Why does argatroban increase inr

The day mortality was Preliminary results of 15 patients with acute stroke enrolled into the argatroban-rTPA study are available Arpino and Hallisey Primary outcome was incidence of ICH and secondary outcome complete re-canalization after 2 hours.

Symptomatic ICH occurred in 2 patients and asymptomatic bleeding in 1 patient and there was 1 death. Complete re-canalization was achieved in 6 patients and partial re-canalization in 4 patients; re-occlusion occurred in 3 patients.

The authors concluded that the safety profile of this protocol may be within acceptable limits and that its efficacy for achieving fast and complete re-canalization is promising, but that further data are needed. Even though a correlation of creatinine clearance and aPTT-adjusted argatroban dose has been described Arpino and Hallisey ; Guzzi et al , a recent retrospective analysis of multicenter trial data suggests this correlation not to be of clinical significance, and initial adaptation of the argatroban dose to renal function was regarded as unnecessary Guzzi et al In a retrospective analysis of 47 patients with HIT and renal failure requiring renal replacement therapy, argatroban provided effective anticoagulation with an acceptable safety profile Reddy et al In ICU patients suffering from renal, but not measurable liver insufficiency, however, dose reductions may be frequently necessary unpublished observations of the author.

Based on this experience, in ICU patients we start argatroban at a reduced dose, provided there is no acute thrombosis. Careful monitoring and dosing are specifically required in this patient population. Similar experiences have also been reported by others de Denus and Spinler ; Guzzi et al Here, decreased cardiac output or hepatic congestion has been discussed as causing reduced argatroban requirements Guzzi et al Whether anticoagulation with argatroban alone always prevents clotting in the extracorporeal circuit is unclear.

In one HIT patient on HD treated with argatroban, marked spontaneous platelet aggregation occurred, perhaps due to HIT together with the additional platelet activation known to occur in HD Koide et al In this case, aspirin was added to achieve patency of the extracorporeal circuit.

Dialytic argatroban clearance by high-flux hemodialyzer membranes is regarded as being clinically insignificant Murray et al ; Tang et al However, as both low-flux and high-flux membranes show significant argatroban sieving Krieger et al , hemofiltration appears to be a suitable rescue measure if rapid removal of argatroban is required, eg, in the case of bleeding or accidental overdose, especially if hepatic clearance is reduced.

Its predominant hepatic elimination makes argatroban favorable for alternative anticoagulation in chronic renal failure. Its role and dosing in ICU patients suffering from acute renal failure requiring renal replacement therapy remain to be defined.

Heparin-induced thrombocytopenia is a not infrequent, severe disease associated with potentially catastrophic thromboembolic complications. The data of the ARG and ARG investigations provide convincing evidence that argatroban enables rapid and effective anticoagulation in this condition and is an effective therapy for HIT-associated complications. Furthermore, in comparison with the direct competitor lepirudin, a DTI which is eliminated exclusively via the renal system, the safety margin of argatroban appears to be extended, as shown by the lower rate of major bleeding events than in the lepirudin studies.

Renal impairment with the need for renal replacement therapy is a frequent complication of HIT, especially in ICU patients. Particularly in this indication argatroban anticoagulation appears to be a very promising option. However, more investigations in this field are needed and reliable protocols for dosing should be established. In the field of PCI in HIT patients data are less convincing and the optimal dose to prevent the frequent need of re-bolusing, for example, has not yet been established.

Data obtained in this special indication with bivalirudin, another short-acting DTI that is emerging as a replacement for heparin in PCI, suggest a more constant dose—effect relation associated with a convincing efficacy and safety profile Lincoff et al ; Mahaffey et al ; Stone et al In the fields outside HIT, results obtained in patients with acute stroke are interesting and deserve further detailed investigation.

However, before data from larger studies are available all studies outside HIT have the character of pilot investigations. Moreover, special patient populations, particularly patients on the ICU, need further attention in order to establish reliable dosing schemes and protocols. The practical problem of transition from argatroban anticoagulation to oral anticoagulants requires a standard protocol for the condition of HIT TS and in non-HIT patients.

Use of more specific assays to monitor argatroban, such as the ECT, may be helpful in this regard. We conclude that argatroban is a valuable drug for the condition of HIT TS that needs more detailed investigation in a large number of special indications and clinical settings. National Center for Biotechnology Information , U. Journal List Biologics v. Author information Copyright and License information Disclaimer. All rights reserved. This article has been cited by other articles in PMC.

Abstract Argatroban is a synthetic direct thrombin inhibitor with a relative short elimination half-life of 45 minutes and elimination which is predominantly performed via hepatic metabolism.

Keywords: anticoagulation, direct thrombin inhibitors, HIT. Introduction Heparins, particularly unfractionated heparins UFH , have been the standard anticoagulants in nearly every field of anticoagulation therapy for decades. Pharmacology of argatroban Argatroban is a synthetic monovalent direct thrombin inhibitor, the molecular structure of which contains an arginine residue.

Transition from argatroban anticoagulation to oral anticoagulants After intravenous anticoagulation, often transition to a prolonged period of oral anticoagulation with coumarin derivates is necessary. Table 1 Efficacy and safety outcomes in the ARG trial. Open in a separate window.

Table 2 Efficacy and safety outcomes in the ARG trial. Argatroban anticoagulation during percutaneous coronary intervention Three prospective studies, the ARG, ARG, and ARG studies, have been performed to evaluate the safety and efficacy of argatroban anticoagulation during PCI [22]. Argatroban anticoagulation in acute ischemic stroke There are only a few small clinical pilot studies in which argatroban anticoagulation has been investigated outside the setting of HIT TS.

