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SAMUEL GOLDHABER, MD: I am Dr. Sam Goldhaber, and welcome to "Translating Evidence to Practice: A Case-Based Approach to Venous Thromboembolism Prevention, Diagnosis and Management."

SAMUEL GOLDHABER, MD: I will start out by discussing the under-utilization of venous thromboembolism prophylaxis with an overview of epidemiology. This will illustrate the concept that outpatient and inpatient venous thromboembolism are actually linked together. The ENDORSE trial, presented at an international meeting in July, showed that the failure to prophylax is not only a regional or American problem; it is across the world. I will also discuss a recently published report from Dr. Amin about failure to prophylax across the United States. Finally, we will explore ways to possibly change behavior.

There are nearly a million pulmonary embolisms (PEs) and deep-venous thromboses (DVTs) each year in the United States alone; close to 300,000 patients might actually die of pulmonary embolism. Most of these are incorrectly attributed to sudden cardiac death or atherosclerosis or myocardial infarction on the death certificate because we do not do autopsies the way we did a generation ago. Most of the cases remain undetected.

We have a great place to intervene because approximately two out of every three cases of venous thromboembolism are actually acquired in the hospital. Working in the hospital, we have a chance to intervene. I like to think of prophylaxis like immunization. We have a chance to immunize our hospitalized patients against DVT and pulmonary embolism. Keep in mind that pulmonary embolism and DVT constitute the number-one preventable cause of death.

Despite everything being done, the incidence of venous thromboembolism in the hospital is actually rising. Why is it rising? It may partly be better detection and awareness, but there are other factors. Our patients are getting older, they have more co-morbid diseases, and we are able to treat cancer survivors much better, who are predisposed to venous thromboembolism. We will hear more from our final speaker about the important interactions between cancer and venous thromboembolism.

Of the 38 million patient discharges from the United States, it is estimated that over 21 million patients meet standard guideline criteria for prophylaxis. More medical than surgical patients meet the ACCP guidelines, but that is still millions of medical and millions of surgical patients.

A recently published study from Spencer at the University of Massachusetts in Worcester shows that, of nearly 1900 episodes of confirmed DVT and pulmonary embolism, three-quarters of the cases developed with the patients as outpatients. Does that mean that these patients were simply in the community and suddenly stricken with DVT or pulmonary embolism? Hardly.

Spencer's group went the extra mile and traced back what had happened to those patients over the prior ninety days. Almost half of them had been in the hospital or had had some surgical procedure, and of those patients, more than half of them did not receive adequate venous thromboembolism prophylaxis. This is a very important study.

What we do in the hospital has a rippling effect for at least the next three months. Even if we are hospital-based, we can control, to some extent, the rate of community-acquired DVT if we do assiduous and guideline-based prophylaxis of our patients.

This is not a problem only in the United States. The ENDORSE trial looked hospitals on five continents to determine how many patients are at risk and should be prophylaxed, according to the American College of Chest Physician guidelines. In addition, of those who should be prophylaxed, what percent actually receive prophylaxis in 32 countries, 358 hospitals and more than 68,000 patients.

Overall, only 50% of the patients who should have received prophylaxis did receive it. I think this is a big indictment of what is going on worldwide. Half the patients are not receiving prophylaxis.

I know there are a lot of surgeons here who run surgical intensive care units. We have vascular and general surgeons, and the surgeons are doing a better job than the internal medicine doctors. Of surgical patients, 59% received venous thromboembolism prophylaxis.

In contrast, only 40% of medical patients received prophylaxis. Particularly for internal medicine doctors, we have to not only practice what we preach, but also talk to our colleagues, medical students, and the residents to make sure they really understand the concept of prophylaxis.

ENDORSE concluded that while the prevalence of patients at risk for venous thromboembolism is high, the prophylaxis rate is quite low. We have to urgently implement new and better prophylaxis strategies. We need systems to assess the risk for each patient and provide appropriate prophylaxis, so we do not have to reinvent the wheel for every new patient.

Within the last month or two was a report from Amin, who studied nearly 200,000 medical service discharges from 227 hospitals across the United States. In patients who should have received prophylaxis, the rate was only 62%, meaning that we have a long way to go.

The evidence is here for pharmacologic prophylaxis. There are three excellent randomized, controlled, double-blind studies, all determining that prophylaxis with once-a-day, low molecular weight heparin or fondaparinux will cut in half the rate of DVT or pulmonary embolism without any significant increase in bleeding complications.

Here is another meta-analysis just published in Annals of Internal Medicine of nearly 20,000 medical patients in nine clinical trials. With routine prophylaxis, they found that we can reduce the rate of fatal pulmonary embolism by 62%. That is so significant. We can also cut in half the rate of DVT. Prophylaxis really does work.

At Brigham & Women's Hospital in Boston where I practice and underwent my training, there is a long tradition in prophylaxis and interest in pulmonary embolism. I thought we would have results in our own quality audits showing that we prophylaxed everybody. That was not the case. We were no better or worse than the other U.S. hospitals I am talking about.

So. A number of us decided to see if we could influence physician behavior in a randomized controlled trial. It is not really a trial of any particular drug; it is a trial of physician behavior.

We found 2506 patients at high risk of venous thromboembolism receiving zero prophylaxis at Brigham & Women's Hospital. They all should have been prophylaxed. Then we had the computer randomize them to either a single electronic alert, so that the doctor got a warning on the computer screen, or the patients would be randomized to no special intervention beyond the multiple seminars and signs we have, saying, "Please make sure you prophylax your patient." The primary endpoint of this trial was clinically diagnosed DVT or pulmonary embolism, symptomatic DVT or pulmonary embolism within ninety days after randomization.

How did we define "high-risk"? I constructed a point system and arbitrarily said four or more points means a patient is high-risk. Three points each for cancer, prior venous thromboembolism or hypercoagulability; two points for major surgery; and one point each for bed rest, advanced age, obesity, hormone replacement therapy, or oral contraceptive.

The electronic alert says, "The patient is at high-risk for DVT, according to our guidelines." So this assessment score is 6, but there are no antiembolism orders and the patient is not on any drug therapy either. It gave the doctor the choice of A, B or C.

Choice A directed doctors to the DVT prophylaxis order set. I would have thought 100% of the doctors would choose that and order prophylaxis. That was not the case.

Choice B directed doctors to a 35-page pdf file a fellow and I wrote on evidence-based prophylaxis. I thought this would appeal to our more cerebral docs who are interested in the evidence. Almost no one chose Choice B.

Choice C was to exit from this and get on with the day's work, which turned out to be the most popular choice. Only one out of three docs receiving this warning actually selected prophylaxis.

Nevertheless, there was something about warning the doctor that the patients who got more prophylaxis than other patients in the intervention group had freedom from DVT and pulmonary embolism. Over the course of the ninety days, the gap between the intervention group and the control group widened, so that by the end those in the control group with four or more risk points had an 8% likelihood of a symptomatic pulmonary embolism or DVT. In the intervention group, the rate was much lower.

In the intervention group, the total DVT rate was cut by 41%, and the rate of acute pulmonary embolism was reduced by 60%. This behavioral modification has a lot of effect on the doctors.

The alerts identified the patients at risk who were not receiving prophylaxis. They increased physicians' use of prophylaxis and reduced overall symptomatic venous thromboembolism rates by 41%.

This was a rather light-handed approach because there were no repercussions if the doctor paid no attention to the warning. Now, however, things are getting revved up a little bit. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) will look at this and determine if hospitals will remain accredited if venous thromboembolism prophylaxis isn't used. The National Quality Forum is working with JCAHO on performance measures that will be used by Medicare to withhold payments to hospitals with poor track records in prophylaxis.

