Early antiplatelet therapy in coronary artery bypass grafting: a calculated benefit

Studies have demonstrated that antagonists of platelet activity, including aspirin and clopidogrel, reduce the risk of major adverse events in patients with acute coronary syndromes. Although antiplatelet agents also convey an increased risk of bleeding, particularly in patients proceeding to coronary artery bypass graft surgery, in most cases, the benefits of early initiation of antiplatelet therapy outweigh the risks. The purpose of this review is to distinguish perceived and actual risk versus the benefit associated with early antiplatelet therapy to help clinicians make informed decisions on using these agents in an acute setting where patients may require coronary artery bypass grafting.     

Antiplatelet therapy--Part I.

We summarize current information about aspirin and other antiplatelet drugs in patients with cardiac and vascular disease. For each indication, we briefly summarize the rationale for the use of antiplatelet therapy and describe the findings of relevant clinical trials. We propose recommendations for the use of these agents in clinical practice. Part I covers the use of antiplatelet therapy for the primary and secondary prevention of myocardial infarction, coronary thrombolysis, unstable and chronic stable angina, and coronary artery-saphenous vein bypass grafts. In part II we review the use of antiplatelet agents in coronary angioplasty, atrial fibrillation, artificial cardiac valves, stroke, and peripheral vascular disease.     

Antiplatelet therapy--Part II.

We summarize current information about aspirin and other antiplatelet drugs in patients with cardiac and vascular disease. For each indication, we briefly summarize the rationale for the use of antiplatelet therapy and describe the findings of relevant clinical trials. We propose recommendations for the use of these agents in clinical practice. In Part 2, we discuss the use of antiplatelet agents in coronary angioplasty, atrial fibrillation, artificial cardiac valves, stroke, and peripheral vascular disease. In Part 1, we reviewed the use of antiplatelet therapy for the primary and secondary prevention of myocardial infarction, in conjunction with coronary thrombolysis, in patients with unstable and chronic stable angina, and following coronary artery-saphenous vein bypass grafting.     

Plateletworks: a novel point of care platelet function screen

Platelet function is critically important in the acute-care settings of cardiopulmonary bypass surgery and percutaneous coronary intervention, which are commonly associated with the adverse vascular events of hemorrhage and thrombosis, respectively. To improve outcomes, it has been suggested that patients should be screened for platelet count and function periprocedurally, and therapeutic intervention including the possible use of thrombolytics and adequate anticoagulation or administration of antiplatelet agents, should be utilized. Antiplatelet therapy including aspirin (acetylsalicylic acid), the thienopyridines (clopidopgrel), and parenteral anti-glycoprotein (GP) IIb/IIIa agents (abciximab, tirofiban, and eptifibatide) are recognized as clinically important in patients at risk of developing thrombotic events. Recently, it has been recognized that empiric therapeutic administration of these agents may be suboptimal in clinical environments because of interpatient variability with regard to platelet count, platelet response, receptor concentration on the platelet, and other factors. Hence there is a clinical need to monitor such therapies on an individual basis. Traditional platelet tests including light transmission aggregometry (LTA) are inconvenient for acute diagnostic testing because of the complexity of the test and the requirement for specialty training. Hence, 'near-patient' test systems have recently been introduced. Plateletworks is an in vitro diagnostic, point-of-care test platform that has demonstrated utility in monitoring platelet response to all current antiplatelet agents including aspirin and clopidogrel.     

Heparin-induced thrombocytopenia

Thrombocytopenia is a frequent and sometimes insidious complication of anticoagulant therapy with heparin. Two types of heparin-induced thrombocytopenia with a distinct aetiology have been recognized. Type I is characterized by a mild thrombocytopenia of early onset which requires careful monitoring but usually not the cessation of heparin therapy. The mild thrombocytopenia is probably due to the mild pro-aggregatory properties of heparin and can be more severe in the presence of other predisposing factors, e.g. sepsis. Type II heparin-induced thrombocytopenia is more severe and usually occurs after a period of 7-10 days. Heparin therapy should be ceased immediately and other anticoagulant therapy initiated. The thrombocytopenia is believed to be due to the development of a heparin-dependent antibody that causes platelet aggregation and release. The precise mechanism of heparin-dependent antibody-platelet interaction is still not entirely clear but probably involves the binding of an antibody-heparin immune complex to the platelet Fc receptor.     

