Clopidogrel dilemma for orthopaedic surgeonsans_5631 774..784
Mitchell J. Steele,* John S. Fox,† John P. Fletcher,‡ Leeanne E. Grigg§ and Gordon Bell¶*Wollongong Hospital†Head Orthopaedic Surgery, Westmead Hospital‡Department of Surgery, University of Sydney, Westmead Hospital§Royal Melbourne Hospital and¶Head Spinal Surgery, Cleveland Clinic, Cleveland, OH, USA
Dr Mitchell J. Steele, Wollongong Hospital, 4 MansionPt Road, Grays Point, Sydney, NSW 2232, Australia.Email: [email protected]
M. J. Steele BE, MB BS; J. S. Fox FRACS, FAOrthoA;J. P. Fletcher MD, FRACS; L. E. Grigg MB BS, FRACP;G. Bell MD.
Authors are not in receipt of any research scholarshipsor funding for this paper.
Accepted for publication 24 October 2010.
doi: 10.1111/j.1445-2197.2010.05631.x
Abstract
Background: Patients medicated with clopidogrel who require orthopaedic surgerypresent a particular challenge. Whether in an emergency or elective situation theorthopaedic surgeon must balance the risks of ceasing clopidogrel versus the risk ofincreased bleeding that dual antiplatelet therapy generates.Method: This paper reviews the current published evidence regarding the risks ofcontinuing clopidogrel, the risks of discontinuing clopidogrel and associated consid-erations such as venous thromboprophylaxis.Results: Little good quality evidence exists in regard to perioperative clopidogrel fororthopaedic surgery. Available evidence across non-cardiac and cardiac surgery wereassessed and presented in regards to current practices, blood loss for orthopaedicoperations, risks when continuing clopidogrel, risks of stopping clopidogrel and alsothe consideration of venous thromboembolism.Conclusions: The patients at greatest risk, when discontinuing clopidogrel therapy,are those with drug eluting stents who may be at risk of stent thrombosis. Wherepossible, efforts should be made to continue clopidogrel therapy through the periop-erative period, taking precautions to minimize bleeding. If the risk of bleeding is toohigh, antiplatelet therapy must be reinstated as soon as considered reasonable aftersurgery. In addition, patients on clopidogrel who sustain a fall or other general traumaneed to be carefully assessed because of the possibility of occult bleeding, such as intothe retroperitoneal space. Until more definitive evidence becomes available, thisreview aims to provide a guide for the orthopaedic surgeon in dealing with the difficultdilemma of the patient on clopidogrel therapy, recommending that orthopaedic sur-geons take a team approach to assess the individual risks for all patients and considercontinuation of clopidogrel therapy perioperatively where possible.
Introduction
The objective of this paper is to review the current evidence regard-ing the use of clopidogrel (Plavix®, Iscover®) during the periopera-tive period.
As medicine advances, patients are presenting with moreco-morbidities and an increasing array of therapeutic treatments.Such treatments often complicate the management algorithm espe-cially when surgical intervention becomes necessary. Patients withorthopaedic problems are a particular subgroup of concern because,often, the orthopaedic issue is acute with conflicting goals of tryingto operate early to stabilize the skeleton, which minimizes bleeding
and allows increased early mobility, but has to be balanced againstthe concern for increased intra-operative bleeding associated withthe use of antiplatelet agents.
This review looks at patients being managed with clopidogrel, atheinopyridine antiplatelet aggregator agent used in the managementof atherosclerotic disease. It is well recognized that clopidogrel mayincrease the risk of perioperative bleeding and this fact alone leadsmany surgeons to discontinue its use preoperatively. However, thismay expose the patient to an increased risk of thrombosis, especiallyin those patients who have drug-eluting stents (DES) and thisincreases the risk of a potentially fatal complication. This risk iscompounded by the prothrombotic state following surgery. In the
case of emergent or urgent surgery, a delay of operation in order tocease clopidogrel may itself translate to an increased morbidity andmortality consequent on the decreased mobility. Orthopaedic sur-geons are faced with the dilemma of whether to continue clopidogrelperioperatively and run the risk of increased bleeding and manage itssequelae, or to withdraw clopidogrel, exposing the patient to cardiacor cerebrovascular events.
This paper reviews the current evidence and proposes options formanagement of those patients who are taking clopidogrel whorequire surgery. Options could include: delay surgery, continue dualantiplatelet therapy, ‘bridge’ the patient with an alternate or singleantiplatelet agent or stop clopidogrel and restart following surgery.1
In order to effectively examine this dilemma, this paper dividespatients taking clopidogrel into separate groups based on the indi-cation for clopidogrel therapy. The reason for treatment has a largeinfluence when the time comes for surgery. Clopidogrel may beprescribed following acute coronary syndrome (ACS) or cere-brovascular attack (CVA) in combination with aspirin or for aspirinintolerance and, in other cases, for primary prevention of vascularevents. Clopidogrel is commonly prescribed in combination withaspirin following percutaneous coronary intervention (PCI)(Fig. 1).
We will look at these groups with regard to two differing ortho-paedic presentations: (i) emergent (or urgent) presentations, such asfractures, and (ii) planned elective procedures, such as joint replace-ment or spine surgery (Table 1).
