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HipFurther Opinion

Extended venous thromboembolism prophylaxis in patients undergoing hip fracture surgery – the SAVE-HIP3 study

WD Fisher, G Agnelli, DJ George, AK Kakkar, MR Lassen, P Mismetti, P Mouret, AGG Turpie
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Bone Joint J 95-B:459-66.

There is a high rate of venous thromboembolism (VTE) after hip fracture. In the absence of thromboprophylaxis, the total rate of DVT after hip fracture surgery (HFS) has been estimated to be 50% and that of proximal DVT 27% from eight prospective studies in which contrast venography was routinely obtained.1

The rate of symptomatic, objectively confirmed VTE is, however, much lower. It occurs in 1.3 to 8.2% of patients within three months among HFS patients who received routine anticoagulant thromboprophylaxis.  The rate of fatal PE is between 0.4 and 7.5% within three months of surgery, higher than that seen after hip or knee replacement. 2

The difference in the rates of asymptomatic and symptomatic VTE was the main reason why, until recently, there was little agreement about guidelines for thromboprophylaxis in orthopaedic patients between the American College of Chest Physicians (ACCP) and American Academy of Orthopaedic Surgeons (AAOS) . Both panels accepted that the prevention of fatal PE is the most important goal of thromboprophylaxis. However, the ACCP included asymptomatic (and symptomatic) DVT as a measure of its efficacy, whereas the AAOS rejected DVT (both asymptomatic and symptomatic) as a valid outcome because the panellists considered the link between DVT and PE in patients undergoing hip or knee surgery to be unproven. 2-3

This discord was resolved by the latest edition of the ACCP guidelines, which are based on data that evaluate symptomatic rather than asymptomatic events. 4  These recommend the use of one of the following for hip fractures, for a minimum of 10 to 14 days: low molecular weight heparin (LMWH), fondaparinux, low-dose unfractionated heparin (LDUH), adjusted-dose vitamin K antagonists (VKA), aspirin (all Grade 1B), or an intermittent pneumatic compression device (IPCD) (Grade 1C). They also suggest the use of LMWH in preference to the other agents they have recommended as alternatives: fondaparinux, LDUH (Grade 2B), adjusted-dose VKA, or aspirin (all Grade 2C).

The paer of Fisher and colleagues looks at Semuloparin, which is a new generation, ultra-LMWH (ULMWH). It has high anti-Factor Xa and low residual anti-Factor IIa activity. All patients received 7 to 10 days of Semuloparin. The first Semuloparin injection was administered 8 ± 1 hours after surgery and once-daily thereafter. Patients were then entered into the double-blind treatment phase of the study in which patients received subcutaneous injections of Semuloparin or placebo for 19 to 23 days after randomisation. The first injection was administered ≥ 12 hours and no later than 24 ± 2 hours after the last injection of the run-in phase.  All patients were followed-up   28 ± 3 days after treatment had been discontinued.

The primary endpoint was of any VTE (any symptomatic or asymptomatic DVT and nonfatal PE) or all-cause death reported during the period from randomisation until day 24 of the double-blind treatment period, or up to the day of the mandatory bilateral venography, whichever came first. A secondary endpoint was any proximal DVT or symptomatic distal DVT, nonfatal PE, or all-cause death. Patient demographic data and characteristics at baseline were well balanced between the two treatment groups for the main safety population

Compared with placebo, Semuloparin significantly reduced the rate of the primary composite efficacy endpoint of any VTE (any DVT and nonfatal PE) or all-cause death (18.6% versus 3.9%, respectively, p < 0.0001).

The rate of the secondary efficacy endpoint (defined as any proximal DVT, symptomatic distal DVT or nonfatal PE) or all-cause death was also significantly reduced by Semuloparin (10.3% versus 1.5%; p = 0.0002)

The percentage of patients needing treatment after VTE assessment was significantly lower in the Semuloparin group than in the placebo group (7.9% versus 1.7 %).

Two patients in the Semuloparin group experienced clinically relevant bleeding compared to none in the placebo group During the double-blind treatment phase, four of 312 (1.3%) patients treated with Semuloparin and one of 157 (0.6%) treated with placebo required a transfusion of ≥ 1 unit of blood.

This study therefore shows that extended prophylaxis with an ultra LMWH significantly reduces asymptomatic VTE without compromising safety.  These findings are in line with those of the PENTHIFRA Plus study, in which subcutaneous fondaparinux, (2.5 mg daily), significantly reduced the incidence of any VTE and symptomatic VTE (a required rate of return of 96% and 89%, respectively) compared with placebo after HFS. 5 The latest ACCP guidelines, however, pooled results of all fondaparinux versus LMWH in trials in knee replacement, hip replacement and HFS. They failed to demonstrate or exclude a beneficial or detrimental effect of fondaparinux on symptomatic DVT and PE despite a substantial reduction in asymptomatic DVT. There was a substantial increase in bleeding requiring reoperation associated with the use of fondaparinux. VTE deaths were rare and similar in both groups. Caution is advised with fondaparinux in patients weighing < 50 kg (110 lbs.) and in elderly and frail patients because bleeding complications may be increased. In summary, based on moderate-quality evidence, the use of fondaparinux compared with LMWH does not appear to reduce patient-important VTE events but may increase major bleeding events by nine per 1,000 4

The strength of this study is that it is a randomised, double-blind prospective study powered to show a difference in asymptomatic VTE. Its weakness is that the authors looked at asymptomatic events without distinguishing them from symptomatic events This was due to the fact that, at the time the study was conducted, surrogate end points such as venography were considered the gold standard for trials.

Despite this weakness, this is an important study as it shows extended prophylaxis decreases asymptomatic VTE without compromising safety.

Further large, practical, RCTs are needed to study thromboprophylaxis after HFS. Those trials should ensure that symptomatic VTE is recorded for three months after surgery, regardless of the duration of intervention.  

Finally, this study recommends extended prophylaxis which will have cost and compliance implications. Any further study should consider these issues. The new oral agents mentioned in this paper may be more practical: further trials should involve these agents.

REFERENCES

1.  Geerts, WH, Pineo, GF, Heit, JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:338S-400S 
2. Geert WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edn). Chest 2008;133(6 suppl):381S-453S. 
3.  American Academy of Orthopaedic Surgeons. Guidelines on preventing venous thrombo­embolic disease in patients undergoing elective hip and knee arthroplasty. Retrieved from www.aaos.org/research/guidelines/VTE/VTE_guideline.asp.
4. Falck-Ytter Y Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141;e278S-e325S.
5. Eriksson, BI, Lassen, MR, for the Pentasaccharide in Hip-Fracture Surgery Plus (PENTHIFRA Plus) Investigators.. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003;163: 1337-1342. 

 

Ivan Brenkel FRCS Ed, Consultant Orthopaedic Surgeon
Department Orthopaedics
Victoria Hospital
Kirkcaly
KY2 5AH
ivanbrenkel@yahoo.co.uk