John R. Bartholomew, MD, FACC

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.

Venous thromboembolism (VTE) includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). Although the exact incidence of VTE is unknown, an estimated 1 million people in the United States are affected each year, with about a third experiencing a recurrence within 10 years.¹ VTE affects hospitalized and nonhospitalized patients, is often overlooked, and results in long-term complications including postthrombotic syndrome (PTS) for DVT, postpulmonary embolism syndrome and chronic thromboembolic pulmonary hypertension for PE, and death.²

TREATMENT

Treatment for VTE should be initiated in the following cases:

• Proximal DVT of the lower extremity
• Symptomatic distal (calf vein) DVT
• Symptomatic upper extremity DVT (axillary-subclavian veins)
• PE
• Subsegmental PE in a patient at risk for recurrence
• Surveillance for subsegmental PE in a patient with no proximal DVT and a low risk of recurrence.

In addition to anticoagulants, other more aggressive therapies for VTE may be appropriate, such as systemic thrombolysis in the case of PE or catheter-directed thrombolytic or pharmacomechnical therapies for DVT or PE, surgical intervention (acute pulmonary embolectomy), or placement of an inferior vena cava (IVC) filter.

This article reviews the management of VTE, highlighting the recent changes in treatment and prevention guidelines from the American College of Chest Physicians (ACCP).³

Risk of bleeding

In assessing a patient’s risk of bleeding for anticoagulation therapy (Table 1), the absence of risk factors is considered low risk for bleeding, the presence of 1 risk factor is considered intermediate risk, and 2 or more risk factors is considered high risk. Compared with low-risk patients, moderate-risk patients have a twofold increased risk of major bleeding and high-risk patients have an eightfold increased risk of major bleeding. This equates to an annualized risk of major bleeding of 0.8% for low-risk patients, 1.6% for moderate-risk patients, and greater than 6.5% for high-risk patients.³

Anticoagulants

Deciding on which anticoagulant to use depends on the indication, the patient’s underlying condition, the patient’s preference, and the patient’s risk of bleeding. Heparin, the LMWHs, fondaparinux and the DOACs (rivaroxaban and apixaban) are the only agents approved by the US Food and Drug Administration (FDA) recommended for the acute treatment phase, while the DOACs and warfarin are anticoagulation options for the long-term and extended treatment phases. The LMWHs should be used for the patient with cancer and during pregnancy.

Unfractionated heparin. UFH is administered parenterally and can be used for the prevention and treatment of VTE. Heparin remains an option for initial treatment of patients with acute VTE and is generally preferred over LMWH for patients who may require advanced therapies, such as for hemodynamically unstable PE or iliofemoral DVT. It is also recommended for patients with renal failure.³ Weight-based dosing (80 U/kg bolus followed by 18 U/kg/hour intravenous infusion) is recommended, targeting an antifactor activated clotting factor (anti-Xa) assay level of 0.3 IU/mL to 0.7 IU/mL. Heparin may also be given subcutaneously in an outpatient setting using an initial bolus of 333 U/kg followed by a subcutaneous dose of 17,500 U twice daily.⁵

Low-molecular-weight heparin. LMWHs are administered as weight-based subcutaneous injections and have indications for patients with acute VTE and for VTE prophylaxis. LMWHs are used for transitioning to warfarin, dabigatran, or edoxaban for long-term anticoagulation and are recommended over warfarin and DOACs for treatment of VTE in patients with cancer and in pregnant women.³

Enoxaparin (Lovenox), the most commonly used agent in the United States, is given either as a once-daily injection (1.5 mg/kg/day) or a twice-daily injection (1 mg/kg every 12 hours). It is also approved for VTE prophylaxis in patients undergoing hip or knee replacement surgery or abdominal surgery, or in patients with severely restricted mobility during acute illness. LMWH can also be given in patients with renal insufficiency (creatinine clearance [CrCL] < 30 mL/minute) after dose adjustment. No monitoring is required, although it is advised in pediatric patients, pregnant women, obese patients, and patients with renal insufficiency. If monitoring is required, an anti-Xa assay using LMWH as a reference standard should be done 4 hours after subcutaneous injection. The therapeutic range for enoxaparin is 0.5 IU/mL to 1.0 IU/mL for the 12-hour regimen and greater than 1.0 IU/mL for the once-daily dose. Other LMWHs available in the United States include dalteparin (Fragmin) and tinzaparin (Innohep). Each has its own specific indications.

Fondaparinux. Fondaparinux is an indirect factor Xa inhibitor, chemically related to LMWH. It is approved for treatment of patients with acute VTE when used in combination with a VKA (warfarin) or dabigatran or edoxaban. It also has approval for VTE prophylaxis in patients undergoing hip fracture, hip or knee replacement, and abdominal surgery. Fondaparinux is administered as a once-daily subcutaneous injection of 2.5 mg for DVT prophylaxis and a body weight-based dose for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to 100 kg; 10 mg > 100 kg).⁶ Fondaparinux is contraindicated in patients with severe renal impairment (CrCL les 30 mL/min) and bacterial endocarditis.⁶

Warfarin. Warfarin, a VKA, was the mainstay of therapy for long-term and extended treatment of VTE until the advent of the DOACs. Warfarin must be coadministered with heparin, LMWH, or fondaparinux initially and continued as overlap therapy for a minimum of 5 days until the international normalized ratio [INR] is at least 2.0 for 24 hours.⁴ Early initiation of a VKA on the first day of parenteral therapy is advised.

Warfarin remains the best option for patients on long-term or extended anticoagulation with liver dysfunction (elevated serum transaminases exceeding twice the upper limits of normal or active liver disease) or renal disease (CrCL < 30 mL/min), as well as patients unable to afford DOACs. Additionally, select patient populations may still be best served by warfarin as these groups were underrepresented or not included in DOAC trials, including pediatric patients, individuals with body weight less than 50 kg or greater than 150 kg, and patients with select types of thrombophilia (eg, antiphospholipid syndrome). Warfarin is also advised for patients with poor compliance, as international normalized ratio of prothrombin time (PT/INR) monitoring is required using a point-of-care testing device or during a visit to an anticoagulation clinic. DOACs do not require monitoring, and noncompliance will not be readily apparent.

Direct oral anticoagulants. The DOACs, which include the factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) and the direct thrombin inhibitor dabigatran (Pradaxa), been studied extensively and shown to be noninferior to VKAs for treatment of VTE.⁷ DOACs are currently recommended by the ACCP for long-term treatment of VTE, and several have extended treatment recommendations for VTE over the VKAs.³

The advantages of DOACs include no need for PT/INR monitoring, a fixed dosage, shorter half-life, rapid onset of action (for monotherapy), and in most cases, no need for bridging for interventional or surgical procedures. Additional advantages may include a decreased burden of care for the physician and improved quality of life for the patient. DOACs are also the agents of choice for patients who prefer oral therapy (avoiding parenteral therapy), have limited access to an anticoagulation clinic (home bound or geographic inaccessibility for PT/INR monitoring), or have food or drug-drug interactions. Patients at risk of gastrointestinal bleeding or dyspepsia should avoid dabigatran, while apixaban may be preferred if there is a history of gastrointestinal bleeding.⁸

Rivaroxaban or apixaban can be used as monotherapy for the initial treatment of VTE, while a 5-day course of heparin, LMWH, or fondaparinux is necessary with dabigatran or edoxaban. Rivaroxaban has been approved by the FDA for use in the prevention and treatment of VTE.^9,10 For VTE prophylaxis, rivaroxaban is given orally at 10 mg once daily for 35 days for patients undergoing total hip replacement surgery and for 12 days for patients undergoing knee replacement surgery. For the treatment of VTE, rivaroxaban is given orally at 15 mg twice a day for the initial 21 days of treatment, followed by once daily at 20 mg per day for long-term treatment. It is also approved for extended-duration therapy in both 10-mg and 20-mg doses. In a recently published randomized double-blind trial of rivaroxaban compared with aspirin, the risk of a recurrent event was lower with either dose of rivaroxaban compared with aspirin without an increase in bleeding.¹¹ Rivaroxaban is contraindicated in patients with renal insufficiency (CrCL < 30 mL/min). Both the 15-mg and 20-mg tablets must be taken with food.

