Lecture 10 Therapeutics Venous Thromboembolism Dr Sura Al

Lecture 10 Therapeutics Venous Thromboembolism Dr Sura Al Zoubi Ph. D, MClin. Pharm 1

References • Pharmacotherapy: A Pathophysiologic Approach, 11 e, Chapter 37: Venous Thromboembolism • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. • Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines • Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines • Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9 th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 2

INTRODUCTION • VTE is a potentially fatal disorder and significant health problem in our aging society • VTE results from clot formation within the venous circulation and is manifested as deep vein thrombosis (DVT) and/or pulmonary embolism (PE) • DVT is rarely fatal, but PE can result in death within minutes of symptom onset, before effective treatment can be given. • Beyond the symptoms produced by the acute event, VTE complications, such as the postthrombotic syndrome and chronic thromboembolic pulmonary hypertension (CTPH), also cause substantial disability and suffering.

EPIDEMIOLOGY • The incidence rate of symptomatic first VTE is estimated at 132 per 100, 000 patient-years • Women (55. 6%)> men. • Asians<whites<blacks • Recurrent VTE rates are highest in the 180 days following the initial event and decline slowly over the next 4 to 10 years. • In the absence of secondary prophylaxis, the 10 -year cumulative recurrent VTE risk is approximately 25. 0%.

ETIOLOGY • A number of identifiable factors increase VTE risk. • Many risk factors fall into categories constituting what is known as Virchow's triad: 1. blood stasis, 2. vascular injury, 3. Hypercoagulability • Approximately a third of VTEs are provoked by identifiable risk factors.

ETIOLOGY

PATHOPHYSIOLOGY • Hemostasis is the process responsible for maintaining circulatory system integrity following blood vessel damage • Hemostatic clots remain localized to the vessel wall and do not greatly impair blood flow. • Pathologic clots like those causing VTE result in blood flow impairment and often cause complete vessel occlusion

• Normal circumstances: • Endothelial cells separate collagen and TF from circulating platelets and clotting factors • Vessel injury platelet activation and TF-mediated clotting factor cascade thrombin formation fibrin clot, which seals the breach • Pathologic VTE: • Often occurs without gross vessel wall damage and may be triggered by TF brought to the growing thrombus by circulating microparticles. • Venous clots are mainly composed of fibrin, platelets, and trapped red blood cells and often occur in areas of disturbed blood flow, like deep leg vein valve cusps

• Vessel damage platelets bind to adhesion proteins like von Willebrand factor and collagen activated platelets additional platelets recruitment activated platelets; 1. change shape and release components critical for sustaining further thrombus formation into the environment surrounding the developing clot. 2. express P-selectin, an adhesion molecule that facilitates capture of blood-borne TF bearing microparticles resulting in fibrin clot formation via the coagulation cascade 3. Provide phospholipid-rich surfaces necessary for coagulation cascade reactions

• Although VTE can form in any part of the venous circulation, most begin in the leg(s). • Thrombus isolated in calf veins is unlikely to break loose (embolize), • Thrombus involving the popliteal and larger veins above it are more likely to embolize and travel through the right side of the heart and cause PE by lodging in the pulmonary artery or one of its branches, occluding blood flow to the lung, and impairing gas exchange. • Without treatment, the affected portion of the lung becomes necrotic and oxygen delivery to other vital organs decreases, potentially resulting in fatal circulatory collapse

CLINICAL PRESENTATION • The symptoms of DVT or PE are nonspecific and objective tests are required to confirm or exclude the diagnosis. • Patients with DVT frequently present with unilateral leg pain and swelling. • Postthrombotic syndrome, a long-term complication of DVT caused by damage to the venous valves, may also result in chronic lower extremity swelling, pain, tenderness, skin discoloration, and, in the most severe cases, ulceration. • PE typically presents with chest pain, shortness of breath, tachypnea, and tachycardia, which in some cases may result in cardiopulmonary collapse.

