Treatm en t an d L o n g - Term M a n a g e m e n t o f Ven o u s T h ro m b o e m b o l i s m Ahmed Al-Badri,
MD
a,
*, Alex C. Spyropoulos,
MD, FRCPC
b
KEYWORDS Venous thromboembolism Bridge therapy Switch therapy Outpatient venous thromboembolism treatment New oral anticoagulants KEY POINTS An increased emphasis on risk stratification and standardization may provide a rationale for inpatient versus outpatient treatment of PE and DVT. Three options are available when treating patients with new onset VTE: monotherapy, bridging therapy, and switch therapy. For provoked VTE, anticoagulation treatment for 3 months is usually considered to be sufficient. For unprovoked VTE, treatment for 3 to 6 months should be considered. After that time, patients should be evaluated for the need for extended anticoagulation treatment. Newer oral anticoagulants have been developed to overcome the drawbacks of other anticoagulation agents, improve patient care, and simplify and improve VTE management. Evidence from several phase III trials suggests that NOACs are effective for secondary prevention of VTE in patients who have completed standard anticoagulation therapy.
INTRODUCTION
The term “venous thromboembolism” (VTE) covers a range of conditions from deep vein thrombosis (DVT) to pulmonary embolism (PE), all of which can be lifethreatening. Thrombi that form in lower-extremity veins can embolize, leading to occlusion of the pulmonary vasculature. As a reflection of this pathophysiologic relationship, most patients with symptomatic PE have DVT and many patients with DVT
Disclosure: Dr A. Al-Badri has no relevant financial or non-financial relationships to disclose; Dr A.C. Spyropoulos is a consultant for Daiichi-Sankyo, Boehringer-Ingelheim, Janssen, Bayer, Bristol-Myers Squibb, Pfizer and Sanofi. a Department of Medicine, Lenox Hill Hospital, NSLIJHS, 130 East 77th Street, 6th Floor, Black Hall Building, New York, NY 10075, USA; b Department of Medicine, Lenox Hill Hospital, NSLIJHS, 130 East 77th Street, 5th Floor, Achilles Building, New York, NY 10075, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.06.011 labmed.theclinics.com 0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Al-Badri & Spyropoulos
have asymptomatic PE.1 The aims of treatment are to alleviate symptoms, to minimize acute morbidity and mortality by preventing the extension or potentially fatal embolization of the initial thrombus, and to avoid postthrombotic syndrome. The anticoagulants heparin and dicumarol were discovered serendipitously in 1916 and 1939, respectively, and heparin has been commercially available to treat blood clots since 1940. In the 1970s, three different research groups in Stockholm, London, and Ontario began work on low-molecular-weight heparin (LMWH) and by the mid-1980s, LMWH preparations were being tested in clinical trials. LMWH first became commercially available in 1993, and was followed by the introduction of fondaparinux and bivalirudin. Because of the advantages of LMWHs compared with unfractionated heparin (UFH) (Box 1), LMWHs have now replaced heparin for most indications. However, their parenteral administration and their restricted use in patients with renal failure limit their use. In the 2010s, a new era of oral anticoagulation has started (Fig. 1). PHASES OF ANTICOAGULATION
Anticoagulant therapy, the mainstay of treatment of VTE, has two goals. First, anticoagulant therapy treats or “turns off” the acute episode of thrombosis, which improves acute symptoms, prevents thrombus extension, and reduces the risk of early PE. Second, anticoagulant therapy prevents new episodes of VTE that do not arise directly from the acute episode of thrombosis.2 There are two main phases during anticoagulation therapy: the acute (ie, active treatment) and chronic phases (ie, secondary prevention) (Fig. 2). Acute Phase
In the acute phase, the risk of thrombus extension and PE is high, but the initiation of treatment rapidly reduces this risk.3,4 Therefore, it is critical that anticoagulant therapy is started as soon as possible when VTE is diagnosed (or is highly suspected).3 Moreover, because there is a high risk of VTE progression in the acute phase, the use of a higher-intensity anticoagulant therapy at the start of treatment is recommended.2,5–7 Furthermore, if anticoagulant therapy is stopped before treatment of the acute episode of thrombosis has been completed, there may be reactivation of the initial thrombosis with a further increase in the risk of recurrent VTE.2,5–7 Four observations support duration for anticoagulant therapy for approximately 3 months for active (acute) treatment of VTE.2,5–7 These reports suggest that treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy.2 Box 1 Advantages of LMWH compared with UFH Less binding to plasma proteins so more predictable dosing response Lower incidence of HIT Less or no monitoring needed Less osteopenia Does not cross the placental barrier Fixed, weight-based dose Abbreviations: HIT, heparin-induced thrombocytopenia; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
Venous Thromboembolism
Fig. 1. Advances in anticoagulation therapy for venous thromboembolism treatment. AC, anticoagulant; DTI, direct thrombin inhibitor; FDA, Food and Drug Administration; LMWH, low-molecular-weight heparin; PS, pentasaccharide (idraparinux, idrabiotapinarux).