Apixaban is also approved for monotherapy of VTE and was found to be noninferior to standard therapy of LMWH and warfarin with less bleeding.¹² Apixaban is used for VTE prophylaxis in patients undergoing hip or knee replacement surgery, given at 2.5 mg twice daily beginning 12 to 24 hours postoperatively for 35 days (hip) or 12 days (knee). The acute-phase dosage is 10 mg twice daily for 7 days followed by 5 mg twice daily for long-term treatment of VTE. The recommended dose should be reduced to 2.5 mg twice daily in patients that meet 2 of the following criteria: age 80 or older; body weight of 60 kg or less; or with a serum creatinine 1.5 mg/dL or greater. Apixaban is also approved for extended treatment of VTE. In a randomized, double-blind study of 2 doses (2.5 mg and 5 mg, twice daily) of apixaban compared with placebo, apixaban reduced the risk of recurrent VTE without increasing the risk of bleeding.¹³

Both dabigatran and edoxaban require an initial 5-day overlap with a parenteral anticoagulant.^14,15  Dabigatran is given at 150 mg orally twice daily if the CrCL is greater than 30 mL/min for the long-term treatment of VTE. Edoxaban is given orally at 60 mg once daily but reduced to 30 mg once daily if the CrCL is 30 mL/min to 50 mL/min, if body weight is 60 kg or less, or with use of certain P-glycoprotein inhibitors. Dabigatran has been evaluated in 2 double-blind, randomized controlled trials comparing the extended use of dabigatran with warfarin or placebo in patients with VTE.¹⁶ Dabigatran carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo. Dabigatran was noninferior to warfarin but significantly reduced the rate of recurrence in the placebo group.¹⁶

The major side effect observed with all DOACs is bleeding, but they have been proven safer particularly in the terms of major bleeding compared with the standard heparin-LMWH-VKA regimen for treatment of VTE.^17–19 The risk of major bleeding, and in particular intracranial bleeding, has been shown to be less with DOACs compared with VKAs in 2 meta-analysis trials.^17,18 Of the 4 new DOACs, only dabigatran currently has an anticoagulant-reversing agent (idarucizumab), although an antidote for the other 3 agents is awaiting FDA approval.²⁰

Subsegmental pulmonary embolism

There is debate as to the need for treatment of patients with subsegmental PE. The most recent guidelines advise clinical surveillance over anticoagulation for patients with a low risk for recurrent VTE and no evidence for a proximal DVT.³ However, individuals who are hospitalized, have reduced mobility, have active cancer or are being treated with chemotherapy, or have a low cardiopulmonary reserve should be considered for anticoagulation unless they have a high bleeding risk.

Thrombolytic therapy

Thrombolytic therapy may be beneficial in select patients with VTE and can be delivered systemically or locally per catheter-directed therapy (CDT). Both routes carry an increased risk of hemorrhage compared with standard anticoagulation. The Catheter-Directed-Venous Thrombolysis (CaVenT) trial and Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial compared CDT with standard therapy.^21,22 In CaVEnT, CDT resulted in increased clinical benefit during the 5-year follow-up but did not result in improved quality of life.²¹ In the TORPEDO trial, patients with proximal DVT receiving percutaneous endovenous intervention and anticoagulation compared with anticoagulation alone demonstrated superiority in the reduction of PTS at greater than 2 years.²² Early results of the Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial show that most patients with DVT did not have a long-term benefit from CDT, buy they did have reduced leg pain and swelling and some had reduced risk of moderate-to-severe PTS.²³

The 2012 and 2016 ACCP guidelines advise anticoagulant therapy over CDT for patients with acute DVT of the leg but suggest patients who may benefit are those with iliofemoral DVT with symptoms for less than 14 days, good functional status, a life expectancy greater than 1 year, and a low risk of bleeding.^3,4 This is in contrast to the 2008 CHEST guidelines that recommended patients who have extensive proximal DVT, who have a high risk of limb gangrene, who are at low risk of bleeding, and who otherwise have good functional status be given CDT if the expertise and resources are available.²⁴ It has been suggested that CDT promotes early recanalization and minimizes the incidence of PTS.

Thrombolytic therapy for acute PE remains controversial because there is no clearly established short-term mortality benefit. In the Pulmonary Embolism Thrombolysis (PEITHO) trial, thrombolysis prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.²⁵ A lower dose (50 mg) of thrombolytic therapy was studied in the Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPET) trial and was found to be safe and effective in the treatment of moderate PE.²⁶

CDT has also been shown to be effective in the treatment of PE. The Ultrasound Acceleration Thrombolysis of Pulmonary Embolism (ULTIMA) trial demonstrated that catheter-directed thrombolysis with ultrasonographic guidance in patients with acute intermediate-risk PE was superior in reversing right ventricular dilatation without an increase in bleeding complications compared with UFH.²⁷ The Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II) study found that this approach decreased right ventricular dilation, decreased pulmonary hypertension, decreased anatomic burden, and minimized the risk of intracranial hemorrhage in patients with massive and submassive PE.²⁸

Alteplase (Activase) is a recombinant tissue-type plasminogen activator approved by the FDA for treatment of acute PE. Alteplase is administered as a 100-mg infusion over 2 hours. Because of favorable outcomes with prompt recognition and anticoagulation for PE, the ACCP guidelines recommend systemic thrombolysis for hemodynamically unstable patients (systolic blood pressure < 90 mm Hg) with acute PE and a low risk of bleeding using a peripheral vein.³ These guidelines also recommend thrombolysis for the patient whose condition deteriorates after starting anticoagulant therapy but who have yet to develop hypotension.

If the appropriate expertise is available, CDT is suggested for patients with acute PE if they have hypotension and a high bleeding risk, have failed systemic thrombolysis, or are in shock that is likely to cause death before systemic thrombolysis can take effect.³ An area of ongoing debate is whether there is a benefit for thrombolytic therapy in patients with submassive PE who are hemodynamically stable but have evidence of right ventricular dysfunction on echocardiography or computed tomographic angiography. Bleeding remains the most serious complication of thrombolytic therapy.⁴

Pulmonary embolectomy. According to ACCP guidelines, surgical pulmonary embolectomy for the initial treatment of PE is reserved for patients with massive PE (documented angiographically, if possible), shock despite heparin and resuscitation efforts, and failure of thrombolytic therapy or a contraindication to its use.⁴ To date, there have been no randomized trials evaluating this procedure. Pooled data published by Stein et al²⁹ reported a 20% operative mortality rate in patients undergoing pulmonary embolectomy between 1985 and 2005 compared with 32% in patients undergoing the procedure before 1985. A more recent retrospective review of 214 patients undergoing surgical embolectomy for massive and submassive PE reported an in-hospital mortality rate of 11.7%, with the highest death rate (32.1%) in patients who had a preoperative cardiac arrest.³⁰ The use of surgical embolectomy has also been reported in patients with intermediate-risk to high-risk conditions (defined as elevated biomarkers and evidence of right heart strain on computed tomographic angiography or echocardiography).¹⁹

IVC filters. Current guidelines recommend against  routine use of IVC filters for patients with DVT or PE who are able to be treated with anticoagulants.³ Absolute indications for the placement of IVC filters include a contraindication to anticoagulation, complications of anticoagulation, and recurrent thromboembolism despite adequate anticoagulant therapy.⁴ Relative indications for IVC filters are massive PE, iliocaval DVT, free-floating proximal DVT, cardiac or pulmonary insufficiency, high risk of complications from anticoagulation (frequent falls, ataxia), and poor compliance.

Retrievable filters may be considered for situations in which anticoagulation is temporarily contraindicated or there is a short duration of PE risk.³¹ The current consensus guidelines advise that indications for placing a retrievable IVC filter are the same as for placing a permanent device.³¹ An IVC filter alone is not effective therapy for VTE, and resumption of anticoagulation is recommended as soon as possible after placement.

DURATION OF TREATMENT

Current guidelines recommend 3 months of anticoagulation (long-term) for patients with an episode of acute proximal or isolated distal DVT of the leg or PE resulting from surgery or a nonsurgical transient cause.³ Patients who have the antiphospholipid syndrome, who are homozygous for factor V Leiden, or who are doubly heterozygous for factor V Leiden and prothrombin gene mutation should be considered for longer (extended) anticoagulation. Extended anticoagulation is also recommended in patients with active cancer and in patients who have unexplained recurrent VTE (Table 2).³

The duration of treatment for unprovoked VTE remains controversial. In the most recent ACCP guidelines, indefinite or extended anticoagulation is indicated for patients with a low or moderate risk of bleeding for a first (and second) unprovoked VTE.⁴ Patients with a high risk of bleeding with a first (or second) unprovoked VTE that is a proximal DVT of the leg or PE be treated for 3 months.^3,4 Three DOACs (rivaroxaban, apixaban, and dabigatran) have extended-duration indications. The 2016 ACCP guidelines suggest aspirin over no treatment for the patient who has decided to stop anticoagulation therapy, although the guidelines do not consider aspirin a reasonable alternative to anticoagulation.^34,35 Use of markers such as residual venous obstruction and D-dimer level in conjunction with the DASH score have been studied in an effort to predict the risk of recurrence and thus the duration of anticoagulation.^36,37 Residual venous obstruction appears to be less useful than the D-dimer level as an indicator for recurrence. The D-dimer used in conjunction with the DASH prediction score may help to calculate recurrence risk based on the following predictors: abnormal D-dimer 3 weeks after stopping anticoagulation, age under 50, male sex, and hormone use at the time of the VTE.³⁸ DASH score assessment may help physicians decide whether to continue anticoagulation therapy but it has not been shown to be helpful in men.⁴ A more recent study confirmed the validity of the DASH score with better prediction in patients under age 65. The recurrence rate was higher in the older population, suggesting that this population should be considered for prolonged treatment if the bleeding risk is acceptable.³⁹ Other prediction tools include the Vienna prediction model and the clinical decision rule “Men continue and HER DOO2”—ie, HER = hyperpigmentation, edema, redness; DOO = D-dimer ≥ 250 μg/L, obesity body mass index ≥ 30 kg/m², old age (≥ 65); 2 = high risk if more than 2 of these factors.^40,41

SCREENING AND PREVENTION

Nearly 60% of all VTE events occur in hospitals and nursing homes.⁴² Yet anticoagulant prophylaxis is used in only 16% to 33% of at-risk hospitalized medical patients compared with 90% of at-risk hospitalized surgical patients.⁴³ Adequate prophylaxis can reduce the incidence of VTE as demonstrated in a meta-analysis involving 19,958 patients, which revealed a 64% reduction in relative risk (RR) of a fatal PE, 58% reduction in RR of a symptomic PE,  and a 53% reduction in RR of a symptomatic DVT.⁴³

The consequences of VTE include symptomatic DVT and PE, fatal PE, the cost of investigating symptomatic patients, the risk and cost of treatment (bleeding), PTS, and chronic thromboembolic pulmonary hypertension. Heparin, enoxaparin, and fondaparinux are approved agents for prophylactic but each agent has specific indications. Factor Xa inhibitors, rivaroxaban, and apixaban are approved for use in patients undergoing total knee or hip replacement. More recently, the factor Xa inhibitor, betrixaban, has been approved for VTE prophylaxis for up to 42 days in adult patients hospitalized for acute medical illness.⁴⁴ For patients with increased bleeding risk who are unable to receive pharmacologic prophylaxis, intermittent pneumatic compression devices or graduated compression stockings should be used.

