THEMED ARTICLE y Thrombosis
Review
Thrombolysis for iliofemoral deep venous thrombosis Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Expert Rev. Cardiovasc. Ther. 11(12), 1631–1638 (2013)
Anthony J Comerota*1,2 and Vijay Kamath2 1 University of Michigan, Section of Vascular Surgery, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USA 2 Jobst Vascular Institute, 2109 Hughes Dr Suite 400, Toledo, OH 43606, USA *Author for correspondence: Tel.: +1 419 291 2080 Fax: +1 419 479 6980 [email protected]
Patients with iliofemoral deep vein thrombosis (DVT) comprise a subset of patients with DVT who are at significant risk for developing the postthrombotic syndrome (PTS) following treatment with anticoagulation alone. PTS can have debilitating effects on patients’ quality of life. Its symptoms range from pain and heaviness to venous ulceration. Treatment techniques that eliminate the thrombus burden from the lower extremity have been shown to reduce the incidence of postthrombotic symptoms by restoring venous patency to the iliofemoral venous system and preserving valvular function. Treatment techniques include operative thrombectomy, catheter-directed thrombolysis and pharmacomechanical thrombolysis. This paper focuses on the latter two techniques and reviews the evidence for adopting the strategy of thrombus removal in patients with iliofemoral DVT. KEYWORDS: catheter-directed thrombolysis • iliofemoral DVT • pharmacomechanical thrombolysis • postthrombotic syndrome • thrombolytic therapy
Extensive deep venous thrombosis (DVT) of the lower extremity is associated with severe postthrombotic morbidity and increased rates of recurrence. Depending upon the extent of the acute thrombus, postthrombotic syndrome (PTS) has been reported in 25–46% of patients [1,2]. Treatment with anticoagulation alone is capable of stopping extension of thrombus and reducing the risk of pulmonary embolism; however, the venous outflow channel remains obstructed. The degree of thrombus resolution depends upon the degree of endogenous fibrinolytic activity. As this activity is often inadequate, venous obstruction persists, resulting in venous hypertension. Large observational studies have demonstrated the association between recurrence and severe postthrombotic morbidity [2]. Moreover, investigators have shown that patients with residual venous thrombus and increased thrombus activity have higher rates of recurrent DVT [3,4]. This review focuses on the treatment of patients who have acute iliofemoral DVT, who indeed are a clinically relevant subset of patient with acute DVT. O’Donnell and colleagues [5] were among the first investigators to emphasize the high incidence of postthrombotic venous ulceration, the recurrent hospitalizations and the loss of financial productivity in this cohort of patients. Akesson et al. [6] reported that 95% of iliofemoral DVT www.expert-reviews.com
10.1586/14779072.2013.852955
patients who were treated with anticoagulation alone had ambulatory venous hypertension at 5 years and 90% had symptoms of chronic venous insufficiency. Delis et al. [7] demonstrated that venous claudication developed in 40% of the patients with iliofemoral DVT treated with anticoagulation alone when studied with exercise testing. Anatomically, the common femoral vein (CFV), external iliac vein and the common iliac vein comprise the single venous outflow channel from the lower extremity. Physiologically, maintaining patency of the iliofemoral venous system is crucial to maintaining reasonable venous return, even in patients with postthrombotic infrainguinal veno-occlusive disease. Many clinicians underestimate the role of residual thrombotic obstruction in the development of PTS. PTS is a combination of signs and symptoms causing pain, itching, heaviness, pain with ambulation, edema, varicose veins, hyperpigmentation and in the worst scenario, skin breakdown with ulceration. The pathophysiology of PTS is ambulatory venous hypertension, defined as an elevated venous pressure during exercise. The higher the ambulatory venous pressures, the more severe the postthrombotic morbidity [8]. Venous pressures in postthrombotic patients were recorded by Labropoulos and colleagues [9] when they measured supine resting and hyperemic venous pressures. They
