Is hip fracture surgery safe for patients on antiplatelet drugs and is it necessary to delay surgery? A systematic review and meta-analysis

Hip fractures are among the main causes of orthopedic surgical admissions and life-threatening injuries that occur worldwide, mainly in elderly individuals. Older patients are particularly vulnerable to sustaining hip fractures because of the high prevalence of osteoporosis or osteopenia. According to the American Academy of Orthopaedic Surgeons, each year, the number of hospital admissions due to hip fractures can reach up to 350,000 [1]. By the year 2040, there will be more than 500,000 people with hip fractures per year, with an annual medical expenditure of at least $9.8 billion [1, 2]. Although the development of surgical instruments and medical technology for early mobilization has advanced significantly, the mortality rate remains high. The cause of this high mortality rate is not entirely clear, and most of the deaths are ascribed to comorbidities, including cardiovascular disease [3, 4]. Antiplatelet drugs are simultaneously used in most hip fracture patients for primary and secondary prevention of cardiovascular or cerebrovascular events. Because the inhibitory action of drugs on platelets is irreversible and mature platelets do not synthesize new proteins, antiplatelet drugs make platelets ineffective for approximately 7 days, the mean lifetime of a platelet [5].

Despite the obvious advantages in the prevention and treatment of cardiovascular diseases, the continued use of antiplatelet drugs perioperatively may have great risks. Clopidogrel therapy in cardiac surgery without preoperative disruption increased hemorrhagic risks, transfusion demands, and infection with a poor prognosis [6]. The potential hematoma risk in orthopedic surgery [7] forces the withdrawal of antiplatelet drugs and delays surgery for at least 5 days to allow platelet function to return to an adequate status. Currently, no agreed upon guidelines exist for the appropriate surgical time for patients suffering hip fractures while on antiplatelet therapy, and there is a marked divergence of opinion on the final results of early and delayed surgical intervention [8].

Therefore, the purpose of this review was to identify whether early surgical intervention can be safely implemented on patients who develop hip fractures while on antiplatelet therapy to promote satisfactory outcomes. A secondary aim was to determine whether early or delayed surgery was more appropriate for those patients. Moreover, we attempt to establish a framework for managing hip fracture patients with antiplatelet therapy.

Hip fracture patients tend to be older, with a high mortality rate, and their quality of life is seriously affected [51]. As the global elderly population is gradually increasing, the number of elderly patients with hip fractures and the socioeconomic burden are also increasing year by year [52, 53]. Most of them usually suffer from cardio-cerebrovascular disease and need antiplatelet therapy. Some believe that it is necessary to withhold antiplatelet therapy to promote platelet function recovery and reduce the risk of perioperative bleeding. Others believe that surgery should be performed as soon as possible without stopping medication. Previous literature has found that there is an absence of a consensus or policies for the treatment of patients who sustain hip fractures while on antiplatelet therapy. A telephone questionnaire data analysis about current practical measures among 110 orthopedics in the UK showed that 56.4% of orthopedics did not have a standard of clopidogrel withdrawal, and the remaining 43.6% stopped clopidogrel before surgery. Among them, 20.9% of the surgeries were delayed by more than 5 days, and 12.7% were delayed by 7–10 days [54].

Although Soo et al. [55] and Doleman et al. [56] tried to identify how to manage these cases, the total number of studies included in these reviews were low, and these studies may result in type II errors and were either limited to one specific antiplatelet drug or confused the presence or absence of antiplatelet drugs with early or delayed surgery. Thus, we performed a more systematic and specific search and analysis to address the issues highlighted from previous research. The important finding of our study is that early surgery for hip fracture patients taking antiplatelet drugs might promote a higher risk of bleeding and more blood transfusion requirements compared to those without antiplatelet therapy. Nevertheless, there were no significant differences in prognosis. Instead, delayed intervention will lead to higher mortality and a longer hospital stay.