Compression stockings

Current ACCP guidelines advise against routine use of compression stockings to prevent PTS in patients who have had a DVT.³ While current evidence suggests compression stockings do not prevent PTS, they reduce symptoms of acute or chronic DVT for some patients.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

In Reply: This is not an error. When we¹ and others² said that dabigatran is a reversible direct thrombin inhibitor, we were referring to its effect at the molecular level, the appropriate description of its mechanism of action. However, we suspect that Dr. Smith means that there is no antidote to give in cases of bleeding or overdose. We share his concern and we discussed this in our article.

Unlike heparin, direct thrombin inhibitors act independently of antithrombin and inhibit thrombin bound to fibrin or fibrin degradation products. There are two types of direct thrombin inhibitors: bivalent (eg, hirudin) and univalent (eg, argatroban, ximelagatran, and dabigatran). The bivalent ones block thrombin at its active site and at an exosite and form an irreversible complex with it. The univalent ones interact with only the active site and reversibly inhibit thrombin, eventually dissociating from it and leaving a small amount of free, enzymatically active thrombin available for hemostatic interactions. Therefore, in contrast to the hirudins, they produce relatively transient thrombin inhibition.^2–4

As we pointed out in our article, the lack of an antidote for dabigatran and the lack of experience in treating bleeding complications are major concerns. Fortunately, the drug has a short half-life (12–14 hours) so that the treatment is to withhold the next dose while maintaining adequate diuresis and giving transfusions as indicated. Activated charcoal, given orally to reduce absorption, is under evaluation but must be given within 1 or 2 hours after the dabigatran dose.¹ Dabigatran can be removed by dialysis (in part because it is a reversible inhibitor), a measure that may be necessary in life-threatening cases. Recombinant activated factor VII or prothrombin complex concentrates may be additional treatment options.^1,4 With time will come experience and, we hope, evidence-based guidelines.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

A major placebo-controlled trial has found that a statin can reduce the risk of venous thromboembolism (VTE).¹

We do not recommend prescribing this class of drugs for this purpose until much more research has been done, and we certainly do not recommend substituting a statin for anticoagulant therapy in a patient at risk of VTE.

Nevertheless, we are excited by the latest findings, and we find comfort in knowing that if a patient is taking a statin for an approved indication, ie, reducing the risk of cardiovascular disease in a patient with hyperlipidemia or a previous cardiovascular event, the drug will also reduce the risk of VTE.

In the pages that follow, we describe and comment on what is known about the effect of statins on the risk of VTE.

ARTERIAL AND VENOUS THROMBOSIS: HOW ARE THEY LINKED?

The causes of arterial thrombosis may not be entirely distinct from those of deep vein thrombosis and pulmonary embolism, collectively referred to as VTE. Some studies have found that risk factors for arterial thrombosis overlap with those for VTE.^2–4 However, other studies have shown no association between venous and arterial events.^5–10

Hyperlipidemia, in particular, has been evaluated to see if it is a risk factor for VTE. As with other risk factors for arterial thrombosis, the data have been mixed, with some reports favoring an association with VTE and others not.^4,5,11 Even so, preventive strategies targeting arterial risk factors have shown promise in reducing VTE events.¹²

Although commonly used to treat hyperlipidemia, statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are believed to reduce the incidence of thrombosis by a number of mechanisms¹³:

• Decreasing platelet aggregation
• Inhibiting expression of tissue factor and plasminogen activator inhibitor 1
• Increasing expression of tissue plasminogen activator
• Increasing expression of thrombomodulin, which can activate protein C and prevent thrombin-induced platelet and factor V activation and fibrinogen clotting.

STATINS AND VTE IN OBSERVATIONAL AND CASE-CONTROL STUDIES

In view of the multiple effects of statins, several studies have looked at whether these drugs reduce the occurrence of both arterial thrombosis and VTE.^14–19

Two prospective observational studies and four case-control studies found that statins reduced the risk of VTE by 20% to 60%.^14–19 Interestingly, two of the case-control studies found that antiplatelet therapy did not reduce the risk of VTE.^18,19

THE JUPITER STUDY

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study primarily sought to determine if rosuvastatin (Crestor) 20 mg/day, compared with placebo, would reduce the rate of first major cardiovascular events.²² A prespecified secondary end point of the trial was VTE, making JUPITER the first randomized, placebo-controlled trial to specifically test whether statins prevent VTE.¹

Inclusion criteria: Normal LDL, high CRP

The study included men age 50 and older and women age 60 and older with no history of cardiovascular disease. In addition, their lowdensity lipoprotein (LDL) cholesterol levels had to be lower than 130 mg/dL (3.4 mmol/L), their triglyceride levels had to be lower than 500 mg/dL (5.6 mmol/L), and their highsensitivity C-reactive protein (hs-CRP) levels had to be 2.0 mg/L or higher.

Since high levels of hs-CRP, a marker of inflammation, predict cardiovascular events and since statins lower hs-CRP levels, the investigators hypothesized that people with elevated hs-CRP but without hyperlipidemia might benefit from statin treatment.²¹

Patients were excluded if they had received lipid-lowering therapy within 6 weeks of the trial screening, had diabetes mellitus or uncontrolled hypertension, were currently using postmenopausal hormone-replacement therapy, or had had cancer within the previous 5 years, except for certain skin cancers.

Candidates who complied well during a 4-week placebo run-in phase were randomly assigned to receive either rosuvastatin 20 mg daily (an intermediate dose) or a matching placebo. In all, 17,802 people were randomized. The two assigned groups appeared to be well matched.

Patients were to come in for visits twice a year for 60 months after randomization to be assessed for symptomatic deep venous thrombosis and pulmonary embolism. New cases of VTE were confirmed by imaging studies, by the initiation of anticoagulation therapy, or by death ascribed to pulmonary embolism.

Idiopathic VTE was classified as unprovoked if it occurred in the absence of trauma, hospitalization, or surgery within 3 months before the event, and in the absence of any diagnosed cancer within 3 months before and after the event. Provoked VTE events were those that occurred in a participant with cancer or when a precipitating event was associated with trauma, hospitalization, or surgery.

Rosuvastatin prevents heart attack, stroke

On the recommendation of the trial’s independent data and safety monitoring board, JUPITER was stopped early because the trial drug showed evidence of efficacy in preventing the combined primary end point of a first major cardiovascular event—ie, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from a cardiovascular cause.²² (The cardiovascular outcomes of the JUPITER study were reviewed by Shishehbor and Hazen²³ in the January 2009 issue of the Cleveland Clinic Journal of Medicine; see doi:10.3949/ccjm.75a.08105).

Formal follow-up for the trial's primary and secondary efficacy end points ended then, but data on VTE continued to be collected until each patient’s closeout visit as part of a safety monitoring protocol. The last closeout visit occurred on August 20, 2008. The primary analysis focused on events occurring up to March 30, 2008, the date the study was stopped.

Secondary end point results: Rosuvastatin prevents VTE

At a median follow-up of 1.9 years, an episode of VTE had occurred in 94 (0.53%) of the 17,802 patients—34 in the rosuvastatin group and 60 in the placebo group.¹ This translates to 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for the rosuvastatin group 0.57, 95% confidence interval [CI] 0.37–0.86, P = .007).

Forty-four cases of VTE were classified as provoked and 50 cases were categorized as unprovoked. The risk reduction was statistically significant for provoked cases (hazard ratio 0.52, 95% CI 0.28–0.96, P = .03), but not for unprovoked events (hazard ratio 0.61, 95% CI 0.35–1.09, P = .09).

Subgroup analysis revealed no significant association between patient characteristics and the impact of rosuvastatin on the risk of a VTE event, but, as expected, more benefit was associated with higher baseline lipid levels.

STILL TOO SOON TO ADVISE ROUTINE STATIN USE TO PREVENT VTE

While the JUPITER trial data show an apparent benefit of statin use on the rate of VTE events, advising routine use of statins to prevent VTE is premature, for three main reasons.

Many must be treated to prevent one case of VTE. The number needed to treat (NNT) with rosuvastatin for 5 years to prevent either a case of VTE or a cardiovascular event was 21, and the NNT to prevent one cardiovascular event was 25. In a review of the two most recent case-control studies investigating the effects of statins on VTE,^18,19 Cushman²⁴ calculated that the NNT to prevent one VTE event each year was 333 for those age 75 and older. Though the Jupiter data did not provide the specific incidence of VTE at 1 year, except graphically, we can estimate that the NNT to prevent one VTE event at 1 year in the study is also very high.

Practically speaking, the perceived benefits of VTE prevention require large numbers to be treated, and the net clinical gain is still largely in preventing arterial events such as heart attack and stroke rather than VTE.

