bmj.com Rapid Responses for Hill et al., 334 (7602) 1053-1054

Rapid Responses to:

PRACTICE:
Jennifer Hill, Tom Treasure on behalf of the Guideline Development Group
Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance
BMJ 2007; 334: 1053-1054 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Using surrogate outcomes may be NICE but is it right?: Colin R. Howie, Adam C. Watts, SpR Orthopaedics (25 May 2007)

Thromboprophylaxis in Spinal Surgery.: Adrian C Gardner, Andre Jackowski Consultant Neurosurgeon, Mel Grainger Consultant Spinal Surgoen, Jonathan Spilsbury Consultant Spinal Surgeon, David Marks Consultant Spinal Surgeon, Alistair Stirling Consultant Spinal Surgeon, Alistair Thompson Consultant Spinal Surgeon. (28 May 2007)

Time to offer patients an alternative to porcine heparin?: David W Eyre (29 May 2007)

Guidance for doctors on venous thromboembolism (VTE): a call for clarity and consistency: Anita J Thomas, Roopen Arya, Trevor Baglin, Jonathan Boyce, Rebecca Brown, Sally Clarke, Alexander Cohen, David Fitzmaurice, Alistair Flowerdew, Simon Gibbs, Beverley J Hunt, Ajay K Kakkar, Adrian Newland, Ed Nichol, John Pasi, David Warwick, Geoff Pope, John Scarpello (1 June 2007)

Reducing the risk of venous thromboembolism in surgical patients: a call for convergence: Trevor P Baglin (4 June 2007)

A response: clarification and convergence: Tom Treasure, Jennifer Hill, Peter Littlejohns, Gillian Leng (6 June 2007)

NICE has got it wrong: Martyn J Parker (29 June 2007)

Using surrogate outcomes may be NICE but is it right? 25 May 2007

Colin R. Howie,
Consultant Orthopaedic Surgeon
New Royal Infirmary, Edinburgh, EH16 4SU,
Adam C. Watts, SpR Orthopaedics
Send response to journal:
Re: Using surrogate outcomes may be NICE but is it right?

Dear Editor.
Recent NICE guidelines on venous thromboembolism prophylaxis in surgery(1) have recommended the use of low molecular weight heparins (LMWH) or fondaparinux as chemoprophylaxis for orthopaedic patients while in hospital. In the foreword Professor Treasure implies that prophylaxis will reduce the number of deaths due to pulmonary embolism (PE) (25,000 annually in the NHS). A point of view stated more explicitly in a current BMJ editorial(2). In developing the guidelines the committee admitted to employing the surrogate of asymptomatic deep vein thrombosis (DVT) as a primary end-point in their considerations. You recently published research(3) with editorial comment(4) emphasising the problem of interpreting data from trials where composite end-points are employed, and the same reservations can apply when considering trials based on surrogate end-points. Surrogate endpoints, such as asymptomatic DVT, are adopted to increase the power of a trial by increasing the number of �episodes� in the same way as composite end-points. The importance of an asymptomatic DVT either to the treating clinician or more importantly to the patient is debatable. The venous thromboembolic complication of undoubted importance to both parties is fatal pulmonary embolism. This is a rare complication but a robust outcome measure when confirmed by post-mortem examination.
All six papers cited in the NICE guidelines to support the recommendation of LMWH(5-10) used surrogate outcome measures of asymptomatic DVT as the primary outcome. Review of the fatal pulmonary embolism rate in five of the six papers reveals no differences in this important measure between those given LMWH and those given no prophylaxis(5-9). In the sixth, a meta-analysis, neither PE nor fatal PE was mentioned(10). Pharmaceutical industry involvement is declared in three of the cited studies(5;7;8) and two meta-analyses are based on studies that were supported by the pharmaceutical industry(6;10) suggesting the potential for conflict of interest. No conflicts of interest were declared in the sixth study(9) but there were no fatal PE in this study and only one PE, which was in the LMWH treatment arm. To our knowledge no studies have shown an effective measure to reduce the fatal PE rate after surgery although aspirin has been shown to reduce the non-PE mortality when compared to heparin(11).
The editorial by Freemantle and Calvert(4) emphasised the potential for sponsors to �game their trials� by adopting composite or surrogate outcome measures. Have we identified two articles in the same volume of your journal(2;12) that highlight the influence of this �gaming� of randomised trials?
References
1. National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007. (NICE clinical guideline No.46.) www.nice.org.uk/CG046.
2. Fitzmaurice DA,.Murray E. Thromboprophylaxis for adults in hospital. BMJ 2007;334:1017-8.
3. Ferreira-Gonzalez I, Busse JW, Heels-Ansdell D, Montori VM, Akl EA, Bryant DM et al. Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials. BMJ 2007;334:786.
4. Freemantle N,.Calvert M. Composite and surrogate outcomes in randomised controlled trials. BMJ 2007;334:756-7.
5. Bergqvist D, Benoni G, Bjorgell O, Fredin H, Hedlundh U, Nicolas S et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N.Engl.J.Med. 1996;335:696-700.
6. Iorio A,.Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta- analysis. Arch.Intern.Med. 2000;160:2327-32.
7. Mismetti P, Laporte S, Darmon JY, Buchmuller A, Decousus H. Meta- analysis of low molecular weight heparin in the prevention of venous thromboembolism in general surgery. Br.J.Surg. 2001;88:913-30.
8. Wirth T, Schneider B, Misselwitz F, Lomb M, Tuylu H, Egbring R et al. Prevention of venous thromboembolism after knee arthroscopy with low- molecular weight heparin (reviparin): Results of a randomized controlled trial. Arthroscopy 2001;17:393-9.
9. Michot M, Conen D, Holtz D, Erni D, Zumstein MD, Ruflin GB et al. Prevention of deep-vein thrombosis in ambulatory arthroscopic knee surgery: A randomized trial of prophylaxis with low--molecular weight heparin. Arthroscopy 2002;18:257-63.
10. Zufferey P, Laporte S, Quenet S, Molliex S, Auboyer C, Decousus H et al. Optimal low-molecular-weight heparin regimen in major orthopaedic surgery. A meta-analysis of randomised trials. Thromb.Haemost. 2003;90:654 -61.
11. Murray DW, Britton AR, Bulstrode CJ. Thromboprophylaxis and death after total hip replacement. J.Bone Joint Surg.Br. 1996;78:863-70.
12. Hill J,.Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. BMJ 2007;334:1053-4.
Competing interests: None declared

