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Editor's Choice – Association Between Peri-OPerative Aspirin ResisTance and CardioVascular Outcome (POPART-CVO): a Prospective Non-Interventional Cohort Study

Published:August 10, 2022DOI:https://doi.org/10.1016/j.ejvs.2022.07.050

      Objective

      New onset aspirin resistance during surgery, known as peri-operative aspirin resistance, is observed in up to 30% of vascular surgery patients and is associated with post-operative myocardial damage; questioning aspirin effectiveness towards peri-operative cardiovascular events. The objective of this study was to prospectively evaluate whether peri-operative aspirin resistance in vascular surgery is associated with an adverse cardiovascular outcome.

      Methods

      Based on a sample size calculation, 194 adult elective vascular or endovascular surgery patients receiving aspirin were analysed in this prospective, single centred, non-interventional cohort study. Platelet function was measured before surgery, one hour after incision, four hours post-operatively, and on the morning of the first and second post-operative days using the Multiplate analyser. The primary outcome was myocardial injury after non-cardiac surgery (MINS). Secondary outcomes included major bleeding, admission to intensive care unit, length of hospital stay, and major adverse cardiac and cerebrovascular events. Subgroup analyses were performed for patients with different cardiovascular risk and for patients who underwent endovascular surgery.

      Results

      Peri-operative aspirin resistance was observed in 27.8% of patients but was not associated with MINS (27.8% vs. 32.1%, aspirin resistance vs. no aspirin resistance, OR 0.812, 95% CI 0.406 – 1.624, p = .56) or with any of the secondary endpoints (all p > .050). In nine of the 10 subgroup analyses, aspirin resistance was not associated with a difference in MINS rate. However, in patients with a low cardiovascular risk profile (RCRI 0–2), MINS occurred more frequently in patients without aspirin resistance (p = .049).

      Conclusion

      This study confirmed previous reports demonstrating that peri-operative aspirin resistance is common in patients undergoing vascular or endovascular surgery. However, in patients who continue aspirin throughout the peri-operative period, aspirin resistance is a phenomenon, which does not appear to be related to MINS. Measuring peri-operative platelet function using the Multiplate analyser with the intention to identify and potentially prevent or treat peri-operative aspirin resistance seems to be dispensable.

      Keywords

      New onset aspirin resistance during or after surgery is observed in up to 30% of vascular surgery patients and has been linked to a post-operative rise in troponin. However, whether peri-operative aspirin resistance in vascular surgery patients is associated with adverse cardiovascular events has not been assessed in a prospective study. The present study has demonstrated that aspirin resistance in vascular surgery patients is not associated with myocardial injury after non-cardiac surgery. Measuring peri-operative platelet function using the Multiplate analyser to identify and potentially prevent or treat peri-operative aspirin resistance in vascular and endovascular surgery is dispensable.

      Introduction

      In patients with cardiovascular diseases, aspirin (acetylsalicylic acid) is widely used for secondary prevention after myocardial infarction and other cardiovascular events.
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      Laboratory aspirin resistance is the inability of aspirin to reduce platelet production of thromboxane-A2, resulting in failure to prevent platelet activation and aggregation.
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      Clinical aspirin resistance includes patients who experience thrombo-embolic events despite continuous antiplatelet therapy.
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      New onset of aspirin resistance during or after surgery, known as peri-operative aspirin resistance, is observed in up to 30% of cardiac
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      and vascular surgery patients.
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      Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?.
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      suggesting that such an inadequate peri-operative response to aspirin might promote an adverse cardiovascular outcome. The objective of the current study was to examine whether peri-operative aspirin resistance is associated with MINS, major bleeding, other cardiovascular endpoints, admission to intensive care unit, or length of hospital stay in vascular surgery patients.