2013 Informa UK Ltd
ISSN 1477-9072
1631
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Review
Comerota & Kamath
demonstrated that iliofemoral DVT patients had the highest resting and hyperemic venous pressure gradients of all DVT patients. Supine venous hypertension and post hyperemic venous pressure elevation only occur in the presence of venous obstruction. Patients with postthrombotic venous obstruction have high ambulatory venous pressures. It should be noted that ‘obstruction’ is not synonymous with occlusion. It has been shown that patients with venous valve dysfunction and luminal obstruction have the highest ambulatory venous pressures and, therefore, the most severe PTS. Unfortunately, obstruction is not easily and always recognized and the severe sequelae of obstruction are frequently overlooked. This is in part due to the difficulty in identifying, much less quantifying, venous obstruction. The difficulty in quantifying venous obstruction is illustrated in FIGURE 1. This patient had acute iliofemoral DVT 10 years earlier and had been treated for severe PTS and venous ulceration. Non-invasive testing demonstrated valvular incompetence but a normal 3 second maximal venous outflow. An ascending phlebogram was interpreted as ‘the classic tree-barking appearance of chronic venous disease. There is no evidence of venous obstruction.’ The following day the patient underwent a classic Linton procedure [10], which included femoral vein ligation with division just below its junction with the profunda femoris vein. A cross-section of the divided femoral vein along with its corresponding level on the ascending phlebogram shows
multiple recanalization channels but substantial luminal obstruction. This severity of luminal obstruction becomes hemodynamically important in the exercising limb, in which substantial increases in arterial flow occur as a result of exercise. Although arterial inflow increases, venous outflow is restricted by the luminal obstruction, causing ambulatory venous hypertension. Of course, the valves within these diseased veins are destroyed, and patients also have valvular incompetence. Kahn et al. [11] confirmed that PTS markedly reduces quality of life. They prospectively followed patients with acute DVT to determine their postthrombotic morbidity over time. They found that the patients’ condition at 1 month post diagnosis was a good predictor of long-term morbidity. They also found that patients with iliofemoral DVT and/or with clot occluding the common femoral vein had a 2.4-times increased risk of PTS and more severe PTS. Since there are no valves, or at most one valve, in the iliofemoral venous system, obstruction is the sole basis for postthrombotic morbidity in patients following iliofemoral DVT limited to the iliofemoral location. On the basis of the accumulated body of evidence regarding the frequency and severity of PTS following iliofemoral DVT, these patients should be considered for a strategy of thrombus removal as their initial therapy. Reliable techniques are available to eliminate thrombus and restore patency to the acutely thrombosed iliofemoral system. Effective postintervention anticoagulation assists in maintaining patency and reducing the risk of rethrombosis. Catheter-directed thrombolysis
Figure 1. Postthrombotic venous disease illustrating the inability to identify obstruction as part of the pathophysiology of chronic venous disease. This patient suffered iliofemoral deep vein thrombosis 10 years earlier and was treated with anticoagulation alone. He developed severe postthrombotic syndrome with multiple hospitalizations for venous ulceration. An ascending phlebogram showed recanalization of the iliofemoral venous system; however, the radiologist’s interpretation was that there was ‘no obstruction’ of the deep venous system and a 3-s maximal venous outflow test was ‘normal.’ A ‘classic Linton procedure’ was performed showing (inset) the crosssection of the femoral vein at the corresponding location on the phlebogram, just below the profunda femoris vein.