Thromboprophylaxis in Spinal Surgery. 28 May 2007

Adrian C Gardner,
SpR Spinal Surgery
Royal Orthopaedic Hospital, Birmingham. B31 2AP,
Andre Jackowski Consultant Neurosurgeon, Mel Grainger Consultant Spinal Surgoen, Jonathan Spilsbury Consultant Spinal Surgeon, David Marks Consultant Spinal Surgeon, Alistair Stirling Consultant Spinal Surgeon, Alistair Thompson Consultant Spinal Surgeon.
Send response to journal:
Re: Thromboprophylaxis in Spinal Surgery.

Dear Sir,
We write to express concern regarding the guidelines recently published about thromboprophylaxis from the National Institute Clinical Excellence in the BMJ (1). These guidelines state that Neurosurgery (including spinal surgery) should be treated with mechanical methods in the absence of risk factors, and low molecular weight heparin when there are risk factors such as age over 60 increasing the perceived risk of developing a venous thromboembolism
The concern of all spinal surgeons is that a postoperative epidural haematoma causing dural compression and neurological dysfunction may develop. The risk of epidural haematoma is greater with a procedure, which opens the spinal canal and exposes the dural sac. The frequent use of epidural catheters for anaesthesia and analgesia during and following surgery also increases the risk of epidural haematoma. The BMJ article and the NICE guidelines (2) make no specific distinction between procedures, which violate the epidural space, either as part of the surgical procedure or anaesthetic management.
The NICE guidelines on which the recent BMJ article is based make an assessment of risk of developing a DVT following neurosurgery as 20%. The guidelines also state that there is an appreciation of the increased risk of complications from thromboprophylactic medication in neuro and spinal surgery, but state that this is a very difficult risk to quantify. The incidence quoted in the full NICE guidelines for epidural haematoma forming at the site of an epidural catheter �is approximately 1 in 150,000�. This is not mentioned in the summary of the NICE guidelines in the BMJ. There is currently a national audit of epidural related complications for all types of surgical procedure, (3) which will report in the near future. This should allow a more accurate assessment of the risk of an epidural bleed.
We are concerned that the authors do not appreciate the catastrophic sequelae of an epidural haematoma following spinal surgery. In surgical operations when spinal osteotomy or vertebrectomy is undertaken, the blanket guidelines seen in the BMJ will lead to an increase in neurological complications, especially as epidural bleeding may be very difficult to control during these operations. It is our policy not to use chemical thromboprophylaxis routinely in spinal surgery but to use mechanical methods and to mobilise patients early with the in patient use of compression stockings. We also encourage patients to perform active foot and ankle movements whilst in bed. Even with this policy the numbers of epidural haematomas seen in our unit is greater than the rate of symptomatic venous thromboembolic episodes.
As a regional spinal unit we also see patients who have had thromboprophylaxis for non-spinal procedures in conjunction with an epidural catheter and have then required emergency spinal decompression for haematoma evacuation. We therefore feel that whilst recognising the need for risk assessment of all patients for venous thromboembolic disease prior to any surgical procedure, spinal surgery (especially when the dura is exposed and an epidural catheter placed) should be treated differently to other orthopaedic surgery. Whilst guidelines in the main should be welcomed, if the information portrayed is not detailed enough or details of specific subgroups of risk are omitted for the sake of brevity, then the potential for significant complications arises.
We are not aware of any evidence base on which the recommendations made by NICE might be based as it concerns spinal surgery. Our concern is exacerbated by the current uncertainties over junior medical staffing and a consequent risk in the loss of continuity of care.
References:
1. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. Hill J, Treasure T on behalf of the Guideline Development Group. BMJ .2007;334;1053-1054
2. Venous Thromboembolism. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. Commissioned by the National Institute for Health and Clinical Excellence. www.nice.org.uk. Accessed 24/5/07
3. 3rd National Anaesthesia Audit, Royal College of Anaesthetists. National audit of major complications of spinal and epidural anaesthesia
Competing interests: None declared