New York is the most disclosing of all states in the United States about physician and hospital performance. In the same way I can look up any cardiac surgeon in New York to learn his or her thirty-day mortality rate for coronary artery bypass grafting, I can also see how each hospital in New York is doing, in terms of venous thromboembolism prophylaxis. The state grades them with one, two or three stars in terms of quality performance. So the system has already changed in New York.

In terms of performance measures, they started with the easy ones because most surgeons are already prophylaxing. In our study at Brigham & Women's, over 80% of the patients were medical patients, not surgical patients. Of the medical patients, about 80% of them had cancer. So the performance measures are already being followed with surgical patients, to a very large extent.

However, the pending risk assessment performance measures will include assessments for all patients within 24 hours of hospital admission, with an emphasis on patients transferring into the intensive care unit.

These surgical care improvement orders (SCIP) address whether venous thromboembolism prophylaxis was ordered and received. The hospitals have had to report their implementation of the SCIP measures since this past January. In 2008, there will be a 2% Medicare withholding for noncompliance. This may not seem like a big amount to withhold, but 2% could have a tremendous impact on budgeting for various parts of the hospital.

SAMUEL GOLDHABER, MD: Now it is my pleasure to introduce Ruth Morrison, who has been working with me in this field directly for the past twenty years. Ruth will tell us about preventing venous thromboembolism in hospitalized patients

RUTH B. MORRISON, RN, BSN, CVN: Thank you, Dr. Goldhaber. As Dr. Goldhaber mentioned, I will discuss preventing venous thromboembolism in hospitalized patients. As he said, it seems like the number of these patients keeps increasing.

To make my first case more personal, I am going to name her "Betty." Betty is 76 years of age. She has community-acquired pneumonia and has had no response to azithromycin. She has been hospitalized for the past six days. She comes up again further on down the road, so keep in mind her risk factors.

The order set reads for her that she has bathroom privileges, as well as visitation privileges. She also has dietary restrictions. She is written for antibiotics, and they did order venous thromboembolism prophylaxis.

There are different methods of venous thromboembolism prophylaxis. I will first go over the mechanical prophylaxis. There are graduated compression stockings, which actually increase venous blood flow and decrease venous stasis.

There are intermittent pneumatic compression devices, which also increase venous blood flow and activate the endogenous fibrinolysis. There are IVC filters, which are mechanical barriers that prevent pulmonary embolism. However, mechanical barriers do not always stop the thrombotic process. Patients often develop deep vein thrombosis of the legs, although it does prevent them from becoming pulmonary embolisms.

There is also pharmacologic prophylaxis, which includes unfractionated heparin, low molecular weight heparin, pentasaccharides, and warfarin. Mechanical and pharmacologic prophylaxis are often combined to prevent venous thromboembolism.

This is an example of graduated compression stockings, and you can see the proven pressure pattern. Various millimeters of mercury absolutely imitate the calf muscles and increase venous blood flow.

This is a picture of a patient wearing an intermittent pneumatic compression device. The patient wears the sleeves on both legs, and the pump is set next to the bed and intermittently squeezes the patient's legs to increase venous flow.

So we are back to Betty, our first case study, and they did order graduated compression stockings. As a reminder, she is 76 years old and has pneumonia.

Obviously, these are American College of Chest Physician guidelines for venous thromboembolism prophylaxis. The guidelines are recommended according to the clinical setting. For the general surgical patient, low-dose unfractionated heparin or low molecular weight heparin is recommended. For total hip or knee arthroplasty, low molecular weight heparin, fondaparinux or warfarin is recommended. For hip fracture surgery, the choices are fondaparinux, low molecular weight heparin, warfarin or low-dose unfractionated heparin.

Betty is one of these acutely ill medical patients suffering from respiratory disease, but other patients with additional risk factors are those with congestive heart failure and those that are confined to bed rest.

The PRINCE study randomized enoxaparin with unfractionated heparin for VTE prophylaxis in patients with heart failure and severe respiratory disease. The researchers randomized 665 patients with heart failure, severe respiratory disease, and patients that were on prolonged bed rest. They were confined to bed for more than sixteen hours a day.

They were randomized to enoxaparin, 40 mg, once daily for eight to twelve days, or unfractionated heparin, 5000 units, three times daily for eight to twelve days. The primary endpoint was VTE detection at less than or equal to one day after treatment, looking at safety.

If you look at this slide, you will see that the adverse events increased in the unfractionated heparin group. The adverse events for this trial were all-inclusive. They included pain at the injection site, hematomas, and elevated liver function studies. You have to remember that these patients received unfractionated heparin, three injections daily compared to the one injection.

Dr. Goldhaber briefly went over this. There are three trials of venous thromboembolism prophylaxis in the hospitalized medical patients. One is MEDENOX, the second one is PREVENT, and the third is ARTEMIS.

MEDENOX is a randomized trial in nine different countries and sixty centers. It was a randomized double-blind study of enoxaparin versus placebo in acutely ill medical patients. There were 1102 hospitalized patients with a projected hospital stay of greater than or equal to six days. They were immobilized less than three days and all over the age of forty.

These patients were randomized to enoxaparin 20 mg once daily, 40 mg one daily, or placebo, all for six to fourteen days. The primary endpoint was the detection of venous thromboembolism between days 1 and day 14 and the detection of venous thromboembolism between days 1 and 110.

There was very little difference, 14.9 to 15.0, between the placebo and enoxaparin 20 mg. However, the patients that received enoxaparin 40 mg subcutaneously once daily had over a 63% decrease in venous thromboembolism. Actually, it looks as though further into the study the benefit may have lasted longer.

In the MEDENOX, the safety, there was virtually no difference between the two treatment groups and were not scientifically significant.

The PREVENT trial was a randomized, double-blind study of dalteparin versus placebo for venous thromboembolism prophylaxis in acutely ill patients. Researchers randomized 3706 acutely ill medical patients who required greater than six days of hospitalization and less than or equal to three days of immobilization. Again, they were all over forty years old.

They were randomized to dalteparin, 5000 units, or placebo for fourteen days. The primary endpoint was a composite of venous thromboembolism and death at day 21 and day 90 and, of course, they also looked at safety.

Looking at the composite of the major hemorrhage, minor hemorrhage and thrombocytopenia, there was statistical significance in the difference between the placebo and the dalteparin group. However, with the composite endpoint, on day 21 and day 90, there was a 45% relative risk reduction, so that is very promising.

ARTEMIS is a randomized controlled trial of fondaparinux in older medical patients. Researchers randomized 849 acute medical illness patients who were immobilized greater than or equal to four days and their age was greater than sixty years old. These patients got a once-daily injection of fondaparinux, 2.5 mg, or a placebo, for six to fourteen days.

The endpoints were VTE diagnosed by venography for up to fifteen days. They also looked at bleeding and death. The relative risk reduction was 49.5% for the patients receiving fondaparinux.

In both cases, there was really no difference in safety.

This next study is pretty exciting, although it is not yet completed. The abstract was presented in July in Geneva, Switzerland, at the 21st Conference for Thrombosis and Hemostasis. It looks at extended venous thromboembolism prophylaxis in patients with acute medical illnesses.

They initially had 5105 hospitalized patients all over the age of 40 who were immobilized less than or equal to three days. Initially, they were all given enoxaparin 40 mg a day for six to fourteen days. They ended up randomizing 5039 patients to enoxaparin 40 mg a day, or a placebo, for 24 to 32 days. The endpoints were the incidence of VTE and mortality at six months and, of course, they looked at safety.

The composite of VTE and overall VTE reduction was greater than 50%, which they divided into asymptomatic and symptomatic DVT. Even out to six months, the results look very promising. There was one major bleed and some smaller, insignificant bleeds. The conclusions of EXCLAIM were that extended duration of enoxaparin significantly reduces the overall incidence of VTE in immobile patients with acute medical illnesses, when compared to a ten-day regimen. The extended duration of enoxaparin was associated with a significant increase in major bleeding, but this incidence was low. The relative risk reduction observed with extended duration was maintained at ninety days after randomization.

