5 Zeph Okeke The Arthur Smith Institute for Urology, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY, USA In the early part of the twentieth century, infectious diseases were the most common causes of death across the globe. Technological advances such as improved sanitation and decreased pollution led to dramatic changes such that by the end of the twentieth century chronic, noncommunicable diseases accounted for the greatest number of deaths [1, 2]. Greater longevity can also be attributed to many of these changes. Diminished smoking, declining homicide rates, improved emergency and trauma care, and declining cancer rates have all contributed to the declining mortality rates. As living standards improved, life expectancy continued to increase such that the average life expectancy at birth was 71.4 years for the global population in 2015 [3]. In the United States, the top four causes of death can be attributed to chronic, age‐related conditions such as heart disease, cancer, chronic respiratory diseases, and stroke [4, 5]. With an aging population and increasing prevalence of chronic diseases comes an ever increasing burden of complex comorbidities that challenge the physicians managing them with other more acute concurrent illnesses [4, 5]. IMS Health, a market research firm, released global sales data for the most prescribed drugs of 2015. Anticoagulants ranked 11th of the top 20 global therapy areas for pharmaceuticals. Out of top 20 prescribed drugs globally, Xarelto (rivaroxaban), an anticoagulant, was ranked 17th [6]. The increasing prevalence of chronic diseases, especially cardiovascular diseases, translates into increasing use of anticoagulants and antiplatelets and the so‐called novel oral anticoagulants (NOACs) in clinical practice. It is not uncommon for surgeons to encounter patients using these agents who need surgical care. Intimate knowledge and mastery of the issues concerning their management in the perioperative setting is imperative. This chapter will articulate the pharmacological mechanisms of action, the indications and clinical applications, and the appropriate interval for interruption and bridging perioperatively. The risks of perioperative bleeding balanced against the risk of thromboembolic events will also be discussed. It is estimated that there are over 6 million patients in the United States on anticoagulation medication for prevention of thromboembolism, and an ever‐increasing number of patients are on dual antiplatelet therapy; 10% of these patients are purported to undergo surgery annually [7, 8]. Discontinuing anitcoagulants or antiplatelets is not without risk. Valve thrombosis carries a 10–20% mortality risk associated with emergency valve replacements. Coronary stent thrombosis carries a greater than 50% mortality in association with a myocardial infarction [9]. Compounding the issues further, hemorrhagic events carry a 9–13% mortality rate; however, long‐term permanent disability is rare [5, 10]. For patients who experience a stroke, 20% are fatal while another 50% result in permanent neurological deficit [5]. The goal is balancing the risks of increased bleeding associated with surgery on anticoagulation while minimizing the risk of thromboembolic events. Heparin is supplied in two general formulations. Unfractionated heparin is a heterogenous mixture of glycosaminoglycans with varying molecular weights from 3000 to 30 000 Da with a mean of 15 000 Da, one‐third of which will be biologically active. Heparin acts by binding to antithrombin and facilitating rapid inactivation of thrombin and factor Xa (Figure 5.1). The complexing of antithrombin and thrombin dissociates heparin and returns it to the circulation. Heparin also acts to inhibit platelet aggregation by its action on inhibition of thrombin [11, 12]. Figure 5.1 Coagulation cascade. Low molecular weight heparins (LMWH) are produced from unfractionated heparin by either chemical or enzymatic depolymerization. They have a molecular weight of 2000–10 000 Daltons with a mean of 4000–6500 Daltons. They are composed of mainly short‐chain heparin molecules. They are unable to bridge antithrombin and thrombin, and mediate their effects mainly by the inhibition of factor Xa [11, 12]. Antithrombin has a low level of activity at baseline, mediated by an arginine center that binds to active serine proteases of the coagulation cascade. The bindings of heparin to antithrombin facilitates it inactivation of thrombin and factor Xa. The binding is specific and reversible and does not inactivate heparin. Once antithrombin is complexed with thrombin, the heparin molecule dissociates and returns to the circulation. Heparin also impairs platelet aggregation by directly binding to platelets. The high molecular weight heparins are the molecules thought to be most active in this mechanism. Reversal of heparin is accomplished by withholding the drug. For emergent cases or when supratherapeutic, protamine sulfate is