      Methods

      Study design and participants

      This was a single centre, prospective, non-interventional cohort study in patients receiving oral aspirin undergoing elective vascular surgery at Heidelberg University Hospital, Heidelberg, Germany. The study protocol conformed to the principles of the Declaration of Helsinki,
      • World Medical Association
      World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.
      and was approved by the Ethics Committee of the Medical Faculty of the Ruprecht-Karls University Heidelberg (S-468/2019, 15 July 2019). The study was registered prior to patient enrolment at clinicaltrials.gov (NCT04053894, Principal investigator: J.L., Date of registration: 13 August 2019) and was conducted according to the Principles of Good Clinical Practice.
      This report follows the STROBE recommendations for observational studies.
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      • Pocock S.J.
      • Gøtzsche P.C.
      • Vandenbroucke J.P.
      The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
      From September 2019 to November 2020, consecutive adult patients with a history of at least 14 days of aspirin undergoing elective vascular or endovascular surgery with an expected three day minimum hospital stay were enrolled after written informed consent. Exclusion criteria were pregnancy, breastfeeding, congenital or acquired platelet malfunction, platelet count < 100 000/μL, regular administration of non-steroidal anti-inflammatory drugs, elevated liver enzymes (serum aspartate transaminase [AST] > 74 U/L / alanine transaminase [ALT] > 70 U/L), elevated creatinine levels (serum creatinine > 2 mg/dL), anaemia (haemoglobin (Hb) < 10 g/dL), or primary aspirin resistance identified pre-operatively by Multiplate analysis. Patients were excluded if they had experienced one of the cardiovascular complications listed as study endpoints within the 28 days before enrolment or if a diagnostic angiogram without surgical intervention was the planned procedure. Surgical procedures, general anaesthesia, monitored anaesthesia care, or regional anaesthesia were performed according to standard operating procedures. According to departmental standards, aspirin was continued peri-operatively including the day of surgery.

      Outcome analysis

      The primary endpoint MINS was chosen as the most sensitive measure for cardiac complications.
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      • et al.
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      Follow up was performed until day 30. The secondary endpoints were major bleeding complications, major adverse cardiac and cerebrovascular events (MACCE) defined as composite of cardiovascular death, MI, acute on chronic limb ischaemia, mesenteric ischaemia and stroke, individual components of the composite endpoint, admission to intensive care unit, and length of hospital stay. Pre-specified subgroup analyses were performed for patients with i) coronary heart disease, ii) diabetes mellitus, and iii) different cardiovascular risk profiles (revised cardiac risk index [RCRI] 0–2 vs. 3–5). RCRI is a classification system to estimate the patient’s risk of post-operative cardiac complications based on pre-operat-ive risk.
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      • Cook E.F.
      • et al.
      Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery.
      Post hoc additional subgroup analyses were conducted for patients iv) on statins, and v) with endovascular surgery. A post-operative 12 lead electrocardiogram (ECG) was recorded on post-operative day (POD) 3, patient charts were screened and if discharged prior to day 30, study participants or their family doctors participated in a scripted telephone interview at the end of follow up.

      Data collection

      Collected demographic data were pre-existing diseases including previous cardiovascular events, peripheral arterial disease according to the Rutherford classification,
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      • Ernst C.
      • Johnston K.W.
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      • Ahn S.
      • et al.
      Recommended standards for reports dealing with lower extremity ischemia: revised version.
      heart failure according to the NYHA (New York Heart Association) classification,
      • Dolgin M.
      NYHACC
      Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels.
      and current medication. Creatinine, AST, and ALT values, the estimated glomerular filtration rate (eGFR using Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]), platelet count, leukocyte count, haemoglobin, and high sensitive cTnT were documented before surgery. A baseline 12 lead ECG was recorded.

      Blood collection, platelet function testing, laboratory, and electrocardiogram analysis

      Blood for platelet function analysis was collected in hirudin tubes (Sarstedt, Nümbrecht, Germany) before and one hour after incision, four hours post-operatively and on the morning of POD1 and POD2 before patients received their aspirin medication. Samples were processed immediately, and platelet aggregation was assessed using the Multiplate analyser (Roche Diagnostics, Rotkreuz, Switzerland). Blood samples were stimulated with arachidonic acid 15 mM. The Multiplate analyser ASPI test was used to detect an aspirin induced inhibition of platelets’ COX. Aspirin resistance was defined according to the manufacturer’s instructions resulting in an area under the curve (AUC) in the ASPI test over 40. Platelet sensitivity to aspirin ex vivo was determined by addition of aspirin to hirudin tubes (final concentrations 20 and 100 μM). Hs-cTnT was determined in lithium heparinised (Sarstedt, Nümbrecht, Germany) blood pre-operatively and daily on POD1–3. Hs-cTnT (Cobas E4111, Roche Diagnostics, Mannheim, Germany) measurements were performed in the central laboratory of the University Hospital. ECGs were analysed by two independent physicians unaware of the clinical or flow cytometry data. All disagreements were discussed with a third physician and were resolved by consensus.