Fig. 2. Phases of anticoagulation and the risk of recurrent venous thromboembolism. LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. (Data from Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e419S–94S; and Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost 2012;10:507–11.)
3
4
Al-Badri & Spyropoulos
Chronic Phase
Once the initial thrombosis (ie, the acute phase) has been adequately treated, further anticoagulation serves as secondary prevention of new, unrelated, episodes of thrombosis (ie, the chronic phase). The treatment of VTE can be continued indefinitely as “secondary prevention” if the risk of recurrence remains unacceptably high having completed treatment during the acute phase. The risk of recurrent VTE after finishing the acute phase of treatment depends on the patient’s intrinsic risk. If a patient’s intrinsic risk of recurrent VTE is not high enough to justify indefinite anticoagulant therapy, it is important to be able to identify when acute treatment has been completed so that anticoagulants can be stopped at that time (ie, absence of VTE-related symptoms).4–7 Primary factors for estimating the risk of recurrence are the presence of a reversible provoking risk factor, unprovoked VTE, or the presence of active cancer,8 which are the most relevant factors that influence risk of recurrent VTE after stopping anticoagulation. Provoking risk factors include recent surgery, estrogen therapy, pregnancy, leg injury, and flights longer than 8 hours in duration.8 Other factors that should be considered in deciding the duration of treatment are whether the DVT is confined to the distal veins, which is estimated to be associated with about half of all recurrences of proximal DVT or PE,9–12 and whether the VTE is a second or subsequent episode of VTE, which is estimated to be associated with about a 50% higher risk of recurrence compared with a first VTE (Table 1).13,14 OUTPATIENT VTE TREATMENT
Validated protocols have been used to identify patients who meet clinical or psychosocial criteria for outpatient DVT treatment with LMWH (Box 2).15–17 One such protocol, the Lovelace Health Systems protocol, defines absolute and relative clinical criteria that stratify patients as high, moderate, or low risk for outpatient DVT treatment and individualizes treatment based on risk category (Box 3).17 These treatment protocols could potentially identify patients for whom outpatient management of DVT with new oral anticoagulants (NOACs) optimizes the risk/benefit ratio. Using these Table 1 Duration of anticoagulation treatment Provoked (eg, Recent Surgery, Estrogen Therapy, Pregnancy, Leg Injury, Flight of >8 h) VTE Location
Unprovoked First Episode
Recurrent
Extended anticoagulation therapya
Extended anticoagulation therapya
Proximal
3 mo
Distal
3 mob
3 mob
3 mob
PE
3 mo
Extended anticoagulation therapya
Extended anticoagulation therapya
a If patient has a low or moderate risk of bleeding. In patients with a high risk of bleeding, 3 months of anticoagulation therapy is acceptable. b Patients in whom a decision has been made to treat with anticoagulation, however not all patients with distal DVT are prescribed anticoagulation. Data from Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e419-94S.
Venous Thromboembolism
Box 2 Exclusionary risk factors for outpatient treatment of DVT Absolute exclusionary risk factors Platelet count less than 100,000/mL Active hemorrhage Gastrointestinal bleed within 6 months Heparin sensitivity Underlying liver disorder Familial bleeding disorder Hypertensive: SBP greater than 220 and DBP greater than 120 mm Hg Catheter-associated DVT Recent surgery Morbid obesity greater than 130% ideal body weight Congenital/acquired hypercoagulable state Iliofemoral thrombosis Comorbid illness Relative exclusionary risk factors Age greater than 75 years Pregnancy PE (clinically unstable or massive PE is absolute exclusionary criterion) Renal insufficiency (CrCl
MD
a,
*, Alex C. Spyropoulos,
MD, FRCPC
b
KEYWORDS Venous thromboembolism Bridge therapy Switch therapy Outpatient venous thromboembolism treatment New oral anticoagulants KEY POINTS An increased emphasis on risk stratification and standardization may provide a rationale for inpatient versus outpatient treatment of PE and DVT. Three options are available when treating patients with new onset VTE: monotherapy, bridging therapy, and switch therapy. For provoked VTE, anticoagulation treatment for 3 months is usually considered to be sufficient. For unprovoked VTE, treatment for 3 to 6 months should be considered. After that time, patients should be evaluated for the need for extended anticoagulation treatment. Newer oral anticoagulants have been developed to overcome the drawbacks of other anticoagulation agents, improve patient care, and simplify and improve VTE management. Evidence from several phase III trials suggests that NOACs are effective for secondary prevention of VTE in patients who have completed standard anticoagulation therapy.
