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Prevention of venous thromboembolism after acute ischaemic stroke
Correspondence
Prevention of venous thromboembolism after acute ischaemic stroke David Sherman and colleagues (April 21, p 1347)1 report that enoxaparin 40 mg subcutaneously once daily is preferable to unfractionated heparin 5000 IU subcutaneously every 12 h for prevention of venous thromboembolism in patients with acute ischaemic stroke in view of its better clinical benefit-to-risk ratio and convenience of administration. The systematic review2 of published randomised trials mentioned in the Discussion showed that unfractionated heparin 5000 IU twice daily reduced the relative risk of venous thromboembolism compared with placebo, but that it was less effective than unfractionated heparin 5000 IU three times daily. When comparing enoxaparin with unfractionated heparin, similar efficacy in preventing venous thromboembolism in nonsurgical patients has been seen only when enoxaparin 40 mg once daily was compared with unfractionated heparin 5000 IU three times daily.3,4 One study did show that enoxaparin once daily was as effective as unfractionated heparin 5000 IU twice daily at preventing venous thromboembolism; however, enoxaparin was used at a dose (20 mg once daily) which the MEDENOX Study5 showed to be ineffective for preventing venous thromboembolism in acutely ill patients. In light of these points, it is noteworthy that there are data to suggest better efficacy with unfractionated heparin given on a three times daily basis, but no data to show that unfractionated heparin twice daily is as effective as either enoxaparin 40 mg once daily or unfractionated heparin 5000 IU three times daily. MJM has received fees as a subinvestigator from Sanofi-Synthelabo and Aventis.
www.thelancet.com Vol 370 September 1, 2007
Marcelo J Melero, Bernardo Bergroth, Damián M Contardo, *Mariano M Mazzei [email protected] Hospital de Clínicas José de San Martín, Buenos Aires University, Buenos Aires, Argentina 1
2
3
4
5
Sherman DG, Albers GW, Bladin Ch, et al, on behalf of the PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369: 1347–55. Yalamanchili K, Sukhija R, Sinha N, Aronow WS, Maguire GP, Lehrman SG. Efficacy of unfractionated heparin for thromboembolism prophylaxis in medical patients. Am J Ther 2005; 12: 293–99. Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non surgical patients: epidemiological data and efficacy/ safety profile of a low-molecular-weight heparin (enoxaparin). Haemostasis 1996; 26 (suppl 2): 49–56. Kleber FX, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614–21. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793–800.
In the Introduction section of their paper, David Sherman and colleagues1 state that “[low-molecular-weight] heparin and unfractionated heparin are... recommended in guidelines from expert consensus groups”. This is not completely true: some authorities2,3 and guidelines4,5 do not recommend routine use of heparin for prevention of deep-vein thrombosis (DVT) in patients with ischaemic stroke, although it is usually suggested for high-risk patients. Sherman and colleagues randomised 1762 patients, but only analysed 1335 (a 24% loss). How many patients did not have doppler scans or venography because of deterioration (perhaps due to haemorrhagic complications)? It is rather likely that the trial was underpowered for picking up some important differences, especially in the rate of haemorrhages. The mean age of the included patients was low compared with that
of patients routinely seen in clinical practice (only a quarter were older than 75 years). Older patients can have a higher risk of haemorrhagic transformation, but also more severe strokes and a higher risk of DVT. In the Discussion, Sherman and colleagues refer to numbers needed to treat for benefit and harm (13 vs 173). The “benefit” actually refers to avoidance of asymptomatic DVT (which is mostly irrelevant) whereas the “harm” refers to events that clinicians thought important—eg, haemorrhages. To justify use of lowmolecular-weight heparin (which is also more expensive) on this basis seems wrong. We are told that the 3-month functional outcome of the patients was measured, but it was not reported. In the Cochrane review,2 a reduction of DVT was seen with heparin, but there was no net effect on death and disability because of the increase in haemorrhages. Can Sherman and colleagues tell us something about outcome in terms of death and disability? Finally, we would like to quote a sentence from the Discussion: “The occurrence of any bleeding was about two-fold higher for patients with a [NIHSS] score of 14 or more than for those with a score less than 14”. These severe strokes are exactly the ones for which we might wish to prescribe heparin. We declare that we have no conflict of interest.
