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This ThrombosisClinic™.com expert commentary features Dr Joseph Caprini. Dr Caprini is Professor of Surgery and Bioengineering at the Feinberg School of Medicine at Northwestern University in Chicago. Dr Caprini has had a lifelong interest in bleeding and clotting problems, and ran a special coagulation laboratory for 25 years, plus a peripheral-vascular laboratory for 30 years. Dr Caprini therefore is eminently qualified to discuss our topic today, which will focus on the seventh American College of Chest Physicians guidelines concerning prophylaxis in a surgical patient. Dr Caprini, welcome. |
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| Good morning, it’s very nice to be here. I know that sounds like I’m exchanging a social insincerity; however, my reason for saying that is that this is all about patient care and improving patient care, and if we can provide anything at all during this presentation that will help physicians and paramedical personnel improve patient care, it will be a real success. That’s why I am so excited to be here. |
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Terrific, Dr Caprini, glad to have you. First question, which issues and changes in the field of thromboprophylaxis and surgery patients have emerged since the Sixth guidelines were published? |
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Well, there are a number of new things in the current guidelines, but I would like to back up a minute and talk about something even more fundamental.
The Chest guidelines themselves clearly show the effect of various risk factors on their contribution to venous thrombosis. Therefore, each and every risk factor is important. I think I would like the audience to of course make your own decision, but how could you possibly approach a surgical or a medical patient and not consider each and every risk factor?
One of the things about detailed risk assessment is that it is a pain, and people do not like to do it because it takes a lot of time.
We have not found a way to get people to really do it. Unfortunately, that, in some cases, leads to omitting certain very important risk factors, and as a result of that, misclassifying the patients. So what we are suggesting is each and every risk factor the patient has, has to be looked at, number one. And number two is that, based on all of these factors, a decision has to be made about prophylaxis. In that regard, the existence of the computerized medical record offers us a way to put that on the medical record for easier understanding and patient and doctor compliance.
One of my suggestions in that regard is to have the patient fill out a brief form of 10 or 11 questions, and that can outline those major risk factors. They hand that form in to a health-care provider that interfaces with the physician or surgeon on the admission of the patient, and then a detailed risk assessment is done. The results of that are placed in the medical record and then the physician is simply asked to question this patient that has so many risk factors for thrombosis—what is your choice of prophylaxis? I think in that way we can implement these guidelines.
I apologize for not answering your question and getting carried off with the risk assessment, but the reason for that is I think it is the central issue to this whole process. As far as what is new in this Chest consensus document, there are some exciting developments. The most exciting development in my opinion is the hip trial for extended prophylaxis after hip fracture, using fondaparinux, where 98.6% of the patients at 30 days had a negative venogram if they took the drug for 30 days. In other words, this particular drug was able to eliminate a disease in a very, very elderly and sick population.
In addition to that, the trials with fondaparinux, especially in the knee patients, and to a lesser extent in the hip patients, is also a new development, and has now resulted in a new level 1 indication in total hips, total knees, and hip fracture. I would also like to remind the audience that fondaparinux is the only FDA-approved treatment or prophylaxis for both short- and long-term indication after hip fractures.
The other thing new in this consensus conference is the emergence of data that has caused them to acknowledge that length of prophylaxis is an important consideration, particularly after total hip procedures and hip fractures. In addition to that, emerging data in the general surgical area for length of prophylaxis has clearly shown that the drug enoxaparin, when given for 30 days after an abdominal surgical cancer operation, statistically significantly lowers the risk of venous thrombosis in this very sick group.
I think that in this regard, Chest guidelines has done a wonderful job in segregating people into various levels of risk. Well, those of us that realize that not every single condition has had a randomized, prospective, double-blind, double-dummy trial in order to prove the point, realize that we can take these data from individual trials, and extrapolate them to other patients that are in the highest risk group. Now, is that perfect? Of course not, but it gives us a way to take people who have an over 40% incidence of DVT with up to 5% mortality from pulmonary embolism, and protect them by giving them the best prophylaxis.
