Slide Lecture with Audio
This activity is based on a 45-minute slide lecture presented by Dr. Geno Merli. This program is available as read only and with accompanying audio.
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Slide 1: Welcome to Safe and Effective Use of Antithrombin Agents in Special Patient Populations. This activity is jointly sponsored by the University of Cincinnati and Princeton CME and is supported by an educational grant from sanofi-aventis U.S.
Slide 2: I am Dr. Geno Merli, Clinical Professor of Medicine and Director of the Vascular Center at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. I will be your presenter.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form. These forms can be easily completed online for immediate receipt of credit at www.princetoncme.com. Thank you again for joining us.
Slide 3: Let us begin by looking at the learning objectives that have been applied in your activity booklet. These areas will be covered during the presentation.
Slide 4: We must first look at Virchow’s Triad since this is the area that we will focus on to try to reduce the incidence of VTE.
Slide 5: If we look at pulmonary embolism as a leading cause of death in the United States, it is clear that pulmonary embolism kills more people than AIDS, breast cancer, and highway fatalities combined. This is a staggering number for us to look at, as clinicians managing this patient population.
Slide 6: If you look closer, a paper by Dr. Sam Goldhaber in The American Journal of Medicine in 1983 highlighted the incidence of fatal pulmonary embolism in medical patients who were not receiving prophylaxis.
These patients did not have any suspicion of pulmonary embolism prior to death and you can see that 37 of the 50 patients had fatal pulmonary embolism, circled for you in the chart. This is a high incidence, as we saw in the previous slide.
Slide 7: Added to that are risk factors. From all this work that has been done, these are considered risk factors specifically highlighting the cancer population. In the far right, you can see that a number of therapeutic agents have an increased incidence of thromboembolism associated with them. We must keep in mind that risk factors do exist and in each patient that we do assess, these risk factors should be gone through in terms of evaluating their status.
Slide 8: VTE and cancer is an important area for us to focus on.
Slide 9: Let’s take a look at the ACCP consensus guidelines on major surgery in cancer patients; those patients not receiving prophylaxis. It is clear to see that fatal pulmonary embolism is present in 1% to 5% of this patient population—which is an unacceptable number—and the proximal clot rate is 10% to 20%.
Slide 10: VV Kakkar, back in 1975, published a landmark paper looking at prophylaxis in an elective major surgical population, and he compared 5000 units of unfractionated heparin every 8 hours versus placebo. This was a landmark paper since it was the first time that prophylaxis was introduced into the surgical arena for preventing VTE, and you can see in this graph that the patients receiving unfractionated heparin had a lower incidence of pulmonary embolism compared to the placebo control, a P-value of less than .005.
Slide 11: Broken down in this study is the area of the patients with cancer, and we can see there were 953 patients that were in the cancer population. This, of course, was not statistically significant since the study was powered for the larger group; but interestingly enough, the patients who received unfractionated heparin had a lower incidence of pulmonary embolism compared to the placebo control in the 953 patients evaluated.
Slide 12: Bleeding complications—there was no difference between the 2 groups with respect to excessive bleeding and wound hematoma, so it dispelled the issue that using prophylaxis would increase bleeding in the perioperative period.
Slide 13: The next trial is the ENOXACAN study published in The British Journal of Surgery in 1997. In this study, LMWH and enoxaparin 40 mgs once per day was compared to unfractionated heparin, and in this study it showed that once per day enoxaparin was as effective or equivalent to heparin 5000 units q 8 hours in the prevention of VTE in a surgical population undergoing cancer surgery via pelvic and abdominal procedures.
Slide 14: Looking at this population, we can see the bleeding incidence, since that is always of concern and, once again, in total bleeding there was no difference between the 2 groups, except for the area of discontinuation of prophylaxis. There was also nonsignificant difference between the 2 groups, but the issue here—total bleeding—was not different between the interventions.
