NIH CLINICAL CENTER GRAND ROUNDS
Episode 2009-023
Time: 58:19
Recorded September 23, 2009
Deep Vein Thrombosis: Old Problems, New Options
Dr. Emily Chew, Deputy Director Division of Epidemiology and Clinical Research at the National Eye Institute
Dr. Robert Nussenblatt, Chief of the Laboratory of Immunology at the NEI and acting Scientific Director of the National Center for Complementary and Alternative Medicine.
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.
(Music establishes, goes under VO)
ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded September 23, 2009.
Today, two speakers from the NIH Clinical Center will discuss the topic, "Deep Vein Thrombosis: Old Problems, New Options." Our speakers are Dr. Jay Lozier, Staff Clinician in the Hematology Service, Department of Laboratory Medicine at the Clinical Center; and Dr. Richard Chang, Chief of the Endocrine and Venous Services Section, Interventional Radiology Section, Radiology and Imaging Sciences at the Clinical Center. We take you now to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland, were Dr. John Gallin, Director of the Clinical Center, will introduce today's speakers.
GALLIN: Good afternoon and welcome. Today we have a presentation from two clinical investigators who is will bring us up to date on deep vein thrombosis, old problems and new options. I'm going to introduce both speakers and they'll have sort of this tandem presentation which will become obvious as they go on.
So first I'm going introduce Dr. Jay Lozier who will be the second speaker, he's with the Department of Laboratory and Hematology Service and then he'll be with Dr. Chang, in the Endocrine And Venous Services Section. In the interventional radiology section. He received his MD, and Ph.D at the University of (...). He was a resident in internal medicine and a fellow in hematology and coagulation at the University of North Carolina at Chapel Hill. He first came here in 1995, as a clinical investigator, in the Clinical Gene Therapy Branch at the National Human Genome Research Institute. Becoming an expert in that branch in 1999 from 2001 to 2006, Dr. Lozier was a senior staff fellow in the Office of Blood, Research and Review, part of the FDA's Center for Biologics Evaluation and Research and he came back to the NIH in 2006. He's a member of the American College of Physicians, the American Association for the Advancement of Science and in addition to deep vein thrombosis, Dr. Lozier's research included clinical studies on the (...) factor used to treat patients with hemophilia.
Our other speaker is Dr. Richard Chang who earned his bachelor's degree at New York Columbia College, a master's degree in physics from Princeton and MD from the Johns Hopkins School of Medicine. After medical internship at St. Luke's Hospital in New York City, he returned to Hopkins to complete a residency in diagnostic radiology. He came here in 1985 to join the Department of Radiology and to work with our renowned and beloved Dr. John Doppman who was at that time the department chief. Dr. Chang was appointed Chief of Interventional Radiology Section in 1993. And his memberships include in the American Society of Interventional and Therapeutic Nerve Radiology in the Society of Interventional Radiology. Dr. Chang's research special interest continue to be improving diagnosis and localization of endocrine tumors and improving treatments for venous thrombosis.
So Dr. Chang, I think you're first.
CHANG: Thank you for that kind introduction. It's a privilege for Dr. Lozier and myself to present here at grand rounds and we'll get started since there's a lot to talk about.
Dr. Lozier and I do not have any financial relationships with any of the pharmaceutical companies or manufactures any of the products discuss indeed this presentation the two NHLBI supported product recalls involve off-label use of tissue plasma activator or TPA, for treatment of DVT under an (...)
Now we're going to break this up and these are the topics we're going to discuss. I will first discuss the normal anatomy and the lower physiology of the extremity situation.
Then Dr. Lozier will discuss the problems of DVT in terms of definition, pathophysiology and epidemiology and he also talk about the treatment of DVT with anticoagulation and I'll talk to (...) and then Dr. Lozier will come back in to talk about the outcomes of the latest protocol as well as the most important part what have we do, if we have time which I'm not sure we will, we can discuss the other recent NHLBI extramural trial which is known as the attract trial.
Now, the--we h we talk about the deep veins we're talking about everything from the IBC, down the iliac veins, down the femoral veins and then into the calf veins and down to what is called the plantar vein and the foot.
