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Communications to the Editor |

Strength of Evidence for Low-Molecular-Weight Heparin FREE TO VIEW

Carlos Alonso-Ortiz del Rio, MD; Alberto Romero-Alonso, MD; Ignacio Marin-Leon, MD; Manuel Rincon-Gomez, MD
Author and Funding Information

Affiliations: Valme University Hospital Seville, Spain,  Sunnybrook and Women’s College Health Sciences Centre Toronto, ON

Correspondence to: C. Alonso-Ortiz del Rio, MD, Internal Medicine Department, Valme University Hospital, Seville, Spain 41014



Chest. 2002;121(6):2078-2079. doi:10.1378/chest.121.6.2078
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To the Editor:

In the Sixth ACCP Consensus Conference on Antithrombotic Therapy, Geerts et al1 recommend (evidence 1A) the use of low-molecular-weight-heparin (LMWH) for prevention of venous thromboembolism in patients with ischemic stroke and impaired mobility. As reported, the recommendation is based on the results of three randomized control trials; one of those trials compared LMWH with unfractioned heparin and yielded no evidence on the disadvantages of nonprevention. The results of the two smaller-sized placebo-controlled trials are in disagreement. We think that this recommendation lacked a clear-cut connection to the evidence.

In support of our opinion, a meta-analysis by Bath et al2assessed the efficacy and safety of treatment with LWMH in patients with acute ischemic stroke. They reported that treatment with LMWH reduced the risk of deep vein thrombosis (relative risk reduction [RRR], 45%; number needed to prevent [NNP] 40) and pulmonary embolism (RRR, 63%; NNP, 80), but it increased the risk of major extracranial bleeding (RRR, 53%; number needed to damage [NND], 80) and probably of intracranial hemorrhage (odds ratio, 1.77; confidence interval, 0.95–3.3), with no change in mortality. This study does not support the routine use of LMWH. However, it might be useful in patients with additional risk factors and greater benefit/risk ratios. Furthermore, most patients with stroke are receiving aspirin, and the baseline risk of venous thromboembolism is likely to be downgraded as a benefit of aspirin treatment.34 Thus, according to our present knowledge, treatment with LMWH can hardly be considered a routine, evidence-based recommendation for prevention of venous thromboembolism in patients with acute ischemic stroke.

Geerts, WH, Heit, JA, Clagett, GP, et al (2001) Prevention of venous thromboembolism.Chest119(suppl),132S-175S
 
Bath, PM, Iddenden, R, Bath, FJ Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials.Stroke2000;31,1770-1778. [PubMed] [CrossRef]
 
Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomized trials of antiplatelet therapy; III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.BMJ1994;308,235-246. [PubMed]
 
Pulmonary Embolism Prevention Trial Collaborative Group.. Prevention of pulmonary embolism and deep venous thrombosis with low dose aspirin.Lancet2000;355,1295-1302. [PubMed]
 
To the Editor:

Dr. Alonso and colleagues suggest that the use of low-molecular-weight heparin (LMWH) should not have been given a grade 1A recommendation as one of the thromboprophylaxis options in patients with ischemic stroke by the Sixth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy.1 I certainly agree that more studies of thromboprophylaxis in stroke patients are needed. However, based on the available literature, our grade 1A recommendation for the use of LMWH (or low-dose heparin) stands.

Four randomized trials have compared prophylactic LMWH to either placebo23 or to low-dose unfractionated heparin (LDUH) in stroke patients.45 In the two LMWH vs placebo trials, prophylaxis with LMWH was associated with a 35% relative risk reduction for deep venous thrombosis (DVT). In the two LMWH vs LDUH studies, the use of LMWH was associated with a 37% relative risk reduction for DVT.

Alonso and colleagues use the meta-analysis by Bath et al6 to support their view. This study identified a DVT rate in stroke patients not receiving prophylaxis that is high enough to warrant prophylaxis (37%). Unfortunately, this review pooled studies of LMWH prophylaxis with those of danaparoid prophylaxis (clearly not a LMWH) and pooled trials of thromboprophylaxis with studies in which therapeutic doses of LMWH were used in the treatment of stroke rather than in the prevention of DVT after stroke. Furthermore, this analysis included a study with an unblinded control group and excluded studies that compared more than one antithrombotic agent. The review of the American College of Chest Physicians, however, restricted the inclusion of trials to those that were published and used prophylactic doses of LMWH. We did not exclude studies that compared more than one antithrombotic agent, but we did exclude studies with an unblinded control group.

