directional atherectomy.20 Argatroban has been successfully used as an anticoagulant in patients with HIT and as a substitute for heparin in PTCA.21 Since the half-life of argatroban is rather short, it has been administered via infusion protocols. For therapeutic anticoagulation, a level of 1-2 [mu]g/mL is indicated, whereas for interventional cardiology procedures a level of 3-7 [mu]g/mL is necessary. Argatroban also exhibits additional actions on blood vessels and may exert its clinical effects via multiple measures.
Direct Xa inhibitors
Due to their weaker anticoagulant effects in global clotting tests, direct factor Xa inhibitors were not considered desirable anticoagulant and antithrombotic agents for developmental purposes. However, because of favorable clinical results with Fondaparinux, strong interest in synthetic anti-factor Xa drugs has reemerged. These agents may be useful in the prophylaxis of both arterial and venous thrombotic disorders and may offer a greater margin of safety than existing drugs. Additional advantages of factor Xa inhibitors over heparin include subcutaneous and oral bioavailability. Although their biologic half -life is usually less than 30 min, coupling to larger agents such as dextran or albumin can prolong their half- life without affecting their pharmacologic actions. Questions about monitoring and antagonism will have to be answered before factor Xa inhibitors can be widely explored in clinical settings. Depending on their specificity for factor Xa, they may be used as adjuncts with other classes of drugs, such as thrombolytic agents for treatment of acute myocardial infarction. Low-molecular-weight thrombin inhibitors and factor Xa inhibitors also may be used for localized delivery, stenting and transdermal delivery.
The pharmacologic actions of these oligosaccharides are dependent on endogenous antithrombin. The US FDA and EMEA have approved the use of synthetic heparin pentasaccharide, Fondaparinux, for the management of postorthopedic surgical thrombosis. However, bleeding risk was unexpectedly higher with this drug and its use is not recommended in underweight patients. Fondaparinux is likely to be equivalent to other modalities in the management of DVT prophylaxis; however, its use in other indications where LMWHs are approved may not provide equivalence or superiority due to its monotherapeutic nature.
Several additional clinical trials are being carried out on Fondaparinux in multiple indications, including treatment of thrombosis. Besides the lack of a clear clinical response, bleeding issues, non-availability 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 on these issues. Heparin and LMWHs are poly- component drugs with multiple actions. Furthermore, these drugs also release tissue factor pathway inhibitor from endogenous sites. Thus, these agents may have a relatively broader therapeutic index.
At the present time, several anti-Xa drugs are currently being developed for various indications (Figure 3). A major interest in the area is to develop oral anti-Xa drugs that can be used for the longterm management of both the arterial and venous thrombosis. Because of their better bioavailability, thrombin inhibitors and factor Xa inhibitors in combination may be more useful than the single agents. Optimal combinations for specific indications may be considered. As in the clinical development of LMWHs, thrombin inhibitors and factor Xa inhibitors should be compared with heparin in terms of safety, efficacy and cost.
Oral anti-IIa and anti-Xa agents
Both the oral antithrombin and anti-Xa agents are currently proposed as potential substitutes for oral anticoagulants for the long-term management of thrombotic and cardiovascular indications. Prior to being taken off the marker, Ximelagatran has undergone extensive clinical trials in DVT prophylaxis and atrial fibrillation.22 In comparison to LMWH and warfarin, it has exhibited variable safety and efficacy. In the atrial fibrillation trial, it was shown to be non-inferior.23 Similarly, some recent clinical trials have also reported on the efficacy of oral anti-Xa agents.24- 25 These agents are in their early clinical development and have some promising initial reports. While there is discussion that oral anticoagulants such as warfarin can be replaced by oral anti-IIa or anti-Xa agents, the use of warfarin is currently being further optimized. With the use of the international normalized ratio (INR), some global harmonization for its use has been achieved. Self- monitoring is providing a patient driven control process analogous to the regulation of insulin therapy. Newer formulations have recently become available. New trials have provided useful data on its efficacy. Thus, optimized use of warfarin may turn out to be as safe and effective as the newly developed anti-Xa and IIa agents. Antiplatelet drugs
The introduction of novel antiplatelet drugs has added a new dimension to the management of arterial thrombosis in particular, thrombotic stroke. The availability of specific antagonists of the ADP receptor (e.g., Ticlopidine) has provided a new approach for several cardiovascular and cerebrovascular indications. The second generation ADP receptor-blocking agents (e.g., Clopidogrel) underwent extensive clinical trials to test their therapeutic efficacy in combined cardiovascular and cerebrovascular endpoints.32 The comparative results reported in several clinical trials have favored Clopidogrel.33 The data oh Clopidogrel alone in various indications is rather limited. Actual clinical trials, where Clopidogrel is compared with aspirin and other drugs, are therefore needed to determine the relative efficacy of this agent. In most studies performed to date, onboard aspirin has been used with Clopidogrel. Clopidogrel has also been proven to be very important in preventing stent thrombosis.34
