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.     

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.     

Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia

We report two patients with deep-vein thrombosis complicating immune heparin-induced thrombocytopenia who developed venous limb gangrene during overlapping therapy with a direct thrombin inhibitor (lepirudin or argatroban) and warfarin. In both patients, therapy with the direct thrombin inhibitor was interrupted during persisting severe athrombocytopenia while warfarin administration continued. Both patients exhibited the typical feature of a supratherapeutic international normalized ratio (INRs, 5.9 and 7.3) that has been linked previously with warfarin-associated venous limb gangrene. These data suggest that warfarin anticoagulation be postponed in patients with acute heparin-induced thrombocytopenia until substantial recovery of the platelet count has occurred.     

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.     

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.     

A comparison of lepirudin and argatroban outcomes.

Although both argatroban and lepirudin are used for the management of heparin-induced thrombocytopenia (HIT), data comparing these agents are lacking. The objective of this project was to compare the clinical outcomes of lepirudin vs argatroban therapy. Patients who received a direct thrombin inhibitor (DTI) from January 2000 to December 2001 were identified. Medical charts were retrospectively reviewed and relevant data extracted. The primary efficacy outcome was effective anticoagulation and the primary safety outcome was major bleeding. Data were analyzed using the t test and Fisher's exact test. Sixty-one lepirudin patients and 29 argatroban patients received a DTI during the study period. A new diagnosis of HIT was the indication for DTI therapy in 44.8% of argatroban patients and 57.4% of lepirudin patients. Effective anticoagulation was achieved in 77.8% of argatroban patients and 69.5% of lepirudin patients (p = .61). Major bleeding occurred in 10.3% and 11.5% of argatroban and lepirudin patients, respectively (p = 1.0). Argatroban and lepirudin demonstrated comparable safety and efficacy outcomes.     

Argatroban therapy for heparin-induced thrombocytopenia in acutely ill patients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated adverse reaction to heparin therapy. To evaluate clinical outcomes and effects of argatroban therapy in acutely ill HIT patients. Retrospective analysis. Hospital in-patient. Acutely ill patients with clinically diagnosed HIT from previous multicenter, historically controlled studies of argatroban therapy in HIT. Argatroban, adjusted to maintain activated partial thromboplastin times 1.5 to 3 times baseline, or historical control therapy (ie, no direct thrombin inhibition). We identified 488 patients who received argatroban (N = 390; mean dose of 1.9 microg/kg/min for a mean 6 days) or historical control therapy (N = 98) for HIT. The primary all-cause composite endpoint of death, amputation, or new thrombosis within 37 days occurred in 133 (34.1%) argatroban-treated patients and 38 (38.8%) controls (P = .41). Argatroban, versus control, significantly reduced the primary thrombosis-related composite endpoint of death because of thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis (17.7% vs 30.6%, P = .007). Significant reductions also occurred in new thrombosis and death because of thrombosis. Major bleeding was similar between groups (7.7% vs 8.2%; P = .84). Adverse outcomes were more likely to occur in patients who were initially diagnosed with HIT and thrombosis, had undergone cardiac surgery, were not white, or had more severe thrombocytopenia. In acutely ill HIT patients, argatroban, versus historical control, provides effective antithrombotic therapy without increasing major bleeding. Patients with more severe thrombocytopenia or HIT-related thrombosis on HIT diagnosis have a poorer prognosis, emphasizing the importance of prompt recognition/ treatment of HIT in acutely ill patients.     

Argatroban anticoagulation in patients with heparin-induced thrombocytopenia

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin. We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS). METHODS: In this multicenter, nonrandomized prospective study, 418 patients with HIT were administered intravenous argatroban, 2 micro g/kg per minute, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days. Comparisons were made with a historical control cohort (n = 185). The prospectively defined, primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis in 37 days. Other end points included the components of the composite, death due to thrombosis, increased platelet count, and bleeding. RESULTS: In the HIT arm, the composite end point was significantly reduced in argatroban-treated patients vs controls (28.0% vs 38.8%; P =.04). In the HITTS arm, the composite end point occurred in 41.5% of argatroban-treated patients vs 56.5% of controls (P =.07). By time-to-event analysis of the composite end point, argatroban therapy was significantly better than historical control therapy in HIT (P =.02) and HITTS (P =.008). Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS. There were no significant between-group differences in all-cause death or amputation. Platelet counts recovered more rapidly in argatroban-treated patients than in controls. Bleeding rates were similar between groups. CONCLUSION: Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.     