Time to offer patients an alternative to porcine heparin? 29 May 2007

David W Eyre,
F1 Doctor, Department of Medicine
John Radcliffe Hospital, Oxford, OX3 9DU
Send response to journal:
Re: Time to offer patients an alternative to porcine heparin?

Recent NICE guidance[1 2] recommends low molecular weight heparin be given to all inpatients undergoing orthopaedic surgery and at risk inpatients having other forms of surgery. Fondaparinux is listed as an alternative for orthopaedic and general surgical prophylaxis.
Low molecular weight heparins are porcine derived. Some patients may object to being given porcine heparin, especially where a synthetic alternative exists. Practising Jewish and Muslim patients in particular may have objections to receiving porcine derived products. This has been raised in this journal before.[3]
Responses to such objections may include the amount of porcine material injected is very small, the material has undergone artificial processing and that injection is not the same as ingestion. Another perhaps more compelling argument is necessity; just as it might be acceptable to eat pork if the only alternative was starving, similarly porcine derived heparin might be acceptable if it is the only way to reduce risk of serious harm.
However for orthopaedic and general surgical patients there is a synthetic alternative. Data accompanying the NICE guidance[4] demonstrates in head- to-head comparisons fondaparinux is at least as effective in these patients as low molecular weight heparins, accepting that there is an increased risk of major bleeding. Fondaparinux is also judged cost effective.
A recent report for the Chief Medical Officer highlights the need to consider venous thromboembolism prophylaxis in all hospital inpatients[5]. In medical inpatients there is some data for using fondaparinux,[6] but it is based around venographic end points, and there is no head-to-head comparison with a low molecular weight heparin. Nevertheless fondaparinux is still a licensed alterative for prophylaxis in this setting.
Good clinical care demands consideration of patients� views. As part of engaging with our patients and respecting their beliefs when considering venous thromboembolism prophylaxis we should probably be asking some of our patients if they would prefer an alternative to porcine derived heparins.
Competing interests: None. The author would be happy receiving a porcine derived low molecular weight heparin himself.
1. National Institute for Health and Clinical Excellence. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007. (NICE clinical guideline No. 46) www.nice.org.uk/CG046.
2. Hill J, Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. BMJ 2007;334:1053-54.
3. White C. Venous thromboembolism, heparins are of porcine origin. BMJ 2006;332:364.
4. Nation Collaborating Centre for Acute Care, Royal College of Surgeons of England. Venous thromboembolism: reducing the risk in surgical inpatients. 2007. http://guidance.nice.org.uk/CG46/guidance/pdf/English
5. Mayor S. Hospital patients should be assessed for risk of thromboembolism. BMJ 2007;334:868-869.
6. Cohen A, Davidson B, Gallus A, Lassen M, Prins M, Tomkowski W, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006;332:325-329.
Competing interests: None declared

Guidance for doctors on venous thromboembolism (VTE): a call for clarity and consistency 1 June 2007

Anita J Thomas,
Consultant Physician in Acute Medicine
Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth PL6 8DH,
Roopen Arya, Trevor Baglin, Jonathan Boyce, Rebecca Brown, Sally Clarke, Alexander Cohen, David Fitzmaurice, Alistair Flowerdew, Simon Gibbs, Beverley J Hunt, Ajay K Kakkar, Adrian Newland, Ed Nichol, John Pasi, David Warwick, Geoff Pope, John Scarpello
Send response to journal:
Re: Guidance for doctors on venous thromboembolism (VTE): a call for clarity and consistency