Statins, though safe, can still have adverse effects. The JUPITER study found a trend (albeit nonsignificant) toward more muscle complaints and elevations on liver function testing in apparently healthy persons taking a statin.²² Although severe complications of statin therapy such as rhabdomyolysis and elevations of creatine phosphokinase are rare, patients taking a statin have a 39% higher risk of an adverse event, most commonly myalgias or abnormalities on liver function testing.²⁵ Were statins to be given routinely to even more people than they are now, more adverse outcomes would be likely.

More study is needed. The JUPITER study did not address a high risk of VTE. In fact, the investigators provided no information as to the VTE history of those enrolled.

Clearly, statins should not be substituted for proven prophylaxis and anticoagulation without further investigation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.

OUR VIEW

The JUPITER study is an important leap forward in adding to our knowledge of how to prevent VTE. For people with another indication for taking a statin (eg, a previous cardiovascular event, hyperlipidemia), it is helpful to know that their risk of VTE may be reduced without exposure to the risks of other kinds of conventional thromboprophylaxis.

We look forward to additional studies to elaborate on the benefits of statins in both the prevention and treatment of VTE for averagerisk and VTE-prone populations.

A major placebo-controlled trial has found that a statin can reduce the risk of venous thromboembolism (VTE).¹

We do not recommend prescribing this class of drugs for this purpose until much more research has been done, and we certainly do not recommend substituting a statin for anticoagulant therapy in a patient at risk of VTE.

Nevertheless, we are excited by the latest findings, and we find comfort in knowing that if a patient is taking a statin for an approved indication, ie, reducing the risk of cardiovascular disease in a patient with hyperlipidemia or a previous cardiovascular event, the drug will also reduce the risk of VTE.

In the pages that follow, we describe and comment on what is known about the effect of statins on the risk of VTE.

ARTERIAL AND VENOUS THROMBOSIS: HOW ARE THEY LINKED?

The causes of arterial thrombosis may not be entirely distinct from those of deep vein thrombosis and pulmonary embolism, collectively referred to as VTE. Some studies have found that risk factors for arterial thrombosis overlap with those for VTE.^2–4 However, other studies have shown no association between venous and arterial events.^5–10

Hyperlipidemia, in particular, has been evaluated to see if it is a risk factor for VTE. As with other risk factors for arterial thrombosis, the data have been mixed, with some reports favoring an association with VTE and others not.^4,5,11 Even so, preventive strategies targeting arterial risk factors have shown promise in reducing VTE events.¹²

Although commonly used to treat hyperlipidemia, statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are believed to reduce the incidence of thrombosis by a number of mechanisms¹³:

• Decreasing platelet aggregation
• Inhibiting expression of tissue factor and plasminogen activator inhibitor 1
• Increasing expression of tissue plasminogen activator
• Increasing expression of thrombomodulin, which can activate protein C and prevent thrombin-induced platelet and factor V activation and fibrinogen clotting.

STATINS AND VTE IN OBSERVATIONAL AND CASE-CONTROL STUDIES

In view of the multiple effects of statins, several studies have looked at whether these drugs reduce the occurrence of both arterial thrombosis and VTE.^14–19

Two prospective observational studies and four case-control studies found that statins reduced the risk of VTE by 20% to 60%.^14–19 Interestingly, two of the case-control studies found that antiplatelet therapy did not reduce the risk of VTE.^18,19

THE JUPITER STUDY

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study primarily sought to determine if rosuvastatin (Crestor) 20 mg/day, compared with placebo, would reduce the rate of first major cardiovascular events.²² A prespecified secondary end point of the trial was VTE, making JUPITER the first randomized, placebo-controlled trial to specifically test whether statins prevent VTE.¹

Inclusion criteria: Normal LDL, high CRP

The study included men age 50 and older and women age 60 and older with no history of cardiovascular disease. In addition, their lowdensity lipoprotein (LDL) cholesterol levels had to be lower than 130 mg/dL (3.4 mmol/L), their triglyceride levels had to be lower than 500 mg/dL (5.6 mmol/L), and their highsensitivity C-reactive protein (hs-CRP) levels had to be 2.0 mg/L or higher.

Since high levels of hs-CRP, a marker of inflammation, predict cardiovascular events and since statins lower hs-CRP levels, the investigators hypothesized that people with elevated hs-CRP but without hyperlipidemia might benefit from statin treatment.²¹

Patients were excluded if they had received lipid-lowering therapy within 6 weeks of the trial screening, had diabetes mellitus or uncontrolled hypertension, were currently using postmenopausal hormone-replacement therapy, or had had cancer within the previous 5 years, except for certain skin cancers.

Candidates who complied well during a 4-week placebo run-in phase were randomly assigned to receive either rosuvastatin 20 mg daily (an intermediate dose) or a matching placebo. In all, 17,802 people were randomized. The two assigned groups appeared to be well matched.

Patients were to come in for visits twice a year for 60 months after randomization to be assessed for symptomatic deep venous thrombosis and pulmonary embolism. New cases of VTE were confirmed by imaging studies, by the initiation of anticoagulation therapy, or by death ascribed to pulmonary embolism.

Idiopathic VTE was classified as unprovoked if it occurred in the absence of trauma, hospitalization, or surgery within 3 months before the event, and in the absence of any diagnosed cancer within 3 months before and after the event. Provoked VTE events were those that occurred in a participant with cancer or when a precipitating event was associated with trauma, hospitalization, or surgery.

Rosuvastatin prevents heart attack, stroke

On the recommendation of the trial’s independent data and safety monitoring board, JUPITER was stopped early because the trial drug showed evidence of efficacy in preventing the combined primary end point of a first major cardiovascular event—ie, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from a cardiovascular cause.²² (The cardiovascular outcomes of the JUPITER study were reviewed by Shishehbor and Hazen²³ in the January 2009 issue of the Cleveland Clinic Journal of Medicine; see doi:10.3949/ccjm.75a.08105).

Formal follow-up for the trial's primary and secondary efficacy end points ended then, but data on VTE continued to be collected until each patient’s closeout visit as part of a safety monitoring protocol. The last closeout visit occurred on August 20, 2008. The primary analysis focused on events occurring up to March 30, 2008, the date the study was stopped.

Secondary end point results: Rosuvastatin prevents VTE

At a median follow-up of 1.9 years, an episode of VTE had occurred in 94 (0.53%) of the 17,802 patients—34 in the rosuvastatin group and 60 in the placebo group.¹ This translates to 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for the rosuvastatin group 0.57, 95% confidence interval [CI] 0.37–0.86, P = .007).

Forty-four cases of VTE were classified as provoked and 50 cases were categorized as unprovoked. The risk reduction was statistically significant for provoked cases (hazard ratio 0.52, 95% CI 0.28–0.96, P = .03), but not for unprovoked events (hazard ratio 0.61, 95% CI 0.35–1.09, P = .09).

Subgroup analysis revealed no significant association between patient characteristics and the impact of rosuvastatin on the risk of a VTE event, but, as expected, more benefit was associated with higher baseline lipid levels.

STILL TOO SOON TO ADVISE ROUTINE STATIN USE TO PREVENT VTE

While the JUPITER trial data show an apparent benefit of statin use on the rate of VTE events, advising routine use of statins to prevent VTE is premature, for three main reasons.

Many must be treated to prevent one case of VTE. The number needed to treat (NNT) with rosuvastatin for 5 years to prevent either a case of VTE or a cardiovascular event was 21, and the NNT to prevent one cardiovascular event was 25. In a review of the two most recent case-control studies investigating the effects of statins on VTE,^18,19 Cushman²⁴ calculated that the NNT to prevent one VTE event each year was 333 for those age 75 and older. Though the Jupiter data did not provide the specific incidence of VTE at 1 year, except graphically, we can estimate that the NNT to prevent one VTE event at 1 year in the study is also very high.

Practically speaking, the perceived benefits of VTE prevention require large numbers to be treated, and the net clinical gain is still largely in preventing arterial events such as heart attack and stroke rather than VTE.

Statins, though safe, can still have adverse effects. The JUPITER study found a trend (albeit nonsignificant) toward more muscle complaints and elevations on liver function testing in apparently healthy persons taking a statin.²² Although severe complications of statin therapy such as rhabdomyolysis and elevations of creatine phosphokinase are rare, patients taking a statin have a 39% higher risk of an adverse event, most commonly myalgias or abnormalities on liver function testing.²⁵ Were statins to be given routinely to even more people than they are now, more adverse outcomes would be likely.

More study is needed. The JUPITER study did not address a high risk of VTE. In fact, the investigators provided no information as to the VTE history of those enrolled.

Clearly, statins should not be substituted for proven prophylaxis and anticoagulation without further investigation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.

OUR VIEW

The JUPITER study is an important leap forward in adding to our knowledge of how to prevent VTE. For people with another indication for taking a statin (eg, a previous cardiovascular event, hyperlipidemia), it is helpful to know that their risk of VTE may be reduced without exposure to the risks of other kinds of conventional thromboprophylaxis.

We look forward to additional studies to elaborate on the benefits of statins in both the prevention and treatment of VTE for averagerisk and VTE-prone populations.

A major placebo-controlled trial has found that a statin can reduce the risk of venous thromboembolism (VTE).¹

We do not recommend prescribing this class of drugs for this purpose until much more research has been done, and we certainly do not recommend substituting a statin for anticoagulant therapy in a patient at risk of VTE.

Nevertheless, we are excited by the latest findings, and we find comfort in knowing that if a patient is taking a statin for an approved indication, ie, reducing the risk of cardiovascular disease in a patient with hyperlipidemia or a previous cardiovascular event, the drug will also reduce the risk of VTE.

