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

Disclosures

BMC Musculoskelet Disord. 2016;17(136) 

In This Article

Background

Femoral neck fractures in the elderly make up a large proportion of Orthopaedic surgical admissions each year and the numbers worldwide are expected to reach 6.26 million cases a year by 2050.[1] These patients often present with numerous co-morbidities including coronary artery disease, cerebrovascular disease and peripheral vascular disease. In fact, recent studies show both a high incidence of cardiovascular disease among operative hip fracture patients (63.3 %), as well as a higher risk of hip fractures among patients with cardiovascular disease.[2–4] Thus, anticoagulant therapy in patients presenting with hip fractures is becoming more and more prevalent.

Increasingly common is the use of clopidogrel, a thienopyridine derivative, which irreversibly binds to the platelet receptor adenosine diphosphonate (ADP) and thus inhibits platelet aggregation and thrombus formation.[5] The National Institute of Clinical Excellence (NICE) guidelines recommends clopidogrel for the prevention and treatment of occlusive vascular events in patients with recent stroke, myocardial infarction, acute coronary syndrome and established peripheral vascular disease.[6] This includes patients who have undergone percutaneous coronary intervention and coronary artery by-pass grafting. The half-life of clopidogrel is 8 h, but the affected platelets remain irreversibly inactivated and are replaced by new platelets after 5 to 7 days. Studies have shown patients to show a complete recovery of platelet function 7 days after the last clopidogrel dose.[7]

Manufacturers and other published guidelines based on the physiological lifespan of the platelets recommend stopping clopidogrel at least 5–7 days before undergoing elective surgery to allow recovery of normal platelet function and avoid the perioperative risks of increased bleeding.[8–11] However there is no consensus regarding guidelines for the perioperative management of clopidogrel in patients with acute femoral neck fractures. In June 2009 the Scottish Intercollegiate Guidance Network (SIGN), published a national guideline for the management of hip fractures in elderly patients and recommended that surgery should not be delayed in patients receiving anti-platelet therapy (aspirin, clopidogrel or dipyridamole).[12]

The difficulty in managing these patients who are on clopidogrel exists because the increased risk of perioperative bleeding and higher risk of spinal haematoma[13] during the use of regional anaesthesia must be weighed against the risks of delayed surgery and the risks associated with the withdrawal of anti-platelet drugs. The difference between clopidogrel and many other anticoagulant medications is that there is no known method of reversing its antithrombotic effects acutely and the effectiveness of a fresh platelet transfusion in the event of excessive bleeding is controversial. There are in vitro and clinical studies that suggest platelet infusions are an effective method of reversing the effects of clopidogrel.[14–16] However more recently, there have been large-scale studies that have been unable to show any effectiveness of emergency platelet transfusions in patients on antiplatelet therapy.[17–19]

The increased bleeding risk of clopidogrel in patients undergoing surgical procedures has been reported however there are limited reports to support this in orthopaedic literature. Most of the studies relate to cardiac surgery and in these studies clopidogrel has been reported to result in a four to five times increased risk of haemorrhage-induced surgical re-exploration and three times increased risk of blood transfusion post coronary artery bypass graft surgery.[20–22] Case reports of extensive retroperitoneal haematoma post lumbar sympathetic blockade and cervical epidural haematoma post epidural injection resulting in quadriparesis have further highlighted the bleeding risks associated with clopidogrel.[23,24]

To minimise the risks of perioperative bleeding related to clopidogrel, surgery can be delayed for at least 5 to 7 days. However the risks of delaying surgery in femoral neck fracture patients is well documented. Numerous studies have shown that a surgical delay in femoral neck fracture patients can lead to significantly poorer patient outcomes including an increased mortality rate, prolonged in-hospital stay time and a reduced rate of return to independent living.[25–29] Delay to surgery greater than 48 h has been shown to be independently associated with a higher mortality rate at 30 days and 1 year.[30] A prospective observational study of 2660 patients and found a significant increase in mortality in hip fracture patients delayed more than 4 days for surgery compared to those operated without delay (10.7 % vs 8.7 %).[31]

Another important consideration is that of the risk of withholding clopidogrel in these hip fracture patients with cardiovascular comorbidities. Studies have shown that fractures, surgical procedures and trauma induce both an inflammatory and coagulatory effect.[32,33] Withholding clopidogrel in hip fracture patients can potentially induce a rebound effect and cause thromboembolic events whilst in this prothrombotic state. There are reports of a perioperative incidence of acute coronary syndrome of up to 20.2 % in patients with femoral neck fractures.[34] In patients who have had coronary stents inserted, cessation of clopidogrel treatment during the first year is associated with a 20 % risk of myocardial infarction and 45 % mortality rate.[35] This risk is of particular concern to those with drug-eluting stents, for which dual-antiplatelet therapy is prescribed on an empirical basis for 3–6 months after implantation, with life-long aspirin. Studies have shown that patients who prematurely cease clopidogrel therapy, have a significantly increased risk of hospitalisation and mortality within the first 11 months due to stent thrombosis.[36] In addition, there have also been rising concerns for patients with drug-eluting stents regarding the risk of late stent occlusion after cessation of clopidogrel.[37] This difficult balancing act in managing these patients has resulted in a lack of consensus about the best practice and safest approach, and this is demonstrated by a wide variation in policies between different Orthopaedic departments. A number of published surveys of orthopaedic departments across the UK and US have demonstrated this variation, each of them largely based on anecdotal evidence.[38–41] One survey of 139 UK orthopaedic departments published in 2007 revealed 41 % stopped clopidogrel and operated immediately, 19 % continued clopidogrel and operated immediately, 21 % stopped clopidogrel for at least 5 days preoperatively and 19 % had various alternative protocols.[38]

The aim of the study was to determine if operating early on patients with neck of femur fractures who are on clopidogrel increases the risk of clinically significant bleeding, reflected in rate of blood transfusions and postoperative decreases in haemoglobin concentrations, when compared to patients who are not on clopidogrel. A secondary aim was to establish a framework for managing neck of femur patients who are on clopidogrel.

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