      Detailed definitions of outcome variables

      MINS was defined as any post-operative peak hs-cTnT ≥ 20 ng/L and < 65 ng/L with an increase of ≥ 5 ng/L or any new hs-cTnT ≥ 65 ng/L with peak hs-cTnT post-operatively
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      • Chan M.T.V.
      • Srinathan S.K.
      • et al.
      Association of postoperative high-sensitivity troponin levels with myocardial injury and 30-day mortality among patients undergoing noncardiac surgery.
      . Cardiac death was defined as any death presumed to be of cardiac origin. Criteria for MI followed the fourth universal definition of MI.
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      • Chaitman B.R.
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      • et al.
      Fourth universal definition of myocardial infarction (2018).
      Stroke was diagnosed as new focal neurological deficit with radiological or angiographic evidence of embolic or thrombotic cause.
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      • Smith A.
      • Schultz M.J.
      • Pelosi P.
      • et al.
      Standards for definitions and use of outcome measures for clinical effectiveness research in peri-operative medicine: European Peri-operative Clinical Outcome (EPCO) definitions: a statement from the ESA-ESICM joint taskforce on peri-operative outcome measures.
      Peripheral arterial occlusion was confirmed by angiography. Major bleeding was recorded using the International Society on Thrombosis and Haemostasis definition (ISTH).
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      • Angerås U.
      • Bergqvist D.
      • Eriksson B.
      • Lassen M.R.
      • Fisher W.
      Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.

      Sample size calculation

      Peri-operative aspirin resistance was observed in approximately one third of the relevant patient population.
      • Kempfert J.
      • Anger K.
      • Rastan A.
      • Krabbes S.
      • Lehmann S.
      • Garbade J.
      • et al.
      Postoperative development of aspirin resistance following coronary artery bypass.
      • Wang Z.
      • Gao F.
      • Men J.
      • Ren J.
      • Modi P.
      • Wei M.
      Aspirin resistance in off-pump coronary artery bypass grafting.
      • Payne D.A.
      • Jones C.I.
      • Hayes P.D.
      • Webster S.E.
      • Ross Naylor A.
      • Goodall A.H.
      Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?.
      The expected rate for the primary endpoint was derived from the preceding LeukoCAPE-2 study.
      • Scholz A.S.
      • Handke J.
      • Gillmann H.J.
      • Zhang Q.
      • Dehne S.
      • Janssen H.
      • et al.
      Frontline Science: low regulatory T cells predict peri-operative major adverse cardiovascular and cerebrovascular events after noncardiac surgery.
      Here, 82 of the recruited patients underwent vascular surgery. Within 30 days, 31 patients (37%) suffered MINS. Therefore, it was assumed that peri-operative aspirin resistance will occur in one third of patients. It was expected that 50% of these patients will experience MINS compared with 30% in the group without aspirin resistance. To find a difference in the rate of the primary endpoint at the expected group ratio of 1:2 at a two sided significance level of 5% with a statistical power of 0.8 using the likelihood chi square test and expecting 6% dropouts, it was estimated that recruitment of 220 patients should be sufficient.

      Statistical analysis

      The MINS rate was compared for patients suffering peri-operative aspirin resistance vs. patients with an adequate aspirin response using a chi square test. If patients were discharged before the POD3 visit, hs-cTnT data were imputed (last observation carried forward analysis). Logistic regression models were calculated to examine the influence of platelet aggregation for MINS considering the influencing variables age, gender, statin, diabetes, RCRI (0–2 vs. 3–5), and CHD. Because the cutoff value specified for the Multiplate assay
      • Multiplate® Roche.
      analyzer: Cut-off-values ADPtest and ASPItest.
      was derived from individuals not undergoing surgery, the diagnostic accuracy of intra-operative platelet aggregation value was examined for this peri-operative population using receiver operating curves (ROC), calculation of AUCs, as well as sensitivity and specificity. A cutoff suitable for the patient population under investigation with regard to the occurrence of MINS (yes/no) was identified using Youden’s J statistic and compared with the published value of 40 for this assay. Time to event analyses were performed using log rank tests and Cox proportional hazards regression models. Descriptive analyses comprised calculation of mean, standard deviation (SD), minimum, maximum, median, first and third quartile for continuous variables, and absolute and relative proportions for categorical variables. Continuous variables between patients exhibiting peri-operative aspirin resistance vs. patients with an adequate aspirin response were compared using the t test or Mann–Whitney U test and categorical variables using the Boschloo test, or chi square test. Statistical analyses were performed using R version 4.0.5 (The R Foundation for Statistical Computing, Vienna, Austria) and SAS 9.4 (Statistical Analysis System, Heidelberg, Germany).

      Results

      From patients scheduled for elective vascular or endovascular surgery taking aspirin as part of their permanent medication, 357 were screened. Of those, 220 patients were enrolled into the study; 137 patients were not enrolled because they did not fulfil the inclusion criteria (n = 12), they did not meet the exclusion criteria (n = 99), or because no surgery was conducted (n = 26). Twenty of the included patients were discharged prior to the POD3 visit and three patients were discharged before the POD2 visit. Three patients withdrew consent and were excluded. In 21 (9.5%) patients, pre-operative aspirin resistance was identified and in two patients, angiograms without surgical intervention were performed. The final analysis set comprised 194 individuals (Fig. 1).
      Figure 1
      Figure 1Participant flow chart of a prospective non-interventional cohort study Peri-operative Aspirin resistance and CardioVascular Outcome (POPART-CVO).

