Argatroban: a direct thrombin inhibitor for heparin-induced thrombocytopenia and other clinical applications

Argatroban, a direct thrombin inhibitor derived from arginine, is an effective anticoagulant indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). Argatroban has been used as an alternative anticoagulant in patients with HIT in various clinical conditions including interventional cardiovascular procedures that require anticoagulation. Satisfactory clinical outcomes with acceptable complications have been reported in these patients. Whether argatroban offers additional clinical advantage over conventional heparin therapy in patients without HIT remains unclear. Argatroban has been evaluated as an alternative anticoagulant to replace heparin in various clinical studies, especially in patients with coronary artery disease or cerebral vascular disease. To date, it remains unclear if argatroban is more effective than heparin, although the agent seems to cause less bleeding complications. This article reviews the pharmacology of argatroban and its clinical application beyond the management of HIT, with particular emphasis on interventional cardiology procedure, acute myocardial infarction, unstable angina pectoris, cerebral thrombosis or ischemic stroke, peripheral obstructive arterial disease, and extracorporeal circulation.     

New Anticoagulants: Anti IIa vs Anti Xa—Is One Better?

Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. A new strategy for the design of new antithrombotic drugs is based on selective inhibition of a specific coagulation factor. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, has shown efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux has demonstrated its efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis.     

Heparin-induced thrombocytopenia: a review

Immune heparin-induced thrombocytopenia (HIT) is a relevant adverse drug reaction consisting in a hypercoagulable state caused by an anticoagulant agent. The incidence is approximately 6.5% in patients receiving unfractionated heparin after orthopedic surgery, and is equal to or lower than 1% in other settings. HIT occurrence is a function of heparin type, duration of heparin administration, patient population, and gender. The pathogenesis is due to an antibody response to the complex heparin/platelet factor 4 in most cases, with secondary activation of platelets and coagulation, and finally increased thrombin generation. Thrombocytopenia, venous or arterial thrombosis, heparin-induced skin necrosis, adrenal hemorrhage, and transient amnesia can characterize the clinical course of HIT. Platelet monitoring in patients receiving heparin is indicated to early detect HIT. A thrombotic event can be the first manifestation of HIT. Laboratory demonstration of heparin-dependent platelet activation confirms the clinical diagnosis; antigenic or functional assays are available. Once HIT is highly likely or confirmed serologically, immediate heparin cessation is mandatory and an alternative therapeutic anticoagulant is needed due to the high risk (or the presence) of thrombotic events. The available nonheparin anticoagulants aim to reduce thrombin generation. Lepirudin, argatroban, and bivalirudin (direct thrombin inhibitors) and danaparoid and fondaparinux (factor Xa inhibitors) represent the current treatment options for HIT. Vitamin K antagonists can be used safely only after a stable platelet count has been obtained.     

Argatroban

Antithrombotic and antiplatelet therapies are the cornerstones of management of cardiovascular disorders today. Due to the safety and efficacy limitations of the classic antithrombotic, unfractionated heparin, considerable effort has been directed at developing novel anticoagulants. Direct thrombin inhibitors as a class of drugs offer inhibition of clot-bound as well as fluid-phase thrombin and a more predictable anticoagulant response. Specifically, argatroban, a synthetic small molecule direct thrombin inhibitor, selectively inhibits the catalytic site of thrombin in a reversible manner. Overall, argatroban's short half-life, ease of monitoring with an activated partial thromboplastin time, and safety in renal failure patients make this drug the preferable mode therapy for prevention of thrombosis in heparin-induced thrombocytopenia. The role of adjunctive argatroban therapy in acute coronary syndromes and during percutaneous coronary intervention is currently being studied.     

Argatroban therapy in patients with coronary artery disease and heparin-induced thrombocytopenia

The efficacy of the direct thrombin inhibitor argatroban was investigated in patients who developed heparin-induced thrombocytopenia following heparin therapy for coronary artery disease. The outcome of 121 patients treated with argatroban was compared with that of 26 patients in a historical control (i.e. patients who did not receive direct thrombin inhibition therapy). Argatroban, compared with controls, significantly reduced the 37-day composite of death, amputation or new thrombosis (30 versus 50%, p = 0.043), primarily driven by a significant decrease in new thrombosis (10 versus 31%, p = 0.01), and led to less bleeding (4 versus 15%, p = 0.046). Therefore, in patients with coronary artery disease who develop heparin-induced thrombocytopenia, argatroban provides safe, effective anticoagulation.     

