BACKGROUND: Clopidogrel is an anti-platelet agent recommended as lifelong treatment for patients following significant cardiovascular and cerebrovascular events. Current recommendations are to cease treatment 7 days prior to elective surgery for such patients, but no such guidelines exist for trauma patients. The aim of this study was to assess the risk of performing hip fracture surgery without delay in patients who were taking clopidogrel.
METHODS: In this retrospective cohort study, data were analyzed from 338 patients diagnosed with either an intertrochanteric or subcapital fracture of the femoral neck between January 2007 and December 2008. The clopidogrel group included 39 patients; the aspirin group 101 patients, and 198 patients without any anti-platelet or anti-thrombotic medication comprised a “nil anticoagulant” (control) group. The three groups were compared with regard to preoperative American Society of Anaesthesiologists (ASA) score, delay to surgery, pre- and post-operative haemoglobin levels, transfusion requirements, inpatient complication rates, length of stay in hospital and 30-day mortality. Additional information gathered included patient demographics, type of operation and type of blood products transfused.
RESULTS: The average age of the 338 patients included in this study was 84 years. 72% of patients in the control group, 72% in the aspirin group and 74% in the clopidogrel group came to surgery within 24 hours of admission (chi square test, p = 0.962). Between their pre- and post-op measurements, the hemoglobin drop averaged 23.5 for the control group, 25.5 for the aspirin group, and 28 for the clopidogrel group (ANOVA on ranks, H = 5.022 with 2 degrees of freedom. (P = 0.081). Thus, significantly larger proportions of patients in the aspirin group (56%, p = 0.004) and clopidogrel group (61%, p = 0.02) required RBC transfusion than in the control group (38%). The inpatient complication rate was 21% for the nil anticoagulant group and 31% for each of the aspirin and clopidogrel groups (p = 0.111). Thirty-day mortality occurred in 2.5% of the control group, 3% of the aspirin group and 0% of the clopidogrel group.
CONCLUSION: This is the largest study to our knowledge on the bleeding risk of clopidogrel in the orthopaedic trauma setting. Undertaking hip fracture surgery within 24 hours on elderly patients who were taking clopidogrel was not associated with increased risk of post-operative complications.
Fractures of the femoral neck are common injuries in the elderly population. It is estimated that 2.6 million such fractures will occur globally in 2025, increasing to 6 million by 20501, 2. One year mortality for hip fractures ranges from 14% to 36% - significant in the context of the prevalence of the such injuries3. In populations of patients with neck of femur fractures, cardiovascular and cerebrovascular diseases are the most prevalent pre-existing comorbidities4. Anti-platelet agents, such as clopidogrel, are frequently prescribed in these populations to combat cardiovascular and cerebrovascular thrombotic events. Hence, the burgeoning ageing population will make the use of clopidogrel even more prevalent amongst patients presenting with femoral neck fractures.
Clopidogrel inhibits platelet aggregation and therefore thrombus formation by irreversibly antagonising the binding of adenosine diphosphonate to its platelet receptor5-7. The effects of the drug are demonstrated within two hours after an oral dose, with the half-life of the circulating active metabolite being approximately eight hours. The anti-platelet effect is irreversible and lasts for the lifespan of the platelet - approximately seven days. Therefore, complete recovery of platelet function is seen approximately seven days after the last clopidogrel dose7-9.
When patients taking clopidogrel sustain a fracture of the femoral neck, there is debate amongst surgeons as to the timing of operative fixation. That is, there is no clear consensus on whether it is safe to proceed without delay or whether the operation must wait seven days. This is largely because there is a paucity of literature on the bleeding complications of clopidogrel in the orthopaedic trauma setting. Similarly, there are no published data outlining when surgery can safely be performed after clopidogrel has been ceased.
Patients that sustain a femoral neck fracture that are taking clopidogrel often have their surgery delayed for fear of peri- and post-operative bleeding complications. This is despite a clear lack of evidence for this in the literature. The delay poses considerable risk to the patient and adds significantly to institutional costs. For this reason, it has been the recent practice of our institution to operate on these patients without delay.
