Prevention of venous thromboembolism after surgery

Recommendations unchanged in neurosurgery, spinal injury, trauma, burns

Recommendations for neurosurgery remain unchanged from the prior (2004) edition of the ACCP guidelines and are still based on the 2000 meta-analysis by Iorio and Agnelli of LMWH prophylaxis in neurosurgery cases.¹¹ In the United States, the standard is overwhelmingly to use mechanical devices for thromboprophylaxis in neurosurgery, even for patients with cancer.

For prophylaxis in surgical patients with spinal cord injury, multisystem trauma, or burns, LMWH is predominantly used, and the ACCP recommendations are unchanged from 2004.

Drug-specific considerations

LMWH vs vitamin K antagonist. Although vitamin K antagonists (warfarin) still appear in the latest ACCP recommendations,¹ LMWH is preferable. A 2004 meta-analysis of studies comparing vitamin K antagonists with LMWH for prophylaxis in patients undergoing orthopedic surgery found that vitamin K antagonists were associated with more episodes of total DVT (relative risk [RR] = 1.51; 95% CI, 1.27–1.79) and proximal DVT (RR = 1.51; 95% CI, 1.04–2.17) compared with LMWH.¹² No difference was found in rates of wound hematoma or major bleeding. This finding of inferiority for vitamin K antagonists came despite the likelihood that warfarin was more often administered correctly (ie, with dose adjustment to achieve an international normalized ratio [INR] of 2.0 to 3.0 within 72 hours after surgery) in the studies in this analysis than it is in real-world practice.

Fondaparinux. The indirect factor Xa–specific inhibitor fondaparinux has had a surprisingly limited clinical adoption despite having been widely studied and found to be safe and effective. This is likely attributable in part to its 17-hour half-life, which raises concerns that it may take 3 days for its effects to stop if a patient begins to bleed. Large phase 3 studies have found fondaparinux to be equivalent to LMWH in VTE prevention after hip replacement, marginally superior to LMWH after knee replacement, and superior to LMWH following hip fracture repair.¹³ Fondaparinux was associated with an increase in bleeding events and instances of transfusion requirement, but only in one of the studies, which was in the setting of knee replacement surgery.¹⁴

Aspirin not recommended by ACCP. Although aspirin reduces the risk of VTE, practice guidelines from both the ACCP¹ and the International Union of Angiology¹⁵ contain no recommendation for its use as prophylaxis because it is considered less effective and more risky than other therapies. In contrast, clinical practice guidelines from the American Academy of Orthopaedic Surgeons suggest that aspirin is reasonable for VTE prophylaxis.¹⁶ The varying recommendations reflect differences in perspective among these different specialties.

Aspirin has the advantages of ease of use and low cost, but it is clearly not the best evidence-based approach for VTE prophylaxis. The only recent randomized trial evidence in support of aspirin comes from the Pulmonary Embolism Prevention trial, a study with a flawed design involving more than 13,000 patients undergoing surgery for hip fracture or elective arthroplasty in five countries.¹⁷ Patients were randomized to receive aspirin 160 mg daily or placebo for 35 days along with any other prophylaxis deemed necessary (an important potential confounder). Aspirin was associated with an absolute reduction in symptomatic events of less than 1% relative to placebo, and no benefit was observed within the first week. The best results with aspirin were among patients with hip fracture. No benefit was shown among patients undergoing hip arthroplasty or knee arthroplasty; in those groups, both the aspirin and placebo recipients were also treated with LMWH. An absolute increase in rates of wound bleeding (0.6% increase) and gastrointestinal bleeding (1.0% increase) was observed in the aspirin group. The absolute increase in complications was greater than the absolute reduction in episodes of symptomatic DVT: for every episode of symptomatic DVT averted, one wound bleed and 10 gastrointestinal bleeds occurred.

SPECIAL PATIENT POPULATIONS

Renal impairment

The 8th edition of the ACCP guidelines recommends that renal function be kept in mind when considering LMWH, fondaparinux, and other antithrombotic drugs that are cleared by the kidneys. Fondaparinux and LMWH can bioaccumulate in patients with renal insufficiency, who have a higher risk of bleeding to begin with, thereby compounding the risk. Options for patients with renal compromise include avoiding drugs that bioaccumulate, using a lower dosage, and monitoring the drug level or anticoagulant effect.¹

Fondaparinux is explicitly contraindicated in patients with low body weight (< 50 kg) or renal impairment (creatinine clearance < 30 mL/min). Renal function should be assessed periodically in any patients receiving the drug.¹⁸

I also would not use fondaparinux or LMWH in patients with rapidly changing renal function. For patients with chronic, stable renal impairment, one can reduce the dose of LMWH empirically; one LMWH, enoxaparin, has specific dosing guidelines in its package insert (one-third reduction in dose), but this option does not hold for patients with rapidly changing renal function.¹⁹

Obesity

The 8th edition of the ACCP guidelines recommends weight-based dosing of thromboprophylactic agents in obese patients. The guidelines particularly recommend that patients undergoing inpatient bariatric surgery be given higher doses of LMWH or unfractionated heparin.^1,20

Frederiksen et al measured the anticoagulant effect of a single fixed dose of a LMWH (using anti-factor Xa heparin activity levels) and found that it was dependent on body weight.²¹ This suggests that fixed doses that are effective in normal-weight patients may have no detectable anti-coagulant effect in patients with very high body weight.

Weight-based dosing: mounting nonprospective evidence. Weight-based dosage adjustment for the morbidly obese has not been directly studied in a prospective, randomized fashion. A nonrandomized study by Scholten et al compared two regimens of enoxaparin (30 mg twice daily vs 40 mg twice daily) among 481 obese patients undergoing bariatric surgery; each regimen was used along with mechanical thromboprophylaxis.²² They found that the higher-dose regimen was associated with significantly fewer postoperative DVT complications (0.6% vs 5.4%; P < .01) without an increase in bleeding complications.

Separately, Shepherd et al used weight-adjusted doses of unfractionated heparin (started on the evening of surgery) to achieve subtherapeutic peak anti–factor Xa heparin activity levels of 0.11 to 0.25 IU/mL in a series of 700 patients undergoing laparoscopic gastric bypass surgery.²³ The resulting doses were greater than those in traditional fixed-rate protocols, but rates of bleeding and VTE events were low and comparable to those reported in patients receiving standard doses. 

Don’t rule out multimodal approaches. Multimodal prophylaxis can also be used in obese patients and need not be abandoned as a result of size considerations. For instance, two intermittent compression therapy devices can be pieced together with a Velcro binder if a single device is too small to be worn.