Optimizing management of hirudin anticoagulation.

Accurate anticoagulation monitoring, critical during cardiac surgery (CS), is especially important for novel therapeutics such as hirudins, for which there are no known antidotes. The activated clotting time (ACT), which is standard for heparin monitoring, has been reported to be insufficiently sensitive to high levels of hirudins. A simple, accurate, and sensitive assay is needed to monitor hirudins at the levels required for CS. During the REPLACE/II clinical trials, the HEMOCHRON Jr. Signature ACT+ was used to monitor Angiomax during percutaneous cardiac intervention (PCI) procedures and was observed to lose sensitivity at bivalirudin concentrations greater than 8-10 microg/mL. A new assay, the ACTT, was developed to increase the linear sensitivity of the ACT+ over the range of 15-30 microg/mL bivalirudin to extend the clinical utility of the assay to CS levels. Both in vitro and ex vivo studies were performed using the ACTT and ACT+. In vitro ACT+ and ACTT clotting times, identical for bivalirudin levels up to approximately 5 microg/mL, diverged from each other near 10 microg/mL. The ACTT showed excellent linearity to bivalirudin at concentrations up to 30 microg/ mL. Reproducibility was also superior with coefficients of variation <15% across 13 donors at clotting times <760 seconds. The ACTT was evaluated for monitoring bivalirudin during PCI in 67 patients. The ex vivo comparison of ACTT to ACT+ <340 seconds, showed a slope near 1.0 and an average difference between the tests of 5%. At higher clotting times this slope increased to near 3.0, with an average difference between tests of 20%. These data suggest that the ACTT displays increased sensitivity to high levels of bivalirudin.

Risk of anaphylaxis after reexposure to intravenous lepirudin in patients with current or past heparin-induced thrombocytopenia.

OBJECTIVE: To retrospectively assess the signs and symptoms indicative of adverse reactions to repeated exposures to lepirudin in patients with heparin-induced thrombocytopenia who received at least 2 courses of lepirudin therapy. PATIENTS AND METHODS: Medical records were retrospectively assessed from adult patients who received at least 2 courses of lepirudin therapy separated by at least 1 week between January 1999 and June 2002 at The Cleveland Clinic, Cleveland, Ohio. We evaluated the list of 289 low-level terms for possible signs and symptoms of anaphylactic reactions In the medical dictionary for regulatory activities as well as patient vital signs to detect manifestations of immediate hypersensitivity reactions. Vital signs from the day before initiation of lepirudin therapy were compared with those from days 1 and 2 after exposure. RESULTS: No cases of anaphylaxis or allergic reaction related to lepirudin administration were identified among 43 adult patients. On day 1 of lepirudin, 10 patients had lower systolic blood pressures (by > or =20 mm Hg) than pre-lepirudin values, and 4 patients had systolic blood pressures of less than 100 mm Hg. CONCLUSIONS: Isolated asymptomatic decreases in blood pressure after patient reexposure to lepirudin most likely do not reflect anaphylaxis due to lepirudin. We believe that isolated and uncommon cases of anaphylaxis temporally related to lepirudin exposure should not preclude its use in patients with heparin-induced thrombocytopenia and past lepirudin exposure.

Heparin-induced thrombocytopenia: principles for early recognition and management.

Heparin-induced thrombocytopenia (HIT) is a potentially devastating complication of therapy with either unfractionated or low-molecular-weight heparin. Thrombocytopenia is no longer essential for the diagnosis of HIT, since a 50% drop in the platelet count may be a more specific indicator. Once HIT is clinically suspected, heparin should be stopped immediately and direct thrombin inhibitor therapy started; waiting for laboratory confirmation may be catastrophic.