In addition to that, there is another side to this, which I think is extremely important. Some people have said, well, what difference does it make, once you know the patient is going to be high risk, then you’ll give them prophylaxis, and if there are other factors on top of that, for example, history of thrombosis, obesity, and other factors, that is increased and scored 8, 9, or 10, what does that mean, because you are already providing prophylaxis? My answer to that is it means a whole lot because I think that one can assume that somebody with 10 to 12 risk factors, depending on what those risk factors are, has a far higher incidence of thrombosis than has been seen in clinical trials with a given condition. For example, the average total hip replacement patient, when given a prophylaxis, will have a 15 to 25% chance of a clot depending on the drug that is used. But that may go up to 30, 40, 50% with a high number of risk factors. What is the point of all of this? In today’s world, an informed-consent decision to the patient, telling them that despite all of the modern drugs we have, and despite all the precautions, that they could still suffer a serious event because of the number of risk factors, I think is important as an informed-consent decision.
Other changes from this document would include the emphasis on the medical patients. We now have 3 large, well-done, prospective trials with appropriate end points that clearly show that dalteparin, fondaparinux, and enoxaparin, all 3 of those drugs statistically significantly lower the incidence of venous thrombosis in patients who are medically ill, admitted to [a] hospital. And I think this is a very important development and one that those of us educators are going to focus on in the future in patient education. |
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Several new surgical patient groups are addressed in the seventh guidelines, including patients undergoing vascular surgery, laparoscopic surgery, and elective spinal surgery. In vascular surgery, prophylaxis is routinely applied, both perioperatively and postoperatively. Are specific recommendations in this patient group necessary, and if so, do the current recommendations provide the necessary guidance to clinicians? |
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In general, large trials have not been done in neurosurgery, in neurology, and in vascular surgery, so we do not have large bodies of data to pick from as we do, for example, in total-joint replacement or in hip fracture. So, this has led some people in those specialties to say various things. For example, we just do not see problems in this group, or, there are no real guidelines in this group because large studies have not been done. So, I think that this is a very, very diligent attempt by the consensus leaders to take available data and to try to identify that data in these patient groups.
In outpatient neurologic, arthroscopy, and orthopedic procedures such as spinal operations, for example, anterior cervical fusion, normally they do not recommend prophylaxis. Then in the next sentence they go on and say, if there are other risk factors, then these risk factors have to be considered in the decision to use prophylaxis.
One has to take a detailed look at each and every risk factor in order to make sure that they are all taken into account; for example, the 22-year-old lady that has an anterior cervical fusion and goes home and gets a blood clot. Eighteen years later, she has to have another anterior cervical fusion at a different level, and guess what? Postoperatively she gets a much more severe blood clot. She almost dies and has severe and debilitating consequences from the DVT. Her surgeon says, well, we do not routinely use prophylaxis because this is normally outpatient surgery. And the guidelines would support that. But that previous history of thrombosis changed the whole paradigm. So, I think in that sense, my interpretation of the new guidelines is that they are really good because what they do is they identify these patient groups as potentially being at risk if one looks at each and every one of the risk factors.
Now, as far as neurosurgery is concerned, which you mentioned, this is a very sticky wicket. And there are trials to show that after several days, that low-molecular-weight heparins are not any more dangerous in this patient group than in other high-risk surgical patient groups. Yet, with the emotion surrounding a bleed into the brain and the finality of a fatal stroke or death, it has been very, very difficult to implement those guidelines, and many times neurosurgeons and other physicians alike will withhold thrombosis prophylaxis in this very high-risk group, because of the risk of bleeding.
As you know, especially if the brain tumor is malignant, this is one of the highest incidences of DVT. |
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Let us talk about major orthopedic surgery for a moment. ACCP 7 states that the timing of initiation of pharmacologic prophylaxis should be based on the efficacy-to-bleeding trade-offs for each particular agent, and that there are only small differences between starting low-molecular-weight heparin pre- or postoperatively and that both options are acceptable. However, it is also mentioned that there is little advantage of administration before surgery and that post-op prophylaxis provides comparable efficacy to pre-op prophylaxis. Do you agree that both options are acceptable, as the guidelines state? |
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Based on not only my analysis of the literature, but the expert analysisand these people are really experts, and I think they do a wonderful job—they have clearly stated to us that there is no advantage in the administration of preoperative anticoagulants in this patient group because all it does is increase the bleeding, not the efficacy. That is clearly shown by the data. So why would not the concluding sentence say that, in the absence of conclusive evidence that preoperative administration of these anticoagulants will improve patient results without any risk of bleeding, then we endorse it. But it does not say that.