There were several limitations to our study. One of the limitations was that the methodological quality of the studies included was not optimal. Only observational studies were included in our analysis, which means that only the inference of association is possible rather than causality; there may be potential confounding variables that bias the outcomes. For instance, there were three main types of hip fracture surgery in included studies: hip repair using internal fixation, partial hip replacement surgery, and total hip replacement surgery. Different surgical methods will affect the outcomes, but most of the included studies did not distinguish and explain so that we were unable to exclude this confounding factor. As expected, the intervention groups in most studies [37, 38, 40, 41, 44, 45, 47] showed a significant increase in the number of cardiovascular or cerebrovascular comorbidities; however, surprisingly, only three of them showed a significant difference in the ASA grade [38, 41, 45]. Moreover, the preoperative hemoglobin values of the intervention group in five studies [30, 33, 45, 46] were significantly lower than those of the control group, which may potentially influence blood transfusions, meaning that the intervention groups required more units of blood. This may be why Zehir et al. [33] was the main source of heterogeneity in the outcomes for the mean number of units for transfusion. A further limitation was that publication bias existed in some studies as shown in the funnel plots; this might be because the number of included trials was less than 10. Finally, although we performed subgroup analysis based on the types of antiplatelet drugs and data were used from patients on one specific drug and not on the others simultaneously as much as possible, most of the trials included patients concurrently treated with aspirin in the clopidogrel subgroup, and this may affect the final results.

Regarding whether early surgery is safe for hip fracture patients taking antiplatelet drugs, the number of patients transfused in the antiplatelet group increased statistically, which was consistent with that in cardiac surgery [57, 58]. However, we found no convincing evidence of an increase in the average blood transfusion demands, except for in the medicine-united group. This suggested that there might indeed be an increased risk of bleeding in intraoperative blood loss or hidden blood loss, especially when antiplatelet drugs are used in combination [35]. However, because of the concerns of antiplatelets from anaesthesiologists and physicians, the patients taking antiplatelet drugs are more likely to have a lower threshold to receive transfusions. No differences in mortality, duration of hospital stay, reoperation rate, or related complications, except acute coronary syndrome, were detected between the two groups. The presence of more vascular comorbidities in the antiplatelet group of most studies may be responsible for the significant increase in acute coronary syndrome.

Regarding whether early or delayed surgery is better for patients with hip fractures on antiplatelet therapy, early surgery was associated with a greater decrease in hemoglobin; however, there were no differences in the transfusion rate or mean number of units for transfusion. This also supports the fact that patients taking antiplatelet drugs are more likely to be transfused owing to potential performance bias. Multiple studies have shown that delays in surgery for more than 2 days for hip fracture patients are closely related to an increased risk of complications due to long-term bedridden and delayed mobilization [59, 60]. Early surgical intervention can significantly reduce postoperative mortality and morbidity, promote a shorter hospital stay, and prompt patients to return to pre­injury ambulation status [61‐65]. However, early surgery for patients on antiplatelet may cause hemorrhagic accidents, as platelet function has not fully recovered [66]. In our study, delayed surgery increased the risk of mortality, and subgroup analysis showed that the point estimate regarding mortality at any time point was increased, especially mortality at 30 days and 3 months, which showed significant differences. Furthermore, hip fractures are more likely to prolong the length of hospital stay than any other musculoskeletal injuries, accounting for more than two-thirds of all hospital stays caused by fractures [67]. Early surgery can effectively shorten the length of hospital stay and reduce social and economic burdens. Unlike previous research studies, our study suggests that there are no differences in the incidence of postoperative complications between early and delayed surgery. Previous studies have demonstrated that sudden withdrawal will lead to conversion to a prothrombotic and proinflammatory condition, which may complicate surgery and lead to adverse clinical events, such as recurrence and death by myocardial infarction, which has already been stabilized by drugs or stents [68]. However, in the meta-analysis reported here, subgroup analysis showed that a surgical delay did not have a higher postoperative incidence of cardiocerebrovascular events or thromboembolic events, and early surgery did not result in a higher incidence of severe bleeding.

In conclusion, our analysis of 24 trials including a total of 5423 patients suggests that early surgery can be safely performed on hip fracture patients receiving antiplatelet drugs upon admission. Current evidence shows that although early surgery carries a high risk of bleeding, it does not lead to substantial blood transfusion demands or hemorrhagic events. Furthermore, compared with delayed surgery, early surgical intervention is associated with a significant decrease in mortality (p = 0.006) and length of hospital stay (p < 0.001). Based on the available evidence, it is unnecessary to delay surgery to restore platelet function when patients with hip fractures receive antiplatelet therapy. Early surgery can significantly reduce mortality and hospital stay, which is conducive to patient recovery. Further large-scale, multi-centered, well-motivated and well-designed randomized trials are required to confirm these findings and develop clearer guidelines for the treatment of these patients.