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JOURNAL CLUB - VTE Prophylaxis

June 2009

Editorial Overview:

Jeffrey Weitz, MD, FACP, FRCPC, FCCP, FAHA

Director, Henderson Research Centre, Professor, Departments of Medicine and Biochemistry and Biomedical Sciences, Canada Research Chair in Thrombosis, HSFO/J.F. Mustard Chair in Cardiovascular Research, McMaster University, Hamilton, Ontario

Venous thromboembolism (VTE) prophylaxis is the guideline-supported standard of care after elective total joint arthroplasty. This guideline stems from the fact that, in the absence of prophylaxis, VTE develops in approximately 50% of individuals who undergo total joint arthroplasty.¹ Although most cases of VTE are silent, the risk from symptomatic VTE is substantial. Thus, the 28-day fatality rate in patients with deep venous thrombosis (DVT) is 9%, reflecting the risk of associated fatal pulmonary embolism (PE). The case-fatality rate increases to 15% in those who present with PE.²

Current guidelines recommend a low molecular-weight heparin (LMWH) such as enoxaparin, fondaparinux or warfarin for thromboprophylaxis after elective hip or knee arthroplasty. Prophylaxis should be given for at least 10 days after surgery, although extended prophylaxis for 14 to 35 days is recommended, particularly in patients who have undergone hip arthroplasty. These recommendations are based on the fact that the risk of VTE persists after hospital discharge.

Although in-hospital compliance is high in most North American centres, the challenge has been providing an effective and convenient method of VTE prophylaxis after hospital discharge. Thus, LMWH and fondaparinux require once-daily subcutaneous injection, whereas warfarin requires coagulation monitoring and dose adjustment. Because of these limitations, many centres stop thromboprophylaxis when patients are discharged. With progressive reductions in the length of hospital stay after joint arthroplasty, this means that many patients are receiving an inadequate VTE prophylaxis.

The introduction of new oral anticoagulants, particularly the direct thrombin inhibitor (DTI) dabigatran etexilate and the factor Xa inhibitor rivaroxaban, provide an opportunity to streamline thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. Because they can be given in fixed doses once-daily without coagulation monitoring, the new oral anticoagulants overcome the limitations of LMWH, fondaparinux and warfarin. Even if injectable agents are used for VTE prophylaxis in hospital, dabigatran etexilate and rivaroxaban will simplify out-of- hospital management, making it easier for patients and physicians to adhere to current practice guidelines.

New Oral Anticoagulants

Dabigatran etexilate and rivaroxaban are oral anticoagulants that are not influenced by food, have a low risk of drug-drug interactions and produce such a predictable level of anticoagulation after fixed-dose administration that routine anticoagulant monitoring is unnecessary. These features render dabigatran etexilate and rivaroxaban ideal for out-of-hospital VTE prophylaxis. With documented efficacy for the prevention of VTE after hip or knee arthroplasty, dabigatran etexilate and rivaroxaban have the potential to simplify outpatient VTE prophylaxis. Building on the promising results in orthopedic patient s , bot h anticoagulants are undergoing extensive phase III evaluation for other indications. For example, a large phase III trial comparing dabigatran etexilate with warfarin for stroke prevention in patients with atrial fibrillation has been completed and the results will soon be reported. Rivaroxaban also is being compared with warfarin for this indication.

Dabigatran etexilate and rivaroxaban differ by class and mechanism of action (Figure 1). As a DTI, dabigatran directly inhibits thrombin, the final effector in coagulation. In addition to blocking thrombin-mediated conversion of fibrinogen to fibrin, dabigatran also blocks thrombin-mediated amplification of coagulation and platelet activation. Compared with indirect thrombin inhibitors, such as heparin or LMWH, which must interact with antithrombin in order to exert their anticoagulant activity, DTIs not only inhibit fluid-phase thrombin, but also inhibit thrombin bound to fibrin.³ In addition, DTIs produce a more predictable anticoagulant response than heparin or LMWH because they do not bind to plasma proteins, the levels of which vary from patient to patient. Furthermore, unlike heparin, DTIs do not bind to platelet factor 4, a cationic protein released from activated platelets. Consequently, DTIs retain activity in the vicinity of platelet-rich thrombi and do not cause heparin-induced thrombocytopenia.