      Patient characteristics

      The main clinical and demographical baseline characteristics are presented in Table 1 and Supplementary Table S1. Peri-operative aspirin resistance was observed in 54 (27.8%) of 194 patients. The mean age was 69 ± 9 years, and seventy six per cent of the participants were male. Patients experiencing peri-operative aspirin resistance were lesslikely to be active smokers, were more likely to have diabetes mellitus controlled by oral medication, and had higher leukocyte counts. Furthermore, peri-operative aspirin resistance was more common in open surgery than in endovascular surgery. There was no difference regarding other baseline characteristics.
      Table 1Clinical baseline characteristics of the study cohort of 194 elective adult vascular or endovascular surgery patients studied for aspirin resistance during surgery
      VariableAnalysis set (n = 194)Peri-operative aspirin resistance (n = 54)No peri-operative aspirin resistance (n = 140)p value
      Age – y69.3 ± 8.7069.4 ± 8.4869.3 ± 8.81.93
      Male147 (75.8)42 (77.8)105 (75.0).83
      BMI – kg/m226.2 ± 4.7627.0 ± 4.8525.9 ± 4.70.13
      Smokers154 (79.4)37 (68.5)117 (83.6).024
       Active69 (35.6)11 (20.4)58 (41.4).009
       Previous85 (43.8)26 (48.1)59 (42.1)
      ASA status
       236 (18.6)12 (22.2)24 (17.1).44
       3154 (79.4)42 (77.8)112 (80.0)
       44 (2.1)0 (0.0)4 (2.9)
      RCRI1.7 ± 1.221.9 ± 1.251.6 ± 1.20.084
       RCRI
       041 (21.1)8 (14.8)33 (23.6).33
       148 (24.7)13 (24.1)35 (25.0)
       247 (24.2)12 (22.2)35 (25.0)
       347 (24.2)17 (31.5)30 (21.4)
       410 (5.2)3 (5.6)7 (5.0)
       51 (0.5)1 (1.9)0 (0.0)
      Surgical risk classification
      Surgical risk classification according to the American College of Cardiology and American Heart Association.
       Low risk3 (1.5)0 (0.0)3 (2.1).28
       Intermediate risk117 (60.3)29 (53.7)88 (62.9)
       High risk74 (38.1)25 (46.3)49 (35.0)
      Type of surgery
       Open surgery138 (71.1)46 (85.1)92 (65.7).007
       Endovascular surgery56 (28.9)8 (14.8)48 (34.3)
       Aortic surgery32 (16.5)14 (25.9)18 (12.9).21
       Carotid surgery66 (34.0)23 (42.6)43 (30.7)
       Lower limb surgery37 (19.1)9 (16.7)28 (20)
       Others3 (1.5)0 (0)3 (2.1)
       Endovascular aortic surgery33 (17.0)4 (7.4)29 (20.7).58
       Percutaneous transluminal angioplasty23 (11.9)4 (7.4)19 (13.6)
      Hypertension172 (88.7)49 (90.7)123 (87.9).76
      Diabetes mellitus48 (24.7)18 (33.3)30 (21.4).084
       Oral medication33 (17.0)15 (27.8)18 (12.9).016
       Insulin dependent10 (5.2)5 (9.3)5 (3.6).13
      Congestive heart failure108 (55.7)35 (64.8)73 (52.1).13
       NYHA °158 (29.9)18 (33.3)40 (28.6).24
       NYHA °240 (20.6)12 (22.2)28 (20.0)
       NYHA °310 (5.2)5 (9.3)5 (3.6)
       NYHA °40 (0)0 (0)0 (0)
      Coronary heart disease93 (47.9)30 (55.6)63 (45.0).19
       Medical treatment93 (47.9)30 (55.6)63 (45.0).19
       History of PCI46 (23.7)17 (31.5)29 (20.7).12
       History of CABG28 (14.4)8 (14.8)20 (14.3)1.0
      Peripheral artery disease84 (43.3)20 (37.0)64 (45.7).31
       Rutherford 05 (2.6)2 (3.7)3 (2.1).34
       Rutherford 1–359 (30.4)11 (20.4)48 (34.3)
       Rutherford 48 (4.1)2 (3.7)6 (4.3)
       Rutherford 5–612 (6.2)5 (9.3)7 (5.0)
      History of myocardial infarction35 (18.0)8 (14.8)27 (19.3).52
      History of stroke37 (19.1)8 (14.8)29 (20.7).40
      History of acute decompensated heart failure8 (4.1)1 (1.9)7 (5.0).42
      Cardiac dysrhythmia23 (11.9)6 (11.1)17 (12.1)1.0
      Anaesthesia
       General anaesthesia111 (57.2)29 (53.7)82 (58.6).61
       Analgosedation73 (37.6)23 (42.6)50 (35.7).39
       Peridural anaesthesia27 (13.9)8 (14.8)19 (13.6).79
       Spinal anaesthesia10 (5.2)0 (0.0)10 (7.1).055
       Regional anaesthesia64 (33.0)24 (44.4)40 (28.6).037
      Data are presented as n (%) or mean ± standard deviation. Continuous data were compared using t test and Mann–Whitney U test. Categorial variables were compared using Boschloo test, Fisher exact test, or chi square test. BMI = body mass index; ASA = risk classification according to the American Society of Anesthesiologists; RCRI = revised cardiac risk index; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting.
      Surgical risk classification according to the American College of Cardiology and American Heart Association.