The newly developed antithrombin, anti-Xa, ADP receptor antagonists and recombinant antithrombotic drugs have only undergone limited and qualified clinical trials. Most of the data obtained from these studies is obtained through industry-sponsored studies. Thus, there is a need for unbiased and objective clinical results, which can only be obtained through postmarketing surveillance. This will require the unqualified regulatory approval of some of the newer drugs for multiple indications in which the conventional drugs have been used for a long time. All drugs exhibit some sort of safety problems. Because of the defined and monotherapeutic nature of the newer drugs, it has been projected that these drugs may have lesser toxicity and adverse reactions. However, even at this early stage, several safety issues with the newer drugs have already been identified. Table III lists some of the reported adverse reactions with the newer anticoagulant and antithrombotic drugs. Bleeding has been one of the most commonly observed problems with these drugs. With the stipulation that fixed dosage may be applicable in all patients, bleeding risks may be higher with the newer drugs, as has been the reported case with Fondaparinux.35 Thrombocytopenia, granulocytopenia and immune thrombocytopenic purpura like syndrome have been reported with the ADP receptor inhibitors such as Ticlopidine and Clopidogrel. The use of oral thrombin inhibitors has been reportedly associated with liver enzyme elevation. The anti-Xa inhibitors have been associated with the hemodynamic compromise and other side effects, whereas the recombinant antithrombin proteins have been associated with antibody generation.
It is now widely believed that the days for the classical anticoagulants are numbered and that in the foreseeable future these drugs may not exist. However, this is not the case when one reads the recommendations of the American College of Chest Physicians (ACCP) and the approval labels for the drugs.36 Considering the results of several new clinical trials, the ACCP and the International Union of Angiology consensus conferences on antithrombotic therapy have included definitive recommendations on the clinical effectiveness of the classical drugs in both arterial and venous diseases. In addition, these recommendations include specific guidelines on additional indications where these drugs will be useful. Thus, it is very likely that heparin, warfarin and aspirin will continue to be important drugs in hematological and oncologic disorders for some time.1,2,37
Anticoagulant drugs in the management of coronary interventions
Anticoagulant drugs are crucial in the management of patients with percutaneous coronary intervention (PCI). Anticoagulants used in patients undergoing PCI should not only prevent coronary events, but also maintain catheter patency to avoid complications. Beside the use of UFH, newer approaches for PCI include LMWHs, and other agents such as Fondaparinux and Bivalirudin. Lepirudin was initially used in PCI, however, because of safety considerations, its use was not considered optimal. Both UFH and Enoxaparin have a good efficacy and safety profile in PCI. In addition, the incidence of procedural complications such as catheter thrombosis is a rare event. In contrast, recent clinical trial data have indicated that factor Xa inhibition with agents such as Fondaparinux may be associated with an increased incidence of catheter thrombosis compared with heparin- based anticoagulants (UFH and LMWH).26 Experimental studies show that the poly-therapeutic agents UFH and Enoxaparin are more effective anticoagulants than certain single-target factor Xa inhibitors, such as Fondaparinux.27 On the other hand, antithrombin agents such as Bivalirudin have been found to be more effective anticoagulants in PCI settings.28 The safety and efficacy of using the direct thrombin inhibitor, Bivalirudin, during PCI was first evaluated in the REPLACE-2 trial, which reported the non- inferiority of Bivalirudin to heparin for this indication.15 In the subsequent ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) study, patients with moderate-to-high risk ACS were randomized to receive Enoxaparin, UFH plus GP IIb/IIIa inhibitors or Bivalirudin with and without GP IIb/IIIa inhibitors.16,18 A subanalysis of patients who underwent PCI indicated similar rates of composite ischemic outcomes across all treatment groups. Rates of major bleeding were similar in patients receiving UFH or Bivalirudin with GP IIb/IIIa inhibitors; however, the rate of major bleeding was significantly lower in the Bivalirudin monotherapy group compared to both UFH and Bivalirudin plus GP IIb/IIIa inhibitors. No cases of catheter-related thrombus formation were reported in patients receiving UFH or Bivalirudin with or without GP IIb/IIIa inhibitors. Bivalirudin monotherapy may therefore be a promising alternative to UFH therapy in a GP IIb/IIIa inhibitor-sparing strategy.