Comparison of Argatroban and Hirudin for the Reperfusion of Thrombotic Arterial Occlusion by Tissue Plasminogen Activator

Despite theoretical advantages of direct thrombin inhibitors, recent clinical studies failed to show the superiority of hirudin over heparin in patients with acute coronary syndromes. However, these inhibitors have important in vitro differences for the inhibition of clot-bound thrombin that may translate into different in vivo relative efficacy. The effects of two direct thrombin inhibitors, argatroban and hirudin, on the reperfusion of thrombotic arterial occlusion by t-PA were compared. In anesthetized rabbits thrombotic occlusion was induced in the femoral artery. t-PA, aspirin, and various doses of argatroban (1.25, 2.5, and 5.0 mg/kg/h) or hirudin (2.5 and 5.0 mg/kg/h) were administered (six animals in each group). Blood flow was measured for 4 hours. Animals treated with 2.5 mg argatroban more rapidly achieved full reperfusion than those treated with high-dose argatroban or hirudin (P < 0.05). At the doses that induced comparable prolongation of bleeding time, argatroban showed a significantly faster and higher level of reperfusion than hirudin. In animals treated with hirudin, there was a positive correlation between the aPTT and the mean reperfusion blood flow (r = 0.70, P < 0.05). In animals treated with argatroban, this correlation did not exist and the high-dose argatroban was paradoxically less effective in promoting thrombolysis despite greater anticoagulation effects. In this animal model of arterial thrombosis, argatroban was more effective than hirudin in inducing rapid, full reperfusion with t-PA. Although they are both direct thrombin inhibitors, these two agents showed important dose-related differences in efficacy and anticoagulant effects.     

Small-molecule direct antithrombins: argatroban

Argatroban represents the first antithrombin agent that was approved for clinical use. It belongs to the peptidomimetic (arginomimetic) group of drugs with multiple pharmacological properties. Unlike the other antithrombin drugs, such as hirudins and hirulogs, argatroban is a reversible antithrombin agent and therefore exhibits a considerably different pharmacological profile. Although argatroban is considered to be a member of the antithrombin family, its mechanisms of action include several other processes that have not been explored fully to date. These include the inhibition of non-thrombin serine proteases, a direct effect on endothelial cells and the vasculature (generation of nitric oxide), and downregulation of various inflammatory and thrombotic cytokines. Due to its lower molecular weight, argatroban is capable of passing through endovascular and cellular barriers and may, therefore, be more effective than heparins and hirudins in the antithrombotic management of microvascular disorders. Argatroban is an effective anticoagulant agent that produces a stronger anticoagulant effect than heparins and hirudins at equivalent anticoagulant levels, as measured by the activated clotting time (ACT) and activated partial thromboplastin time (APTT). At comparable ACT (300 seconds) and APTT (75-90 seconds), argatroban produces stronger inhibition of thrombin generation, as measured by in-vitro assays. Argatroban does not generate any neutralizing or non-neutralizing antibodies, and has predictable antithrombotic effects in different patients. In addition to the inhibition of thrombogenesis, argatroban also facilitates blood flow, inhibition of platelet activation and endothelial cell stimulation, mechanisms that are not necessarily related to thrombin inhibition. Despite these pharmacological advantages, additional clinical investigations are needed to validate the use of argatroban in clinical indications other than those for which it is currently approved, namely, heparin-induced thrombocytopenia and support of percutaneous coronary angioplasty.     

Catheter-directed thrombolysis of acute lower extremity arterial thrombosis in a patient with heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an underdiagnosed problem, and the optimal treatment of arterial thrombosis in patients with HIT remains controversial. There are many angiographic procedures which require heparin as an adjunctive agent; however, some of the heparin-related complications and their management remains unclear. We are presenting a 77-year-old male patient with HIT, who developed acute lower extremity limb threatening ischemia due to arterial thrombosis. In our case, the patient has been successfully treated with percutaneous catheter-directed thrombolysis with tissue plasminogen activator and a direct thrombin inhibitor argatroban.     

