The Cochrane Library
The Cochrane Library – Feedback
Anticoagulation for cerebral sinus thrombosis
J Stam, SFTM Bruijn, G DeVeber
DOI:
10.1002/14651858.CD002005
Add feedback to this review/protocol
David K. Cundiff, MD
Date received:
February 17, 2007
Cite this comment as:
http://www.cochranefeedback.com/cf/cda/citation.do?id=9604#9604
The strong implication in the authors’ conclusion is that heparin is effective for cerebral sinus venous thrombosis (CSVT), although the two small trials showed no statistically significant reduction in mortality. The nonsignificant trend depends on a single small trial that was subject to early termination bias.
A meta-analysis Landefeld and Beyth of published studies shows that the average daily frequencies of fatal and major bleeding during heparin therapy were 0.05% and 0.8%, respectively.1 Risk of bleeding from heparin in clinical settings with physicians who are not experienced anticoagulation researchers are probably higher. The authors of this CSVT review called heparin safe on the basis of only 40 cases (about 800 days of heparinization). Based on the large meta-analysis of Landefeld and Beyth, the expected incidences of fatal and major bleeding in these 40 cases would be about 0.4 and 3.2, respectively. The fact that, in these 40 cases, the fatal and major bleeds were 0 and 1 does not imply that the bleeding risk of heparin is less than for heparin used in other indications or that heparin is safe.
In a series of 27 patients who died of cerebral sinus venous thromobsis (CSVT), 25 were treated with heparin or LMWH. Of those treated with a heparin, 15 died due to cerebral hemorrhage. The percentage of survivors who received heparins was not reported but said to be about the same as the percentage who died after receiving heparin. Deaths due to the heparin could not be ruled out.2
The protocols of the two small trials in this review did not include heparin induced thrombocytopenia with thrombosis (HITT) as an outcome for systematic assessment. Consequently, because of the small number of cases in this review, the risk of HITT in patients with CSVT treated with heparin cannot be estimated but would probably be significant.
Underlying conditions of those dying in these two trials were not indicated (e.g., advanced cancer, infection, CHF, etc.). Underlying diseases (e.g., CHF, infection and cancer) increase the mortality of CSVT.2 Were attempts made to determine any underlying medical conditions of the nine patients who died?
Further placebo controlled RCTs were inappropriately discouraged (“….patients and doctors may be reluctant to embark upon a new trial that includes a placebo group.”). The implications for research did not include recommending further placebo controlled RCTs. Instead, the implications for research suggested finding high risk subgroups of CSVT patients to test more aggressive, and probably more hazardous, therapies. The evidence from this review does not justify RCTs with very risky treatments such as thrombolysis or thrombosuction presumably compared with heparin as the control.
The prognosis of CSVT is better than previously thought, and most prospective studies have reported a survival of 90% or more. The largest study, “Causes and Predictors of Death in Cerebral Venous Thrombosis” (624 patients), had an acute fatality rate of 4% and 30 day mortality of 7%. In those that died, death was most likely due to cerebral hemorrhage. Heparin use was not associated with a lower mortality.2 CSVT is a disease with a wide spectrum of symptoms and a large range of severity. More and more incidental and asymptomatic cases have been recognized with improved noninvasive imaging techniques.3 Why was no mention made of incidental and asymptomatic cases in this CSVT review?
The bleeding and thrombosis risks of heparin are significant in general and probably more so in patients with CNS bleeding, like many of those with CSVT. Given the overall favorable prognosis of CSVT and the unproven efficacy and the risks of heparin, anticoagulation would seem a poor treatment choice. The implications for practice should state:
1. Heparin is unproven to be effective in reducing morbidity or mortality in CSVT patients.
2. CSVT patients should not be given heparin or other anticoagulants outside of a placebo controlled RCT setting.
1. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. American Journal of Medicine. 1993;95(3):315-328.
2. Canhao P, Ferro JM, Lindgren AG, et al. Causes and Predictors of Death in Cerebral Venous Thrombosis. 10.1161/01.STR.0000173152.84438.1c. Stroke. August 1, 2005;36(8):1720-1725.
