Prevention of venous thromboembolism after surgery

EMERGING ANTICOAGULANT OPTIONS

For many years, unfractionated heparin was the only available parenteral anticoagulant. While heparin has broad anticoagulant properties, it also has well-established limitations, including the need for parenteral delivery, recent problems related to contamination (it is derived from pig intestines), and of course heparin-induced thrombocytopenia (HIT). HIT is an immune-mediated form of platelet activation that can lead to widespread thrombosis throughout the body. It is more commonly associated with venous thrombosis, but arterial events with limb-threatening ischemia may also occur. LMWH is associated with a reduced risk of HIT, but LMWH does not avoid the risk entirely.

Beyond the issue of avoiding HIT, newer anticoagulant therapies are being developed with the aim of oral administration and more targeted inhibition of coagulation factors IIa (thrombin) and Xa.²⁴

Oral direct thrombin inhibitors

One of the two most promising classes of emerging anticoagulants is the direct thrombin inhibitors, most of which are being developed for oral administration. There were high hopes for the initial compound in this class, ximelagatran, but it was abandoned about 5 years ago because of hepatotoxicity.

Dabigatran is the direct thrombin inhibitor furthest along in development today. Currently approved in Europe for prevention of VTE in patients undergoing total hip or knee replacement surgery, dabigatran is likely to be available soon in the United States. It is administered orally, has a rapid onset of action (< 1 hour), and has a predictable anticoagulant response that requires no monitoring.²⁴ Because dabigatran is excreted essentially unchanged by the kidneys and may bioaccumulate, it should not be used in patients with renal impairment or rapidly changing renal function.

In phase 3 clinical trials for VTE prevention in knee replacement surgery, dabigatran was at least as effective as enoxaparin 40 mg once daily and had a comparable safety profile,²⁵ but it was slightly less effective than enoxaparin 30 mg twice daily.²⁶ In a phase 3 trial in patients under­going hip replacement surgery, dabigatran was equivalent in efficacy and safety to enoxaparin 40 mg once daily.²⁷

Oral direct factor Xa inhibitors

A key rationale for direct inhibition of factor Xa is that it results in inhibition of thrombin production on the activated platelet. Whereas fondaparinux is an indirect inhibitor of factor Xa, direct factor Xa inhibitors offer an advantage in that they inhibit factor Xa within the prothrombinase complex, which occurs on the surface of a platelet and is the main site for thrombin development (very little thrombin is actually produced on endothelial cells). Recall the adage that “thrombin begets more thrombin”: it activates not only platelets but the intrinsic and extrinsic pathways.²⁸

Factor Xa may be a better target than thrombin for a number of other reasons:

• Factor Xa is believed to have few functions (compared with thrombin) outside of coagulation

• In vitro studies show that factor Xa has a wider therapeutic window than thrombin, which translates to greater separation between drug levels that will confer efficacy and bleeding
• Thrombin inhibitors are associated with rebound thrombin generation (there is no evidence of this with factor Xa inhibitors)
• The efficacy of heparin-based anticoagulants improves as selectivity for factor Xa increases (unfractionated heparin is less effective than LMWH, which is less effective than fondaparinux).

Two direct factor Xa inhibitors—both administered orally—are far along in development, as detailed below.

Apixaban has shown promise, but the phase 3 ADVANCE-1 study of apixaban for VTE prevention in patients undergoing knee surgery did not meet statistical criteria for noninferiority compared with enoxaparin 30 mg twice daily.²⁹ This prompted a delay in regulatory filings for apixaban in the United States, and the drug’s prospects for approval for VTE prevention may be unclear until release of results from two other comparative phase 3 trials with enoxaparin in 2009 and 2010.

Rivaroxaban is more likely to become clinically available soon, in light of recent results from the phase 3 RECORD4 trial demonstrating that it was significantly superior to enoxaparin 30 mg twice daily in preventing VTE following knee replacement surgery with comparable rates of major bleeding.³⁰

DISCUSSION

Question from the audience: Some surgeons in my hospital prescribe warfarin immediately after surgery without a bridge of LMWH. Is that appropriate?