1632
Catheter-directed thrombolysis refers to the infusion of a plasminogen activator directly into the thrombus using ultrasound-guided access to the deep venous system and fluoroscopic positioning of the catheter into the thrombus. Direct infusion into the thrombus takes advantage of accelerated thrombolysis by virtue of the plasminogen activator binding to fibrin-bound LYS-plasminogen. During the past 20 years, there has been an evolution of catheter-directed thrombolysis to improve outcome and reduce procedural risk. BOX 1 summarizes the key principles of catheter-directed thrombolysis. While the goal of treating patients with a strategy of thrombus removal is to prevent PTS, the clinician cannot discover whether or not that has been achieved until after the early management of the patient has been completed. However, there are several measures that can be assessed to predict the likelihood of success. As mentioned earlier, patency and valve function are important elements predictive of the patient’s postthrombotic course. Restoring patency to provide unobstructed venous Expert Rev. Cardiovasc. Ther. 11(12), (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Thrombolysis for iliofemoral DVT
drainage into the vena cava ensures that iliofemoral obstruction will not contribute to the venous hypertension required for postthrombotic morbidity. Venous valve function is important in maintaining good venous health and normal ambulatory venous pressures. A frequently asked question is whether venous valves are destroyed soon after the onset of acute DVT. The answer is no, valves can function normally after the venous segment has been involved with DVT if the thrombus has been successfully eliminated. We can state this on the basis of natural history studies of acute DVT [12], the basic science of venous endothelial function and personal observation. The studies performed by Sevitt [13,14] over 30 years ago demonstrated that acute DVT often does not attach to the valve leaflet. That means that while the thrombus surrounds the valve, it is attached to the vein wall and has little or no attachment to the valve cusp itself. This observation raises the question as to whether the endothelium on the valve is different from the endothelium on the vein wall. Brooks et al. [15] studied vein valve endothelium and vein wall endothelium in normal saphenous veins harvested for coronary artery bypass. They studied endothelial protein C expression, thrombomodulin and von Willebrand factor expression. They demonstrated that there was much higher endothelial protein C receptor and thrombomodulin expression from the endothelium of the vein valve and lower von Willebrand factor expression. This clearly indicates that the vein valve endothelium offers more inherent protection against clot adherence. Therefore, if the thrombus can be successfully eliminated before it organizes and evolves to collagen, vein valves are likely to retain their function. Several early studies of catheter-directed thrombolysis reported success rates of 80–90% [16–18]. Valuable principles learned from these early studies included the importance of placing the catheter directly into the clot and correcting underlying venous lesions. These studies also underscored the correlation of the degree of lytic success with long-term benefit. The National Venous Registry was a multicenter USA registry of patients with acute DVT treated with urokinase. A subsequent, cohort-controlled, QoL study by Comerota et al. of iliofemoral DVT patients treated in the National Venous Registry with catheter-directed thrombolysis versus similar patients treated with anticoagulation alone [19]. The group of patients with iliofemoral DVT treated with catheter-directed thrombolysis were matched with similar patients from the same institutions who were treated with anticoagulation alone. All of the patients treated with anticoagulation alone were candidates for lysis; however, treatment was determined by physician preference. After 16 and 22 months of treatment, patients were evaluated using a validated QoL instrument [20]. Patients treated with catheter-directed thrombolysis had significantly better QoL as measured by the Health Utilities Index. Their physical functioning, appreciation of health distress, the stigma of chronic disease and their overall symptoms were much improved (TABLE 1) compared with patients treated with anticoagulation alone. www.expert-reviews.com
Review
These observations were subsequently supported by Broholm et al. [21] when they studied 109 patients with iliofemoral DVT treated with catheter-directed thrombolysis. They confirmed that PTS was associated with worse QoL. Only a small number of patients treated with catheter-directed thrombolysis developed PTS. Patients with patent veins and functional valves had higher QoL scores than patients with valvular incompetence and occluded veins. Grewal and colleagues [22] also performed a QoL study following catheter-directed thrombolysis in patients with iliofemoral DVT, correlating patients’ eventual QoL with lytic success. They performed a blinded analysis of QoL versus residual thrombus remaining at the end of lytic therapy and found a significant correlation demonstrating that the more successful the course of catheter-directed thrombolysis, the better the QoL over the long term. Baekgaard et al. [23] reported the 6-year outcomes of 103 patients treated with catheter-directed thrombolysis. An impressive 86% had patent veins with normal valve function at 6 years. Randomized trials of thrombolysis for iliofemoral DVT
The results of two randomized trials have been reported thus far. Elsharawy et al. [24] randomized 35 patients with iliofemoral DVT to catheter-directed thrombolysis or anticoagulation alone. Patency was restored in 72% of the lytic group compared to 12% in the anticoagulation group (p < 0.001). Normal valve function at 6 months was observed in 89% of the lytic patients compared to 59% in the anticoagulation group (p = 0.041). Since a large number of the patients in the anticoagulation group had persistent obstruction, they could not demonstrate valvular incompetence. Once recanalization occurs, the benefit of lysis will be magnified. Enden et al. [25] recently reported the long-term results of the Catheter-directed Venous Thrombolysis (CaVenT) trial. Box 1. Principles of catheter-directed thrombolysis. • Safe and precise access to the deep venous system using
ultrasound guidance. • Good imaging of the inferior vena cava to rule out caval
involvement. • Placement of IVC filter for non-occlusive thrombus in the
inferior vena cava • Proper positioning of infusion catheters within thrombus. • Substantial reduction in dose of plasminogen activator (0.5–
• • •
•
1.0 mg rt-PA/h) but delivered in larger volumes of infusate (50–100 cc/h). Add mechanical catheter-based techniques to shorten treatment time and improve success. Treat patient to achieve maximal thrombus clearance. Correct underlying venous lesions with venoplasty and stenting with the goal of providing unobstructed venous drainage into the vena cava. Therapeutic long-term anticoagulation.
