Clopidogrel in Orthopaedic patients: a review of current practice in Scotland
© Joseph et al; licensee BioMed Central Ltd. 2007
Received: 30 November 2006
Accepted: 25 May 2007
Published: 25 May 2007
Clopidogrel bisulfate is an antiplatelet agent used to prevent ischaemic events in patients with vascular disease. Current guidelines recommend withholding clopidogrel for 7 days pre-operatively. However these are not based on orthopaedic patients. We therefore decided to survey current orthopaedic practice to see whether this complied with available clinical data.
A questionnaire was sent to all orthopaedic consultants in Scotland.
Four haematology departments, and the manufacturers, were contacted to ask for their recommendations, and a database search was performed.
140 questionnaires were sent with a 60.7% response. 84.7% of respondents have encountered patients on clopidogrel. Of those, 13.9% did not routinely stop it, and 86.1% stopped it 5–21 days pre-operatively (47.2% at 7 days).
45.9% had a unit policy on stopping clopidogrel, and the majority (69.4%) did not consult their haematology department prior to instituting their policy.
Increased peri-operative bleeding was the most reported complication (22.6%). However this was only noted in those who stopped clopidogrel greater-than 7 days pre-operatively.
Haematology advice ranged from continuing clopidogrel peri-operatively to stopping it 7 days pre-operatively and starting low-molecular-weight-heparin for thrombo-prophylaxis. The manufacturers suggested stopping clopidogrel 7 days pre-operatively. An internet search did not reveal any data on the effect of clopidogrel peri-operatively in orthopaedic patients.
Recommendations on stopping clopidogrel have evolved from studies conducted on patients undergoing cardio-thoracic surgery. There is no data available on the effect of clopidogrel in orthopaedic practice. Our survey indicates that increased bleeding has not been found in patients who continue clopidogrel peri-operatively.
Almost half of respondents complied with current recommendations, stopping clopidogrel 7 days pre-operatively. However there remains a lack of consensus amongst orthopaedic surgeons.
Currently elective patients should stop clopidogrel 7 days pre-operatively, and emergency patients should stop clopidogrel on admission, however their operation should not be delayed due to clopidogrel usage.
Clopidogrel bisulfate (Plavix®) is an antiplatelet agent that is used in the secondary prevention of ischaemic events in patients with ischaemic heart disease or peripheral vascular disease that are intolerant of aspirin, or in those who require additional antiplatelet therapy in combination with aspirin .
Atherosclerotic disease of both peripheral and central arteries is extremely common in the British population . Combination therapy with statins and antiplatelet agents such as aspirin and clopidogrel is increasingly being used to combat the morbidity and mortality associated with these conditions . Therefore, it is probable that more patients presenting to hospital for elective or emergency orthopaedic surgery will be on an antiplatelet agent. For patients taking the antiplatelet agent aspirin, current Scottish Intercollegiate Guidelines Network (SIGN) recommendations state that aspirin can be continued peri-operatively and used as deep venous thrombosis (DVT) prophylaxis . There is however no SIGN recommendation for patients taking clopidogrel.
We have audited the current orthopaedic practice in Scotland with regards to patients taking clopidogrel admitted both in the trauma and elective setting. Our aim in this study was to compare current practice with evidence based recommendations, the pharmaceutical industry advice, and haematology advice, in order to ascertain whether or not there was a consensus. We highlight the need to develop a uniform protocol based on current best evidence in dealing with these patients.
The pharmaceutical company responsible for manufacturing Plavix ® (Bristol-Myers Squibb) was contacted to see whether they had any recommendations specific to orthopaedic patients, and to ascertain if any research had been conducted in order to support their recommendations. The current British National Formulary (BNF 51) recommendation was also noted, and a review of available literature was performed through google, pub med, medline, and Cochrane database searches.
When do you routinely stop clopidogrel
When Do You Stop Clopidogrel
Do not stop
No time given
Perioperative complications in patients taking clopidogrel
Do you routinely stop clopigorel
Have you found increased peri-operative complications in patients taking clopidogrel
Yes – 16 (25.8%)
Bleeding – 14 (22.6%) Haematoma – 2 (3.2%) Wound infection – 2 (3.2%) CVE * – 1 (1.6%)
No – 46 (74.2%)
No – 10 (100%)
Should clopidogrel be stopped
If stopped when
What DVT prophylaxis should be used
No (if not on aspirin)
Yes (if on aspirin also)
2 – 3 days
Fondaparinux if high risk otherwise none
7 – 10 days
LMWH if high risk otherwise none
The manufacturers of clopidogrel, Bristol-Myers Squibb (UK), were of the opinion that if an antiplatelet effect is not desired, clopidogrel should be stopped 7 days in advance of surgery. However no studies were undertaken specifically on orthopaedic patients. The current volume of the BNF states that clopidogrel should be stopped 7 days pre-operatively . There was no specific advice for orthopaedic patients. Literature review did not reveal any published data on the effect of continuing or discontinuing clopidogrel in orthopaedic elective and trauma patients. There was also no data available on using clopidogrel as peri-operative DVT prophylaxis in orthopaedic patients.