The larger-scale HORIZONS AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (AMI) trial compared the use of Bivalirudin monotherapy with UFH plus GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction (STEMI).17 In the subpopulation of patients who underwent primary PCI, Bivalirudin monotherapy was associated with a significant 24% reduction in the risk of net adverse clinical events up to 30 days postrandomization, largely driven by a 40% reduction in the risk of non-coronary artery bypass graft-related major bleeding. However, the authors also reported a significantly greater incidence of acute stent thrombosis (occurring
Argatroban represented the very first parenteral antithrombin agent used for various indications in Japan. It was later developed for the alternate anticoagulant management of heparin compromised patients.20, 21 This agent has also been used in several clinical trials for the anticoagulation in PCI.29 However, it is not approved for this indication at this time. In the US, argatroban is widely used for anticoagulation of patients who develop antibodies to heparins (HIT antibodies).
Novel anticoagulants that directly inhibit factor Xa are also currently in development. In the Xa Neutralization for Atherosclerotic Disease Understanding (XaNADU) phase II trial, the safety of the direct factor Xa-inhibitor DX-9065a was assessed in patients undergoing elective, nativevessel PCI.30 During the PCI procedure, patients received either one of three dosages of DX- 9065a, or the standard regimen of UFH. However, use of the lowest dose regimen was halted abruptly following a serious thrombotic incident in the 7th patient to receive this dose. Procedural complications were also commonly reported in patients receiving the other DX-9065a dosages. Side branch closure after stent implantation was reported in 3 patients (2.1%) in stage 1 , and one stage 4- patient (2.2%) suffered subacute stent thrombosis requiring urgent revascularization approximately 12 h post-PCI. Of the patients receiving UFH, no procedural complications were reported. Although this study concluded that the use of DX-9065a during PCI merited further investigation, the development of this particular factor Xa- inhibitor was not continued.
More recently, another direct factor Xa inhibitor, Otamixaban, was assessed in a double-blind, double-dummy, dose-ranging trial (SEPIA-PCI) in patients undergoing non-urgent PCI.31 In this trial, patients were randomized to receive one of five Otamixaban drug regimens, or UFH with or without concomitant use of GP IIb/IIIa inhibitors. The highest dose of Otamixaban reduced the plasma concentration of F 1+2 prothrombin fragments significantly more than UFH without causing increased bleeding. Only two serious cases of catheter-related thrombosis were reported during this trial, both occurring in patients receiving the lowest dose of Otamixaban. No coronary artery or catheter-related thrombi in patients receiving alternative Otamixaban doses or UFH during this study were considered to be serious. Further studies are required to evaluate the safety and efficacy of Otamixaban for this indication. Recently, oral antithrombin agents such as Dabigatran and Factor Xa inhibitors such Apixaban and Rivaroxiban were developed for the long-term management of ACS. While their role in the management of PCI may be limited, these drugs in modified formulations can be used in PCI. Additionally, combined use of anti-Xa and anti-IIa drugs has also emerged in PCI. The coming years will witness major changes in anticoagulation therapy; however, the heparins will continue to play an important role in this area.
Conventional anticoagulants
The classic anticoagulants have been described in recent publications as “bad” drugs with many adverse effects. In fact, the classical anticoagulants may not have any more adverse effects than the new drugs. Needless to say, all pharmacologic agents have their limitations. Heparin, aspirin and warfarin certainly have problems, some of which have already been addressed and improvements have been made.
