Clopidogrel and Proximal Femoral Fractures:Does Timing of Surgery Affect Blood Lossand Length of Admission? A PreliminaryStudy Prior to Multicenter TrialGeorge Cox1, Charlie Talbot1, Katerina Topp2, Peter Templeton1

AbstractIntroduction: Clopidogrel is a potent oral antiplateletagent that is commonly prescribed to patients withcardiovascular disease. Patients presenting withproximal femoral fractures often have cardiovascularcomorbidity, with many taking clopidogrel on admis-sion. Scientific literature reports increased surgicalbleeding in patients receiving clopidogrel, though notspecifically hip surgery. This study looked at whetherpatients who had a seven-day delay prior to operativetreatment had less bleeding than those who did not,and looked at the differences in length of admissionbetween the two groups.Methods: A retrospective review was undertaken.Patients were identified from the in-patient pharmacystock records from July 2005 to July 2006. Data wasstatistically analyzed using the chi-squared test.Results: Of 21 patients identified, 20 met the inclusioncriteria, nine had a seven-day delay before operation(Group A), and 11 had a mean one-day delay (Group B).Mean drop in postoperative hemoglobin was 1.8 g/l inGroup A compared to 3.1 g/l in Group B (p < 0.05).Number of complications was similar (Group A = 8 vs.Group B = 9) as was mortality (Group A = 1 vs. GroupB = 2). Admission length was longer in patients whohad a seven-day delay in surgery (Group A = 32 vs.Group B = 22 days) (p < 0.05).Conclusion: Patients should be considered for earlyoperation provided there are no additional bleedingrisk factors, as although postoperative hemoglobin islower, mortality and complication rates are similar,and length of admission is shorter.

Key WordsPlavix Æ Clopidogrel Æ Femur Æ Fracture ÆNeck Æ Hip Æ Bleeding Æ Blood

Eur J Trauma Emerg Surg 2009;35:291–5

DOI 10.1007/s00068-008-8093-x

IntroductionFractures of the proximal femur are common injuries,with approximately 57,500 cases per year in the UK [1].Patients sustaining this injury are often elderly, withstudies showing that mean age is in the early eighties[2]. The majority of these patients have at least onecomorbidity, with cardiovascular disease being themost prevalent [2].

Clopidogrel [Plavix (Bristol-Myers Squibb Phar-maceuticals Ltd)] is a commonly used antiplatelet drugthat has many indications [3]. The National Institute forClinical Excellence (NICE) recommends its lifelongprescription for the prevention of occlusive vascularevents, including the treatment of cerebrovascularaccidents, peripheral vascular disease, non-ST segmentelevation acute coronary syndrome, patients intolerentof aspirin, and the prevention of postmyocardialinfarction atherothrombosis. It is also used followingthe insertion of percutaneous coronary stents [4].

Clopidogrel is a thienopyridine derivative thatinhibits platelet aggregation and thrombus formationby irreversibly antagonizing the binding of adenosinediphosphorate to its platelet receptor. This alters the

1 Leeds General Infirmary, Trauma and Orthopaedics, Leeds, UK,2 Leeds General Infirmary, Healthcare of the Elderly, Leeds, UK.

Received: June 12, 2008; revision accepted: September 22, 2008;Published Online: October 22, 2008

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ADP-dependent activation of the Gp IIb-IIIa complex,which is the primary fibrinogen surface receptor onplatelets [5, 6]. For clopidogrel to become pharmaco-logically active, it must be metabolized in vivo to forman active metabolite. The half-life of the metabolite isonly 8 h but the antiplatelet effect persists, as thebinding is irreversible, until new platelets are manu-factured to replace the inhibited ones (8–9 days). An invivo study showed complete recovery of plateletfunction seven days after the last clopidogrel dose [7].

The manufacturer’s advice for patients takingclopidogrel who are undergoing elective surgery is todiscontinue its use seven days prior to surgery, if anantiplatelet effect is not desired [8]. There are no rec-ommendations for trauma patients admitted as anemergency. Many papers report increased surgicalbleeding in patients who are operated on whilst theirplatelets are deactivated by clopidogrel [9–13], al-though other reports contest this [14]. Most of this lit-erature is with reference to cardiothoracic procedures;however, this effect should be sustained for all surgery.