We write as members of the Chief Medical Officer�s independent expert working group on the prevention of venous thromboembolism (VTE) in hospitalised patients (1). We broadly welcome the publication of NICE guidance on this issue but we are concerned that the article by Jennifer Hill and Tom Treasure (2) in the 18th May 2007 edition of the BMJ could create a climate of confusion around the risk assessment and thromboprophylaxis of surgical patients. Such confusion would impede the successful implementation of a national VTE strategy and ultimately hinder work to reduce preventable death and serious illness.
Prevention of VTE is an important issue of patient safety and it is vital that patients, clinicians, managers and other healthcare professionals are provided with clear guidance on the implementation of risk assessment and thromboprophylaxis so that they may manage patients appropriately and according to the informed patient�s wish.
Following an excellent report on this subject by the House of Commons Health Committee (3), the Chief Medical Officer (CM0) established an Independent Expert Working Group in 2005 with the remit to make recommendations concerning VTE in hospitalised patients (1).
The CMO launched his report on 19 April 2007; he recommended mandatory risk assessment for all hospital patients and gave guidance on thromboprophylaxis for all medical, and for low and intermediate risk surgical patients, supported by analysis of existing best practice guidelines from across the world. The CMO also wrote that day to all doctors in England to bring their attention to these specific recommendations for thromboprophylaxis for all medical, and intermediate and low risk surgical patients (4). These three areas were chosen to avoid overlap and potential confusion with the remit of the forthcoming NICE guidelines on high risk surgical and orthopaedic patients.
The Department of Health (DH) had previously invited the independent expert group to advise on the DH response to the NICE consultation on high risk surgical patients. The DH expressed concern to NICE about potential confusion over any duplicate guidance for non-high risk surgical patients. NICE subsequently confirmed, �We have kept to our remit of high risk surgery�� (5)
NICE have now published guidelines outside of their remit on two groups of patients: low and intermediate risk surgical patients (6). NICE have not consulted stakeholders on either group (2), and both groups are already covered by the CMO�s letter to all doctors in England. Moreover, the NICE guideline is presented in a different format to the CMO�s guidance, uses a different risk categorization and offers different advice for low risk surgical patients. This will inevitably lead to confusion.
The DH�s response to the NICE consultation (5) highlighted two major concerns: weak evidence for the recommendation that mechanical methods be the default option for prophylaxis; and the inappropriate age cut-off point for considering a patient for prophylaxis, resulting in many patients under the age of sixty years of age being exposed to the risk of death from VTE.
The DH commented, �NICE guidance�is not taking the full opportunity to contribute to saving the 25,000 lives that are lost each year ��
The CMO�s report contains recommendations for a comprehensive national VTE implementation strategy including the recognition of exemplar centres, programmes of education and public awareness, research, and a healthcare systems approach that allows evaluation of implementation on relevant health outcomes. The CMO has established a VTE Implementation Working Group (7) to provide oversight and leadership for the work required to develop a national VTE risk assessment process.
We feel sure that NICE, an organisation with an international reputation for the quality of its advice to doctors, will wish to withdraw the elements of VTE guidance not relating to high risk surgical and orthopaedic patients. This will remove any confusion and allow all of us to pursue our shared aim of reducing mortality and morbidity from this common and largely preventable condition.
We would also welcome NICE�s collaboration with the CMO�s VTE Implementation Group which holds responsibility for national VTE strategy, including implementing future NICE guidance on the prevention of venous thromboembolism in hospitalised patients when NICE have made a full review of the evidence and followed a proper and complete process of consultation.
Members of the Chief Medical Officer�s independent expert working group on venous thromboembolism in hospitalised patients (Role on the independent group indicated in brackets).
Dr Anita Thomas
Consultant Physician in Acute Medicine, Plymouth Hospitals NHS Trust (Chair),
Dr Roopen Arya
Consultant Haematologist, King�s College Hospital NHS Foundation Trust,
Dr Trevor Baglin
Consultant Haematologist, Department of Haematology, Cambridge University Hospitals NHS Foundation Trust,
Dr Jonathan Boyce
Head of External Outputs, Healthcare Commission (Healthcare Commission),
Ms Rebecca Brown
Thromboprophylaxis and anticoagulation Course tutor, University of Hertfordshire (Nurses� Representative),
Ms Sally Clarke
(Victim of VTE),
Dr Alexander Cohen
Honorary Consultant Vascular Physician, Department of Surgery, Guy�s, King�s and St Thomas� School of Medicine, London; Vascular Physician, University Hospital Lewisham and St George�s Hospital, London,
Professor David Fitzmaurice
GP and Professor of Primary Care, Department of General Practice and Primary Care, University of Birmingham,
Mr Alistair Flowerdew
Medical Director, Salisbury NHS Foundation Trust (NHS Confederation,
Dr Simon Gibbs
Cardiologist, Hammersmith Hospital, London (British Cardiovascular Society),
Dr Beverley J Hunt
Departments of Haematology, Pathology and Rheumatology, Guy's and St Thomas' Trust, Medical Director, Lifeblood: the thrombosis charity,
Professor Ajay K Kakkar
Professor of Surgical Science and Consultant Surgeon, Barts and The London, Queen Mary�s School of Medicine and Dentistry,
Professor Adrian Newland
President, Royal College of Pathologists; Professor of Haematology, Centre for Haematology, Barts and the London, Queen Mary�s School of Medicine and Dentistry (Academy of Medical Royal Colleges),
Squadron Leader Ed Nicol
Specialist Registrar in Cardiology and General Internal Medicine, Royal Brompton and Harefield NHS Trust,
Professor John Pasi
Professor of Haemostasis and Thrombosis, Centre for Haematology, Institute of Cell and Molecular Science, Barts and The London, Queen Mary�s School of Medicine and Dentistry,
Mr David Warwick Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust,
Mr Geoff Pope
Patient Adviser, Citizens Advice (Citizens Advice),
Dr John Scarpello
Consultant Physician, Department of Diabetes and Endocrinology, University Hospital of North Staffordshire, Stoke-on-Trent (National Patient Safety Agency).
Competing Interests; all members of the independent expert group registered competing interests of relevance on joining the group(1).
Address for correspondence; anitajanethomas@msn.com
(1) Department of Health 2007. Report of the independent expert working group on the prevention of venous thromboembolism in hospitalised patients. http://www.dh.gov.uk/vte published 19th April 2007, accessed 18th May 2007
(2) Hill J, Treasure T. NICE Guidelines; reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. BMJ 2007 334 1053- 1054.
(3) House of Commons Health Committee. The Prevention of Venous Thromboembolism in Hospitalised Patients, Second Report of Session 2004�05. March 2005. http://www.publications.parliament.uk/pa/cm200405/cmselect/cmhealth/99/99.pdf, published 19th April 2007, accessed 18th May 2007
(4) Chief Medical Officer. Recommendations of the expert working group on the prevention of thromboembolism (VTE) in hospitalised patients. http://www.dh.gov.uk/en/Publicationsandstatistics/Lettersandcirculars published 19th April 2007, accessed 18th April 2007
(5) Venous thromboembolism: Consultation - responses to comment
http://guidance.nice.org.uk/page.aspx?o=424694 published 25 April 2007, accessed 18 May 2007.
(6) NICE Clinical Guideline 46. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007;
http://guidance.nice.org.uk/CG46.
(7) Department of Health. New report will help reduce venous thromboembolism (vte) in hospitals. http://www.gnn.gov.uk/environment/dh/ published 19th April 2007, accessed 18th May 2007
Competing interests: all members of the expert group established by the Chief Medical Officer registered competing interests on joining the group