Now there are multiple divisions along the way that are also considered deep veins that's the internal iliac vein issues there's a deep femoral vein, there is (...) or muscular branch that join the popliteal directly and there are the calf veins are usually triplicate. Each one is a pair and they receive flow from the muscular veins of the calf. This is the superficial vein, a lesser saphenoous and then there are (...) veins between the superficial and the deep system.
Now this is a large system, this is over a (...)length if you combine these vessels, and the capacity is much larger than the artery. That's the first difference. So when thrombosis occurs and it can occur in all of these segments it can be quite a big clot burden.
The second difference between the artery and vein is of course the presence of valves. And these valves are not there just to frustrate the interventional radiologist in the vascular surgeon who does bypass, the valves are important in insuring blood flows in the proper direction and they're important in the heart when there's a pump involved and what is known is that in the--these veins that run in the calf and the thigh between muscle groups involve a pump action very similar to the heart and the most commonly--well known pump is the calf muscle pump, then there's the thigh muscle pump and I'll talk about the most recently discovered pump which is known as the foot pump, but during, walking when you first your calf muscles contract, the first thing is that the perforating veins are closed off and then blood is injected bases of the valves, the blood is forced up into the thigh vein. Later on when the thigh muscle contracts, these valves close so it doesn't go retrograde and the thigh muscle contracts and the blood goes up into the iliac veins and at the same time, you'll see these calf muscles relax, they'll fill from the superficial veins to the deep veins.
Now before I go on next, the veins are very thin vessels, very slender, walled and they're what is called compliance or compassion vessels, so by that I mean when they're (...) the pressure in the calf veins and low and it remains low until completely fill and then and only then when they're completed fills does the pressure suddenly go up.
Okay, there you go. Okay, so what happens? What is the pressure like in the deep veins? People don't realize that the pressure in the deep veins, the upper curve is the lower and the other vein and this little mark when the muscle of the calf contracts, when the muscle of the calf is contracting when you are walking the systolic pressure, I'll call it systolic during muscular contraction rises up to 150 (...) mercury which is over systolic measures in many patients with arterial pressure. And the reason you don't feel it is because the perforator have been closed off during the (...) and the superficial veins don't see that pressure and after the calf veins are completely empty, they're flaccid, the pressure during the actually goes low. This graph is an artist rendition of a book and this curve drops below the superficial vein.
At that point the pressure in the deep vein system lower, and the peripherator veins open, muscles relaxed and the blood flow from the superficial veins flows into the deep veins and in fact if you look at this, you'll see that at rest, the measure is hard and the average measure pressure in the (...) is the same. And that's related to this curve, so at rest, the measure is high, normal exercise, the superficial vein expression, actually drops, below the ambient pressure. This is an example of a thigh pump with the muscle relax, the superficial femoral vein of the thigh is filled but as soon as they contract it's ejected upward into the iliac system. But this is the most recent pump discovered only discovered in 1983 by Gardener and Fox, they went to a museum and obtained this picture of a venous flexus in the foot. It's largely known as the plantar vein and what they found this, is where the plantar vein is located over this area here, here's a radiograph with it fill indeed a cadaver and here's the lateral view showing where it lies here.
Now the interesting thing is when you put-- when the foot is relaxed, this vein gets filled but as soon as you put the foot down this, is a cadaver so there's no muscular contraction, this vein is empty and the blood, the contrast here is ejected into the posterior tibial and they describe the action as tensing of a bone strain, so when you put the foot down and the bones move a little bit, it can eject blood as soon as the foot is put down.
Okay, so this is how they envision when the foot is off the ground, top, plantar vein fills when you dorsiflex, the lower calf veins contract and drive it upward, then when you put your foot down, of course the plantar vein ejects up and then later what you left off, the calf vein in the upper calf contracts. So there's a sequence of flow.
Now this is--this is composite of data from 2700 venograms this, is a study I believe it can be done today because most diagnosis is done by (...) but they found almost 900 cases of DVT and they categorized where the clot was found and 83% of these patients had some clot in the calf vein, the most common is the perineal vein which is (...) the largest and most important vein in the calf, so calf vein is where most DVT actually resides.