In the pages that follow, we describe and comment on what is known about the effect of statins on the risk of VTE.

ARTERIAL AND VENOUS THROMBOSIS: HOW ARE THEY LINKED?

The causes of arterial thrombosis may not be entirely distinct from those of deep vein thrombosis and pulmonary embolism, collectively referred to as VTE. Some studies have found that risk factors for arterial thrombosis overlap with those for VTE.^2–4 However, other studies have shown no association between venous and arterial events.^5–10

Hyperlipidemia, in particular, has been evaluated to see if it is a risk factor for VTE. As with other risk factors for arterial thrombosis, the data have been mixed, with some reports favoring an association with VTE and others not.^4,5,11 Even so, preventive strategies targeting arterial risk factors have shown promise in reducing VTE events.¹²

Although commonly used to treat hyperlipidemia, statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are believed to reduce the incidence of thrombosis by a number of mechanisms¹³:

• Decreasing platelet aggregation
• Inhibiting expression of tissue factor and plasminogen activator inhibitor 1
• Increasing expression of tissue plasminogen activator
• Increasing expression of thrombomodulin, which can activate protein C and prevent thrombin-induced platelet and factor V activation and fibrinogen clotting.

STATINS AND VTE IN OBSERVATIONAL AND CASE-CONTROL STUDIES

In view of the multiple effects of statins, several studies have looked at whether these drugs reduce the occurrence of both arterial thrombosis and VTE.^14–19

Two prospective observational studies and four case-control studies found that statins reduced the risk of VTE by 20% to 60%.^14–19 Interestingly, two of the case-control studies found that antiplatelet therapy did not reduce the risk of VTE.^18,19

THE JUPITER STUDY

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study primarily sought to determine if rosuvastatin (Crestor) 20 mg/day, compared with placebo, would reduce the rate of first major cardiovascular events.²² A prespecified secondary end point of the trial was VTE, making JUPITER the first randomized, placebo-controlled trial to specifically test whether statins prevent VTE.¹

Inclusion criteria: Normal LDL, high CRP

The study included men age 50 and older and women age 60 and older with no history of cardiovascular disease. In addition, their lowdensity lipoprotein (LDL) cholesterol levels had to be lower than 130 mg/dL (3.4 mmol/L), their triglyceride levels had to be lower than 500 mg/dL (5.6 mmol/L), and their highsensitivity C-reactive protein (hs-CRP) levels had to be 2.0 mg/L or higher.

Since high levels of hs-CRP, a marker of inflammation, predict cardiovascular events and since statins lower hs-CRP levels, the investigators hypothesized that people with elevated hs-CRP but without hyperlipidemia might benefit from statin treatment.²¹

Patients were excluded if they had received lipid-lowering therapy within 6 weeks of the trial screening, had diabetes mellitus or uncontrolled hypertension, were currently using postmenopausal hormone-replacement therapy, or had had cancer within the previous 5 years, except for certain skin cancers.

Candidates who complied well during a 4-week placebo run-in phase were randomly assigned to receive either rosuvastatin 20 mg daily (an intermediate dose) or a matching placebo. In all, 17,802 people were randomized. The two assigned groups appeared to be well matched.

Patients were to come in for visits twice a year for 60 months after randomization to be assessed for symptomatic deep venous thrombosis and pulmonary embolism. New cases of VTE were confirmed by imaging studies, by the initiation of anticoagulation therapy, or by death ascribed to pulmonary embolism.

Idiopathic VTE was classified as unprovoked if it occurred in the absence of trauma, hospitalization, or surgery within 3 months before the event, and in the absence of any diagnosed cancer within 3 months before and after the event. Provoked VTE events were those that occurred in a participant with cancer or when a precipitating event was associated with trauma, hospitalization, or surgery.

Rosuvastatin prevents heart attack, stroke

On the recommendation of the trial’s independent data and safety monitoring board, JUPITER was stopped early because the trial drug showed evidence of efficacy in preventing the combined primary end point of a first major cardiovascular event—ie, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from a cardiovascular cause.²² (The cardiovascular outcomes of the JUPITER study were reviewed by Shishehbor and Hazen²³ in the January 2009 issue of the Cleveland Clinic Journal of Medicine; see doi:10.3949/ccjm.75a.08105).

Formal follow-up for the trial's primary and secondary efficacy end points ended then, but data on VTE continued to be collected until each patient’s closeout visit as part of a safety monitoring protocol. The last closeout visit occurred on August 20, 2008. The primary analysis focused on events occurring up to March 30, 2008, the date the study was stopped.

Secondary end point results: Rosuvastatin prevents VTE

At a median follow-up of 1.9 years, an episode of VTE had occurred in 94 (0.53%) of the 17,802 patients—34 in the rosuvastatin group and 60 in the placebo group.¹ This translates to 0.18 and 0.32 events per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for the rosuvastatin group 0.57, 95% confidence interval [CI] 0.37–0.86, P = .007).

Forty-four cases of VTE were classified as provoked and 50 cases were categorized as unprovoked. The risk reduction was statistically significant for provoked cases (hazard ratio 0.52, 95% CI 0.28–0.96, P = .03), but not for unprovoked events (hazard ratio 0.61, 95% CI 0.35–1.09, P = .09).

Subgroup analysis revealed no significant association between patient characteristics and the impact of rosuvastatin on the risk of a VTE event, but, as expected, more benefit was associated with higher baseline lipid levels.

STILL TOO SOON TO ADVISE ROUTINE STATIN USE TO PREVENT VTE

While the JUPITER trial data show an apparent benefit of statin use on the rate of VTE events, advising routine use of statins to prevent VTE is premature, for three main reasons.

Many must be treated to prevent one case of VTE. The number needed to treat (NNT) with rosuvastatin for 5 years to prevent either a case of VTE or a cardiovascular event was 21, and the NNT to prevent one cardiovascular event was 25. In a review of the two most recent case-control studies investigating the effects of statins on VTE,^18,19 Cushman²⁴ calculated that the NNT to prevent one VTE event each year was 333 for those age 75 and older. Though the Jupiter data did not provide the specific incidence of VTE at 1 year, except graphically, we can estimate that the NNT to prevent one VTE event at 1 year in the study is also very high.

Practically speaking, the perceived benefits of VTE prevention require large numbers to be treated, and the net clinical gain is still largely in preventing arterial events such as heart attack and stroke rather than VTE.

Statins, though safe, can still have adverse effects. The JUPITER study found a trend (albeit nonsignificant) toward more muscle complaints and elevations on liver function testing in apparently healthy persons taking a statin.²² Although severe complications of statin therapy such as rhabdomyolysis and elevations of creatine phosphokinase are rare, patients taking a statin have a 39% higher risk of an adverse event, most commonly myalgias or abnormalities on liver function testing.²⁵ Were statins to be given routinely to even more people than they are now, more adverse outcomes would be likely.

More study is needed. The JUPITER study did not address a high risk of VTE. In fact, the investigators provided no information as to the VTE history of those enrolled.

Clearly, statins should not be substituted for proven prophylaxis and anticoagulation without further investigation, especially for patients with recurrent deep venous thrombosis, hospitalized patients, postoperative patients, and other patients prone to VTE.

OUR VIEW

The JUPITER study is an important leap forward in adding to our knowledge of how to prevent VTE. For people with another indication for taking a statin (eg, a previous cardiovascular event, hyperlipidemia), it is helpful to know that their risk of VTE may be reduced without exposure to the risks of other kinds of conventional thromboprophylaxis.

We look forward to additional studies to elaborate on the benefits of statins in both the prevention and treatment of VTE for averagerisk and VTE-prone populations.

Warfarin (coumadin) differs from most other drugs in that the dosage required to achieve a desired therapeutic effect varies greatly among individuals. This variability can lead to therapeutic failure, potentially resulting in new thrombosis, or, at the other extreme, to life-threatening bleeding.

Further, there is no reliable means to identify patients who require unusually high doses of warfarin, although genetic testing may become available in the future.

See related patient information

Warfarin, a coumarin derivative first synthesized in 1948, is still the only oral anticoagulant available for long-term use in the United States. Indications for its use include the treatment and, to a lesser extent, the prevention of arterial and venous thromboembolism. It is also used for long-term anticoagulation in patients with atrial arrhythmias (atrial fibrillation and atrial flutter) and mechanical heart valves.

In the paragraphs that follow, we review the causes of warfarin resistance and how to recognize and manage it.

WHAT IS WARFARIN RESISTANCE?

Resistance to warfarin has been described as the inability to prolong the prothrombin time or raise the international normalized ratio (INR) into the therapeutic range when the drug is given at normally prescribed doses.¹

However, a higher warfarin requirement does not itself establish the diagnosis of warfarin resistance. The prevalence of warfarin resistance varies by patient population and is difficult to determine. The difficulty lies largely in accounting for dietary factors and in defining normal metabolic variations among individuals.

The range of normally recommended daily or weekly warfarin doses to maintain a therapeutic prothrombin time or INR depends on the study population. Nevertheless, patients who need more than 105 mg per week (15 mg/day) should be considered warfarin-resistant. These patients are likely to be in the top 5% for warfarin doses within an anticoagulated cohort.

Warfarin resistance is different than warfarin failure, which is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases.

An important characteristic of warfarin resistance is that patients need much smaller doses of vitamin K to reverse the effect of warfarin.² Thijssen³ showed that, in warfarin-resistant rats, warfarin did not irreversibly inhibit vitamin K₁ 2,3-epoxide reductase (VKORC1) activity. This is consistent with the vitamin K hypersensitivity observed in warfarin-resistant people.^2,3

WHAT CAUSES WARFARIN RESISTANCE?

