Clopidogrel and Hip Fractures, Is It Safe?

A Systematic Review and Meta-Analysis

Christopher G. K. M. Soo; Paul K. Della Torre; Tristan J. Yolland; Michael A. Shatwell


BMC Musculoskelet Disord. 2016;17(136) 

In This Article


This systematic review and meta-analysis of the 14 comparative studies provides evidence that operating early on neck of femur patients who are on clopidogrel is safe and poses no increased risk of bleeding when compared to patients not on clopidogrel.

In review of the literature, there is a paucity of high-level evidence to guide the perioperative management of patients with neck of femur fractures who are also on clopidogrel. Most of the literature is retrospective and non-randomised, and this leads to weak conclusions. Out of all the literature, only fourteen of the available studies are comparative, none of which are RCTs, and only two of which is prospective. Meta-analyses of observational studies also possess limitations due to the inherent biases that exist in nonrandomized, unblinded studies. The difficulty in creating large scale randomised clinical trials lies in the complexity of the patient with femur fractures and their individual and variable medical comorbidities.

Search Strategy

The electronic search strategy proved to be effective, generating all 13 of the 14 included studies. Only one of the included studies was not generated from the electronic searches, and this was from a reference search of an included study.

Primary Outcomes

The assessment and analysis of the data for the primary outcome measures was difficult due to the studies presenting their outcomes in different formats.

Most of the studies (13 out of 14) had good patient demographic data to assess whether the CG and control group were similar. The most useful was assessment of age, ASA score, type of surgery and type of fracture, and most of the studies had matched groups. Only one study reported a significant difference in age between the two groups.[63] As expected most studies showed a significantly higher number of either cardiovascular or cerebrovascular disease comorbidities in the intervention group, however surprisingly only two studies showed a significant difference in ASA grade.[62,64] One study reported a significantly higher number of premorbid cerebrovascular accidents and transient ischaemic attacks in CG potentially introducing bias for providing blood transfusions (doctors may have a lower threshold to transfuse these patients). Of the four studies reporting the type of anaesthesia used during surgery, there was no statistically significant differences between the two groups.[54,55,58,61] Despite the potential risk of spinal haematoma in patients using clopidogrel, no anaesthetic complications were reported in any of the four studies.

In comparing the primary outcomes between the CG and the controls, the best guide to assess blood loss and blood replacement is the postoperative Hb. However this was poorly recorded in some studies, and it was also reported at different times postoperatively e.g. immediately post op, 24 h post op, 48 h post op, at point of discharge. Some also only documented the lowest Hb recorded during the postoperative period. Ideally it should be taken at point of discharge because some patients had blood transfusions after the operation and before discharge.

The drop in Hb was poorly reported but the number of transfusion exposures and the mean units transfused per patient were generally well reported.

In the studies that reported on transfusion exposures, and mean units transfused per patient, most found no statistically significant difference between the groups. Only one study showed a significant increase in transfusion exposures in the CG.[63] In terms of Hb concentrations, there were two studies that reported a significantly higher drop in Hb in the CG.[56,58] One study described a significant increase in perioperative blood loss (which was not part of our outcome measures due to rarity and inconsistency of reporting), however they found no significant difference in transfusion rates.[52] Thus there appears to be good evidence to suggest clopidogrel use does not increase transfusion rates or have significantly more effect on Hb falls.

A potential confounding factor in the results may be the concurrent use of aspirin in these patients. Dual-antiplatelet therapy is the mainstay of postoperative management of cardiac stent patients. Aspirin use has been described in a number of studies to be a risk factor for increased blood loss and transfusion requirements in hip fractures and hip fracture surgery.[65–67]

In our report 8 out of the 14 studies reported on aspirin use. Only one of these studies showed a significant increase in aspirin use in the CG compared to controls and this study reported no significant difference in transfusion rates or Hb concentrations between the groups.[55] Only one study reported on blood loss in patients on clopidogrel as well as in patients on clopidogrel and aspirin combined.[52] Their results showed a significant increase in perioperative blood loss in both these groups when compared to patients not on any antiplatelet therapy, however there was no difference in transfusion rates or Hb concentrations.

Secondary Outcomes

The time to theatre was a well reported in most studies and it provided data not only comparing CG and controls but also on the effect of early surgery versus delayed surgery in patients on clopidogrel. Four studies assessed the differences in outcomes between early and delayed surgery in CG patients and none of these studies found a significant difference in bleeding outcomes. However three of these studies reported increased complications in the delayed surgery group such as pulmonary emboli, cardiovascular complications and decubitus ulcers. The results of these studies suggests that it is unnecessary to delay surgery for patients on clopidogrel, and on the contrary, delaying surgery may in fact pose risks of serious complications. One of the significant concerns for patients on clopidogrel is the implications of ceasing the antiplatelet therapy. It is well reported that discontinuation of antiplatelet therapy in patients with stents (especially drug-eluting) significantly increases the risks of cardiac stent thrombosis and death. In correlation with the results of our study, which suggest an increase in cardiovascular complications relating to the with-holding of clopidogrel prior to surgery, we recommend that patients with stents should continue clopidogrel or at very least require special consideration and discussion with the treating cardiologist about continuing or ceasing anti-platelet therapy.

Seven studies provided data on length of stay and this varied widely between studies. This probably represented differences in health care systems and policies in different areas and countries. Four of these studies found that being on clopidogrel significantly prolongs the length of stay in hospital but it is important to note that two of them had significant delays to surgery.

The reporting and statistical analysis of other adverse outcomes such as haematoma, haemorrhage, cardiovascular episodes and mortality was variable between studies. There were no significant differences in adverse outcomes between CG and controls, except in one study which showed a significantly increased mortality rate in the CG.[68]

This study's results differ slightly with a recently published systematic review and meta-analysis by Doleman and Moppett[69] which found that in the seven studies they included in their meta-analysis, there was an overall increase in the proportion of patients receiving blood transfusions in the clopidogrel group when compared to the control group (p = 0.05). This difference is accounted for by the different studies included in the meta-analyses (nine studies included in our meta-analysis). However the authors found no difference in mean units transfused and stated that the under-powering of the included studies prevented detection of any differences in postoperative complications.