These features help explain the predictable pharmacokinetics and anticoagulant effects of DTIs, which circumvent the need for coagulation monitoring.⁴

Acting further upstream, direct factor Xa inhibitors like rivaroxaban attenuate thrombin generation.⁵ Unlike indirect factor Xa inhibitors such as fondaparinux, which have limited activity against factor Xa when it is incorporated within the prothrombinase complex, direct factor Xa inhibitors block free factor Xa and factor Xa within the prothrombinase complex equally well. This feature may provide direct factor Xa inhibitors with a mechanistic advantage over indirect inhibitors.

With any anticoagulant, there is a critical balance between effective blockade of thrombus formation and bleeding risk. Despite the modest increase in bleeding associated with the use of LMWH, fondaparinux or warfarin for VTE prophylaxis after elective hip or knee arthroplasty, the overall benefits have led the American College of Chest Physicians (ACCP) to confer a grade 1A recommendation, their strongest endorsement, for any of these agents after total joint arthroplasty. For evaluation of the new oral anticoagulants, enoxaparin was used as the comparator because it is the agent that is most widely used for VTE prophylaxis in North America. On the basis of these studies, both dabigatran etexilate and rivaroxaban have been licensed in Canada and Europe for VTE prophylaxis after elective hip or knee arthroplasty. Although the drugs have yet to be compared head-to-head, the individual trials against the common comparator of enoxaparin suggest potential differences in benefit-to-risk ratio at the recommended dosages.

VTE Prevention with Dabigatran Etexilate: RE-NOVATE, RE-MOBILIZE, RE-MODEL trials

The key registration trial evaluating dabigatran etexilate for VTE prophylaxis after elective hip arthroplasty was the RE-NOVATE trial.⁶ In this double-blind trial, 3494 patients were randomized to one of three arms: 220 mg dabigatran, 150 mg dabigatran or 40 mg enoxaparin, all administered once daily. Both regimens of dabigatran were initiated at half-dose one to four hours after surgery. Enoxaparin was started the evening before surgery. The planned prophylaxis was for 28 to 33 days. The primary efficacy end point was total VTE, a composite of symptomatic or venographic DVT, non-fatal PE and all-cause mortality during treatment. The primary end point was reached in 6.0% of patients randomized to the higher dose of dabigatran, 8.6% of those receiving the lower dose and 6.7% of those given enoxaparin. Major bleeding rates were 2.0% or less in all groups and did not differ significantly. Major VTE (a composite of proximal or symptomatic DVT, non-fatal PE and VTE-related mortality) was lower with the higher dose of dabigatran than it was with enoxaparin (3.1% and. 3.9%, respectively). Based on these results, the authors concluded that dabigatran etexilate was as effective as enoxaparin for VTE prophylaxis after elective hip arthroplasty and offered a similar safety profile.

Figure 1.

The key registration trial for VTE prophylaxis after elective knee arthroplasty was the RE-MODEL trial.⁷ In this double-blind trial, 2076 patients were randomized to the same three regimens evaluated in RE-NOVATE except that prophylaxis was given for 7 days. When compared for the same primary efficacy outcome of total VTE, this end point was reached by 36.4% on the higher dose of dabigatran, 40.5% on the lower dose and by 37.7% of those given enoxaparin. Again, major VTE was lower with the higher dose of dabigatran than it was with enoxaparin (2.6% and 3.5%, respectively). The rates of major bleeding rates were low (1.3% to 1.5%) and almost identical in all three study groups. Based on these data, the authors considered dabigatran etexilate to be at least as effective as enoxaparin for VTE prophylaxis after elective knee arthroplasty with comparable safety.

A third trial, called RE-MOBILIZE, compared the same doses of dabigatran with a higher dose of enoxaparin (30 mg twice daily) started 12 to 24 hours after surgery.⁸ With this higher-dose enoxaparin regimen, total VTE was significantly lower than it was with either the higher or lower dose of dabigatran etexilate (25%, 31% and 34%, respectively). However, the study also highlighted the tenuous balance between efficacy and safety because the rate of major bleeding was twice as high with enoxaparin as it was with either dose of dabigatran etexilate (1.4%, 0.6% and 0.6%, respectively) (Figure 2).

