Incidence of aspirin resistance in high‐risk patients following elective total hip and knee arthroplasty

Abstract

Aspirin resistance (AR) is linked to increased morbidity and mortality after cardiovascular and neurovascular procedures but has not been investigated after total hip arthroplasty (THA) and total knee arthroplasty (TKA). To investigate the incidence of AR in high‐risk patients after elective THA/TKA, we conducted a prospective cohort study of elective THA/TKA in patients with thromboembolic risk factors: obesity (body mass index [BMI] ≥30 kg/m²), diabetes and/or advanced age (≥65 years) who were administered aspirin for venous thromboembolism prophylaxis. AR was confirmed using a platelet function analyser. Forty patients were included with a mean±standard deviation age of 66.1±10.4 years and BMI of 32.2±6.0 kg/m² and eight (20.0%) had diabetes. Overall, 52.5% of patients were aspirin resistant, with no statistically significant relationships between patient variables and AR (P > 0.05). AR after THA/TKA was an observed phenomenon; however, larger trials are required to determine the clinical consequences of AR and to guide prophylaxis strategies in this population.

The use of aspirin for venous thromboembolism (VTE) prophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) has increased in recent years. ¹ , ² However, its use is controversial and international treatment guidelines have conflicting recommendations. ³ Aspirin resistance (AR) in patients with cardiovascular and neurovascular diseases is reported to be 30% and linked to increased rates of thromboembolism and death. ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ However, the incidence of AR in patients after THA/TKA has not been explored. ³

AR has numerous risk factors, and three of importance in THA/TKA are diabetes, obesity and advanced age, which are also risk factors for VTE, further increasing the patient's thrombotic risk. ³ , ¹⁰ Furthermore, these risks also predispose patients to osteoarthritis, a major indication for THA/TKA. ³ Therefore, patients are likely to have one, if not multiple, risk factors. This was confirmed by an Australian retrospective multisite study that demonstrated that of patients undergoing elective THA/TKA, 93.6% had at least one risk factor for AR, and 25.5% had three or more concurrent risk factors. ¹¹ If THA/TKA confers a similar rate of AR as cardiovascular and neurovascular diseases, then this cohort is also at risk of poor outcomes. With more than 2.5 million THA/TKA occurring globally each year, which continues to grow with an ageing population, there is a great need to quantify the incidence and risk factors for AR after THA/TKA. ¹² Therefore, we aimed to determine the incidence of AR in high‐risk patients following elective THA/TKA.

This was done through a prospective cohort study, in an Australian quaternary hospital between February 2020 and September 2021. Patients were eligible if prescribed aspirin for VTE prophylaxis after an elective THA/TKA surgery, had documented diabetes, were obese (body mass index (BMI) ≥30 kg/m²) or of advanced age (age ≥ 65 years). Patients using aspirin pre‐operatively for an alternative indication (i.e., prevention of cardiovascular disease) were excluded. The study was approved by the local Human Ethics committee (HREC/2019/QMD/59169). The primary outcome was the presence of AR, and the secondary outcome was VTE or haemorrhagic complications.

All patients who met eligibility criteria were approached for inclusion into the study. Patients who consented to participate were dispensed the exact number of aspirin tablets as the planned duration of VTE prophylaxis after hospital discharge. At the routine post‐operative follow‐up with their orthopaedic surgeon, adherence to aspirin was confirmed verbally and via tablet count. Blood samples were collected to quantify AR.

A diagnosis of AR was confirmed using a platelet function analyser (PFA) with a normal closure time (CT) reference range of 80–200 s for collagen/epinephrine and 69–140 s for collagen/adenosine diphosphate (ADP) cartridges. ¹³ Normal CT to both agonists was expected for AR, whereas normal CT to collagen/ADP and prolonged CT to collagen/epinephrine was expected with aspirin‐sensitive patients. Patients who were non‐adherent to aspirin had <7 days of aspirin usage before blood sampling, were using anticoagulants, had thrombocytopenia (platelet count <100 × 10⁹/L) or abnormal haematocrit and haemoglobin were excluded from the study. Patients were followed for 60 days using electronic medical records to determine whether they were readmitted to a Queensland Health public hospital or underwent private investigations for VTE (i.e. D‐Dimer, calf venous Doppler ultrasound).

Data were analysed using R statistical software (version 3.5.2). The difference between variables in aspirin‐resistant and ‐sensitive patients was evaluated by independent sample t tests (continuous variables) and Pearson chi‐square analysis for independence (categorical variables) with statistical significance taken to be P ≤ 0.05.