Slide 15: Another study published by Bergqvist in The British Journal of Surgery in 1995 compared 2 different doses of LMWH—in this case, dalteparin 2500 units versus 5000 units—and you can see that the 5000-unit dose was much better in reducing the incidence of VTE in patients with malignancy versus those receiving 2500 units. In this case, getting the right dose was the focus of the trial.
Slide 16: When we look at these issues, we need to look at prophylaxis in the cancer population, which we consider very high risk, and extended prophylaxis in this group.
Slide 17: The CHEST guidelines report that in the very high risk surgery group that IPC, intermittent pneumatic compression, plus LMWH—either enoxaparin or dalteparin—were the prophylaxis of choice for preventing VTE. The same combination of IPC plus unfractionated heparin 5000 units q 8 hours is also an effective prophylaxis. And the reason that 1C recommendation is given is that these are extrapolated to other trials in which pneumatic devices were used and found to be effective.
Slide 18: If we look at the gynecologic group for malignancy surgery, we can see there appears to be a little difference, but not very much. In this case, the use of heparin 5000 units q 8 hours was given a 1A recommendation, as well as either enoxaparin or dalteparin 5000 units once per day. The pneumatic compression sleeve combination, as you saw in the previous slide, is also recommended as an option for management and, of course, IPCs alone, but these must be worn continuously. I think the issue of using the compression sleeves with pharmacologic therapy gives an option to clinicians managing the patient, in that there may be a high risk of bleeding in the 24-to-48 hours postprocedure, and therefore pneumatic devices may be useful in that area and then the addition of pharmacologic therapy as part of the management can be added.
Slide 19: Looking at extended prophylaxis in this group—I have 2 papers, one by Scurr and the other by Lausen, and these were in the early 90s, looking at this incidence of DVT in patients undergoing general surgery who had cancer procedures. And when you look at these 2 trials, you can see that the incidence of DVT after discharge, 4 to 10 days out in the Scurr paper, was 25%. This was by fibrinogen scanning. The Lausen paper did a comparison of placebo versus LMWH and they found an incidence of 15.6% in the placebo group, and this was an ultrasound endpoint trial. What it does tell us is that there is an incidence in the cancer population that may be developing after the discharge from the hospitalization, so that continued risk may be present.
Slide 20: The ENOXACAN II trial attempted to answer this question, and this was published by Bergqvist in The New England Journal of Medicine in 2002, in which enoxaparin 40 mgs once per day was given to patients 8 plus-or-minus 2 days and then, upon discharge, the patients were randomized to enoxaparin 40 once per day versus placebo. All patients were followed for a period of 28 plus-or-minus 3 days, and venography was then performed bilaterally to assess for thrombosis.
Slide 21: From this trial, we see that the incidence of DVT after discharge in the cancer patient population undergoing pelvic and abdominal procedures was 12% in the placebo group and 4.8% in the intervention group with enoxaparin. The proximal clot rate was 1.8% in the placebo group and 0.6% in the enoxaparin group. It shows us that the predominant clots are calf vein thrombi in this population, but there is definitely an incidence following discharge in that first 30 days out from the discharge from the hospitalization. We can see the cumulative effect over 3 months and this is not that new thrombi developed in 13.8% in the group, but it was additive from the 12%, and also additive from the 4.8% to 5.5%. The risk continues but becomes less after the 30-day period.
Slide 22: A second study that I would like to highlight is a comparison study, and the Bergqvist paper is on the left at 5% and 12%, as we remember from the previous slide, but the Rasmussen paper used dalteparin versus placebo; you can see they had a 6% incidence in the treatment group and 16% in the placebo group, once again showing us that there is an incidence of VTE following discharge and that prophylaxis is indicated in this population.
Slide 23: The @RISTOS project, done by Jean Carlo Agnelli, looked at 2373 patients, prospectively, in general surgery, gynecologic, and urologic surgery—all for malignancies—and looked at the incidence of VTE, clinically, in this population.
Slide 24: What this slide shows us is that 40% of the cases of VTE occurred from day 16 on to greater than day 30 in this patient population. In the 21 days after discharge from the hospital, 40% of the cases of VTE occurred.