Trials with Rivaroxaban: The RECORD Program

Rivaroxaban was compared with enoxaparin for VTE prevention in the RECORD program. RECORD 1 and 2 compared rivaroxaban with enoxaparin for VTE prophylaxis after elective hip arthroplasty,^9,10 whereas RECORD 3 and 4 made the same comparison in patients undergoing elective knee arthroplasty.^11,12 All four trials used the same dose of rivaroxaban, 10 mg once daily started 6 to 8 hours after surgery. In RECORD 1 and 2, treatment was given for about 35 days, whereas treatment was given for 10 to 12 days in RECORD 3 and 4. The comparator for all trials was enoxaparin. The dose of enoxaparin was 40 mg once daily starting the evening before surgery in RECORD 1, 2 and 3 and 30 mg twice daily starting 12 to 24 hours after surgery in RECORD 4. Enoxaparin was given for 35 days in RECORD 1, for 14 days in RECORD 2 and for 10 to
and 4.

Figure 2.

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In all four trials, rivaroxaban produced a statistically significant reduction in total VTE. Furthermore, a pre-specified meta-analysis of the results of these trials revealed a significant reduction in total VTE with rivaroxaban (HR 0.42; 95% CI, 0.29-0.63; P<0.001). Although there was a trend for more major bleeding with rivaroxaban, this difference did not reach statistical significance (HR 1.31; 95% CI, 0.99-1.73; P=0.06). When major and clinically relevant non-major bleeding events were combined at the end of the treatment period, there was a small and statistically significant increase in events with rivaroxaban compared with enoxaparin (HR 1.25; 95% CI, 1.01-1.54; P=0.039). Nonetheless, despite this small increase in bleeding, the net clinical benefit favours rivaroxaban and at recent regulatory hearings in the US, the advisory committee recommended drug approval by a large majority.¹³

The data with the new oral anticoagulants, like the data with all previous anticoagulants, confirm that there is an important balance between efficacy and safety. Thus, a greater reduction in VTE often comes with an increase in bleeding. Finding the delicate balance between efficacy and safety is the key to optimal use of anticoagulants. Nonetheless, the new oral anticoagulants offer substantial benefits. With fixed dosing and no monitoring, these agents are ideal for long-term use. The results of clinical trials comparing dabigatran etexilate or rivaroxaban with enoxaparin for VTE prophylaxis after hip or knee arthroplasty are promising and there is no doubt that these agents will streamline VTE prophylaxis in this setting. However, the greater unmet medical need is to find a replacement for warfarin for long-term indications such as stroke prevention in atrial fibrillation. If dabigatran etexilate and rivaroxaban fare as well against warfarin as they do against enoxaparin, these agents have the potential to replace warfarin. This would revolutionize longterm anticoagulation therapy by simplifying dosing and eliminating the multiple food and drug-drug interactions related to warfarin treatment. The results of the first clinical trial in atrial fibrillation will soon be available. With these data, we will know whether the new oral anticoagulants can meet our expectations. If so, other indications will soon follow and oral anticoagulation therapy will change forever.

Summary

Dabigatran etexilate and rivaroxaban are important new options for VTE prophylaxis after total joint arthroplasty. As oral agents that can be given in fixed doses without coagulation monitoring, these new drugs will simplify VTE prophylaxis and make it easier for patients and physicians to adhere to current pract ice guidel ines that recommend thromboprophylaxis for at least 10 days and up to 35 days, particularly in patients undergoing hip arthroplasty.

References

1. Lieberman JR, Hsu WK. Prevention of venous thromboembolic disease after total hip and knee arthroplasty. J Bone Joint Surg Am 2005;87:2097-112.

2. Cushman et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004;117:19-25.

3. DiNisio M, Middeldorp S, Buller HR. Direct thrombin inhibitors. N Engl J Med 2005;353:1028-40.

4. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998;97:251-6.

5. Weitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843-53.

6. Eriksson et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomized, double-blind, non-inferiority trial. Lancet 2007;370:949-56.

7. Eriksson et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemostas 2007;5:2178-85.

8. RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs. North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24:1-9.

