CCH_Anticoagulation

Anticoagulation
Mindy J. Lacey
Chia L. Chang

I. BACKGROUND.
 Pharmacologic modulation of coagulation is commonly employed to prevent inappropriate thrombosis or end-organ pathology in various disease entities, often atherosclerotic in origin. The basic premise of therapy with agents that hinder the normal clotting machinery involves sufficiently inhibiting the formation of new thrombi while avoiding hemorrhagic complications
The principal uses of anticoagulation in common clinical practice involve the prevention and treatment of myocardial infarction, stroke, pulmonary embolus, deep venous thrombosis, and other states of acquired and hereditary hypercoagulability .

II. PATHOPHYSIOLOGY.
Coagulation involves both primary and secondary hemostasis: primary referring to the formation of a platelet plug at the site of endothelial injury within minutes, and secondary referring to the generation of fibrin to cross-link the platelet plug, ensure tensile strength, and long stability in blood flow. Secondary hemostasis is the result of a complex interconnected cascade of serine protease-mediated reactions allowing for simultaneous amplification and regulation. Pharmacologic anticoagulation usually alters one of these pathways preferentially (Table 7.2.1). The therapeutic effects, as well as the complications of excesses (i.e., platelet vs. coagulation factor type bleeding), are a result of a given agent’s target.
TABLE 7.2.1 Physiologic Targets of Commonly Used Anticoagulants

Agent

Target

Mechanism

Some Oral Anticoagulants for VTE

Vitamin K Antagonist

Drug	FDA-Approved	Usual Adult Treatment Dosage	Usual Adult Prophylaxis Dosage1	Some Adverse Effects	Comments	Cost2
Warfarin – generic Coumadin (BMS) Jantoven (USL)	▶ Prophylaxis of DVT and PE ▶ Treatment of DVT and PE	2-10 mg once/d	2-10 mg once/d	urticaria, abdominal pain, bloating, nausea, vomiting, diarrhea, skin necrosis	Drug Interactions: Numerous drug interactions3 ▶ Monitor INR daily during initiation and adjust dose until INR is in therapeutic range (2-3) ▶ Can take up to 7 days to achieve full therapeutic effect ▶ For treatment of VTE, requires overlap with LMWH, fondaparinux, or UFH for ≥5 days and until INR is ≥2 for at least 24 hours ▶ Can be used for long-term treatment of VTE in patients without active cancer; however, a direct oral anticoagulant is preferred ▶ No dosage adjustments required in patients with renal impairment ▶ Recommended for treatment of VTE in patients with CrCl <30 min="" ml="" o:p="">