An update on heparins at the beginning of the new millennium

Unfractionated heparin has enjoyed the sole anticoagulant status for almost half a century. Besides an effective anticoagulant, this drug has been used in several additional indications. Despite the development of newer anticoagulant drugs, unfractionated heparin has remained the drug of choice for surgical anticoagulation and interventional cardiology. In the area of hematology and transfusion medicine, unfractionated heparin has continued to play a major role as an anticoagulant drug. The development of low-molecular-weight heparins (LMWHs) represents a refinement for the use of heparin. These drugs represent a class of depolymerized heparin derivatives with a distinct pharmacologic profile that is largely determined by their composition. These drugs produce their major effects by combining with antithrombin and exerting antithrombin and anti-Xa inhibition. In addition, the LMWHs also increase non-antithrombin-dependent effects such as TFPI release, modulation of adhesion molecules, and release of profibrinolytic and antithrombotic mediators from the blood vessels. The cumulative effects of each of the different LMWHs differ and each product exhibits a distinct profile. Initially these agents were developed for the prophylaxis of postsurgical deep-vein thrombosis. However, at this time these drugs are used not only for prophylaxis, but also for the treatment of thrombotic disorders of both the venous and arterial type. To a large extent, the LMWHs have replaced unfractionated heparin in most subcutaneous indications. With the use of these refined heparins, outpatient anticoagulant management has gone through a dramatic evolution. For the first time, patients with thrombotic disorders can be treated in an outpatient setting. Thus, the introduction of LMWHs represents a major advance in improving the use of heparin. The development of the oral formulation of heparin and LMWHs also provides an important area that may impact on the use of heparin and LMWHs. The increased awareness of heparin-induced thrombocytopenia has necessitated the development of newer methods to identify patients at risk of developing this catastrophic syndrome. Furthermore, a strong interest has developed in alternate drugs or the management of patients with this syndrome. Despite the development of alternate anticoagulants that are mostly antithrombin derived (hirudins, hirulog), these agents have failed to provide similar clinical outcome as heparin in many indications. However, antithrombin drugs are useful in the anticoagulant management of heparin-compromised patients. The FDA has approved a recombinant hirudin (Refludan) and a synthetic antithrombin agent, argatroban (Novastan), for this indication. The development of synthetic heparin pentasaccharide and anti-Xa agents may have an impact on the prophylaxis of thrombotic disorders. However, these monotherapeutic agents do not mimic the polytherapeutic actions of heparin. Furthermore, these agents do not inhibit thrombin. Heparin and LMWHs are capable of inhibiting not only factor Xa and thrombin, but other serine proteases in the coagulation network. The only way the newer drugs can mimic the actions of heparin is in combination modalities (polytherapeutic approaches). It has been suggested that newer antiplatelet drugs also exhibit anticoagulant actions. While these drugs may exhibit weak effects on thrombin generation, none of the currently available antiplatelet drugs exhibit any degree of antithrombin actions. It is likely that heparins synergize or augment the effects of the new antiplatelet drugs. Currently, combination approaches are used to anticoagulate patients in these studies. The dosage of heparins has been arbitrarily reduced. This may not be an optimal procedure. Additional clinical studies are needed to study these combinations where the alterations of these drugs are compared. Such combinations will require newer monitoring approaches. The development of oral thrombin agents, GP IIb     

Thrombocytopenia following heparin flush

A total of 23 patients who developed heparin-induced thrombocytopenia following exposure to heparin solely due to intravascular catheter or filter flush were the subjects of prospective studies of argatroban therapy. Heparin doses were 10-13,000 U, with a mean exposure of 8+/-4 days. Following heparin-induced thrombocytopenia diagnosis and heparin cessation, 13 patients received argatroban (mean dose of 1.8+/-1.1 mg/kg/min for 5.5+/-3.9 days), achieving activated partial thromboplastin times of 63+/-23 seconds, and 10 historical control patients received no direct thrombin inhibitors. Platelet count recovered to a mean of 207+/-153 x 10(9)/L (n=12) after 5.5+/-3.9 days of argatroban therapy and to a mean of 127+/-63 x 10(9)/L (n=8) 5 days after baseline in the control group. A composite end point of death, amputation, or new thrombosis within 37 days occurred in five (38.5%) argatroban-treated patients and four (40%) controls. Death was the most common untoward outcome (approximately 30% of each group). No argatroban-treated patient and two (20%) control patients experienced new thrombosis. Major bleeding was comparable between groups. Heparin-induced thrombocytopenia can occur following minimal heparin exposure, including heparin flushes; in these patients, argatroban provides effective alternative anticoagulation as compared with historical controls.     