Clopidogrel is an antiplatelet agent that is being increasingly prescribed in both general practice and hospital medicine due to its synergistic action with aspirin, and also for those intolerant of aspirin. The mechanism of action is by irreversibly inhibiting binding of adenosine diphosphate (ADP) to its platelet receptor. This inhibits ADP-mediated activation of glycoprotein IIb/IIIa complex. This in turn inhibits platelet aggregation . As the receptor modification is irreversible, platelet aggregation is impaired for the remainder of the platelets lifespan, generally 7 days. It is because of this permanent effect that the manufacturers, and the current BNF guidelines, recommend stopping clopidogrel 7 days in advance of elective surgery if the antiplatelet effect is not desired . Therefore current practice for the majority reflects the current recommendation.
This recommendation however was based on studies that showed increased rate of post-operative bleeding, need for transfusion, and re-operation rate in patients undergoing cardiothoracic surgery that had clopidogrel continued pre-operatively [6–9]. To our knowledge there has been no research into continued use of clopidogrel peri-operatively in orthopaedic patients.
Patients undergoing orthopaedic surgery have a high incidence of thrombo-embolic complications , especially if no DVT prophylaxis is used . DVT prophylaxis can be both mechanical and pharmacological, and both methods have been shown to decrease thrombo-embolic phenomena in orthopaedic patients [12–14]. Although the new National Institute for Clinical Excellence (NICE) guidelines do not mention it , the Scottish Intercollegiate Guidelines Network (SIGN guidelines) suggests that one method of DVT prophylaxis is aspirin . This was also supported by one of the haematology departments we contacted. It has been shown that aspirin reduces the risk of thrombo-embolic disease, and that the risk of increased postoperative bleeding, haematoma, or infection is low . Therefore we pose the question that although the mechanism of action of both aspirin and clopidogrel is different (aspirin inhibits the cyclo-oxygenase dependent production of thromboxane A2); if aspirin has been shown to be a safe and effective method of DVT prophylaxis in orthopaedic patients could clopidogrel not be used in patients already taking the medication? Currently there appears to be no data available to support this and clopidogrel is not currently licensed for use in DVT prophylaxis.
In our survey 13.9% of respondents did not routinely stop clopidogrel pre-operatively. None of these respondents reported any increased incidence of pre-operative or post-operative complications. This anecdotally seems to suggest that continued use of clopidogrel in patients undergoing orthopaedic surgery may not result in increased risk of complications such as bleeding. This is however contrasted by the reports of increased peri-operative complications (namely bleeding) in those who stop the medication pre-operatively. The finding of increased complications attributable to clopidogrel in those who stop the medication compared with those who do not is paradoxical. There is no literature available to suggest a rebound coagulopathy in patients' that stop clopidogrel pre-operatively. Indeed the likely alternative explanation is that as assessment of bleeding is subjective, consultants who are aware of the complications of clopidogrel may attribute any bleeding to the medication despite having stopped it for a period greater than its' supposed physiologic effect; and those who do not stop the medication may not attribute any increased complications to it. This may be due to a lack of understanding of the mechanism of action of the drug and its effects. There is also the possibility that those who continue clopidogrel are more meticulous with haemostasis due to knowledge of the potential for increased complications. However we are unable to draw any firm conclusions due to the small sample size of our survey.
Our study indicates that there is a lack of uniformity amongst orthopaedic surgeons, and haematologists in Scotland, with regards the need to stop clopidogrel preoperatively. There also appears to be some confusion as to whether additional DVT prophylaxis is needed. Most orthopaedic units did not have a policy to deal with these patients, and the majority did not contact the haematology department at their hospital prior to instituting a policy on stopping clopidogrel. The majority of orthopaedic surgeons also felt that further guidelines in this area would be useful. In order to best manage these patients a multidisciplinary approach is needed to fully assess risk of bleeding compared to risk of an ischemic event when assessing need for anticoagulation.
Our survey raises the following issues. First, is it safe to continue taking clopidogrel in the perioperative period, and if so, is any additional DVT prophylaxis needed or is clopidogrel alone sufficient? Second, in the absence of any current guidelines, are there medico-legal implications if surgeons fail to conform to the British National Formulary advice of stopping clopidogrel 7 days preoperatively? Third, should elective/emergency surgery be delayed until the antiplatelet effect of clopidogrel has worn off?