Alonso and colleagues also suggest that aspirin may provide sufficient prevention against venous thromboembolism to preclude the need for specific thromboprophylaxis. The use of aspirin is widespread in these patients and, based on extensive data, is recommended (grade 1A by the American College of Chest Physicians) as secondary prophylaxis for all patients with noncardioembolic ischemic stroke who do not have contraindications.7Both the International Stroke Trial and the Chinese Acute Stroke Trial found that aspirin reduced the incidence of recurrent stroke but not of pulmonary embolism.89 We believe that aspirin plus an anticoagulant prophylactic agent should be used in these patients if there are no contraindications.1,7

References
Geerts, WH, Heit, JA, Clagett, GP, et al Prevention of venous thromboembolism.Chest2001;119(suppl),132S-175S
 
Prins, MH, Gelsema, R, Sing, AK, et al Prophylaxis of deep venous thrombosis with a low-molecular-weight heparin (Kabi 2165/Fragmin) in stroke patients.Haemostasis1989;19,245-250. [PubMed]
 
Sandset, PM, Dahl, T, Stiris, M, et al A double-blind and randomized placebo-controlled trial of low-molecular-weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke.Semin Thromb Hemost1990;16(suppl),25-33. [PubMed]
 
Hillbom, M, Erila, T, Sotaniemi, CW, et al Comparison of the efficacy and safety of the low-molecular-weight heparin enoxaparin with unfractionated heparin in the prevention of deep venous thrombosis in patients with acute ischemic stroke [abstract]. Blood. 1999;;94(suppl 1) ,.:183a
 
Harenberg, J, Schomaker, U, Flosbach, CW Enoxaparin is superior to unfractionated heparin in the prevention of thromboembolic events in medical patients at increased thromboembolic risk [abstract]. Blood. 1999;;94(suppl) ,.:399a
 
Bath, PMW, Iddenden, R, Bath, FJ Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials.Stroke2000;31,1770-1778. [PubMed] [CrossRef]
 
Albers, GW, Amarenco, P, Easton, JD, et al Antithrombotic and thrombolytic therapy for ischemic stroke.Chest2001;119(suppl),300S-320S
 
International Stroke Trial Collaborative Group.. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke.Lancet1997;349,1569-1581. [PubMed]
 
CAST (Chinese Acute Stroke Trial) Collaborative Group.. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke.Lancet1997;349,1641-1649. [PubMed]
 

Figures

Tables

References

Geerts, WH, Heit, JA, Clagett, GP, et al (2001) Prevention of venous thromboembolism.Chest119(suppl),132S-175S
 
Bath, PM, Iddenden, R, Bath, FJ Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials.Stroke2000;31,1770-1778. [PubMed] [CrossRef]
 
Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomized trials of antiplatelet therapy; III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients.BMJ1994;308,235-246. [PubMed]
 
Pulmonary Embolism Prevention Trial Collaborative Group.. Prevention of pulmonary embolism and deep venous thrombosis with low dose aspirin.Lancet2000;355,1295-1302. [PubMed]
 
Geerts, WH, Heit, JA, Clagett, GP, et al Prevention of venous thromboembolism.Chest2001;119(suppl),132S-175S
 
Prins, MH, Gelsema, R, Sing, AK, et al Prophylaxis of deep venous thrombosis with a low-molecular-weight heparin (Kabi 2165/Fragmin) in stroke patients.Haemostasis1989;19,245-250. [PubMed]
 
Sandset, PM, Dahl, T, Stiris, M, et al A double-blind and randomized placebo-controlled trial of low-molecular-weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke.Semin Thromb Hemost1990;16(suppl),25-33. [PubMed]
 
Hillbom, M, Erila, T, Sotaniemi, CW, et al Comparison of the efficacy and safety of the low-molecular-weight heparin enoxaparin with unfractionated heparin in the prevention of deep venous thrombosis in patients with acute ischemic stroke [abstract]. Blood. 1999;;94(suppl 1) ,.:183a
 
Harenberg, J, Schomaker, U, Flosbach, CW Enoxaparin is superior to unfractionated heparin in the prevention of thromboembolic events in medical patients at increased thromboembolic risk [abstract]. Blood. 1999;;94(suppl) ,.:399a
 
Bath, PMW, Iddenden, R, Bath, FJ Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials.Stroke2000;31,1770-1778. [PubMed] [CrossRef]
 
Albers, GW, Amarenco, P, Easton, JD, et al Antithrombotic and thrombolytic therapy for ischemic stroke.Chest2001;119(suppl),300S-320S
 
International Stroke Trial Collaborative Group.. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischemic stroke.Lancet1997;349,1569-1581. [PubMed]
 
CAST (Chinese Acute Stroke Trial) Collaborative Group.. CAST: randomized placebo-controlled trial of early aspirin use in 20,000 patients with acute ischemic stroke.Lancet1997;349,1641-1649. [PubMed]
 
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