The development of LMWHs is an example of the optimized use of a pharmacologic agent. Their use has nearly eliminated the risk of HIT, and these drugs have achieved standard of care status for many venous and arterial thrombosis indications. LMWHs have gradually replaced heparin in subcutaneous indications and are currently being examined for their effectiveness as surgical and interventional anticoagulation. Improved monitoring and dosage optimization are currently being pursued. Another example is the SPORTIF trial in which the oral anticoagulant, warfarin, was found to be essentially equivalent to the new oral anti-thrombin agent, Ximelagatran, without risk of significant bleeding.38 Moreover, warfarin use was not associated with elevation of liver enzymes.39
Despite the reported problem of HIT, heparin has remained the drug of choice for surgical anticoagulation. This is due to the high bleeding risk associated with the new antithrombin agents when used at higher doses coupled with the lack of antagonists. Heparin has a well tolerate antagonist, protamine, and the heparin-protamine combination has been used with much success for many years. Therefore, currently, UFH is the only reliable anticoagulant that can be used in surgical and interventional indications.
It is noteworthy to state that thrombosis is a polycomponent syndrome, which optimally requires a multiple target therapeutic approach. However, with the advanced understanding of the molecular and vascular biology of thrombotic disorders, only mono- therapeutic drugs that have a single target of action have been developed. These mono-therapeutic agents like Fondaparinux, Dabigatran and Rivaroxiban are molecularly and functionally defined. Their applications have been validated in well-designed, sponsored clinical trials for specific indications. But, like the classical drugs, these new drugs were also found to have adverse effects. Bleeding and lack of dose response as well as monitoring and antidotes for over-dosage remain problematic issues.
Conventional drugs such as heparin, oral anticoagulants, and aspirin will remain the gold standards despite their known drawbacks. They require further optimization, but can still currently be used for various indications in a cost-effective manner. The newer drugs may, however, provide alternatives that in the next few years could lead to improved cost-compliant treatments. The actions of the non-anticoagulant drugs such as the cholesterol lowering agents (statins), specific inhibitors of cyclooxygenase, drugs capable of donating nitric oxide or upregulating its mediators and drugs modulating endothelial function will also impact the combination therapy of thrombotic and cardiovascular diseases.
New anticoagulants
Initial attempts to develop an orally bioavailable product to replace warfarin have so far failed. The development of orally bioavailable thrombin inhibitors has also been initially targeted. Ximelagatran underwent extensive clinical trials in various indications, such as DVT prophylaxis in orthopedic surgery, atrial fibrillation, and secondary prevention of thromboembolism, with the obvious hope that it will replace warfarin for all indications. Its use was associated with elevation of liver enzymes in up to 8-10% of patients and a greater frequency of ACS complications in patients treated for the prophylaxis of DVT after orthopedic surgery. Subsequently, the US FDA rejected the approval of Ximelagatran for the triple indications. All of the orally bioavailable direct thrombin and Xa inhibitors, such as Ximelagatran, Dabigatran, Rivaroxiban and Apixiban represent synthetic organomimetic compounds with certain structural similarities to Ximelagatran and are likely to be metabolized by the liver (Figure 4). Moreover, all of these compounds pass through the placental barrier and have a potential to rebound. It is likely that regulatory bodies will require additional studies on the safety of these drugs. Although there is an apparent need to replace warfarin and related oral anticoagulants by more effective, predictable, and safer drugs, the FDAs concern is valid and not until these safety issues are resolved will the anti-Xa and anti-IIa drugs be clinically accepted.
There are several other oral thrombin inhibitors currently being developed by different companies (Figure 5). Most of these represent synthetic heterocyclic compounds. It is conceivable that all of these agents may have a similar performance profile as discussed above. An additional concern, however, is the fact that thrombin exhibits several regulatory functions. Of major importance is the thrombin-thrombomodulin pathway. All thrombin inhibitors that produce a sustained inhibition of thrombin are expected to produce an inhibition of this pathway leading to varying degrees of hemostatic regulatory compromise. Oral thrombin inhibitors may exhibit a class effect unless there are major modifications in the molecular design of these agents.
Table IV shows a comparison of the half-life, renal clearance and the potential for placental passage for various anti-Xa and anti- IIa agents with warfarin. All of these drugs exhibit similar characteristics to warfarin and are cleared through both renal and hepatic mechanisms. All are capable of passing the placental passage. Therefore, the toxicity associated with warfarin may also be observed with these drugs.