▶ Numerous dietary restrictions

▶ Should not be used in patients with an increased

INR at baseline who have chronic liver disease

▶ Not recommended for use during pregnancy

▶ Treatment with vitamin K can normalize the INR

within 12-24 hours

▶ A 4-factor prothrombin complex concentrate

(Kcentra) is approved for urgent reversal of warfarin

anticoagulation in adults with acute major

bleeding

$7.80

64.50

10.80



Direct Thrombin Inhibitor

Drug	FDA-Approved	Usual Adult Treatment Dosage	Usual Adult Prophylaxis Dosage1	Some Adverse Effects	Comments	Cost2
Dabigatran etexilate – Pradaxa (Boehringer Ingelheim)	▶ Prophylaxis of DVT and PE following hip replacement surgery ▶ Treatment of DVT and PE following 5-10 days of initial therapy with a paren-teral anticoagulant ▶ Reduction in the risk of recurrent DVT and PE following initial therapy	CrCl >30 mL/min: 150 mg bid Should not be used in patients with CrCl ≤30 mL/min	CrCl >30 mL/min: 110 mg once, then 220 mg once/d Should not be used in patients with CrCl ≤30 mL/min	Dyspepsia and gastritis-like symptoms Drug Interactions: Substrate of P-gp; interacts with inhibitors and inducers of P-gp4; NSAIDs and other antiplatelet drugs can increase the risk of bleeding Avoid coadministration with P-glycoprotein (P-gp) inhibitors in patients with CrCl <50 mL/min.	▶ Does not require INR monitoring ▶ Recommended over warfarin for long-term treatment of VTE in patients without active cancer ▶ As effective as warfarin in treating VTE, with a lower risk of intracranial bleeding ▶ As effective and safe as warfarin in preventing recurrent VTE in patients treated initially with UFH or LMWH ▶ Noninferior to warfarin for extended treatment of VTE ▶ Lower risk of intracranial bleeding and death than with warfarin, but dabigatran has a higher risk of GI bleeding ▶ Associated with an increased risk of acute coronary events and not recommended for treatment of VTE in patients with coronary artery disease ▶ Idarucizumab (Praxbind) is approved for urgent reversal of anticoagulant effect	$400.60
Drug	FDA-Approved	Usual Adult Treatment Dosage	Usual Adult Prophylaxis Dosage1	Some Adverse Effects	Comments	Cost2
Apixaban – Eliquis (BMS)	▶ Prophylaxis of DVT following hip or knee replacement surgery ▶ Treatment of DVT and PE ▶ Reduction in the risk of recurrent DVT and PE following initial treatment lasting at least 6 months	10 mg bid x 7 days, then 5 mg bid5 With dual P-gp/strong CYP3A4 inhibitor: reduce dose by 50%6	2.5 mg bid6	Epistaxis, contusion, nausea, increased serum transaminases, anemia Drug Interactions: Substrate of CYP3A4 and P-gp; interacts with inhibitors and inducers of CYP3A4 and P-gp4; NSAIDs and other antiplatelet drugs can increase the risk of bleeding Should not be used concurrently with dual P-gp/ strong CYP3A4 inducers	▶ Do not require INR monitoring ▶ Apixaban, edoxaban, rivaroxaban are recommended over warfarin for long-term treatment of VTE in patients without active cancer ▶ Apixaban and rivaroxaban are oral alternatives for initial use as monotherapy for treatment of VTE in patients without active cancer ▶ Apixaban, edoxaban, and rivaroxaban are as effective as warfarin in treating VTE, with a lower risk of intracranial bleeding ▶ Apixaban and rivaroxaban are oral alternatives for primary prevention of VTE in patients undergoing knee or hip replacement surgery ▶ Extended treatment for one year (after 6-12 months of anticoagulation therapy) with low doses of apixaban or rivaroxaban can prevent symptomatic recurrences of VTE ▶ Apixaban may have the lowest rate of bleeding ▶ Have shorter half-lives than warfarin, which increases the risk of thrombosis with missed doses ▶ Betrixaban is an oral alternative to parenteral treatment in patients hospitalized for an acute medical illness who are at increased risk of thrombosis ▶ Prothrombin complex concentrates can reverse the anticoagulant effects of factor Xa inhibitor	$420
Betrixaban – Bevyxxa (Portola)	▶ Prophylaxis of VTE in patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE	Not an FDA-approved indication	160 mg once, then 80 mg once/d for a total of 35-42 days With P-gp inhibitor: 80 mg once, then 40 mg once/d for a total of 35-42 days CrCl ≥15 to <30 mL/ min: 80 mg once, then 40 mg once/d for a total of 35-42 days Should not be used in patients with CrCl <15 mL/min	Epistaxis, UTI, constipation, hypokalemia, hypertension, headache, nausea, diarrhea Drug Interactions: Substrate of P-gp; interacts with inhibitors and inducers of P-gp4; NSAIDs and other antiplatelet drugs can increase the risk of bleeding	See above	450.
Edoxaban – Savaysa (Daiichi-Sankyo)	▶ Treatment of DVT and PE following 5-10 days of initial therapy with a parenteral anticoagulant	60 mg once/d CrCl: 15-50 mL/min: 30 mg once/d With P-gp inhibitor: 30 mg once/d ≤60 kg: 30 mg once/d	Not FDA-approved	Rash, abnormal liver function tests, anemia Drug Interactions: Substrate of P-gp; interacts with inhibitors of P-gp4; should not be used with the P-gp epistaxis inducer rifampin; NSAIDs and other antiplatelet drugs can increase the risk of bleeding	See above	337
Rivaroxaban – Xarelto Janssen)	▶ Prophylaxis of DVT following hip or knee replacement surgery ▶ Treatment of DVT and PE ▶ Reduction in the risk of recurrent DVT and/ or PE following initial treatment lasting at least 6 months	15 mg bid x 3 weeks, then 20 mg once/d7 Should not be used in patients with CrCl <30 mL/min, in those taking dual P-gp/strong CYP3A4 inducers or inhibitors, or in those with CrCl 15-<80 mL/ min taking dual P-gp/ moderate CYP3A4 inhibitors	10 mg once/d Should not be used in patients with CrCl <30 mL/min, in those taking dual P-gp/strong CYP3A4 inducers or inhibitors, or in those with CrCl 15-<80 mL/min taking dual P-gp/ moderate CYP3A4 inhibitors	Abdominal pain, fatigue, back pain, muscle, spasms, dizziness, anxiety, depression, insomnia, pruritus, wound secretion, UTI, increased serum transaminases Drug Interactions: Substrate of CYP3A4 and P-gp; interacts with inhibitors and inducers of CYP3A4 and P-gp4; NSAIDs and other antiplatelet drugs can increase the risk of bleeding Should not be used in patients taking dual P-gp/strong CYP3A4 inducers or inhibitors or in those with CrCl 15-<80 mL/min taking dual P-gp/moderate CYP3A4 inhibitors	See above	334