Target Specific Anticoagulant Peptides: A Review

Anticoagulant drugs are of crucial importance for the treatment and prophylaxis of thrombotic disorders. The use of traditional anticoagulants like heparin and warfarin is majorly associated with bleeding complications. In the quest for safer anticoagulation therapy, the interest for the isolation of novel anticoagulant compounds has shifted towards natural sources. Peptides can be considered as better alternative due to their therapeutic potential in the treatment of diseases. Peptides from hematophagous (blood-feeding) and venomous organisms have been recognized as potential anticoagulant agents. Of late, peptides derived from the hydrolysis of food proteins, including edible seaweeds, milk and seed proteins, have also shown to possess promising in vitro anticoagulant activity. To overcome the problems associated with regular anticoagulants, peptides targeting vital steps in the clotting cascade have been studied. This review focuses on anticoagulant peptides with known targets, inhibiting crucial factors in the coagulation cascade such as FXa, FXIa, FXIIa and FVIIa/TF complex, as well as peptides with unknown targets.     

Anticoagulant effects of the heparin-proline complex

In the present work, the formation of the proline-heparin complex has been established. The way to synthesize the complex in vitro has been developed. The complex synthesized with the molar ratio of proline to heparin of 3: 1 extended the time of formation of a fibrin clot, reduced platelet aggregation, and showed a lytic effect towards nonstabilized fibrin in vitro conditions. Ten minutes after intravenous administration of the proline-heparin complex, there was an increase in levels of fibrin-depolymerization, anticoagulant, antifibrin-stabilizing and antiplatelet activity in blood of animals, whereas its components, proline and heparin, did not have such effects.     

Collaborative overview of randomised trials of antiplatelet therapy--III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists' Collaboration.

OBJECTIVE--To determine the efficacy of antiplatelet therapy as prophylaxis against deep venous thrombosis or pulmonary embolism in surgical and high risk medical patients. DESIGN--Overviews of all randomised trials of antiplatelet therapy that could have been available by March 1990 and in which deep venous thrombosis was assessed systematically. SETTING--53 trials (total 8400 patients) of an average of two weeks of antiplatelet therapy versus control in general or orthopaedic surgery; nine trials (600 patients) of antiplatelet therapy versus control in other types of immobility; 18 trials (1000 patients) of one antiplatelet regimen versus another. RESULTS--Overall, a few weeks of antiplatelet therapy produced a highly significant (2P < 0.00001) reduction in deep venous thrombosis. 25% of patients allocated antiplatelet therapy versus 34% of appropriately adjusted controls had deep venous thrombosis detected by systematic fibrinogen scanning or venography, representing prevention in about 90 patients per 1000 allocated antiplatelet therapy. There was an even greater proportional reduction in pulmonary embolism: such emboli were detected among 47 (1.0%) antiplatelet allocated patients versus an adjusted control total of 129 (2.7%), representing prevention among about 17 patients per 1000 treated (2P < 0.00001). In analyses confined to surgical trials, the proportional reductions were similar and separately significant for nonfatal pulmonary embolism (0.7% antiplatelet therapy v 1.8% control; 2P < 0.00001) and for deaths attributed to pulmonary embolism (0.2% v 0.9%; 2P = 0.0001). There was a slight but non-significant excess of deaths from other causes (1.0% v 0.7%), which made the difference in total mortality nonsignificant, though still favourable (1.2% v 1.5%). Information on adding antiplatelet therapy to heparin was limited but, at least for pulmonary embolism, suggested more protection from the combination than from heparin alone. The proportional reduction in the odds of suffering a deep venous thrombosis was roughly the same in patients having general surgery, traumatic orthopaedic surgery, and elective orthopaedic surgery (and in medical patients who were at increased risk of thromboembolism). For pulmonary embolism the numbers affected were smaller, but again the reductions were highly significant both in general surgery (16 (0.5%) v 58 (1.7%) pulmonary emboli; 2P < 0.0001) and in orthopaedic surgery (28 (2.7%) v 63 (6.1%) pulmonary emboli; 2P < 0.0002). CONCLUSION--It had previously been supposed that antiplatelet therapy did not influence venous thromboembolism, and many surgeons and physicians do not use it routinely for thromboprophylaxis, even for patients who are at substantial risk of deep venous thrombosis or pulmonary embolism. These results indicate that antiplatelet therapy--either alone or, for greater effect, in addition to other proved forms of thromboprophylaxis (such as subcutaneous heparin)--should be considered.     