Slide 25: Now, Agnelli located the key elements here of risk factors, and these are the elements that he highlighted. There were 5 and the odds ratios are listed for you here, ranging from 2.6 to as high as 5.98 in previous VTE. When he looked at these same risk factors, he found that these risk factors were identical to those for the patients in the 21 days after discharge who developed VTE. These odds ratios were the same for the group. What I think this points out to us is that patients undergoing cancer surgery need a risk assessment done at the time of discharge to plan for extended prophylaxis in this population, knowing that these risk factors will definitely increase that chance of patients developing VTE.
Slide 26: Here are the ACCP recommendations for extended prophylaxis, as of 2004. Now we are awaiting the new guidelines that will be coming out this year, in 2008. We see that in selected high-risk general surgery patients, including those who have undergone major cancer surgery, the recommendation is enoxaparin 40 mgs once per day, dalteparin 5000 units once per day. We can see that from the 2 studies I presented. In the patients undergoing gynecologic cancer surgery who are over 60 and have a previous VTE, the recommendations are 2 to 4 weeks of prophylaxis with enoxaparin and dalteparin, same dosing as above. Now, I think the issue of the second recommendation is the number of patients that were in the 2 trials that I reviewed, but you can see that extended prophylaxis is recommended for this patient population with cancer.
Slide 27: If we look at another trial, the MEDENOX trial, and look at multivariate logistic regression modeling, we can see that having cancer had an odds ratio of 1.66 for the development of VTE. Cancer itself, the chemo that is used with cancer, the immobility after surgical procedure, or even patients hospitalized with cancer—for, say, neutropenic fever or hypercalcemia—are all at risk for developing VTE during the confinement.
Slide 28: We can see the EXCLAIM study that was reported in abstract form from the ISTH meeting that took place in Geneva, Switzerland—that is the International Society of Thrombosis and Hemostasis. This trial showed that with extended prophylaxis after discharge in a medically ill population, receiving enoxaparin 40 mgs, at home, once per day compared to placebo. There was a 2.8% incidence, overall, in the enoxaparin group and 4.9% in the placebo group. We are awaiting more data as to the populations but for now, this study shows us that even the medically ill population has risk after discharge from the hospital.
Slide 29: Here are the ACCP recommendations for the at-risk medical patient, including those with malignancy. As you can see, we have highlighted the recommendations that those patients should receive LMWH and enoxaparin 40 mgs once per day, dalteparin 5000 units once per day, or fondaparinux 2.5 mgs once per day. This latter medication was added most recently from 1 trial that was completed. The low-dose unfractionated heparin recommendation 1A is 5000 units every 8 hours or every 12 hours, as recommended in the CHEST guidelines. My preference is that patients receive 5000 units every 8 hours if you are going to use unfractionated heparin in this medically ill population.
Slide 30: Let’s turn our sights to VTE treatment and the cancer patient.
Slide 31: The first study that I would like to focus on is from The Annals of Internal Medicine and our group published this study in a large international trial. What we showed in this trial was that enoxaparin given at 1.5 mg/kg once per day, versus 1 mg/kg twice per day, versus standard unfractionated heparin were the same with respect to the incidence of recurrent VTE. There were 900 patients in this trial. We also showed that there was no increased incidence of major bleeding in either of the categories.
Slide 32: What I would like to highlight for us is a subsection of this study in which we looked at the 2 different doses with respect to the cancer group. What this study highlighted was that patients who received 1.5 mg/kg once daily of enoxaparin versus 1 mg/kg twice per day, it appears there was a higher recurrence rate in the patients who received once per day dosing versus twice per day. Now, this did not achieve statistical significance because the study was powered for the overall group of recurrent VTE and not special patient populations, but there is a trend, as you can see from the slide.
