Rakesh Wahi

Survival of Heparins, Oral Anticoagulants, and Aspirin after the Year 2010

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants, and aspirin. Despite remarkable progress in life sciences, these drugs still remain a challenge and a mystery to us, and their use is far from optimized. The development of low-molecular-weight heparins and the synthesis of heparinomimetics, such as the chemically synthesized pentasaccharide, represent a refined use of heparin. Additional drugs from this knowledge 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, glycoprotein IIb/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 as the approach of choice to manage thrombotic disorders. The new anticoagulant targets, including specific sites in the hemostatic network such as tissue factor, individual clotting factors (IIa, VIIa, IXa, Xa, XIIa, and XIIIa), recombinant forms of serpins (antithrombin, heparin cofactor II, and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin, and site-specific serine protease inhibitor complexes have also been developed. There is a major thrust on the development of orally bioavailable anticoagulant drugs (anti-Xa and anti-IIa agents), which are slated to replace oral anticoagulants. Both the anti-factor Xa and antithrombin agents have been developed for oral use and have provided impressive clinical outcomes in sponsor trials for the postsurgical prophylaxis of venous thrombosis; however, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the U.S. Food and Drug Administration did not approve the orally active antithrombin agent ximelagatran for several indications. The synthetic pentasaccharide (fondaparinux) has undergone an aggressive 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 cyclooxygenase (COX)-1 and P2Y (12) receptors as targets for new drug development. Prasugrel, a novel thienopyridine, cangrelor, and AZD 6140 represent newer P2Y (12) antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas prasugrel requires metabolic activation. Though clinically effective, recent results have prompted a closure of a large clinical trial with prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive for several reasons; 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 beyond 2010.

Product Individuality of Commercially Available Low-Molecular-Weight Heparins and Their Generic Versions: Therapeutic Implications:

The currently available brand-name low-molecular-weight heparins (LMWHs) in the United States include dalteparin (Pfizer), enoxaparin (Aventis), and tinzaparin (Pharmion). Other products available, in Europe, include certoparin (Novartis), reviparin (Abbott), nadroparin (GlaxoSmithkline), and parnaparin (Alpha-Wasserman). Each of these LMWHs has a characteristic molecular weight profile and biological activity in terms of an anti-FXa and anti-FIIa potency. The mean molecular weight of these drugs ranges from 4.0 kDa to 7.0 kDa and the anti-FXa:anti-FIIa ratio ranges from 1.5 to 3.5. These agents may also be characterized by the presence of specific chemical end groups such as 2-O-sulfo-4-enepyranosuronic acid at the nonreducing terminus (enoxaparin) or 2,5-anhydro-D-mannose at the reducing terminus (dalteparin). Further, the component oligosaccharide chains exhibit product-specific distribution profiles. It is now widely accepted that individual LMWHs are chemically unique agents and cannot be interchanged therapeutically. Each commercial LMWH has been individually developed for specific clinical indications, which are dose and product dependent. Recently, several generic LMWHs have become available in India (Cutenox and Markaparin) and South America (dilutol, clenox, dripanina), and three companies have filed for regulatory approval of a generic version of enoxaparin in the United States. As the primary aim of a generic drug is to reduce cost without compromising patient care, a generic drug is required to be chemically and biologically equivalent to the pioneer drug. Because LMWHs represent complex natural mucopolysaccharide drugs that have undergone chemical and enzymatic modifications, physicochemical and biological information in addition to molecular weight and anti-FXa:anti-FIIa ratio should be used to determine generic equivalency to the branded drug. We have utilized a previously reported approach to systematically compare three generic versions of enoxaparin obtained from India and Brazil with the branded enoxaparin (Lovenox) available in the United States. Testing included molecular and structural profiling, evaluation in clot-based and amidolytic anti-FXa and anti-FIIa assays, and heparinase-I digestion profiles. While the molecular profiles (4.8 ± 1.8kD) and anticoagulant potencies as determined by activated partial thromboplastin time (APTT) were comparable for all four agents, the generic products showed variations in the thrombin time (TT) and Heptest assays. Two generic and the branded enoxaparin were readily digested by heparinase-I, losing most of their anticoagulant activity, but one generic product resisted digestion. This may have been due to a unique structural feature in this product. These studies show that, while generic LMWHs may exhibit acceptable molecular weight and anti-FXa profiles, they can exhibit assay-based differences and digestion profiles. Testing in animal models to determine safety, efficacy, and pharmacodynamic parameters may be important to verify equivalence. In order to assure that the generic LMWHs are equivalent to branded LMWHs such that equivalent clinical results are obtained, there is a need to develop clear stepwise guidelines that will establish equivalency in terms of physical, chemical, biochemical, pharmacokinetic, and pharmacodynamic properties for these anticoagulant drugs.