So now here's the case of 54 year-old man who came from Oklahoma, could not put his foot down. Came in a big motor home across country because his brother was willing to drive him. He never had to stand up but on his venogram you'll notice something's missing. We don't see the plantar vein and that should be our first suspicion there's a problem here and in fact, when we cross through the clotted posterior tibial vein and get down and inject the plantar vein, you see there's a big calf or clot in the vein there.
Okay, can you--okay. So, now, if you follow up, there's no--these are all superficial veins so the calf veins are clotted and then as you follow, you finally see that the superficial femoral vein of the thigh is also clotted so this patient had both compromised, the foot vein pump that the camp main pump and the thigh pump essentially all pumps that are involved with the intra venous returns from the leg.
I'll leave this for Dr. Lozier.
LOZIER: Thank you. So I will talk about DVT and tell you the general terms of what it is, who gets it, what are the risk factors and tell you about any coagulate treatment for DVT and the long-term consequences which precept a problem we hope to solve with thrombolytic treatment.
So DVT occurs when blood clots form and obstruct the return ever blood to the heart and this is for the purpose of this talk, dealing exclusively with the lower extremity although there can be DVT and this role organs or in the upper extremity and the acute DVT symptoms include, pain, swelling, discoloration or two other (...) of the leg.
This is a painting depicting what is probably the first reported case--recorded case by surgeon 600 to 800 years BC discussing a swollen leg and difficult to treat. We assume it was DVT. It's been around for thousands of years.
Now in the United States, the recent call to action on the venous thrombolytic disease is estimated at 1000 per year, about half of which are DVT. So there's about 350,000 Americans who are likely to have DVT or (...) each year.
It's estimate that half of the cases are not diagnosed and we've seen in the radio graphic studies of patient who is have (...) DVT there's evidence for older damaged veins, either related to or not related to the clots we see.
But regardless of the true incidence, the problem in the united states will inevitably increase the population as the we age because the risk for DVT increases with age.
So DVT is often caused by one or more of the predisposing factor known for accounts triad which is basis of flow, inflammatory Change or injuries of vessels and prothrombotic conditions of the blood, deficiency of any coagulate proteins which is the seen here, excessive clotting factors, as a consequence of the factor of gene polymorphism, or support other activities and recent paper and blood regarding vessel wall, and expression of the gene and the endothelium around the bowels and there may be differences in expression of (...) factor and the endothelial protein receptor in the endothelium near the valves which may differ between people and may be a difference may account for the increased risk of thrombosis.
Giving some people based on the observation that people may have not only stasis around these valves but also the local hyper coaguable state. And now the triad applies to both arteries and veins, we don't have atherosclerosis in the veins but we do have peculiar problems. Particularly venous puncture, stasis can be due to mobilization, usually casts or fractures or paralytic conditions. There can also be tumor compression or congenital with the large vein segment to give you stasis and also you can have anticoagulate deficiencies and coagulate excess and systemic conditions and cancer, inflammation, any possible antibodies or some metabolic disorders, may cause increased risk of bases of hypercoagulability of the blood and you can have more than one of these at a time and if you have all of these you have what you might call a perfect storm when you have the highest risk for thrombosis.
So, the first thing we're talk about as far as treatment is anticoagulation, anticoagulation doesn't become possible in theory until about 1916 when heparin was discovered in Johns Hopkins University and it was purified first but was made commercially available in the 1930s by labratories, [indiscernible] or intestine and this was led by Charles best with best investments so it's two major drugs to his credit.
In the 1950s, active agents caused hemorrhagic disease in cattle was found to be--low molecular weight in the 1980s allowing subcutaneous injection and treatment of out patient oppose to intra venous heparin, so since the introduction of the anticoagulate therapy in the 50s mortality of DVT has been drastically reduce (...) 40-80% depending on the series you're looking at to approximately one% and this is mainly due to prevention of fatal PE at the secondary consequence.
