December 28, 2011 — The low–molecular weight heparin enoxaparin did not reduce the rate of death from any cause among hospitalized, acutely ill medical patients, according to the findings of the large, randomized International, Multi-Center, Randomized, Double Blind Study to Compare the Overall Mortality in Acutely Ill Medical Patients Treated With Enoxaparin Versus Placebo in Addition to Graduated Elastic Stockings (LIFENOX) trial.
Ajay K. Kakkar, MBBS, PhD, from the Thrombosis Research Institute and University College London, United Kingdom, and colleagues reported their findings in the December 29 issue of the New England Journal of Medicine.
According to the researchers, thromboprophylaxis has been shown to reduce the rate of venous thromboembolic events in both surgical and medical patients, and current guidelines clearly recommend its use in both these patient populations. However, lower use in acutely medically ill patients "may reflect a lack of evidence for a mortality reduction associated with pharmacologic prophylaxis in acutely ill medical patients."
The current study sought to evaluate the effect of thromboprophylaxis enoxaparin on the rate of death from any cause in acutely ill medical patients.
A total of 8307 patients were included in the trial. Participants were at least 40 years of age with 1 of the following conditions: acute decompensation of heart failure, active cancer, or severe systemic infection in addition to chronic pulmonary disease, obesity, history of venous thromboembolism, or an age of 60 years or older. Expected duration of hospitalization was at least 6 days.
Patients were randomly assigned to receive either subcutaneous enoxaparin, given at a dose of 40 mg/day, or placebo, and all patients were assigned to wear elastic stockings with graduated compression.
The primary endpoint of rate of death from any cause at day 30 was comparable with enoxaparin vs placebo (4.9% vs 4.8%; risk ratio, 1.0; 95% confidence interval [CI], 0.8 - 1.2; P = .83). The rate of major bleeding was also similar, at 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio with enoxaparin, 1.4; 95% CI, 0.7 - 3.1; P = .35).
"These findings appear to be counterintuitive, given the fact that pharmacologic prophylaxis has been shown to reduce the risk of venous thromboembolism, including asymptomatic deep-vein thrombosis, by at least 45% in hospitalized, acutely ill medical patients," Dr. Kakkar and colleagues report.
They add that their study "may have been underpowered to show a between-group difference in mortality."
According to the researchers, although no reduction in risk for death was observed in the current trial, pharmacologic thromboprophylaxis is known to prevent venous thromboembolism, thus reducing the need for treatment with high doses of anticoagulant agents during a prolonged period.
Frank A. Lederle, MD, director of the Minneapolis VA Center for Epidemiological and Clinical Research in Minnesota, was lead author on a recent independent systematic review of heparin prophylaxis (various types, not just enoxaparin) that also showed little or no net benefit in improving mortality.
"As we noted, the available data do not indicate a clinically important net benefit from heparin prophylaxis in medical or stroke patients," he told Medscape Medical News. "We did observe a nonsignificant trend toward lower overall mortality with heparin, but the new findings by Kakkar and colleagues suggest this trend may not be meaningful," he added.
"In my view, the strongly prescriptive guidelines that put great pressure on physicians to use heparin prophylaxis are not justified and should be changed in favor of individual judgment," he said. "In particular, the Joint Commission standard that requires prophylaxis or an explanation of why not for any inpatient over 18 years old is seriously misguided."
According to Dr. Lederle, the overall answers of no reduction in mortality and no important net gain in morbidity are "unlikely to be wrong." He added that for those who still wish to use heparin prophylaxis in medical patients, it would be useful to know in which patients the practice is most likely to be favorable. "However, without significant effects in large combined populations, the chance of identifying favorable subgroups is unfortunately rather small," he said.
The study was supported by sanofi-aventis, the manufacturer of enoxaparin. Dr. Kakkar reports receiving consulting fees, grant support through his institution, and lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, and sanofi-aventis. The other authors also report multiple commercial relationships. Dr. Lederle has disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2463-2472.
Ajay K. Kakkar, MBBS, PhD, from the Thrombosis Research Institute and University College London, United Kingdom, and colleagues reported their findings in the December 29 issue of the New England Journal of Medicine.
According to the researchers, thromboprophylaxis has been shown to reduce the rate of venous thromboembolic events in both surgical and medical patients, and current guidelines clearly recommend its use in both these patient populations. However, lower use in acutely medically ill patients "may reflect a lack of evidence for a mortality reduction associated with pharmacologic prophylaxis in acutely ill medical patients."
The current study sought to evaluate the effect of thromboprophylaxis enoxaparin on the rate of death from any cause in acutely ill medical patients.
A total of 8307 patients were included in the trial. Participants were at least 40 years of age with 1 of the following conditions: acute decompensation of heart failure, active cancer, or severe systemic infection in addition to chronic pulmonary disease, obesity, history of venous thromboembolism, or an age of 60 years or older. Expected duration of hospitalization was at least 6 days.
Patients were randomly assigned to receive either subcutaneous enoxaparin, given at a dose of 40 mg/day, or placebo, and all patients were assigned to wear elastic stockings with graduated compression.
The primary endpoint of rate of death from any cause at day 30 was comparable with enoxaparin vs placebo (4.9% vs 4.8%; risk ratio, 1.0; 95% confidence interval [CI], 0.8 - 1.2; P = .83). The rate of major bleeding was also similar, at 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio with enoxaparin, 1.4; 95% CI, 0.7 - 3.1; P = .35).
"These findings appear to be counterintuitive, given the fact that pharmacologic prophylaxis has been shown to reduce the risk of venous thromboembolism, including asymptomatic deep-vein thrombosis, by at least 45% in hospitalized, acutely ill medical patients," Dr. Kakkar and colleagues report.
They add that their study "may have been underpowered to show a between-group difference in mortality."
According to the researchers, although no reduction in risk for death was observed in the current trial, pharmacologic thromboprophylaxis is known to prevent venous thromboembolism, thus reducing the need for treatment with high doses of anticoagulant agents during a prolonged period.
Frank A. Lederle, MD, director of the Minneapolis VA Center for Epidemiological and Clinical Research in Minnesota, was lead author on a recent independent systematic review of heparin prophylaxis (various types, not just enoxaparin) that also showed little or no net benefit in improving mortality.
"As we noted, the available data do not indicate a clinically important net benefit from heparin prophylaxis in medical or stroke patients," he told Medscape Medical News. "We did observe a nonsignificant trend toward lower overall mortality with heparin, but the new findings by Kakkar and colleagues suggest this trend may not be meaningful," he added.
"In my view, the strongly prescriptive guidelines that put great pressure on physicians to use heparin prophylaxis are not justified and should be changed in favor of individual judgment," he said. "In particular, the Joint Commission standard that requires prophylaxis or an explanation of why not for any inpatient over 18 years old is seriously misguided."
According to Dr. Lederle, the overall answers of no reduction in mortality and no important net gain in morbidity are "unlikely to be wrong." He added that for those who still wish to use heparin prophylaxis in medical patients, it would be useful to know in which patients the practice is most likely to be favorable. "However, without significant effects in large combined populations, the chance of identifying favorable subgroups is unfortunately rather small," he said.
The study was supported by sanofi-aventis, the manufacturer of enoxaparin. Dr. Kakkar reports receiving consulting fees, grant support through his institution, and lecture fees from Bayer Healthcare, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, and sanofi-aventis. The other authors also report multiple commercial relationships. Dr. Lederle has disclosed no relevant financial relationships.
N Engl J Med. 2011;365:2463-2472.
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