An anesthesia provider's perspective of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a pathology manifested as clinically induced destruction of platelets. There are 2 forms of HIT, type I and type II; type II is the more serious. HIT type I is a transient, non-immune-mediated form manifesting with mild thrombocytopenia. Type II is a drug-induced, immune-mediated syndrome that may cause life- or limb-threatening thromboembolic events. Induction of general anesthesia for a person with HIT type II is no different from that for a person in the general population. Treatment modalities vary only if heparin will be used during the case. The initial indicator of HIT is decreased platelet count, with or without thrombosis. Clinical criteria and advanced serological testing are available for the definitive diagnosis of HIT. Clinical suspicion of HIT remains key to early cessation of heparin (all routes) and initiation of alternative treatments.

Delayed-onset heparin-induced thrombocytopenia.

Delayed-onset heparin-induced thrombocytopenia is a syndrome in which thrombocytopenia and thrombosis begin several days after heparin discontinuation. Delayed-onset heparin-induced thrombocytopenia is caused by immunoglobulin G antibodies that are reactive against the heparin-platelet factor 4 complex in the absence of circulating heparin. We describe 2 patients with delayed-onset heparin-induced thrombocytopenia who presented to the emergency department. An 88-year-old man and a 62-year-old man experienced thrombocytopenia and thrombosis 9 or more days after heparin cessation and demonstrated a further decrease in platelet count on reexposure to heparin. Delayed-onset heparin-induced thrombocytopenia should be included in the differential diagnosis of a patient with recent heparin exposure who presents with thrombosis or thrombocytopenia.

[Use of ecarin clotting time in whole blood for monitoring recombinant hirudine treatment during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia]. / Utilisation du temps de coagulation par l'écarine en sang total pour la surveillance d'un traitement anticoagulant par lépirudine (Refludan au cours de circulation extracorporelle dans un contexte de thrombopénie induite par l'héparine.

Lepirudin (Refludan is a recombinant hirudin, approved for anticoagulation treatment of heparin-induced thrombocytopenia patients with thrombosis. We report here our method for laboratory monitoring with ecarin clotting time (ECT) of hirudin therapy as anticoagulation for cardiac surgery. Ecarin is extracted from the Echis carinatus snake venom and directly converts prothrombin to its intermediate, meizothrombin. This one binds in a stoechiometric way to hirudin to be proportioned in whole blood. The activation of coagulation starts up only when the totality of the hirudin is bound to the meizothrombin. To minimize the effect of dilution related to the CEC on the prothrombin and fibrinogen levels, thus lengthening the ECT, the specimen to be tested is diluted with normal whole blood. In 1997, when we have performed our first surgery with cardiopulmonary bypass, only one team (Pötzsch et al., 1997) had described the use of the ECT in whole blood. We describe in this work our assay to dose hirudin with ECT after dilution in whole blood. This assay was used during 8 CEC among 7 patients affected with HIT (n = 6) or potentially sensitized with heparin (n = 1). Experimental conditions and interpretation of the assay are reported here. This test is fast enough to provide useful information for adjusting the dose during cardiopulmonary bypass.

Effectiveness and safety of bivalirudin during percutaneous coronary intervention in a single medical center.

A recent large-scale, randomized trial demonstrated the noninferiority of a strategy of bivalirudin with provisional glycoprotein (GP) IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. There is a paucity of outcome data with bivalirudin use in the setting of real-world experience. We evaluated 6,996 patients who underwent percutaneous coronary intervention between January 2001 and December 2004 to compare early and late outcomes with a bivalirudin-based antithrombotic regimen with those with a heparin-based regimen. Propensity adjustment was performed to correct for baseline differences in patient characteristics. Bivalirudin-based therapy was used in 1,070 patients, heparin only in 801 patients, and heparin plus GP IIb/IIIa inhibitors in 5,125 patients. Compared with patients who received heparin or those who received heparin plus GP IIb/IIIa inhibitors, patients who received bivalirudin had lower incidences of bleeding (blood transfusion rate 1.7% vs 4.0%, p <0.001) and periprocedural myonecrosis (creatine kinase-MB >5 times the upper limit of normal 2.7% vs 4.3%, p = 0.016). Differences in bleeding end points remained significant after adjusting for the propensity to receive bivalirudin, but there was no difference in ischemic events. There was no difference in unadjusted long-term survival rate (log-rank test p = 0.46, total number of deaths 412, mean follow-up 17 months) or in propensity-adjusted long-term survival rate (hazard ratio 1.37, 95% confidence interval 0.90 to 2.08, p = 0.14). Compared with heparin with or without GP IIb/IIIa inhibition, the use of bivalirudin in a large consecutive patient registry at a tertiary care center was associated with fewer bleeding events and no evident increase in the incidence of ischemic complications.