9. Eriksson et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765-75.

10. Kakkar et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31-9.

11. Lassen et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:276-86.

12. Turpie et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009:Epub ahead of print.

13. Xu Q. Xarelto: Cardiovascular and Renal Drugs Advisory Committee Meeting. Presentation slides on line: http://www.fda.gov/ohrms/dockets/ac/09/ slides/2009-4418s1-04-FDA-Xu.pdf. Accessed May 14, 2009.

questions and answers

Panel

Normand Blais, MD, FRCPC, CHUM-Hôpital Notre-Dame, Montreal, Quebec

Russell D. Hull, MD, FRCPC, University of Calgary, Calgary, Alberta

James Waddell, MD, FRCSC, St. Michael’s Hospital, Toronto, Ontario

1. Surveys indicate that most patients receive some form of VTE prophylaxis after total joint arthroplasty, but far fewer receive prophylaxis for periods commensurate with guidelines, particularly the 28 to 35 days of VTE prophylaxis recommended after hip arthroplasty. What are the obstacles?

Dr. Waddell: There are several issues. One is that some physicians may have a lingering doubt about the benefit-to-risk ratio of an extended period of prophylaxis that prevents them from keeping patients on an anticoagulant through the whole recommended period. Another important issue is that patients generally go home on day 3 after surgery. While prophylaxis can be easily controlled in the hospital, there may be a loss of urgency outside of the hospital, particularly if prophylaxis requires injection. There are some data from Quebec suggesting that there is an increase in mortality in individuals who do not receive the full period of prophylaxis, so this is an important issue.

Dr. Hull: It is incorrect to suggest that prophylaxis for thromboembolism is underemployed. Data suggest that 95% of total hip arthroplasty patients receive prophylaxis. The question is whether patients are receiving an optimal duration of thromboprophylaxis. The key unmet need has been an oral agent that does not require blood monitoring. This is an important advance for facilitating protection. In Canada, we now have two oral agents, so maintaining patients on thromboprophylaxis is easier, but oral agents do not entirely replace LMWH. Injectable agents are still best for some individuals, such as those experiencing nausea and vomiting that make them poor candidates for an oral agent.

Dr. Blais: One of the obstacles is a lack of a consistent approach. VTE prophylaxis is not usually employed as a marker for quality of care in most Canadian hospitals. In those hospitals which do establish very strong policies for VTE prophylaxis, there is usually a leader who has enlisted a coordinated effort that involves all those who need to participate, which includes surgeons, physicians, pharmacists and nurses. One of the most effective approaches to ensuring compliance with guidelines is to create prewritten orders for all joint replacement patients, forcing surgeons to opt out rather than write a prescription for VTE prophylaxis.

2. Warfarin is generally considered difficult to use, but does the difficulty stem from the need for monitoring, the interpatient variability in response, some other cause, or a combination of issues?

Dr. Hull: The vitamin K antagonists are generally used only in North America, and it is clear they pose more risks than the LMWHs because of the difficulty of maintaining patients in the therapeutic range. Although the recommended INR range is 2.0 to 3.0, some orthopedists aim for an INR of 1.5 to 2.0 in order to reduce the bleeding risk, although this raises concern about providing adequate prophylaxis for thromboembolism. As alternative oral agents, the newer oral agents simplify management because they do not require monitoring. This is helpful for short-term prophylaxis after total joint surgery, but it will be even more important for long-term anticoagulant regimens, such as those employed to prevent cardiovascular events in patients with atrial fibrillation.

Dr. Blais: For physicians who have experience with warfarin, the dosage adjustments may not be a big hurdle, but I come from a different generation where training was primarily with LMWHs, which are less cumbersome to use and are more effective than warfarin. While the need for dose adjustments is one problem, I think the real reason that LMWHs have largely replaced warfarin is the evidence that warfarin is inferior for VTE prophylaxis.

Dr. Waddell: One reason I have been reluctant to use warfarin is the slow onset. Data suggest that patients are not fully anticoagulated until day 3 after starting the agent. In addition, the need for dose adjustment is inconvenient for both the patient and the physician. At sites where there is an anticoagulation clinic, this may not be such a problem. But for a surgeon who is trying to maintain two or three dozen total hip arthroplasty patients at any given time on warfarin, it means a great deal of work and responsibility, particularly when maintaining patients on this agent for the full recommended period of anticoagulation.

3. Is the need for injection the major limitation to LMWH use outside of the hospital?

Dr. Hull: The problem of injection is overemphasized if one considers the fact that many diabetics inject themselves with insulin several times per day without difficulty. What is needed is a systematic approach for educating and managing patients. An anticoagulation clinic can be an effective approach for meeting this need. However, in its absence, an oral therapy that does not need monitoring is obviously going to make VTE prophylaxis easier.

