AIM: To identify the rate of non-responders to clopidogrel treatment in hip fracture patients and study how non-responders differ from controls.

METHODS: In a retrospective case-control study we included 28 cases of acute proximal femoral fracture with clopidogrel treatment 2011 to 2013. Eighty-four controls from the same time period were included. Data collected included response to clopidogrel measured with multiple electrode aggregometry (MEA), intraoperative bleeding, erythrocyte transfusion, time to surgery and the incidence of adverse events up to 3 mo after surgery.

RESULTS: Eight (29%) of the 28 cases were non-responders. The median intraoperative bleeding was 300 mL (range, 0-1500), and was lower for non-responders (50 mL) but did not reach statistical significance. Erythrocyte transfusions did not differ between responders, non-responders and controls. Forty-five (40%) of 112 patients had adverse events postoperatively but the rate did not differ between patients with and without clopidogrel treatment.

CONCLUSION: Almost one-third of patients with clopidogrel treatment and an acute proximal femoral fracture are non-responders to antiplatelet therapy and can be operated without delay.

An increasing number of elderly patients are managed with long term antiplatelet therapy after cardiovascular and cerebrovascular events[1]. Clopidogrel is a frequently used antiplatelet drug which irreversibly inhibits ADP-induced platelet aggregation through blockade of the platelet P2Y12 receptor. Although the drug has been shown to be very effective in large clinical trials, there is a considerable inter-individual response to this drug. Depending on the platelet function method used and cut-off values set, between 5%-44% of patients have been shown to have reduced platelet inhibiting effect of the drug. The reason for this variability is likely multifactorial and include, e.g., genotype, drug interactions and compliance to drug treatment[2-4].

Approximately 1 in 5 of patients with clopidogrel treatment will need non-cardiac surgery within two years[5]. It is well known that patients with clopidogrel treatment undergoing cardiovascular surgery have an increased risk of bleeding events during and after surgery. They also have a higher percentage of post-operative hemorrhagic complications and transfusions[6,7]. Clinical guidelines recommend that patients on clopidogrel treatment should interrupt their therapy 5-7 d before surgery to avoid increased intraoperative bleeding, even though recent studies of patients undergoing hip fracture surgery is inconsistent if the risk of perioperative bleeding is increased or not[8].

Patients suffering a hip fracture are elderly, and because of multiple co-morbidities attributed to age, they are one of the most fragile patient-groups in orthopedics, with a high morbidity and mortality following surgical treatment. Delayed surgery is associated with both increased frequency of medical complications and increased mortality[9,10]. Thus, the demand for rapid surgery is, for hip fracture patients with simultaneous clopidogrel treatment, contrasted against the bleeding risk for these patients.

Laboratory tests have recently been developed in order to examine platelet function bedside. One of these methods is multiple electrode aggregometry (MEA)[11]. This method can be used to assess platelet aggregation during treatment with platelet inhibiting agents such as clopidogrel, aspirin and other new platelet inhibitors in a venous whole blood sample (Figure 1)[11].

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Figure 1 Schematic illustration of multiple electrode aggregometry. A: Whole blood sample is put in a twin impedance sensor; B: Addition of a platelet agonist activates platelets to adhere to the electrodes; C: When platelets adhere to electrodes there will be an increase in electrical resistance between electrodes. Electrical resistance is measured as a value of platelet activity. Platelets affected by clopidogrel treatment adhere less to electrodes.

The rate of non-responders and responders for clopidogrel treated patients in hip fracture patients has, to the best of our knowledge, not been published in peer-reviewed literature. The aim of this study was to identify the rate of non-responders to clopidogrel treatment in hip fracture patients and to study if responders and non-responders differ from patients without clopidogrel in intraoperative bleeding and adverse events.

In this retrospective case-control study on patients with a proximal femoral fracture and concurrent clopidogrel treatment almost one third of patients with clopidogrel were non-responders, indicating that they had no effect of this treatment, or that they were not compliant to medication. Thus, the incidence of non-responsiveness is similar to what we found in patients with ischemic stroke or TIA treated with clopidogrel at our institution[17]. By continuously using MEA at our department, we were able to fast-track non-responders to surgery within the same time as the control group (Table 2).