Slide 33: When we look at the cancer population, the other aspect we need to keep in mind is the risk of bleeding in the cancer patient who is treated with LMWH or standard heparin, then converted to warfarin therapy for ongoing management. We can see from this slide in the recurrent VTE group that, even depending upon the INR range, there appear to be no correlations. Even those with an INR of greater than 3 had an 18.4 event rate per 100 patient years compared to the noncancer group. Of course, even in the bleeding section, we can see there was no correlation between the INR. It appears that in the cancer population the use of warfarin therapy may be associated with recurrent disease and also an increased incidence of bleeding.
Slide 34: Let us turn our attention to the issue of some studies that were completed using LMWHs against warfarin therapy for the secondary prevention of VTE in the cancer population. In this study, by Agnes Lee in The New England Journal of Medicine, dalteparin was compared to warfarin therapy and, in this case, dalteparin was given at 200 U/kg, once per day, for 1 month and then 150 U/kg, once per day, for the remaining 5 months. The patients were treated with warfarin. The comparator group had an INR of 2 to 3 and we can see from this study that the recurrent rate in the population was increased in the patients who were on warfarin versus those who received LMWH/dalteparin. The incidence of major bleeding was 6% in the LMWH group and 4% in the warfarin group.
Slide 35: The ONCENOX trial compared 2 different doses of LMWH, 1 mg/kg twice per day in the far left bar graph that you can see, and then converted to 1 mg/kg once daily for 175 days. In the center bar, patients were given 1 mg/kg twice per day and then converted to 1.5 mg/kg once per day, and the final group was given enoxaparin 1 mg/kg twice per day and then warfarin INR 2 to 3. The studies showed that there was no difference between the 3 groups with respect to recurrent disease.
Slide 36: The LITE trial, which was published by Russell Hall last year in The American Journal of Medicine, looked at tinzaparin, 175 mg/kg once per day versus unfractionated heparin followed by warfarin. Also, in this study they showed no difference in the recurrence of VTE in the 2 groups, but what it does tell us is that we can safely use LMWHs in the treatment of VTE versus warfarin therapy.
Slide 37: In the large meta-analysis of cancer mortality, unfractionated heparin versus LMWH, I want to call the audience’s attention to the issue of the mortality in the LMWH group versus unfractionated heparin. I think we need to be cautious here in interpreting this data because many of us might think that giving LMWH to the cancer patient may reduce mortality from their cancer. I think that needs to be proven. I think the issue is it reduces the incidence of thromboembolic problems and, therefore, may reduce the mortality from that standpoint. I think you need to keep that aspect in mind.
Slide 38: What are the recommendations for ACCP? The recommendations for ACCP are that the patients who have active cancer and DVT should be treated for 3 to 6 months, a 1A recommendation, with LMWHs, as you can see from the studies we showed you, and then followed by warfarin therapy, and after that 2 to 3 for an indefinite period. That is the current recommendation.
Slide 39: The agents that can be used for the treatment of VTE are dalteparin, enoxaparin, tinzaparin, and now fondaparinux has been added to the regimen, but this has not been studied in the cancer population, as I have shown you above, with the other studies.
Slide 40: Having done the prophylaxis and treatment area, let’s then turn our attention to the issue of renal insufficiency in the patients that we need to focus on.
Slide 41: Let’s take a look at a short background, in terms of the trials, since they excluded patients with creatinine clearances of less than 30 ccs. There are no extremes of weight and, of course, very few of the trials monitored anti-Xa levels, and there appears to be no correlation between anti-Xa and bleeding.
Slide 42: Looking at renal insufficiency with the LMWHs, we have to do a balancing act here of underdosing the patient and then causing a thrombotic recurrence, or overdosing the patient and causing bleeding.
Slide 43: Let’s look at a couple of areas in terms of pharmacokinetics, pharmacodynamics, and clinical outcomes.
Slide 44: The first study is by Chow, which shows that patients whose creatinine clearances were, as you can see, starting to trend downward from 40, those patients, when we measured anti-Xa levels using enoxaparin 1 mg/kg twice per day, you can see that the Xa levels were extremely high in the therapeutic range, which was anywhere from .5 to 1.0. Creatinine clearance less than 30 ccs, using LMWH—drugs are renally excreted, you are going to get a high anti-Xa effect in the patient.