Dr. Waddell: Often the patient or a family member can be taught to administer injectable drugs, but instruction is time-consuming. In a busy centre with a high volume of total joint arthroplasties, this diverts staff from other services. For people who are not comfortable with administering an injection, the alternative is a visiting nurse, which can be inconvenient for patients and expensive. LMWHs are very effective and easily administered in the hospital, but there are several barriers that make them more difficult after discharge.

Dr. Blais: Teaching a patient or a caregiver to provide an injection is not the only problem. The bigger problem is that it is often difficult to control the anticoagulant regimen once the patient leaves the hospital. For example, some patients may be discharged to a rehabilitation facility where they have their own protocol. In patients who are discharged home, a twicedaily injection of LMWH may not be practical if a visiting nurse gives injection. We do not have a problem with reimbursement in Quebec, but this can be an issue in other provinces. An oral anticoagulant which does not need monitoring could be helpful in improving the standardization of care after discharge.

4. Most of the studies with newer oral anticoagulants are non-inferiority studies, usually with enoxaparin. Is this a reasonable standard for comparison? If an oral agent is non-inferior to an injectable agent for VTE prophylaxis, is it superior from a practical standpoint because of the greater ease of use?

Dr. Waddell: Enoxaparin is a reasonable comparator because its efficacy is well accepted and it is probably the most widely used anticoagulant in Canada. The concept of a non-inferiority trial is that the two drugs are comparable for safety and efficacy for their clinical application. However, if one of the drugs is just as effective and well tolerated but easier to use, it is clear that the drug that is easier to use will be first-line, so the drugs are not interchangeable on that level.

Dr. Hull: There have been four studies with rivaroxaban and three studies with dabigatran. All compared these newer oral anticoagulants to enoxaparin. The first two dabigatran studies found this agent to be non-inferior to enoxaparin. In the third study, dabigatran was inferior for preventing thromboembolism when compared to a relatively aggressive dose of enoxaparin, but dabigatran was associated with less bleeding. In the studies overall, dabigatran has been very safe. Rivaroxaban demonstrated superiority to enoxaparin in all four trials, but bleeding rates have generally been higher. When all four rivaroxaban trials are pooled, the higher rate of bleeding on rivaroxaban relative to enoxaparin was significant. This suggests that patients and physicians will have to decide their risk tolerance. Historically, physicians have been risk-adverse, suggesting dabigatran will be favoured, but time will tell.

Dr. Blais: Both physicians and patients have been waiting for an effective and easy-to-use oral anticoagulant because of the cumbersome aspect of an injectable drug. We do know that enoxaparin and the other LMWHs are safe and effective, so showing that a once-daily oral anticoagulant with predictable activity that does not require monitoring is just as effective, this is a major advantage compared to the standard. For one thing, I think it is reasonable to suggest that an oral therapy which is just as effective as an injectable therapy would offer an advantage on the basis of quality of life.

5. Efficacy against VTE is very closely related to risk of bleeding. When weighing options, do you consider bleeding risk as important as efficacy in assessing the value of treatment?

Dr. Blais: Different specialists see these issues very differently. I think the most important issue for most orthopedic surgeons is bleeding. They are concerned about VTE, but they are very worried about giving a therapy that could increase hemorrhage in the wound. Bleeding events can postpone rehabilitation, increase pain and jeopardize the surgical result. For the hematologist, it is probably the opposite. They are concerned about bleeding, but the failure to offer enough anticoagulant to prevent a VTE is their first priority. Very well-controlled clinical trials are needed because both groups must be reassured that they are providing the optimal benefit-to-risk ratio, because the efficacy of VTE prophylaxis and bleeding events are related.

Dr. Hull: The most recent dabigatran study, RE-MOBILIZE, illustrates the issues. Unlike the previous studies in which dabigatran was compared to 40 mg enoxaparin once daily started preoperatively, the more recent study compared dabigatran to 30 mg enoxaparin twice daily starting after surgery. This is not the favoured regimen in North America because of concern about the bleeding risk. I think that clinically relevant bleeding is at the forefront of the minds of most physicians. Most would opt for harm avoidance rather than a more effective regimen that might also produce a greater risk of significant bleeding.

