Title: BACKGROUND AND SIGNIFICANCE
Author: University of Michigan
Last saved by: Glen Bennett
Company: University of Michigan Medical Center

Final Version sent 4/10/2006

AGGRESSIVE THERAPIES FOR VENOUS THROMBOEMBOLIC DISEASE

Prepared for the Surgeon General’s Workshop on Deep Vein Thrombosis
Bethesda, MD
May 8, 9, 2006

Thomas W. Wakefield MD
S. Martin Lindenauer Professor of Surgery
Section Head, Vascular Surgery
University of Michigan
Ann Arbor, MI  48109-0329
734-936-5820
734-647-9867 (FAX)
thomasww@umich.edu

	DEEP VENOUS THROMBOSIS:  A blood clot in the leg is called deep vein thrombosis (DVT).  A blood clot that travels to the lungs from the legs is called a pulmonary embolism (PE).  For DVT, the goals of therapy are 1) to prevent the extension or recurrence of the DVT and the development of PE and 2) minimize the early and late results of the DVT. Although blood thinning medication (anticoagulants) accomplish the former, they contribute little or nothing to limit the development of pain and swelling in the leg resulting from the DVT, called the post-thrombotic syndrome.  Blood thinning medicines do not dissolve clot, but prevent clot extension or movement to other places such as the lungs.  Structures in the veins called valves normally direct the blood flow towards the heart and prevent the blood from backing down the leg by the pull of gravity.  When valves are destroyed by the clotting process or by the inflammation associated with clotting, an abnormal collection of blood in the lower leg occurs, which is called venous “pooling”.  When DVT occurs (especially at the level of the knee or above), severe pain and swelling can result from the loss of the function of these valves, or a portion of the vein that does not reopen.  Occasionally, DVT can lead to such severe leg swelling that amputation needs to be performed, but this is quite rare.  
	Blood clots are not static; they are dynamic biologic processes.  They scar, re-open, and even travel from the legs to the lungs.  When the clot resolves the vein usually reopens within the first few months of the event.  Approximately half of patients will show complete re-opening within 6 to 9 months of the clotting process.  Clinical trials have demonstrated symptomatic recurrent DVT to occur in approximately 1 in 10 patients treated with standard blood thinning medicine and natural history studies have demonstrated that the incidence of events that are not symptomatic may be higher than those that are symptomatic.  We follow the progression of clots with ultrasound scans.  Serial ultrasound scans have demonstrated progression of clot in approximately a third of treated patients within the first few weeks of presentation (1,2).  In a large series of 177 patients followed for a median of 9 months, recurrent clotting occurred in approximately half the patients (3).  Thus, standard blood thinning medication, heparin, while preventing fatal PE, is not perfect therapy (4). 
	The outcome after a DVT can thus be thought of as resulting in either dysfunction of the vein valves and the development of pooling of blood in the leg, persistent blockage of the vein that does not re-open from the clot which turns to scar tissue, or the combination of both of these events.  Patients with both blockage and dysfunction of valves often have severe pain and swelling making treatment difficult.
	In order to limit the consequences of the blood clotting process, its early removal appears to be the best solution.  A clot in a vein is called a thrombus.  It has been found that the longer a thrombus is in association with a vein valve, the more chance that valve will no longer function (5).  Additionally, the thrombus initiates an inflammatory reaction between itself and the vein wall.  Not only does valve dysfunction occur, but vein wall dysfunction can also occur as the vein wall scars (6).  This also contributes to the valves not working properly.
	A common mistake is for doctors to treat all DVT patients the same with only blood thinning medicine.  It is clear that not all DVTs are the same, and treatment should be individualized.  The long-term results from DVT in the most proximal part of the leg, the iliofemoral system, are generally more severe than for blood clots in the lower part of the leg.  Recently there has been a push to use heparin shots, called low molecular weight heparin (LMWH), instead of standard heparin given by intravenous infusion (IV) in patient who have DVT.  These heparin shots do not need to be monitored in the same way as heparin given by IV.  They are more convenient and allow home treatment.  There is a danger however that the convenience of this treatment will prevent consideration for more aggressive treatment for those patients who might benefit the most from such aggressive treatment.
	The two ways to remove clot are mechanical (thrombectomy) or with medication (thrombolysis).  The best evidence for effectiveness of treatment is called level 1 evidence.  Level 1 evidence on the effectiveness of dissolving blood clots with medication compared to blood thinning medicines does not exist, although there is level 1 evidence for removing clot mechanically by surgery.  This procedure, called venous thrombectomy, has been associated with long-term improvements in the vein staying open and the rates of pain and swelling in the leg compared to standard heparin anticoagulation, both at 6 months and at 10 years follow-up (7,8).  Dissolving the DVT  with thrombolytic drugs has been evaluated with a number of quality of life scales and has been associated with improvements in many aspects of quality of life, leading to a decrease in long-term symptoms of pain and swelling (9).  Three large studies have demonstrated that excellent opening up the venous system can be achieved with administration of dissolving agents directly into the thrombus (10-12).  A recent small randomized trial of dissolving medicine versus blood thinning medicine alone has confirmed this observation (13).	
	In addition to these more traditional methods to remove DVT, newer mechanical devices have been developed or are being developed for this process.  More than ten devices are currently available for clearing thrombus from clotted kidney dialysis fistulas grafts.  However, only one of these devices is approved by the FDA for use in DVT patients. One of the most common devices is a catheter that uses high pressure jets of saline solution for creating an effect called the Venturi effect.  This allows for dissolving thrombus and evacuation through the catheter.  There are some drawbacks with this catheter, however.  Another catheter combines the use of a mechanical wire and the infusion of agents that dissolve clot. The drug that dissolves clot is contained between two occlusive balloons, thus preventing the drug from getting into the systemic circulation and producing side-effects such as bleeding.  After the balloons are blown up, thombolytic dissolving drug is infused into the thrombus and then the wire rotates to bring the agent and thrombus into close contact.  After the thrombus is thus macerated the byproducts are suctioned and the balloons deflated. Data is available comparing these two devices (14).  Another technique is the use of ultrasound to explode microbubbles that can cause either mechanical thrombus dissolution or release dissolving agents which are contained within the bubbles.	 
	The conclusions from the above studies are clear:  Early removal of the thrombus conveys significant benefits, and the earlier and more complete the removal, the better the outcome.   The main limitations to early thrombus removal are twofold – the therapy is complicated, taking time to accomplish with the risk of bleeding (compared to outpatient LMWH), and there is lack of strong evidence defining the long-term value of such therapy.  Two national/international summits have recently identified the need for studies in this area to be the most important priority for venous research at the present time – both from the Society of Interventional Radiology (15) and the American Venous Forum Pacific Vascular V Summit (J Vasc Surg, In preparation).
 