Slide 45: Similarly, in the Cadroy paper, looking at the patients with chronic renal failure, 12 patients with the small boxes at the top of the curve, you can see that the time after, in terms of the Xa level, remain elevated in this patient group, receiving a single dose of enoxaparin 0.5 mg/kg, one dose in this patient group.
Slide 46: If we look at clinical outcomes in patients who had renal insufficiency in this study by Gerlach, there were 53 patients, and of the 53, 20 patients were on dialysis. In the dialysis patients there was a 45% incidence of major bleeding receiving LMWHs. I want to show you this bar graph because I want to highlight the area where patients who receive LMWH with renal impairment had a high incidence of major bleeding, and it was not even correlated with the dosing of the patients in this study.
Slide 47: Some patients received 30 mgs twice per day; some received therapeutic dosing, and some received the prophylactic dose for the medically ill population. You can see that it is not correlated, specifically, with the dose, but I think the issue is if you have renal impairment and you are using LMWHs, your increased incidence of bleeding is significant.
Slide 48: Also using tinzaparin and different creatinine clearances—as you can see, in this study, they showed that using tinzaparin at 175 U/kg, there was no increase in the clearance observed in any of the groups, and secondly that there was no correlation between the clearance and anti-Xa levels.
Slide 49: If we look at the TIMI 11B and the ESSENCE data from NSTEMI patients, we can see also that in patients with total renal impairment, comparing the enoxaparin plus the unfractionated heparin group, the patients who had renal impairment had a higher incidence of major bleeding, in both groups, enoxaparin and unfractionated heparin. What is the point? The point is that renal insufficiency increases the risk of bleeding using LMWHs.
Slide 50: If we look at another study by Sanderink, in patients who had renal impairment of different degrees and looking at 40 mgs once per day, a dose that you would use in the medically ill population, what do we find in this study?
Slide 51: I think people can see, in the top graph, the diamond-shaped areas, we can see that if you are taking 40 mgs once per day of enoxaparin for 4 days with the different degrees of renal impairment—this was severe, less than 30 ccs creatinine clearance—you can see that your anti-Xa levels remain elevated far beyond the 2 bars, the parallel bars, which is the prophylactic range. You can accumulate drug, and it is something to keep in mind.
Slide 52: And dalteparin, looking at the Kucher paper from Archives in Internal Medicine, they looked at 5000 U daily of dalteparin in this patient group and they looked at the area of the elderly population who had renal impairment, and it showed that there was no increased incidence of bleeding reported in this trial.
Slide 53: A large meta-analysis, as you can see, from the Lim paper from The Annals of Internal Medicine in 2006, shows us that patients who are using LMWHs have an increased incidence of bleeding, creatinine clearance less than 30 ccs, and you can see, on the bottom part of the meta-analysis, that there is a definite trend in bleeding in this patient group. It is not that you cannot use these agents, LMWHs, in patients with renal impairment. You need to use the appropriate dose and keep that in mind.
Slide 54: Here is a chart from the MICROMEDEX health series, looking at renal impairment in patients using enoxaparin who have specific recommendations in the package insert and from MICROMEDEX on the dosing of the medication. You can see in the medically ill, we would use 30 mgs once per day versus 40, as recommended without renal impairment or abdominal surgery, 30 once per day versus the 40.
Slide 55: I think the issues are, adjust the dose of LMWH for VTE prophylaxis as recommended, adjust the dose for treatment, and, of course, in special populations and only if you have this capability, anti-Xa monitoring would be utilized. I would advise against this if you do not have that capability or protocols that follow how to manage this patient group.
Slide 56: The next large group to look at is the obesity patient.
Slide 57: Just like in the renal impairment patient, I think we have to balance thrombosis versus bleeding, the overdosing for the bleeding and underdosing for thrombosis. This can easily be a problem in the obese patient since we would be more likely to lower the dose for fear of giving too much drug to the patient, therefore increasing the thrombotic risk.