Lupus anticoagulant and antiplatelet properties of human hybridoma autoantibodies

The clinical association of lupus anticoagulant antibodies with thrombocytopenia and thrombosis was the rationale for investigating the in vitro reactivity of these human hybridoma lupus anticoagulant antibodies with platelets. Fifty human hybridoma antibodies from 13 patients with systemic lupus erythematosus, 2 women with multiple spontaneous abortions, and 4 normal individuals were analyzed for lupus anticoagulant, antiplatelet, anti-DNA, and antiphospholipid reactivities. Of the hybridoma antibodies studied, 25 had lupus anticoagulant activity, 21 had antiplatelet reactivity, and 7 of these antibodies had both lupus anticoagulant and antiplatelet properties. No correlation was found between lupus anticoagulant antibody activity and antiplatelet, anti-denatured DNA, anticardiolipin, anti-egg phosphatidylethanolamine, antiphosphatidylserine, antiphosphatidylinositol, and antiphosphatidylcholine reactions. In contrast, antiplatelet activity was strongly correlated with antiphosphatidylethanolamine (rho = 0.761, p less than 0.001), anticardiolipin (rho = 0.748, p less than 0.001), and anti-dDNA (rho = 0.745, p less than 0.001) reactivities. Pretreatment of platelets with deoxyribonuclease, ribonuclease, trypsin, or phospholipases A2 and C resulted in different effects on the binding of individual hybridoma antibodies to platelets, suggesting that antiplatelet antibodies may recognize different epitopes on the platelet membrane. Our data demonstrate that most hybridoma lupus anticoagulant antibodies did not bind directly to platelets in vitro. This suggests that additional serum factors may be required in vivo to explain the association of these antibodies with thrombocytopenia and thrombosis.     

A monoclonal antibody reacting with platelets for monitoring thrombolysis

Thrombus immunoscintigraphy with radiolabeled monoclonal antibodies are presently undergoing intense clinical evaluations. Reports on clinical trials of radiolabeled antifibrins are very encouraging and results of antiplatelet antibody evaluations are forthcoming. Animal studies with antiplatelet antibodies indicate that a diagnosis can be made within the critical “lytic window” of 4–6 h, and thus the imaging procedure may be used as an adjunct to thrombolytic therapy, i.e. screening of patients.We now report on a potentially new application of monoclonal antibodies, immunoimaging for monitoring thrombolysis. In vitro studies were performed with “standardized clots” incubated with ^99mTc 50H.19 and re-incubated with streptokinase (SK), urokinase (UK) or recombinant tissue plasminogen activator (rt-PA). The decrease in clot-bound ^99mTc 50H.19 activity after SK, UK or rt-PA incubation was proportional to the decrease in clot weight (r = 0.90–0.98). The direct effects of these thrombolytic agents on the labeled antibody and the possible interference of aspirin, warfarin and heparin in thrombus immunoimaging were also investigated. Aspirin, heparin and warfarin did not interfere with clot-binding of ^99mTc 50H.19. Thrombolytic agents did not affect the stability of the radiolabel or immunoreactivity of 50H.19. These results indicate that ^99mTc 50H.19 is a promising agent that may enable monitoring thrombolysis in addition to thrombus immunoimaging.     

HEPARIN IN ACUTE MYOCARDIAL INFARCTION—Observations Indicating the Potential Advantages of Using It as the Sole Anticoagulant in Therapy

There is a considerable body of experimental evidence that heparin is superior as an anticoagulant to any prothrombin depressing drugs. Furthermore its lipemia-clearing action affords other benefits which result from the removal of fat from the bloodstream. Important among these beneficial effects is the increased tissue and myocardial oxygen consumption which results from the injection of heparin in atherosclerotic patients.Because of these advantages of heparin over oral anticoagulants, the use of heparin as the sole anticoagulant for three weeks in patients with severe acute myocardial infarction was evaluated as opposed to the customary therapy where heparin is given for several days and then oral anticoagulants are used. The mortality in the dicoumarin treated group was 38 per cent, as compared with 28 per cent in the patients who received only heparin for three weeks.     

Interaction of heparin with two synthetic peptides that neutralize the anticoagulant activity of heparin