And remarkably little has changed and some will be some direct inhibitor and some factor (...) inhibitor and those at this point are not yell available.
So any coagulation certainly prevents PE and it's useful but it doesn't reserve the means function and only about five or six percent of these patients will show significant clearance of thrombosis during the first ten days or so of anticoagulation so typically people have pain and edema and problems with leg function early on and then incomplete clearance of the clot and valve damage may lead to the most [indiscernible] syndrome. It's an entity that consists of swelling, pain, and skin functions, can you break down ulcers in the worst cases and it's due to valve obstruction and DVT.
So how do people do on anticoagulation? You look at the series of the Annals of Internal Medicine, there were 35,000 patients that were followed for five to eight years after their first DVT and of these, a quarter will remain asymptomatic of their initial DVT, a about a quarter will have recurrent thrombosis, 1 quarter will die from some cause related or not to the original thrombosis, mainly cancer and myocardial infarction and stroke and about 25% will have some evidence of the post (...) syndrome of which nine are severe cases so if you think about the numbers in the u.s., it's a pick public health problem, there accounted be a hundred thousand, 2 million patients each year with post (...) syndrome that we have to worry about if we stick to just anticoagulation.
So Dr. Chang will tell us about (...) as another aproach.
CHANG: So it's been known for some time that there was something in 1933, that was used to in 1958 pretty much for myocardial infarction for coronary clots. How streptokinase worked ten years after discovery and--and there's (...) and once activated by (...), as you're (...) which are the natural ones found in the human body, it's converted to an active form and it's plasmid that's capable of breaking down fibers in clots. Plasmid is pretty non--it'll break down fibrin o gene as well.
Now the body has checks and balances in the coagulation as well as the pathway. Which complexes with these and neutralizes and prevents them. Similarly the plasmid is activated there's inhibitor of plasmids and antiplasmids in the circulation to prevent too much plasmid build up in the circulation.
LOZIER: Okay, now there are--we won't talk about streptokinase because of antigen problems with the bacterial (...) enzyme but there are four enzymes that have achieved some sort of application and been tested.
[technical issues]
They represent human (...) with the dna and modifying and selecting out properties that they think are helpful, turns out your kinase and are similar and all the plates have similarities which I'll go over later.
Now how did we administer these agents, let first administration was thrombolitic by an id route and this was done with streptokinase and letter with your streptokinase and these were performed--these were performed for AMI in 1958 and then later in the 60s for PE and then DVT in the late 60s. And occasionally streptokinase and still used for AMI and it's off the market and typically now, we use TPA and it takes about a hundred milligrams of TPA to treat a few millimeters of clot that you'll find in a coronary or cereberal artery during AMI or a stroke. So that's not efficient if you're dealing with a clot.
The next way of delivering it was thrombolytic was introduced by daughter when he was treating arterial occlusions and basically it involves placing a catheter in the clot and doing continuous infusion of a thrombolytic agent until the clot dissolved. This catheter directs infusion has been used for every thrombolytic agent successfully that has been developed since streptokinase.
This shows systematically if you give peripheral id, how successful are you in getting a clearance of the clot.
Well it turns out, it's not--it's not that, it's 47% successful in clearing the clot. Compared to four to six% if you use heparin. So, by far, thrombolytic therapy is much more effective in clearing clot. This just repeats that, now when you go to cath-directed therapy the success rate goes up regardless to which of these four agents that you use. The down side is the problem of bleeding.
With systemic (...), there was the 16%, instance of major pleading meaning symptomatic bleeding and bleeding that required transfusion. There was a .8% of inter cranial hemorrhage and it went in to cath directed therapy, it is (...) of internal bleeding and hemorrhage bleeding did decrease but they're elevated. And although it's a five percent risk of bleeding with anticoagulate, usually statistics are obtained after following patients for three-six months for anticoagulation is much lower which is administered only over three to six days. So the risk for day is much higher with (...) therapy.