The leaders of this group have chosen to take an editorial stand, whereby they say that in all of these studies, we pay a high premium on bleeding, and a lower premium on prevention of thrombosis. I would suggest to you that in 2004, that is an inappropriate statement. Bleeding is a problem that results after an operative procedure, which may or may not be related to an anticoagulant, number one.
Number two, if the patient requires the use of one of these more modern, more focused, more powerful anticoagulants that may indeed increase somewhat the risk of bleeding, it has to be done in a setting that is justified. That setting that is justified would include patients that may have a 1% to 5% chance of dying from their blood clot, or even worse, what is now being more and more recognized is through a patent foramen ovale, have a fatal or disabling stroke.
I would have liked them to have taken the more high ground and said that we balance equally bleeding and thrombosis because if bleeding problems occur, you know, most of the time they are not fatal and most of the time the patient does not die. |
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When dealing with general surgery patients, who have multiple risk factors, or who are at high risk of bleeding, mechanical prophylaxis with graduated compression stockings and intermittent pneumatic compression is recommended. Distinction between these 2 different methods of mechanical prophylaxis is not made. What is your opinion about this? |
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I fail to understand that conclusion. Anybody who has done this, and used these modalities for years, recognizes that the graduated compression stockings, while they provide a small degree of protection compared to placebo, do not achieve the level of risk reduction that can occur with pneumatic compression devices.
The literature to prove that is in the 797 articles. I fail to understand why they did not make a decision, a distinction between graduated compression stockings as a method of prophylaxis and sequential compression devices or pneumatic compression devices.
The second thing I was disappointed in is, if you carefully look at the studies in which intermittent pneumatic compression, now not the stockings, but intermittent pneumatic compression, has been used in patients with 2 risk factors, they are equivalent to the anticoagulant modalities. An example of this would be in a hernia patient over the age of 40 undergoing an operative procedure with no other risk factors. Now, once additional risk factors, and I think the Chest consensus group has done a nice, nice job by having 2 risk factors be moderate risk, and then based on the literature, 3 to 4 risk factors is high risk. And as you know, they properly pointed out, based on those 797 articles, the incidence of DVT jumps from 10 to 20% to 20 to 40%. Under those circumstances now, it is my opinion from looking at all this literature that the anticoagulants work better than pneumatic compression in that particular group, particularly if the risk factor has a hematologic backing (i.e. inflammatory bowel disease where stool is getting into the blood stream and triggering clotting.) |
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For the first time the ACCP guidelines address the important issue of dosing in patients with renal impairment. They state that renal impairment should be considered when dosing low-molecular-weight heparin, fondaparinux, direct thrombin inhibitors, and other antithrombotic drugs that are cleared by the kidneys, particularly in elderly patients and patients at high risk for bleeding. Also, that for each antithrombotic agent, the clinician should consider the manufacturer’s suggested dosing guidelines. Do you think this recommendation is sufficient guidance for clinicians who deal with complex renal patients, such as elderly, underweight patients with additional morbidities, and what about agents without clear dosing recommendations for renal patients? |
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These patients are not going to do well whatever is done to them. They tend to bleed, they tend to have complications, and so I think that as far as what the Chest guidelines have done is they have begun to point their finger at some of these issues. It would be unrealistic for them to come up with a set of recommendations that would cover all scenarios, and be something that we could use all the time, but I think it is a good start.
Number one, I think,”What does the clinician need to take away from this, first and foremost?” To know that the low-molecular-weight heparins, the pentasaccharides, the direct thrombin inhibitors, are all, almost all, renally excreted. Argatroban, for example, is a thrombin inhibitor that is not. If the person does not know the renal status of the patient, particularly if a patient has a creatinine clearance of less than 30 cc a minute, these drugs can have nasty side effects, and that may sour the clinician on using these drugs in those circumstances.