1633
Review
Comerota & Kamath
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Table 1. Quality of life outcomes in patients treated with catheter-directed thrombolysis versus anticoagulation alone. QoL measure
Catheterdirected thrombolysis
Anticoagulation alone
p-value
Health utilities index
0.83
0.74
0.032
Role physical
75.6
64.1
0.013
Health distress
82.4
64.1
0.007
Stigma
85.9
71.3
0.033
Overall symptom
78.5
55.5
1 s versus 65% treated with CDT (p = 0.42). An interesting observation was that 31% of the patients with unilateral iliofemoral DVT had valvular reflux. The best predictor of reflux in the treated limb was reflux in the untreated contralateral limb. Pharmacomechanical thrombolysis does not adversely affect valve function compared with CDT alone. Outcomes of catheter-based intervention for iliofemoral DVT
Contemporary results of CDT, using the drip technique alone or by adding PMT, have improved patient outcomes compared to anticoagulation alone. Large single-center observational studies [22,23,35] have demonstrated the improved QoL of patients treated with catheter-based techniques and their reduction in postthrombotic morbidity [36] directly correlated with the success of lysis. The large thrombus burden of iliofemoral DVT is associated with significantly higher recurrence rates compared to patients with infrainguinal DVT alone [8]. It has been our observation that patients treated with CDT for extensive venous thrombosis had a low incidence of recurrence. This was further analyzed by Aziz et al., [37] who recently reported that patients with iliofemoral DVT who were treated with CDT or pharmacomechanical thrombolysis had lower than expected recurrence rates. They also showed that residual thrombus at the end of lysis correlated with recurrence. Patients with a large residual thrombus burden had a significantly higher rate of recurrence than patients who had little residual thrombus at the completion of catheter-directed thrombolysis. Recurrent DVT
Recurrent DVT is a common and serious problem following management of patients with acute iliofemoral DVT [38]. Importantly, recurrent DVT is associated with a sixfold increased risk of PTS. DVT recurrence has been shown to be an independent predictor of postthrombotic morbidity (hazard ratio [HR]: 6.4). Most studies of DVT recurrence fail to address the location of the patient’s initial acute DVT. It has been our observation that patients with iliofemoral DVT treated with anticoagulation alone 1636
have a significantly higher risk of recurrence than patients with infrainguinal DVT. This observation has been substantiated by Douketis et al., [39] who followed 1149 patients with acute DVT treated with anticoagulation alone. They demonstrated that patients with iliofemoral DVT had nearly a 12% 3 month rate of recurrence, which was 2.4 times that of patients with infrainguinal DVT (p = 0.05). These observations fit with those of others that residual thrombus [3] and persistent thrombus activity [40] are associated with significantly higher risk of recurrence compared to patients without residual venous obstruction and ongoing thrombus activity. It makes intuitive sense that, if one eliminates the thrombus, there will be no residual venous obstruction, and the absence of thrombus suggests that there should be no thrombus activity (normal D-dimer levels). Baekgaard and colleagues [23] observed a surprisingly low 6% incidence of recurrence during their 6-year follow-up of IFDVT patients treated with catheter-directed thrombolysis. In our consecutive series of 75 patients during a 35 month mean follow-up, we observed a 9% incidence of recurrence. That was much lower that one would have anticipated. Aziz et al., [37] studied these patients to determine that if there was a correlation of residual thrombus following catheter-directed thrombolysis and subsequent recurrence. The individuals evaluating the phlebograms were blinded to the patients’ long-term outcome. The patients were divided into two groups for ease of analysis; group 1 had
Review
