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:
[E]{.underline}[arly]{.underline} 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]{.underline}: 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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