Additive effects between platelet concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor eptifibatide.

BACKGROUND: Platelet (PLT) glycoprotein (GP) IIb/IIIa receptor antagonists have demonstrated efficacy in decreasing ischemic complications of percutaneous coronary intervention and/or unstable angina. In case of bleeding, the drug can be stopped and PLT transfusions can be given. STUDY DESIGN AND METHODS: This crossover study tested the additive effects of PLT concentrates (PCs) after desmopressin (DDAVP) infusion in antagonizing the anti-PLT effects of GPIIb/IIIa inhibitors and aspirin. After eptifibatide and aspirin infusion (at standard dosages), 10 healthy volunteers received DDAVP or placebo. Thereafter, increasing amounts of PLTs from fresh single-donor apheresis concentrates were added in vitro to blood samples of all volunteers to increase PLT counts by 30 x 10(9), 60 x 10(9), or 120 x 10(9) per L. RESULTS: Adding platelets in vitro further improved PLT function after DDAVP: it shortened collagen-adenosine diphosphate closure times (p < 0.01), to normal ranges as measured by the PLT function analyzer (PFA-100). In contrast, normal PLT function could not be restored even when PLT counts were increased by 50 percent (120 x 10(9)/L) in the placebo group. CONCLUSION: Combined use of PLTs from fresh apheresis PC and DDAVP additively enhances recovery of normal PLT function after eptifibatide infusion. Such a strategy may help to avoid excessive transfusion of PC.

The management of patients with heparin-induced thrombocytopenia who require anticoagulant therapy.

For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT.

Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia.

Recommendations for transitioning from therapy with heparin or a low-molecular-weight heparin preparation to therapy with an oral anticoagulant in patients with acute venous or arterial thromboembolism have undergone several changes during the last two decades. Physicians are now comfortable with beginning treatment with an oral anticoagulant once the diagnosis is confirmed, and loading doses are no longer considered to be necessary. Exceptions to early transition may be necessary in patients with an extensive iliofemoral or axillary-subclavian vein thrombosis or pulmonary embolism where thrombolytic agents may be indicated, or in individuals who require surgery or other invasive procedures, or if there are concerns about bleeding. The avoidance of early transition to oral anticoagulants in patients with acute heparin-induced thrombocytopenia also has been advised because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.

Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial).

Among patients who undergo percutaneous coronary intervention, renal impairment is associated with an excessive risk of bleeding and ischemic events. Bivalirudin provides comparable suppression of ischemic events with a decrease in bleeding events compared with heparin and glycoprotein IIb/IIIa inhibition. We examined the relation between adverse events, renal impairment, and antithrombotic therapy within a randomized comparison. The Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events per-protocol study population was assessed. Renal function was defined as calculated creatinine clearance <60 ml/min. Events within the overall study population and within each study arm were assessed. Thirty-day events by renal function were compared by chi-square test and logistic regression. Late mortality was compared by log-rank test. Interaction analyses were performed. Among 5,710 patients, renal impairment was associated with increased ischemic events (hazard ratio 1.45, 95% confidence interval 1.13 to 1.88, p = 0.004), bleeding complications (hazard ratio 1.72, 95% confidence interval 1.06 to 2.80, p = 0.028), and excessive 12-month mortality (hazard ratio 3.85, 95% confidence interval 2.67 to 5.54, p <0.001). Bivalirudin provided suppression of ischemic events that was comparable to heparin and glycoprotein IIb/IIIa inhibition regardless of renal impairment. Fewer bleeding events with bivalirudin were also evident irrespective of renal dysfunction. No interaction between treatment assignment, bleeding or ischemic complications, and renal impairment was observed. The safety and efficacy of bivalirudin compared with heparin and planned glycoprotein IIb/IIIa inhibition in this high-risk group are comparable and consistent with the results of the overall trial.