PULMONARY EMBOLISM (PE):  The use of dissolving medication for PE has been well defined for those in shock related to poor heart function (16).   This is an important issue, as patients who die from PE usually do so within the first hour after the PE occurs.  However, what is poorly defined at the present time is what to do with patients who have right heart dysfunction but no systemic hemodynamic instability, in other words their blood pressure is not abnormally low.  Blood pressure may not be a sensitive enough indicator to decide who should and who should not receive dissolving medication.  In these situations, assessment of right heart function is likely the most important parameter to measure.  A study in which dissolving medications were compared to dissolving medications plus blood thinning medications for large PE (producing right heart dysfunction) found that the dissolving treatment reduced the need to escalate therapy.  This included the use of a ventilator and the use of agents to increase blood pressure (17).  However, since no improvement in overall death rates have been shown with the use of these agents, the use of dissolving agents is controversial (18,19).  The most important long term consequence of PE is elevated pulmonary artery (lung) pressures.

	FILTERS:  The main vein in the abdomen is called the inferior vena cava (IVC).  A filter is a device placed in the IVC to act like a screen to prevent a blood clot from passing to the lungs from the legs.  It is indicated when standard blood thinning medicine is not able to be given due to a complication, a contraindication and/or failure of that therapy.  Protection from PE (a clot to the lungs) has been greater than 95% successful using cone-shaped wire-based permanent IVC filters over the past 30 years (20).  
Over time, the success achieved with filters has expanded the indications to using them to prevent PE from occurring.  These include when a clot longer than 5cm is free-floating (21), anticoagulation risk is excessive (as for example an older patient with DVT or following major trauma [22]), when the risk of PE is felt to be sufficiently high (as in certain bone and gastric bypass operations [23]), and to allow for the use of perioperative epidural anesthesia.  Filters can be permanent or temporary (retrievable).  If a temporary filter is left in to become a permanent filter, its long-term fate has not yet been defined.
Filters are usually placed below the kidney veins.  Filters may also be placed in either the location above the kidney veins or in the superior vena caval in the chest in special circumstances to prevent clot from the arms passing to the lungs.  For placement above the kidney veins, indications include: high-lying clot, pregnancy or a women of childbearing potential, or a previous device that has filled with clot or failed.  Severe infection called sepsis is not a contraindication to the use of wire-based filters since the trapped material can be sterilized with antibiotics. However, IVCs  larger than 28mm usually require a different approach than cone-shaped wire-based devices.  Although traditionally filters have been placed under x-ray guidance, percutaneous techniques for filter insertion using bedside ultrasound or external ultrasound to reduce exposure to x-rays have now been developed.  Transabdominal external ultrasound is ineffective in the face of patients who are obese, if there is overlying bowel gas, or if there are open abdominal wounds.  In these instances, intravascular ultrasound has been found to be more successful (24).  

 Nonpharmacological Treatments:   The rate and severity of pain and swelling after above the knee DVT can be decreased by half by the use of strong surgical compression stockings (25).  Walking with good compression does not increase the risk of PE, while significantly decreasing the incidence and severity of pain and swelling after DVT (26,27).  It is recommended that once patients are therapeutic on blood thinning medicine they ambulate while wearing compression stocking if they have a DVT.
In addition to the long-term problems related to DVT and PE, there is an associated increased death rate.  In a study involving 665,248 patients from the Nationwide Inpatient Sample, occurrence of either DVT or PE was associated with increased death rate and unfavorable discharge (discharge to rehabilitation facility, nursing home, or another hospital) in patients admitted to the hospital for common medical illnesses.  These included heart attack, heart failure, pneumonia, or stroke (28).  Venous thromboembolism was also associated with increased cost and length of stay.    Not surprisingly, venous thromboembolism appears to confer a significant risk of death in addition to its risk to the legs and to the lungs.

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