Slide 58: When we look at the trials, we look at how they have been organized and the issue of the trials—that they have not been organized to exclude obese patients; therefore everyone received fixed dosing as part of this process, and anti-Xa levels were monitored in some of the trials to look at a comparison.
Slide 59: If we actually look at one of the LMWHs, fondaparinux, their recommendation for weight adjustment for the treatment is that you use different doses for different weights. Now, it does not go specifically (ie specific weight for dosing) but a category of dosing of the fondaparinux. They recommend fixed dosing for all prophylaxis despite the weight of the patient.
Slide 60: If we also look at fondaparinux as a new agent, in the field of LMWHs—and this is considered pentasaccharide—we can see that the key area here is its long half-life, 17 to 21 hours. It is renally excreted like the LMWHs but there is no reversing agent for this drug, and I think you have to keep that in mind. It is an effective agent but you need to know some of the parameters and management.
Slide 61: Now, let’s take a look at one study by Kovacs, who tried to evaluate the impact of weight and Xa levels and the outcome of VTE, and I think that is how you would want to compare patients. In this study, they looked at total hip and total knee replacement patients, 97 in each group. They had an incidence of DVT of 6 and 5 in each of the respective patients studied.
Slide 62: In this study, they looked only at the trough levels of the LMWH enoxaparin and then you had the mean weight. It does not appear the patients were too heavy in this trial, but what they showed is that there was no correlation between Xa and body weight, the trough level, and there was a poor correlation between the weight, the trough level, and those who developed VTE. The recommendations were to use the fixed dose of enoxaparin, and for those who were greater than 150 kilos that maybe monitoring Xa levels would be recommended. Now, they did not study that but recommended that.
Slide 63: If we look at the bariatric surgery population, this trial by Scholten in Obesity Surgery in 2002 looked at 481 patients. I think the audience needs to focus in on the 92 patients that were in the enoxaparin 30 mg twice per day dosing schedule versus the enoxaparin 40 twice per day. You can see there are only 92 patients in the one group versus 389 in the 40 mgs twice per day group, so the study was not well designed, but it did show that there was a reduction in the incidence of VTE and no increased incidence of bleeding in this obesity surgery population.
Slide 64: There were a total of 7 events; 2 DVTs and 4 nonfatal pulmonary emboli that occurred in the study population versus the patients who were in the 40 mgs twice per day dosing group. You can see it was only 0.06 incidence of VTE.
Slide 65: If we looked again at the NSTEMI data, TIMI 11B and the ESSENCE meta-analysis, it appears there was no increased incidence in major bleeding in the patients who received enoxaparin or unfractionated heparin, in the obese patient group versus the non obese, unlike the renal insufficiency group where we saw that there was a definite difference between the 2 groups.
Slide 66: In the study that we reported earlier on from The Annals of Internal Medicine, I wanted to highlight the obesity group here and, once again, the study was not powered to look at obesity but it appeared a trend that there was less VTE in the patients receiving enoxaparin twice per day versus once per day in an obese population.
Slide 67: If we look at Sanderink once again, he had completed the initial study looking at renal insufficiency. Let’s look at obesity and the pharmacokinetics and dynamics in this population. There were 24 patients in each group and they looked at 1.5 mg/kg IV over 6 hours, followed by 1.5 mg/kg once per day for 4 days and they measured anti-Xa levels.
Slide 68: You can see the triangles at the top were the patients who are obese and the squares are the patients who were non obese, and you can see the curves look pretty much identical. It appears that anti-Xa levels, in patients who are obese versus nonobese, are the same. It tells us we need to dose the patients appropriately based upon their actual body weight and that there is no increased incidence of over anticoagulating these patients using this schedule. Now, it does not say they are not going to bleed, it just says that their anti-Xa levels are going to be relatively stable, like a nonobese patient.