Thrombolysis for iliofemoral deep venous thrombosis Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Expert Rev. Cardiovasc. Ther. 11(12), 1631–1638 (2013)
Anthony J Comerota*1,2 and Vijay Kamath2 1 University of Michigan, Section of Vascular Surgery, 1500 E. Medical Center Dr, Ann Arbor, MI 48109, USA 2 Jobst Vascular Institute, 2109 Hughes Dr Suite 400, Toledo, OH 43606, USA *Author for correspondence: Tel.: +1 419 291 2080 Fax: +1 419 479 6980 [email protected]
Patients with iliofemoral deep vein thrombosis (DVT) comprise a subset of patients with DVT who are at significant risk for developing the postthrombotic syndrome (PTS) following treatment with anticoagulation alone. PTS can have debilitating effects on patients’ quality of life. Its symptoms range from pain and heaviness to venous ulceration. Treatment techniques that eliminate the thrombus burden from the lower extremity have been shown to reduce the incidence of postthrombotic symptoms by restoring venous patency to the iliofemoral venous system and preserving valvular function. Treatment techniques include operative thrombectomy, catheter-directed thrombolysis and pharmacomechanical thrombolysis. This paper focuses on the latter two techniques and reviews the evidence for adopting the strategy of thrombus removal in patients with iliofemoral DVT. KEYWORDS: catheter-directed thrombolysis • iliofemoral DVT • pharmacomechanical thrombolysis • postthrombotic syndrome • thrombolytic therapy
Extensive deep venous thrombosis (DVT) of the lower extremity is associated with severe postthrombotic morbidity and increased rates of recurrence. Depending upon the extent of the acute thrombus, postthrombotic syndrome (PTS) has been reported in 25–46% of patients [1,2]. Treatment with anticoagulation alone is capable of stopping extension of thrombus and reducing the risk of pulmonary embolism; however, the venous outflow channel remains obstructed. The degree of thrombus resolution depends upon the degree of endogenous fibrinolytic activity. As this activity is often inadequate, venous obstruction persists, resulting in venous hypertension. Large observational studies have demonstrated the association between recurrence and severe postthrombotic morbidity [2]. Moreover, investigators have shown that patients with residual venous thrombus and increased thrombus activity have higher rates of recurrent DVT [3,4]. This review focuses on the treatment of patients who have acute iliofemoral DVT, who indeed are a clinically relevant subset of patient with acute DVT. O’Donnell and colleagues [5] were among the first investigators to emphasize the high incidence of postthrombotic venous ulceration, the recurrent hospitalizations and the loss of financial productivity in this cohort of patients. Akesson et al. [6] reported that 95% of iliofemoral DVT www.expert-reviews.com
10.1586/14779072.2013.852955
patients who were treated with anticoagulation alone had ambulatory venous hypertension at 5 years and 90% had symptoms of chronic venous insufficiency. Delis et al. [7] demonstrated that venous claudication developed in 40% of the patients with iliofemoral DVT treated with anticoagulation alone when studied with exercise testing. Anatomically, the common femoral vein (CFV), external iliac vein and the common iliac vein comprise the single venous outflow channel from the lower extremity. Physiologically, maintaining patency of the iliofemoral venous system is crucial to maintaining reasonable venous return, even in patients with postthrombotic infrainguinal veno-occlusive disease. Many clinicians underestimate the role of residual thrombotic obstruction in the development of PTS. PTS is a combination of signs and symptoms causing pain, itching, heaviness, pain with ambulation, edema, varicose veins, hyperpigmentation and in the worst scenario, skin breakdown with ulceration. The pathophysiology of PTS is ambulatory venous hypertension, defined as an elevated venous pressure during exercise. The higher the ambulatory venous pressures, the more severe the postthrombotic morbidity [8]. Venous pressures in postthrombotic patients were recorded by Labropoulos and colleagues [9] when they measured supine resting and hyperemic venous pressures. They
