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Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures
Helen HG Handoll, Mark J Farrar, Julie McBirnie, Graham M Tytherleigh-Strong, Alan A Milne, William J Gillespie
DOI:10.1002/14651858.CD000305
Date received: July 22, 2008
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9849#9849
I thank Drs. Handoll and Gillespie for their reply.
I question whether the reference to the SIGN Guideline No. 561 belongs in the ‘Implications for Practice’ section. This guideline is not referenced elsewhere in this review and the reasoning behind the SIGN Guideline is not explained. Even after reading the relevant sections of the SIGN Guideline, it is puzzling why they recommended injectable anticoagulant prophylaxis for any hip fracture patients. Concerning the definition of hip fracture patients at “high risk of VTE,” the SIGN Guideline contained the following two passages:
1. Hip fracture surgery carries high risk of assymptomatic DVT (45%), symptomatic DVT (1-11%), symptomatic PE (3-13%), and fatal PE (1-7%) in the absence of VTE prophylaxis.2
2. Heparin should be reserved for selected patients at high risk for VTE after hip fracture due to
• Multiple risk factors*
• Contraindications to standard mechanical prophylaxis and/or aspirin
* Age > 80 years, obesity (BMI >30), varicose veins, previous VTE, thrombophilias, heart failure, recent MI or stroke (ed. “recent” not defined), severe infection, inflammatory bowel disease, nephrotic syndrome, polycythaemia, paraproteinemia, Bechet’s disease, paroxysmal noctural haemaglobinuria, hormone replacement therapy, tamoxifen, paralysis, and malignancy.
Passage #1 indicates that all patients are at high risk of VTE. However, only certain patients, defined in passage #2, should get heparin. No validation studies are referenced that supports the net benefit of heparin in patients designated at “high risk” by the SIGN criteria.
It should be noted that in the original Cochrane review (1998),3 there was a non significant increase in overall mortality in the heparin group (46/420 (11.0%) versus 35/423 (8.3%); Peto odds ratio 1.39; 95% confidence interval 0.86 to 2.23). However, in the current version of this review, published in 2002, the non significant increase in overall mortality in the heparin group has diminished as the total number of patients and number of deaths had changed (42/356 (11.8%) versus 38/374 (10.2%); Peto odds ratio 1.16 (0.77- 1.74)).4 This discrepancy should be explained.
Concerning the incidence of fatal PE, this review states, “Fatal PE reported in eight trials was confirmed by autopsy data in at least some patients in five trials.” Estimating the mortality of PE from death certificates has been shown to be grossly inaccurate with a sensitivity of less than 40% and the predictive value of a positive diagnosis of less than 50%.5 Therefore, given the apparent minority of patients who died having autopsies, nothing can be concluded about the non significant trend toward reduced fatal PEs (5/356 versus 14/374; Peto odds ratio 0.47 (0.19 – 1.14)), especially with the borderline significant increase in non PE mortality in patients receiving heparins (37/356 versus 24/374 Peto odds ratio 1.58 (0.98 – 2.55).
While nothing can be inferred from the fatal PE data, the overall mortality trend favoring the control group is important because of the potential clinical effect of rebound hypercoagulability on withdrawal of heparins. Assessing the full extent of deaths from rebound hypercoagulability requires at least two months of followup after discontinuing the heparin. (See my feedback letter regarding the Cochrane anticoagulation review by Kakkos and colleagues6). Most rebound hypercoagulability deaths would be missed in this hip fracture review, since only 1/15 RCTs of any heparin had a surveillance period of at least four weeks and 3/15 had less than 10 days surveillance. Given the trend to increased deaths with heparins (stronger in the original version than the current one) in the short followup periods of the RCTs in this review, the possibility of heparin prophylaxis causing increased mortality is quite troubling.
Referencing the original version of this Cochrane hip fracture VTE prophylaxis review (1998),3 the SIGN Guideline stated, “There was insufficient data to evaluate the effect of heparin on symptomatic VTE, mortality, or bleeding.” If the SIGN Guideline is referenced in this Cochrane review, this sentence, rather than the non evidence-based heparin recommendation for “high risk” patients, would be appropriate to quote. Otherwise, explain why recent data on prophylactic anticoagulants in hip fracture patients in your new review shows more benefit than risk.
Given the likelihood of an increase in mortality due to rebound hypercoagulability in hip fracture patients receiving injectable anticoagulants and the lack of data on adverse effects, the ‘Implications for Practice’ for this review should recommend that no injectable anticoagulants be given to any hip fracture patient outside of a RCT.
Regarding the ‘implications for research,’ any future anticoagulant prophylaxis trial should have at least two months of followup after the discontinuation of the anticoagulant to assess a possible increase in mortality due to rebound hypercoagulability.
1. Prevention and Management of Hip Fracture in Older People. Scottish Intercollegiate Guidelines Network (SIGN) Publication No. 56. 2002. Available at: http://www.sign.ac.uk/guidelines/fulltext/56/index.html. Accessed July 10, 2008.
2. Gillespie W, Murray G, Gregg PJ, Warwick D. Risks and Benefits of prophylaxis against venous thromboembolism in orthopedic surgery. J. of Bone and Joint Surgery (Br). 2000;82-B:475-479.
3. HHG Handoll, MJ Farrar, J McBirnie, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database of Systematic Reviews. 1998(Issue 2):Oxford: Update Software.
4. Handoll HHG, Farrar MJ, McBirnie J, Tytherleigh-Strong G, Milne AA, Gillespie WJ. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures (Cochrane Review). The Cochrane Libary. 2002(Issue 4):Art. No.: CD000305. DOI: 000310.001002/14651858.CD14000305.
5. Dismuke SE, VanderZwaag R. Accuracy and epidemiological implications of the death certificate diagnosis of pulmonary embolism. J Chronic Dis. 1984;37(1):67-73.
6. Kakkos S, Geroulakos G, Caprini J, Nicolaides AN, Stansby G. Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high risk patients (Protocol). Cochrane Database of Systematic Reviews. 2005(Issue 2):Art. No.: CD005258. DOI: 005210.001002/14651858.CD14005258.