Dr. Waddell: Bleeding at the surgical site can compromise the arthroplasty, and I think many surgeons feel that this is insufficiently recognized by hematologists evaluating the tradeoff between VTE and bleeding risk. There is a great deal of emphasis on avoiding major bleeding away from the surgical site, such as in the GI tract, which is clearly important, but surgeons also want to avoid even relatively minor bleeding at the wound. This is particularly true in the knees, which can lead to stiffness and a delayed recovery or even a worse surgical result.

6. Different trials have used various definitions of bleeding, thereby complicating comparisons. Is there a single definition you feel is appropriate for evaluating risk?

Dr. Waddell: I think the lack of a wellaccepted definition of bleeding has been a problem for interpreting the clinical studies. Often surgical site bleedings are listed under minor bleeding events or, in some studies, not included at all, but for an orthopedist, this is a very important outcome. We are particularly interested in knowing how many surgical site bleeds resulted in a return to the operating room for evacuation of the hematoma. Minor bleeding may be defined differently by an orthopedic surgeon than a hematologist. This is a critical problem with interpretation of clinical trials, which have employed different types of definitions and not always the definitions that are most helpful to surgeons.

Dr. Hull: It is important to recognize that bleeding rates were calculated differently in the trials conducted with dabigatran and rivaroxaban. The latter set of studies did not include major operative site bleeds in the major bleed category. However, the Canadian regulatory authorities have required all major bleeds to be included so the drugs can be accurately compared by the product monographs. The fact that major bleeding rates are six or seven times higher with rivaroxaban than reported in the published studies raises an important point. Most major bleeds do occur at the operative site, and it is important to include all major bleeds when trying to develop an accurate benefit-to-risk analysis.

Dr. Blais: If you are not counting surgical site bleeds in any given analysis of bleeding rates after total joint arthroplasty, then you are not respecting the surgical intent. The first priority of the surgeon is to have a good surgical outcome, and bleeding, as I said before, can compromise the outcome. It is important to include all bleeding events, not just the major events, and to understand this risk in a way that is relevant to surgery. I think not enough attention has been given to the definitions of bleeding. Rather than just major bleeds or minor bleeds, it would be useful to know more about clinically significant surgical site bleeds specifically and what steps were taken when these bleeds occurred.

7. If physicians feel more confident about relative risks and benefits, do you believe VTE prophylaxis would be used more frequently in accordance with current guidelines?

Dr. Blais: The problem is not that surgeons do not know the guidelines for VTE prophylaxis. I think most surgeons understand them very well. However, these are not followed in daily practice because of a lack of confidence that these guidelines are relevant to all patients. Also, I think we are all very influenced by our clinical experiences. For example, a surgeon is likely to be very aggressive for VTE prophylaxis if he or she has ever had a patient develop a pulmonary embolism. In contrast, a surgeon who has had bad results because of bleeding may have a different perspective. Communication between specialists that would permit an agreement on guidelines would be helpful, but this will depend on the ability of different specialists to also agree on end points other than rates of VTE or bleeding, such as quality of life. More surgeons would offer full doses of recommended agents for the full period of prophylaxis with clear and consistent evidence that benefits outweigh risk.

Dr. Hull: Again, there is no simple answer to the question of whether one of the newer oral anticoagulants is better than another. If the key issue is harm avoidance, dabigatran will be the first choice. It has shown to be not inferior to enoxaparin in currently used regimens, and it is reasonably safe. Rivaroxaban was superior to enoxaparin but produced more bleeding. Dabigatran and rivaroxaban have not been directly compared. Although the data suggest that dabigatran may not be quite as effective as rivaroxaban, physicians need to consider both the risks and the benefits of either drug when making a choice.

Dr. Waddell: The development of oral agents that do not need monitoring is going to lead more physicians to provide anticoagulation for the full periods now recommended by the guidelines, but we do not know whether these recommendations are the absolute best way to protect patients for several reasons. We have never had a trial to compare strategies for prevention of the real events we are trying to prevent, which includes symptomatic DVT and pulmonary embolism, rather than the surrogate of VTE on venography. Such a trial will probably never be conducted because of the large number of patients that would be required. It would also be helpful to know whether prophylaxis for more than 35 days, which is now practical with an oral agent, would offer even greater protection. However, the evidence that the newer oral therapies appear to be as effective and safe as enoxaparin is an important step forward.