used as a reversal agent [11, 12]. Warfarin is the most commonly used vitamin K antagonist. It acts via the intrinsic pathway by inhibition of factors II, VII, IX, and X, and proteins C, S, and Z (Figure 5.1). Warfarin is available as an intravenous preparation, but is most administered orally, is water soluble, and rapidly absorbed. It has high bioavailability and reaches maximal serum concentration within 90 minutes of administration. It has a half‐life of 36–42 hours. It circulates bound to albumin and other plasma proteins and is eliminated by the liver. Therefore, its activity is highly influenced by drug–drug interactions, diet (particularly foods rich in vitamin K), comorbidities, genetic variability, and diet. After initial administration, there is a period of hypercoagulability as a result of the transient reduction of vitamin K‐dependent anticoagulant proteins. Hence, initiation of warfarin therapy is often accompanied by a period of concomitant heparinization with unfractionated or LMWH. The full anticoagulation effect of warfarin may not be seen for 6 days. Frequent prothrombin time and international normalized ratio (PT/INR) monitoring is done until full therapeutic dose is achieved. Warfarin is indicated for the treatment of atrial fibrillation, atrial flutter, venous thromboembolism (VTE) prophylaxis, deep venous thrombosis (DVT), pulmonary embolism, hypercoagulable states, and valvular disease [11, 12]. Reversal of the effect of warfarin is accomplished by withholding the medication. The PT/INR will slowly normalize over a period of 5 days. More rapid reversal can be achieved by oral administration of low‐dose vitamin K (2–2.5 mg) as recommended by the guidelines of the American College of Chest Physicians (ACCP) [8]. Administration of fresh frozen plasma may be required also. Dabigatran etexilate is an oral direct factor IIA (thrombin) inhibitor (Figure 5.1). Once ingested, dabigatran etexilate is converted to its active form, dabigatran, a potent, competitive, and reversible direct inhibitor that binds to the active site on thrombin, thereby inactivating both fibrin‐bound and unbound thrombin. Plasma levels reach a peak at 1.25–3 hours after ingestion. Therapeutic effect is achieved 2–3 hours after ingestion and it has a half‐life of 12–14 hours. Excretion is predominantly renal; therefore, dosing is adjusted according to creatinine clearance. It is not recommended in patients with a creatinine clearance of <15 ml/minute. Discontinuation of dabigatran should be done 24–48 hours before surgery, and preferably 5 days ahead for cases where severe risk of bleeding is expected. Reversal of the action of dabigatran is possible with a newly approved monoclonal antibody antidote, idarucizumab (Praxbind), which directly targets dabigatran and can reverse the anticoagulant effects of dabigatran within minutes of administration [11, 12]. Rivaroxaban is an oral selective inhibitor of factor Xa. It targets both free factor Xa and bound factor Xa in the prothrombinase complex (Figure 5.1). The half‐life of rivaroxaban is 11–13 hours and reaches peak plasma concentration 2–4 hours after oral administration. As with dabigatran, bridging with heparin is not needed when discontinued or restarted after interruption. It is approved for stroke prevention in patients with nonvalvular atrial fibrillation. Clinical indications have been expanded to include treatment of DVT and VTE events, prevention of DVT, and pulmonary embolism after hip or knee arthroplasty. Cessation prior to surgery is recommended 24–48 hours before surgery and resumption 6–10 hours after surgery, or when hemostasis is deemed adequate or the risk of severe hemorrhage has diminished [11, 12]. Apixaban is another oral selective direct inhibitor of free and clot‐bound factor Xa (Figure 5.1). After oral administration, peak plasma concentrations are achieved within 1–4 hours. It is predominantly metabolized by the liver and has several important drug interaction cautions against concomitant usage with drugs affecting CYP3A4. It has no antiplatelet activity. It is currently approved for the prevention of stroke and thromboembolic events in patients with nonvalvular atrial fibrillation. It is used for prophylaxis against DVT and pulmonary embolism after recent knee or hip replacement, and treatment of DVT and pulmonary embolism, and there is a reduction in risk of recurrence following initial therapy [11, 12]. Edoxaban is another oral anticoagulant drug which acts as a reversible, direct factor Xa inhibitor, that binds to blocks the active site of factor Xa. It inhibits free factor Xa and prothrombinase complex activity and inhibits thrombin‐induced platelet aggregation (Figure 5.1). Primarily, it is excreted as unchanged drug in urine; metabolism and biliary/intestinal excretion account for the remainder of its clearance. Peak plasma concentration is achieved within 1–2 hours of oral administration. The half life of edoxaban is 