Warfarin resistance can be classified in practical terms as acquired vs hereditary, or in mechanistic terms as pharmacokinetic vs pharmacodynamic.

Acquired vs hereditary resistance

Hulse⁴ categorizes warfarin resistance as either acquired or hereditary.

Acquired resistance to warfarin may result from:

• Poor patient compliance (the most common cause)
• High consumption of vitamin K
• 
  Decreased absorption of warfarin
• Increased clearance (see Warfarin is metabolized by P450 enzymes^5–11)
• Drug interactions (Table 1).^12,13

Hereditary resistance has been postulated to be caused by genetic factors that result either in faster metabolism of the drug (a form of pharmacokinetic resistance) or in lower activity of the drug (pharmacodynamic resistance). Polymorphisms may play a role, as some VKORC1 and CYP2C9 variant alleles are known to be associated with increased sensitivity to warfarin.¹⁴

However, the genetic mechanisms of warfarin resistance are not clearly understood, despite several case reports of hereditary resistance confirmed by similar patterns of resistance in immediate family members.^15–19 More than one mechanism is likely. There is ample room for further insight into genetic polymorphisms underlying hereditary warfarin resistance. More on this topic is included in the sections below.

Pharmacokinetic resistance can result from diminished absorption or increased elimination of the drug. Causes of diminished absorption include emesis, diarrhea, and malabsorption syndrome.

The mechanism of increased warfarin clearance has not been delineated, although the following have been implicated.

Genetic factors. Duplication or multiplication of cytochrome P450 enzyme genes has been described as contributing to a phenotype of ultrarapid metabolism. Some people may carry multiple copies of the CYP2C9 gene, as has already been reported for cytochrome P450 CYP2D6 and CYP2A6.^7,8 It is also plausible that rare allelic variants of CYP2C9 exist that are associated with higher-than-normal activity, given that there are alleles known to predispose to warfarin sensitivity.

Hypoalbuminemia may increase the free fraction of warfarin, leading to enhanced rates of clearance and a shorter plasma half-life.¹⁵

Hyperalbuminemia may paradoxically also contribute to warfarin resistance via drug binding.

Hyperlipidemia. Several observers have found that lowering serum lipids, primarily triglycerides, increases the sensitivity to warfarin irrespective of the means used to achieve this decrease.²⁰ This most likely results in a decreased pool of vitamin K, some of which is bound to triglycerides.²¹ Conversely, patients receiving intravenous lipids with total parenteral nutrition have also been diagnosed clinically with warfarin resistance,²² and rat models have shown an association between a lipidrich diet and increased vitamin K-dependent factor activity.²³

Diuretics may decrease the response to warfarin by reducing the plasma volume, with a subsequent increase in clotting factor activity.²⁴

Pharmacodynamic resistance

Potential mechanisms of pharmacodynamic warfarin resistance described in rats and in people include:

• Increased affinity of vitamin K₁, 2,3-epoxide reductase complex (VKOR) for vitamin K^25,26 (see How warfarin works^{2,10,11,27–30})
• Prolongation of normal clotting factor activity¹⁶
• Production of clotting factors that is not dependent on vitamin K¹⁶
• Decreased VKOR sensitivity to warfarin.²⁶

In rats, these mechanisms are manifested by relatively high doses of warfarin being required to achieve poisoning. In humans, they result in high doses being needed to achieve a therapeutic effect in the setting of normal warfarin pharmacokinetics, normal warfarin concentration, and normal half-lives of blood clotting proteins.

Genetics of pharmacodynamic resistance. Pharmacodynamic warfarin resistance has also been described with inheritance of a monogenetic dominant trait. An early study by O’Reilly²⁴ traced anticoagulation resistance to a genetically linked abnormality of interaction between warfarin and a putative vitamin K receptor.

In one patient with hereditary resistance and high warfarin requirements, a heterozygous point mutation in the VKORC1 gene was identified.³¹ This results in a substitution that lies in a conserved (normally constant or unchanging DNA sequence in a genome) region of VKORC1 that contains three of four previously identified amino acid substitutions associated with warfarin resistance (Val29Leu, Val45Ala, and Arg58Gly). Further investigation is required to fully characterize the structure-function relationship for VKORC1 and to determine the relationship between the VKORC1 genotype and other pharmacogenetic determinants of warfarin dose-response.

Separately, Loebstein et al³² reported a new mutation, Asp36Tyr, which was common in Jewish ethnic groups of Ethiopian descent (in whom the prevalence is 5%) and Ashkenazi descent (prevalence 4%). In that study, Asp36Tyr carriers needed doses of more than 70 mg per week, placing them towards the high end of the usual warfarin dosing range.

Daly and Aithal⁷ discovered that warfarinresistant rats overexpressed a protein known as calumenin. This protein is situated in the endoplasmic reticulum and appears to interact with VKOR, decreasing the binding of warfarin. In mice, the calumenin gene is located on chromosome 7, where the gene for VKORC1 is also located.

DIAGNOSIS BY HISTORY AND LABORATORY STUDIES

A full drug and diet history is invaluable in diagnosing potential causes of warfarin resistance (Table 1).

Plasma warfarin levels that are subtherapeutic should raise suspicion of intestinal malabsorption or poor compliance. Poor compliance might be more appropriately seen as a mimic of warfarin resistance. Studies in humans suggest that a therapeutic total plasma warfarin level lies between 0.5 μg/mL and 3.0 μg/mL,¹⁰ though the range may vary among laboratories and patient populations.

Warfarin absorption and clearance can be evaluated by analyzing plasma levels at specific intervals after administration, eg, every 60 to 180 minutes. The drug’s half-life can be determined on the basis of its concentrations in different time samples. Normally, the S-enantiomer of warfarin is cleared at twice the rate of the R-enantiomer (5.2 vs 2.5 mL/min/70 kg).⁸ A normal clearance rate confirms that resistance to warfarin is not due to enhanced elimination.

Clotting assays of factors II, VII, IX, and X may be a more precise way to assess the pharmacodynamics of warfarin,¹⁰ although there is no strong evidence to support routine use of such assays. Some studies suggest targeting factor II and factor X activity levels of 10% to 30% of normal biologic activity for a therapeutic warfarin effect in patients with an unreliable or prolonged baseline prothrombin time and INR, such as those with lupus anticoagulant.

TREAT THE CAUSE

Once the type of warfarin resistance has been determined, treatment should be oriented toward the cause.

Educate the patient

The importance of compliance should be reinforced. Educating the patient about diet and other medications that may interact with warfarin is also important. (See an example of patient education material.)

Increase the warfarin dose

If the patient truly has hereditary resistance, there are two approaches to treatment.

The first is to increase the warfarin dose until the prothrombin time and INR are in the therapeutic ranges. When indicated, the warfarin dose can be safely titrated upward to more than 100 mg per day in patients who are monitored regularly—as all patients on chronic warfarin therapy should be—and whose other medications are otherwise stable. One such example is reported in a warfarinresistant patient who needed 145 mg/day to maintain a therapeutic prothrombin time.²²

Try other anticoagulants?

The second approach is to change to another type of anticoagulant. However, there is no strong evidence in favor of this approach over prescribing larger dosages of warfarin.

Other anticoagulant drugs currently available in the United States include subcutaneous heparins (unfractionated and low-molecular-weight heparins) and the subcutaneous factor Xa inhibitor fondaparinux (Arixtra).

Agents not available in the United States include the following.

Dabigatran, an oral direct thrombin inhibitor, is undergoing phase 3 studies of its use for long-term anticoagulation.

Rivaroxaban (a direct factor Xa inhibitor) and dabigatran have been approved in Canada and the European Union to prevent venous thromboembolism after knee and hip arthroplasty, based on prospective comparisons with enoxaparin (Lovenox).^34–37

Vitamin K antagonists other than warfarin that are not available in the United States include bishydroxycoumarin (which has limitations including slow absorption and high frequency of gastrointestinal side effects), phenprocoumon, and acenocoumarol. Another is phenindione, which has been associated with serious hypersensitivity reactions, some of which proved fatal and occurred within a few weeks of initiating therapy.

Warfarin (coumadin) differs from most other drugs in that the dosage required to achieve a desired therapeutic effect varies greatly among individuals. This variability can lead to therapeutic failure, potentially resulting in new thrombosis, or, at the other extreme, to life-threatening bleeding.

Further, there is no reliable means to identify patients who require unusually high doses of warfarin, although genetic testing may become available in the future.

See related patient information

Warfarin, a coumarin derivative first synthesized in 1948, is still the only oral anticoagulant available for long-term use in the United States. Indications for its use include the treatment and, to a lesser extent, the prevention of arterial and venous thromboembolism. It is also used for long-term anticoagulation in patients with atrial arrhythmias (atrial fibrillation and atrial flutter) and mechanical heart valves.

In the paragraphs that follow, we review the causes of warfarin resistance and how to recognize and manage it.

WHAT IS WARFARIN RESISTANCE?

Resistance to warfarin has been described as the inability to prolong the prothrombin time or raise the international normalized ratio (INR) into the therapeutic range when the drug is given at normally prescribed doses.¹

However, a higher warfarin requirement does not itself establish the diagnosis of warfarin resistance. The prevalence of warfarin resistance varies by patient population and is difficult to determine. The difficulty lies largely in accounting for dietary factors and in defining normal metabolic variations among individuals.