      Myocardial injury after non-cardiac surgery

      In total, 60 patients (30.9%) experienced the primary endpoint of MINS during the 30 day follow up. Peri-operative aspirin resistance did not correlate with the rate of MINS (27.8% vs. 32.1%, aspirin resistance vs. no aspirin resistance, OR 0.812, 95% CI 0.406 – 1.624, p = .56). Logistic regression for the dependent variable MINS identified age, sex, and RCRI to have an influence on the occurrence of MINS. In contrast, steady platelet aggregation level, statin medication, diabetes mellitus, and CHD did not (Table 2).
      Table 2Effect of platelet function on myocardial injury after non-cardiac surgery (MINS) in 194 elective adult vascular or endovascular surgery patients
      VariableOdds ratio (95% CI)p value
      Maximum ASPI0.984 (0.958–1.009).22
      Age1.13 (1.077–1.193)<.001
      Male3.422 (1.37–9.553).012
      Statin medication0.809 (0.276–2.511).70
      Diabetes mellitus1.086 (0.469–2.456).84
      RCRI (3–5)7.507 (2.748–22.402)<.001
      CHD0.944 (0.357–2.399).91
      Odds ratio estimated from the logistic regression. Continuous variables were compared using the t test or Mann–Whitney U test and categorical variables using the Boschloo test or chi square test. ASPI = platelet response to aspirin for arachidonic acid mediated aggregation; CI = confidence intervals; MINS = myocardial injury after non-cardiac surgery; CHD = coronary heart disease; OR = odds ratio; RCRI = revised cardiac risk index.
      As there were more dropouts than expected, 194 patients were analysed instead of 207. Therefore, two additional analyses were conducted assuming extreme scenarios in which it was assumed that i) all of the 13 “missing” patients experienced aspirin resistance or it was assumed that ii) none of the 13 missing patients experienced aspirin resistance. No association between aspirin resistance and MINS was observed in either of the extreme scenarios (all p > .050).

      Secondary endpoints and ex vivo experiments

      Major bleeding occurred in nine patients (4.6%). Peri-operative aspirin resistance did not affect the incidence of major bleeding (Table 3).
      Table 3Secondary endpoints in 194 elective adult vascular or endovascular surgery patients studied for aspirin resistance during surgery
      VariablePeri-operative aspirin resistance (n = 54)No peri-operative aspirin resistance (n = 140)Odds ratio (95% CI)p value
      Major bleeding2 (3.7)7 (5)0.731 (0.147–3.633).70
      Cardiovascular death1 (1.9)2 (1.4)1.302 (0.116–14.659).83
      Myocardial infarction1 (1.9)8 (5.7)0.311 (0.038–2.550).25
      Stroke2 (3.7)1 (0.7)5.346 (0.475–60.213).13
      Acute on chronic limb ischaemia0 (0)2 (1.4)0.986 (0.966–1.006)1.0
      Mesenteric artery thrombosis0 (0)2 (1.4)0.986 (0.966–1.006)1.0
      MACCE4 (7.4)12 (8.6)0.853 (0.263–2.771).79
      Length of hospital stay – d
       Mean ± SD10.7 ± 6.749.9 ± 6.74
       Median (IQR)10 (5–14)7 (5–12)
       Range2–322–32
      Admission to intensive care unit16 (29.6)38 (27.1)1.130 (0.565–2.260).73
      Data are presented as n (%) unless stated otherwise. p values refer to the distribution of the patients in the four field tables and were calculated using chi square test. CI = confidence intervals; MACCE = major adverse cardiac and cerebrovascular events; ICU = intensive care unit; SD = standard deviation; IQR = interquartile range.
      Within 30 days of surgery, three patients (1.5%) suffered cardiovascular death. MI occurred in nine patients (4.6%) and three patients (1.5%) suffered stroke. Sixteen patients (8.2%) experienced MACCE. Acute peripheral arterial occlusion and mesenteric artery thrombosis each occurred in two patients (1%). Peri-operative aspirin resistance did not affect the incidence of cardiovascular complications (Table 3).
      The mean duration of hospital stay was 10.1 ± 6.73 days and did not differ between groups. Patients with peri-operative aspirin resistance were not treated more frequently in intensive care (Table 3).
      In the ex vivo experiments, a reduction of platelet aggregation was achieved by the addition of aspirin (Supplementary Table S2, Supplementary Fig. S1).