This paper focuses on two major points of evidence: ‘does clopi-dogrel lead to increased complications, particularly perioperativebleeding?’, and secondly, ‘does withholding clopidogrel lead toadverse outcomes associated with the underlying condition for
which the clopidogrel was prescribed?’ Aspirin is commonly pre-scribed in combination with clopidogrel, especially post-stent inser-tion, and it, too, must be considered. It is important to differentiatebetween the procedures to be performed in regard to rates of perio-perative blood loss.
Methods
The methodology applied is a literature review of currently avail-able published evidence. Searches were conducted utilizingPubmed, Medline and Cochrane. Relevant clinical trials, observa-tional registry data, and other studies relevant to patients on clo-pidogrel treatment, including guideline recommendations, wereselected from articles generated with the following search terms:clopidogrel, theinopyridine, antiplatelet therapy, orthopaedicsurgery, orthopaedics, surgery, bleeding, stent thrombosis, throm-boprophylaxis, early surgery, hip fracture, cardiac surgery, non-cardiac surgery.
Clopidogrel and its use
Platelets have an established role in the pathophysiology of ath-erosclerotic disease and thrombotic events. Long-term use of anti-platelet drugs has shown consistent benefit in the prevention ofischaemic stroke, myocardial infarction and vascular death inpatients at increased risk of such outcomes, including those withestablished atherosclerosis or a history of atherothrombosis.2 Clo-pidogrel is an effective antiplatelet agent for use in atherothrom-botic disease.3 It is a specific and potent inhibitor of plateletaggregation. Clopidogrel is indicated in combination with aspirinfor use as prophylaxis of thromboembolic disorders in ACS(unstable angina, myocardial infarction +/- ST segment elevation)and post-PCI.
Clopidogrel is a thienopyridine that selectively binds to the ade-nylate cyclase-coupled adenosine diphosphate (ADP) receptor onthe surface of the platelet, thus reducing the binding of pro-aggregating substances to the platelet surface.4 Biotransformation ofclopidogrel is necessary to produce inhibition of platelet aggrega-tion. The active metabolite, a thiol derivative, is formed by oxidationof clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. Theactive thiol metabolite binds rapidly and irreversibly to platelet ADPreceptors, P2Y12, thus inhibiting platelet aggregation. Clopidogrelalso inhibits platelet aggregation induced by other agonists by block-ing the amplification of platelet activation by released ADP. Due tothe irreversible binding, platelets exposed are affected for the
Post PCI
Drug eluting stent
Secondary prevention
following ACS or CVA
Primaryprevention of
ACS, CVA
Balloonangio
Metalstent
or CVA
Fig. 1. Indication for clopidogreltherapy (angioplasty, bare metal stent).ACS, acute coronary syndrome; CVA,cerebrovascular attack; PCI, percutane-ous coronary intervention.
Table 1 Examples of orthopaedic presentations
Emergency/Urgent cases
Threatened limbsMultiple traumaFractures requiring external or internal fixationSeptic arthritis
remainder of their lifespan, approximately 7 days, and recovery ofnormal platelet function occurs at a rate consistent with plateletturnover.2 Clopidogrel has a half-life of 7–8 h, although these timesmay be longer in the elderly and in the case of extended use.5
Aspirin works through the separate thromboxane A2 pathway, andhence, clopidogrel is used as an alternative to or, as in manyinstances, in combination with aspirin.6
Clopidogrel is used for patients with or at risk of atherothromboticdisease. Aspirin (100 mg/day) and clopidogrel (75 mg/day) are rec-ommended for 4 weeks following PCI with bare metal stents (BMS).In the case of DES, the minimum treatment time recommended is 12months.7
Results
Current practice
There is a lack of consensus on whether or not one should stopclopidogrel prior to operating. Bleeding time is prolonged withclopidogrel, so it has been recommended that if a patient is toundergo elective surgery and an antiplatelet effect is not desired,clopidogrel should be discontinued at least 5 days prior to surgery.2
With respect to orthopaedic surgery, much of the debate hassurrounded the dilemma related to the management of trauma-related patients who present while on clopidogrel. The problem hasbeen to find the correct balance between operating early, in order tominimize the risks and discomfort related to immobilization andimmobilization-related complications, versus operating late. That is,delaying any surgical intervention until the effects of clopidogrel areno longer a significant variable while dealing with the risks of chestcomplications, pressure sores and the increased mortality8 associ-ated with delaying hip fracture surgery.
There are a number of papers debating best practice regardingorthopaedic trauma patients based on surveys of surgeons.9–12
Surveys only examined the management of clopidogrel use prior tosurgery. Patient outcomes were not examined.
A survey of orthopaedic surgeons in Scotland found that almosthalf (47.2%) of respondents stopped clopidogrel 7 days preopera-tively, while 13.9% did not routinely stop the medication. The remain-ing 38.9% stopped the medication at a variable interval between 5 and21 days before surgery, for elective and emergency cases.10
A survey of orthopaedic departments across the United Kingdomdemonstrated a wide variety of practices, largely based on anecdotalevidence, regarding the perioperative management of traumapatients admitted on clopidogrel. Of the 137 centres, 41% stoppedclopidogrel and operated immediately (n = 56), 19% continuedclopidogrel and operated immediately (n = 26), 10% stopped clopi-dogrel for 10 days preoperatively (n = 14) and 30% had an alternateprotocol.11
Another UK survey9 looking at discontinuation of clopidogrel inpatients with fracture of femoral neck awaiting surgery had substan-tial variation in clinical practice. There were 62 departments (56.4%)with no formal policy on stopping clopidogrel versus 48 depart-ments (43.6%) that did. Of those departments that discontinuedclopidogrel, the most common length of cessation preoperativelywas 1 day (13.6%), but there was a wide variation from 1 to 10 days.