2013 Informa UK Ltd
ISSN 1477-9072
1631
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Review
Comerota & Kamath
demonstrated that iliofemoral DVT patients had the highest resting and hyperemic venous pressure gradients of all DVT patients. Supine venous hypertension and post hyperemic venous pressure elevation only occur in the presence of venous obstruction. Patients with postthrombotic venous obstruction have high ambulatory venous pressures. It should be noted that ‘obstruction’ is not synonymous with occlusion. It has been shown that patients with venous valve dysfunction and luminal obstruction have the highest ambulatory venous pressures and, therefore, the most severe PTS. Unfortunately, obstruction is not easily and always recognized and the severe sequelae of obstruction are frequently overlooked. This is in part due to the difficulty in identifying, much less quantifying, venous obstruction. The difficulty in quantifying venous obstruction is illustrated in FIGURE 1. This patient had acute iliofemoral DVT 10 years earlier and had been treated for severe PTS and venous ulceration. Non-invasive testing demonstrated valvular incompetence but a normal 3 second maximal venous outflow. An ascending phlebogram was interpreted as ‘the classic tree-barking appearance of chronic venous disease. There is no evidence of venous obstruction.’ The following day the patient underwent a classic Linton procedure [10], which included femoral vein ligation with division just below its junction with the profunda femoris vein. A cross-section of the divided femoral vein along with its corresponding level on the ascending phlebogram shows
multiple recanalization channels but substantial luminal obstruction. This severity of luminal obstruction becomes hemodynamically important in the exercising limb, in which substantial increases in arterial flow occur as a result of exercise. Although arterial inflow increases, venous outflow is restricted by the luminal obstruction, causing ambulatory venous hypertension. Of course, the valves within these diseased veins are destroyed, and patients also have valvular incompetence. Kahn et al. [11] confirmed that PTS markedly reduces quality of life. They prospectively followed patients with acute DVT to determine their postthrombotic morbidity over time. They found that the patients’ condition at 1 month post diagnosis was a good predictor of long-term morbidity. They also found that patients with iliofemoral DVT and/or with clot occluding the common femoral vein had a 2.4-times increased risk of PTS and more severe PTS. Since there are no valves, or at most one valve, in the iliofemoral venous system, obstruction is the sole basis for postthrombotic morbidity in patients following iliofemoral DVT limited to the iliofemoral location. On the basis of the accumulated body of evidence regarding the frequency and severity of PTS following iliofemoral DVT, these patients should be considered for a strategy of thrombus removal as their initial therapy. Reliable techniques are available to eliminate thrombus and restore patency to the acutely thrombosed iliofemoral system. Effective postintervention anticoagulation assists in maintaining patency and reducing the risk of rethrombosis. Catheter-directed thrombolysis
Figure 1. Postthrombotic venous disease illustrating the inability to identify obstruction as part of the pathophysiology of chronic venous disease. This patient suffered iliofemoral deep vein thrombosis 10 years earlier and was treated with anticoagulation alone. He developed severe postthrombotic syndrome with multiple hospitalizations for venous ulceration. An ascending phlebogram showed recanalization of the iliofemoral venous system; however, the radiologist’s interpretation was that there was ‘no obstruction’ of the deep venous system and a 3-s maximal venous outflow test was ‘normal.’ A ‘classic Linton procedure’ was performed showing (inset) the crosssection of the femoral vein at the corresponding location on the phlebogram, just below the profunda femoris vein.