      Subgroup analysis

      In the subgroup of patients with a RCRI of 0 – 2, patients with peri-operative aspirin resistance less frequently suffered MINS (9% vs. 25%, aspirin resistance vs. no aspirin resistance, OR 0.296, 95% CI 0.083 – 1.052, p = .049). With regard to the other subgroups, peri-operative aspirin resistance did not influence the occurrence of MINS (Table 4).
      Table 4Subgroup analysis of 194 elective adult vascular or endovascular surgery patients studied for aspirin resistance during surgery
      Patient subgroupPeri-operative aspirin resistance (n = 54)No peri-operative aspirin resistance (n = 140)Odds ratio (95% CI)p value
      nMINSnMINS
      Patients with CHD3012 (40)6327 (43)0.889 (0.367–2.153).79
      Subgroup of patients without CHD241 (2)778 (6)0.468 (0.125–1.753)
      Subgroup of patients with DM186 (33)3013 (43)0.654 (0.194–2.209).49
      Subgroup of patients without DM369 (25)11032 (29)0.813 (0.344–1.919).64
      Subgroup of patients with RCRI 3–52112 (57)3719 (51)1.263 (0.430–3.713).67
      Subgroup of patients with RCRI 0–2333 (9)10326 (25)0.296 (0.083–1.052).049
      Subgroup of patients with open surgery4614 (30)9229 (32)0.950 (0.442–2.046).90
      Subgroup of patients with endovascular surgery81 (13)4816 (33)0.286 (0.032–2.526).24
      Subgroup of patients with statin medication4514 (31)11838 (32)0.951 (0.454–1.992).89
      Subgroup of patients without statin medication91 (11)227 (32)0.268 (0.028–2.578).23
      Data are presented as n (%) unless stated otherwise. p values refer to the distribution of the patients in the four field tables and were calculated using chi square test. CHD = coronary heart disease; CI = confidence intervals; DM = diabetes mellitus; RCRI = revised cardiac risk index; MINS = myocardial injury after non-cardiac surgery.

      ASPI test cutoff value optimised for peri-operative vascular and endovascular surgery patients

      The median AUC value of the ASPI test in patients without MINS was 30 (Q1 – Q3: 20 – 41). Patients who suffered MINS had a median AUC value of 26.5 (Q1 – Q3: 21 – 39.5).
      The optimised threshold for the AUC value of the ASPI test to best predict MINS was 32.5. This cutoff value had a specificity of 0.45 and a sensitivity of 0.7 (Fig. 2).
      Figure 2
      Figure 2Receiver operating characteristics curve of the ability of the Multiplate analyser ASPI test to predict occurrence of myocardial injury after non-cardiac surgery (MINS) in 194 elective adult vascular or endovascular surgery patients. The new optimised threshold for the area under the curve value was 32.5, which accomplished a specificity of .45 and a sensitivity of .70.