The range of normally recommended daily or weekly warfarin doses to maintain a therapeutic prothrombin time or INR depends on the study population. Nevertheless, patients who need more than 105 mg per week (15 mg/day) should be considered warfarin-resistant. These patients are likely to be in the top 5% for warfarin doses within an anticoagulated cohort.

Warfarin resistance is different than warfarin failure, which is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases.

An important characteristic of warfarin resistance is that patients need much smaller doses of vitamin K to reverse the effect of warfarin.² Thijssen³ showed that, in warfarin-resistant rats, warfarin did not irreversibly inhibit vitamin K₁ 2,3-epoxide reductase (VKORC1) activity. This is consistent with the vitamin K hypersensitivity observed in warfarin-resistant people.^2,3

WHAT CAUSES WARFARIN RESISTANCE?

Warfarin resistance can be classified in practical terms as acquired vs hereditary, or in mechanistic terms as pharmacokinetic vs pharmacodynamic.

Acquired vs hereditary resistance

Hulse⁴ categorizes warfarin resistance as either acquired or hereditary.

Acquired resistance to warfarin may result from:

• Poor patient compliance (the most common cause)
• High consumption of vitamin K
• 
  Decreased absorption of warfarin
• Increased clearance (see Warfarin is metabolized by P450 enzymes^5–11)
• Drug interactions (Table 1).^12,13

Hereditary resistance has been postulated to be caused by genetic factors that result either in faster metabolism of the drug (a form of pharmacokinetic resistance) or in lower activity of the drug (pharmacodynamic resistance). Polymorphisms may play a role, as some VKORC1 and CYP2C9 variant alleles are known to be associated with increased sensitivity to warfarin.¹⁴

However, the genetic mechanisms of warfarin resistance are not clearly understood, despite several case reports of hereditary resistance confirmed by similar patterns of resistance in immediate family members.^15–19 More than one mechanism is likely. There is ample room for further insight into genetic polymorphisms underlying hereditary warfarin resistance. More on this topic is included in the sections below.

Pharmacokinetic resistance can result from diminished absorption or increased elimination of the drug. Causes of diminished absorption include emesis, diarrhea, and malabsorption syndrome.

The mechanism of increased warfarin clearance has not been delineated, although the following have been implicated.

Genetic factors. Duplication or multiplication of cytochrome P450 enzyme genes has been described as contributing to a phenotype of ultrarapid metabolism. Some people may carry multiple copies of the CYP2C9 gene, as has already been reported for cytochrome P450 CYP2D6 and CYP2A6.^7,8 It is also plausible that rare allelic variants of CYP2C9 exist that are associated with higher-than-normal activity, given that there are alleles known to predispose to warfarin sensitivity.

Hypoalbuminemia may increase the free fraction of warfarin, leading to enhanced rates of clearance and a shorter plasma half-life.¹⁵

Hyperalbuminemia may paradoxically also contribute to warfarin resistance via drug binding.

Hyperlipidemia. Several observers have found that lowering serum lipids, primarily triglycerides, increases the sensitivity to warfarin irrespective of the means used to achieve this decrease.²⁰ This most likely results in a decreased pool of vitamin K, some of which is bound to triglycerides.²¹ Conversely, patients receiving intravenous lipids with total parenteral nutrition have also been diagnosed clinically with warfarin resistance,²² and rat models have shown an association between a lipidrich diet and increased vitamin K-dependent factor activity.²³

Diuretics may decrease the response to warfarin by reducing the plasma volume, with a subsequent increase in clotting factor activity.²⁴

Pharmacodynamic resistance

Potential mechanisms of pharmacodynamic warfarin resistance described in rats and in people include:

• Increased affinity of vitamin K₁, 2,3-epoxide reductase complex (VKOR) for vitamin K^25,26 (see How warfarin works^{2,10,11,27–30})
• Prolongation of normal clotting factor activity¹⁶
• Production of clotting factors that is not dependent on vitamin K¹⁶
• Decreased VKOR sensitivity to warfarin.²⁶

In rats, these mechanisms are manifested by relatively high doses of warfarin being required to achieve poisoning. In humans, they result in high doses being needed to achieve a therapeutic effect in the setting of normal warfarin pharmacokinetics, normal warfarin concentration, and normal half-lives of blood clotting proteins.

Genetics of pharmacodynamic resistance. Pharmacodynamic warfarin resistance has also been described with inheritance of a monogenetic dominant trait. An early study by O’Reilly²⁴ traced anticoagulation resistance to a genetically linked abnormality of interaction between warfarin and a putative vitamin K receptor.

In one patient with hereditary resistance and high warfarin requirements, a heterozygous point mutation in the VKORC1 gene was identified.³¹ This results in a substitution that lies in a conserved (normally constant or unchanging DNA sequence in a genome) region of VKORC1 that contains three of four previously identified amino acid substitutions associated with warfarin resistance (Val29Leu, Val45Ala, and Arg58Gly). Further investigation is required to fully characterize the structure-function relationship for VKORC1 and to determine the relationship between the VKORC1 genotype and other pharmacogenetic determinants of warfarin dose-response.

Separately, Loebstein et al³² reported a new mutation, Asp36Tyr, which was common in Jewish ethnic groups of Ethiopian descent (in whom the prevalence is 5%) and Ashkenazi descent (prevalence 4%). In that study, Asp36Tyr carriers needed doses of more than 70 mg per week, placing them towards the high end of the usual warfarin dosing range.

Daly and Aithal⁷ discovered that warfarinresistant rats overexpressed a protein known as calumenin. This protein is situated in the endoplasmic reticulum and appears to interact with VKOR, decreasing the binding of warfarin. In mice, the calumenin gene is located on chromosome 7, where the gene for VKORC1 is also located.

DIAGNOSIS BY HISTORY AND LABORATORY STUDIES

A full drug and diet history is invaluable in diagnosing potential causes of warfarin resistance (Table 1).

Plasma warfarin levels that are subtherapeutic should raise suspicion of intestinal malabsorption or poor compliance. Poor compliance might be more appropriately seen as a mimic of warfarin resistance. Studies in humans suggest that a therapeutic total plasma warfarin level lies between 0.5 μg/mL and 3.0 μg/mL,¹⁰ though the range may vary among laboratories and patient populations.

Warfarin absorption and clearance can be evaluated by analyzing plasma levels at specific intervals after administration, eg, every 60 to 180 minutes. The drug’s half-life can be determined on the basis of its concentrations in different time samples. Normally, the S-enantiomer of warfarin is cleared at twice the rate of the R-enantiomer (5.2 vs 2.5 mL/min/70 kg).⁸ A normal clearance rate confirms that resistance to warfarin is not due to enhanced elimination.

Clotting assays of factors II, VII, IX, and X may be a more precise way to assess the pharmacodynamics of warfarin,¹⁰ although there is no strong evidence to support routine use of such assays. Some studies suggest targeting factor II and factor X activity levels of 10% to 30% of normal biologic activity for a therapeutic warfarin effect in patients with an unreliable or prolonged baseline prothrombin time and INR, such as those with lupus anticoagulant.

TREAT THE CAUSE

Once the type of warfarin resistance has been determined, treatment should be oriented toward the cause.

Educate the patient

The importance of compliance should be reinforced. Educating the patient about diet and other medications that may interact with warfarin is also important. (See an example of patient education material.)

Increase the warfarin dose

If the patient truly has hereditary resistance, there are two approaches to treatment.

The first is to increase the warfarin dose until the prothrombin time and INR are in the therapeutic ranges. When indicated, the warfarin dose can be safely titrated upward to more than 100 mg per day in patients who are monitored regularly—as all patients on chronic warfarin therapy should be—and whose other medications are otherwise stable. One such example is reported in a warfarinresistant patient who needed 145 mg/day to maintain a therapeutic prothrombin time.²²

Try other anticoagulants?

The second approach is to change to another type of anticoagulant. However, there is no strong evidence in favor of this approach over prescribing larger dosages of warfarin.

Other anticoagulant drugs currently available in the United States include subcutaneous heparins (unfractionated and low-molecular-weight heparins) and the subcutaneous factor Xa inhibitor fondaparinux (Arixtra).

Agents not available in the United States include the following.

Dabigatran, an oral direct thrombin inhibitor, is undergoing phase 3 studies of its use for long-term anticoagulation.

Rivaroxaban (a direct factor Xa inhibitor) and dabigatran have been approved in Canada and the European Union to prevent venous thromboembolism after knee and hip arthroplasty, based on prospective comparisons with enoxaparin (Lovenox).^34–37

Vitamin K antagonists other than warfarin that are not available in the United States include bishydroxycoumarin (which has limitations including slow absorption and high frequency of gastrointestinal side effects), phenprocoumon, and acenocoumarol. Another is phenindione, which has been associated with serious hypersensitivity reactions, some of which proved fatal and occurred within a few weeks of initiating therapy.

Warfarin (coumadin) differs from most other drugs in that the dosage required to achieve a desired therapeutic effect varies greatly among individuals. This variability can lead to therapeutic failure, potentially resulting in new thrombosis, or, at the other extreme, to life-threatening bleeding.

Further, there is no reliable means to identify patients who require unusually high doses of warfarin, although genetic testing may become available in the future.

See related patient information

Warfarin, a coumarin derivative first synthesized in 1948, is still the only oral anticoagulant available for long-term use in the United States. Indications for its use include the treatment and, to a lesser extent, the prevention of arterial and venous thromboembolism. It is also used for long-term anticoagulation in patients with atrial arrhythmias (atrial fibrillation and atrial flutter) and mechanical heart valves.