• General • DVT most commonly develops in patients with identifiable risk factors. Some may have asymptomatic disease. • Symptoms • The patient may complain of leg swelling, pain, or warmth. Symptoms are nonspecific and objective testing must be performed to establish the diagnosis • Signs • The patient's superficial veins may be dilated and a “palpable cord” may be felt in the affected leg. • The patient may experience pain in back of the knee when the examiner dorsiflexes the foot of the affected leg (Homan's sign). • Laboratory tests • Serum concentration of D-dimer, a by-product of fibrin degradation, is nearly always elevated. • D-dimer values <500 ng/m. L (mcg/L) combined with clinical decision rules are useful in ruling out the diagnosis of DVT.

Diagnostic tests • Compression ultrasound is the most commonly used test to diagnose DVT • Venography is the gold standard for the diagnosis of DVT. However, it is an invasive test that involves injection of radiopaque contrast dye into a foot vein. It is expensive and can cause anaphylaxis and nephrotoxicity. • Clinical assessment significantly improves the diagnostic accuracy of noninvasive tests such as compression ultrasound (CUS), computed tomography pulmonary angiography (CTPA), and D-dimer. • Simple clinical assessment checklists such as the Wells score can be used to determine if a patient is "likely" or "unlikely" to have DVT or PE

• In general, patients with an unlikely probability of VTE should first have their Ddimer tested. If the D-dimer result is below the defined cutoff point, VTE is ruled out; if above the cutoff point, the patient should have appropriate diagnostic imaging (either CUS for suspected DVT or CTPA for suspected PE)

Deep vein thrombosis diagnostic algorithm

Pulmonary embolism diagnostic algorithm

PREVENTION AND TREATMENT

Desired Outcomes • Prevention strategies in at-risk populations positively impact patient outcomes because VTE is potentially fatal and costly to treat. • Treatment of VTE is aimed at preventing thrombus extension and embolization, reducing recurrence risk, and preventing long-term complications such as the postthrombotic syndrome and CTPH. • Carefully managed anticoagulant drug use is important to reduce the risk of bleeding associated with these agents.

Prevention of Venous Thromboembolism • Effective prophylaxis can reduce the risk of fatal PE in high-risk surgical and medical populations. • Early ambulation is often sufficient for those at low risk of VTE. • Up to one-third of hospitalized patients at high VTE risk without contraindications to anticoagulant therapy still do not receive appropriate prophylaxis

Patients Admitted to Hospital for a Medical Illness • For acutely ill hospitalized medical patients at increased risk of thrombosis, thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) twice or thrice daily, or fondaparinux is recommended (Grade 1 B). a Betrixaban is also approved for this indication. • For acutely ill hospitalized medical patients at low risk of thrombosis, use of pharmacologic prophylaxis or mechanical prophylaxis is not recommended (Grade 1 B). • For acutely ill hospitalized medical patients who are bleeding or at high risk for bleeding, anticoagulant thromboprophylaxis is not recommended (Grade 1 B). • For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or at high risk for major bleeding, optimal use of mechanical thromboprophylaxis with graduated compression stockings or intermittent pneumatic compression (IPC) is suggested (Grade 2 C). When bleeding risk decreases, and if venous thromboembolism (VTE) risk persists, substitution of pharmacologic thromboprophylaxis for mechanical thromboprophylaxis is suggested (Grade 2 B). • For critically ill patients, thromboprophylaxis with LMWH or LDUH is suggested over no prophylaxis (Grade 2 C).

Out Patients and admitted to Hospital • For critically ill patients who are bleeding, or are at high risk for major bleeding, mechanical thromboprophylaxis with graduated compression stockings or IPC is suggested (Grade 2 C). When bleeding risk decreases, substitution of pharmacologic thromboprophylaxis for mechanical thromboprophylaxis is suggested (Grade 2 C). • In outpatients with cancer who have no additional risk factors for VTE, routine prophylaxis is not recommended with LMWH or LDUH (Grade 2 B) or warfarin (Grade 1 B). • Routine thromboprophylaxis is not recommended for chronically immobilized persons residing at home or at a nursing home (Grade 2 C). • For long-distance travelers at increased risk of VTE (including previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilia disorder), frequent ambulation, calf muscle exercise, sitting in an aisle seat or below-the-knee graduated compression stockings providing 15 -30 mm Hg (2 -4 k. Pa) pressure at the ankle are suggested (Grade 2 C). • In persons with thrombophilia but no previous history of VTE, the long-term daily use of mechanical or pharmacologic thromboprophylaxis to prevent VTE is not recommended (Grade 1 C).