      Discussion

      In this study, peri-operative aspirin resistance during vascular or endovascular surgery was not associated with MINS or with any of the pre-specified secondary endpoints. In nine of the 10 subgroup analyses, aspirin resistance was not associated with a difference in MINS rates. However, in patients with a low cardiovascular risk profile, MINS occurred more frequently in patients without aspirin resistance. An ASPI test cutoff value specifically derived for peri-operative vascular and endovascular surgery patients had a low specificity and medium sensitivity for prediction of MINS.
      Aspirin resistance, independent of surgical intervention, has been shown to be associated with cardiac complications, more severe stroke, more pronounced atherosclerotic burden, and a higher rate of hospitalised cardiovascular events.
      • Oh M.S.
      • Yu K.H.
      • Lee J.H.
      • Jung S.
      • Kim C.
      • Jang M.U.
      • et al.
      Aspirin resistance is associated with increased stroke severity and infarct volume.
      • Kahraman S.
      • Dogan A.
      • Ziyrek M.
      • Usta E.
      • Demiroz O.
      • Ciftci C.
      The association between aspirin resistance and extent and severity of coronary atherosclerosis.
      • Ebrahimi P.
      • Farhadi Z.
      • Behzadifar M.
      • Shabaninejad H.
      • Abolghasem Gorji H.
      • Taheri Mirghaed M.
      • et al.
      Prevalence rate of laboratory defined aspirin resistance in cardiovascular disease patients: a systematic review and meta-analysis.
      • Chen H.Y.
      • Chou P.
      PFA-100-measured aspirin resistance is the predominant risk factor for hospitalized cardiovascular events in aspirin-treated patients: a 5-year cohort study.
      Testing for aspirin resistance is not routinely recommended but is often performed in symptomatic patients receiving aspirin therapy.
      • Wang T.H.
      • Bhatt D.L.
      • Topol E.J.
      Aspirin and clopidogrel resistance: an emerging clinical entity.
      • Mărginean A.
      • Bănescu C.
      • Scridon A.
      • Dobreanu M.
      Anti-platelet therapy resistance - concept, mechanisms and platelet function tests in intensive care facilities.
      • Grundmann K.
      • Jaschonek K.
      • Kleine B.
      • Dichgans J.
      • Topka H.
      Aspirin non-responder status in patients with recurrent cerebral ischemic attacks.
      Until now, no clinical guidelines have been implemented to manage aspirin resistance.
      • Baigent C.
      • Blackwell L.
      • Collins R.
      • Emberson J.
      • Godwin J.
      • Peto R.
      • et al.
      Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.
      ,
      • Abacı O.
      • Kılıçkesmez K.O.
      Aspirin resistance: where are we now?.
      Increasing aspirin dosage is one possible strategy to treat aspirin resistance.
      • Kahraman S.
      • Dogan A.
      • Ziyrek M.
      • Usta E.
      • Demiroz O.
      • Ciftci C.
      The association between aspirin resistance and extent and severity of coronary atherosclerosis.
      ,
      • Cotter G.
      • Shemesh E.
      • Zehavi M.
      • Dinur I.
      • Rudnick A.
      • Milo O.
      • et al.
      Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?.
      Previous reports were confir-med
      • Kempfert J.
      • Anger K.
      • Rastan A.
      • Krabbes S.
      • Lehmann S.
      • Garbade J.
      • et al.
      Postoperative development of aspirin resistance following coronary artery bypass.
      • Wang Z.
      • Gao F.
      • Men J.
      • Ren J.
      • Modi P.
      • Wei M.
      Aspirin resistance in off-pump coronary artery bypass grafting.
      • Payne D.A.
      • Jones C.I.
      • Hayes P.D.
      • Webster S.E.
      • Ross Naylor A.
      • Goodall A.H.
      Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?.
      that transient aspirin resistance is a common phenomenon in peri-operative patients. In this study, 27.8% of vascular or endovascular surgery patients suffered aspirin resistance during surgery or within POD1 and POD2. This finding is in line with previous studies reporting 27.5% of patients with aspirin resistance in a cohort of vascular surgery patients on POD1.
      • Hummel T.
      • Meves S.H.
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      • Düsterwald J.-O.
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      • Mumme A.
      • et al.
      Peri-operative changes of response to antiplatelet medication in vascular surgery patients.
      Potential underlying mechanisms include an increased platelet turnover which has been found during cardiac surgery, infection, and inflammation.
      • Zimmermann N.
      • Wenk A.
      • Kim U.
      • Kienzle P.
      • Weber A.A.
      • Gams E.
      • et al.
      Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery.
      Due to the short half life of aspirin, the result is an increased proportion of aspirin naive platelets during the 24 hour dosing interval.
      • Zimmermann N.
      • Wenk A.
      • Kim U.
      • Kienzle P.
      • Weber A.A.
      • Gams E.
      • et al.
      Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery.
      The severity of surgical trauma also appears to influence the incidence of peri-operative aspirin resistance. Potentially, more severe trauma leads to increased mobilisation of aspirin naive platelets from the bone marrow. Consistently, patients undergoing endovascular surgery were less likely to experience peri-operative aspirin resistance. Reasons for peri-operative aspirin resistance might be transient. That aspirin resistance was reversible during the observation period in the majority of patients may be the reason that cardiovascular outcome was not affected. To date, it is unclear whether the aspirin resistance observed by the present authors and others is clinically relevant. Rajagopalan et al. demonstrated, that patients with elevated post-operative cardiac troponin I (cTnI) had a higher incidence of non-response to aspirin compared with patients without cTnI elevation.
      • Rajagopalan S.
      • Ford I.
      • Bachoo P.
      • Hillis G.S.
      • Croal B.
      • Greaves M.
      • et al.
      Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery.
      They assessed platelet aggregation in 136 patients undergoing major vascular surgery at the following timepoints: pre-operatively, immediately after surgery, and on POD1, 2, 3, and 5. As in the present study, Rajagopalan et al. continued aspirin use throughout the peri-operative period. Pre-operatively, non-response to aspirin for arachidonic acid mediated aggregation was observed in 22% of the patients who subsequently had a rise in troponin compared with 14% in patients without a troponin increase.
      • Rajagopalan S.
      • Ford I.
      • Bachoo P.
      • Hillis G.S.
      • Croal B.
      • Greaves M.
      • et al.
      Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery.
      Post-operatively, the rate of non-response to aspirin increased to a maximum of 48% in troponin positive patients compared with 26% in the patients without troponin elevation on POD2.
      • Rajagopalan S.
      • Ford I.
      • Bachoo P.
      • Hillis G.S.
      • Croal B.
      • Greaves M.
      • et al.
      Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery.
      In addition to the observed troponin kinetics, five patients had significant ischaemic changes in ECG recordings.
      • Rajagopalan S.
      • Ford I.
      • Bachoo P.
      • Hillis G.S.
      • Croal B.
      • Greaves M.
      • et al.
      Platelet activation, myocardial ischemic events and postoperative non-response to aspirin in patients undergoing major vascular surgery.
      This work raised fears that peri-operative aspirin resistance might lead to adverse cardiovascular outcome and that preventive measures such as dual platelet inhibition might be warranted in high risk patients.
      Therefore, in the current study, the hypothesis was tested that patients with peri-operative aspirin resistance are at increased risk of the primary endpoint MINS or cardiovascular complications documented as secondary endpoints. No effects were observed on MINS or any of the secondary endpoints. Also, aspirin resistance was not associated with MINS in nine of 10 subgroup analyses. However, in the subgroup of patients with a low RCRI, patients with peri-operative aspirin resistance suffered MINS less frequently. The present authors cannot offer a reasonable underlying mechanism that could explain this surprising finding; it might be just a random observation.
      The present study has some limitations that need to be addressed. About 10% of patients were discharged before POD3, accordingly, the observation period was shortened and data had to be imputed. It is unclear whether factors that differ between aspirin resistant patients and patients without aspirin resistance might interfere with the assay. However, the present authors are not aware of any literature demonstrating that diabetes, leukocyte counts, or smoking would affect the precision of the multiplate assay. Because there were more dropouts than expected, the study did not reach the intended sample size. However, neither a best case nor a worst case scenario, assuming all of the 13 “missing” patients to be in one or the other group, respectively, found a statistically significant association between aspirin resistance and MINS.
      In conclusion, this study has demonstrated that peri-operative aspirin resistance occurred in 27.8% of patients undergoing vascular or endovascular surgery. However, peri-operative aspirin resistance is a phenomenon that does not appear to be related to MINS. Therefore, in patients who continue aspirin medication throughout vascular and endovascular surgery, potential aspirin resistance seems not to be relevant to peri-operative cardiovascular outcome. According to the present results, measuring peri-operative platelet function using the Multiplate analyser with the intention to identify and potentially prevent or treat peri-operative aspirin resistance in vascular and endovascular surgery seems to be dispensable.