Two synthetic analogues of the heparin-binding domain of heparin/heparan sulfate-interacting protein (Ac-SRGKAKVKAKVKDQTK-NH2) and the all-d-amino acid version of the same peptide (l-HIPAP and d-HIPAP, respectively) were synthesized, and their efficacy as agents for neutralization of the anticoagulant activity of heparin was assayed. The two analogue peptides were found to be equally effective for neutralization of the anticoagulant activity of heparin, as measured by restoration of the activity of serine protease factor Xa by the Coatest heparin method. The finding that l-HIPAP and d-HIPAP are equally effective suggests that d-amino acid peptides show promise as proteolytically stable therapeutic agents for neutralization of the anticoagulant activity of heparin. The interaction of l-HIPAP and d-HIPAP with heparin was characterized by 1H NMR, isothermal titration calorimetry (ITC), and heparin affinity chromatography. The two peptides were found to interact identically with heparin. Analysis of the dependence of heparin-peptide binding constants on Na+ concentration by counterion condensation theory indicates that, on average, 2.35 Na+ ions are displaced from heparin per peptide molecule bound and one peptide molecule binds per hexasaccharide segment of heparin. The analysis also indicates that both ionic and nonionic interactions contribute to the binding constant, with the ionic contribution decreasing as the Na+ concentration increases.     

Optimal pharmacological therapy in ST-elevation myocardial infarction—a review

Antithrombotic therapy is an essential component in the optimisation of clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. There are currently several intravenous anticoagulant drugs available for primary percutaneous coronary intervention. Dual antiplatelet therapy comprising aspirin and P2Y12 inhibitor represents the cornerstone treatment for STEMI. However, these effective treatment strategies may be associated with bleeding complications. Compared with clopidogrel, prasugrel and ticagrelor are more potent and predictable, which translates into better clinical outcomes. Therefore, these agents are the first-line treatment in primary percutaneous coronary intervention. However, patients can still experience adverse ischaemic events, which might be in part attributed to alternative pathways triggering thrombosis. In this review, we provide a critical and updated review of currently available antithrombotic therapies used in patients with STEMI undergoing primary PCI. Finding a balance that minimises both thrombotic and bleeding risk is difficult, but crucial. Further randomised trials for this optimal balance are needed.     

Antiplatelet/Anticoagulant Agents and Chronic Subdural Hematoma in the Elderly

Background and Purpose

In the last decade there has been an increasing use of antiplatelet/anticoagulant agents in the elderly. The aim of the study was to evaluate the association between exposure to anticoagulant/antiplatelet therapy and chronic subdural haematoma-CSDH.

Methods

Single institution case-control study involving 138786 patients older than 60 years who visited our academic tertiary care Emergency Department from January 1st 2001 to December 31st 2010. 345 patients with CSDH (cases) were identified by review of ICD-9 codes 432.1 and 852.2x. Case and controls were matched with a 1∶3 ratio for gender, age (±5 years), year of admission and recent trauma. A conditional logistic model was built. A stratified analysis was performed with respect to the presence (842 patients) or absence (536 patients) of recent trauma.

Results

There were 345 cases and 1035 controls. Both anticoagulant and antiplatelet agents were associated with an increased risk of CSDH with an OR of 2.46 (CI 95% 1.66–3.64) and 1.42 (CI 95% 1.07–1.89), respectively. OR was 2.70 (CI 95% 1.75–4.15), 1.90 (CI 95% 1.13–3.20), and 1.37(CI 95% 0.99–1.90) for patients receiving oral anticoagulants, ADP-antagonists, or Cox-inhibitors, respectively. History of recent trauma was an effect modifier of the association between anticoagulants and CSDH, with an OR 1.71 (CI 95% 0.99–2.96) for patients with history of trauma and 4.30 (CI 95% 2.23–8.32) for patients without history of trauma.

Conclusions

Anticoagulant and antiplatelet therapy have a significant association with an increased risk of CSDH. This association, for patients under anticoagulant therapy, appears even stronger in those patients who develop a CSDH in the absence of a recent trauma.     

The use of adjunctive GPIIb/IIIa inhibitors in patients with unstable angina/non-Q-wave MI undergoing percutaneous coronary intervention

Glycoprotein IIb/IIIa receptor inhibitors represent a relatively new therapeutic approach in the field of antiplatelet therapy. Following the development of abciximab a number of small molecule GPIIb/IIIa inhibitors have been introduced such as tirofiban and eptifibatide. In this fast-moving field the interventional cardiologist needs a framework to guide decision-making for the individual patient. This review covers the efficacy and safety data from the clinical trials of GPIIb/IIIa inhibitors in the context of patients undergoing percutaneous coronary intervention for unstable angina/non-Q-wave myocardial infarction. There is an increasing body of evidence to support the efficacy of GPIIb/IIIa inhibitors in reducing the risk of adverse ischemic events in high and low risk patients undergoing percutaneous coronary intervention. A number of unresolved efficacy and safety issues remain, including the duration of treatment before and after intervention; whether a reduction in the heparin dose would further decrease the risk of hemorrhage without affecting the periprocedural thrombotic rate in patients undergoing PTCA with adjunctive GPIIb/IIIa inhibitors; and the cost-effectiveness of this therapy. When a thorough analysis of cost-effectiveness has been made, it will be easier to advocate the widespread use of these agents in all patients undergoing coronary intervention.     