Novel oral anticoagulants for heparin-induced thrombocytopenia

To review the use of the novel oral anticoagulant (NOAC) agents for the treatment of heparin-induced thrombocytopenia (HIT) from relevant clinical trial data. A MEDLINE, International Pharmaceutical Abstracts, ClinicalTrials.gov, and Google-Scholar searches (1966–March 2016) were conducted using the keywords: thrombocytopenia, NOACs, dabigatran, apixaban, rivaroxaban, edoxaban, Xa inhibitor, direct thrombin inhibitor. Articles evaluating the new oral anticoagulants for thrombocytopenia published in English and using human subjects were selected. Eight clinical trials were identified. References cited in identified articles were used for additional citations. Approximately 12 million hospitalized patients each year are exposed to heparin for thromboprophylaxis. HIT, an immune-mediated, prothrombotic adverse reaction is a potential complication of heparin therapy. As a result, heparin products must be immediately withdrawn and replaced by alternative anticoagulants to compensate for the thrombotic risk associated with HIT. Limitations exist with the only currently FDA approved heparin alternative, argatroban. NOACs have been considered as potential alternatives to traditional agents based on their pharmacologic activity. Case reports have indicated positive results in patients, with clinical outcomes and tolerability supporting the use of the NOACs as alternative agents in the treatment of HIT. Positive results have been reported for the use of NOACs in the treatment of HIT. Further robust studies are needed for definitive decision making by clinicians.     

Predictors of clinical outcome in patients with heparin-induced thrombocytopenia treated with direct thrombin inhibition

We aimed to identify predictors of poor outcome in patients with heparin-induced thrombocytopenia, a serious immune-mediated reaction to heparin. All patients were treated with direct thrombin inhibition therapy, as part of two prospective studies. We performed a risk factor analysis of adverse outcomes (defined as death, amputation, new thrombosis, or their composite within a 37-day study period) in 809 patients from two reported prospective studies of the direct thrombin inhibitor argatroban in clinically diagnosed heparin-induced thrombocytopenia. We initially identified from among 14 baseline variables the significant predictors of poor outcome in the first study (304 patients), and then tested our resultant hypothesis in the second, independent study (505 patients), using multivariate analysis. Seven significant predictors were identified in the first study; three were confirmed in the second study. The strongest relationship occurred between the baseline platelet count and the composite of death, amputation, or new thrombosis (P = 0.0001), with the most severely thrombocytopenic patients being at greatest risk. The other significant associations were between renal impairment and death (odds ratio = 2.13, 95% confidence interval = 1.23-3.66, P = 0.007), and between cardiovascular surgery (particularly peripheral vascular surgery) and amputation (odds ratio = 3.39, 95% confidence interval = 1.65-6.95, P = 0.0009). In conclusion, in patients with clinically diagnosed heparin-induced thrombocytopenia, the severity of the baseline thrombocytopenia is the best predictor of death, amputation or thrombotic progression. The identification of higher risk subgroups for poor outcomes, such as patients with more severe thrombocytopenia or a history of renal impairment or peripheral vascular surgery, could allow more targeted therapy.     

Pharmacology of argatroban

Argatroban is a synthetic, small-molecule direct thrombin inhibitor that is approved in the USA, the EU and Japan for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and for anticoagulation of HIT patients undergoing PCI. Argatroban binds reversibly to, and inhibits both soluble and clot-bound thrombin. Argatroban does not generate antibodies, is not susceptible to degradation by proteases and is cleared hepatically. It has a predictable anticoagulant effect and there is a good correlation between dose, plasma concentration and pharmacodynamic effect. Initial clinical studies suggest that further investigations to establish the use of argatroban in ischemic stroke, acute coronary syndrome, hemodialysis, blood oxygenation, off-pump cardiac surgery and other clinical indications are warranted.     