Now the euro kinase was the most popular used and this is the largest studies of any agent that are obtain (...), by 19, report 21, 87 support, 90, 97 and this is the multicenter trial with 312 patients recorded. Their success rates are not bad, 72%, 86%, for ilial femoral, 63% for femoral popliteal. And here I have to explain how DVT has been classified. Some like to distinguish it between upper clot, usually upper femoral, it may involve the iliac vein, may extend down, but only in extreme cases has it reached the popliteal. The other is called the femoral popliteal vein which is the lower segment. This is actually a misnomer because most of the clot I've shown you already begins in the calf and the calf veins never get a billing, it's like the calf vein segments are the Rodney Dangerfield of this disease, nobody seems to be too concerned about them when they develop a clot in terms of pulmonary embolisms and few people seem interested in terms of thrombolytic therapy except for those who understand the calf pusm mechanisms of venous return.
At any rate, the problems with these trials, they show seven percent incidence of major hemorrhage, 11%, that's pretty high for a benign condition. So when you use a cost of these it was about a thousand dollars, so an average cost of 4.9 million units translates to almost $5000 worth of enzyme. These people used an average of ten million units almost $10,000 just for the enzyme.
So the cost of thrombolytic, the duration of the infusion was 30 hours on the average issues went up as much as 74 for three days and that was spent in the icu and in this case, it was 75 hours, quite I bit longer, they used up to 247 that's about ten days and similar duration is fairly high for a continuous infusion therapy and most of the time it's spent in the ICU.
Now the fourth problem with what we know about thrombolytic therapy in the past is this problem of durability and immediately after this they had 86%. But if you waited a (...) and looked at him, only 63% remain patent, similarly the registry was 300 with similar numbers. There's a significant loss of pain. It works with femoral popliteal disease and when you get down to a 40% patency of one year, that's not that far from doing anticoagulation therapy, so if it's not results are not durable, why do it?
So this a graphical demonstration of the same data I've shown you, you'll see that most of the failure rate, occurs in the first three months. It's not the five or six month point, most of patient lost patency within the first or second month, even so why is that. I'm sure the answer is multifactorial. Sometimes maybe patient selection, more chronic DVT than they should have tackled but I think a big part is their approach, (...) for femoral popliteal DVT is the most common approach is to go up from the popliteal because that's an easy puncture and to forget and basically you're treating awe all the clot above the knee but you're not dealing with the calf veins and DVT problems that are commonly found in popliteal DVT.
So based on these lessons we learned, what did we learn.
We learned one thing that all these plasmid activator k's dissolve clots and that's not a surprise because the final enzyme is plasmid and they all activate plasmin o begin to plasmid. So if they all activate plasmin gene then they all desolve the clot. But there are different properties and we'll show you that we thought that this was our opportunity to exploit these properties to impact safety {indiscernible].
The third thing is the method of delivery. The most common delivery was to use a continuous infusion of the thrombolytic and everybody thought this was probably the best way to do it but we don't believe this is the best way for all plasmin o gene activators and here's why. You're o kinase is different from TPA. Euro kinase as soon as you introduce them to blood stream. Even in the circulation.
So, it will--as soon as you introduce it, it activates plasmid, doesn't require the presence of clot but tell start to dissolve, as soon as it's there.
So we call at this time promiscuous plasmid activator but TPA is pretty low by itself, but once it binds the clot to fibrin clot, as a receptor it will undergo a confirmational change and the ability to activate goes up several hundred fold, so this is called a fibrin selected or smart plasmin begin activator. And when we look at the new agents, retia place, it's the one that was engineered, looks just like euro kinase and the other engineered enzyme is connected or TNK, also bibbeds the fibrid and it's behavior is similar to TPA. The only difference is the half life. This TPA is natural enzyme has a significantly shorter half willful than any of these other agents.
So what happens? These are test tube experiment which is show you what happen when you take an agent that has little fibrin binding oppose tan agent which has a lot of TPA, this is euro kinase would be the PAM. The red indicator marks the distribution of the actor, or the fibrin clot that has inhibitors against the clot or have a deficiency against plasmin gene so there's nothing to activate but when you look at--put in enzyme above the tube it diffuses freely into the clot.