There were 22 (20.9%) departments that delayed surgery for morethan 5 days; of these, 15 (13.6%) departments delayed for more than7 days.
Program directors of academic orthopaedic surgery residencytraining programs in the USA were surveyed and asked how longsurgery should be delayed for an ‘urgent’ case (e.g. hip fracture)versus ‘emergent’ case (e.g. threatened limbs, compartment syn-drome) when the patient is on clopidogrel.12 Seventy-three percentof orthopaedic residency programs felt that waiting 3 days or less forurgent operative interventions on patients on clopidogrel was accept-able, and 23% felt that no delay at all is necessary.
For patients requiring emergent surgery, 89% of residencyprogram directors reported that there should be no delay in gettingpatients on clopidogrel to the operating room, However, the remain-ing 11% of responses suggested that either a delay of 4 h wasappropriate or they had no protocol.12
These surveys tend to support the hypothesis that in an emergencypresentation, operating early on patients on clopidogrel leads tobetter outcomes than delaying surgery, despite the risk of increasedperioperative bleeding. However, there remains significant variationin clinical practice. These findings highlight the need to developguidelines for the preoperative management of these patients.
Blood loss in orthopaedic operations
It is important to identify the potential rates of perioperative bloodloss and the criticality of haematoma formation associated withindividual procedures, as it will have significant influence on thedecision regarding clopidogrel. Some orthopaedic procedures willhave minimal blood loss such as closed reductions or high rates ofblood loss in the case of total hip replacements (Fig. 2). On top ofperioperative blood loss, it is also important to consider the conse-quences of haematoma formation especially following implantationof prostheses, or in spinal surgery.
In the case of elective spinal orthopaedic surgery, bleeding com-plications include epidural haematoma, spinal cord and caudaequina compression. As such, any increase in bleeding is unaccept-able due to the disastrous consequences of bleeding complications.Limited evidence exists around clopidogrel and elective orthopaedic
Minor
• Joint aspirations
• Closed reductions
• K-wire fixation
Moderate
• Knee arthroscope
• Arthroscopic ligament reconstruction
• Open reductions internal fixations (ORIF)
Major • Total knee replacement (TKR)
• Total hip replacement (THR)
Blood loss unnacceptable
• Spinal orthopaedic surgery
Fig. 2. Examples of rates blood loss in orthopaedic procedures.
spinal surgery; it is generally accepted that clopidogrel must beceased. There is also debate regarding anticoagulation ofthese patients as it exposes patients to increased risks of epiduralhaematomas.13
This is also an important consideration if any operation is plannedaround a regional spinal or epidural anaesthetic. Clopidogrel iscontraindicated in regional anaesthesia due to the risk of spinalhaematoma.14 Again, there is little evidence related to use of clopi-dogrel; some evidence exists in relation to aspirin and suggests thatits use does not actually increase the risk of spinal haematoma.15
Clopidogrel will generally be withdrawn for 7 days whereas alter-native options are a decision for the treating anaesthetists, hence theimportance of their involvement in decision-making.
Increased perioperative risk for patientstaking clopidogrel
Continuing clopidogrel in the operative period can lead to bleeding-related complications. Because patients who are being treated withclopidogrel have underlying atherosclerotic and cardiac disease, it isnot surprising that most evidence regarding preoperative use ofclopidogrel arises from cardiac surgery. However, although the ben-efits of antiplatelet drugs in the long-term reduction of vascularevents have been established,3 evidence supporting their use in theperioperative period is scarce.
Patients with ACS are commonly prescribed and treated withaspirin and clopidogrel. This group of patients has a higher-than-average probability of requiring cardiac surgery, and thus, there issignificantly more evidence related to clopidogrel use in the preop-erative period for this group.
Dunning et al.16 suggested guidelines for the management of anti-platelet and anticoagulation agents in cardiac surgery. They recom-mended that patients who need urgent cardiac surgery should stopclopidogrel 5 to 7 days before surgery if their clinical conditionallows. The benefit in reducing perioperative blood loss,re-exploration and blood product usage is at the expense of a 1%increase in the risk of myocardial infarction while awaiting surgery(Grade B recommendation based on individual level 1a and 1bstudies).
Results of recent studies are still divided. Pickard et al.17 foundclopidogrel exposure within 7 days before coronary artery bypassgrafting (CABG) is associated with an increase in major bleeding,haemorrhage-related complications and transfusion requirements,potentially leading to greater consumption of health-care resources.The overall risks and benefits for each patient should be consideredbefore continuing the drug preoperatively.
Maltais et al.18 found that blood loss is higher in off-pump coro-nary artery bypass (OPCAB) patients receiving clopidogrel beforesurgery. However, discontinuation of clopidogrel 3 days (72 h) priorto the operation demonstrated a similar blood loss pattern comparedto a control group. Clopidogrel was associated with more platelet butnot red blood cell transfusions following OPCAB surgery.