In previous publications, anti-platelet treated hip fracture patients have been delayed to surgery, often with negative effects on complication rate and mortality. Harty et al[18] included 21 patients on clopidogrel with acute hip fracture in a case-control study and found that patients on clopidogrel in mean waited 7 d for surgery, and 30-d mortality for these patients were 29%, compared to the control group who had surgery within 2 d and had a 30-d mortality of 4%. The authors conclude that surgery should not be postponed. A high rate of complications due to prolonged time to surgery was also observed in a study made of Johansen et al[19], where clopidogrel treated patients who waited 5 d for surgery had a higher rate of complications and they also found an increased intraoperative bleeding for patients who had surgery immediately. This result is in line with Chechik et al[20] study of 44 patients where clopidogrel was continued throughout surgery. In contrast to these findings, there are reports that have failed to find a difference in bleeding and complication rate between patients on clopidogrel and controls[21,22]. These inconsistences between existing studies is possibly, as in our study, due to the fact that a large proportion of patients are non-responders[23,24]. These relatively recent studies of hip fracture patients with clopidogrel treatment have not considered the individual responsiveness to the drug, which may be an important reason for the inconsistency in their results[18,20-22]. If almost one third of the patients with clopidogrel (as in our study) have no effect of treatment the non-responders could even out the results a group level and hide the actual bleeding risk for responders. More research is needed in this area but clearly observational and interventional studies on hip fracture patients with concurrent antiplatelet therapy need to take this into consideration for bleeding endpoints.

The clinical recommendation to discontinue clopidogrel treatment 5-7 d ahead of surgery is based on studies made for cardiological interventions. They have reported that continuation, or late (i.e., 1 d) discontinuation of clopidogrel treatment is associated with increased intra- and postoperative bleeding and increased need for transfusions after coronary bypass surgery, compared to earlier discontinuation (i.e., 3-5 d)[6,7,25]. For hip fracture patients, this discontinuation is in stark contrast to the need for rapid surgery. Delayed surgery is associated with both increased morbidity and mortality[12,26]. Both the 30-d all-cause mortality as well as minor and major medical complications are significant higher in hip fracture patients with surgical delay over 48 h[9,10].

When patients with increased risk of bleeding are identified, preoperative treatment can be customized. In the above mentioned studies of hip fracture surgery and clopidogrel treatment, it is not reported if preoperative treatment differ between clopidogrel treated patients and controls. Wallace and Hossain report that all patients were medically optimized before surgery but do not mention if preoperative transfusion with platelets were given[22,27]. In our study patients with pronounced effect of the drug received platelet transfusions to higher extent than controls and those patients with none or low effect, and intraoperative bleeding did not differ between the groups. Neither did post-operative erythrocyte transfusion differ between the groups. Platelet transfusions should be administered with care, as whole blood transfusions, due to transfusion related complications such as infections, allergic reactions and febrile non-heamolytic transfusion[28]. This is why we find it important to identify patients that are at high risk for bleeding, so that we do not treat patients with platelet transfusion preoperatively if not needed.

In our study, non-responders were operated within the same time as controls, which likely reduces the risk of complications caused by delayed surgery. Patients with good response to the drug could either be optimized with platelet transfusion and operated immediately, or if their medical condition allowed, wait for surgery until a second analysis showed regression of clopidogrel effect. This is the reason why responders wait for surgery in mean 45 h compared to non-responders and controls who have surgery approximately within a day.

Analysis of platelet aggregation variability was also for help when planning for anaesthetics. Regional anaesthetics is associated with less risk for the patient compared to general anaesthetics and shortens operation time[29,30]. Hossain et al[27] reported in their study of 50 hip fractures and clopidogrel treatment that 88% of the patients had surgery in general anaesthesia, compared to controls were only 6% had general anaesthesia. In our study, patients eligible for spinal anaesthesia despite anti-platelet therapy could be identified preoperatively.

Variability of platelet function was, in the present study, evaluated with the MEA method. It is a standardized method to determine platelet function with high sensitivity and reproducibility[11]. The analysis is, compared to many other platelet function methods, a simple and rapid assay that can be used bedside in every day clinical practice. No centrifugation step which may influence platelet function is needed, as the analysis is made in a whole blood sample. Compared to template bleeding time which has previously been used to assess the risk of increased bleeding, the risk for user dependent variation is low since the method is easier to perform[11,14,31,32].

This is, to the best of our knowledge, the first published study where analysis of variability in platelet aggregation is used for patients with an acute proximal femoral fracture. We were able to obtain sound data on all studied outcome variable and found well matched controls for our cases. The main limitations of the study are the small sample size, retrospective design and relatively short follow-up. Thus, even though our groups did not differ in the incidence of adverse events or mortality rate, the study is not sufficiently powered for these outcomes. We have used intraoperative bleeding as a proxy for this, and most surgeons would agree that it is important to minimize blood loss for hip fracture patients. The study is also limited by intervention bias; MEA test was used to make clinical decisions such as platelet transfusions and surgical timing. These interventions could clearly have an effect on the results such as intraoperative bleeding as well as outcomes and differences between groups. This is however inherent in the method when using MEA and we believe that it is therefore this analysis is helpful for clinicians when making decision on timing of surgery.

In this pilot study, almost one-third of patients with clopidogrel treatment and a acute proximal femoral fracture are non-responders to antiplatelet therapy when presenting at the hospital. Analysis of variability in platelet aggregation can be used when fast tracking patients and we recommend this for emergency hospitals treating patients with acute proximal femoral fractures.