Interpretation of Benefit-Risk of Enoxaparin as Comparator in the RECORD Program: Rivaroxaban Oral Tablets (10 milligrams) for Use in Prophylaxis in Deep Vein Thrombosis and Pulmonary Embolism in Patients Undergoing Hip or Knee Replacement Surgery

The Regulation of Coagulation in Major Orthopedic surgery reducing the Risk of DVT and PE (RECORD) clinical program of rivaroxaban consists of 4 phase III clinical trials comparing rivaroxaban with enoxaparin for the prevention of venous thromboembolism (VTE) in patients undergoing either total hip or total knee replacement surgery. Despite the comprehensive and extensive nature of this program, it had some logistic issues that included the dosing of the enoxaparin which was not only inconsistent with the recommendations but the dosages used were not optimal. The duration of treatment while consistent with rivaroxaban did vary with enoxaparin and was somewhat short. The bleeding definitions and safety evaluations were not consistent in accordance with the current recommendations. Moreover, the RECORD program has no power to show differences in major bleeding. The cardiovascular rebound phenomenon should have been adequately addressed and may require additional clinical validation to establish the safety of rivaroxaban. Although the US Food and Drug Administration (FDA) advisory committee has recommended approval of rivaroxaban, the reported analysis strongly suggests additional clinical validation on the claimed benefit/risk ratio of this monotherapeutic anticoagulant.

Are All Low Molecular Weight Heparins Equivalent in the Management of Venous Thromboembolism

Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.

Contaminant in the Recalled Unfractionated Heparin Preparations: Where is the Problem?

In a recently held press conference, the USFDA (United States Food and Drug Administration) briefed the press that the potential contaminant in the recalled Baxter product is a heparin-like substance. The USFDA commented that heparin-like molecules have been identified using high-tech methods. No specifics regarding these contaminants were given. The manufacturing process of heparin is such that other heparin-like contaminants, such as the dermatan sulfate, heparan sulfate, and chondroitin sulfate are removed effectively. These represent the main contaminants in heparin. However, these contaminants are unlikely to produce any allergic effects, nor the reported adverse reactions, because some of the antithrombotic drugs contain significant amounts of these heparin-like substances. Because of the carbohydrate nature of the contaminants identified by a special method of nuclear magnetic resonance (NMR), it is quite disturbing to note that such contaminants may have inadvertently been added to the recalled heparin. Heparin-like materials have been isolated from the shellfish, marine plants, bones, or skin of mammalian origin for several therapeutic purposes. Although structurally similar, these heparin-like substances exhibit different biochemical and pharmacologic effects. There are also various protein contaminants that can be expected along with the carbohydrates. Thus, it is likely that besides the carbohydrate contaminants, some unknown protein contaminants may also be present in these products. The statement that a heparin-like material was identified using high-tech methods is ambiguous and misleading. Such statements should be specific and clear regarding the methods used and the nature In late January, Baxter Healthcare Corporation voluntarily recalled the following lots of heparin: 107054, 117085, 047056, 097081, 107024, 107064, 107066, 107074, and 107111. These products were labeled as heparin 1000 U/mL in 10 mL vials and heparin 1000 U/mL in 30 mL vials. The reason for this recall was the reported adverse reactions, which were associated with the use of these heparin batches. These included abdominal pain, hypotension, burning, chest pain, diarrhea, dizziness, dyspepsia, dyspnea, arrhythmia, flushing, headache, hyperthyroidism, hypoesthesia, increased lacrimation, loss of consciousness, malaise, nausea, pallor, palpitation, paresthesia, pharyngeal edema, restlessness, vomiting, stomach discomfort, tachycardia, thirst, trismus, unresponsiveness to stimuli, and drug ineffectiveness. These adverse reactions were reported in hundreds of patients treated with these heparins in the USA. Initially 19 deaths were linked with the use of the recalled heparins. However, this figure has now reached 81, and it is likely that it will go even higher. These multiple adverse reactions were later attributed to heparin manufactured by Baxter’s [Deerfield, IL] suppliers using Chinese raw material from SPL Changzhou, China. Subsequently, Baxter recalled all of the remaining lots and doses of its heparin sodium injection multidose, single dose vials, and Hep-lock heparin flush product.