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.     

Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia

STUDY OBJECTIVES: We investigated the effects of the direct thrombin inhibitor argatroban, patient demographics, and the platelet count on thrombotic risks in heparin-induced thrombocytopenia (HIT), a serious thrombotic condition, to determine if argatroban provides effective antithrombotic therapy in patients with HIT without increasing bleeding. DESIGN: We retrospectively analyzed thrombotic outcomes in 882 HIT patients (697 patients receiving mean argatroban doses of 1.7 to 2.0 mug/kg/min for 5 to 7 days, plus 185 historical control subjects) from previously reported prospective studies. Time-to-event analyses of our primary end point-a thrombotic composite of death due to thrombosis, amputation secondary to HIT-associated thrombosis, or new thrombosis within 37 days-and the individual components were conducted, with hazard ratios estimated for treatment with and without adjustments for patient age, gender, race, weight, and baseline platelet count. MEASUREMENTS AND RESULTS: Argatroban, vs control, significantly reduced the thrombotic composite risk (HIT: hazard ratio, 0.33; 95% confidence interval [CI], 0.20 to 0.54, p < 0.001; HIT with thrombosis: hazard ratio, 0.39; 95% CI, 0.25 to 0.62, p < 0.001), regardless of covariate adjustments. More argatroban-treated patients than control subjects remained thrombotic event free during follow-up, regardless of whether baseline thrombosis was absent (91% vs 73%) or present (72% vs 50%). Argatroban significantly reduced new thrombosis (p < 0.001) and death due to thrombosis (p 相似文献   

Argatroban: update

Unfractionated heparin has historically been used as the anticoagulant of choice in the management of a number of thrombotic diseases. Recognition of the limitations of heparin has led to the development of a newer class of anticoagulants, the direct thrombin inhibitors. Argatroban is a synthetic small molecule that selectively inhibits thrombin at its active site. In preclinical studies, argatroban has been shown to be more effective than heparin in preventing arterial thrombosis and in promoting vessel patency in conjunction with thrombolysis in a number of animal models. In clinical trials, argatroban has been shown to be as effective as heparin in the management of ST-segment elevation myocardial infarction in conjunction with thrombolysis. It has been shown to be an effective anticoagulant in patients undergoing percutaneous coronary interventions. In patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia complicated by thrombosis, argatroban significantly decreases the risk of thrombotic events. Small studies have demonstrated a potential role for its use in ischemic stroke and hemodialysis. Additional studies are warranted to confirm argatroban's efficacy in a wide variety of clinical settings.     

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.     

阿加曲班研究进展

阿加曲班是合成的小分子药物,为一价直接凝血酶抑制剂,阿加曲班直接与凝血酶的催化活性位点结合,不但灭活液相凝血酶,还能够灭活与纤维蛋白血栓结合的凝血酶,目前已批准用于肝素诱导的血小板减少及血栓症、经皮冠状动脉介入治疗、脑卒中溶栓等血栓性疾病.体内外研究表明,它还抑制凝血酶的其他作用,如可以抑制肿瘤转移、炎症过程及血管成形术后的再狭窄等.     

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.     

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.     

Safety and efficacy of argatroban in patients with heparin-induced thrombocytopenia

Argatroban is a synthetic direct thrombin inhibitor. It is indicated for use in patients with heparin-induced thrombocytopenia (HIT). The greatest experience is in prevention and treatment of the disorder, but argatroban is also indicated for percutaneous coronary interventions in patients with HIT. There is somewhat limited experience with its use in a number of other clinical scenarios in these patients. The current data on the use of argatroban in patients with HIT are reviewed.     

Argatroban use during pediatric interventional cardiac catheterization.

Argatroban is a synthetic direct thrombin inhibitor that does not interact with or induce heparin-dependent antibodies. It is approved for use in adults for prevention and treatment of thrombosis associated with heparin-induced thrombocytopenia (HIT). It has been administered safely in adults with HIT during coronary interventions. There are no reports of argatroban use for anticoagulation in pediatric patients. The present case describes the use of argatroban during coil embolization of a Fontan fenestration in a child with a history of HIT. The patient received a single bolus dose of 150 microg/kg of argatroban at the onset of the intervention. The fenestration was successfully occluded with a detachable coil. The activated clotting time (ACT) was > 200 sec throughout the procedure. The ACT returned to baseline 72 min after the bolus. No complications occurred. This case demonstrates the safe and successful use of argatroban during a transcatheter intervention in a pediatric patient with a history of HIT. The use of argatroban is promising for anticoagulation in children who require an alternative to heparin.     