Reducing the risk of venous thromboembolism in surgical patients: a call for convergence 4 June 2007

Trevor P Baglin,
Chairman, Haemostasis and Thrombosis Task Force for British Committee for Standards in Haematology
Addenbrookes NHS Trust, Cambridge CB2 0QQ
Send response to journal:
Re: Reducing the risk of venous thromboembolism in surgical patients: a call for convergence

Sir
A summary of NICE Clinical Guideline 46 �Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolus) undergoing surgery� was published in the journal on 19th May 1. The initial scope of the guideline was the prevention of venous thromboembolism in patients undergoing orthopaedic surgery and other high risk surgical procedures 2. The published guideline is for all inpatient surgical procedures 3. The BCSH submitted comments with other stakeholders during the consultation and the NICE response to these comments is published on the NICE website 4. The main concerns of the BCSH related to the preference for mechanical rather than pharmacological methods as the primary intervention and the age of 60 years, rather than 40, as a threshold for defining high risk on the basis of age. The BCSH comments concluded; �The BCSH is extremely worried that if the finalised NICE guideline contains the same recommendations (as the consultation document) fewer patients, not more patients, will receive LMWH and therefore more patients will be deprived of the most effective form of thromboprophylaxis.�
The publication of the final NICE guideline illustrates the problem of different interpretation of primary data by different expert groups. The American College of Chest Physicians (ACCP) 2004 recommendations on prevention of venous thromboembolism 5 were produced by systematic review 6. The conclusion of the ACCP was that mechanical methods of prophylaxis should be used primarily in patients at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis. The reasons for this recommendation were: no mechanical prophylaxis method has been shown to reduce the risk of death or pulmonary embolus (PE), most trials of mechanical prophylaxis were not blinded, and finally because of relatively poor compliance mechanical methods may not perform as well in routine clinical practice 5. In contrast meta-analysis of studies of unfractionated heparin have shown a reduction in fatal PE and all-cause mortality 7 and low molecular weight heparins are at least as effective as unfractionated heparin and probably safer 8. The NICE Guideline Development Group chose a reduced relative risk of any type of deep vein thrombosis (DVT) by any mechanical method as sufficient evidence for their primary recommendation and concluded; �We found no reliable evidence of a difference in the effectiveness between mechanical and pharmacological methods of prophylaxis� (page 82 of report) 9. In practice the NICE recommendation would translate into widespread use of graduated compression stockings (GCS) as the primary method of thromboprophylaxis for surgical patients. The relative risk reduction with GCS was recognised by the ACCP but that expert group was concerned that the effect of GCS on the risk of proximal DVT or symptomatic PE remains unknown, a finding confirmed in a recent Health Technology Assessment 10. In contrast it is known that heparins reduce the incidence of symptomatic proximal DVT and non-fatal and fatal PE 7.
Age is a continuous variable associated with an increasing risk of venous thrombosis following surgery. Two studies were cited by NICE in their response to the BCSH comments on age, as justification for not adopting an age threshold of 40 years 11 12. The BCSH opinion remains that a lower age than 60 should be used as a threshold for defining high risk. The two papers cited by NICE support this view 11 12. In the study of the effect of age on incidence of venous thromboembolism after major surgery the risk increased steadily between the ages of 40 and 60 years and levelled off over 65 years 12. Therefore, using a threshold of 60 years only identifies patients in the highest risk category by virtue of age. The second citation was a review that concluded �patients greater than 40 years of age are at significantly increased risk compared to younger patients and risk approximately doubles with each subsequent decade� 11.