In the paragraphs that follow, we review the causes of warfarin resistance and how to recognize and manage it.

WHAT IS WARFARIN RESISTANCE?

Resistance to warfarin has been described as the inability to prolong the prothrombin time or raise the international normalized ratio (INR) into the therapeutic range when the drug is given at normally prescribed doses.¹

However, a higher warfarin requirement does not itself establish the diagnosis of warfarin resistance. The prevalence of warfarin resistance varies by patient population and is difficult to determine. The difficulty lies largely in accounting for dietary factors and in defining normal metabolic variations among individuals.

The range of normally recommended daily or weekly warfarin doses to maintain a therapeutic prothrombin time or INR depends on the study population. Nevertheless, patients who need more than 105 mg per week (15 mg/day) should be considered warfarin-resistant. These patients are likely to be in the top 5% for warfarin doses within an anticoagulated cohort.

Warfarin resistance is different than warfarin failure, which is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases.

An important characteristic of warfarin resistance is that patients need much smaller doses of vitamin K to reverse the effect of warfarin.² Thijssen³ showed that, in warfarin-resistant rats, warfarin did not irreversibly inhibit vitamin K₁ 2,3-epoxide reductase (VKORC1) activity. This is consistent with the vitamin K hypersensitivity observed in warfarin-resistant people.^2,3

WHAT CAUSES WARFARIN RESISTANCE?

Warfarin resistance can be classified in practical terms as acquired vs hereditary, or in mechanistic terms as pharmacokinetic vs pharmacodynamic.

Acquired vs hereditary resistance

Hulse⁴ categorizes warfarin resistance as either acquired or hereditary.

Acquired resistance to warfarin may result from:

• Poor patient compliance (the most common cause)
• High consumption of vitamin K
• 
  Decreased absorption of warfarin
• Increased clearance (see Warfarin is metabolized by P450 enzymes^5–11)
• Drug interactions (Table 1).^12,13

Hereditary resistance has been postulated to be caused by genetic factors that result either in faster metabolism of the drug (a form of pharmacokinetic resistance) or in lower activity of the drug (pharmacodynamic resistance). Polymorphisms may play a role, as some VKORC1 and CYP2C9 variant alleles are known to be associated with increased sensitivity to warfarin.¹⁴

However, the genetic mechanisms of warfarin resistance are not clearly understood, despite several case reports of hereditary resistance confirmed by similar patterns of resistance in immediate family members.^15–19 More than one mechanism is likely. There is ample room for further insight into genetic polymorphisms underlying hereditary warfarin resistance. More on this topic is included in the sections below.

Pharmacokinetic resistance can result from diminished absorption or increased elimination of the drug. Causes of diminished absorption include emesis, diarrhea, and malabsorption syndrome.

The mechanism of increased warfarin clearance has not been delineated, although the following have been implicated.

Genetic factors. Duplication or multiplication of cytochrome P450 enzyme genes has been described as contributing to a phenotype of ultrarapid metabolism. Some people may carry multiple copies of the CYP2C9 gene, as has already been reported for cytochrome P450 CYP2D6 and CYP2A6.^7,8 It is also plausible that rare allelic variants of CYP2C9 exist that are associated with higher-than-normal activity, given that there are alleles known to predispose to warfarin sensitivity.

Hypoalbuminemia may increase the free fraction of warfarin, leading to enhanced rates of clearance and a shorter plasma half-life.¹⁵

Hyperalbuminemia may paradoxically also contribute to warfarin resistance via drug binding.

Hyperlipidemia. Several observers have found that lowering serum lipids, primarily triglycerides, increases the sensitivity to warfarin irrespective of the means used to achieve this decrease.²⁰ This most likely results in a decreased pool of vitamin K, some of which is bound to triglycerides.²¹ Conversely, patients receiving intravenous lipids with total parenteral nutrition have also been diagnosed clinically with warfarin resistance,²² and rat models have shown an association between a lipidrich diet and increased vitamin K-dependent factor activity.²³

Diuretics may decrease the response to warfarin by reducing the plasma volume, with a subsequent increase in clotting factor activity.²⁴

Pharmacodynamic resistance

Potential mechanisms of pharmacodynamic warfarin resistance described in rats and in people include:

• Increased affinity of vitamin K₁, 2,3-epoxide reductase complex (VKOR) for vitamin K^25,26 (see How warfarin works^{2,10,11,27–30})
• Prolongation of normal clotting factor activity¹⁶
• Production of clotting factors that is not dependent on vitamin K¹⁶
• Decreased VKOR sensitivity to warfarin.²⁶

In rats, these mechanisms are manifested by relatively high doses of warfarin being required to achieve poisoning. In humans, they result in high doses being needed to achieve a therapeutic effect in the setting of normal warfarin pharmacokinetics, normal warfarin concentration, and normal half-lives of blood clotting proteins.

Genetics of pharmacodynamic resistance. Pharmacodynamic warfarin resistance has also been described with inheritance of a monogenetic dominant trait. An early study by O’Reilly²⁴ traced anticoagulation resistance to a genetically linked abnormality of interaction between warfarin and a putative vitamin K receptor.

In one patient with hereditary resistance and high warfarin requirements, a heterozygous point mutation in the VKORC1 gene was identified.³¹ This results in a substitution that lies in a conserved (normally constant or unchanging DNA sequence in a genome) region of VKORC1 that contains three of four previously identified amino acid substitutions associated with warfarin resistance (Val29Leu, Val45Ala, and Arg58Gly). Further investigation is required to fully characterize the structure-function relationship for VKORC1 and to determine the relationship between the VKORC1 genotype and other pharmacogenetic determinants of warfarin dose-response.

Separately, Loebstein et al³² reported a new mutation, Asp36Tyr, which was common in Jewish ethnic groups of Ethiopian descent (in whom the prevalence is 5%) and Ashkenazi descent (prevalence 4%). In that study, Asp36Tyr carriers needed doses of more than 70 mg per week, placing them towards the high end of the usual warfarin dosing range.

Daly and Aithal⁷ discovered that warfarinresistant rats overexpressed a protein known as calumenin. This protein is situated in the endoplasmic reticulum and appears to interact with VKOR, decreasing the binding of warfarin. In mice, the calumenin gene is located on chromosome 7, where the gene for VKORC1 is also located.

DIAGNOSIS BY HISTORY AND LABORATORY STUDIES

A full drug and diet history is invaluable in diagnosing potential causes of warfarin resistance (Table 1).

Plasma warfarin levels that are subtherapeutic should raise suspicion of intestinal malabsorption or poor compliance. Poor compliance might be more appropriately seen as a mimic of warfarin resistance. Studies in humans suggest that a therapeutic total plasma warfarin level lies between 0.5 μg/mL and 3.0 μg/mL,¹⁰ though the range may vary among laboratories and patient populations.

Warfarin absorption and clearance can be evaluated by analyzing plasma levels at specific intervals after administration, eg, every 60 to 180 minutes. The drug’s half-life can be determined on the basis of its concentrations in different time samples. Normally, the S-enantiomer of warfarin is cleared at twice the rate of the R-enantiomer (5.2 vs 2.5 mL/min/70 kg).⁸ A normal clearance rate confirms that resistance to warfarin is not due to enhanced elimination.

Clotting assays of factors II, VII, IX, and X may be a more precise way to assess the pharmacodynamics of warfarin,¹⁰ although there is no strong evidence to support routine use of such assays. Some studies suggest targeting factor II and factor X activity levels of 10% to 30% of normal biologic activity for a therapeutic warfarin effect in patients with an unreliable or prolonged baseline prothrombin time and INR, such as those with lupus anticoagulant.

TREAT THE CAUSE

Once the type of warfarin resistance has been determined, treatment should be oriented toward the cause.

Educate the patient

The importance of compliance should be reinforced. Educating the patient about diet and other medications that may interact with warfarin is also important. (See an example of patient education material.)

Increase the warfarin dose

If the patient truly has hereditary resistance, there are two approaches to treatment.

The first is to increase the warfarin dose until the prothrombin time and INR are in the therapeutic ranges. When indicated, the warfarin dose can be safely titrated upward to more than 100 mg per day in patients who are monitored regularly—as all patients on chronic warfarin therapy should be—and whose other medications are otherwise stable. One such example is reported in a warfarinresistant patient who needed 145 mg/day to maintain a therapeutic prothrombin time.²²

Try other anticoagulants?

The second approach is to change to another type of anticoagulant. However, there is no strong evidence in favor of this approach over prescribing larger dosages of warfarin.

Other anticoagulant drugs currently available in the United States include subcutaneous heparins (unfractionated and low-molecular-weight heparins) and the subcutaneous factor Xa inhibitor fondaparinux (Arixtra).

Agents not available in the United States include the following.

Dabigatran, an oral direct thrombin inhibitor, is undergoing phase 3 studies of its use for long-term anticoagulation.

Rivaroxaban (a direct factor Xa inhibitor) and dabigatran have been approved in Canada and the European Union to prevent venous thromboembolism after knee and hip arthroplasty, based on prospective comparisons with enoxaparin (Lovenox).^34–37

Vitamin K antagonists other than warfarin that are not available in the United States include bishydroxycoumarin (which has limitations including slow absorption and high frequency of gastrointestinal side effects), phenprocoumon, and acenocoumarol. Another is phenindione, which has been associated with serious hypersensitivity reactions, some of which proved fatal and occurred within a few weeks of initiating therapy.