1632
Catheter-directed thrombolysis refers to the infusion of a plasminogen activator directly into the thrombus using ultrasound-guided access to the deep venous system and fluoroscopic positioning of the catheter into the thrombus. Direct infusion into the thrombus takes advantage of accelerated thrombolysis by virtue of the plasminogen activator binding to fibrin-bound LYS-plasminogen. During the past 20 years, there has been an evolution of catheter-directed thrombolysis to improve outcome and reduce procedural risk. BOX 1 summarizes the key principles of catheter-directed thrombolysis. While the goal of treating patients with a strategy of thrombus removal is to prevent PTS, the clinician cannot discover whether or not that has been achieved until after the early management of the patient has been completed. However, there are several measures that can be assessed to predict the likelihood of success. As mentioned earlier, patency and valve function are important elements predictive of the patient’s postthrombotic course. Restoring patency to provide unobstructed venous Expert Rev. Cardiovasc. Ther. 11(12), (2013)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Thrombolysis for iliofemoral DVT
drainage into the vena cava ensures that iliofemoral obstruction will not contribute to the venous hypertension required for postthrombotic morbidity. Venous valve function is important in maintaining good venous health and normal ambulatory venous pressures. A frequently asked question is whether venous valves are destroyed soon after the onset of acute DVT. The answer is no, valves can function normally after the venous segment has been involved with DVT if the thrombus has been successfully eliminated. We can state this on the basis of natural history studies of acute DVT [12], the basic science of venous endothelial function and personal observation. The studies performed by Sevitt [13,14] over 30 years ago demonstrated that acute DVT often does not attach to the valve leaflet. That means that while the thrombus surrounds the valve, it is attached to the vein wall and has little or no attachment to the valve cusp itself. This observation raises the question as to whether the endothelium on the valve is different from the endothelium on the vein wall. Brooks et al. [15] studied vein valve endothelium and vein wall endothelium in normal saphenous veins harvested for coronary artery bypass. They studied endothelial protein C expression, thrombomodulin and von Willebrand factor expression. They demonstrated that there was much higher endothelial protein C receptor and thrombomodulin expression from the endothelium of the vein valve and lower von Willebrand factor expression. This clearly indicates that the vein valve endothelium offers more inherent protection against clot adherence. Therefore, if the thrombus can be successfully eliminated before it organizes and evolves to collagen, vein valves are likely to retain their function. Several early studies of catheter-directed thrombolysis reported success rates of 80–90% [16–18]. Valuable principles learned from these early studies included the importance of placing the catheter directly into the clot and correcting underlying venous lesions. These studies also underscored the correlation of the degree of lytic success with long-term benefit. The National Venous Registry was a multicenter USA registry of patients with acute DVT treated with urokinase. A subsequent, cohort-controlled, QoL study by Comerota et al. of iliofemoral DVT patients treated in the National Venous Registry with catheter-directed thrombolysis versus similar patients treated with anticoagulation alone [19]. The group of patients with iliofemoral DVT treated with catheter-directed thrombolysis were matched with similar patients from the same institutions who were treated with anticoagulation alone. All of the patients treated with anticoagulation alone were candidates for lysis; however, treatment was determined by physician preference. After 16 and 22 months of treatment, patients were evaluated using a validated QoL instrument [20]. Patients treated with catheter-directed thrombolysis had significantly better QoL as measured by the Health Utilities Index. Their physical functioning, appreciation of health distress, the stigma of chronic disease and their overall symptoms were much improved (TABLE 1) compared with patients treated with anticoagulation alone. www.expert-reviews.com
Review
These observations were subsequently supported by Broholm et al. [21] when they studied 109 patients with iliofemoral DVT treated with catheter-directed thrombolysis. They confirmed that PTS was associated with worse QoL. Only a small number of patients treated with catheter-directed thrombolysis developed PTS. Patients with patent veins and functional valves had higher QoL scores than patients with valvular incompetence and occluded veins. Grewal and colleagues [22] also performed a QoL study following catheter-directed thrombolysis in patients with iliofemoral DVT, correlating patients’ eventual QoL with lytic success. They performed a blinded analysis of QoL versus residual thrombus remaining at the end of lytic therapy and found a significant correlation demonstrating that the more successful the course of catheter-directed thrombolysis, the better the QoL over the long term. Baekgaard et al. [23] reported the 6-year outcomes of 103 patients treated with catheter-directed thrombolysis. An impressive 86% had patent veins with normal valve function at 6 years. Randomized trials of thrombolysis for iliofemoral DVT
The results of two randomized trials have been reported thus far. Elsharawy et al. [24] randomized 35 patients with iliofemoral DVT to catheter-directed thrombolysis or anticoagulation alone. Patency was restored in 72% of the lytic group compared to 12% in the anticoagulation group (p < 0.001). Normal valve function at 6 months was observed in 89% of the lytic patients compared to 59% in the anticoagulation group (p = 0.041). Since a large number of the patients in the anticoagulation group had persistent obstruction, they could not demonstrate valvular incompetence. Once recanalization occurs, the benefit of lysis will be magnified. Enden et al. [25] recently reported the long-term results of the Catheter-directed Venous Thrombolysis (CaVenT) trial. Box 1. Principles of catheter-directed thrombolysis. • Safe and precise access to the deep venous system using
ultrasound guidance. • Good imaging of the inferior vena cava to rule out caval
involvement. • Placement of IVC filter for non-occlusive thrombus in the
inferior vena cava • Proper positioning of infusion catheters within thrombus. • Substantial reduction in dose of plasminogen activator (0.5–
• • •
•
1.0 mg rt-PA/h) but delivered in larger volumes of infusate (50–100 cc/h). Add mechanical catheter-based techniques to shorten treatment time and improve success. Treat patient to achieve maximal thrombus clearance. Correct underlying venous lesions with venoplasty and stenting with the goal of providing unobstructed venous drainage into the vena cava. Therapeutic long-term anticoagulation.