Patients Undergoing a Surgical Procedure (Excluding Orthopedic Surgery) • For general and abdominal–pelvic surgery patients at very low risk for VTE, no specific pharmacologic (Grade 1 B) or mechanical (Grade 2 C) prophylaxis other than early ambulation is recommended. • For patients at low risk of VTE after abdominal–pelvic surgery or cardiac surgery with an uncomplicated course, mechanical prophylaxis, preferably with IPC, over no prophylaxis is suggested (Grade 2 C). • For patients at moderate VTE risk after general, abdominal–pelvic, or thoracic surgery, or cardiac surgery with a prolonged course not at high risk for major bleeding complications, LMWH or LDUH (Grade 2 B), or mechanical prophylaxis, preferably with IPC (Grade 2 C), is suggested over no prophylaxis. • For patients at moderate risk for VTE after general, abdominal–pelvic surgery, thoracic surgery, or cardiac surgery who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe, mechanical prophylaxis, preferably with IPC, is suggested over no prophylaxis (Grade 2 C). • For patients at high risk for VTE after general, abdominal–pelvic, and thoracic surgery who are not at high risk for major bleeding complications, pharmacologic prophylaxis with LMWH (Grade 1 B) or LDUH (Grade 1 B) is suggested over no prophylaxis. Combination with graduated compression stockings or IPC is also suggested (Grade 2 C).

Patients Undergoing a Surgical Procedure (Excluding Orthopedic Surgery) • For high-VTE-risk general, abdominal–pelvic, and thoracic surgery patients who are at high risk for major bleeding complications or those in whom the consequences of bleeding are thought to be particularly severe, the use of mechanical prophylaxis, preferably with IPC, is suggested over no prophylaxis until the risk of bleeding diminishes and pharmacologic prophylaxis may be initiated (Grade 2 C). • For high-VTE-risk patients undergoing abdominal or pelvic surgery for cancer who are not otherwise at high risk for major bleeding complications, extendedduration pharmacologic prophylaxis (4 weeks) with LMWH is recommended over shorter-duration prophylaxis (Grade 1 B). • For general and abdominal–pelvic surgery patients at high risk for VTE in whom both LMWH and LDUH are contraindicated or unavailable and who are not at high risk for major bleeding complications, low-dose aspirin (Grade 2 C), fondaparinux (Grade 2 C), or mechanical prophylaxis, preferably with IPC (Grade 2 C), is suggested over no prophylaxis. • For general and abdominal–pelvic surgery patients, an inferior vena cava (IVC) filter is not recommended for primary VTE prevention (Grade 2 C).

Patients Undergoing an Orthopedic Surgery • In patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA), use of one of the following for a minimum of 10 -14 days is recommended: LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH, adjusted-dose warfarin, aspirin (all Grade 1 B), or IPC (Grade 1 C) Rivaroxaban for up to 5 days following surgery followed by aspirin 81 mg daily for 9 days (TKA) and 30 days (THA) is also an option. • In patients undergoing hip fracture surgery (HFS), use of one of the following is recommended: antithrombotic prophylaxis for a minimum of 10 -14 days, LMWH, fondaparinux, LDUH, adjusted-dose warfarin, aspirin (all Grade 1 B), or IPC (Grade 1 C). • For patients undergoing major orthopedic surgery (THA, TKA, HFS) and receiving LMWH as thromboprophylaxis, starting either 12 hours or more preoperatively or 12 hours or more postoperatively is recommended over starting within 4 hours or less preoperatively or 4 hours or less postoperatively (Grade 1 B). • In patients undergoing THA, TKA, or HFS, irrespective of the concomitant use of IPC or length of treatment, the use of LMWH is suggested over other recommended alternatives, including fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all Grade 2 B), adjusted-dose warfarin, or aspirin (all Grade 2 C). • For patients undergoing major orthopedic surgery, extending thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery is suggested (Grade 2 B).