Identification and treatment of arterial thrombophilia

Opinion statement Once the diagnosis of a thrombophilic state has been established, management must include one or more strategies designed to attenuate thrombotic risk and the likelihood of clinical events. In the case of drug-induced arterial thrombosis provoked by oral contraceptives, hormone replacement therapy, heparinoids, cocaine, or thienopyridine-related thrombotic thrombocytopenic purpura (TTP), the offending agent should be discontinued immediately. Anticoagulant therapy and platelet-directed therapies, either alone or in combination, should be considered for patients experiencing a single arterial or venous thrombosis (secondary prevention), with treatment duration determined by diagnostic studies and the persistence of a prothrombotic state. Other specific therapies should be directed at the underlying thrombophilic disorder. These treatments include direct thrombin inhibitors such as argatroban for heparin-induced thrombocytopenia (HIT), myelosuppressive drugs such as hydroxyurea for essential thrombocytosis, plasma exchange for thrombotic thrombocytopenic purpura, and phlebotomy for polycythemia vera. Additionally, the treating physician must seek input early from a hematologist or rheumatologist when managing patients with known or suspected HIT, TTP, and myeloproliferative disorders, or the antiphospholipid syndrome, respectively. This interdisciplinary interface is critical to ensure an optimal outcome when treating patients with arterial thrombophilia.     

Successful Coronary Interventions Performed with Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

Patients with heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) frequently have coincident vascular disease. Patients with HITTS who require vascular procedures have often been excluded from vascular intervention because intravascular procedures require heparin. Re-exposure to heparin places these patients at great risk for reactivation of thrombosis related to HIT antibody. We present our initial experience with an alternative anticoagulant to heparin, argatroban in patients with HIT antibody who underwent 14 coronary interventions. All 14 coronary lesions were treated successfully and no patient suffered an HITTS-related or an argatroban-related complication.     

A Synopsis of the Clinical Uses of Argatroban

Argatroban, a direct thrombin inhibitor, has been used in Japan since the early 1980's and was recently approved for use in the United States for patients with heparin-induced thrombocytopenia. However, its use has been studied in other clinical settings including, myocardial infarction, percutaneous coronary intervention and cerebral thrombosis. The doses used in the different clinical situations vary, but argatroban offers the advantage of not requiring renal adjustment. Because of its small molecular weight, argatroban has the ability to inhibit both clot bound and soluble thrombin. This paper provides a comprehensive review of both indicated and off label uses of argatroban. Pharmacology, pharmacokinetics, adverse events and drug interactions with argatroban are also discussed.     

A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with Novastan and TPA (MINT) study

OBJECTIVES

This study examined the effect of a small-molecule, direct thrombin inhibitor, argatroban, on reperfusion induced by tissue plasminogen activator (TPA) in patients with acute myocardial infarction (AMI).

BACKGROUND

Thrombin plays a crucial role in thrombosis and thrombolysis. In vitro and in vivo studies have shown that argatroban has advantages over heparin for the inhibition of clot-bound thrombin and for the enhancement of thrombolysis with TPA.

METHODS

One hundred and twenty-five patients with AMI within 6 h were randomized to heparin, low-dose argatroban or high-dose argatroban in addition to TPA. The primary end point was the rate of thrombolysis in myocardial infarction (TIMI) grade 3 flow at 90 min.

RESULTS

TIMI grade 3 flow was achieved in 42.1% of heparin, 56.8% of low-dose argatroban (p = 0.20 vs. heparin) and 58.7% of high-dose argatroban patients (p = 0.13 vs. heparin). In patients presenting after 3 h, TIMI grade 3 flow was significantly more frequent in high-dose argatroban versus heparin patients: 57.1% versus 20.0% (p = 0.03 vs. heparin). Major bleeding was observed in 10.0% of heparin, and in 2.6% and 4.3% of low-dose and high-dose argatroban patients, respectively. The composite of death, recurrent myocardial infarction, cardiogenic shock or congestive heart failure, revascularization and recurrent ischemia at 30 days occurred in 37.5% of heparin, 32.0% of low-dose argatroban and 25.5% of high-dose argatroban patients (p = 0.23).

CONCLUSIONS

Argatroban, as compared with heparin, appears to enhance reperfusion with TPA in patients with AMI, particularly in those patients with delayed presentation. The incidences of major bleeding and adverse clinical outcome were lower in the patients receiving argatroban.     