Effect of lepirudin on the international normalized ratio.

BACKGROUND: Many patients receiving direct thrombin inhibitor (DTI) therapy require transition to warfarin. This transition may be complicated by DTI-induced elevations in the international normalized ratio (INR). While the effect of argatroban on the INR has been characterized, data assessing the effect of lepirudin on the INR are limited. OBJECTIVE: To evaluate the effect of lepirudin on the INR. METHODS: Patients receiving lepirudin therapy between January 2000 and May 2001 were identified using the pharmacy database, and a retrospective chart review was conducted. Patients were included for analysis if they had paired activated partial thromboplastin time (aPTT) and INR data while receiving lepirudin monotherapy. RESULTS: Fifty-three paired aPTT and INR data points from 8 patients receiving lepirudin monotherapy were collected. The Organon MDA 180 instrument was used for aPTT and prothrombin time (PT) determination. Organon MDA Platelin L reagent was used for the aPTT and Organon Simplastin L reagent was used for the PT. The international sensitivity index (ISI) of the Simplastin L thromboplastin was 2.0. The mean +/- SD lepirudin dose was 0.05 +/- 0.04 mg/kg/h. Linear regression was used to identify the INRs that correspond to a therapeutic aPTT value of 45-75 seconds (1.5-2.5 times mean laboratory normal of 30 sec). The correlation between aPTT and INR was 0.77. An aPTT of 45-75 seconds with lepirudin correlated to an INR of 1.6-3.2. CONCLUSIONS: Based on laboratory results, when using a thromboplastin with an ISI of 2, lepirudin appears to elevate the INR in the absence of warfarin.

Heparin-induced thrombocytopenia in the cardiovascular patient: diagnostic and treatment guidelines.

Heparin-induced thrombocytopenia/thrombosis is an immunologic reaction to unfractionated heparin characterized by thrombocytopenia, platelet activation and thrombosis. A high index of suspicion is required for timely diagnosis and treatment. Treatment is complex and outcome maybe less then satisfactory.

Complement C5a is a key mediator of meconium-induced neutrophil activation.

Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconium-induced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60-70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response.

Excessive anticoagulation and anaphylactic reaction after rechallenge with lepirudin in a patient with heparin-induced thrombocytopenia.

Approximately 40% of patients who receive lepirudin for 5-10 days develop antihirudin antibodies. These antibodies lead to decreased renal elimination of lepirudin, ultimately resulting in elevated activated partial thromboplastin times (aPTTs). A small percentage of patients with antihirudin antibodies develop hypersensitivity reactions to lepirudin with reexposure. Thus, patients who are reexposed to lepirudin must be monitored closely for hypersensitivity. A 45-year-old African-American woman received lepirudin for anticoagulation after being diagnosed with heparin-induced thrombocytopenia type II. She developed supratherapeutic aPTTs after 10 days of lepirudin therapy. Lepirudin was then withheld for 6 days, during which her aPTT remained supratherapeutic. After lepirudin infusion was restarted, the patient developed an anaphylactic reaction. She was treated appropriately with an antihistamine, a corticosteroid, and an anxiolytic agent. After the reaction resolved, the patient was rechallenged with lepirudin, and the anaphylactic reaction recurred.

Alternatives to heparin infusion.

This article offers an overview of the pathophysiology, diagnosis, and treatment of heparin-induced thrombocytopenia (HIT). This disorder is an immune-mediated reduction of platelets with subsequently increased generation of thrombin and increased risk of arterial and venous thrombosis. Heparin-induced thrombocytopenia can occur as an isolated incident or with acute thrombosis (HIT with thrombosis syndrome [HITTS]). Proper recognition, cessation of all forms of heparin (and compounds that cross-react with heparin), and rapid initiation of nonheparin anticoagulation are essential steps in reducing the risk of death, limb amputation, and new thrombotic events. Current alternatives to heparin are reviewed.