Song et al.19 looked at the effects of continuous clopidogrel useduring OPCAB. They concluded that preoperative continuousadministration of clopidogrel did not increase the risk ofhaemorrhagic-related complications in patients with ACS undergo-ing isolated OPCAB. Interestingly, it was also found that operation
time was increased in the clopidogrel group, suggesting that moredelicate anastomotic techniques and more meticulous haemostasismay decrease haemorrhagic complications and improve immediateand long-term surgical outcomes.
The results of a further study suggest that preoperative use ofclopidogrel is not associated with increased bleeding and need forsurgical exploration as well as risk of blood and blood producttransfusion after CABG.20
The cohort study by Ernst et al.21 looking at the effect of clopi-dogrel use on bleeding complications after transbronchial lungbiopsy was stopped early due to the significantly higher rates ofbleeding in the clopidogrel group. The bleeding rate in theclopidogrel-only group was excessive (89% versus 3.4%) and also inthe group receiving clopidogrel and aspirin (100% versus 3.4%).Bleeding rates were significantly higher in the clopidogrel group foreach degree of bleeding severity: mild (27% versus 1.5%), moderate(34% versus 1.5%) and severe (27% versus 0.3%; P > 0.001 for allcomparisons). All 12 patients receiving both aspirin and clopidogrelhad bleeding which was moderate in six patients and severe in sixpatients. All bleeding was controlled by endoscopic means. Therewere no fatalities or need for blood transfusions in the patientsenrolled in the trial. It was recommended that clopidogrel be stoppedbefore transbronchial lung biopsy.21
It is important to note that although bleeding was significantlyincreased in the clopidogrel group, there were no adverse clinicaloutcomes. Bleeding responded to topical endoscopic treatment, andno patients required intubation or admission to critical care areas andno patients required blood transfusion.21 When considering thepotentially catastrophic events associated with stent thrombosis pre-sented in this paper, the recommendation to stop clopidogrel may notbe the best management for this patient group.
An alternative interpretation of the study’s findings might be:‘Continuation of clopidogrel during bronchoscopy with biopsyappears to be safe (defined as no significant increase in the need fortransfusions, hospitalization or death); however, there may be a needfor additional endoscopic treatment. Continuation of clopidogrelduring bronchoscopy with biopsy should therefore be considered asa viable option in patients who may be at risk of catastrophiccomplications after clopidogrel discontinuation, such as patientswith prior (especially recent and drug-eluting) coronary stentimplantation’.22
Most risks associated with bleeding are in the operative and earlypost-operative period. It is well recognized that there is a potentialfor long-term problems associated with bleeding, particularly ashaematoma is the most important local risk factor for the develop-ment of a wound infection after surgery.23 This is particularly impor-tant following arthroplasty as surgical site infection is associatedwith joint prosthesis infection.24 The study by Saleh et al. found thatboth haematoma formation and persistent wound drainage are pred-icative of superficial surgical site infection, which has a strongcorrelation with deep-wound infection.25
Parvizi et al.26 studied the effect of ‘excessive’ anticoagulationand found that a mean international normalized ratio (INR) ofgreater than 1.5 was more prevalent in patients who developedpost-operative wound complications and subsequent periprostheticinfection and reported that ‘cautious anticoagulation to prevent
hematoma formation and/or wound drainage is critical to preventperiprosthetic infection and its undesirable consequences.’ Thesefindings could be extrapolated, due to the increase in bleedingcaused by clopidogrel, in that clopidogrel could potentially increasethe risk of periprosthetic infection.
Chassot et al. suggest that blood loss is effectively increased by30–50% when continuing clopidogrel and aspirin perioperatively,27
although this may be less in orthopaedic surgery as most evidence isfrom cardiac surgery with intraoperative heparinization. Except forintracranial surgery, there is no evidence of increase in bleeding-related surgical mortality, although a small increase in complicationshave been reported.27 In patients undergoing orthopaedic, vascularand visceral surgery after PCI and stent implantation, the transfusionrate was 38.5% in controls and 42.6% in patients taking dual anti-platelet therapy.28
Associated risks of stopping clopidogrelperioperatively
Ho et al.29 observed a clustering of adverse events in the initial 90days after stopping clopidogrel among those treated for preventionof vascular events and post PCI-treated patients, supporting thepossibility of a clopidogrel rebound effect. Patients who discontinueclopidogrel therapy early are more likely to die, as seen whenlooking at patients with DES ceasing therapy less than 30 daysfollowing PCI.30
Stent thrombosis
Stent thrombosis is an uncommon yet potentially disastrous compli-cation. Discontinuing clopidogrel in the patient due to surgery mayincrease the risk of stent thrombosis. In particular, there have beenrising concerns for patients with DES regarding the potential for latestent thromboses related to delayed endothelialization of the stentstruts after discontinuation of clopidogrel.31 In the context of surgery,stent thrombosis has been related to a number of factors: incompletestent endothelialization early after implantation, hypercoagulabilityrelated to surgery and omission of antiplatelet aggregation therapy inorder to reduce bleeding.32 There are limited studies looking at stentthrombosis, particularly in the perioperative period, and increasingcase reports of stent thrombosis with adverse outcomes includingmyocardial infarction and death in many instances.