Patients Undergoing an Orthopedic Surgery • In patients undergoing major orthopedic surgery, dual prophylaxis with an antithrombotic agent and IPC is suggested during the hospital stay (Grade 2 C). • In patients undergoing major orthopedic surgery who decline injections or IPC, apixaban or dabigatran (alternatively rivaroxaban or adjusted-dose warfarin) is recommended over alternative forms of prophylaxis (all Grade 1 B). • For primary prevention of VTE after major orthopedic surgery, no thromboprophylaxis is suggested over placement of an IVC filter in patients with an increased bleeding risk or contraindications to both pharmacologic and mechanical thromboprophylaxis (Grade 2 C). • The use of screening compression ultrasound in asymptomatic patients following major orthopedic surgery is not recommended (Grade 1 B). • No prophylaxis is suggested rather than pharmacologic thromboprophylaxis in patients with isolated lower leg injuries requiring leg immobilization (Grade 2 C). • For patients undergoing knee arthroscopy without a history of prior VTE, no thromboprophylaxis is suggested (Grade 2 B).

Nonpharmacologic Therapy • Compression stockings and intermittent pneumatic compression (IPC) devices prevent VTE by increasing the velocity of venous blood flow through graded pressure application. • IPC devices utilize a series of cuffs wrapped around the patient's legs that inflate in continuous 1 - to 2 -minute cycles from the ankles to the knees or thighs. • IPC devices should be worn at least 18 hr/day for optimal effectiveness. • Graduated compression stockings do not reliably reduce VTE in medically ill patients. However, they reduce the incidence of VTE (including asymptomatic and distal DVT) by approximately 65% when used after orthopedic surgery, cardiac surgery, gynecologic surgery, or neurosurgery. • IPC reduces the risk of VTE by more than 60% following general surgery, neurosurgery, and orthopedic surgery. Both modalities can be used in combination with anticoagulation to maximize VTE prevention. • Mechanical methods do not increase bleeding risk, which makes them attractive for postoperative VTE prophylaxis, especially in patients with contraindications to pharmacologic therapies. However, they are not risk-free, as discomfort, skin breakdown, and ulceration can occur.

• Inferior vena cava (IVC) filters can provide short-term protection against PE in very high-risk patients by blocking embolization of thrombus formed below the filter. • Percutaneous insertion of an IVC filter is a minimally invasive procedure performed using fluoroscopic imaging to verify placement. • Limited nonrandomized data support the effectiveness and long-term safety of IVC filters for PE prevention. Frequently “retrievable” IVC filters are never retrieved, increasing risk for long-term complications such as DVT, filter migration, IVC occlusion, and insertion site thrombosis. • As such, IVC filters should be reserved for patients at highest VTE risk in whom other prophylactic strategies cannot be used. IVC filters should be removed when VTE risk has passed or when anticoagulation is no longer contraindicated.

Duration of Therapy • Optimal VTE prophylaxis duration following surgery is not well established. • Prophylaxis should be given throughout the period of increased VTE risk. • For general surgical procedures once patients are able to ambulate regularly and other risk factors are no longer present, prophylaxis can be discontinued. • Because of relatively high VTE incidence in the month following hospital discharge among patients undergoing lower extremity orthopedic procedures, extended prophylaxis appears to be beneficial. • Most clinical trials support the use of antithrombotic prophylaxis for 15 to 42 days following total knee or hip replacement surgery

GENERAL APPROACH TO TREATMENT OF VTE • Anticoagulation is the primary treatment for VTE; DVT and PE are treated similarly • After VTE is confirmed objectively, therapy with a rapid-acting anticoagulant should be instituted as soon as possible. Anticoagulants can be administered in the outpatient setting in most patients with DVT and in carefully selected hemodynamically stable patients with PE. • Three months is the appropriate initial duration of anticoagulation therapy for the acute first episode of VTE for all patients. This duration is also recommended when the initial thrombotic event was associated with a major transient or reversible risk factor (eg, surgery, hospitalization). • Continuing anticoagulation is required to prevent new VTE episodes not directly related to the preceding episode. Extended therapy beyond 3 months should be considered for patients with a first unprovoked (idiopathic) VTE when feasible because of a relatively high recurrence rate. • In patients with VTE and active cancer, extended therapy is rarely stopped because of a high recurrence risk.