10–14 hours, achieving total clearance in about 22 hours. Therefore, cessation is advised at least 24 hours prior to invasive or surgical intervention. Parenteral anticoagulant administration is advised prior to initiation of edoxaban. Edoxaban is approved for the treatment of DVT and pulmonary embolism, prevention of stroke, and systemic embolism in patients with nonvalvular atrial fibrillation [11–13]. Clopidogrel is a prodrug which upon activation by CY2C19 acts by irreversibly inhibiting the P2Y12 subtype of the adenosine diphosphate (ADP) receptor on platelet cell membranes. The P2Y12 subtype of the ADP receptor is important in activation of platelets and eventual crosslinking by the protein fibrin. Platelet inhibition can be seen 2 hours after oral administration of a single dose. However, the onset of action is slow, hence a loading dose is recommended if rapid effect is needed. The elimination half‐life of clopidogrel is 0.5–1.0 h. Some 50% was excreted in the urine and 46% in the feces in the 5 days after dosing. It inhibits aggregation for the life of the platelet, typically 7–10 days. Bleeding time and platelet function return to baseline after 5 days. Cessation is recommended 7–10 days prior to any planned surgery [11, 12]. Ticlopidine is another oral thienopyridine, similar in action and mechanism to clopidogrel. It exhibits high bioavailability up to 80% with rapid absorption. The drug is metabolized into its active form which irreversibly blocks the ADP receptor on the surface of platelets. Antiplatelet effect is demonstrated within 2 days of initiation of therapy and reaches maximum effect after 6 days. The drug is metabolized by the liver, with elimination via renal and fecal routes. After the first dose the half life is 12.6 hours, but this is prolonged to 4–5 days with repeated dosing. The effects persist for 3 days after discontinuing ticlopidine although it may take 1–2 weeks for platelet function to return to normalize [11, 12]. Prasugrel is yet another oral thienopyridine class of ADP receptor inhibitors, Similar in mechanism and action to clopidorgel and ticlopidine, it acts by irreversible binding to P2Y12 receptors in platelets and thus prevents platelet aggregation. Prasugrel is a prodrug that is rapidly metabolized by esterases in the intestine and blood serum to an inactive thiolactone, which is then further converted to a pharmacologically active metabolite via CYP450‐mediated oxidation, primarily CYP3A4 and CYP2B6. It has an elimination half‐life of 2–15 hours. Antiplatelet activity is seen within 1 hour of oral administration. Maximal effect is seen after about 3–5 days of dosing at 10 mg daily following a loading dose of 60 mg. Platelet aggregation returns to baseline in 5–9 days after cessation of the drug. Since the inhibition is irreversible, the return to normal platelet function reflects the production of new platelets [11, 12]. Ticagrelor blocks ADP receptors of subtype P2Y12. Its binding site is different from ADP and the binding is reversible. It does not rely on hepatic activation via the CYP2C19 enzyme; therefore, it is potentially more useful in patients with genetic variants of the enzyme. Ticagrelor, once administered orally, reaches its peak concentration after about 1.5 hours. The main metabolite is formed quickly via CYP3A4 and peaks after about 2.5 hours. Both ticagrelor and its metabolite are pharmacologically active. Excretion of the drug and its metabolite are mainly via bile and feces [11, 12]. The decision of whether or not to interrupt or hold anticoagulants and antiplatelets before surgery can sometimes be complex and prove to be a significant challenge for the surgeon. Interrupting or reversing anticoagulation therapy may lead to transient rebound hypercoagulability as a result of stopping and subsequently restarting anticoagulation therapy. Therefore, the risk of cessation needs stratification and to be weighed against the risk of bleeding from the surgery if the patient is to remain on anticoagulation throughout. The indication for anticoagulation therapy and the length of therapy must be evaluated. Before coming to a decision on interruption and resumption of anticoagulation, the indications for surgery need to be considered, alternatives to surgery and other surgical options assessed, and the associated bleeding risks evaluated. The underlying disease requiring the anticoagulation and coexisting cardiovascular diseases need to be considered in conjunction with the risk of thrombosis.
Management of the Anticoagulated Patient
Introduction
Challenges
Anticoagulants and mechanisms of action
Heparin
Unfractionated heparin
Low molecular weight heparin
Mechanism of action
Warfarin
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Clopidogrel
Ticlopidine
Prasugrel
Ticagrelor
Safety of antithrombotics and risk stratification
Atrial fibrillation, risk of thromboembolism, and bleeding risk
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