A total of 237 patients was screened for inclusion, with 88 patients meeting eligibility criteria and 85 patients consenting. Forty‐five patients were subsequently excluded as their VTE prophylaxis drug regimens were altered, leaving 40 patients for analysis. All patients received an aspirin dose of 150 mg daily. These patients had a mean±standard deviation (SD) age of 66.1±10.4 years and 19 (47.5%) were women (Table 1). Twenty‐nine (72.5%) patients were obese, eight (20.0%) had diabetes and 25 (62.5%) were of advanced age. Patients were inpatients for a mean±SD of 3.75±2.4 days, and 95% were prescribed inpatient anticoagulant VTE prophylaxis such as heparin or low‐molecular‐weight heparin before starting aspirin. All patients included were compliant with aspirin treatment, administering 98% of doses.

Table 1.

Patient demographics, surgical factors and laboratory results

Characteristics	Aspirin resistant (n = 21)	Aspirin sensitive (n = 19)	All patients (N = 40)
Patient demographics
Age (year)	64.6 ± 10.8	67.8 ± 9.9	66.1 ± 10.4
Women sex, no. (%)	12 (57.1)	7 (36.8)	19 (47.5)
BMI (kg/m2)	31.0 ± 5.8	33.6 ± 6.17	32.2 ± 6.0
Surgical factors
THA, no. (%)	10 (47.6)	12 (54.5)	22 (55.0)
TKA, no. (%)	11 (52.4)	7 (36.8)	18 (45.0)
Length of anaesthesia (min)	118.4 ± 34.6	132.8 ± 44.7	125 ± 39.9
Length of admission (day)	4.0 ± 2.6	3.5 ± 2.1	3.75 ± 2.4
Risk factors, no. (%)
Previous VTE	1 (4.8)	0.0 (0.0)	1 (2.5)
Active cancer	1 (4.8)	2 (10.5)	3 (7.5)
Active smoker	4 (19.0)	1 (5.3)	5 (12.5)
Age ≥ 65 years	12 (57.1)	13 (68.4)	25 (62.5)
BMI > 30 kg/m2	14 (66.7)	15 (78.9)	29 (72.5)
Diabetes	4 (19.0)	4 (21.1)	8 (20.0)
Dyslipidaemia	6 (29.6)	10 (52.6)	16 (40.0)
Use of NSAIDs	5 (23.8)	5 (26.3)	10 (25.0)
Use of PPIs	2 (9.5)	6 (31.6)	8 (20.0)
Laboratory results
Haematocrit (L/L)	0.38 ± 0.04	0.37 ± 0.04	0.37 ± 0.04
Platelet count (×109 L)	229.0 ± 46.9	236.1 ± 74.0	232.4 ± 60.6
Haemoglobin (g/L)	112.8 ± 19.3	108.8 ± 15.2	110.9 ± 17.4
eGFR (mL/min)	76.8 ± 20.7	79.7 ± 17.0	78.2 ± 18.8
Concurrent risk factors†
One risk factor	12 (57.1)	8 (42.1)	20 (50.0)
Two risk factors	9 (42.9)	9 (47.4)	18 (45.0)
Three risk factors	0 (0.0)	2 (10.5)	2 (5.0)

^†Concurrent risk factors include diabetes, obesity and/or advanced age.

Abbreviations: BMI, body mass index; CT, closure time; eGFR, estimated glomeruler filtration rate; N/A, not applicable; NSAID, non‐steroidal anti‐inflammatory drug; PPI, proton pump inhibitor; THA, total hip arthroplasty; TKA, total knee arthroplasty; VTE, venous thromboembolism.

AR was identified in 21 (52.5%) patients (Fig. 1), with a mean duration of aspirin use of 17.1 days (range: 7–42 days) before blood sample analysis. Aspirin‐resistant patients had similar major AR risk factors (diabetes, obesity and advanced age) compared to those who were aspirin sensitive (Table 1). There was no statistically significant difference in patient demographics, surgical factors, risk factors or laboratory results (P > 0.05) between the two groups. Two patients were re‐admitted to hospital within 30 days of discharge: one for an ischaemic stroke and the second for multiple bilateral pulmonary emboli; both patients were aspirin sensitive. A further three patients were readmitted within 60 days for non‐thrombotic and non‐haemorrhagic reasons. In addition, one patient was diagnosed with a deep vein thrombosis by their general practitioner and was aspirin resistant.