Stent thrombosis occurred in 0.8% of patients after DES implan-tation during long-term follow-up.33 The incidence of late (1 monthpost-stent implantation) stent thrombosis was 0.6%, similar to thatfor BMS. The predictors of late stent thrombosis were prematureantiplatelet therapy interruption, primary stenting in acute myocar-dial infarction and total stent length. In another study, angiographi-cally proven stent thrombosis occurs with an incidence of at least0.35% in patients treated with DES.34 Importantly, it may also occurwhen patients are stable on antiplatelet monotherapy (aspirin only).In this study, there were no occurrences in patients on clopidogreland aspirin therapy. In a further study, stent thrombosis occurredoverall in 0.6% DES patients, 0.44% occurring after clopidogreltreatment was discontinued in all except one patient.35
The previous studies looked at overall cohorts of patients withDES thrombosis. A study by Rhee et al. looked at clopidogrel use
specifically in the perioperative period. They found that during theperioperative period, patients had a 5% risk of stent thrombosis,related to duration of discontinuation of clopidogrel, older age and aTaxus stent.36 There were no stent thromboses in patients in whomclopidogrel was discontinued for less than 14 days.
Mcfadden et al. presented three cases of late stent thrombosisafter clopidogrel was stopped for non-cardiac surgery.31 Barthwalet al. presented a case of late stent thrombosis, supported with angio-graphic evidence, occurring 9 days following discontinuation ofclopidogrel for a laparoscopic cholecystectomy 3 years post-DESimplantation.37
Nasser et al. present two cases of late stent thrombosis 4 and 21months following implantation of sirolimus-eluting stent. The twopatients were taking aspirin but were no longer on clopidogrel.Aspirin was stopped preoperatively in both cases.32 The case of latestent thrombosis 21 months after implantation occurred 11 daysfollowing a total hip replacement. Enoxaparin was given post-operatively. In another case, stent thrombosis occurred shortly afterdiscontinuation of clopidogrel, possibly also related to late stentmalposition.38
Other case reports have shown stent thrombosis long after clopi-dogrel cessation: 41 months after implantation, following 6 monthsclopidogrel therapy,39 21 months following clopidogrel discontinu-ation,40 27 months and 13 months after clopidogrel cessation onaspirin monotherapy41
It is important to mention that there have also been reports of latestent (DES) thrombosis with continuation of clopidogrel and aspi-rin.35,42 It has been reported that 4% to 30% of patients treated on astandard dose of clopidogrel have an inadequate platelet response.43
This may, in part, be able to explain these occurrences.Discontinuation of dual antiplatelet therapy is the greatest predic-
tor of stent thrombosis.44 The potential risk of stent occlusion shouldbe considered when discontinuation of antiplatelet therapy is con-templated in patients with DES. As the use of DES becomes wide-spread, careful long-term follow-up of patients with such stents isneeded to assess an accurate rate of late thrombosis.31
Patients on clopidogrel following insertion of coronary stentsneed special consideration and discussion with the interventionalcardiologist involved concerning the safety of stopping versus theadvisability of continuing clopidogrel.11 Surgeons and anaesthetistsmanaging patients with DES face the challenge of balancing therisks of bleeding versus perioperative stent thrombosis.45
Patients undergoing non-cardiac surgery relatively soon after PCImay be at risk of coronary artery thrombosis from the combinedprothrombotic effects of PCI and non-cardiac surgery possibly par-tially explaining the poor outcome of surgery shortly after stentimplantation.46 In general, due to a significant risk of stent throm-bosis if clopidogrel is stopped less than 2 weeks after BMS47 and 4weeks after DES,33 elective surgery must be deferred during thistime. More recent evidence suggests that the above time periods maybe insufficient for preventing thrombosis following cessation of clo-pidogrel. Douketis et al. recommend continuing aspirin and clopi-dogrel in the perioperative period, in patients with a bare metalcoronary stent who require surgery within 6 weeks of stent place-ment and in patients with a drug-eluting coronary stent who requiresurgery within 12 months of stent placement.48
Risk factors that increase the risk of late stent thrombosis includestenting of small vessels, multiple lesions, long stents, bifurcationlesions, suboptimal stent result, low ejection fraction, advanced age,renal failure and diabetes mellitus.14 The cardiologist involvement inaccessing the risk of adverse events after withdrawing clopidogrel isparamount for all PCI-treated patients and medically treated patientsalike.
Delaying emergency surgery
Reversing the effects of clopidogrel would require 7 days; hence, inthe case of hip fracture, this would mean a 7-day longer hospital stay,exposing the patient to numerous other risks: nosocomial bacterialcolonization, risk of deep vein thrombosis (DVT), pressure areas.Early surgery in patients with hip fracture has shown decreasedmortality and morbidity with improved patient outcomes.8,49,50 Earlysurgery is believed to decrease the risk of infection, venous throm-boembolism and decubitus ulceration, resulting in shorter hospitalstays and lower costs. Delay to surgery of greater than 48 h has beenshown to be independently associated with a higher mortality at 1year.51 Shiga et al.’s systematic review found that delay to surgery,for hip fracture patients, greater than 48 h may increase the risk ofall-cause mortality at 30 days and 1 year.52
Surgical delay in elderly patients on antiplatelet agents with hipfracture has been shown to be associated with higher mortality.53 Inclopidogrel and control groups, respectively, the mean times tosurgery were 7.2 and 2.1 days. The 30-day mortalities were 6/21(29%) and 6/159 (4%), a statistically significant result. Despite therisk of increased bleeding, early surgery is recommended.53
Duration of clopidogrel therapy followingstent implantation
Delaying surgery beyond the prescribed duration of dual antiplatelettherapy is a well-recognized approach for elective surgery in PCI-treated patients. It is important for the surgeon to appreciate that asfurther evidence becomes available, clopidogrel treatment may wellbe prolonged beyond the initial 1-year prescription in patients withDES, affecting decisions to delay surgery in these patients.
