Prevention of venous thromboembolism in the cancer surgery patient
ABSTRACT
Cancer patients, especially those undergoing surgery for cancer, are at extremely high risk for developing venous thromboembolism (VTE), even with appropriate thromboprophylaxis. Anticoagulant prophylaxis in cancer surgery patients has reduced the incidence of VTE events by approximately one-half in placebo-controlled trials, and extended prophylaxis (for up to 1 month) has also significantly reduced out-of-hospital VTE events in clinical trials in this population. Clinical trials show no difference between low-molecular-weight heparin (LMWH) and unfractionated heparin in VTE prophylaxis efficacy or bleeding risk in this population, although the incidence of heparin-induced thrombocytopenia is lower with LMWH. The risk-benefit profile of low-dose anticoagulant prophylaxis appears to be favorable even in many cancer patients undergoing neurosurgery, for whom pharmacologic VTE prophylaxis has been controversial because of bleeding risks.
Extended prophylaxis
Two additional randomized trials have evaluated extended prophylaxis with LMWH in surgical cancer patients—ENOXACAN II23 and the Fragmin After Major Abdominal Surgery (FAME) study.24
In ENOXACAN II, patients undergoing surgery for abdominal or pelvic cancer first received 6 to 10 days of prophylaxis with enoxaparin 40 mg once daily and then were randomized in a double-blind fashion to an additional 21 days of enoxaparin or placebo.23 Among 332 patients in the intent-to-treat analysis, the rate of VTE at the end of the double-blind phase was reduced from 12.0% with placebo to 4.8% with extended-duration enoxaparin (P = .02), an effect that was maintained at 3-month follow-up (P = .01). There was no significant difference between the two groups in rates of major bleeding events or any bleeding events.
In FAME, patients received 5,000 IU of dalteparin once daily for 1 week following major abdominal surgery and then were randomized in open-label fashion to either placebo or extended prophylaxis with dalteparin for 3 more weeks; a subanalysis examined outcomes in the 198 FAME participants whose abdominal surgery was for cancer.24 Among these 198 cancer surgery patients, the rate of venography-documented VTE at 4 weeks was reduced from 19.6% with placebo to 8.8% with extended-duration dalteparin, a relative reduction of 55% (P = .03). The rate of proximal DVT was reduced from 10.4% to 2.2% with extended prophylaxis, a relative reduction of 79% (P = .02).
The number needed to treat with extended LMWH prophylaxis to prevent one VTE event was 14 in ENOXACAN II23 and 9 in the FAME subanalysis of cancer surgery patients.24
New systematic review of relevant trials
Leonardi et al recently published a systematic review of 26 randomized controlled trials of DVT prophylaxis in 7,639 cancer surgery patients.25 They found the overall incidence of DVT to be 12.7% in those who received pharmacologic prophylaxis compared with 35.2% in controls. They also found high-dose LMWH therapy (> 3,400 U daily) to be associated with a significantly lower incidence of DVT than low-dose LMWH therapy (≤ 3,400 U daily) (7.9% vs 14.5%, respectively; P < .01). No differences were demonstrated between LMWH and UFH in preventing DVT, DVT location, or bleeding. Bleeding complications requiring discontinuation of pharmacologic prophylaxis occurred in 3% of patients overall.
Implications of HIT
The sequelae of heparin-induced thrombocytopenia (HIT) can have major consequences for cancer surgery patients. The incidence of HIT is markedly lower with LMWH than with UFH, as demonstrated in a nested case-control study by Creekmore et al.26 These researchers also found that the average cost of an admission during which HIT developed was nearly four times as great as the average cost of an admission during which UFH or LMWH was given without development of HIT ($56,364 vs $15,231; P < .001).
EVIDENCE IN SPECIFIC ONCOLOGIC POPULATIONS
Most of the patients in the trials reviewed above underwent abdominal surgery for malignancy. Although studies of VTE prophylaxis in patients undergoing nonabdominal cancer surgery are relatively few, some data are available for a few other specific oncologic populations, as reviewed below.
Surgery for gynecologic cancer
There is a paucity of randomized controlled trials or prospective observational studies on VTE and its prevention in the gynecologic cancer surgery population. Based on small historical studies, the postoperative risk of VTE in this population varies from 12% to 35%.27,28 Twice-daily administration of UFH 5,000 U appears to be ineffective as VTE prophylaxis in this population, but increasing the frequency to three times daily reduces VTE risk by 50% to 60% compared with placebo. Once-daily LMWH is comparable to three-times-daily UFH in efficacy and safety in this population.
A systematic Cochrane review of eight randomized controlled trials in patients undergoing major gynecologic surgery revealed that heparin prophylaxis (either UFH or LMWH) reduces the risk of DVT by 70% compared with no prophylaxis, with an identical risk reduction specifically among women with malignancy (odds ratio, 0.30; 95% CI, 0.10 to 0.89).29 This review found no evidence that anticoagulation reduces the risk of PE following major gynecologic surgery. LMWH and UFH were similar in efficacy for preventing DVT and had a comparable risk of bleeding complications.
Surgery for urologic cancer
The risk of VTE and the benefits of thromboprophylaxis also are poorly studied in patients undergoing surgery for urologic cancer.
The risk of VTE varies with the type of urologic surgery and the method used to diagnose VTE. For instance, patients undergoing radical retropubic prostatectomy have been reported to develop DVT at rates of 1% to 3%, PE at rates of 1% to 3%, and fatal PE at a rate of 0.6%, whereas the incidences of these events are somewhat higher in patients undergoing cystectomy: 8% for DVT, 2% to 4% for PE, and 2% for fatal PE. Radiologic diagnosis of thromboembolism in pelvic surgery patients has yielded higher incidences, with DVT rates of 21% to 51% and PE rates of 11% to 22%.30
Small studies suggest that prophylaxis with either low-dose UFH or LMWH is both effective in reducing VTE risk and safe in urologic cancer surgery patients, although pharmacologic prophylaxis poses a possible increased risk of pelvic hematoma and lymphocele formation in this population.30
Neurosurgery
Most neurosurgical procedures are performed for malignancies. The risk of venography-confirmed VTE in patients undergoing neurosurgery is approximately 30% to 40%.31,32 Likewise, the risks of intracranial or intraspinal hemorrhage in these patients are high. For this reason, mechanical methods of VTE prophylaxis are preferred in these patients. The use of anticoagulant prophylaxis remains controversial in this setting, although more recent data suggest that it might be safer than previously recognized.