And on the other hand if you take the same thing with TPA which is the binding and you put it on top of this column, you'll localize significantly right at the top and stay there, at the top of the clot, so TPA, because of this binding has limited diffusion and it's a surface agent.
So this is why we use something called pulse spring injection, if we were to infuse any--continuous infusion, what would happen with the (...) come out and it's a little (...) it would just coat this channel around the catheter and that's all that would penetrate so in order to go volume agent, we actually mechanically force it, right by vigorous (...), the second reason why TPA is helpful. It relates to this.
After the column is loaded with rete place which has no fibrin binds and you would pass saline over the top, pretty soon the one (...) and gets washed out if you take the sap thing with TPA which is stuck at the top, and wash it multiple time its doesn't wash out and this is particularly in important in terms of cost and efficacy.
So this translates to theoretical for the--euro kinase, get the cost, this little orange purple spheres represent the kinase, it will cross over, a little bit of penetrate when the concentration is low, when it's high, tell be much more penetration as it defuses throughout the clot but as soon as you turn off and it's over, there is the t pa that was diffused in the clot will leach out and that will be the end of any thrombolytic action, so this is an agent which requires a continuous infusion. TPA comes in and a little bit is absorbed through the surface, you take more concentration and more sources. And then at the end of the infusion, instead of the TPA coming offer, it's bound to the surface of the clot. And tell continue to work on the clot.
So you get much more thrombolisis from every unit of TPA given, but the pharmakinec is different here also.
It's the insane method as it is for agents that bibbed using the molecular imaging, what happens is, the amount of TPA that is--absorbed by the clot is dependent on total TPA that crosses over this. This is a relation of flow, integrates the amount of enzyme seen screws the agent more or less.
So this explains (...) if have you a clot and it sits in your--in your vein in your leg, it's not likely to dissolve very well, but as soon as that clot breaks off and goes to the lung, we find we don't have to worry too much about anticoagulation in that clot and that's related to the fact that when a clot goes to the lung, the blood flow in the pulmonary artery is so much, it brings so much more TPA cross that clot, than it would ever in the leg, that the clot will dissolve much better in the lung.
So we modified our thrombolytic therapy due to two things.
First of all was to select TPA and it was abandoned and in favor of lacing the clot once a day with TPA and you use farm o kinetic data to access the exposure, meaning we measured how much TPA doesn't get absorbed, how much exposes circulation to risks of bleeding. And we--because we don't have to do continuous infusion, we don't have to keep our cath in one vein segment, we can move it to the next and inject that vein segment and keep moving until we covered the vein sugments that are affected by clots and it do the calf veins I usually go down. I don't take a popliteal route up, I go down in order to treat all the segments in the calf vein. And this shows that you patient remember he had no clotted vein, but if you are able to treat all those things can you restore the vein and you can restore the femoral vein as well.
So the reason our protocol involved TPA, it has a strong vibrant binding prolonged action and has a short half life because any TPA that research will be quickly cleared and by stopping the infusion, we don't have prolonged introduction of more TPA into the circulation.
We basically start our patients with venogram and ultrasound evaluate the extent of disease and we give a--at the old protocol, we use the up to 50-milligrams a day.
Now the decision to use 15-milligrams a day was really not our totally rational. We realize that people were dissolving a millimeter of clot with a hundred millimeters in the coronary artery so it doesn't seem like a big dose when you're dealing with a meter or so of (...) however the reason we use that is the vile size, the TPA came in only 50 and hundred milligram vile sizes and we chose the smaller.
We don't do a venogram right away we check on venogram the next day because the lytic affect takes time.
And at that point in the second day we decided whether it needs another treatment and we're allowed to do this cycle for up to three or four treatments. We then hopefully have achieved patency and we recheck to see if there's still pain within one or two months which I showed you with the rapid fall off in pains you see on the other trials and then we again, study them at six months to see whether there are still patent and anticoagulation is throughout the period, during thrombolytic therapy and we start with heparin and switch to love in ox when we're transitioning to coumadin.
So 20 subjects in the first trial and the average date of the clot was about 9.3 days. About five out of 20 or 25% of the iliofemoral disease remainder had various combinations mostly calf vein disease. The main treatment was between two and three days. 2.2 treatment days. The total dose over those 2.2 days would be about 78-milligrams was used during that period. We achieved patency of 80%.