In addition, they have longer half-lives. They are harder, or impossible, to reverse, and so that I think the prudent clinician is going to interpret the guidelinesand I think that the guidelines are structured in such a way that the clinician can do this interpretation—to maybe restrict the use of these agents when getting into all of those risk factors, and going with more traditional anticoagulants that are more familiar to generations of clinicians dealing with these disorders. |
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Exploring the dosing issue a bit further, there has always been a lot of controversy around the efficacy of bid, unfractionated heparin as prophylaxis. In moderate-risk general surgery patients, the guidelines regard prophylaxis with LDUH, 5,000 units bid, equal to prophylaxis with low-molecular-weight heparin, less than or equal to 3400 units once daily. Which type of prophylaxis would you choose for these patients and why? |
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Well, this is an interesting distinction that they have extrapolated from the literature, and that is in the patient with 2 risk factors, they do not have a very high incidence of thrombosis. And so I think they quite properly pointed out that in the studies using patients like that, 5000 units of heparin bid or the lower dose of low-molecular-weight heparins be it tinzaparin, dalteparin, or enoxaparin, which have all been studied, are actually adequate. I would have liked to have seen an additional sentence there, saying that IPC is in that same category for the 2 risk-factor patient.
I do not think there is any question however, that there is another issue here, and I’m not so sure that I came away with a real clean understanding of it from the Chest guidelines. Twice a day unfractionated heparin is overused. It is even treated this way in the guidelines, when we know there is no large randomized, prospective, double-blind trial in medical patients that clearly shows the efficacy of bid heparin. There is plenty of data from smaller trials, to show that bid heparin is equivalent to enoxaparin 20 mg, which was the dose in the MEDENOX trial that did not prevent venous thrombosis, and it was only the 40-mg dose of enoxaparin that prevented venous thrombosis. And as I said since that time, 5000 units of dalteparin and 2.5 mg of fondaparinux have all been shown to produce that effect in the medically ill patient of reducing thrombosis. Those surgical patients with 3 or 4 risk factors or more, in my opinion, there are no good data to suggest that BID heparin is just as good as tid heparin. There is the one Canadian colorectal trial, which is an outlier to the statement, and that trial would require further discussion that is beyond the scope of this present discussion. |
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In some patient groups, recommendations are given for a class of drugs despite the fact that evidence is not available for all the drugs within that class, or even 1 drug of that class. What is your opinion on that? |
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| Enoxaparin had gotten 7 FDA indications for that, and the other drugs did not have that. But then all of a sudden, as time went along, for example, dalteparin also had it in general surgery, then dalteparin got a really good hip study, the NAFT trial, done, and so as time has gone on, I’m less and less bothered about those conclusions because it seems that within a class of drugs, the drugs do pretty well. And I’m still not to the point where I think that they are interchangeable, and I think that one should best use the drug in the trial that has been shown to, for example, be FDA approved. And so 2 of the 3 drugs for example are approved for DVT treatment, and I think that one ought to go along those guidelines. |
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Duration of prophylaxis is another important issue that is currently addressed by various studies, including the EXCLAIM study in medical patients. The guidelines include recommendations on prolonged prophylaxis after hospital discharge of surgery patients, mainly based on studies done in patients with cancer, including ENOXACAN II. The recommendations for general surgery patients are less specific, and of a different grade than those for gynecological patients, grade 2A versus 2C. What could be the reason for this, and does this influence the value of the recommendation in clinicians' eyes? |
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That is a very, very good question and as far as I can tell, the reason they were written the way they were was because of the limitation of the trials that were done.
So in the absence of these data, they’ve said that, well, for example in 1 group, I think for example ENOXACAN II using enoxaparin for 30 days in abdominal surgery cancer patients, is a very well-done trial. We do not have those trials in gynecologic surgery per se, so that I think is one difference there. But as far as the clinician, do not forget when you talk about a clinician, you are talking about a person that does not just use evidence-based guidelines, but also uses what? Logic, emotion, and experience, and based on all of those factors put together, treats the patient. I would like to also point out to the people writing the guidelines that I would have liked to have seen a little more emphasis… if they are going to editorialize about bleeding and thrombosis in hip surgery for example, I think they ought to take the liberty to do the same thing with terms of extended prophylaxis. Anyone who has ever had a loved one that has had out-of-hospital care with a serious illness, a bilateral total knee, a cancer operation, abdominal perineal resection with colostomy and hyperalimentation and wound infection and dressing changes; they go home to their recliners, where they are in a state of early angulation, not early ambulation.