1633
Review
Comerota & Kamath
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
Table 1. Quality of life outcomes in patients treated with catheter-directed thrombolysis versus anticoagulation alone. QoL measure
Catheterdirected thrombolysis
Anticoagulation alone
p-value
Health utilities index
0.83
0.74
0.032
Role physical
75.6
64.1
0.013
Health distress
82.4
64.1
0.007
Stigma
85.9
71.3
0.033
Overall symptom
78.5
55.5
1 s versus 65% treated with CDT (p = 0.42). An interesting observation was that 31% of the patients with unilateral iliofemoral DVT had valvular reflux. The best predictor of reflux in the treated limb was reflux in the untreated contralateral limb. Pharmacomechanical thrombolysis does not adversely affect valve function compared with CDT alone. Outcomes of catheter-based intervention for iliofemoral DVT
Contemporary results of CDT, using the drip technique alone or by adding PMT, have improved patient outcomes compared to anticoagulation alone. Large single-center observational studies [22,23,35] have demonstrated the improved QoL of patients treated with catheter-based techniques and their reduction in postthrombotic morbidity [36] directly correlated with the success of lysis. The large thrombus burden of iliofemoral DVT is associated with significantly higher recurrence rates compared to patients with infrainguinal DVT alone [8]. It has been our observation that patients treated with CDT for extensive venous thrombosis had a low incidence of recurrence. This was further analyzed by Aziz et al., [37] who recently reported that patients with iliofemoral DVT who were treated with CDT or pharmacomechanical thrombolysis had lower than expected recurrence rates. They also showed that residual thrombus at the end of lysis correlated with recurrence. Patients with a large residual thrombus burden had a significantly higher rate of recurrence than patients who had little residual thrombus at the completion of catheter-directed thrombolysis. Recurrent DVT
Recurrent DVT is a common and serious problem following management of patients with acute iliofemoral DVT [38]. Importantly, recurrent DVT is associated with a sixfold increased risk of PTS. DVT recurrence has been shown to be an independent predictor of postthrombotic morbidity (hazard ratio [HR]: 6.4). Most studies of DVT recurrence fail to address the location of the patient’s initial acute DVT. It has been our observation that patients with iliofemoral DVT treated with anticoagulation alone 1636
have a significantly higher risk of recurrence than patients with infrainguinal DVT. This observation has been substantiated by Douketis et al., [39] who followed 1149 patients with acute DVT treated with anticoagulation alone. They demonstrated that patients with iliofemoral DVT had nearly a 12% 3 month rate of recurrence, which was 2.4 times that of patients with infrainguinal DVT (p = 0.05). These observations fit with those of others that residual thrombus [3] and persistent thrombus activity [40] are associated with significantly higher risk of recurrence compared to patients without residual venous obstruction and ongoing thrombus activity. It makes intuitive sense that, if one eliminates the thrombus, there will be no residual venous obstruction, and the absence of thrombus suggests that there should be no thrombus activity (normal D-dimer levels). Baekgaard and colleagues [23] observed a surprisingly low 6% incidence of recurrence during their 6-year follow-up of IFDVT patients treated with catheter-directed thrombolysis. In our consecutive series of 75 patients during a 35 month mean follow-up, we observed a 9% incidence of recurrence. That was much lower that one would have anticipated. Aziz et al., [37] studied these patients to determine that if there was a correlation of residual thrombus following catheter-directed thrombolysis and subsequent recurrence. The individuals evaluating the phlebograms were blinded to the patients’ long-term outcome. The patients were divided into two groups for ease of analysis; group 1 had