The necessary duration of clopidogrel therapy following stentimplantation is still debatable, particularly for DES. The observa-tional study by Eisenstein et al.54 found that extended use of clopi-dogrel was associated with statistically significant lower rates ofdeath or myocardial infarction (MI). This stood true for patientsevent-free at 12 months, showing decreased rates of death or MI inthe clopidogrel group.54 These results support extended duration ofclopidogrel use, as yet there are no trials available to determine theoptimum length of treatment.
The joint science advisory by Grines et al. stresses the importanceof 12 months of dual antiplatelet therapy after placement of a DESand educating the patient and health-care providers about thehazards of premature discontinuation. It also recommends postpon-ing elective surgery for 1 year, and if surgery cannot be deferred,considering the continuation of aspirin during the perioperativeperiod in high-risk patients with DES.55
In a large consecutive cohort of contemporary patients receivingPCI, the long-term risk for death and major cardiac events was
significantly increased among patients in the DES group who haddiscontinued clopidogrel therapy at 6 or 12 months. Extended dura-tion clopidogrel therapy following DES implantation was associatedwith a lower incidence of death or MI.54 For patients treated withDES, longer (�12 months) planned duration of clopidogrel resultsin reduced 12-month mortality and premature cessation of clopi-dogrel results in significantly higher event rates.56
Venous thromboembolism prophylaxisand clopidogrel
Venous thromboembolism (VTE) is a common complication and awell-known major cause of morbidity and mortality following majororthopaedic surgery. The incidence of DVT and pulmonary embo-lism (PE) differs for different types of operations. The most impor-tant general risk factors are a history of VTE, family history,increasing age, obesity and history of previous thrombosis.57
The risk of DVT and PE can be reduced by physical methods orprophylactic medications. Physical methods vary, from as simple aselevation of the limb, elastic stockings and early mobilization. Othermethods include devices such as external sequential pneumatic com-pression boots and intermittent pneumatic compression, the effec-tiveness of which is more established particularly for proximalthrombi. Patient dissatisfaction with these devices is common andcompliance can be problematic.57,58 The most commonly used pro-phylactic agents in orthopaedic surgery are fondaparinux, low-molecular-weight heparin (LMWH), warfarin and aspirin.58
Clopidogrel has not been studied in regard to venous thrombopro-phylaxis, and replacing clopidogrel with LMWH will not protectagainst stent thrombosis. Similarly, clopidogrel will not substitute forLMWH for thromboprophylaxis. Combining clopidogrel, aspirin andLMWH may lead to even higher rates of perioperative bleeding,posing another issue for the surgeon. In cardiac surgery (where pa-tients are heparinized), increases in rates of blood loss up to 50% havebeen reported when dual antiplatelet therapy has been continued.27
Aspirin, although offering some protection, has not been shown tobe effective in prophylaxis after total hip arthroplasty, total kneearthroplasty or hip fracture surgeries.59 Geerts et al. recommendagainst the use of aspirin alone as thromboprophylaxis for anypatient group (Grade 1A).60
Thromboprophylaxis is more important for major orthopaedicoperations. Handoll et al.’s61 review of randomized trials found thatboth heparin and mechanical pumping devices significantly decreasethe incidence of DVT following surgery for hip fractures.
Thromboprophylaxis has a smaller effect in less major operations.Ramos et al.’s62 meta-analysis suggests that LMWH reduces theincidence of distal DVT diagnosed by sonogram. The clinical benefitof this is uncertain. No strong evidence was found to conclude thatthromboprophylaxis is effective to prevent thromboembolic eventsand is safe in people with unknown risk factors for thrombosis,undergoing knee arthroscopy.
For patients undergoing elective hip or knee arthroplasty, one ofthe following three anticoagulants is suggested60: LMWH, fonda-parinux or a vitamin K antagonist (VKA), with INR target of 2.5,range 2.0 to 3.0 (each Grade 1A). For patients undergoing hipfracture surgery, the routine use of fondaparinux (Grade 1A),LMWH (Grade 1B), a VKA (target of 2.5, range, 2.0 to 3.0) (Grade
1B) or low-dose unfractionated heparin (LDUH) (Grade 1B) is rec-ommended. Patients undergoing hip or knee arthroplasty or hipfracture surgery should receive thromboprophylaxis for a minimumof 10 days (Grade 1A); for hip arthroplasty and hip fracture surgery,Geerts et al.60 recommend continuing thromboprophylaxis >10 daysand up to 35 days (Grade 1A).