Decision algorithm: Acute treatment of VTE

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) • In patients with acute DVT of the leg or PE, a DOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) is suggested over warfarin therapy (Grade 2 B). • In patients with acute DVT of the leg or PE treated with warfarin therapy, initial treatment with LMWH, fondaparinux, IV UFH, or SC UFH is recommended (Grade 1 B). • In patients with acute DVT of the leg or PE, early initiation of warfarin (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2 or above for at least 24 hours are recommended (Grade 1 B). • In patients with acute DVT of the leg or PE, LMWH or fondaparinux is suggested over IV UFH (Grade 2 C [2 B for fondaparinux in PE]) and over SC UFH (Grade 2 B for LMWH; Grade 2 C for fondaparinux). • In patients with proximal DVT of the leg or PE provoked by surgery, treatment with anticoagulation for 3 months is recommended over treatment of a shorter period (Grade 1 B), treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1 B), or extended therapy (Grade 1 B regardless of bleeding risk). • In patients with proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, treatment with anticoagulation for 3 months is recommended over treatment of a shorter period (Grade 1 B), treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1 B), and extended therapy if there is a high bleeding risk (Grade 1 B); anticoagulation for 3 months is suggested over extended therapy if there is a low or moderate bleeding risk (Grade 2 B).

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) • In patients with a first unprovoked DVT of the leg or PE, treatment with anticoagulation for at least 3 months is recommended over treatment of a shorter duration (Grade 1 B); after 3 months of treatment, the risk-to-benefit ratio of extended therapy should be evaluated; for patients with low or moderate bleeding risk, extended anticoagulant therapy is suggested over 3 months of therapy (Grade 2 B); for patients with high bleeding risk, 3 months of anticoagulant therapy is recommended over extended therapy (Grade 1 B). • In patients with recurrent unprovoked VTE, extended anticoagulant therapy is recommended over 3 months of therapy in those with low bleeding risk (Grade 1 B), and suggested in those with moderate bleeding risk (Grade 2 B); in patients with high bleeding risk, 3 months of therapy is suggested over extended therapy (Grade 2 B). • In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually). • In patients with DVT of the leg or PE who are treated with warfarin, a therapeutic INR range of 2 -3 (target INR of 2. 5) is recommended for all treatment durations (Grade 1 B). • In patients with DVT of the leg or PE and no cancer and not treated with a DOAC, warfarin therapy is suggested over LMWH for long-term therapy (Grade 2 C). • In patients with DVT of the leg or PE and cancer, LMWH or a DOAC is suggested over warfarin therapy (DOACs should be used with caution in patients with cancer of the gastrointestinal tract).

Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE) • In patients with DVT of the leg or PE who receive extended therapy, there is no need to change the choice of anticoagulant after the first 3 months unless patient circumstances dictate a change in therapy (Grade 2 C). • In patients with acute DVT of the leg or PE, the use of an inferior vena cava (IVC) filter in addition to anticoagulants is not recommended (Grade 1 B) unless anticoagulation therapy is contraindicated (Grade 1 B); a conventional course of anticoagulant therapy is suggested if the risk of bleeding resolves (Grade 2 B). • In patients who are incidentally found to have asymptomatic DVT of the leg or PE, the same initial and longterm anticoagulation as for comparable patients with symptomatic DVT of PE is suggested (Grade 2 B). • In patients with unprovoked proximal DVT of the leg or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, aspirin is suggested over no aspirin to prevent recurrent VTE (Grade 2 C). • In patients with subsegmental PE (no involvement of more proximal pulmonary arteries) and no proximal DVT in the legs who have a low risk for recurrent VTE, clinical surveillance is suggested over anticoagulation (Grade 2 C); if high risk for recurrent VTE anticoagulation is suggested over clinical surveillance (Grade 2 C). • In patients with recurrent VTE while on warfarin therapy (in therapeutic range) or on DOAC (and believed to be compliant), switching to treatment with LMWH at least temporarily is suggested (Grade 2 C). • In patients who have recurrent VTE while on long-term LMWH (and are believed to be compliant), increasing the LMWH dose by about one-quarter to one-third is suggested (Grade 2 C).