*Stefano Ricci, Maria Grazia Celani, Enrico Righetti, Martin Dennis, Peter Sandercock [email protected] AUSL 2, Perugia, Italy (SR, MGC, ER); and Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK (MD, PS) 1
2
Sherman DG, Albers GW, Bladin C, et al, on behalf of the PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369: 1347–55. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2004; 3: CD000024.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
735
Prevention of venous thromboembolism after acute ischaemic stroke David Sherman and colleagues (April 21, p 1347)1 report that enoxaparin 40 mg subcutaneously once daily is preferable to unfractionated heparin 5000 IU subcutaneously every 12 h for prevention of venous thromboembolism in patients with acute ischaemic stroke in view of its better clinical benefit-to-risk ratio and convenience of administration. The systematic review2 of published randomised trials mentioned in the Discussion showed that unfractionated heparin 5000 IU twice daily reduced the relative risk of venous thromboembolism compared with placebo, but that it was less effective than unfractionated heparin 5000 IU three times daily. When comparing enoxaparin with unfractionated heparin, similar efficacy in preventing venous thromboembolism in nonsurgical patients has been seen only when enoxaparin 40 mg once daily was compared with unfractionated heparin 5000 IU three times daily.3,4 One study did show that enoxaparin once daily was as effective as unfractionated heparin 5000 IU twice daily at preventing venous thromboembolism; however, enoxaparin was used at a dose (20 mg once daily) which the MEDENOX Study5 showed to be ineffective for preventing venous thromboembolism in acutely ill patients. In light of these points, it is noteworthy that there are data to suggest better efficacy with unfractionated heparin given on a three times daily basis, but no data to show that unfractionated heparin twice daily is as effective as either enoxaparin 40 mg once daily or unfractionated heparin 5000 IU three times daily. MJM has received fees as a subinvestigator from Sanofi-Synthelabo and Aventis.
www.thelancet.com Vol 370 September 1, 2007
Marcelo J Melero, Bernardo Bergroth, Damián M Contardo, *Mariano M Mazzei [email protected] Hospital de Clínicas José de San Martín, Buenos Aires University, Buenos Aires, Argentina 1
2
3
4
5
Sherman DG, Albers GW, Bladin Ch, et al, on behalf of the PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369: 1347–55. Yalamanchili K, Sukhija R, Sinha N, Aronow WS, Maguire GP, Lehrman SG. Efficacy of unfractionated heparin for thromboembolism prophylaxis in medical patients. Am J Ther 2005; 12: 293–99. Lechler E, Schramm W, Flosbach CW. The venous thrombotic risk in non surgical patients: epidemiological data and efficacy/ safety profile of a low-molecular-weight heparin (enoxaparin). Haemostasis 1996; 26 (suppl 2): 49–56. Kleber FX, Witt C, Vogel G, Koppenhagen K, Schomaker U, Flosbach CW. Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease. Am Heart J 2003; 145: 614–21. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341: 793–800.
In the Introduction section of their paper, David Sherman and colleagues1 state that “[low-molecular-weight] heparin and unfractionated heparin are... recommended in guidelines from expert consensus groups”. This is not completely true: some authorities2,3 and guidelines4,5 do not recommend routine use of heparin for prevention of deep-vein thrombosis (DVT) in patients with ischaemic stroke, although it is usually suggested for high-risk patients. Sherman and colleagues randomised 1762 patients, but only analysed 1335 (a 24% loss). How many patients did not have doppler scans or venography because of deterioration (perhaps due to haemorrhagic complications)? It is rather likely that the trial was underpowered for picking up some important differences, especially in the rate of haemorrhages. The mean age of the included patients was low compared with that
of patients routinely seen in clinical practice (only a quarter were older than 75 years). Older patients can have a higher risk of haemorrhagic transformation, but also more severe strokes and a higher risk of DVT. In the Discussion, Sherman and colleagues refer to numbers needed to treat for benefit and harm (13 vs 173). The “benefit” actually refers to avoidance of asymptomatic DVT (which is mostly irrelevant) whereas the “harm” refers to events that clinicians thought important—eg, haemorrhages. To justify use of lowmolecular-weight heparin (which is also more expensive) on this basis seems wrong. We are told that the 3-month functional outcome of the patients was measured, but it was not reported. In the Cochrane review,2 a reduction of DVT was seen with heparin, but there was no net effect on death and disability because of the increase in haemorrhages. Can Sherman and colleagues tell us something about outcome in terms of death and disability? Finally, we would like to quote a sentence from the Discussion: “The occurrence of any bleeding was about two-fold higher for patients with a [NIHSS] score of 14 or more than for those with a score less than 14”. These severe strokes are exactly the ones for which we might wish to prescribe heparin. We declare that we have no conflict of interest.
*Stefano Ricci, Maria Grazia Celani, Enrico Righetti, Martin Dennis, Peter Sandercock [email protected] AUSL 2, Perugia, Italy (SR, MGC, ER); and Division of Clinical Neurosciences, University of Edinburgh, Edinburgh, UK (MD, PS) 1
2
Sherman DG, Albers GW, Bladin C, et al, on behalf of the PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison. Lancet 2007; 369: 1347–55. Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2004; 3: CD000024.
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
735