A potential problem occurs in patients who takeclopidogrel, require urgent surgery and in whom a se-ven-day delay may have deleterious effects. In patientswho are acutely compromised, the decision to operate –albeit with an increased risk of bleeding – is usuallyclear. However, it is unclear what is best for patients inwhom early operation would be advantageous but notessential. Patients who have sustained proximal femoralfractures (PFF) fall into this group, with several paperssupporting early operation and mobilization, and it isthis evidence that promotes current orthopedic practice[15, 16]. It is unclear whether these patients wouldbenefit most from early operation or from a delay togive time for fresh, active platelets to be produced.

Delaying operation should be avoided if there is noadverse effect on clinical outcome. This is to reduce thelength of time patients suffer pain whilst being nursedwith unfixed fractures, and because of the financialimplications of unnecessary bed occupancy and thehigh level of nursing care that these patients require.

A recent paper looked at current practice oforthopedic surgeons with regard to these patients inUK trauma units; this highlighted the lack of consensusof opinion [17]. No study has directly compared pa-tients in whom surgery is delayed and patients in whomit is not. This study aims to rectify this and comparesthe practices of two different sites of the same NHSTrust. At one site, all patients had a seven-day delay tooperation, whilst at the other site surgery was per-formed as soon as possible.

Patients and MethodsTwenty-one patients who had sustained PFF and weretaking clopidogrel on admission were identified be-tween September 2006 and September 2007. This wasby means of pharmacy stock transaction records. Casenotes were retrospectively reviewed and patients wereexcluded if surgery was delayed for reasons other thanto allow the formation of new platelets (this excludedone patient).

Our institution receives and treats approximately750 PFF per annum. The institutional policy is that theon-call consultant dictates the plan of management ofadmitted patients based on their physiological stateand fracture personality. All 20 patients underwentoperative management of their fracture; intracapsularfractures were treated with hemiarthroplasty whilstextracapsular fractures were treated with dynamic hipscrew (DHS). There were no subtrochanteric fractures.All patients received prophylactic antibiotic therapy(second-generation cephalosporin) at induction fol-lowed by two more doses perioperatively, as well aschemical or mechanical thromboprophylaxis asappropriate.

The transfusion trigger was set at 7 g/dl, or whencardiovascular signs or symptoms of anemia werepresent. Transfusion was determined by the consul-tant-led orthogeriatric team, who performed regularpostoperative ward rounds.

Statistical analysis was performed using Stata 7.0statistical software (StataCorporation, College Station,TX, USA). The chi-square test was used, and p val-ues < 0.05 were considered statistically significant.

ResultsOf the 20 patients who met the inclusion criteria, ninepatients had a seven-day delay prior to surgery (GroupA), and 11 had no delay prior to surgery (mean = 1.1days) (Group B). Demographic data were recorded(Table 1), as were operation, anesthetic and personneldetails (Table 2). Postoperative hemoglobin and bloodtransfusion rates are displayed in Table 3, with peri-operative complications shown in Table 4. No patientin either group required reoperation for woundhematoma. Mortality rates were similar at six months,with one patient dying from Group A (one of nine)following a separate admission six weeks after dis-charge with bronchopneumonia. Two patients diedfrom Group B, one following a MI during admissionand the other following a CVA four months after dis-charge. A comparison between lengths of admission

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between the two groups is shown in Table 5, with andwithout data from patients who died.

DiscussionDemographically, both groups were similar: ASA 3.2versus 2.9; male-to-female ratios of 7:2 versus 6:5; andmean ages of 82 versus 80; direct comparisons betweenthe groups were therefore made.

The grades of surgeon operating and principalanesthetist were similar in both groups. Delay prior tosurgery resulted in a higher rate of spinal anesthesiacompared to no delay (eight vs. three). This may bedue to reports of epidural hematoma when spinalanesthesia has been performed on patients who takeclopidogrel [18–20]. It is often suggested that PFF pa-tients often ‘‘look better’’ following regional anesthesiacompared to general anesthesia. However, no differ-ence in short-term or long-term mortality or in func-tional outcome has been shown between the twotechniques [21, 22]. This difference should not be seenas a confounding factor.

There was a higher proportion of dynamic hipscrews (DHS) in Group B compared to Group A (eightvs. four) and a lower proportion of hip hemiarthro-plasty (three vs. five). This may be a confounding fac-tor, as some studies have suggested increased bloodlosses in DHS fixation rather than hemiarthroplasty[23]. Thus, the increased blood loss seen in Group Bmay in part be due to this difference as well as thedelay in surgery allowing the formation of new plate-lets in Group A.

