Oral anticoagulation for prolonging survival in patients with cancer.
BACKGROUND
A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect.


OBJECTIVE
To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer.


METHODS
A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed.


METHODS
Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism.


METHODS
Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding.


RESULTS
Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype.


CONCLUSIONS
Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.
Akl
E A
EA
State University of New York at Buffalo, Medicine, ECMC, CC-142, 462 Girder Street, Buffalo, New York 14215, USA. elieakl@buffalo.edu
Kamath
G
G
Kim
S Y
SY
Yosuico
V
V
Barba
M
M
Terrenato
I
I
Sperati
F
F
Schünemann
H J
HJ
D000284:Administration, Oral; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects; D018288:Carcinoma, Small Cell / Q000401:mortality; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality; D009369:Neoplasms / Q000401:mortality*; D016032:Randomized Controlled Trials as Topic; D013923:Thromboembolism / Q000517:prevention & control; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects
D000925:Anticoagulants; D014859:Warfarin