The Chief Medical Officer�s (CMO) Independent Expert Working Group on Venous Thromboembolism published its report in March 2007 13. The Group identified guidelines systematically and the search strategy and results are included in the report. An analysis of points of convergence of current evidence-based guidelines was conducted. The report concluded that �higher risk general surgery patients are those undergoing non-major surgery and are > 60 years of age or have additional risk factors, or patients undergoing major surgery who are > 40 years of age or have additional risk factors�. Therefore, two conflicting guidelines were published within a month of each other. If a patient aged 50 was admitted for non-cancer bowel surgery they would be given low dose low molecular weight heparin according to the Expert Working Group recommendation but would be given GCS according to the NICE guideline. One of the primary objectives of thromboprophylaxis is to prevent death. When comparing GCS and heparin we have one intervention that possibly/probably reduces fatal PE risk (GCS) and one that definitely reduces fatal PE risk (heparin). Why recommend an intervention that possibly/probably does when there is an option that definitely does? Each modality has a downside. Heparin will increase minor bleeding in a small subset of patients but does not increase the risk of major bleeding. GCS may compromise the circulation in patients with peripheral vascular disease and they may not be applied effectively. Risk of post-operative PE increases with age so why restrict prophylaxis for the highest risk group only?
Unfortunately, the publication of two reports with conflicting messages may cause confusion which could undermine the effort made by the CMO to reduce fatal PE in UK hospitals. Convergence is required. All experts seem to be agreed that VTE is a problem, all are agreed that mandatory risk assessment is required, all are agreed that intervention is required in patients considered to be at risk by such assessment. At the moment there are two schools of thought in the UK on the most appropriate intervention. However, we can be reasonably optimistic that convergence will be achieved; a new NICE guideline on prevention of venous thromboembolism in all hospital patients is planned 14; an Implementation Working Group (IWG) has been established at the request of the CMO with a remit to provide oversight and leadership to implement a VTE strategy; the ACCP will publish a new guideline later this year. These activities will coincide and hopefully in the near future VTE risk assessment will be mandatory in all patients receiving hospital-based treatment in the UK and risk reduction through intervention will be as routine as checking the patient�s pulse and blood pressure on admission.
Trevor Baglin
Chairman, Haemostasis and Thrombosis Task Force for the British Committee for Standards in Haematology
1. Hill J, Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. British Medical Journal 2007;334(7602):1053-4.
2. NICE. Scope: the prevention of venous thromboembolism in patients undergoing orthopaedic surgery and other high risk surgical procedures. 2004; http://www.dh.gov.uk/en/AdvanceSearchResult/index.htm?searchTerms=vte.
3. NICE Clinical Guideline 46. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007; http://guidance.nice.org.uk/CG46.
4. NICE consultation: responses to comments vt. 2007; http://guidance.nice.org.uk/page.aspx?o=424694.
5. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S- 400S.
6. Schunemann HJ, Munger H, Brower S, O'Donnell M, Crowther M, Cook D, et al. Methodology for guideline development for the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):174S-178S.
7. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. New England Journal of Medicine 1988;318(18):1162-73.
8. Koch A, Ziegler S, Breitschwerdt H, Victor N. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta- analysis based on original patient data. Thrombosis Research 2001;102(4):295-309.
9. NICE Clinical Guidleine 46. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007; http://guidance.nice.org.uk/CG46.
10. Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis. Health Technology Assessment Reports 2005;9:Number 49.
11. Anderson FA, Jr., Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107(23 Suppl 1):I9-16.
12. White RH, Zhou H, Gage BF. Effect of age on the incidence of venous thromboembolism after major surgery. Journal of Thrombosis and Haemostasis 2004;2(8):1327-33.
13. Department of Health. Report of the independent expert working group on the prevention of venous thromboembolism in hospitalised patients. 2007; http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_073944.
14. NICE. The prevention of venous thromboembolism in all hospital patients. 2007; http://guidance.nice.org.uk/page.aspx?o=429276.
Competing interests: None declared

A response: clarification and convergence 6 June 2007

Tom Treasure,
Consultant thoracic surgeon
Guy's Hospital, London, SE1 9RT,
Jennifer Hill, Peter Littlejohns, Gillian Leng
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Re: A response: clarification and convergence