DVT Specific • In patients with acute DVT of the leg and whose home circumstances are adequate, initial treatment at home is recommended over treatment in hospital (Grade 1 B). • In patients with acute DVT of the leg, early ambulation is suggested over initial bed rest (Grade 2 C). • In patients with acute proximal DVT of the leg, anticoagulant therapy alone is suggested over catheterdirected thrombolysis (Grade 2 C). • In patients with acute symptomatic DVT of the leg, the routine use of graduated compression stockings for the purpose of preventing postthrombotic syndrome is not suggested (Grade 2 B).

PHARMACOLOGIC THERAPY

Direct Oral Anticoagulants (DOACs) • Rivaroxaban, apixaban, and edoxaban are oral selective inhibitors of both free and clotbound factor Xa and do not require antithrombin to exert their anticoagulant effect. Dabigatran (Pradaxa) is an oral selective, reversible, direct factor IIa inhibitor. • DOACs should be used with caution in patients with renal dysfunction. • Single-drug oral therapy with rivaroxaban or apixaban is noninferior to traditional therapy with warfarin overlapped with enoxaparin for acute DVT and PE with similar rates of recurrent VTE and perhaps less major bleeding. Both drugs are initiated with a higher dose with eventual transition to maintenance dosing. • Until further data are available, these drugs should not be used in patients with creatinine clearance (Cr. Cl) less than 25 m. L/min (0. 42 m. L/s), active cancer, and patients requiring thrombolytic therapy. Neither drug requires routine anticoagulation monitoring. Both drugs have a high acquisition cost. • Edoxaban and dabigatran must be given only after at least 5 days of subcutaneous (SC) anticoagulation with UFH, LMWH, or fondaparinux. • These regimens were noninferior to warfarin in patients with acute VTE for the outcome of recurrent VTE.

• Compared to warfarin, dabigatran caused similar major bleeding and edoxaban caused significantly less bleeding. • Until further data are available, these agents should not be given to patients with hemodynamically unstable PE or at high bleeding risk. • Bleeding is the most common adverse effect with DOAC therapy. Patients experiencing significant bleeding should receive routine supportive care and discontinuation of anticoagulant therapy. • Idarucizumab (Praxbind) 5 g IV rapidly reverses the dabigatran anticoagulant effect when needed during emergency situations (eg, lifethreatening bleeding) and need for urgent surgical intervention. • Adding aspirin to DOAC therapy nearly doubles bleeding rates and should be avoided in most patients with VTE. • • Rivaroxaban and apixaban are subject to interactions involving inhibitors or inducers of CYP 3 A 4.

Low-Molecular-Weight Heparin • LMWH fragments produced by either chemical or enzymatic depolymerization of UFH are heterogeneous mixtures of sulfated glycosaminoglycans with approximately one-third the mean UFH molecular weight. LMWH prevents thrombus propagation by accelerating the activity of antithrombin similar to UFH. • LMWH given SC in fixed, weight-based doses is at least as effective as UFH given IV for VTE treatment. LMWH has largely replaced UFH for initial VTE treatment due to improved pharmacokinetic and pharmacodynamic profiles and ease of use. Advantages of LMWH over UFH include: predictable anticoagulation dose response; improved SC bioavailability; dose-independent clearance; longer biologic half-life; lower incidence of thrombocytopenia; and less need for routine laboratory monitoring. 1. 2. 3. 4. 5. 6. • Stable patients with DVT or PE who have normal vital signs, low bleeding risk, and no other uncontrolled comorbid conditions requiring hospitalization can be discharged early or treated entirely on an outpatient basis (if considered appropriate candidates). Hemodynamically unstable patients with PE should generally be admitted for initiation of anticoagulation therapy.

• Recommended doses (based on actual body weight) include: ✓ Enoxaparin (Lovenox): For acute DVT treatment with or without PE, 1 mg/kg SC every 12 hours or 1. 5 mg/kg every 24 hours ✓ Dalteparin (Fragmin): For acute DVT treatment, 200 units/kg SC every 24 hours (not FDA approved in the U. S. for this indication). For VTE in patients with cancer, 200 units/kg SC every 24 hours for 30 days, followed by 150 units SC every 24 hours. The maximum total daily dose is 18, 000 units. • In patients without cancer, acute LMWH treatment is generally transitioned to long-term warfarin therapy after 5 to 10 days.