The aim of this study was to examine the bleeding risk and complication rate of hip fracture surgery without delay in patients who were taking clopidogrel
Materials and methods:
A retrospective cohort study was performed. Data were obtained from medical records and operating theatre databases from two major teaching hospitals. The study cohort comprised 394 consecutive patients diagnosed with either an intertrochanteric or subcapital fracture of the femoral neck, spanning a two-year period from January 2007 to December 2008. The patients had one of four operations for hip repair: HEMI (hemiarthroplasty), DHS (dynamic hip screw), CS (cannulated screw) or IMN (intramedullary nail) for hip fracture.
Each of the 394 patients were then categorised according to the type of antithrombotic or anticoagulant medication they were taking. Patients that were taking warfarin (n = 56) were excluded from this study due to the well-documented high rates of bleeding complications. A clopidogrel group included 39 patients, with 22 taking clopidogrel as the only anti-platelet agent and 17 taking it together with aspirin. Another group comprised 101 patients taking aspirin alone. The control group consisted of 198 patients who took neither anti-platelet nor anti-thrombotic medications.
Hip fracture surgery was performed on the next available trauma list after the patient was considered to be medically stable. Clopidogrel use alone did not result in a delay to surgery. All groups were compared with regard to preoperative American Society of Anaesthesiologists (ASA) score, delay to surgery, pre- and post-operative haemoglobin levels, transfusion requirements, inpatient complication rates, and 30-day mortality. Additional information gathered included patient demographics, type of operation and type of blood products transfused. Approval for this study was obtained from the South East Sydney Illawarra Area Health Service Research and Ethics Committee.
Data were analysed using SigmaStat (Systat Software Inc., Point Richmond, CA USA). The statistical tests used here were chi-square for proportions, Student’s t-test, Mann-Whitney rank sum test, one-way ANOVA, Kruskal-Wallis one-way ANOVA on ranks, Pearson’s product moment correlation (correlation coefficient “r”) and Spearman’s rank sum correlation (correlation coefficient “rs“. Statistical significance was set at p<0.05.
Results of the 22 “clopidogrel only” cohort were compared with results from the cohort of 17 patients that took “clopidogrel plus aspirin” to assess whether these two groups were either significantly different from each other or sufficiently similar to be combined. Both cohorts had a median ASA score of 3.0 (Mann-Whitney, p > 0.05. 82% of the clopidogrel only cohort came to surgery within 24 hours compared to 65% of the clopidogrel plus aspirin cohort (p = 0.755). Their mean hemoglobin drops were 28.0 for the clopidogrel only patients and 26.2 for the clopidogrel plus aspirin patients (t-test, p = 0.634). Thirteen of the 22 patients (59%) in the clopidogrel only cohort required RBC transfusion as did 10/17 patients (59%) of the clopidogrel plus aspirin cohort. Six patients in each of these groups had complications (chi square, p = 0.851). None of the clopidogrel patients in either cohort died within 30 days of surgery. Due to their similarities and lack of significant difference, the two clopidogrel cohorts were combined into a single clopidogrel group. This left three groups for anticoagulant comparisons: (1) the group with nil anticoagulants (Nil AC); (2) the aspirin group; and (3) the clopidogrel group.
The average age of the 338 patients included in this study was 84 (range 44 to 102) years (see Table 1). The three anti-coagulant groups had similar median ages: 83 (Nil AC), 85 (aspirin) and 83 (clopidogrel) years, respectively (Kruskal-Wallis ANOVA on ranks, H = 4.700 with 2 degrees of freedom, p = 0.095).
The proportions of the three anticoagulant groups that came to surgery within 24 hours of admission were similar: (72% for Nil AC, 72% for the aspirin group and 74% for the clopidogrel group). Consistent with previously published results, our data indicated that delay to surgery correlates with an increased incidence of complications (Pearson correlation, r = 0.130; p = 0.016).
The pre-operatively-determined ASA scores were highly age-dependent (Pearson’s correlation, r = 0.455; p = 0.000). ASA scores were 3.0 ± 0.6 (mean ± SD) for the Nil AC group, 3.1 ± 0.6 for the aspirin group and 3.2 ± 0.6 for the clopidogrel group. A one-way ANOVA on ranks test showed significant difference between the three groups with H = 9.050, two degrees of freedom, and p = 0.011). Post hoc tests showed that both clopidogrel and aspirin groups had significantly higher scores than the Nil AC group. However, the clopidogrel and aspirin groups were not significantly different with each other. ASA scores correlated positively with the inpatient complication rate (rs = 0.169; p = 0.002) and 30-day mortality rate (rs = 0.188; p = 0.000) but not with the need for transfusion or the number of days elapsing before patients came to surgery (both p > 0.05).
