As NACs become more pervasive in the clinical setting, used for both therapeutic and prophylactic purposes, it will become essential for the emergency physician to become aware of the indications to start specific drugs, as well as unique complications and recommended reversal methods for such agents.
An intimate knowledge of these drugs will be required for the ideal management. Unfortunately, while the clinical efficacy of NACs has been established, much less is known about the risks of adverse reactions as well as the ability to reverse these agents. This article provides a review of the literature as it focuses on both the risks associated with anticoagulants, as well as reversal agents of the most commonly used NACs to help guide management in the emergency setting.
Comparison table for anticoagulants. Vitamin K antagonists VKAs such as warfarin function by blocking the vitamin K-epoxide reductase, thereby preventing formation of the active form of the vitamin K-dependent clotting factors. Federal Drug Administration indications for use include long-term anticoagulation following a thrombotic event or prevention of thrombotic events in patients at high risk, including post-operative states, atrial fibrillation, and those with artificial valves.
Warfarin is taken orally, at doses typically ranging from 5—10mg daily, tailored based on the international normalized ratio INR , the universal monitoring index based on pro-thrombin time PT.
Warfarin is primarily metabolized through the P system. Hemorrhage is the most significant adverse effect associated with warfarin and is directly related to the level of INR; the risk of hemorrhage is increased if the INR is greater than five. While the use of rfVIIa has been demonstrated to provide a rapid reduction in the INR, its use is not associated with improved clinical outcomes.
Drugs that augment the function of AT3 serve as anticoagulants. UFH is indicated for numerous conditions including the treatment and prophylaxis of venous thromboembolisms VTE , thrombus prophylaxis in atrial fibrillation, and treatment of disseminated intravascular coagulation. UFH has much faster onset of action as compared to warfarin; when used intravenously, therapeutic efficacy occurs almost immediately, while therapeutic efficacy is reached within 20—60 minutes when administered subcutaneously.
Hemorrhage is a main adverse event in those receiving UFH. The incidence of major bleeding varies based on the indication of its use, dosage and route of administration. However, on average, UFH is associated with a 2. Typically, protamine is dosed based on the amount of UFH administered, not based on laboratory abnormalities. A dose of 1mg will reverse units of UFH.
Another significant and well-documented adverse outcome of UFH use is the development of heparin-induced thrombocytopenia HIT. A detailed discussion of HIT, however, is beyond the scope of this review. The LMWH are parenterally-administered drugs, and include dalteparin, enoxaparin, and tinzaparin.
Acute bleed is the major risk associated with LMWH. When used prophylactically the incidence of major bleeding associated with the LMWH is approximately 1. A second dose of 0. Factor Xa inhibitors are used for prophylaxis and treatment of VTE, as well as for prophylaxis of embolic disease in non-valvular atrial fibrillation, and as an alternative anticoagulant in the setting of HIT.
These drugs inhibit factor Xa, the first step in the common pathway, either directly or indirectly. The inhibition occurs in a dose-dependent manner. These drugs also inhibit prothrombinase activity.
Thus, its use in patients with renal insufficiency is contraindicated as its use in this patient population may increase the risk of hemorrhage. There are no specific laboratory parameters available to monitor the anticoagulant impact of factor Xa inhibitors.
A dose-dependent prolongation of aPTT and PT may be seen 1—4 hours after administration of direct Xa inhibitors such as rivaroxiban, matching the peak plasma level; however, this increase is short lived and in general PT, aPTT and bleeding time should not be affected at therapeutic levels of these drugs.
Adverse events related to Xa inhibitors include hemorrhage, as is the case with all anticoagulants. Thrombocytopenia has also been reported following the use of Xa inhibitors; however, the mechanism is unclear. However, at present, there is insufficient data to clearly support any reversal agent or to develop a standard of care.
As their name implies, the direct thrombin inhibitors DTIs inhibit the intrinsic activity of the thrombin. Unlike heparin, which also inhibits thrombin, the DTIs do not require a factor, and can inhibit thrombin directly. These drugs are used for prophylaxis and treatment of VTE and ACS, and for prophylaxis of thrombus formation in non-valvular atrial fibrillation. They are also used as anticoagulation alternatives in the setting of HIT. Dabigatran, the only orally available DTI, is approved for treatment of VTE in patients treated with concomitant parenteral anticoagulation for at least five days, and for the treatment of thrombus secondary to non-valvular atrial fibrillation.
The primary toxicity of patients on DTIs is hemorrhage, including gastrointestinal bleeding and intracranial hemorrhage. The rate of bleeding is dose dependent, and is more common in those over 75 years of age.
The American College of Cardiology Foundation and the American Heart Association recommend transfusion of packed red blood cells and FFP, in addition to surgical intervention, if feasible, to control bleeding. The antithrombotic effect of fibrinolytics, which include tissue plasminogen activator tPA and urokinase, is achieved by inducing the conversion of inactive plasminogen into the active enzyme plasmin, which degrades the fibrin matrix responsible for stabilizing a thrombus.
Alteplase, an unmodified form of human tPA, along with reteplase and tenecteplase, a modified form of human tPA, are the most commonly used drugs in this class. The incidence of hemorrhage varies depending on the indication for the fibrinolytic. In the event of acute hemorrhage the administration of blood products, including FFP, PCC, and platelets, have been found to have poor efficacy, and other agents, including tranexamic acid TXA and epsilon-aminocaproic acid EACA , have been considered.
Acute hemorrhage is the most feared adverse event associated with all anticoagulants. While it is relatively uncommon that patients present with a life-threatening hemorrhage while on systemic anticoaguation, prompt recognition and management is vital. As the NAC become more frequently used in clinical settings, it will be imperative that the emergency physician has a thorough understanding of these agents, and is knowledgeable about potential reversal strategies, when available.
A clear policy before a dose is due. Thus The use of drugs that influence coagulation must be a the pre-operative dose may be omitted or, alternatively, concern to anaesthetists who use regional methods, may be given in the anaesthetic room after the block has although it is essential to maintain a sense of proportion been instituted.
Much of the current concern about risks. It is a source of reassurance to many that Odoom coagulation disorders and regional anaesthesia is related and Sih have documented the safe administration of to the use of low-dose aspirin in the control of pre- epidurals to patients receiving anticoagulant drugs, eclampsia. Aspirin, by its effects on platelet aggregation, albeit with very strict guidelines.
This is a new clinical situa- know neither the numerator nor the denominator. Is tion and it is difficult to give categorical advice, but it is there a place for a national registry of the condition as a important to remember that the changes in platelet basis for future risk assessment?
It has been argued that the clinically relevant test is The Royal Injrmary J. Is the combination safe? Anaesthesia technique to produce reliable results. Cannulation of the epidural establish the variability in results produced when the space: a comparison of and gauge needles. Until the results of such 3. Compressive and Vascular Disorders of the studies are available the risks of false negative and spinal Cord. In: Miller JD ed. Edinburgh: Blackwell Scientific Publications, Pathology in the extradural space.
British Peroperative anticoagulant therapy. Central nerve Journal of Anaesthesia ; Paraplegia following general anaesthesia. Epidurals, spinals and bleeding disorders in preg- an hour of institution of the block so that any bleeding nancy: a review. Anaesthesia and Intensive Care ; caused at that time has every opportunity to stop.
Some 3 Neurological sequelae of spinal catheter insertion is an indication for postponing the anaesthesia. British Journal of Anaesthesia ; 6 3 New such a disruptive policy. Some, particularly those who England Journal of Medicine ; Is this content inappropriate?
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