They are very thrombosis-prone; those risk factors of thrombosis have not gone away. So under the category of immobility, those people need long-term protection, and I would have liked to have seen that. Is there going to be a trial in all of these patients? I do not think there is any money for that and I do not think that that will be done. But that does not change what the picture is in providing the best patient care to that group, and that means using immobility as criteria for extending prophylaxis. |
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In moderate-risk and higher-risk general surgery patients, mechanical prophylaxis with graduated compression stockings and intermittent pneumatic compression is no longer recommended in ACCP 7. What is your opinion about that? |
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Well, it is too bad because there are small individual trials that show the value of pneumatic compression especially with stockings, and I would look at the Cochrane analysis for some data in that regard published in 2003. But a large trial involving fondaparinux and pneumatic compression is about to be released, and I think that when people see that trial, that will affirm the value of not only fondaparinux as a good drug in general surgery prevention, which we already know from the European studies, but also pneumatic compression as an effective form of thrombosis prophylaxis.
If you take a look at general surgical practices in the United States, the most commonly used prophylaxis is intermittent pneumatic compression. It has been very, very successful, and a number of studies have also been done to show it is successful. Why they would make that omission is not clear to me. |
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Dr Caprini, what are your thoughts on calf-vein thrombosis in particular? |
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This is an area of particular interest to me because since 1986 in our vascular laboratories we have routinely been examining the entire leg for the presence of calf-vein thrombosis. Those scans used to take an hour per leg, and now we are down to 18 minutes per leg. Some people have said that we’ve wasted years and years and years of valuable time looking at something that does not mean anything, and I would like to make a few comments about this.
Number one, in many good vascular laboratories throughout the country, we were able to identify thrombi in the axial veins, particularly the posterior tibial and the peroneal veins, and that these clots have also been associated with a number of things.
For example, Hugo Partsch identified the fact that a third of patients with calf-only thrombosis had positive lung scans when they were admitted to the hospital, and of course those of us interested in this area feel that that is because there was a bigger clot and the calf part was all that was left once the more proximal clot went off and went to the lungs.
The second thing is that in 2 autopsy series, the incidence of fatalities that were attributable to pulmonary emboli—and the only evidence that they could find of clots in these patients were calf clots—were 2 series in which the incidence was 13 and 15% respectively.
The next point is that in my own practice, patients with calf-only thrombosis had a 25% incidence of having a positive marker for thrombophilia, and in my opinion, calf-vein thrombosis therefore was a tip-off to something more serious, as if the patients had relatives and birth control pills were in the picture, pregnancies and so forth. This may have been an important clinical item.
And finally, the patient develops a clinical clot, the calf clot. That patient in my opinion is labeled like somebody with a prison record as a clotter. That means if they have a recurrent clot that they could have an increased chance of a DVT, but what else do we know which has not really been emphasized in the Chest document? Patients with recurrent thrombosis have a 6 times higher prevalence of the post-thrombotic syndrome than the first time around. So that if the first time around was a calf clot, nobody diagnosed it, nobody was even worrying about it, and then the patient comes back and gets another clot. Now they have a lifelong permanent disability. |
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In light of the new ACCP 7 guidelines, what are your clinical recommendations on the use of fondaparinux versus low-molecular-weight heparin, versus unfractionated heparin, versus warfarin, etc? |
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Well, this is a very interesting dilemma in my opinion. And let us roll the clock back down to November 19, 1993, when Russell Hull published in the New England Journal that the venographic incidence of DVT after total hip and total knee with warfarin prophylaxis was as high as 25 to 45%.
The next thing is that over 7400 patients were studied in this massive fondaparinux program in total hips, total knees, and in hip fracture patients, and then subsequently another study in hip fracture extended prophylaxis. And the incidence venographically of venous thrombosis, was startlingly low. It was very, very low, it was dramatically low, dramatically lower than low-molecular-weight heparin for example, in total knees. The Lechler trial was used to register enoxaparin for use for total knees because the incidence of DVT with the prophylaxis was only 33% venographically. Well, when the fondaparinux trial did it in the enoxaparin arm, that incidence was reduced to 27% with enoxaparin, but in the fondaparinux group, it was 12%.
Now, let us just shift here for a second, just keep that in mind; the dramatic difference between heparin, low-molecular-weight heparin, warfarin, and fondaparinux in the orthopedic patients, and now let us take a look at extended prophylaxis. The Penthifra-Plus trial, the single most successful thrombosis prophylaxis trial ever, because it eliminated 98% of the clots, was not even mentioned in the hip fracture section at Chest; only in the prophylaxis section for extended prophylaxis. In my mind, since it was the single most important trial ever done, it should have been mentioned twice, so the people, when they are thinking about hip fracture for primary prophylaxis, would not forget about it. That was number one.