Percutaneous interventions in patients with immune-mediated heparin-induced thrombocytopenia

The use of unfractionated heparin, the traditional antithrombotic agent during percutaneous coronary interventions (PCI), is associated with the risk of heparin-induced thrombocytopenia, a rare but often fatal clinical condition. This article focuses on several issues related to heparin-induced immune-mediated thrombocytopenia (HIT, type II) and alternative modes of periprocedural anticoagulation in patients with suspected or known HIT. The hypercoagulable state characterizing HIT, along with mechanical plaque disruption resulting from PCI place patients with HIT at particular risk of thrombosis during PCI. Given that a diagnosis of HIT precludes any further use of heparin, other treatment modalities are essential. Direct thrombin inhibitors are the drugs of choice in this challenging situation. These agents offer several advantages as anticoagulants for patients with HIT: (1) the ability to inhibit both thrombin that is bound to fibrin (clot-bound thrombin) and fluid-phase free thrombin; (2) rapid achievement of steady state; and (3) no cross-reactivity with HIT antibodies. Recent data on the use of bivalirudin, lepirudin, and argatroban in the setting of PCI in patients with HIT are encouraging. Optimal dosing regimens for argatroban, lepirudin, and bivalirudin should be further established in PCI patients.     

Direct thrombin inhibitors in the treatment of immune-mediated heparin-induced thrombocytopenia

Heparin was first discovered in 1916 and at present is used in more than 12 million patients a year. In the 1950s, several physicians noticed an uncommon paradoxical phenomenon in which heparin appeared to function as a procoagulant instead of an anticoagulant. This phenomenon is now known as the immune-mediated heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS). Our understanding of this syndrome has evolved over the last 2 to 3 decades, and therapeutic options are arising. This article will focus on the most extensively studied therapy for HIT, which is the class of drugs known as the direct thrombin inhibitors. Specifically, we will focus on the mechanisms by which direct thrombin inhibitors may be useful in this syndrome, the evidence for their use, and the unique characteristics of the two FDA-approved agents in this class, lepirudin and argatroban.     

The cost-effectiveness of argatroban treatment in heparin-induced thrombocytopenia: the effect of early versus delayed treatment

A decision-tree analysis was used to estimate the average cost per patient using the direct thrombin inhibitor argatroban for early treatment (<48 hours after thrombocytopenia onset) compared with delayed treatment (> or =48 hours after thrombocytopenia onset) of immune-mediated heparin-induced thrombocytopenia (HIT) with or without thrombosis. Clinical probability data used to populate the model were obtained from argatroban clinical trials and from published clinical literature. Resource utilization data and cost data were also obtained from available literature, the 2003 Physician's Fee Reference, the Healthcare Cost and Utilization Project 2000, the 2003 Drug Topics RedBook, and a modified Delphi panel. The total per-patient cost included hospital days, diagnostic tests, heparin, argatroban, major hemorrhagic events, and patient outcomes (ie, amputation, new thrombosis, stroke, or death), multiplied by the probability of each event. The incremental cost-effectiveness ratio was calculated by dividing the incremental cost between patients with and without argatroban treatment by the incremental effectiveness, or the cost per new thrombosis event avoided. The mean cost per HIT patient without thrombosis who did not receive argatroban was $38,046. The mean cost decreased by 6.85% for patients who were treated earlier with argatroban therapy (average cost, $35,441), representing a $2605 saving per patient compared with those not treated with argatroban. For those receiving delayed argatroban therapy, the mean cost increased by $9024 per patient compared with those receiving early treatment with argatroban. The mean cost for HIT patients with thrombosis who did not receive argatroban was $48,101, which was 9.0% higher than for those receiving early argatroban therapy, representing a $3957 savings per patient. For HIT with thrombosis, mean costs increased by 18.2% in patients whose argatroban was delayed, representing a cost increase of $8020 per patient compared with early treatment (mean cost $44,144 for early treatment and $52,164 for delayed treatment). The results of this analysis support the recommendation to initiate early argatroban treatment upon suspicion of HIT to reduce the thrombotic consequences of HIT and associated healthcare costs. Argatroban therapy should not be delayed pending the results of HIT diagnostic tests.