INTRODUCTION
The term “venous thromboembolism” (VTE) covers a range of conditions from deep vein thrombosis (DVT) to pulmonary embolism (PE), all of which can be lifethreatening. Thrombi that form in lower-extremity veins can embolize, leading to occlusion of the pulmonary vasculature. As a reflection of this pathophysiologic relationship, most patients with symptomatic PE have DVT and many patients with DVT
Disclosure: Dr A. Al-Badri has no relevant financial or non-financial relationships to disclose; Dr A.C. Spyropoulos is a consultant for Daiichi-Sankyo, Boehringer-Ingelheim, Janssen, Bayer, Bristol-Myers Squibb, Pfizer and Sanofi. a Department of Medicine, Lenox Hill Hospital, NSLIJHS, 130 East 77th Street, 6th Floor, Black Hall Building, New York, NY 10075, USA; b Department of Medicine, Lenox Hill Hospital, NSLIJHS, 130 East 77th Street, 5th Floor, Achilles Building, New York, NY 10075, USA * Corresponding author. E-mail address: [email protected] Clin Lab Med - (2014) -–http://dx.doi.org/10.1016/j.cll.2014.06.011 labmed.theclinics.com 0272-2712/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2
Al-Badri & Spyropoulos
have asymptomatic PE.1 The aims of treatment are to alleviate symptoms, to minimize acute morbidity and mortality by preventing the extension or potentially fatal embolization of the initial thrombus, and to avoid postthrombotic syndrome. The anticoagulants heparin and dicumarol were discovered serendipitously in 1916 and 1939, respectively, and heparin has been commercially available to treat blood clots since 1940. In the 1970s, three different research groups in Stockholm, London, and Ontario began work on low-molecular-weight heparin (LMWH) and by the mid-1980s, LMWH preparations were being tested in clinical trials. LMWH first became commercially available in 1993, and was followed by the introduction of fondaparinux and bivalirudin. Because of the advantages of LMWHs compared with unfractionated heparin (UFH) (Box 1), LMWHs have now replaced heparin for most indications. However, their parenteral administration and their restricted use in patients with renal failure limit their use. In the 2010s, a new era of oral anticoagulation has started (Fig. 1). PHASES OF ANTICOAGULATION
Anticoagulant therapy, the mainstay of treatment of VTE, has two goals. First, anticoagulant therapy treats or “turns off” the acute episode of thrombosis, which improves acute symptoms, prevents thrombus extension, and reduces the risk of early PE. Second, anticoagulant therapy prevents new episodes of VTE that do not arise directly from the acute episode of thrombosis.2 There are two main phases during anticoagulation therapy: the acute (ie, active treatment) and chronic phases (ie, secondary prevention) (Fig. 2). Acute Phase
In the acute phase, the risk of thrombus extension and PE is high, but the initiation of treatment rapidly reduces this risk.3,4 Therefore, it is critical that anticoagulant therapy is started as soon as possible when VTE is diagnosed (or is highly suspected).3 Moreover, because there is a high risk of VTE progression in the acute phase, the use of a higher-intensity anticoagulant therapy at the start of treatment is recommended.2,5–7 Furthermore, if anticoagulant therapy is stopped before treatment of the acute episode of thrombosis has been completed, there may be reactivation of the initial thrombosis with a further increase in the risk of recurrent VTE.2,5–7 Four observations support duration for anticoagulant therapy for approximately 3 months for active (acute) treatment of VTE.2,5–7 These reports suggest that treatment for 3 months is associated with the same risk of recurrent VTE as treatment for 6 months or longer, suggesting that 3 months is adequate therapy.2 Box 1 Advantages of LMWH compared with UFH Less binding to plasma proteins so more predictable dosing response Lower incidence of HIT Less or no monitoring needed Less osteopenia Does not cross the placental barrier Fixed, weight-based dose Abbreviations: HIT, heparin-induced thrombocytopenia; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.