Once-daily injected anticoagulation prophylaxis in these three trials (this was before EXCLAIM) reduced DVT and PE by greater than or equal to a half without increasing major bleeding compared with placebo. Low molecular weight heparin is at least as effective as unfractionated heparin for venous thromboembolism prophylaxis. Finally, low molecular weight heparin prophylaxis can be safely administered over an extended period of time and definitely reduces the risk of venous thromboembolism.

Let’s return to our case study, Betty, who was prescribed graduated compression stockings and low molecular weight heparin, according to the ACCP guidelines. She did quite well.

She responded well to her antibiotics. The treatment with low molecular weight heparin prevented the occurrence of a thromboembolic event, and she was discharged uneventfully after fourteen days. In conclusion, venous thromboembolism is much easier and less expensive to prevent than to diagnose and treat. The ACCP guidelines recommend VTE prophylaxis in general surgical patients, those undergoing total hip arthroplasty, knee surgery, hip fracture surgery, and patients with acute medical illnesses. Once-daily injected anticoagulant prophylaxis reduces the incidence of VTE by greater than 50%, without increasing major bleeding compared to placebo.

SAMUEL GOLDHABER, MD: That was terrific, Ruth. I hope you are filling out comments and questions on your cards because that is going to be a fun part of this evening.

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SAMUEL GOLDHABER, MD: I would now like to introduce Dr. Sylvia McKean. Sylvia is one of this country's most-renowned hospitalists. Not only does she run a 27 hospitalist program at Brigham & Women's Hospital and at Faulkner Hospital, but she is very involved in the leadership of the Society for Hospital Medicine, where hospitalists are the most-growing specialty.

So, Sylvia, I want to welcome you to the program.

SYLVIA McKEAN, MD: Thank you.

Today I will discuss the methods for diagnosing venous thromboembolism in the hospitalized patient, as well as treatment goals for all patients who have venous thromboembolism. Finally, I will highlight our options for patients with deep venous thrombosis and for patients with pulmonary embolism.

Our first case study is “Sam.” He is 55 years of age, and all his jogging caused him to need a hip replacement. He has been immobilized for five days. Now, he has swollen legs, which may be caused by a number of factors. It could be because he received a lot of fluids on the orthopedic service. He may also have had a touch of congestive heart failure. He may have varicose veins, or it is possible that he just has some swelling because of his surgery. Nevertheless, he is at very high risk of developing a deep venous thrombosis.

After reviewing his orders, it was recommended that he be out of bed with assistance of a physical therapist, so very aggressive with the ortho patients. There are visitation privileges, but his wife was traveling in Europe and did not come to see him. His pain medication was as needed and, of course, DVT prophylaxis was ordered.

So you are very concerned because this is a prominent physician that you will see, and you do not want to overlook a deep venous thrombosis in Sam. You have a choice of some studies that you can perform. There is the D-dimer assay, but the D-dimer is likely to be elevated in a hospitalized patient, especially one who has just had surgery.

There is also compression ultrasound, which is preferred in American hospitals because it is readily available, relatively easy to perform, noninvasive and relatively inexpensive. However, it is not very helpful for diagnosing asymptomatic deep venous thrombosis. If you have an inexperienced vascular technician performing the study, a deep venous thrombosis could be overlooked.

We also have contrast CT venography. However, in many hospitals, this is not routinely performed. If it is performed, there are only a few cuts taken of the pelvic, iliac, and femoral veins. Of course, deep venous thrombosis can be missed. Contrast venography and MR of the venous system are other options.

For pulmonary emboli, we have the same tests as we do for deep venous thrombosis. If we identify a clot in the legs, it really does not alter management to do yet another test. We would presumably treat the patient appropriately for pulmonary embolism and a DVT.

We have MRI, ventilation perfusion scanning, pulmonary angiography and chest CT using a PE protocol. Now, this is preferred over ventilation perfusion scanning for most patients because most patients in the hospital do not have normal chest X-rays. In addition, most patients who undergo a VT scan will have an indeterminant reading, which really is not enough for us to make a diagnosis.

The D-dimer assay is a easy-to-perform blood test and is available in almost every hospital. It also has a very high negative predictive value, so if a healthy person with no medical problems comes to your emergency room with complaints that make you worry about VTE, a D-dimer can be extremely useful in ruling out a deep venous thrombosis.

However, in a patient who has high risk for a DVT and PE, especially a postoperative patient, the D-dimer is not helpful, even if positive. You have to order additional diagnostic tests to determine whether your clinical suspicion for VTE is indeed correct.

Contrast venography is something that we have had for years and really is the gold standard. It can distinguish clots from other obstructions in the veins. It helps us evaluate the deep venous system, the valve, and it can be used for people undergoing coronary artery bypass grafting. However, it is expensive, invasive and probably painful every time it is performed.

We have available now CT scanning using a PE protocol and, as you can see here, it is very easy to identify thrombus. This is a nice image here, with the thrombus here and here. The problem with this modality is that there are limitations.

There can be subjective interpretations that differ from one radiologist to another. In addition, the quality of the scan can vary depending on whether the patient is obese or not or the timing of the contrast bolus. Also, the image quality can be reduced in patients with coexisting cardiopulmonary disorders. Detection of small, isolated clots can also be missed in the periphery.

However, it is noninvasive, easy to perform, and cost-effective. It is often the initial test for patients suspected of having pulmonary embolism in the hospital setting. This is, of course, dependent on their renal sufficiency.

Pulmonary angiography is the gold standard. This is the most reliable method for diagnosing acute pulmonary embolism. It can identify peripheral or chronic emboli, and it detects emboli in the vessels along the axial plane. However, it is invasive, difficult to perform, and expensive. I suspect if I were in the hospital, I would prefer not to undergo a pulmonary angiogram if I could avoid it.

I want to return to our case study of Sam. He undergoes compression ultrasound of his lower extremities, and it is confirmed that he has deep venous thrombosis. What are we going to do for him?

What are the treatment goals for patients with deep venous thrombosis? First, we do not want them to die. We want to prevent thrombus extension, embolization, and prevent early and late recurrence. We also want to prevent any disabling postthrombotic syndrome; often doctors in the hospital do not see it because it becomes an outpatient problem which may be long after the primary event. In addition, we want to prevent proximal conversion in the case of calf DVT.

It is really beyond the scope of this talk today to discuss thrombolytic strategies to reestablish venous patency, but that is another treatment goal in an evolving area of medicine.

We are going to talk about anticoagulation. We are not going to discuss pharmacologic lysis in the case of DVT, nor will we discuss mechanical removal of clots, either in the cath lab, the OR or even the indications for IVC filters.

So we have Sam with a deep venous thrombosis, and he is all set to leave the hospital. This was hospital day 5. According to his orthopedic guideline, he should be back home now. What should we be doing? Can he go into the outpatient setting with low molecular weight heparin? Does he need to stay in the hospital another 24 hours? Does he need to remain in the hospital, possibly receiving unfractionated heparin?

In thinking about outpatient treatment for deep venous thrombosis, you need to think of which patients cannot safely go home. First of all, you think about the pregnant patient. If a patient comes in with a DVT who is pregnant, you really want to make sure the fetus is viable and get high-risk OB involved. You also want to have time to talk to the patient and the family. That usually takes at least a day. That person would not go home from the emergency room.

Other patients may have illnesses that would cause you to consider admission to the hospital. Perhaps you feel the patient does not understand your instructions, so you would need time for patient and family education. You might also hospitalize somebody if they could not obtain low molecular weight heparin in the outpatient setting, either because they had no insurance or their insurance plan did not cover it. Finally, you may have concerns about the patient, regarding the possibility of falling, bleeding, or if they are otherwise unable to manage because they are blind or cognitively impaired.