• Routine laboratory monitoring is unnecessary. However, prior to initiating therapy, obtain a baseline complete blood cell count (CBC) with platelet count and serum creatinine. • Check the CBC every 5 to 10 days during the first 2 weeks of LMWH therapy and every 2 to 4 weeks thereafter to monitor for occult bleeding. • Measuring anti–factor Xa activity is the most widely used method to monitor LMWH; routine measurement is unnecessary in stable and uncomplicated patients. • Monitoring may be helpful in patients who have significant renal impairment, weigh less than 50 kg, are morbidly obese, or require therapy longer than 14 days. • As with other anticoagulants, bleeding is the most common adverse effect of LMWH therapy, but major bleeding may be less common than with UFH. • If major bleeding occurs, IV protamine sulfate can be administered, but it cannot neutralize the anticoagulant effect completely. • The recommended protamine sulfate dose is 1 mg per 1 mg of enoxaparin or 1 mg per 100 anti–factor Xa units of dalteparin administered in the previous 8 hours. A second dose of 0. 5 mg per 1 mg or 100 anti– factor Xa units can be given if bleeding continues. • Smaller protamine doses can be used if the LMWH dose was given in the previous 8 to 12 hours. • Protamine sulfate is not recommended if the LMWH was given more than 12 hours earlier. • Thrombocytopenia can occur with LMWHs, but the incidence of heparin-induced thrombocytopenia (HIT) is three times lower than with UFH. • LMWH has been associated with osteopenia, but the risk of osteoporosis appears to be lower with LMWH than with UFH.

Fondaparinux • It prevents thrombus generation and clot formation by indirectly inhibiting factor Xa activity through its interaction with antithrombin. • Unlike UFH or LMWH, fondaparinux inhibits only factor Xa activity. • Fondaparinux is a safe and effective alternative to LMWH for acute VTE treatment and is likewise followed by long-term warfarin therapy. • Fondaparinux is dosed once daily via weight-based SC injection: 1. 5 mg if less than 50 kg, 2. 7. 5 mg if 50 to 100 kg, and 3. 10 mg if more than 100 kg. • Patients receiving fondaparinux do not require routine coagulation testing. • Determine baseline kidney function before starting therapy because fondaparinux is contraindicated if Cr. Cl is less than 30 m. L/min (0. 5 m. L/s). Bleeding is the primary adverse effect associated with fondaparinux therapy. Measure CBC at baseline and periodically thereafter to detect occult bleeding. Monitor for signs and symptoms of bleeding daily. There is no specific antidote to reverse the antithrombotic activity of fondaparinux. • •

Unfractionated Heparin • Unfractionated heparin binds to antithrombin, provoking a conformation change that makes it much more potent in inhibiting the activity of factors IXa, XIIa, and IIa. • This prevents thrombus growth and propagation allowing endogenous thrombolytic systems to lyse the clot. Because some patients fail to achieve an adequate response, IV UFH has largely been replaced by LMWH or fondaparinux. • UFH continues to have a role in patients with Cr. Cl less than 30 m. L/min (0. 5 m. L/s). • When immediate and full anticoagulation is required, a weight-based IV loading dose followed by a continuous IV infusion is. • Fixed dosing (eg, 5000 -unit bolus followed by 1000 -units/h continuous infusion) produces similar clinical outcomes. • Weight-based SC UFH (initial dose 333 units/kg SC followed by 250 units/kg every 12 hours) without coagulation monitoring also provides adequate anticoagulation and is a less costly option for select patients.