Antiplatelet and anticoagulant therapy in elective percutaneous coronary intervention

Thrombosis plays a major role in acute vessel closure both after coronary balloon angioplasty and after stenting. This review will address the role of antiplatelet and anticoagulant therapy in preventing early thrombotic complications after percutaneous coronary intervention. The focus will be on agents that are routinely available and commonly used.     

A comparison of the strength of binding of antithrombin III,protamine and poly(l-lysine) to heparin samples of different anicoagulant activities

The limiting concentrations, i.e., those concentrations of sodium chloride required to completely disrupt the complexes of heparin with antithrombin III, protamine and poly(l-lysine), were determined using fluorescence techniques, in order to compare the binding strengths of these complexes. From the limiting salt concentration values, poly(l-lysine)_always exhibited stronger binding to heparin of a particular anticoagulant potentcy (degree of sulphation) than did protamine. The binding strengths of both complexes decreased as the degree of sulphation of the heparin participating in the complex was reduced. In contrast, the limiting salt concentration values for complexes formed between antithrombin III and heparin did not change with either the degree of sulphation or the biological potency of the heparin samples. A low-potency heparin simply contained a smaller amount of molecules which possessed the intact antithrombin III binding site (thus being fully ‘anticoagulant active’) than a high-potency sample. Low-affinity heparin did not contain these binding sites and thus showed a low affinity for antithrombin III. High-potency heparin, being highly sulphated, possessed a higher affinity for protamine and poly(l-lysine) than for antithrombin III. However, after partial N-desulphation of heparin, the subsequent heparin-protamine complex was more weakly bound than a significant proportion of the corresponding heparin-antithrombin III complexes. These in vitro findinds may have particular relevance in relation to the clinical condition termed ‘hheparin rebound’.     

Variability in the response to antiplatelet treatment in diabetes mellitus

Atherothrombosis is a leading cause of death in patients with diabetes mellitus. Among factors contributing to the diabetic prothrombotic state, platelet activation plays a pivotal role. Numerous studies have investigated the benefits of antiplatelet therapy for primary and secondary cardiovascular prevention in diabetic patients. However, there are limited evidences that low-dose aspirin may be effective in this clinical setting. Several disease-specific factors have been identified as potential determinants of aspirin treatment failure. In this review, the main determinants of interindividual variability in response to antiplatelet agents are discussed, with particular emphasis on the pharmacokinetic and pharmacodynamic mechanisms of clinical efficacy and safety of antiplatelet drugs in patients with diabetes mellitus.     

Structure-activity relationship of antithrombotic polysaccharide derivatives

Heparin has been the drug of choice in clinical pre-surgical and post-surgical prophylaxis of thrombotic events. However, because of its side-effects, such as bleeding and other disadvantages (i.e. chemical inhomogeneity and variability of its physiological activities), alternatives to heparin are an important field of research. A necessary procedure in the development of new drugs is the evaluation of structure-activity relationships. Genuine neutral polysaccharides were chemically modified and examined for their anticoagulant activities. The linear β-1,3-glucan curdlan, an easily available bacterial polysaccharide, served as the basic polymer. It could be established that the anticoagulant activity was dependent on the degree of sulfation and the molecular weight. For heparin, the sulfation pattern, i.e. the actual location of the sulfate groups along the heparin chain, was of importance in addition to the degree of sulfation. Therefore, we investigated whether there was also a relationship between the substitution pattern of the curdlan sulfates and their anticoagulant activity. For determination of the substitution pattern of the sulfated polysaccharides, a method was developed that is based on synthesis of the partially alkylated alditol acetates of the polymer and examination of these derivatives using combined gas chromatographymass spectrometry. In addition to the analytical data, the structure-activity relationship of anticoagulative curdlan sulfates is presented.     

New advances in the discovery of thrombin and factor Xa inhibitors

The search for the ideal anticoagulant has spanned decades and has resulted in several strategies including the clinical use of heparin, low molecular weight heparins, and the vitamin K antagonist warfarin. Over the past five years, many groups have reported preclinical results with direct-acting thrombin inhibitors and several of these are now moving into clinical trials. In addition, many groups have disclosed the discovery of potent, orally bioavailable factor Xa inhibitors. Several of these compounds are now in early clinical trials and the results are forthcoming.