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.     

Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction

STUDY OBJECTIVES: We evaluated the dosing requirements in argatroban-treated patients with heparin-induced thrombocytopenia (HIT) and hepatic dysfunction, and compared efficacy and safety outcomes with historical control patients. DESIGN: Retrospective analysis. SETTING: Inpatient setting. PATIENTS: Patients with hepatic dysfunction, defined as total bilirubin > 25.5 micromol/L (1.5 mg/dL), aspartate aminotransferase >100 IU/L, and/or alanine aminotransferase >100 IU/L, were identified from previous multicenter, historical-controlled studies of argatroban therapy in HIT. INTERVENTIONS: Argatroban, adjusted to maintain activated partial thromboplastin times (aPTTs) 1.5 to 3 times baseline in the experimental group, vs no direct thrombin inhibition in the historical control patients. MEASUREMENTS AND RESULTS: The analysis population included 82 argatroban patients and 34 historical control patients with hepatic impairment, of whom approximately 50% in each group had renal dysfunction (defined as a serum creatinine level > 1.3 mg/dL). The argatroban dosage was 1.6 +/- 1.1 microg/kg/min (mean +/- SD) over a mean 5-day course of therapy. Significantly lower doses were used in patients with elevated vs normal total bilirubin levels (0.8 +/- 0.6 microg/kg/min vs 1.7 +/- 0.8 microg/kg/min, p = 0.0063) and in patients with hepatic/renal dysfunction vs hepatic dysfunction alone (1.2 +/- 1.1 microg/kg/min vs 2.0 +/- 1.1 microg/kg/min, p < 0.001). The aPTT 24 h after argatroban initiation was 69 +/- 22 s, with 80% of patients having a therapeutic level of anticoagulation. Thirty-four argatroban-treated patients (41.5%) and 17 control patients (50.0%) experienced the 37-day composite end point of death, amputation, or new thrombosis (p = 0.32). Argatroban significantly reduced new thrombosis (8.5% vs 26.5%, p = 0.012). Major bleeding was similar between treatment groups (4.9% vs 2.9%, p = 0.684). CONCLUSIONS: Hepatic dysfunction affects argatroban dosing, with reduced doses required particularly in patients with serum total bilirubin levels > 25.5 micromol/L (1.5 mg/dL) or combined hepatic/renal dysfunction. Individual mean aPTT-adjusted doses typically remain > or = 0.5 microg/kg/min, supporting the recommendation of 0.5 microg/kg/min as a conservative initial dose for most patients with hepatic impairment. Argatroban, with proper initial dosing and monitoring, can provide safe and effective antithrombotic therapy in patients with HIT and hepatic impairment.     

Heparin-induced thrombocytopenia from venous thromboembolism treatment

OBJECTIVES: We aimed to characterize the clinical experiences of patients in whom heparin-induced thrombocytopenia (HIT) complicated heparin therapy for venous thromboembolism (VTE) and who switched to argatroban. DESIGN: A retrospective analysis of previously reported prospective, multicentre, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT. SETTING: Inpatient. SUBJECTS: Patients (n = 145) administered heparin for VTE and who developed HIT were identified. INTERVENTIONS: Patients were treated with argatroban 2 mcg kg(-1) min(-1) for up to 14 days, adjusted to maintain activated partial thromboplastin times 1.5 to three times baseline. Patient characteristics, anticoagulation and outcomes were summarized. The primary end-point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation. RESULTS: During heparin therapy, platelet counts decreased (mean +/- SD nadir: 78 +/- 67 x 10(9) L(-1)), and 75 (52%) patients developed thrombosis. After heparin was discontinued, patients received argatroban (mean dose 2.1 +/- 1.2 mcg kg(-1) min(-1)) for 6.8 +/- 4.3 days. By day 6 of argatroban therapy, the mean platelet count rose to >150 x 10(9) L(-1). The primary end-point occurred in 41 (28.3%) patients (values of 26-44% are reported for argatroban therapy of HIT from any heparin indication). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis whilst on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n = 10). Seven (4.8%) patients experienced major bleeding. CONCLUSIONS: For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for other argatroban-treated HIT patients. New thrombosis in this setting occurred most often in patients with existing HIT-associated thrombosis, before HIT recognition or either at/after argatroban discontinuation.