Between the pre-op and post-op hemoglobin (Hb) values, there was a median Hb drop of 23.5 g/L for all Nil AC patients, 25.5 g/L for those on aspirin, and 27.2 g/L for those that took clopidogrel. ANOVA on ranks testing showed no significant difference in Hb drop for these three patient groups (H = 5.540 with 3 degrees of freedom, p = 0.136).
The need for transfusion significantly correlated with anticoagulant usage and anticoagulant type. Fewer patients in the Nil AC group (38%) had need for transfusion than all other patients in this study who took anticoagulants (57%). These proportions are significantly different (chi square = 10.870 with two degrees of freedom, p < 0.001). Also, the proportions of patients who required transfusion in the Nil AC group (76/198 or 38%), aspirin group (57/101 or 56%), and clopidogrel group (24/39 or 61%) were significantly different (chi square = 12.797 with 2 degrees of freedom, p = 0.002). Post-hoc tests showed significantly larger proportions of patients in the aspirin and clopidogrel groups required transfusion than those in the Nil AC group (p = 0.004 and p = 0.02, respectively) and showed no significant difference between the transfusion requirements of the aspirin and clopidogrel groups (p = 0.785).
The patients’ age correlated significantly with their Hb drop (r = 0.163, p = 0.003) and the inpatient complication rate (rs = 0.170, p = 000) but not with the 30-day mortality rate (rs = 0.081, p = 0.140). The delay to surgery correlated positively with their 30-day mortality rate (rs = 0.111, p = 0.042) but less well with their Hb drop, need for transfusion, and inpatient complication rate (all > 0.05).
For the Nil AC group, 41/198 or 21% of patients had complications compared to 31/101 or 31% in the aspirin group and 12/39 or 31% of patients in the clopidogrel group (chi square =4.398 with 2 degrees of freedom, p > 0.05). The proportion of NIL AC patients who died within 30 days of surgery was 5/198 or 2.5%. The aspirin group had a mortality rate of 31/101 or 3%, and the clopidogrel group had 0/29 deaths or 0% 30-day mortality. These proportions were not significantly different when analyzed with the chi-square test.
Analysis was also performed for the subgroup of patients who received a hemiarthoplasty as treatment for their fractures. The three subgroups were compared for Hb drop, transfusion and complication rates. There was no significant difference in Hb drop or complication rate between all three subgroups (p<0.08). There was a higher transfusion rate for both clopidogrel and aspirin groups relative to the group with nil anticoagulant with a median transfusion of 2.0 units of packed RBC (p<0.006). There was no significant difference between the aspirin and clopidogrel groups in transfusion rates (p=0.62).
Randomised controlled trials have established the efficacy of clopidogrel therapy in acute coronary syndrome for patients treated either medically or with percutaneous coronary intervention10-13. Current guidelines recommend clopidogrel therapy for up to one year for patients treated medically or with a bare metal stent, and at least one year for patients treated with a drug-eluting stent. These recommendations are categorised as class IA, indicating support from the highest level of evidence14.
Clopidogrel is routinely discontinued at the time of admission for hip fracture due to the perceived bleeding risk posed by its anti-platelet action. This poses significant risk to patients as recent evidence suggests there is a pro-thrombotic period soon after clopidogrel therapy is ceased due to rebound platelet activation5, 14-22. In particular, a national cohort of over 3000 patients following hospitalisation for acute coronary syndrome found a higher incidence of death and myocardial infarction during the initial period after stopping treatment with clopidogrel14. These findings, coupled with prior physiological studies5-9 highlight the danger of withdrawing clopidogrel therapy prior to orthopaedic procedures.
The dilemma created when a patient taking clopidogrel presents with a hip fracture is fast becoming a familiar occurrence in the orthopaedic trauma setting. Surgery without delay will minimise the risk of complications related to immobilisation and repeated fasting, but carries a theoretical risk of increased bleeding due to the effects of clopidogrel on platelet function. Conversely, withdrawing clopidogrel and delaying surgery will increase the risk of cardiovascular and cerebrovascular events that the drug was originally prescribed to prevent23, 24.