3. Stolz E, Gerriets T, Bodeker RH, Hugens-Penzel M, Kaps M. Intracranial Venous Hemodynamics Is a Factor Related to a Favorable Outcome in Cerebral Venous Thrombosis. 10.1161/01.STR.0000016507.94646.E6. Stroke. June 1, 2002;33(6):1645-1650.
Date received: February 17, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9604#9604
The strong implication in the authors’ conclusion is that heparin is effective for cerebral sinus venous thrombosis (CSVT), although the two small trials showed no statistically significant reduction in mortality. The nonsignificant trend depends on a single small trial that was subject to early termination bias.
A meta-analysis Landefeld and Beyth of published studies shows that the average daily frequencies of fatal and major bleeding during heparin therapy were 0.05% and 0.8%, respectively.1 Risk of bleeding from heparin in clinical settings with physicians who are not experienced anticoagulation researchers are probably higher. The authors of this CSVT review called heparin safe on the basis of only 40 cases (about 800 days of heparinization). Based on the large meta-analysis of Landefeld and Beyth, the expected incidences of fatal and major bleeding in these 40 cases would be about 0.4 and 3.2, respectively. The fact that, in these 40 cases, the fatal and major bleeds were 0 and 1 does not imply that the bleeding risk of heparin is less than for heparin used in other indications or that heparin is safe.
In a series of 27 patients who died of cerebral sinus venous thromobsis (CSVT), 25 were treated with heparin or LMWH. Of those treated with a heparin, 15 died due to cerebral hemorrhage. The percentage of survivors who received heparins was not reported but said to be about the same as the percentage who died after receiving heparin. Deaths due to the heparin could not be ruled out.2
The protocols of the two small trials in this review did not include heparin induced thrombocytopenia with thrombosis (HITT) as an outcome for systematic assessment. Consequently, because of the small number of cases in this review, the risk of HITT in patients with CSVT treated with heparin cannot be estimated but would probably be significant.
Underlying conditions of those dying in these two trials were not indicated (e.g., advanced cancer, infection, CHF, etc.). Underlying diseases (e.g., CHF, infection and cancer) increase the mortality of CSVT.2 Were attempts made to determine any underlying medical conditions of the nine patients who died?
Further placebo controlled RCTs were inappropriately discouraged (“….patients and doctors may be reluctant to embark upon a new trial that includes a placebo group.”). The implications for research did not include recommending further placebo controlled RCTs. Instead, the implications for research suggested finding high risk subgroups of CSVT patients to test more aggressive, and probably more hazardous, therapies. The evidence from this review does not justify RCTs with very risky treatments such as thrombolysis or thrombosuction presumably compared with heparin as the control.
The prognosis of CSVT is better than previously thought, and most prospective studies have reported a survival of 90% or more. The largest study, “Causes and Predictors of Death in Cerebral Venous Thrombosis” (624 patients), had an acute fatality rate of 4% and 30 day mortality of 7%. In those that died, death was most likely due to cerebral hemorrhage. Heparin use was not associated with a lower mortality.2 CSVT is a disease with a wide spectrum of symptoms and a large range of severity. More and more incidental and asymptomatic cases have been recognized with improved noninvasive imaging techniques.3 Why was no mention made of incidental and asymptomatic cases in this CSVT review?
The bleeding and thrombosis risks of heparin are significant in general and probably more so in patients with CNS bleeding, like many of those with CSVT. Given the overall favorable prognosis of CSVT and the unproven efficacy and the risks of heparin, anticoagulation would seem a poor treatment choice. The implications for practice should state:
1. Heparin is unproven to be effective in reducing morbidity or mortality in CSVT patients.
2. CSVT patients should not be given heparin or other anticoagulants outside of a placebo controlled RCT setting.
1. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. American Journal of Medicine. 1993;95(3):315-328.
2. Canhao P, Ferro JM, Lindgren AG, et al. Causes and Predictors of Death in Cerebral Venous Thrombosis. 10.1161/01.STR.0000173152.84438.1c. Stroke. August 1, 2005;36(8):1720-1725.
3. Stolz E, Gerriets T, Bodeker RH, Hugens-Penzel M, Kaps M. Intracranial Venous Hemodynamics Is a Factor Related to a Favorable Outcome in Cerebral Venous Thrombosis. 10.1161/01.STR.0000016507.94646.E6. Stroke. June 1, 2002;33(6):1645-1650.