Figure 1.

Comparison of PFA results in aspirin‐resistant and aspirin‐sensitive patients. PFA used two different cartridges, in patients diagnosed as aspirin resistant and aspirin sensitive. This includes: (A) PFA with a collagen/ADP cartridge and (B) PFA with a collagen/epinephrine cartridge. Black lines represent mean results and accompanying error bars are the 95% confidence interval. ***P < 0.001. ADP, adenosine diphosphate; Coll, collagen; Epi, epinephrine; ns, non‐statistically significant; PFA, platelet‐function analyser.

Discussion

To our knowledge, this is the first study to quantify the incidence of AR in patients with elective THA/TKA. We found that more than half the patients (52.5%) had AR using the PFA method. This incidence is higher than reported in systematic reviews and meta‐analyses in cardiovascular and neurological patients (approximately 30%). ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹

We observed a high incidence of AR; however, there was no statistically significant relationship with individual risk factors between aspirin‐resistant and ‐sensitive groups. This may reflect the small sample size, or, alternatively, the high incidence may not be due to obesity, advanced age or diabetes. A potential hypothesis is that the cause of AR after THA/TKA may be the surgery itself. Aspirin's short half‐life, in combination with increased platelet turnover seen in surgery due to a physiological response to stress and inflammation, may result in AR. ³ , ¹⁴ This phenomenon was observed after coronary artery bypass graft surgery, where patients were temporarily resistant to low‐dose aspirin and was attributed to increased expression of multidrug resistance protein‐4 (MRP4). ¹⁴ , ¹⁵ The role of MRP4 in orthopaedic surgery has not been investigated, but a surgery‐induced mechanism may contribute to AR after THA/TKA.

Aspirin for VTE prophylaxis has benefits including its low cost and reduced rates of bleeding compared to anticoagulants; however, these benefits may not outweigh the potential risk of AR and VTE. ¹⁶ , ¹⁷ Although the major trials concluded aspirin to be non‐inferior to anticoagulants in rates of VTE, these studies included a low number of patients with risk factors for AR. ¹⁶ , ¹⁷ Compared to our study, they had a younger cohort, lower BMI and a decreased incidence of diabetes. Therefore, these studies would not have seen the effect of AR in the lower‐risk cohort. Although our study had a small sample size, the large proportion of patients with AR observed highlights the seriousness of this potential risk. At a clinical level, the risk of AR and potential VTE could outweigh the safety benefits of aspirin over anticoagulants in VTE prophylaxis. These findings raise concerns about aspirin use in high‐risk patients, and alternative anticoagulants may be more appropriate.

A large multicentre trial is required to determine the clinical outcomes in patients who are aspirin resistant after orthopaedic surgery. Based on a VTE rate of 3.7% in aspirin‐sensitive patients, consistent with Australian observational data, and using a minimal clinically important difference of 1.0%, a two‐sided comparison with 80% power and an alpha of 0.05 would require approximately 10 800 participants to be included (5400 per group). ¹¹ Given the impracticality of routine platelet function testing due to financial cost, logistical challenges and inter‐individual variability, findings from such a trial could support a simplified risk‐stratified approach. Patients with identifiable clinical risk factors for AR may benefit from an alternative anticoagulant that has demonstrated safety and efficacy in this context. Another interesting theory that requires investigation is whether a ‘one‐dose‐fits‐all’ approach for aspirin therapy is appropriate for everyone. Rather, should prescribing be tailored based on patients' individual characteristics and risk factors? For example, patients with increased platelet turnover, as seen in diabetes, may require twice‐daily dosing of aspirin rather than once‐daily.

The study occurred during the COVID‐19 pandemic when elective surgery was reduced, and the recruitment of patients was considerably lower than expected. However, the results are hypothesis‐generating. There are other methods to measure adherence, but these were not considered practical at the time. Lastly, the study was conducted at one hospital, so generalisability is limited; however, it was a major orthopaedic centre.

In conclusion, this study highlights a notably high incidence of AR among patients undergoing elective THA/TKA, prompting critical reconsideration of aspirin's reliability as a VTE prophylaxis strategy in this population. While limited by sample size and single‐center design, these findings underscore the need to reconsider aspirin's role in VTE prophylaxis and explore alternative individualised prophylactic approaches to optimise post‐operative outcomes.

Ethics statement

This study obtained ethical approval from the Metro South Human Research Ethics Committee (HREC/2019/QMD/59169).

Data availability statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.