Now we will shift gears and talk about acute pulmonary embolism. What should be the treatment? The first thing to do is perform a risk assessment. Consider a patient who is hypotensive, with massive thromboembolism and shock. That is a very complicated situation, and you need to obtain appropriate consultation immediately. Perhaps cardiac surgery will be part of it, and you will consider thrombolysis. If there is a contraindication to thrombolysis, then you have to think about surgical embolectomy.

However, the majority of patients with acute pulmonary embolism are hemodynamically stable, fortunately, except for the 10% that die in the hospital that Sam talked about. For those patients, you want to consider right ventricular compromise.

First of all, you have ordered a chest CT, PE protocol, and the result has come back positive for acute pulmonary embolism. You want to see the size of the right ventricle on that CAT scan that you have already performed. If the radiologist measures it out and it is larger than the left ventricle, or even if it is the same size as the left ventricle, that is a poor prognostic sign. That indicates right ventricular enlargement.

We will now discuss obtaining cardiac enzymes. An elevated troponin would indicate microinfarction of the right ventricle. An echo gives you pressure measurements of the right ventricle and also of the pulmonary artery. Then we have BNP, which could indicate right ventricular stress if elevated.

What are the guidelines that we have at this time? The key is that we have to treat these patients immediately, whether they have a DVT or a PE. You can then go on and get the appropriate tests to confirm it, but if you have a high index of suspicion that they have a DVT or a PE, initiate immediate therapy and then obtain the appropriate study.

Currently, the immediate therapy is either unfractionated heparin or low molecular weight heparin, as well as adding warfarin. Long-term therapy for DVT indicates warfarin or low molecular weight heparin. We are very fortunate because a speaker later is going to talk about oncology patients and what they should receive.

What are the advantages of low molecular weight heparin over unfractionated heparin? We know that the pharmacology, is much more complicated for unfractionated heparin. You cannot predict the right dose. There is nonspecific binding affinity to factor Xa. It has unpredictable pharmacokinetics.

If you use subcutaneous unfractionated heparin to treat a DVT or a PE, you have to administer b.i.d. or t.i.d. Most people use continuous unfractionated heparin in an IV infusion, but it requires a lot of laboratory monitoring. This is in contrast to low molecular weight heparin, which does not require laboratory monitoring and can be prescribed in the outpatient setting. It has been shown that it is just as safe and effective to treat those with DVT in the outpatient setting as in the inpatient setting. It is important that the patients are properly selected, but there is overall greater patient and family satisfaction.

Looking at once-daily or twice-daily low molecular weight heparin compared to unfractionated heparin for the treatment of venous thromboembolism, there were 900 patients. They had acute venous thromboembolism. Their age was greater than eighteen years and there were no contraindications to pharmacologic therapy. They had adequate renal function, which is very important. However, it is beyond the scope of this talk to go over special populations.

To highlight, we are not going to talk about patients with renal insufficiency, which means creatinine clearances less than or equal to 30 mL/minute. We are also not going to talk about patients who are morbidly obese, patients with HIT, or heparin-induced thrombocytopenia with thrombosis. Excluding those patients today, we will talk about the treatment.

These 900 patients were randomized to either receive unfractionated heparin as a bolus followed by the infusion and then warfarin with a target INR between 2 and 3 or enoxaparin, 1 mg/kg twice a day subcutaneously, and then warfarin with the same target INR or enoxaparin, 1.5 mg/kg subcutaneously once a day and warfarin. The endpoints were venous thromboembolism and also safety.

Please look at twice-daily low molecular weight heparin. Based on the results of the study, we would be more inclined to go with twice-daily low molecular weight heparin.

The MATISSE study looked at fondaparinux and compared it to enoxaparin for the initial treatment of deep venous thrombosis. Fondaparinux is not a low molecular weight heparin. This is a factor Xa inhibitor. It is a pentasaccharide, so it is different than enoxaparin.

There were 2205 patients in this study. They were diagnosed with acute deep venous thrombosis. They had to be over 18 years of age with no contraindications to anticoagulant therapy. Fondaparinux was compared to enoxaparin with the endpoints of venous thromboembolism, bleeding and death.

Fondaparinux is dosed according to weight; if you are less than 50 kg, you receive 5 mg. If you are between 50 and 100 kg, you receive 7.5 mg. You receive 10 mg if you are greater than 100 kg. This dosing is different than with low molecular weight heparin.

This slide shows that fondaparinux and enoxaparin are roughly equivalent, in terms of preventing recurrent venous thromboembolism in patients with their first DVT.

Comparing adverse events, again, in terms of safety, there does not appear to be much difference.

To summarize, unfractionated heparin and low molecular weight heparin are suitable treatments for patients with venous thromboembolism, and they appear to have similar safety profiles. The incidence of major bleeding was lower in patients treated with low molecular weight heparin than in those who were treated with unfractionated heparin. Finally, fondaparinux is non-inferior to low molecular weight heparin.

Going back to this patient, Sam, the treatment prescribed was low molecular weight heparin and warfarin, and he was able to be discharged to home.

The patient recovered from a total hip arthroplasty without additional complications. Warfarin therapy was continued for three months after discharge. The duration of therapy was three months because it was felt that this was a complication of surgery, so there was an identifiable cause for this patient's DVT.

If, however, he had a second DVT, or if he had a known hypercoagulable state, or if there was not a surgical situation, the duration of treatments would have been different.

To summarize, there are several methods for diagnosing venous thromboembolism in the hospitalized patient. I think most people would start with compression ultrasound for those patients for whom they suspect has a deep venous thrombosis of the lower extremities. For patients with pulmonary embolism, most clinicians would start with a spiral CT using a PE protocol, assuming the patient’s renal function was normal.

The ACCP guidelines recommend unfractionated heparin or low molecular weight heparin and/or warfarin for the immediate treatment of venous thromboembolism in hospitalized patients. The appropriate course of treatment depends on risk stratification of the patients and may dictate whether you can treat them as an inpatient or outpatient.

SAMUEL GOLDHABER, MD: Thank you, Sylvia. I am glad that that fictional patient survived the hospitalization without any undue complications.

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We have been giving Dr. Jay Groce a big buildup, saying how important cancer is and talking about the cancer patients not getting prophylaxis. This is a very fast-moving field and Dr. Groce has national recognition as one of the premier academic pharmacists involved in public policy, anticoagulation, and pharmacoeconomics. When we have a really tough case, he is definitely a go-to person. He will now talk to us about managing VTE in patients with cancer.

JAMES B. GROCE, III, PharmD, CACP: Thank you very much, Dr. Goldhaber, for the opportunity to be here to discuss this important topic, managing VTE in patients with cancer.

When we look at the incidence of cancer in patients who have acute venous thromboembolism, there are really three subgroups of patients. There are those patients who present to hospital with acute diagnosis of VTE, DVT or pulmonary embolism with a known cancer or other risk factors and this represents between 15 and 20% of the patient population, relative to the incidence.

Similarly, we have patients who present to our hospitals with no known risk factors prior to development of their venous embolic episode. Interestingly, it can be the first declaration of oncologic disease and, at that time, cancer being diagnosed upon presentation of their index VTE, DVT or PE at a rate of between 2 and 5%.

Finally, there are patients who present to our practice with unexplained or idiopathic VTE and subsequent cancer followup or diagnosis. In an appropriate diagnostic strategy for such patients who do present with idiopathic VTE, cancer is diagnosed or detected during followup at roughly 5 to 10% of the time.

This is very important information, published in Circulation 2003 by Agnes Lee.

We look at the incidence of cancer in patients who have acute VTE and we know that patients who have cancer are at a higher risk of recurrence of their likelihood of having VTE. They are also likely to have an increased rate of bleeding on the anticoagulant or antithrombotic drug therapies, as well as a higher rate of risk of dying than patients who present to hospital without oncologic disease. We know, too, that VTE is the second-leading cause of death in hospitalized oncology patients.