Now there was no major pleading complications that we see.
There was one case of a bicep hematoma in a patient who had been taking aspirin and we asked them about when this occurred, he said the pain started during the treatment when we were giving TPA actively, because of this automatic blood pressure monitor that we've been using and when we thought of that, we realized we were giving trauma to the vesicle probably at the time the peak (...) after we stopped doing--we never had occurrence.
CHANG: We found that after we did the TPA,--over shoot of TPA and 500 or--he says well over about five times what we would expect. Over the normal circulating, but within two hours. The buzz of the five minute half life of TPA this would be cleared. Now how do we know? Our theory of course is that we found TPA. We know that because we know that the activity of TPA goes up more than a couple hundredfold once it's bound to the clot itself. So that's the TPA.
So the fiber break down is done by the TPA, but how long does it--well, it turns out that we receive the peak occurs within four to six hours but it's delayed. It doesn't--we don't look at the venogram right away for this very reason, you don't see immediate break down but it takes four to six hours and then you might see it significant break down and over the rest of the day, the activity is around fibrolytic activation. 50-milligrams was effective and about 80% of patients.
In the (...) study, from the onset of symptoms from the time of treatment with TPA, or the disease limited to iliofemoral region and the remainder had various combinations of segments including calf or popliteal veins. So one-third had the 2210 and there were two subjects that had mildly depressed antithrombin three levels employing. --which was 97% at the time of discharge from the first hospitalization following (...) treatment was this was done with two and half treatment days on average more than 7-milligrams, daily dose of TPA, and the total dose average just a little less than 20-milligrams so with a lot less TPA we got as good or better results. There was no major bleeding in this study or this series. There were three superficial hematomas that occurred up front in the TPA phase of the protocol and none required cessation of the TPA treatment or any Change in the anticoagulation.
This is an interesting case of an 18 year-old with factor five live with extensive clot of the IBC and the bladder clots immobilized in bed and concern for how anticoagulate giving TPA to a patient like this and you can see he has extensive iliofemoral and calf vein disease and because we had the catheters in the clot, we were able to use regional anticoagulation in relatively low doses of heparin.
And he was between eight, ten and 9-grams of TPA and in this leg and had good restoration of flow, so this is another advantage in the ability to do regional coagulation and high risk of bleeding.
Now you remember the form cokinetics such that the first higher dose protocol had peak levels between five and 600 units per mill. Here with have much less than that, of the order of that level, and getting cleared within an hour or two. The pie one was consumed entirely at the time of this over--this pharmacologic dose. This is part of the basis for being able to take people from the interventional radiology suites after minimal requiring an icu bed, high one recovers quickly after the TPA injection and restores the normal situation where there's high one access to TPA.
We don't need continuous infusions, because of our if this persists after the intra clot injection of TPA and this also I think argues for simultaneous segments which permits the license to occur throughout the whole involved area before there's the pi-one rebound. This improved safety through reduction and amount of the TPA or alytic treatment and I think this argues for the more comprehensive treatment particularly of the small calf vessels, and again, we eliminate the need for the ICU with this and one thing we'd like to investigate ultimately is if this could in some way be made safe enough to be done as an outpatient sort of treatment.
The cost of the drug is in the low dose protocol and much less than actually the cost of our o kinase historically and the catheter is probably the more important issue as far as cost.
As far as what it costs the patient in terms of an in patient admission several days, the question will be do we get long-term benefit in terms of preventing post (...) syndrome and the acute relief of symptoms worth the increased risk for bleeding which is something we need to discern on the basis of the long-term incidence of post (...) syndrome.
Don Horn was the PI of the first trial before I came and he still works with me and drive to all of these pharmacokinetic data. Richard has a cast of many people who are willing to come at 10:00 o'clock at night and start a case that goes until the wee hours. And we have a good nursing staff that is able to keep track of these patients and keep us honest. We have people who assess ultrasounds and function and I think at that point, shy mention that we're grateful for Dr. Kahnon's support and the lab support we get from DLM from doing all the clinical studies that have to be processed in the wee hours of the morning.