. Prophylaxis is recommended for a minimum of 10-14 days and for up to 35 days after major orthopedic surgery (Y Falck-Ytter et al. Chest 2012; 141:e278S).

2. Approximate WAC for 30 days’ treatment at the lowest usual adult dosage for treatment. Cost of betrixaban is based on dosage for prophylaxis. WAC = wholesaler acquisition cost or manufacturer’s published price

to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. February 5, 2018. Reprinted with permission by First Databank,

Inc. All rights reserved. ©2018. www.fdbhealth.com/policies/drug-pricing-policy.

3. Acetaminophen, amiodarone, cefazolin, cefotetan, ceftriaxone, clarithromycin, fluconazole, fluorquinolones, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, metronidazole, phenytoin (initial use), rosuvastatin, trimethoprim-

sulfamethoxazole, and voriconazole can increase the anticoagulant effect of warfarin. Barbiturates, carbamazepine, cholestyramine, colestipol, dicloxacillin, nafcillin, phenytoin, rifampin, St. John’s wort,

and sucralfate can decrease the anticoagulant effect of warfarin (Drug Interactions from The Medical Letter. Available at: medicalletter.org/druginteractions. Accessed March 1, 2018).

4. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med Lett Drugs Ther 2017 September 18 (epub). Available at: medicalletter.org/downloads/CYP_PGP_Tables.pdf. Accessed March 1, 2018.

5. For extended treatment after at least 6 months of treatment for DVT or PE, the dosage for reduction in risk of recurrence of VTE is 2.5 mg bid.

6. Patients taking 2.5 mg bid should not take dual P-gp/strong CYP3A4 inhibitors.

7. For extended treatment after at least 6 months of treatment for DVT or PE, the dosage for reduction in risk of recurrence of VTE is 10 mg once/d.