Twenty percent of all VTE cases occur in patients with cancer, approximately 0.5% of patients with cancer will have symptomatic disease, and less than 50% have VTE at autopsy. The highest incidence of VTE is in those patients who have mucinous carcinomas of the pancreas, GI tract, lung and ovarian cancer. Central venous catheters also contribute to the likelihood of developing a VTE, particularly in an upper extremity. We are finding that increasing within our own patient population. Some of the newer cytotoxic chemotherapeutic agents promote the release of procoagulant factors and cytokines as well as activate the clotting cascade. This puts a higher percentage of patients with oncologic disease at risk.

VTE incidence in various oncology settings is depicted on this slide, and you see an increasing rate as we progress down this slide. By the time patients have gliomas, multiple myeloma, renal cell carcinoma and maybe solid tumor, we find an increased incidence of VTE. In addition to the oncologic disease itself, there has been suggestion in the literature that some of these newer agents used to treat these patients might account for the higher incidence in this patient population, not the least of which would be thalidomide.

This particular graph demonstrates the problem that patients face when they come to our hospitals and that we face as clinicians in caring for this patient population. This particular graph by Levitan, et al., appeared in Medicine in 1999. The probability of dying when presenting to hospital is clearly lessened for patients with nonmalignant disease who actually have venous embolic disease, DVT or PE and concomitant malignant disease. There, of course, the probability of death is quite striking, relative to the other disease states alone.

We are going to look at a case, and since this case involves oncology, it is going to remain sine nomine; I am not going to assign any names. This is a female patient, age 56, postmenopausal, with stage IV breast cancer. Estrogen-negative. Disease progression with taxane-based chemotherapy was seen by the oncologist seeing the patient. The patient was found to have confirmed deep vein thrombosis by contrast venography.

The orders for this patient at this time include doublet chemotherapy, this regimen of capecitabine and gemcitabine. The patient was put to bed rest in the hospital, and she was to be prophylaxed appropriately for the likelihood of DVT or PE in this very high-risk patient population.

That brings us next to the guidelines. The National Comprehensive Cancer Network (NCCN) have guidelines for venous thromboembolic prophylaxis in patients who have cancer within our hospitals. They advocate for low molecular weight heparin. In one, they used dalteparin, 5000 IU subcutaneously administered once daily, or enoxaparin, 40 mg subcutaneously administered once daily, or tinzaparin, 4500 IU once daily or can actually be weight-based at 75 IU/kg per day and, again, administered subcutaneously. They also suggest the role of the pentasaccharide, fondaparinux, at a fixed dose of 2.5 mg, once daily, subcutaneously administered, or the potential role of unfractionated heparin, 5000 units administered probably in a b.i.d. or t.i.d. fashion for this very high-risk patient population.

Guidelines for the immediate treatment of a patient who has oncologic disease and is diagnosed with VTE, DVT or PE or concomitant disease, may advocate for subcutaneous low molecular weight heparin with concomitant warfarin therapy and treatment doses now. It is important to distinguish between the treatment doses versus those used for prophylaxis, but a treatment dose of dalteparin would be 200 units/kg once daily or enoxaparin, 1 mg/kg subcu administered b.i.d. or Q12 hours, or tinzaparin, 175 units subcutaneously administered once daily.

I want to add the role of the pentasaccharide administered subcutaneously, fondaparinux with concomitant warfarin therapy. This would be individualized based upon the patient's body weight. A 5 mg dose per day for those patients weighing less than 50 kg; 7.5 mg subcutaneously once daily for those weighing between 50 and 100 kg; and for those patients weighing greater than 100 kg, a 10 mg subcutaneous, once-daily dose would be administered.

Of course, you are also given the option of continuous infusion unfractionated heparin with concomitant warfarin. This should really be weight-based dosing, aPTT-guided. Additionally, 80 units/kg load with an 18 unit/kg per hour continuous infusion targeting the aPTT value between 2 and roughly 3 times the control rate for your clinical practice in your hospital.

In addition, for patients who have long-term sequelae of their initial or indexed VTE and now need continued prophylaxis against recurrence of that, these new guidelines by NCCN advocate for low molecular weight heparin monotherapy in this very high-risk patient population. In subsequent slides, we will discuss the reasons why this new guideline has been promulgated by this particular body as well as the American College of Chest Physicians.

In this very high-risk patient population, for our efforts for continued prophylaxis against VTE, they do advocate for low molecular weight heparin monotherapy for patients who may have proximal DVT or PE. This is to prevent recurrence of VTE in patients with advanced or metastatic disease.

Warfarin may be given between 2.5 and 5 mg per day initially and then subsequent dosing based upon the INR value, targeting a range of between 2 to 3 for your INR value. In the setting of oncologic disease, DVT should be treated for three to six months. If we have the oncology patient who has VTE, specifically pulmonary embolism, we now would treat that patient for six to twelve months. Duration of therapy is very important for this continued high-risk patient population.

The American College of Chest Physicians most recently published their guidelines as a supplement to the journal, Chest, in 2004 and I think most of us eagerly await the new guidelines that will be published in early spring of 2008 to really address several new issues and continue to give us guidance as it related to prevention, treatment and diagnosis of VTE.

The ACCP guidelines relative to cancer patients for prevention of VTE cite that when patients on our service undergo surgical procedures, those patients should receive prophylaxis that is appropriate for their current risk state. This carries the highest recommendation by Chest, that of a 1A recommendation, so this was from randomized prospective controlled trials.

Bedridden hospitalized patients with an acute medical illness should receive prophylaxis that is appropriate for their current risk state; again, this is a 1A recommendation. Then they cite that prophylaxis should not be routinely used to prevent thrombosis related to long-term indwelling central venous catheters. That is an important consideration and a change from the previous 2001 and perhaps even earlier supplements to the journal, Chest. That, though, is a 2B recommendation. Specifically, they cite that low molecular weight heparins should not be used, nor are the vitamin K antagonists or oral anticoagulants, warfarin recommended. That is given a level 1B recommendation.

Let’s transition to the necessity of having to treat these patients who now have oncologic disease with VTE. For patients with deep vein thrombosis and cancer, the recommendation is for low molecular weight heparin for the first three to six months as monotherapy. The recommendation is three to six months as monotherapy for patients who have concomitant VTE and oncologic disease. Then a long-term therapy is continued for that patient after the initial three to six months of monotherapy with low molecular weight heparin. This is a 1A recommendation.

For patients who have pulmonary embolism and cancer, low molecular weight heparin for the first three to six months of long-term therapy is recommended, and it will have a 1A recommendation. These patients should then continue their anticoagulant therapy indefinitely or until such time that the cancer is resolved; this is cited as a 1C recommendation.

That brings us back to this issue, "Why now have these two different organizations come out with recommendations suggesting the use of low molecular weight heparins as monotherapy?" That gives us pause to reflect over some of the problems many of us have had in regulating this specific patient population with the role of the oral anticoagulant or antithrombotic agent, that of warfarin.

The coumarins (an example, again, warfarin) we know are difficult to monitor in patients who have oncologic disease. In many instances, when patients are in the hospital, we need to have venous access for procedures with these patients. This can be an important factor for managing this patient population appropriately. Certainly it is an area of not only drug-drug interactions but drug-food interactions as well.

Frequent treatment interruptions happened often in our hospitals in patients who have active cancer disease as well as concomitant VTE. In some instances, these interruptions may be necessary due to our chemotherapeutic agents which cause platelet count nadir in these patients. This results in profound thrombocytopenia, putting them at marked increased risk of bleeding. This is problematic as such patients often undergo surgical procedures.

Warfarin resistance can lead to the risk of recurrence of VTE and bleeding complications in patients with cancer, as we continue to push that dose of warfarin higher and higher.