Patients in Group A had a higher rate of preoper-ative complications but a lower rate of postoperativecomplications compared with Group B. Overall rates ofcomplications were equivalent for both (eight of ninevs. nine of eleven), as were mortality rates (one of ninevs. two of eleven). Given the small sizes of the groups,this may represent a ‘‘type 2’’ error, and a study withhigher power would be beneficial. However, such astudy would be problematic because of the relatively

Table 2. Comparison of operation, anesthetic and personnel databetween Groups A and B.

Group A Group B

Operation typeHemiarthroplasty 5 3Dynamic hip screw 4 8

Grade of lead surgeonConsultant surgeon 1 3Nonconsultant surgeon 8 8

Type of anestheticSpinal anesthetic 8 3General anesthetic 1 8

Grade of lead anesthetistConsultant anesthetist 3 3Nonconsultant anesthetist 6 8

Table 3. Comparison of postoperative hemoglobin and number ofunits of blood transfused between Groups A and B.

Group A Group B

Drop in Hb (g/l) 1.8* 3.1*Number of units of blood transfused 0.2 0.9

*Statistically significant p < 0.05

Table 4. Comparison of perioperative complications betweenGroups A and B.

Type of complication Preoperativecomplications

Postoperativecomplications

Group A Group B Group A Group B

Urinary tract infection 2 0 1 3Lower respiratory tract infection 2 0 1 0Acute renal failure 0 0 0 2Acute on chronic renal failure 0 0 1 0Orchitis 0 0 0 1Type II respiratory failure 1 0 0 0Atrial fibrillation 0 0 0 1Myocardial infarction 0 0 0 1Uncontrolled blood sugars 0 0 0 1Total 5 0 3 9

Table 1. Comparison of the demographics of Groups A and B.

Group A Group B

Age 82 80Men 2 5Women 7 6ASA 3.2 2.9

Table 5. Comparison of length of admission between Groups Aand B.

Group A Group B

Admission length in days (deaths included) 30* 25*Admission length in days (deaths not included) 32** 22**

*Statistically significant p < 0.05**Statistically significant p < 0.01

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low incidence of clopidogrel and PFF (21 of 750), andmight only be possible with a multicenter trial.

Admission lengths for patients were longer inGroup A (30 vs. 25 days, p < 0.05), with greater sig-nificance observed once mortality data were removed(32 vs. 22, p < 0.01). This reflects the seven-day dif-ference prior to operation between the two groups, andalso suggests a further three-day delay to recovery forGroup A patients.

Anesthetic guidelines recommend that all patientstaking clopidogrel should have at least a 24-h delay tosurgery, so that excessive bleeding can be treated withtransfusions of platelets that will not be deactivated bythe clopidogrel active metabolite (8-h half-life) [24]. Inaddition, treatment with aprotonin has been shown toreduce postoperative bleeding and transfusion rates inpatients undergoing CABG, and it should be availablefor use [25]. Neither platelet transfusion nor aprotinintherapy was used in our study, and this represents anarea in which practice could be potentially improved.

ConclusionImmediate hip fracture surgery in patients who takeclopidogrel results in lower postoperative hemoglobinswhen compared to patients in whom clopidogrel hasbeen stopped and there has been a seven-day delayprior to surgery. However, length of admission is sig-nificantly longer in patients who have this delay priorto surgery. There is no difference in complication rateor mortality between the two groups.

We cautiously recommend that patients shouldproceed for early surgical intervention, as outcomesare similar and the shorter admission time represents areduced financial burden to the healthcare provider.However, we would like to reinforce that it is prudentfor units to ensure that platelets and aprotinin areavailable, and that this approach may not be appro-priate for subgroups of the patient population whowould tolerate blood loss poorly or have additionalbleeding risk factors.

A randomized control trial is recommended toidentify the optimum timing for hip surgery in patientstaking clopidogrel, hopefully leading to improvedclinical outcomes in an increasingly large population.

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Address for CorrespondenceGeorge Cox36 Stone Mill CourtLS6 4RQLeeds, UKPhone (+44) 7949375745e-mail: georgecox@doctors.net.uk

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