Conclusion Heparin-induced thrombocytopenia is a not infrequent, severe disease associated with potentially catastrophic thromboembolic complications. Effect of renal function on the pharmacodynamics of argatroban. Ann Pharmacother. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia:an analysis of outcomes in patients with elevated international normalized ratio INR J Thromb Thrombolysis.

Transition to an oral anticoagulant in patients with heparin-induced thrombocytopenia. Argatroban anticoagulation in critical ill patients. Effects of the synthetic thrombin inhibitor argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and recombinant Hirudin. Thromb Haemost. Lack of pharmacokinetic interactions between argatroban and warfarin. Am J Health Syst Pharm. Decreased argatroban clearance unaffected by hemodialysis in anasarca.

Direct thrombin inhibitors. N Engl J Med. Effect of argatroban on the activated partial thromboplastin time:a comparison of 21 commercial reagents. Blood Coagul Fibrinolysis.

Lepirudin recombinant hirudin for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Recombinant hirudin lepirudin provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia:a prospective study. Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia.

J Thromb Thrombolysis. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. Investigation of the interaction between argatroban and acetaminophen, lidocaine, or digoxin. 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.

J Am Coll Cardiol. Anticoagulation for heparin-induced thrombocytopenia with spontaneous platelet aggregation in a patient requiring haemodialysis. Nephrol Dial Transplant. Anticoagulation with argatroban in patients with heparin-induced thrombocytopenia antibodies after cardiac surgery with cardiopulmonary bypass:first results from the ARG-E03 trial.

J Thorac Cardiovasc Surg. Hemodialyzer membranes allow for removal of argatroban. Argatroban anticoagulation in patents with acute ischemic stroke ARGIS-1 :a randomized, placebo-controlled safety study. Argatroban anticoagulation in heparin-induced thrombocytopenia with hepatic dysfunction. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Cathet Cardiovasc Intervent.

Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Inter Med. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia ATBAT study: main results.

J Invasive Cardiol. Argatroban for anticoagulation during cardiac surgery. As a general rule, warfarin and argatroban should overlap for at least five days before discontinuing argatroban and continuing with warfarin monotherapy. Heparin-induced thrombocytopenia : Discontinue heparin and obtain baseline PTT. Lower doses are used in critically ill patients, e. In a study by Beiderlinden M.

Monitoring: Monitor PTT target range of 1. Titration of the dose should continue until ACT is in the therapeutic range between and seconds. In such patients, a lower dose should be used starting infusion rate from 0. The most common adverse effect of argatroban, as with other anticoagulants, is bleeding, which can manifest as gastrointestinal, genitourinary, intracranial, retroperitoneal bleeding, hemoptysis, and other minor bleedings.

When used in PCI, chest pain, back pain, nausea, vomiting, hypotension, and headache can occur. Argatroban, like other anticoagulants, is contraindicated in overt bleeding. When argatroban is used in patients with increased bleeding risk like severe hypertension, after major surgery, immediately following lumbar puncture, spinal anesthesia, particular caution and vigilance are necessary. Avoid argatroban in patients with a history of hypersensitivity to it or any of its components in the dosage form.

The PTT should also be obtained 2 hours after the initiation of therapy and after any change in dosage. The toxicity of argatroban from supratherapeutic dosage is related to its anticoagulant effect. There is no antidote to reverse its actions.

In such patients, the reversal of its effect takes a longer time. Heparin products see frequent use in hospitals, including line flushes, catheters, to DVT prophylaxis in patients with prolonged hospitalization. It is reasonable to obtain platelet counts after heparin therapy. Any fall in platelet count requires evaluation, and a 4T score degree of thrombocytopenia, timing relative to heparin exposure, presence of thrombosis, other causes for thrombocytopenia should be calculated if HIT is suspected.

Clinicians, pharmacists, and nurses should be aware of HIT pathology. Type I HIT can be differentiated from Type II by a milder drop in platelet count, earlier onset of thrombocytopenia, and absence of antibodies.

Since argatroban is expensive and can have potential bleeding complications, it is necessary to ensure its use is in the correct clinical scenario. Patients on argatroban therapy should have frequent monitoring of PTT or ACT, and any signs suggestive of bleeding or fall in hemoglobin should be promptly reported to the healthcare team so that the clinician can promptly discontinue argatroban and initiate transfusion therapy.

Kikelj D, Peptidomimetic thrombin inhibitors. Pathophysiology of haemostasis and thrombosis. Expert opinion on investigational drugs. Journal of thrombosis and thrombolysis. Annual review of medicine. Grouzi E, Update on argatroban for the prophylaxis and treatment of heparin-induced thrombocytopenia type II.

Journal of blood medicine. Seminars in thrombosis and hemostasis. Ikoma H, Development of argatroban as an anticoagulant and antithrombin agent in Japan. PloS one. Therapeutic advances in chronic disease. The Annals of pharmacotherapy. Journal of cardiothoracic surgery. American journal of hematology. Continuing Education Activity Argatroban is a medication used to manage heparin-induced thrombocytopenia HIT , which is a rare, life-threatening complication of heparin therapy. Indications Argatroban is a direct thrombin inhibitor DTI first introduced in Japan in for the treatment of peripheral vascular diseases.

Argatroban produces an effective and predictable anticoagulant effect, is non-immune, and increases the platelet count. As an anticoagulant during cardiopulmonary bypass in HIT. As an anticoagulant during renal replacement therapy with or without HIT [6] 3.