The next slide is entitled "Anticoagulations -- Anticoagulants Do Not Just Prevent Clots in Patients with Cancer." This particular citation published in the Journal of Clinical Oncology in 2005 really spoke to the potential role of low molecular weight heparins for the antiangiogenesis effect. This was a study of 302 patients who had metastasized disease or locally advanced solid tumors with no venous thromboembolism. 90% of these patients had metastatic disease.

They were given nadroparin, a low molecular weight heparin, subcutaneously twice daily for fourteen days and followed once daily for four weeks. Then they continued to follow this patient population for outcomes through twelve months.

The results revealed the median survival was 6.6 months in the placebo group and eight months in the nadroparin group. This was found to be statistically significant for this patient population. The advantage was even more pronounced among patients with a life expectancy of six months or longer, the median survival being 9.4 months versus 15.4 months for the patient who received the low molecular weight heparin. Risk of major bleeding was not statistically significantly increased.

These authors concluded that low molecular weight heparins interfere with angiogenesis, adhesion of cancer cells to the vascular endothelium and the potential of invasion.

So we are back to our patient now in Case 3. Since the patient has now been diagnosed with VTE, we have to institute an appropriate form of immediate treatment for your venous embolic episode. Warfarin could be administered with concomitant low molecular weight heparin for the patient.

That brings us to some of the clinical trials. It provides these guidelines for the immediate treatments. I want to emphasize immediate treatment because many of these patients are subsequently discharged. We will talk about some of those very important clinical trials as well.

The CLOT trial looked at low molecular weight heparin versus a coumarin to prevent recurrence of VTE in patients with cancer. 676 patients with active malignancy and newly diagnosed VTE, were randomized to receive dalteparin 200 IU/kg once daily for five to seven days with concomitant Coumadin therapy, maintaining their INR between 2 to 3. The initial dose these investigators chose is 2.5 mg of Coumadin once daily. The second group of patients was randomized to dalteparin, 200 IU/kg once daily for one month. Then they reduced the dose by 25% to a 150 international unit/kg dose, once daily administered, for the next five months for a completion total date of six months therapy. They looked at the very important clinical endpoints of the incidence of recurrence of VTE during the study period as well as hemorrhagic complications.

There was a statistically significant reduction and, of course, it was clinically significant for those patients who had received monotherapy with low molecular weight heparin in this particular trial of dalteparin. There was an 8% incidence of recurrence of VTE versus 15.8% for those who had received concomitant drug therapy, that of dalteparin plus Coumadin.

Relative to the important issue of safety in this particular clinical trial, there was found to be no statistical difference for the endpoints of any major bleeding or six-month mortality.

A trial by Steve Deitcher, et al., published in Clinical Applications in Thrombosis and Hemostasis in 2006, the ONCENOX trial, was a randomized, open-label study of enoxaparin alone versus enoxaparin with warfarin for VTE patients with oncologic disease. The 102 patients, again, were age 18 or greater, had histologically or cytologically confirmed cancer and acute VTE.

They were then randomized to one of three different treatment strategies. The first received enoxaparin 1.0 mg/kg b.i.d. for five days, and then there was a dose reduction to 1 mg/kg once daily for an additional 175 days. The second group received enoxaparin 1 mg/kg b.i.d. for five days, and then reduced to 1.5 mg/kg once daily for 175 days. The last group received enoxaparin 1.0 mg/kg b.i.d. for five days with concomitant warfarin, maintaining their INR value of between 2 and 3 for 180 days. They looked at the clinical endpoints of compliance to this regimen or any of the three of these regimens, efficacy and safety.

The results relative to VTE incidence or that of efficacy cited the enoxaparin 1 mg/kg group of patients had a 6.9% incidence rate. For the 1.5 mg/kg once daily, a higher dose, a 6.3% incidence and, in those patients who had received warfarin, there was a 10% incidence of recurrence of VTE.

On the safety side, relative to Dr. Deitcher's study, there was found to be no statistically significant difference for being randomized to the 1 mg/kg dose of enoxaparin versus the 1.5 mg/kg once-daily dose versus that of warfarin. This was a long-term clinical trial, after the acute initial treatment of patients who had oncologic disease.

Another study, the Main-Lite cancer trial, was performed by Dr. Russell Hull and published in the American Journal of Medicine in 2006. It was a study of long-term low molecular weight heparin versus usual care in proximal-vein thrombosis in oncologic patients.

They enrolled 200 patients, one group of which were randomized to tinzaparin, a low molecular weight heparin at 175 IU/kg once daily for three months. The second group was randomized to receive unfractionated heparin, a 5000 IU bolus and then 1000 units of heparin. There was the usual care with respect to heparin therapy, not weight-based. In this patient population, they received concomitant warfarin therapy with doses that ranged between 5 and 10 mg by mouth once daily, adjusted to an INR between 2 and 3 for three months. They also looked at the endpoints of recurrence of VTE or death at three and twelve months.

The findings by Dr. Hull and his group were that the VTE at three months was not statistically significantly different. At twelve months, however, the VTE rate was statistically significantly reduced, favoring the role of monotherapy with the low molecular weight heparin versus that of usual care of unfractionated heparin with concomitant warfarin therapy.

Major bleeding, minor bleeding, and death at three and twelve months were found not to be statistically significantly different.

In summary, low molecular weight heparins are well tolerated in patients with oncologic disease or cancer. Low molecular weight heparin appears to be more effective than warfarin in reducing the risk of recurrence of VTE in patients without increasing the risk of bleeding. Larger studies are needed to confirm these observations and continue to examine this patient population.

For our case study, the patient did receive immediate treatment for deep vein thrombosis with warfarin then low molecular weight heparin from their physician. For continued prophylaxis against recurrence, it is important to transition the patient onto long-term treatment with a low molecular weight heparin as monotherapy.

No recurrence of DVT was observed in the patient at six months after initiation of treatment. Sadly, the patient passed away shortly thereafter due to complications from their breast cancer.

Patients with cancer who are undergoing chemotherapy are at very high risk for developing VTE. Long-term low molecular weight heparin appears to be more effective than warfarin for preventing recurrence of VTE in patients with cancer and has a lower risk of bleeding.

I will now ask Dr. Goldhaber to open up the Q&A session at this time. Thank you very much.

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SAMUEL GOLDHABER, MD: Thank you for that learned talk.

SAMUEL GOLDHABER, MD: While our panel is assembling, I will say that we are getting a number of questions about pregnancy. I will ask Ruth, "Can you use low molecular weight heparin in the pregnant patient?"

RUTH B. MORRISON, RN, BSN, CVN: Absolutely. For a pregnant woman with a history of DVT or pulmonary embolism, for prophylaxis, we give 40 mg of enoxaparin subcutaneously once daily. For treatment of DVT or pulmonary embolism, we would give a weight-adjusted dose split into two doses daily.

SAMUEL GOLDHABER, MD: This question deals with a 21-year-old patient, Sylvia, who is three months pregnant and did not receive prophylaxis after being diagnosed with a pulmonary embolism and DVT. How do you manage her?

SYLVIA McKEAN, MD: If you do not treat her, she could potentially die, so I would treat her with full dose low molecular weight heparin in the hospital setting.

SAMUEL GOLDHABER, MD: Full dose. Jay, any comment on that?

JAMES B. GROCE, III, PharmD, CACP: I think there are some important pharmacologic issues as well as clinically important issues that we need to remember. The reason that you hear low molecular weight heparin cited solely as a monotherapy relates back to the role of warfarin in this pregnant woman. We know that it carries a pregnancy category rating X by FDA and should not be used in the setting of pregnant women.

If you have a woman of childbearing age who presents at the hospital with a deep vein thrombosis or pulmonary embolism, before initiating warfarin therapy, it may bode well for us to get a serum pregnancy test to make certain that she is not pregnant before commencing warfarin therapy. That relates back to the issue of why we would use monotherapy of low molecular weight heparin.