Reducing life-threatening venous thromboembolism in patients who have undergone surgery has long been a controversial area(1). Despite being highlighted as a key area for improvement in the UK(2) and other countries(3) there remains much room for improvement.
The National Institute for Health and Clinical Excellence (NICE) was invited by the Secretary of State and the Welsh Assembly Government in 2003 to develop guidance for high risk surgical patients. These were published in April 2007 on time and according to the rigorous and consultative processes required by the Institute(4). The NICE guideline is evidence-based, in its preparation four existing guidelines were reviewed and 21,000 articles (both clinical and economic) were identified of which 587 were included in the analysis. The underlying evidence base and all the consultation comments and Guideline Development Group (GDG) responses are publicly available. The Institute has now been commissioned to develop guidance for reducing venous thromboembolism in all hospitalised patients.
In March 2005 the Health Select Committee published its report on this issue(5) and added their concerns about the continuing levels of morbidity and mortality due to thromboembolism. Later that year the Chief Medical Officer of England established a working group to report to him by July 2006. Their terms of reference were �to recommend action for implementation pending publication of NICE VTE guidance� and they �were to limit their recommendations to implementation of existing VTE guidance and good practice�. This report was published in April 2007(6).
At the core of the NICE guideline is a recommendation that all surgical in-patients are assessed and a stepwise approach to prevention is taken according to the risk of the operation and the risks inherent in each patient. The guideline recommends that all surgical inpatients should receive prophylaxis for VTE. Mechanical methods (such as graduated compression stockings which are effective but carry no risk of bleeding) are recommended for all but a few patients. For patients at higher risk due to their own risk factors or the type of surgery, a combination of mechanical and pharmacological methods, which do carry a risk of bleeding, are recommended.
Two articles were published in the BMJ on the 19th May. One by Jennifer Hill and Tom Treasure(7) summarising the NICE guidance, and an editorial by David Fitzmaurice (member of the CMO working group) and Ellen Murray referring to the NICE guidance and the broadly similar recommendations of the working group report(8). Both articles have generated extensive correspondence, the nature of which provides a clue to why management in this area remains substandard.
In some patients as highlighted by Gardner and colleagues(9) even a very small bleed, insignificant in other contexts, might be devastating. Thus they have interpreted the guidelines as being too aggressive, a view shared by many orthopaedic surgeons. This issue was debated extensively by the GDG. Guidelines are however what they say they are: guidelines - not directives and on every NICE Guideline is a statement that healthcare professionals are expected to take the guideline fully into account when exercising their clinical judgement. The guidance does not, however, override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. Clinical policy coloured by a recent tragedy (in this instance a bleed) which leads to subsequently not using anticoagulation (and ignoring the entirety of the evidence base) can disadvantage subsequent patients who suffer thrombosis(10,11).
On the other hand other critics (including members of the CMO working party) feel that the guidance is not aggressive enough. So this guideline has been challenged with equal force for advocating both too much and too little heparin usage. We would suggest that the Institute and its advisors have got it about right.
Howie and Watts raise the issue of surrogate endpoints(12). If the GDG had ample randomised evidence with the important endpoints of fatal bleeds versus fatal embolism then they would have used them alone, but such data are very limited. The GDG did find that where both the major and lesser outcomes were available there was a proportionality which ran through individual studies and their meta-analyses. The GDG therefore decided to take the line that there was a continuum from fatal PE down to asymptomatic DVT and if lower limb thrombosis was reduced that would translate into lives saved from PE. This is plausible and uses the available data rather than wasting it. The importance of additional research, particularly to find the current risks of VTE and bleeding hazards associated with different types of surgery, has been highlighted by the NICE guideline in one of the recommendations for research.
So in summary we have a significant clinical issue with differing professional perceptions of risk, an inadequate evidence base and disagreement over the appropriate level of intervention. This lack of consensus is probably contributing to the poor uptake of good practice in this field. There is a wealth of data to show that when faced with such a situation in health care no weight of top down directives (how ever authoritative and well meaning) will bring about change in practice. In this context understanding the barriers to implementation as well as active guidance, dissemination and support is crucial to achieving uniform good practice. NICE has already established a dialogue with the orthopaedic professional groups and will have a series of meetings to facilitate a mutual understanding of the evidence base and what it means for their patients.
It is heartening that there is uniformity in opinion on the importance of reducing the number of patients suffering VTE and broad agreement that most surgical patients should be receiving some form of prophylaxis. Ultimately it will require a dialogue between patients and their doctors on what the risks are for them individually, based on the best information.
Professor Tom Treasure, Chairman of Guideline Development Group.
Dr Jennifer Hill, Director, National Collaborating Centre for Acute Care.
Professor Peter Littlejohns, Clinical and Public Health Director, NICE.
Dr Gillian Leng, Implementation Director, NICE.
Reference List
1. Treasure T, Griffin S. Postoperative thromboembolic disease: a tantalizing enigma. In Hadfield J, Hobsley M, Treasure T, eds. Current Surgical Practice (Volume 5), pp 38-51. London: Edward Arnold, 1990.
2. Department of Health Expert Group (Chairman CMO). An organisation with a memory: report of an expert group on learning from adverse events in the NHS chaired by the Chief Medical Officer. 2000. London, Stationary Office.
3. Kohn, L. T., Corrigan, J. M., and Donaldson, M. S. To err is human: building a safer health system. Institute of Medicine. 2000. Washington DC, National Academy Press.
4. National Institute for Health and Clinical Excellence. Venous thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. 2007. London, National Institute for Health and Clinical Excellence. NICE clinical guideline no. 46.
5. House of Commons Health Committee. The prevention of venous thromboembolism in hospitalised patients. HC 99. 2005. London, The Stationery Office Limited.
6. Department of Health. Report of the independent expert working group on the prevention of venous thromboembolism (VTE) in hospitalised patients. 2007. London, Department of Health.
7. Hill J,.Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients having surgery: summary of NICE guidance. BMJ 2007;334:1053-4.
8. Fitzmaurice DA,.Murray E. Thromboprophylaxis for adults in hospital: an intervention that would save many lives is still not being implemented. BMJ 2007;334:1017-8.
9. Gardner, A. C., Jackowski, A., Grainger, M., Spilsbury, J., Marks, D., Stirling, A., and Thompson, A. Thromboprophylaxis in spinal surgery. A rapid response to Hill and Treasure, BMJ, 2007, 334:1053-1054. http://www.bmj.com/cgi/eletters/334/7602/1053 334, 1053-1054. 2007. 5-6- 2007.
10.Choudhry NK, Anderson GM, Laupacis A, Ross-Degnan D, Normand SL, Soumerai SB. Impact of adverse events on prescribing warfarin in patients with atrial fibrillation: matched pair analysis. BMJ 2006;332:141-5.
11.Treasure T. How a single adverse event can affect future prescribing: matched pair analysis. Student BMJ 2006;14:162-3.
12.Howie, C. R. and Watts, A. C. Using surrogate outcomes may be NICE but is it right? A rapid response to Hill and Treasure, BMJ, 2007, 334:1053-1054. http://www.bmj.com/cgi/eletters/334/7602/1053 334, 1053- 1054. 2007. 5-6-2007.
Competing interests: None declared

