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


Search Results

The literature search identified 4220 possible eligible studies (Fig. 1) Initial screening of titles and removal of duplicates left 182 articles remaining. Exclusion criteria were studies comparing the use of other anticoagulant medication and surgical procedures not involving treatment of fracture of the femoral neck. The abstracts of these citations were reviewed and an additional 161 were rejected. This left 21 articles to be retrieved in full text and to be assessed for eligibility. 14 articles were included in the qualitative synthesis and 7 excluded. Of the 7 articles excluded: two were review articles,[45,46] one was a cohort study without a comparison,[47] two were published abstracts from an international meeting and not published peer reviewed articles,[48,49] and two studies which included no primary outcome measures (only secondary outcome measure of complications).[50,51]

Figure 1.

Flow diagram of literature search

Study Characteristics

All the reports were from a single centre except Chechick et al.[52] and Nydick et al.[53] who enrolled study patients from two orthopaedic trauma centres, and Feely et al.[54] which was a population based study using the records of health care providers in the Olmsted County, Minnesota (as part of the Rochester Epidemiology Project). The earliest study was from 2007, and the most recent was from 2014. The total number of patients across all the studies was 2938. The largest population size was 1225 patients, with 30 in the clopidogrel group (CG) and 1195 in the control or non-clopidogrel group (NCG) (Wordsworth et al.[55]). The study characteristics of all the included studies are summarized in Table 1.

All of the studies were comparative cohort studies, ten of which compared neck of femur fracture patients who were on clopidogrel (CG) with control patients who had never been on clopidogrel (NCG). Five studies performed comparative analysis of clopidogrel patients who had surgery within 5 or 7 days (CG < 5 or <7), and those who were on clopidogrel but had their surgery delayed for a minimum of 5 or 7 days (CG > 5 or >7).[56–60] One study included both types of comparative analysis.[57]

Primary Outcomes

Thirteen out of the fourteen studies included either the number of transfusion exposures or the average number of units transfused per patient. Twelve out of fourteen studies described postoperative haemoglobin or a drop in haemoglobin. The primary outcomes for the studies are summarized in the Table 2.

Most studies presented good preoperative data to help assess the matching of the two groups. The most useful of these were patient age and sex, type of fracture and type of surgery, and ASA (American Society of Anesthesiologists) score. In terms of primary outcome data comparison, we felt the best guide was the postoperative Haemoglobin (Hb) or the drop in Hb, even though this in itself is an indirect measure of blood loss, influenced by several other patient and perioperative factors. This was unfortunately poorly recorded in some studies and often described at different time points e.g. immediately post op, day 1 post op, day 2 post op, at the point of discharge. Some studies described the lowest haemoglobin level during the postoperative period. The ideal point of time for the Hb level would be immediately postoperatively because this would usually be prior to blood transfusions (Except those given preoperatively or intraoperatively).

The other primary outcome measure we used was transfusion exposures and mean total units transfused per patient. Ten of the studies included data on both measures. However describing blood loss in terms of transfusion requirements is difficult due to the variability in transfusion protocols, reflected by the wide variation in transfusion rates between studies (from 5.8 % total exposures as reported by Hossain et al.[61] up to 55.3 % as reported by Collinge et al.[62]).

Secondary Outcomes

Secondary outcome measures were also recorded from the included studies if available. These were average time to surgery, length of stay in hospital and postoperative complications (including haematoma, cardiovascular, cerebrovascular, thromboembolic events and death). The secondary outcomes are summarised in Table 3.

The most consistently reported secondary outcome measures were time from admission to theatre and mortality rate, with eleven out of the fourteen studies having reported both of these. Average time to theatre was a good outcome measure to help assess the effect of time to surgery on primary outcomes, and also to help assess for confounding. Five studies[56–60] specifically grouped their study patients according to time to surgery as their primary aim. Out of the remaining nine studies that did not separate the groups in terms of time to surgery, seven of them had a standard protocol of operating on all patients (including the patients on clopidogrel) as soon as possible without delay. This helps reduce the possible confounding factor of trying to compare the Clopidogrel group and control group with different times from admission to theatre.

Other complications and length of hospital stay were less consistently reported. Average length of hospital stay showed a wide variation, most likely reflecting the differences in hospital protocols or health care systems in different regions and countries.


Meta-analysis was performed on all primary outcome measures. Forest plots are presented for each measure (Figs. 2, 3, 4 and 5). The forest plot for transfusion exposures (TE) (Fig. 2) shows the Odds Ratio (OR) for the relevant studies and we found no evidence of significant heterogeneity between the trials (Heterogeneity: Chi2 = 12.22, df = 8 (P = 0.14); I2 = 35 %). The pooled OR for the nine studies that reported TE was 1.24 (95 % confidence interval 0.91 to 1.71) with weighting towards increased transfusion exposures in the control group however this was not statistically significant (p = 0.18).

Figure 2.

Meta-analysis of clopidogrel group and non-clopidogrel group: transfusions exposures

Figure 3.

Meta-analysis of clopidogrel group and non-clopidogrel group: total units transfused per patient

Figure 4.

Meta-analysis of clopidogrel group and non-clopidogrel group: postoperative haemoglobin

Figure 5.

Meta-analysis of clopidogrel group and non-clopidogrel group: drop in haemoglobin

The forest plots for the remaining three primary outcome measures, total units transfused per patient (TUT), post-operative haemoglobin (POH) and drop in haemoglobin (DH) (Figs. 3, 4 and 5) show minimal mean differences between clopidogrel and control groups. Further, any significant mean difference was found to be not statistically significant: TUT mean difference 0.12 (95 % CI -018 to 0.43, p = 0.44), POH mean difference -0.12 (95 % CI -0.35 to 0.11, p = 0.30), DH mean difference -0.10 (95 % CI -0.51 to 0.31, p = 0.64). No significant heterogeneity being found between studies for each outcome.