Low molecular weight heparin has a pregnancy category rating of B for treating pregnant women with VTE.

SAMUEL GOLDHABER, MD: Sylvia, I assume, as a hospitalist, you transfer many bedridden patients from the hospital to the nursing home. Should we use medication to prevent DVT?

SYLVIA McKEAN, MD: That is a very good question, and the answer is yes. In terms of nursing homes and skilled nursing facilities, it is a challenge if low molecular weight heparin is more expensive than other modalities. This can be a problem, in terms of financial reimbursements, but the extended prophylaxis does save lives. For most of these patients, we transition from the hospital to a skilled nursing facility a skill set.

SAMUEL GOLDHABER, MD: Do you write orders?

SYLVIA McKEAN, MD: I communicate with the receiving doctor because different facilities may have different low molecular weight heparins on formulary; I do not want to write an order for something they do not have. The communication piece is very important, and there may be questions as to how long should the person receive pharmacologic prophylaxis.

SAMUEL GOLDHABER, MD: What about the 27 hospitalists working for you? Did they say, "The patient is leaving the hospital and the guidelines are for hospitalized patients, so we do not need to prophylax any more"?

SYLVIA McKEAN, MD: Well, as you know from your wonderful DVT free registry, half of these patients develop the DVT after they leave the hospital. Therefore, the patients are still at high risk, and we should communicate that to the receiving doctor.

SAMUEL GOLDHABER, MD: Ruth, can we use unfractionated heparin for knee and hip surgery patients for DVT prophylaxis?

RUTH B. MORRISON, RN, BSN, CVN: We do not.

SAMUEL GOLDHABER, MD: We do not use it because the studies don't show that it is useful. However, that gets us then we get into a policy issue. Some insurance companies apparently do not pay for low molecular weight heparin, so what should a healthcare professional do under these circumstances? Jay, do you have any thoughts on this?

JAMES B. GROCE, III, PharmD, CACP: I would distinguish whether they pay for it in the inpatient acute care setting versus the outpatient setting. This is another example where you have to invoke the case manager within your healthcare system or hospital to be an advocate for the patient. They are also your advocate to make sure that the right thing is done for your patient. In many instances, by placing the required call, we can get the healthcare providers or the insurers, to appropriately reimburse these drugs, certainly in the inpatient setting. I have never heard any controversy regarding that.

Even in the outpatient setting, with a well-placed call by case management, often we can get patients reimbursed for the drugs. This includes Medicare Part D for the elder patient population, which is now covered relative to the new guidelines. This was an important barrier to overcome relative to Medicare Part D.

SAMUEL GOLDHABER, MD: Sylvia, how often will you screen a patient with unexplained venous thromboembolism for cancer? What diagnostic tools will you use for men compared with women?

SYLVIA McKEAN, MD: My understanding of the question, Sam, is "What type of screening would I do for somebody who appears on my doorstep with a new deep venous thrombosis?"

SAMUEL GOLDHABER, MD: In your hospital service.

SYLVIA McKEAN, MD: Right. First, I look at the situation. Is this hospital-acquired deep venous thrombosis? If it is, you do not need to do any additional screening beyond what is recommended by the American Cancer Society for the age group and gender.

SAMUEL GOLDHABER, MD: Okay. Let's says the patient comes from out of hospital.

SYLVIA McKEAN, MD: There is no substitution for a very careful history and physical examination. At the very least, I would obtain a chest X-ray and, for women, a mammogram and a gynecologic exam. If there was a family history of ovarian and breast cancer, for example, there might even be further testing. It has to be somewhat individualized. Certainly, you would also want to perform a prostate exam, a CBC, and a blood profile.

SAMUEL GOLDHABER, MD: Mm-hm. It seems to me that by the time the patient comes up from the emergency department, they have already had their chest CT. This allows you to find small lung cancers and other cancers that way as the CT goes down to the adrenals. Do you get the abdominal or pelvic CT scan?

SYLVIA McKEAN, MD: I have.

SAMUEL GOLDHABER, MD: Have you in the patients who come from home?

SYLVIA McKEAN, MD: I have not been doing that. In a man, I do a testicular exam. But I have not been obtaining total-body CAT scans.

SAMUEL GOLDHABER, MD: Ruth?

RUTH B. MORRISON, RN, BSN, CVN: In the outpatient setting, we just make sure that they have had all their screening done that is age-appropriate. For VTE prophylaxis for a certain age group, this may mean a colonoscopy, mammogram, or Pap smear.

SAMUEL GOLDHABER, MD: What are our thoughts about the population defined here as greater than 85 years old, in the management of venous thromboembolism, PE and DVT? Since this population has a higher risk of bleeding and a higher risk of falling, how do we balance all these things?

RUTH B. MORRISON, RN, BSN, CVN: We have a lot of older people in our anticoagulation service, and I think you have to see each one of them individually. We have octogenarians that are driving, taking good care of themselves, some have just stopped working, as a matter of fact. They are at very low risk for bleeds, usually, if they are that independent. We do, however, have patients that fall frequently, and I think you have to watch those people more frequently and have them come in for their INRs. You may want to keep their INRs target a little lower than normal and just keep a close eye on them.

SYLVIA McKEAN, MD: That is especially true the first month of therapy.

RUTH B. MORRISON, RN, BSN, CVN: Yes.

SAMUEL GOLDHABER, MD: I have a question for Jay. This participant lists three doses of aspirin, 81 mg, 150 mg and 325 mg. In patients receiving these three different dosing regimens of aspirin daily, how safe is surgery with respect to bleeding?

JAMES B. GROCE, III, PharmD, CACP: I have to rely upon my experience of observation. Not being a physician, that is observation of the practice of our physicians and surgeons, particularly in my location. Typically, if they can stop the aspirin, regardless of the dose, the antiplatelet effect lasts for about seven days. The surgeons are taking their patients off of aspirin for seven to ten days prior to a major surgery.

I do not think it is really a dose phenomenon, but simply the role of aspirin for its antiplatelet effect. At least in our community, the standard is to have that patient off of aspirin for about seven to ten days. There are instances that patients come to hospital and are not afforded the luxury of having seven to ten days. In that case, the patient goes to surgery, but we have to be aware of the potential increased risk of bleeding from the antiplatelet effect of the role of aspirin.

SAMUEL GOLDHABER, MD: A related question is "How soon do you have to stop Plavix 75 mg daily prior to major surgery?" Just to remind you that President Bill Clinton was in a situation where he was receiving Plavix in New York, and there were a lot of healthcare people asking how soon he could undergo coronary artery bypass grafting.

JAMES B. GROCE, III, PharmD, CACP: I am not a cardiovascular-thoracic surgeon, an internist or a physician, so I rely on what I see in our own clinical setting. In Greensboro, the issue with Plavix is addressed the same way. If we can stop the role of the clopidogrel in an elective patient, then we try to do that. If it is an emergent procedure, then we cannot stop the clopidogrel. I can remember in surgical grand rounds where they said, "We welcome your patient to our operating room, and we will do all the things that we typically do to try to control the role of bleeding, but recall it is an emergent situation."

I think there was great controversy over how long President Clinton did wait. I think there was a delay, if I remember correctly.

FEMALE SPEAKER: Four days.

SAMUEL GOLDHABER, MD: It was four days.

JAMES B. GROCE, III, PharmD, CACP: Yes.

SAMUEL GOLDHABER, MD: I am speaking as a cardiologist in this controversy about whether he should have undergone multivessel angioplasty as opposed to bypass surgery. There was a lot of controversy, and it all happened a few miles from here.

JAMES B. GROCE, III, PharmD, CACP: I will defer to the physicians here, in case if they have any other management strategies relative to either of those questions.

SAMUEL GOLDHABER, MD: I would like to come back to the pregnancy theme, Sylvia and Ruth. How do you work up a pregnant woman if you suspect a pulmonary embolism, assuming that the lower-extremity, Doppler, compression ultrasound exam is normal?