LOZIER: I'll stop here, I think.
I don't think we have time to really talk about the track trial per se. We can open it up for questions.
[ applause ]
GALLIN: Well this, was wonderful. Thank you very much and not only have you done terrific work on tackling a tough clinical question, you've thought of cost effectiveness which is timely and appropriate. I have one question before I turn it open and that is, can you project how many vibes you've spared or would spare if this was implemented routinely around the country from the complications of pulmonary embolism and others that we know happen from this problem?
I think that's a difficult question to answer, but you know we're not predicting against pulmonary embolism because anticoagulation does that really well. It's preventing the post syndrome, if we think about 25% of patients may get a post leavittic syndrome and the number being 600,000 potentially candidates a year who get DVT, you're talking about pretty large numbers, 150,000, but potentially benefit however, as said now, the technique we use is technically challenges so we hope to make it simpler so they can go it a more wide spread practice. And hope to keep that cost down also.
QUESTION: So thank you for an excellent tag team presentation. That was informative. I know most of the patients were a week or two following presumed onset of DVT is there a point for diminishing returns is there a point following tvt where you thought going through the process is not worth the effort or did you not hit the limit?
LOZIER: We do have patients who are not treat wide research exemptions for protocol but not doing the (...) at that time data and did have one person who was treated for leg DVT, he had a DVT, actually works in area and was a scientific meting in San Diego, PE, wasn't allowed to travel and he was treated actually at day one or so, and he had good results.
We also had recently a patient who an arm DVT that was probably 20-21 days so we--we were able to treat her actually as an outpatient and lace that clot with working with Dr. Chang and using a catheter and bringing her back on two or three days and that 20 or 21 day clot also lies.
So one thing I'm interested in is could we have a stratified trial where we enroll more pates and go up to day 21 or 28.
I think you will lose the efficacy obviously because over time this will essentially turn into collagen and scar down and I think you're limited to matter a matter of a few weeks during which time you might be able to use t pa.
There's also the use of plasmin gene in the clot and it gets (...) are as the clot gets older and the tee pa, would not work, now, there actually is a clinical trial with the plies mid, purified from plays that that Bayer is running for declotting dialysis catheters and a synthetic or recombinant protein that has a direct activity on fibrinogen might be something to try in some of these outliers. I think that's important question because, there was a practical matter, most of these patients find out about our trial, day ten, by the time they get here it's Friday afternoon and it's time to get them in under the bell and I -- you know I think we could probably treat and have treated some people past that time point and it would be nice if we didn't are to have an arbitrary limit like that. I think it'll be a diminishing return after 21 days though.
QUESTION: I think Richard answered my questions after I stood up but do have you any patients who present with a symptomatic pulmonary embolism and extensive distal clotting in the distal veins?
ANSWER: it's known you can accelerate thrombolieis from a pulmonary embolism and get that clot to here within a couple days. Most of the time however, pulmonary embolism part does clear within a week or two so less pressure to treat that area. However, the DVT that persists, the reason we treat is to restore quality of life and there's no guarantee then when you start any on coagulation that you'll recover the venous segments you need to have that quality of life.
So really the treatment we focus on is treating the leg because anticoagulation has done pretty good job and there are some trials though that will--that relate to treating you know PE and this, is apropos for me, I have aircraft who's a staff member here who was seen in my clinic on Monday and diagnosed with a significant DVT up to the lower calving to the mid-thigh and we started him on Lovonox, on (...) so he's still having leg pain are although the swelling has gone done and my question is, would he be a candidate for your protocol now that we've already started the lovonox?
???: Yeah, most of our patients have started anticoagulation, our protocol actually finished because we reached our limit but being an NIH patient, an NIH patients it could be treated and how old is the clot?
>> He's an outpatient.
>> No the clot.
>> Oh then she should respond and he probably get a good result if he's interested.
GALLIN: Thank you very much, a great presentation.
[ applause ]
ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds, recorded September 16, 2009. You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.