      Acknowledgements

      We gratefully acknowledge Manuela Schwegler, Melanie Wickert, and Ute Krauser, Department of Anaesthetics, University of Heidelberg, Heidelberg, Germany for technical and administrative support and help with manuscript editing. We also want to express our gratitude to the BBraun Foundation for their financial support of this project.

      Conflict of interest

      None.

      Funding

      This study was supported by departmental funds, Department of Anaesthetics, University Hospital Heidelberg, Heidelberg, Germany, and by a grant from B. Braun awarded to Sarah Dehne (BBST-D-19–00121R1). The B. Braun Foundation was not involved in the design of the study, collection, analysis, or interpretation of the data.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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      Linked Article

      • Aspirin Mediated Platelet Reactivity Following Vascular Procedures: The Path of Least Resistance is to Ignore it
        European Journal of Vascular and Endovascular SurgeryVol. 64Issue 4
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          Dehne et al. have examined aspirin resistance after vascular intervention in this issue of the European Journal of Vascular and Endovascular Surgery.1 Antiplatelet resistance comes in several forms. It can be genetic, such as a platelet surface receptor mutation, which decreases the ability of a drug to bind and subsequently inhibits platelet function.2 More commonly it can be due to changes in metabolism, such as those seen during the response to surgical trauma, as examined by Dehne et al.1 Patients will also have normal platelet function if they do not take their medication.
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