On the other hand, the OTLs such as Argatroban, Lepirudin, and Bivalirudin have been extremely useful in the acute and short-term management of heparin compromised patients who require treatment or anticoagulation for interventional procedures. The 7th ACCP guidelines have provided specific recommendations for the use of DTIs in heparin-compromised patients. However, the data is somewhat limited. At comparable anticoagulant levels (e.g., using activated partial thromboplastin time or activated clotting time activity) the pharmacologic profiles of the different DTIs are distinct from each another. These drugs also exhibit different degrees of interactions with other drugs.
The parenteral DTIs are currently administered by intravenous bolus or infusion. However, subcutaneous formulations for these agents will soon become available. As the patents of some DTIs are near expiration or have expired, generic versions of these DTIs will become available. Since these drugs are synthetic or biosynthetic (recombinant), applicable guidelines developed for specific groups must apply. Currently there are no guidelines available. Furthermore, the pharmacological differences among these drugs are not addressed at this time. It is expected that newer trials may provide some insight on the differentiation of these agents.37
A comparison of warfarin and Enoxaparin with the newly developed anti-Xa and anti-IIa agents is shown on Table V. The clinical indication for these agents are similar; however, warfarin has a broader usage. Warfarin was approved in 1954 for arterial venous thrombosis. The first LMWH, Enoxaparin was approved in the US in 1983 for VTE and later ACS. In 2004, Fondaparinux was approved for postsurgical VTE management. Now it is being considered for ACS; however, there are several safety issues. Dabigatran is slated to be approved in 2010, whereas Rivaroxiban was initially targeted for approval in 2009. Because of the liver enzyme issues and thrombosis rebound, the regulatory approval of these drugs may be delayed.
The progress in the development of newer antithrombotic and anticoagulant drugs has been remarkable in the past decade. However, the focus of these developments has been towards the introduction of mono-therapeutic agents with known targets. For this reason anti- thrombin, anti-FXa, anti-tissue factor, and specific inhibitors towards active coagulation enzymes such as FVIIa, FLXa, FXIIa, and FXIIIa are also being developed. Many of these drugs have undergone Phase I and Phase II clinical trials, but despite high expectations, have failed to provide expected outcomes. As thrombosis is a poly- pathologic process, it requires a poly-pharmacologic agent for management. Single targeting of thrombotic and cardiovascular diseases may not provide desirable outcomes. Thus, drugs with a poly- therapeutic profile such as the LMWHs and combination regimens may be more effective in the management of thrombosis.
The withdrawal of Rofecoxib (Vioxx) by Merck is a case in point for the need of poly-targeting approaches. Aspirin and NSAIDs, besides being anti-inflammatory, also have specific effects by regulating COX-I and COX-II. An intricate balance is needed between these enzymes to regulate physiologic functions. To manage inflammation, COX-II inhibition was targeted and COX-I processes were untouched. This distorted the natural balance, resulting in the reported cardiovascular complications in patients treated with Vioxx. Similarly, in the case of mono-targeting anti-FXa, anti- thrombin, and anti-tissue factor drugs the poly-pharmacologic effects of heparins and oral anticoagulants are compromised. This may be the reason why DTIs exhibit rebound and other observed vascular complications. The events leading to the rejection of Ximelagatran by the US FDA advisory committee and the voluntary withdrawal of Vioxx by Merck are a clear testimony to the problems related to antithrombotic drug development. This should alert pharmaceutical industry to a greater need for carrying out more extensive preclinical pharmacologic studies. This will help identify major problems at the initial stages of the development of new antithrombotic drugs and will reduce unforeseen patient compromise at the later stages of development. At the same time, besides evaluating the major clinical endpoints, sub-studies within clinical trials can be designed to monitor endogenous physiological/ hemostatic effects of new drugs, as well as drug combinations, and to project therapeutic indices. This was apparently not done with Vioxx and Ximelagatran. As a rule, the pharmaceutical industry has resisted such opportunities due to fiscal and logistic constraints. However, major catastrophic and fiscal losses can be avoided by properly designing a drug development program.