There is ample evidence in the literature on the impact of delaying surgery in patients with a fractured neck of femur25-30. For example, a large prospective observational study found that patients with medical conditions that delayed hip fracture surgery had 2.5 fold increases in 30-day mortality. Moreover, delay of more than four days in those otherwise fit for surgery significantly increased the number of deaths27. Similarly, two recent studies of over 50 000 and 100 000 hip fracture patients respectively found that, even after adjusting for comorbidities and other covariates, delaying surgery significantly increased mortality and remained an important independent predictor of death at all time intervals25, 26. Thus, it would seem that the longer hip fracture surgery is delayed, the worse the outcome.
The primary concern with operating without delay on patients taking clopidogrel is the perceived risk of bleeding from surgery. This is largely due to the well-documented period of impaired platelet function following clopidogrel cessation6-9, 31, 32. However, evidence for the increased bleeding risk during surgery is almost solely limited to the cardiothoracic literature. Preoperative exposure to clopidogrel within five days before coronary artery by-pass grafting has been shown to increase early mortality and morbidity, particularly if the drug is given within 48 hours of surgery33. Whilst other studies have reported similar risks and complications33-42, these findings are not necessarily applicable to hip fracture surgery as the extent of vascular handling and injury is far less during the latter. Hence, by comparison, orthopaedic procedures pose less risk in terms of blood loss and would not necessarily be subjected to the same complications when patients have been taking clopidogrel. Data on the bleeding complications of clopidogrel in hip fracture surgery are scarce. This is evidenced by the wide variation in practice amongst orthopaedic units when hip fracture patients are taking clopidogrel6, 43. If it could be shown that operating without delay does not increase bleeding complications or mortality, surgery could be commenced promptly in many cases and the adverse effects of immobility and repeated fasting could be avoided. Furthermore, patients with drug-eluting stents that have had their clopidogrel ceased would not be subjected to prolonged periods without anti-platelet cover.
In our study, patients that were taking clopidogrel and presented with hip fracture did not experience worse outcomes when operated on without delay. In particular, the bleeding risk and complication rate showed no difference between groups. These findings are of high importance to orthopaedic surgeons as they suggest that early hip fracture surgery may be safe in patients taking clopidogrel. Whilst it is difficult to support these findings due to the paucity of studies on clopidogrel in the orthopaedic trauma literature, they are in accordance with those published in other discliplines44-51 .
Patients that are taking aspirin and present with a hip fracture typically have their surgery performed without delay. Aspirin is therefore considered to have less of a surgical bleeding risk than clopidogrel. If this were true, one might expect the transfusion requirement, haemoglobin drop and complication rate to be higher in those patients taking clopidogrel when operated on early. But our findings showed that patients in both the aspirin and clopidogrel group had similar rates of transfusion requirements and complications. Moreover, the mean delay to surgery in both groups was one day.
Our findings do not suggest that it is safe to perform early hip fracture surgery on patients taking clopidogrel. However, it can be said that it appeared to be safe in our cohort of patients. More focused, randomised studies are needed to support our findings and further our understanding of this very important problem.
Our study was limited by the nature and number of data collected. Several known predictors of mortality in hip fracture patients, such as pre-fracture mobility, cognitive status and body mass index, were not collected in our data. In addition, despite the large number of patients in the study, the total number taking clopidogrel was only thirty nine. Thus, there was a potential for bias. Further studies addressing these limitations may help to strengthen our findings.
In closing, unless there are acute medical conditions that make surgery and anaesthesia unsafe, we advocate operative fixation without delay for patients on clopidogrel that present with hip fracture. If there is intra-operative concern regarding the extent of bleeding, platelet transfusions may be given and continued if necessary over the post-operative period. Another solution may be to use aprotinin, a broad-spectrum antifibrinolytic, as its use has been highly successful in the context of clopidogrel use in the cardiothoracic surgery setting7, 23, 24, 38, 52-56.
This is the largest study to our knowledge on the bleeding risk of clopidogrel in the orthopaedic trauma setting. Undertaking hip fracture surgery within 48 hours on elderly patients who were taking clopidogrel does not appear to be associated with increased risk of post-operative complications. If clopidogrel use is the only indication for delaying surgery, operating without delay appears to be safe but more research is needed before firm conclusions can be made.
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