Slide 69: Another study by Smith looked at dalteparin in terms of 100 U/kg twice per day versus 200 U twice per day in this patient group. You see the mean weight, 118 kilos, and once again, showing that the anti-Xa levels are pretty much stable in these patient groups, dosing by the actual body weight.
Slide 70: In Kucher’s paper from The Archives of Internal Medicine, in which they looked at dalteparin and obesity, you can see that, in the boxed area, the 35 to 39.9 and then greater than 40, it appears that the relative risk in this group, in terms of bleeding in the population, it appears that there was no difference in patients who are obese versus non obese in this group.
Slide 71: And also Hainer’s paper in Thrombosis and Hemostasis in 2002, showed the different BMIs. If you look at the anti-Xa level in the top, and what you see there is the BMI of 26 to 61, you can see that the curve looks identical; almost looks just like Sanderink’s paper which showed that the patients in the obese group versus non obese, the curves appeared the same. The message is that, with obese patients, you have to dose by their weight so that you can appropriately manage the patients.
Slide 72: Hainer also looked at tinzaparin’s pharmacokinetics in 2 different doses. The first is 75 U/kg, this would be in the prophylactic dosing range, and then 175 U/kg in the therapeutic dosing range, and he looked at the normal subjects versus the heavy-weight subjects. You can see both diagrams appear to be identical in terms of their area under the curve, with respect to anti-Xa levels, so once again, dosing the patient appropriately, by their weight, achieves a therapeutic range or prophylactic range for patients who are obese versus non-obese.
Slide 73: Kucher also broke this out, with respect to adverse events according to age, thinking that age might have an impact on dosing of LMWH. You can see, when you look at this chart, for the patients over the age of 75, it appears that there was no increased incidence of mortality in the group, and also there was no increased incidence of major bleeding in the group in patients who were older.
Slide 74: If we look at obese and non obese, we can see once again that there was no increased incidence of mortality, both at 21 and 90 days, and also no increased incidence of major hemorrhage in the group. I think the conclusion here, for the obese population, is that you need to dose this patient population appropriately, fixed dose for prophylaxis, and, of course, therapeutic dosing by their actual body weight.
Slide 75: If we look at the whole component in the Kucher paper, looking at the primary endpoint according to BMI and age together, once again in this chart we can see as we go across the board that in the obese and non obese, age greater than 75 or age less than 75, we can see there was no difference in the outcome of sudden death, PE, fatal PE, symptomatic PE, or proximal DVT in either of the groups.
Slide 76: What kind of a conclusion could we draw from all of this data on the obesity section? We know that fixed dose, LMWH is the recommendation for VTE prophylaxis. We would not adjust that dose except in the bariatric patient population where it appears that the larger dose, 40 mgs twice per day, was the more effective dose. But remember, this was not a well-designed trial, and more studies will be coming out sooner and, of course, I have highlighted that in the second bullet, saying that this dose needs to be looked at. Finally, when we are treating patients with VTE, we need to appropriately give the therapeutic dose for that patient, based upon the actual body weight dosing. I think that is a critical piece to keep in mind. And finally, monitoring anti-Xa levels in special populations. I know when you look at the Buller paper in CHEST, you will see the point highlighted that, in patients who are morbidly obese, in terms of dosing of the drug based upon actual body weight, that maybe monitoring anti-Xa levels would assure that you are not overdosing the patient or underdosing the patient. But once again, I think you need this kind of capability at your facility to accomplish that target therapy.
Slide 77: In conclusion, I think we need to highlight that all patients should be assessed for VTE risk. The risk assessment tool that we applied in the beginning of this presentation needs to be done on every patient on admission to the hospital. I would also consider using this on discharge from the hospital, specifically in the surgical population and the medically ill group because of that potential risk after discharge. I think appropriate VTE prophylaxis must be applied to all patients universally as part of their management in the hospital, and I think that special populations, such as the cancer group, renal insufficiency, and obesity, must be considered in appropriately applying VTE prophylaxis, as well as treatment.
I would like to thank you, again, for joining us.