RUTH B. MORRISON, RN, BSN, CVN: We order a D-dimer first and see if that is elevated.

SAMUEL GOLDHABER, MD: What if it is elevated?

SYLVIA McKEAN, MD: It is going to be elevated.

RUTH B. MORRISON, RN, BSN, CVN: I am sorry; it will be elevated because she is pregnant.

SYLVIA McKEAN, MD: It is a little controversial. Some radiologists will tell you, if you do a ventilation perfusion scan, the radionuclei, you are urinating it out in the bladder and it is near the uterus. Other people say, "Don't worry about it, just do a PE protocol CT." At our institution, generally the chest radiologists tell us to do a PE protocol CT.

SAMUEL GOLDHABER, MD: When we do those CTs, we do not do the leg veins.

FEMALE SPEAKER: Exactly.

SAMUEL GOLDHABER, MD: Did any of you have questions that you would prefer to stand up and shout? Please identify yourself and start shouting out.

MALE SPEAKER: I had a female patient who had an embolism and coded. She underwent excision for the thoracic aortic aneurysm repair. They put her on full-dose heparin, and apparently surgery went well. Then they had a problem of oozing. I think it was some kind of bleeding.

I left the patient at 10:30 at night, and they told me everything was rosy. She was mentioning blood pressure and circulation. By 11:30, before I reached home, they called me to tell me that she was dead. When I went to view her body the next day, it was bloated beyond recognition. What could have possibly gone wrong? It is a little bit off the track for you.

SAMUEL GOLDHABER, MD: I will say it is unusual to start full-dose unfractionated heparin so soon after cardiopulmonary bypass.

MALE SPEAKER: She also had cancer, so that she does not develop a coagulative process.

SAMUEL GOLDHABER, MD: Yes.

MALE SPEAKER: That is why they probably heparinized her during the surgery.

SAMUEL GOLDHABER, MD: Yes. Often when the patient goes on cardiopulmonary bypass, the patient has had 20 to 30,000 units of unfractionated heparin. That is reversed with protamine toward the end of the case, but it is unusual in our practice and our cardiac unit to start unfractionated heparin so soon postoperatively. Obviously, that was a very tragic ending for this particular patient.

Please stand up, tell us who you are, and where you practice.

FEMALE SPEAKER: I am an internist here in Manhattan. Let's take a person who is on low-dose aspirin for secondary prophylaxis for a heart attack, has a hip fracture, and needs to be on low-dose molecular weight heparin for prophylaxis of another clot. Can you give them both? How do you weigh them?

SAMUEL GOLDHABER, MD: First of all, most cardiologists are on low-dose aspirin anyway. To add a hip fracture, it is perfectly guideline-mandated to give the low molecular weight heparin to prevent pulmonary embolism on top of the baby aspirin. Both should probably be continued postoperatively.

Are there other questions before we go to some of the panel discussion?

Sylvia, you are the preeminent educator and enforcer of prophylaxis at our hospital. Why do we still have a problem? You are a pretty forceful speaker, and the data that you present are compelling. Why aren't 100% of our patients in high risk on the medical service being prophylaxed? I am not talking about the surgical service, which may be close to 100% at our hospital. What is the deal with the general medical service and the subspecialty medical services? You have even had personal experience within your own family with this phenomenon. What is going on here?

SYLVIA McKEAN, MD: First of all, sometimes people just overlook prophylaxis. They are faced with a critically ill patient and, for whatever reason, they are just trying to resuscitate the patient. Then when the patient stabilizes, they do not think about prophylaxis.

There was a case with my 86-year-old father who they thought had myelodysplasia, and he had a severe infection and was immobilized. They overestimated the risk of bleeding compared to the risk of clotting. In terms of your point system, he had eight points and should have been prophylaxed. There is no evidence, if your platelet count is stable and greater than 50,000, that pharmacologic prophylaxis, should be contraindicated.

I also think there are patients that do not fit into the randomized controlled trials. None of the controlled trials included cirrhotics with portal hypertension and other people at high risk of bleeding. A lot of physicians do not know what to do with those patients and, somehow, mechanical prophylaxis, is still better than nothing. In my father's case, he got nothing. For those patients who are deemed high-risk of bleeding such as the cirrhotic with portal hypertension and maybe gastropathy, physicians should be prescribing medication and sequential compression devices.

Somehow it is not quite on the radar screen in the same way, or it is ordered and the nurses do not apply it. The patient has a lot of different tests, and it is only for a few hours a day.

SAMUEL GOLDHABER, MD: I would like to hear from the participants and also from Jay and Ruth, how do we change things? Are there any suggestions?

MALE SPEAKER: Medicare and Medicaid should be told to do that.

SAMUEL GOLDHABER, MD: Medicare should tell us to do that. Jay? You are a policy guy.

JAMES B. GROCE, III, PharmD, CACP: I think this is a segue to what this gentleman has cited. We are going to have a forcing function for every patient, including your father, a risk-grading assessment which will lay out everything we should be thinking about. This includes what puts the patient at risk not only for bleeding, but also the likelihood of developing VTE. Hopefully the forcing function will enable us to make better clinical decisions for this patient population.

SAMUEL GOLDHABER, MD: Ruth, what is the nurse's role in all this?

RUTH B. MORRISON, RN, BSN, CVN: To help with prevention, I think it should start in nursing school. I do not think they get enough education as far as prevention of DVT and pulmonary embolism. Even in medical school, I am not sure it is as important as the other cardiovascular diseases. As we see with the epidemiology, there should be a lot more emphasis on DVT and PE.

SAMUEL GOLDHABER, MD: Your daughter is in her fourth year of nursing school, and she grew up in a household very sensitive about this. What sort of training is she getting? What is the responsibility of the staff nurse in this whole process? Is it just the doctor's fault if the patient does not get prophylaxed?

RUTH B. MORRISON, RN, BSN, CVN: No, it is not just the doctor's fault. Actually, a nurse should be doing a risk assessment on the nursing forms when the patient is admitted. The nurse should bring it up to the physician what risks the patient has with a very careful history and physical. It is a collaboration between the physician and the nurse; it is actually both their faults if that does not happen.

SYLVIA McKEAN, MD: There is also the pharmacist. Actually, pharmacists are very helpful.

SAMUEL GOLDHABER, MD: I think another important way is that pharmacists look to see if the antibiotics match. Are they appropriate? The pharmacists should be looking for sins of omission as well as sins of commission.

MALE SPEAKER: Why do we not have a DVT nurse who specializes in that field to keep an eye on these cases who are not on prophylaxis treatment or are developing signs of DVT? The nurses have more discipline than the doctors.

SAMUEL GOLDHABER, MD: Your point is very well-taken. In other words, there are specialty nurses who do ulcer treatment, and maybe we need to enlarge the job description.

SAMUEL GOLDHABER, MD: Now we will have a thirty-second-only final comment from each of our faculty.

JAMES B. GROCE, III, PharmD, CACP: Very high-risk patient populations with oncologic disease have an increased likelihood of developing DVT or PE. It is necessary to continue prophylaxis with the newer recommendations, both by NCCN as well as the ACCP. They advocate for the role of monotherapy with low molecular weight heparin over that of warfarin, due to the problems of warfarin administration.

SYLVIA McKEAN, MD: From my perspective, it is much harder to diagnose and treat deep venous thrombosis in an acute pulmonary embolism than to prevent it in the first place.

RUTH B. MORRISON, RN, BSN, CVN: I think prevention is it. You learned a lot about diagnosis and a lot of different studies, but I think we really have to put prevention at the top of the radar screen.

SAMUEL GOLDHABER, MD: I would like to thank our participants for joining us after a busy day at the office and hospital. Please be sure to complete your evaluation forms and to hand them in while exiting. I also want to thank our distinguished faculty. Have a good night.

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