Number two is the 30-day result, what did they show? If you gave 30 days of the drug, there was a 1.4% venographic incidence, but there was also 1 patient in the clinical group who also got a clot. When you look at the patients that got only 7 days of fondaparinux, what do we see? At 30 days, 35% of them, a third of them, had a positive venogram. Whereas only, and again this was statistically significant, 2.5% had a clinical clot. So, this study showed that a statistically significant difference in both venographic and the clinical incidence of DVT in a particular study.
Now, if you couple that with the 8 studies that were done after total hip replacement, using either fondaparinux, dalteparin, or coumadin, where the 30-day results were better than the 7 day results, they showed not only venographical superiority, but clinical superiority, so where am I going with all of this?
I feel that venography, based on the literature, had now become a viable surrogate marker for clinical events. In other words, if you do 600 or 700 patients, and you get a venographic and a clinical difference that is significant, if you did 50,000 patients, you’d see an enormous clinical difference. See, those are the kinds of numbers you need for clinical incidences because they are much smaller than venographic, but the link is there.
Now, based on that link, why in the world would people still recommend 1A for coumadin or warfarin, when the best that warfarin could do was in the high 30% or 40% range as far as protection, and in the knees it was 45% or higher with prophylaxis, in fact it was 55%. [The] warfarin arm in the tinzaparin/warfarin trial was 55% in total knees, 12% with fondaparinux. These are data; I’m not making any of this up. The guidelines group should be pointing out these differences to us.
In my mind, certainly one can argue whether or not in a total-hip population you are going to use fondaparinux or dalteparin or enoxaparin; there are good data for all of those. But why in the world would you put that on a level with warfarin when the incidences are so much higher, and in knees for example where it’s unbelievably higher, 55% for warfarin, 12% for fondaparinux, 27% for enoxaparin, are not these data reported with venographic end points? Why are we not dissecting with a microscope these data instead of lumping them all in and saying, all these alternatives are acceptable. I do not really think they are all acceptable.
I think the benefit:risk ratio of each individual patient has to be calculated, and then on the basis of that, a decision has to be made, and that decision has to involve the reported venographic end points for these diseases because there now is ample evidence that these venographic end points mirror clinical events.
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Dr Caprini, in your practice, you perform bariatric surgery frequently. How useful do you find the guidelines on prophylaxis in patients undergoing this type of surgery? Do they help in making decisions on clinical issues in current practice such as weight-based-dose versus fixed-dose administration? |
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The trials that are out there help to show us what would be safe and in some sense effective. But I don’t think we really have enough data yet, and I think individual bariatric surgery programs have to make their own decisions regarding thrombosis prophylaxis protocols, which have to include not only the available science in Chest, but also logic, emotion, and experience. And in that regard, a lot of other issues come into play.
I don’t really believe now that there’s going to be that great a difference in weight-based versus fixed. I think that one can dose them by weight, and that the heavier they are, the more they need. I think that that’s an emerging consideration, but we really don’t have enough data. Each individual program certainly has to have a thrombosis prophylaxis protocol, and I would remind the listener that if you look at the bariatric surgical survey, which was a survey of surgeons talking about their own experience, and you know what we do is, we always tend to forget about the bad stuff and talk about the good stuff, and talk in front of each and every individual record. Well, in the view of those bariatric surgeons, the overall impression was that 1 out of 85 of those patients were dying of a fatal pulmonary embolism, so that they realized that there is a problem, and I think as such will construct these protocols for patient safety. |
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To conclude, what is your opinion on the applicability of the seventh ACCP guidelines in general? To what extent do they provide practical guidance to surgeons in their decision-making on prophylaxis in surgery patients? |
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| I think these guidelines are the best yet, and those of us in the field are extremely excited to have them. One has to understand what they are, and they are a compilation of the evidence that has been analyzed by world experts. As such, they are all human beings, and they also contain editorial comments, just like in this interview, I have expressed to you some very strong editorial comments. I think that what we have to do is go beyond those guidelines, and go into clinical practice and make sure what we are doing conforms not only to academic Chest guidelines, but also to clinical-practice guidelines that have been the purview of very busy, successful clinical practitioners, and with more time and more work, then one needs to put these things eventually together. |
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Dr Caprini, thank you very much for this expert commentary and for your contribution to ThrombosisClinic™.com. |
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| Thank you for the opportunity to express these views. |
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