Platelets

Cyclooxygenase inhibition

Clopidogrel

Platelets

Glycoprotein IIb/IIIa blocking

Prevents the activation of glycoprotein IIb/IIIa (platelet aggregation) via inhibition of adenosine diphosphate (ADP) receptors

Warfarin

Coagulation cascade

Vitamin K antagonist

Heparin (high and low molecular weight)/heparinoids

Coagulation cascade

Heparin combines with antithrombin III to accelerate its activity to inactive thrombin and then inactivates Factor X and inhibits prothrombin’s conversion to thrombin. This also prevents fibrin formation from fibrinogen during active thrombosis

Low molecular weight heparin (LMWH) (Lovenox) similar as heparin but its effect is more selective as anti-factor Xa and anti-factor IIa (anti-thrombin)

Dabigatran

Coagulation cascade

Direct thrombin inhibitor

Rivaroxaban

Coagulation cascade

Factor Xa inhibitor




III. EVALUATION. A thorough clinical history and physical examination are critical in the diagnosis of thrombosis and states of anticoagulant overdose, as well as guiding the choice of therapy. Briefly, the clinical phenotype is often that of the underlying disease process prompting anticoagulation (i.e., cerebrovascualr accident), and evaluation of these patients treated with anticoagulation often centers on the identification of hemorrhagic complications such as easy brusing, prolonged bleeding, and other bleeding diathesis. It is critical to obtain a history of current/chronic anticoagulation therapy (including herbals) prior to invasive procedures or the initiation of treatment with other drugs that may alter the metabolism of drugs affecting hemostasis.
III. DIAGNOSIS. Barring overt clinical stigmata of abnormalites of coagulation, laboratory evaluation is the cornerstone of regulating therapy. The three main assays utilized include the international normalized ratio (INR), partial prothrombin time (PTT), and less frequently bleeding time. INR, a standardized system for reporting prothrombin time, is a tool used for monitoring the function of the extrinsic coagulation cascade and is typically a measure of the effects of warfarin. PTT is a marker of the degree of inhibition of the intrinsic coagulation cascade by heparin and other related compounds, with the exception of low-molecular-weight heparins that often do not require routine laboratory monitoring. While bleeding time is a measure of primary hemostasis/platelet function and related drugs, the test is often cumbersome to use in daily practice and clinical features (bruising, etc.) are more commonly employed to assess the effects of antiplatelet agents.
IV. TREATMENT. See Table 7.2.2.
P.118

Condition	Common treatment	Therapeutic target

TABLE 7.2.2 Pharmacotherapy of Commonly Encountered Conditions Requiring Anticoagulation
Condition

Common treatment

Therapeutic target

Duration of therapy

Atrial fibrillation

Treatment based on CHADS 2 score:

Warfarin: INR 2-3

Lifelong

Aspirin (ASA),

ASA+Plavix, Warfarin, Pradaxa, Xarelto

Deep venous thrombosis

Warfarin

Warfarin: INR 2-3

Warfarin: Depending on factors:

Heparin/LMWH during acute treatment

provoking vs. non-provoking, and risks of bleeding

3 mo to lifelong

Pulmonary embolus

Warfarin

Warfarin: INR 2-3

Warfarin: Depending on factors:

Heparin/LMWH during actue treatment

provoking vs. non-provoking, and risks of bleeding

3 mo to lifelong

Cerebrovascular accident

Thrombotic type: ASA, Plavix, Aggrenox

Warfarin: INR 2-3

Lifelong

Cardioembolic type: Warfarin

Myocardial infarction

ASA, Plavix

None

Lifelong

Mesenteric/visceral thrombosis

LMWH: acute tx Warfarin

Warfarin: INR 2-3

Lifelong

Prosthetic heart valve—mechanical

Aortic: Warfarin

Aortic: INR 2-3

Lifelong

Mitral: Warfarin

Mitral: INR 2.5-3.5

Prosthetic heart valve— biomechanical

Aortic: ASA

Warfarin: INR 2-3

Lifelong

Mitral: Warfarin × 3 mo then ASA

Antiphospholipid antibody syndrome

Warfarin

Wafarin: INR 2-3

Lifelong

LMWH for actue siturations

Factor V Leiden

ASA or warfarin depending on risks

Warfarin: INR 2-3

Lifelong

LMWH for acute situations

INR, international normalized ratio.