Venous Thromboembolism
Fig. 1. Advances in anticoagulation therapy for venous thromboembolism treatment. AC, anticoagulant; DTI, direct thrombin inhibitor; FDA, Food and Drug Administration; LMWH, low-molecular-weight heparin; PS, pentasaccharide (idraparinux, idrabiotapinarux).
Fig. 2. Phases of anticoagulation and the risk of recurrent venous thromboembolism. LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. (Data from Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e419S–94S; and Kearon C. A conceptual framework for two phases of anticoagulant treatment of venous thromboembolism. J Thromb Haemost 2012;10:507–11.)
3
4
Al-Badri & Spyropoulos
Chronic Phase
Once the initial thrombosis (ie, the acute phase) has been adequately treated, further anticoagulation serves as secondary prevention of new, unrelated, episodes of thrombosis (ie, the chronic phase). The treatment of VTE can be continued indefinitely as “secondary prevention” if the risk of recurrence remains unacceptably high having completed treatment during the acute phase. The risk of recurrent VTE after finishing the acute phase of treatment depends on the patient’s intrinsic risk. If a patient’s intrinsic risk of recurrent VTE is not high enough to justify indefinite anticoagulant therapy, it is important to be able to identify when acute treatment has been completed so that anticoagulants can be stopped at that time (ie, absence of VTE-related symptoms).4–7 Primary factors for estimating the risk of recurrence are the presence of a reversible provoking risk factor, unprovoked VTE, or the presence of active cancer,8 which are the most relevant factors that influence risk of recurrent VTE after stopping anticoagulation. Provoking risk factors include recent surgery, estrogen therapy, pregnancy, leg injury, and flights longer than 8 hours in duration.8 Other factors that should be considered in deciding the duration of treatment are whether the DVT is confined to the distal veins, which is estimated to be associated with about half of all recurrences of proximal DVT or PE,9–12 and whether the VTE is a second or subsequent episode of VTE, which is estimated to be associated with about a 50% higher risk of recurrence compared with a first VTE (Table 1).13,14 OUTPATIENT VTE TREATMENT
Validated protocols have been used to identify patients who meet clinical or psychosocial criteria for outpatient DVT treatment with LMWH (Box 2).15–17 One such protocol, the Lovelace Health Systems protocol, defines absolute and relative clinical criteria that stratify patients as high, moderate, or low risk for outpatient DVT treatment and individualizes treatment based on risk category (Box 3).17 These treatment protocols could potentially identify patients for whom outpatient management of DVT with new oral anticoagulants (NOACs) optimizes the risk/benefit ratio. Using these Table 1 Duration of anticoagulation treatment Provoked (eg, Recent Surgery, Estrogen Therapy, Pregnancy, Leg Injury, Flight of >8 h) VTE Location
Unprovoked First Episode
Recurrent
Extended anticoagulation therapya
Extended anticoagulation therapya
Proximal
3 mo
Distal
3 mob
3 mob
3 mob
PE
3 mo
Extended anticoagulation therapya
Extended anticoagulation therapya
a If patient has a low or moderate risk of bleeding. In patients with a high risk of bleeding, 3 months of anticoagulation therapy is acceptable. b Patients in whom a decision has been made to treat with anticoagulation, however not all patients with distal DVT are prescribed anticoagulation. Data from Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e419-94S.
Venous Thromboembolism
Box 2 Exclusionary risk factors for outpatient treatment of DVT Absolute exclusionary risk factors Platelet count less than 100,000/mL Active hemorrhage Gastrointestinal bleed within 6 months Heparin sensitivity Underlying liver disorder Familial bleeding disorder Hypertensive: SBP greater than 220 and DBP greater than 120 mm Hg Catheter-associated DVT Recent surgery Morbid obesity greater than 130% ideal body weight Congenital/acquired hypercoagulable state Iliofemoral thrombosis Comorbid illness Relative exclusionary risk factors Age greater than 75 years Pregnancy PE (clinically unstable or massive PE is absolute exclusionary criterion) Renal insufficiency (CrCl