For patients being continued on clopidogrel, as much as possible,mechanical methods of thromboprophylaxis should be utilized.Geerts et al.60 recommend that mechanical methods of thrombopro-phylaxis be used primarily for patients at high bleeding risk (Grade1A) or possibly as an adjunct to anticoagulant thromboprophylaxis(Grade 2A). When bleeding risk is thought to be high, or when thereis a low risk of DVT, mechanical methods alone should be used. Ifthe risk of DVT is high and bleeding risk is low, then an anticoagu-lant such as LMWH may be necessary with the addition of mechani-cal methods.
Occult bleeding following trauma
Besides the medical management issues mentioned above, whenmanaging the patient presenting with a fracture or other trauma, thetreating team needs to be aware of the potential for occult bleeding.Retroperitoneal bleeding is a well-recognized complication of clo-pidogrel use63 and it is easy for the team to be focused on the fractureand to fail to consider other sources of blood loss with potentiallyserious consequences.
Cases involving spontaneous spinal haematomas, in patients onclopidogrel, have been reported in the literature.64–66 All medicalprofessionals must be cautious of patients on clopidogrel therapy, asthe increased risk of bleeding can lead to disastrous outcomes.
Alternative options
The risks for patients with DES are related to excessive bleeding as aresult of continued, combined antiplatelet therapy on the one handand stent thrombosis as a result of withdrawal of combined antiplate-let therapy on the other. Alternative solutions have also been trialledsuch as a short-acting antiplatelet agent, tirofiban, substituting forclopidogrel at the time of surgery. This would protect the coronaryartery lesion and prevent excessive bleeding at the time of surgery.67
For managing patients with a predicted high risk of bleeding andhigh risk of stent thrombosis, Bigalke et al.68 use a short-actingintravenous GPIIb–IIIa-inhibitor to bridge dual antiplatelet therapy.Platelet aggregometry testing was used preoperatively to assessplatelet function.68
It has been suggested based on platelet physiology that a freshplatelet transfusion could be of benefit. Clopidogrel appears to haveits effect on the platelet precursor, the megakaryocyte, not themature platelet, so transfused platelets should not be affected.12 Infact, platelet transfusion is the only intraoperative treatment forexcessive bleeding for patients on clopidogrel.14 When clopidogrelcannot be stopped before surgery, platelet transfusion can safely begiven post-operatively to correct the coagulopathy.18
Aprotinin and other anti-fibrinolytics can also be given at the timeof surgery for better haemostasis,11,69,70 although only limited docu-mented evidence has been reported and Aprotinin is not commonlyused as there are concerns over its safety.
Recommendations
The orthopaedic surgeon must adopt a team approach to all patientspresenting on clopidogrel. All information regarding the patient’sreason for treatment and any information regarding stents must beobtained. Discussions must be undertaken with the anaesthetist andthe treating cardiologist who is essential in assessing the patients’ riskof cardiac events. If the anaesthetist is to use an epidural or spinalanaesthesia, then clopidogrel will need to be stopped, 7 days ahead, asan epidural haematoma can be catastrophic. It is important thateveryone involved are educated in clopidogrel use and its associatedrisks in the perioperative period. It is also imperative that patients andtheir families are aware of the options available and the risks involved.
Continuing dual antiplatelet therapy in the perioperative periodshould be considered in most cases. Acknowledging the possibilityof increased bleeding and applying skilled surgical techniques com-bined with vigilant, effective preparation may minimize operativecomplications. Surgeons should be prepared for the possibility ofincreased blood loss and patients should be cross-matched foradequate quantities of red blood cells and platelets.53
If a patient on clopidogrel requires emergency surgery, such as inthe case of a threatened limb, there should not be any delay in gettingthe patient to the operating theatre. Platelet and blood products mustbe made available.
For urgent surgery, as in the case of hip fracture, it is possible todelay surgery for 7 days in order to decrease blood loss. If the risksof cardiac events upon ceasing clopidogrel are low or if the expectedblood loss is too high, then delaying surgery and withholding clo-pidogrel may be the best option. It has also been suggested thatsurgery be delayed for 24 h after last dose; then intraoperative plate-let transfusion can be utilized if uncontrollable bleeding occurs.11
In the acute setting, the combined risks of adverse cardiac eventssuch as stent thrombosis and risks associated with delaying surgerywill mean that the best management for many patients who are onclopidogrel therapy is to operate while the patient is on clopidogrel.This must also be considered if the cause of initial presentation iscausing significant bleeding, in this situation taking the patient to thetheatre to secure that a fracture will stop ongoing blood loss.
Management decisions can be tailored to minimize blood loss forpatients requiring surgical intervention while on clopidogrel therapy.This may include choosing a surgical procedure that has a lowerexpected rate of blood loss, for example, use of cannulated screws orselecting hemiarthroplasty over total arthroplasty.
In the case of scheduled surgery, delaying the operation would bea feasible option for post-PCI-treated patients. The AmericanCollege of Cardiology/American Heart Association guidelines47
put forward suggested time periods between PCI and non-cardiacsurgery. Consistent with most published evidence, it recommends adelay of >14 days for balloon angioplasty, >30–45 days for BMS and>365 days for DES. If the patient is within the suggested timeperiods of clopidogrel and aspirin therapy following PCI, then dualantiplatelet therapy should be continued perioperatively47,48 (Fig. 3).