As this paper was an observational study, there are limitations. Although more than 60% of consultants responded there is the potential for bias as those who responded may have more interest in this subject perhaps due to knowledge of the medication or previous experience of complications. There is also the possibility that those who did not respond do not stop the medication and experienced complications. This would alter the results and therefore the conclusions drawn. However the purpose of this study was to audit the current practice in Scotland and highlight a potential lack of uniformity and the need for further guidance on peri-operative management of these patients.
This is an area of orthopaedic practice that requires further research, as there is great variation in practice. At present it appears that patients having elective surgery should ideally stop clopidogrel 7 days in advance of surgery and that if additional DVT prophylaxis is needed a LMWH or fondaparinux should be used. This should only be done once the patients' condition has been discussed with a haematologist and/or a cardiologist and the benefit/risk of anticoagulation considered. In the emergency setting (trauma), patients need to be assessed on a case-by-case basis. In situations where the risk of intra-operative bleeding in patients taking clopidogrel is less than the morbidity/mortality of delaying treatment, (e.g. fractured neck of femur [16–18]), surgery should not be delayed. Surgeons should be aware of the mechanism of action of clopidogrel and its potential side effects, and surgical technique should be modified accordingly.
I would like to acknowledge the advice given by:
Professor Greeves (Consultant Haematologist, Aberdeen Royal Infirmary),
Professor Ludlam (Consultant Haematologist, Edinburgh Royal Infirmary),
Dr. Gelly (Consultant Haematologist Dundee Ninewells Hospital),
Dr. Tate (Consultant Haematologist, Glasgow Royal Infirmary),
- Indications for use and mechanism of action of clopidogrel[http://www.plavix.com]
- Unal B, Critchley JA, Capewell S: Modelling the decline in coronary heart disease deaths in England and Wales, 1981–2000: comparing contributions from primary prevention and secondary prevention. BMJ 2005, 331: 614. 10.1136/bmj.38561.633345.8FPubMed CentralView ArticlePubMedGoogle Scholar
- Ramsay SE, Whincup PH, Lawlor DA, et al.: Secondary prevention of coronary heart disease in older patients after the national service framework: population based study. BMJ 2006, 332: 144-5. 10.1136/bmj.38704.770127.BEPubMed CentralView ArticlePubMedGoogle Scholar
- Scottish Intercollegiate Guidelines Network: SIGN 62. 2002.Google Scholar
- British National Formulary (51) Section 2.9; 127Google Scholar
- Hongo RH, Ley J, Dick SE, et al.: The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002, 40(2):231-7. 10.1016/S0735-1097(02)01954-XView ArticlePubMedGoogle Scholar
- Yende S, Wunderink RG: Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001, 29(12):2271-5. 10.1097/00003246-200112000-00006View ArticlePubMedGoogle Scholar
- Swarup V, Oh CJ, Richard EN, et al.: Risk of post-operative hemorrhage associated with ticlopidine or clopidogrel use prior to coronary artery bypass grafting. Circulation 2000., 102(8 Suppl 2): Abstract 3145.Google Scholar
- Fox KA, Mehta SR, Peters R, et al.: Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004, 110(10):1202-8. 10.1161/01.CIR.0000140675.85342.1BView ArticlePubMedGoogle Scholar
- Ennis RS: Postoperative deep vein thrombosis prophylaxis: a retrospective analysis in 1000 consecutive hip fracture patients treated in a community hospital setting. J South Orthop Assoc 2003, 12(1):10-7.PubMedGoogle Scholar
- Gillespie W, Murray D, Gregg PJ, et al.: Prophylaxis against deep vein thrombosis following total hip replacement: risks and benefits of prophylaxis against venous thromboembolism in orthopaedic surgery. J Bone Joint Surg Br 2000, 82: 475-9. 10.1302/0301-620X.82B4.10452View ArticlePubMedGoogle Scholar
- Cochrane Review: Heparin, Low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Library 2001., (3):Google Scholar
- Collaborative group: Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000, 355: 1295-1302. 10.1016/S0140-6736(00)02110-3View ArticleGoogle Scholar
- Todd CJ, Freeman CJ, Camilleri-Ferrante C, et al.: Differences in mortality after fracture of hip: the east Anglian audit. BMJ 1995, 310: 904-8.PubMed CentralView ArticlePubMedGoogle Scholar
- National Institute for Clinical Excellence guideline: NICE 46. Venous Thromboembolism: reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients undergoing surgery 2007.Google Scholar
- Scottish Intercollegiate Guidelines Network: SIGN 56. 2002.Google Scholar
- Villar RN, Allen SM, Barnes SJ: Hip fractures in healthy patients: operative delay versus prognosis. Br Med J (Clin Res Ed) 1986, 293: 1203-4.View ArticleGoogle Scholar
- Hefley FG Jr, Nelson CL, Puskarich-May CL: Effect of delayed admission to the hospital on the preoperative prevalence of deep-vein thrombosis associated with fractures about the hip. J Bone Joint Surg Am 1996, 78: 581-3.PubMedGoogle Scholar
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