NICE has got it wrong 29 June 2007

Martyn J Parker,
Orthopaedic Research Fellow
Peterborough District Hospital, Peterborough, PE67NJ
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Re: NICE has got it wrong

Having read the draft NICE review on this topic and the subsequent article by Hill and Treasure(1), I regret I have serious reservations about the review and its conclusions.
In essence there seems to be a compete obsession from the NICE guideline on surrogate end points (asymptomatic deep vein thrombosis) and a lack of emphasis on clinical outcomes of pulmonary embolism, mortality and side effects of therapy. This is shown by the opening comment of the article by Hill and Treasure of a 40% incidence of deep vein thrombosis in orthopaedic surgery, omitting the word �asymptomatic�. The NICE guidelines have concentrated almost exclusively on this surrogate outcome measure and neglected to consider clinical outcomes.
The essence of any method of thromboprophylaxis is does the advantages of therapy outweigh the adverse effects. These features are barely mentioned in the NICE guidelines with scant regard to adverse effects.
Much of the problem of course is there is a lack of large independently run randomised trials on this issue and we are left with small industry sponsored studies using surrogate end points. The end points of such studies are of asymptomatic deep vein thrombosis, which is of questionable clinical relevance. Much more important is for example will heparins reduce the mortality after hip fracture. If thromboembolic complications are that important to cause so many deaths, then for hip fracture there should at least be some trend to a reduced mortality in those patients allocated to receive prophylaxis.
The Cochrane review on heparins for hip fractures clearly showed that heparins did indeed reduce the surrogate end point of asymptomatic deep vein thrombosis, but they had no statistically significant effect on mortality(2). In fact of considerable concern there was a tendency to increased mortality in those allocated to heparin. There are therefore concerns that in this population, heparins will increase mortality. This may be even more prominent if heparins are used for extended prophylaxis as controversially suggested by NICE.
Mechanical methods are also of questionable clinical benefit for the hip fracture population as shown by the Cochrane review(2). There are also enormous cost implications that have not been correctly addressed in this review. Furthermore the SIGN guidelines for hip fracture also reviewed the literature and stated that graduated stocking have not been shown to be of any value in hip fracture patients(3). The SIGN guideline also using an �evidence based� review of the literature concluded there was inadequate evidence to support the use of either graduated stockings or heparin for routine thromboprophylaxis after hip fracture. Aspirin was recommended instead.
It is therefore worrying that apart from the enormous cost implications of the NICE guidelines in the provision of anti-embolism stockings, carers to apply them and district nurses to administer heparins, they may also be a detrimentally effect with an increase mortality after hip fracture. The guidelines show a complete lack of focus on clinical issues and outcomes and are seriously flawed. I would implore those responsible for these so called �evidence based guidelines� to reconsider their entire approach to how the review was conducted and the conclusions in regard to hip fracture patients.
1. Hill J, Treasure T. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients having surgery: summary of NICE guideline Br Med j 2007;334:1053-4.
2. 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 Database of Systematic Reviews 2002, Issue 4.
3. Scottish Intercollegiate Guidelines Network (SIGN). Prevention and management of hip fracture in older people; a national clinical guideline. Royal College of Physicians. Edinburgh. No.56 2002. www.sign.ac.uk.
Competing interests: None declared