Reduced Immunogenic Potential of Membrane Filtered Bovine Thrombin Preparations for Hemostatic Application

There is concern that exposure to bovine thrombin can result in the development of antibodies, usually against factor V/Va, which can lead to hemostatic abnormalities. It is thought that purer preparations of bovine thrombin might be less immunogenic. Utilizing newer methods including a membrane filtration step, bovine crude thrombin is further purified into thrombin 4A and 4B preparations which exhibit a higher specific activity and are devoid of some of the protein contaminants. Bovine crude thrombin and its purified versions were administered intravenously to individual groups of rabbits using standard immunologic protocols. Antiserum was drawn from each rabbit and the pooled antisera were purified to obtain the IgGs using protein G affinity columns. The results suggest that the reported purification process, including filtration, resulted in the removal of most of the antigens found in crude thrombin, and that none of these preparations generated any detectable antibodies against bovine factor V related antigens.

Safety and efficacy of thrombin-JMI: A multidisciplinary expert group consensus

Background: The use of bovine thrombin has been an effective approach to aiding hemostasis during surgery for over 60 years. Its use has a reported association with the development of antibodies to coagulation factors with limited evidence to the clinical significance. Methods: The Collaborative Delphi survey methodology was used to develop a consensus on specified topic areas from a panel of 12 surgeons/scientists who have had experience with topical thrombins; it consisted of 2 rounds of a Web-based survey and a final live discussion. Results: Some key issues that reached consensus included: bovine, human plasma-derived and recombinant human thrombin are equally effective hemostatic agents with similar adverse event rates, and immunogenicity to a topical protein rarely translate into adverse events. Conclusions: Although a risk of immunogenicity is associated with all topical thrombins, no conclusive clinical evidence is available that these antibodies have any significant effect on short- and long-term clinical consequences.

Contaminated Heparin Preparations, Severe Adverse Events and the Contact System

To the Editor: A recently published article ‘‘Contaminated heparin associated with adverse clinical events and activation of the contact system,’’ Kishimoto et al, New England Journal of Medicine, 2008;358:2457-2467 discussed the role of oversulfated chondroitin sulfate (OSCS) in contaminated heparin in reference to adverse clinical events and the activation of the contact system. The authors concluded that this article provided is scientific rationale for the potential biologic link between OSCS and observed clinical events. Moreover, the authors suggested that a simple nonspecific amidolytic method for the generation of kallikrein could be used for the screening of OSCS and other highly sulfated polysaccharide components in heparin. This article implied that contact activation leading to the generation of kallikrein and subsequent formation of bradykinin is responsible for the anaphylactic responses in patients anticoagulated with heparin. The authors are to be commended for the expeditious work of the preliminary experiments to address their hypothesis which, OSCS is primarily responsible for the reported adverse events after the administration of contaminated heparin. However, most of the interpretations are based on speculation and the reported data are grossly overinterpreted. The reported adverse reactions and death with the use of contaminated heparin represents complex pathophysiologic responses with multifactorial etiologies where OSCS mediated contact activation, may or may not have played a role. Although OSCS represents one of the main detectable contaminants, the recalled heparin preparations may also contain several other heparin-like and nonheparin substances, which have not been fully investigated, and their association with the reported adverse events is not established at this time. The contaminated heparins also contained highmolecular-weight dermatan sulfate which itself may have complex interactions with heparin and OSCS. The single-case reports described by the authors on the patient developing hypotension and other adverse reactions during dialysis represents an incidental finding and the authors fail to describe the nature of anaphylactoid reaction. Moreover, none of the plasma markers and other workups for anaphylaxis was reported. In addition, the authors did not provide the amount of contaminant in the heparin preparation that this patient was exposed. This single-case report does not prove cause/effect for OSCS in producing anaphylaxis. In a recent news article in the Chicago Tribune, Wednesday, July 30, 2008/Section 3, the Food and Drug Administration (FDA) said ‘‘it completed its review of 93 deaths reports related to heparin that the agency reviewed from Jan. 1st to March 31st, when reports of heparin adverse reactions peaked.’’ Of the 10 cases of severe anaphylaxis and hypotension, only 3 of those were reported traced to the lot numbers of heparins that tested positive for OSCS. The cause for the other 7 deaths was not determined. Of the remaining 83 reports, the cause of deaths was complex and included bleeding. The details of the 3 reported deaths, which were linked to OSCS containing heparin, were not available. It is important that supportive data on the levels of contact mediated activation products such as bradykinin, From Jobst Vascular Center, Toledo, Ohio (ER); and Loyola University Medical Center, Maywood, Illinois (RW, HLM).