In a sense heparins and warfarin both represent polypharmacologic agents. These drugs produce their effects via multiple mechanism besides inhibiting thrombin and Xa, which are the primary target of the anti-Xa and anti-IIa drugs. Table VI shows that LMWHs produce their effects by multiple mechanisms, whereas the direct anti-Xa and anti-IIa agents have a much narrower spectrum. Therefore, it is unlikely that the newly developed synthetic anti-Xa and anti-IIa drugs will produce similar effects as the one achieved by heparin and warfarin.
Currently, Rivaroxiban and Apixiban represent the two oral anticoagulants, which are in advanced clinical development for the management of venous thrombosis and atrial fibrillation. In addition, these agents are also aggressively developed for arterial thrombosis and venous thrombosis in medical patients. Dabigatran represents the lead antithrombin agent, which is developed for the same indications as the oral anti-Xa agents, such as Apixiban and Rivaroxiban. One of the most commonly asked questions is related to the comparison of the anti-Xa and anti-IIa agents, as these agents represent different targets. Remarkably, in the clinical trials, both classes of drugs have performed similarly. Although the safety issues such as bleeding with anti-Xa agents are reportedly less concerning than the anti-IIa agents, thrombosis rebound and liver enzyme elevation has been reported with this class of drugs. The long-term use of thrombin inhibitors may inhibit the regulatory functions of thrombin such as the activation of protein C and thrombin activatable fibrinolytic inhibitor. Also, hemostatic effects, including thrombin receptor activation in platelets and activation of factors V and XIII may be impaired. This may be the reason for enhanced bleeding with antithrombin agents. On the other hand, the Xa inhibitors may exhibit reduced efficacy in patients with preformed thrombin, which can only be inhibited using antithrombin agents. For this reason, newer agents with both anti- Xa and antiIIa activities are being developed. It is too early to tell on the relative safety and efficacy of these two classes of drugs. However, the parenteral use of antithrombin agents has been clinically validated. It is unlikely that factor Xa agents will have similar performance as the parenteral antithrombin agents.
It is likely that the newly developed monotherapeutic agents may also exhibit additional unknown effects, which have not been completely explored at this time. Moreover, these agents represent organomimetic drugs, which can be metabolized into active agents whose pharmacologic profile is unknown at this time. All of newly developed anti-Xa and anti-IIa agents represent nitrogen containing heterocyclic compounds. Some of these may contribute to the regulation of nitric oxide and produce hemodynamic modulation. Similarly, the new antiplatelet agents may also transform into active and inactive metabolites with differential pharmacologic effects. The behavior of these drugs may differ in different populations and generic polymorphism may strongly influence their therapeutic profile. Thus, unlike heparin, warfarin and aspirin where the safety and efficacy profiles are now well-known, the same level of information on the newer drugs is not available and will take some time to generate for the optimization process.
Finally, the regulatory bodies will have to assume a greater responsibility in directing pharmaceutical industry towards objective approaches to evaluate a new drug in a given indication. This will require the creation of a dedicated division within the FDA and EMEA with expertise in hemostasis and thrombosis. At the same time, closer interactions between the different divisions within the FDA should be encouraged. This will facilitate the recognition of specific issues related to the development of new antithrombotic and anticoagulant drugs, which represent a diverse group of therapeutic agents with both structural and biological heterogeneity. Moreover, a stronger scrutiny of drug development programs with more stringent monitoring of the different phases of the clinical development by the FDA is warranted to assure unbiased clinical trial conduct.
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J. FAREED1, O. IQBAL 1, J. CUNANAN1, M. DEMIR2, R. WAHI3, M. CLARKE1, C. ADIGUZEL1, R. BICK4
1 Hemostasis and Thrombosis Research Laboratoires, Loyola University Medical Center, Maywood, IL, USA
2 Trakya University School of Medicine, Edime, Turkey
3 Grant Memorial Hospital, Peterburg, West Virginia, PA, USA
4 Southwestern Medical Center, University of Texas, Dallas, TX, USA
Address reprint requests to: J. Fareed, Ph.D., Professor of Pathology and Pharmacology, Director of Hemostasis and Thrombosis Research Laboratories, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. E-mail:jfareed@lumc.edu
Copyright Edizioni Minerva Medica Jun 2008
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