Dr. Michota: Warfarin is an option for prophylaxis in orthopedic surgery, beginning on the day of surgery. It could even be started the day before surgery, but the dose should be monitored to achieve an INR between 2.0 and 3.0 within 72 hours of the procedure. If the INR is not in this optimum range, prophylactic doses of LMWH can be given until it is therapeutic.

Follow-up question: In practice, do you actually encourage INR monitoring? Usually we just put patients on a certain dose without monitoring. When we do check the INR, it’s usually 1.4 or 1.5.

Dr. Michota: Warfarin was shown to be effective in reducing VTE risk in orthopedic surgery with dose adjustment based on INR monitoring. On that basis, warfarin remains in the guideline recommendations. Unmonitored, warfarin has not been shown to reduce risk, so to give it that way would not be evidence-based.

Question from the audience: I work with several plastic surgeons who use compression stockings intraoperatively because they’ve heard of several patients who developed a PE during surgery. Is there any benefit to using compression stockings for 2 to 3 hours and then sending the patient home?

Dr. Michota: I don’t know. Theoretically, a device that is on and working before induction may reduce stasis.

The plastic surgery societies do have guidelines. Risk depends on the type of plastic surgery procedure; for example, risk probably increases due to inflammation in procedures that involve scraping the fat pads.

This is an area where we don’t have much data. These patients may be at risk, but we don’t know the best way to mitigate it. It is important that risks be discussed with patients in the informed-consent process and be documented. If the surgeon thinks it is reasonable to give pharmacologic prophylaxis after surgery, I wouldn’t hesitate to do that, but any form of bleeding in the setting of plastic surgery is catastrophic because it defeats the reason for which the surgery was done in the first place.

Question from the audience: How do the guidelines address being aggressive with pharmacologic thromboprophylaxis when a patient is already taking dual antiplatelet therapy?

Dr. Michota: For patients with an indication for VTE prophylaxis in a setting for which there is a specific strategy, the ACCP guidelines recommend that they be put on that regimen whether they are on antiplatelet agents or not. For example, consider a high-risk patient having colorectal surgery who should get unfractionated heparin or LMWH postoperatively and who is currently taking clopidogrel and aspirin. There is no evidence that the dual aspirin–clopidogrel therapy alone is effective in decreasing the risk of DVT. However, we do know that if we add on additional agents, the risk of bleeding is increased. The guidelines consider risk and benefit, and they recommend adding the agents that we know work to prevent DVT.

Question from the audience: You briefly mentioned prophylaxis for knee arthroscopy, which is the most frequently performed orthopedic procedure. Do these recommendations apply to all patients undergoing knee arthroscopy?

Dr. Michota: No. Prophylaxis is indicated only for patients with what the ACCP considers to be additional risk factors for thrombosis. They didn’t specify which risk factors, but good indications for prophylaxis would include morbid obesity, limited mobility after the procedure, a personal history of DVT, features of stasis noted on physical examination, stasis dermatitis (or other features that could indicate prior thrombosis), advanced age, and malignancy. If a patient undergoing knee arthroscopy has other nonmodifiable risk factors, you should also think about prophylaxis. But the vast majority of patients do not need it.

Question from the audience: I’m an academic hospitalist who works closely with orthopedic surgeons. Certain surgeons will only use aspirin for prophylaxis, and it is nonnegotiable. Where does that leave me from a medicolegal standpoint? Our model is to follow ACCP recommendations, but these orthopedic surgeons still use only aspirin.

Dr. Michota: You must do everything you can to come to a consensus with your surgeon colleagues. If you are uncomfortable, as a group you must say to the surgeons, “We are uncomfortable. This is how we view the data. How do you view the data?” If they answer, “We’re doing it because it’s easy, and the American Academy of Orthopaedic Surgeons says we can do it,” I don’t have a good response. But it is more likely that their use of aspirin is based on their own observations; they may not see many clots. Of course, the problem with observational data is that the numbers are not large and they are not generated in a randomized and prospective fashion. Perhaps you can come to some middle ground, but you could always make the difficult choice and say, “I’m just not going to follow your patients.”