• The activated partial thromboplastin time (a. PTT) is generally recommended for monitoring UFH, provided that institution-specific therapeutic ranges are defined. Measure a. PTT prior to initiation of therapy and 6 hours after the start of therapy or a dose change. Adjust the UFH dose based on patient response and the institution-specific a. PTT therapeutic range. • Monitor patients closely for bleeding signs and symptoms during UFH therapy. If major bleeding occurs, discontinue UFH immediately, identify and treat the underlying bleeding source, and give protamine sulfate by slow IV infusion over 10 minutes (1 mg/100 units of UFH infused during the previous 4 hours; maximum 50 mg). • Heparin-induced thrombocytopenia (HIT) is a rare immunologic reaction requiring immediate intervention and that may be fatal. • The most common complication of HIT is VTE; arterial thrombosis occurs less frequently. Thrombocytopenia is the most common clinical manifestation, but serologic confirmation of heparin antibodies is required to diagnose HIT. Use of a clinical prediction rule, such as the 4 Ts score (Thrombocytopenia, Timing of platelet count fall or thrombosis, Thrombosis, o. Ther explanation for thrombocytopenia), can improve the predictive value of platelet count monitoring and heparin antibody testing. Discontinue all heparin if new thrombosis occurs in the setting of falling platelets in conjunction with a moderate or high 4 Ts score. Alternative anticoagulation with a direct thrombin inhibitor should then be initiated. • Using UFH doses of 20, 000 units/day or more for longer than 6 months, especially during pregnancy, is associated with significant bone loss and may lead to osteoporosis.

Warfarin • Warfarin inhibits enzymes responsible for cyclic interconversion of vitamin K in the liver. • Because of its slow onset of effect, warfarin must be started concurrently with injectable anticoagulant therapy (UFH, LMWH, or fondaparinux) with an overlap of at least 5 days and until an INR of 2 or greater has been achieved for at least 24 hours. • The initial warfarin dose should be 5 to 10 mg for most patients and periodically adjusted to achieve and maintain an INR between 2 and 3. • Lower starting doses may be acceptable in patients with advanced age, malnutrition, liver disease, or heart failure. Starting doses more than 10 mg should be avoided. • In general, maintenance dose changes should not be made more frequently than every 3 days. Adjust maintenance doses by calculating the weekly dose and reducing or increasing it by 5% to 25%. The full effect of a dose changes may not become evident for 5 to 7 days. • Nonhemorrhagic adverse effects of warfarin include the rare “purple toe” syndrome and skin necrosis. • Because of the large number of food–drug and drug–drug interactions with warfarin, close monitoring and additional INR determinations may be indicated whenever other medications are initiated, discontinued, or an alteration in consumption of vitamin K– containing foods is noted.

• Warfarin’s primary adverse effect is bleeding that can range from mild to life threatening. It does not cause bleeding per se, but it exacerbates bleeding from existing lesions and enables massive bleeding from ordinarily minor sources. The likelihood of bleeding rises with increased intensity of anticoagulation therapy; therefore, correcting high INR values is important to reduce bleeding risk: – ✓ When the INR >4. 5 withholding warfarin, adjusting the dose of warfarin, and/or providing a small dose of vitamin K to shorten the time to return to normal INR. Although vitamin K can be given parenterally or orally, the oral route is preferred in the absence of serious bleeding. – ✓ If the INR 5 -10 and no bleeding is present, routine vitamin K use is not recommended because it has not been shown to affect the risk of developing subsequent bleeding or thromboembolism compared to simply withholding warfarin alone. – ✓ For INR >10 oral vitamin K (phytonadione 2. 5 mg) is suggested. Use vitamin K with caution in patients at high risk of recurrent thromboembolism because of the possibility of INR overcorrection. • Patients with warfarin-associated major bleeding require supportive care. Rapid reversal of anticoagulation with a four-factor prothrombin complex concentrate and 5 to 10 mg of vitamin K given by slow IV injection are also recommended.

EVALUATION OF THERAPEUTIC OUTCOMES • Monitor patients for resolution of symptoms, development of recurrent thrombosis, symptoms of the postthrombotic syndrome, and adverse effects from anticoagulants. • Monitor hemoglobin, hematocrit, and blood pressure carefully to detect bleeding from anticoagulant therapy. • Perform coagulation tests (a. PTT, PT, and INR) prior to initiating therapy to establish the patient’s baseline values and guide later anticoagulation. • Ask outpatients taking warfarin about medication adherence to prior dosing instructions, other medication use, changes in health status, and symptoms related to bleeding and thromboembolic complications. Any changes in concurrent medications should be carefully explored, and dietary intake of vitamin K-rich foods should be assessed.

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