As there have been multiple reports of late stent thrombosis,consideration should be given to continuing dual-antiplatelet therapyperioperatively beyond the recommended time frame in any patientat high risk for the consequences of stent thrombosis, such as
patients in whom previous stent thrombosis has occurred, after leftmain stenting, after multivessel stenting and after stent placement inthe only remaining coronary artery or graft conduit.47
Douketis et al.48 suggest that if a patient is at low risk of cardiacevents, then clopidogrel and aspirin can be temporarily interruptedfor non-cardiac surgery. If the patient is at high risk of cardiacevents, exclusive of stent placement, then aspirin should be contin-ued perioperatively and clopidogrel temporarily interrupted.48 Withall patients, the expected blood loss should be considered, and ifexpected blood loss is low and an increase in bleeding is tolerable,then patients who are at higher risk, even those not treated with PCI,should be considered for continuation of clopidogrel (Fig. 4).
If bleeding risk is too high to continue clopidogrel, aspirin shouldalways be continued where possible. If aspirin or clopidogrel arestopped, then they should be restarted 24 h, or next morning, post-operatively as long as effective haemostasis has been achieved.When restarting clopidogrel, following withdrawal for surgery, itshould be with a 300-mg loading dose.14 The managing team must bevigilant of any symptoms suggesting ACS or CVA. With the risk ofacute stent thrombosis, it would be advisable to have access to aninterventional cardiology team, in the event of an acute stent throm-bosis or coronary or cerebrovascular accident.
For PCI-treated patients, consultation with the treating cardiolo-gist is important and as much information as possible should beobtained. Preoperative evaluation should include all pertinentcardiac studies including angiography, stent types and diameters,lengths, locations and cardiology contact information.7
For spinal surgery in the medullary canal, it has been suggested thatclopidogrel be ceased while continuing aspirin, as small post-operative bleeding can be fatal.14 For operations external to the spinalcanal, such as hernial disc repair, it may be possible to perform theoperation without stopping clopidogrel.14 At this stage, very limitedevidence exists, and as such, delaying surgery and stopping clopi-dogrel is likely to be the safest option for spinal orthopaedic surgery.
Finally, all medical professionals must be aware of the possibilityof bleeding when patients are presenting while on dual antiplatelettherapy. The decision regarding the cessation of clopidogrel prior tooperating must be a balance of risks of bleeding and risk of cardiacevent when the patient is off clopidogrel (Figs 5,6).
Post PCI
Drug -eluting stent
Secondary prevention
following ACS or CVA
Primaryprevention of
ACS, CVA
Balloonangio
Metalstent
In combination with aspirin or clopidogrel due to aspirin intolerance Continue clopidogrel within initial weeks above
2 wks 6 wks 52 wks
Higher tolerance for ceasing Clopidogrel
Low tolerance for ceasing Clopidogrel
Continue clopidogrel therapy beyond these times where possible
Fig. 3. Tolerance for clopidogrel basedon indication for treatment. ACS, acutecoronary syndrome; CVA, cerebrovas-cular attack; PCI, percutaneous coro-nary intervention.
Minor
• Jt aspirations
• Closed reductions
• K-wire fixation
High tolerance for continuing clopidogrel
Moderate
• Knee arthroscope
• ACL reconstruction
• ORIF
Major • TKR
• THR
Low tolerance for continuing clopidogrel
Blood loss unnacceptable
• Spinal orthopaedic surgery
Do not continue clopidogrel
Fig. 4. Tolerance for clopidogrel based on expected rates blood. ORIF,open reductions internal fixations; THR, total hip replacement; TKR, totalknee replacement.
Fig. 5. Bleeding risk versus indication for clopidogrel. PCI, percutaneouscoronary intervention.
Although the effects and the complications of clopidogrel use arewell recognized, there is limited amount of conclusive evidence thatexists regarding the decision whether or not to continue clopidogrelin the perioperative period and this has led to much disparity inrecommendations. A review of the literature confirms that there arewide variations in clinical practice and no commonly agreed guide-lines. To determine such guidelines will require a large multi-centrewell-designed randomized trial with enough patients to yield statis-tically significant result in regard to morbidity and mortality.
This paper has aimed to gather together the best evidence avail-able from orthopaedic surgery and other fields of medicine. It is clearthat the decision to stop clopidogrel must not be taken lightly; thereis a risk of severe consequences related to delaying emergencysurgery and the risk of stent thrombosis. Wherever possible, attemptsshould be made to continue clopidogrel in the perioperative periodwhile taking precautions due to the increased potential for bleeding.
Recommendations have been presented based on minimizingpatient risk. Discussion must be undertaken between the operating
surgeons, the treating cardiologist, the anaesthetist and the patientwith a management plan tailored to each individual situation.Finally, the team must maintain a diligent approach to all patientson clopidogrel, particularly in the trauma patient on clopidogrelbecause of the possibility of occult bleeding.
The authors believe that the conclusions and recommendationsreached in this article are in line with recent published evidencewithin non-cardiac surgery.
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Beyond the expected duration of treatment >2 weeks – for balloon angioplasty >6weeks– BMS >12 months – DES Variable for post ACS and CVA patients Clopidogrel therapy may be indefinite Beyond expected duration
Operate whilst patient is taking clopidogrel
Should be considered where possible Particularly for emergent surgery, low expected rates blood loss and patients with high risk of vascular events
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