The Angiomax Peripheral Procedure Registry of Vascular Events Trial (APPROVE): in-hospital and 30-day results.

BACKGROUND: High-risk patient characteristics and complexity of percutaneous peripheral intervention (PPI) procedures suggest a need for predictable and reliable anticoagulation. We undertook this study to assess the safety and efficacy of bivalirudin as the procedural anticoagulant in patients undergoing PPI of the renal, iliac, or femoral artery. METHODS: This was a prospective, open-label, single arm study inpatients undergoing PPI of the renal, iliac, or femoral vessels to assessbivalirudin as the sole procedural anticoagulant (0.75 mg/kg bolus/1.75 mg/kg/hr infusion). The primary endpoint was procedural success defined as residual stenosis < 20%. Secondary endpoints included ischemic events (death, myocardial infarction, unplanned revascularization, and amputation), and bleeding complications, as well as ACT values and times to sheath removal, ambulation, and discharge. RESULTS: 505 patients were enrolled at 26 sites. Procedural success was achieved in 95.0% of patients. Ischemic events were low (1.4%) and similar between vessel types. Protocol-defined major hemorrhage and TIMI major hemorrhage rates were 2.2% and 0.4%, respectively. Mean ACTs were similar among treatment groups (renal 353.8 seconds(s); iliac 335.9s, femoral, 343.5s). CONCLUSION: Bivalirudin provided consistent anticoagulation and similar outcomes in all vessel types treated at the dose tested. Ischemic and bleeding event rates were low, demonstrating the safe use of bivalirudin as a procedural anticoagulant in PPI.

Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial.

OBJECTIVES: The purpose of this study was to compare the cost of percutaneous coronary intervention (PCI) using bivalirudin with provisional platelet glycoprotein (GP) IIb/IIIa inhibition with that of heparin + routine GP IIb/IIIa inhibition. BACKGROUND: Although GP IIb/IIIa inhibition has been shown to reduce ischemic complications in a broad range of patients undergoing PCI, many patients currently do not receive such therapy because of concerns about bleeding complications or cost. Recently, bivalirudin with provisional GP IIb/IIIa inhibition has been validated as an alternative to heparin + routine GP IIb/IIIa inhibition for patients undergoing PCI. However, the cost-effectiveness of this novel strategy is unknown. METHODS: In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, 4,651 U.S. patients undergoing non-emergent PCI were randomized to receive bivalirudin with provisional GP IIb/IIIa (n = 2,319) versus heparin + routine GP IIb/IIIa (n = 2,332). Resource utilization data were collected prospectively through 30-day follow-up on all U.S. patients. Medical care costs were estimated using standard methods including bottom-up accounting (for procedural costs), the Medicare fee schedule (for physician services), hospital billing data (for 2,821 of 4,862 admissions), and regression-based approaches for the remaining hospitalizations. RESULTS: Among the bivalirudin group, 7.7% required provisional GP IIb/IIIa. Thirty-day ischemic outcomes including death or myocardial infarction were similar for the bivalirudin and GP IIb/IIIa groups, but bivalirudin resulted in lower rates of major bleeding (2.8% vs. 4.5%, p = 0.002) and minor bleeding (15.1% vs. 28.1%, p < 0.001). Compared with routine GP IIb/IIIa, in-hospital and 30-day costs were reduced by $405 (95% confidence interval [CI] $37 to $773) and $374 (95% CI $61 to $688) per patient with bivalirudin (p < 0.001 for both). Regression modeling demonstrated that, in addition to the costs of the anticoagulants themselves, hospital savings were due primarily to reductions in major bleeding (cost savings = $107/patient), minor bleeding ($52/patient), and thrombocytopenia ($47/patient). CONCLUSIONS: Compared with heparin + routine GP IIb/IIIa inhibition, bivalirudin + provisional GP IIb/IIIa inhibition resulted in similar acute ischemic events and cost savings of $375 to $400/patient depending on the analytic perspective.