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Coronary artery disease
Original research
Antiplatelet therapy and long-term mortality in patients with myocardial injury after non-cardiac surgery
  1. Jihoon Kim1,
  2. Jungchan Park2,
  3. Ji-hye Kwon2,
  4. Jong Hwan Lee2,
  5. Kwangmo Yang3,
  6. Jeong Jin Min2,
  7. Sang-Chol Lee1,
  8. Seung Woo Park1 and
  9. Seung-Hwa Lee4
  1. 1Division of Cardiology, Heart Vascular Stroke Institute, Samsung Medical Center, Seoul, South Korea
  2. 2Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Seoul, South Korea
  3. 3Centers for Health Promotion, Samsung Medical Center, Seoul, South Korea
  4. 4Division of Cardiology, Wiltse Memorial Hospital, Suwon-si, Gyeonggi-do, South Korea
  1. Correspondence to Dr Seung-Hwa Lee; shua9999{at}gmail.com

Abstract

Backgrounds Myocardial injury after non-cardiac surgery (MINS) has recently been accepted as a common complication associated with increased mortality. However, little is known about the treatment of MINS. The aim of this study was to investigate an association between antiplatelet therapy and long-term mortality after MINS.

Methods From 2010 to 2019, patients with MINS, defined as having a peak high-sensitivity troponin I higher than 40 ng/L within 30 days after non-cardiac surgery, were screened at a tertiary centre. Patients were excluded if they had a history of coronary revascularisation before or during index hospitalisation. Clinical outcomes at 1 year were compared between patients with and without antiplatelet therapy at hospital discharge. The primary outcome was death, and the secondary outcome was major bleeding.

Results Of the 3818 eligible patients with MINS, 940 (24.6%) received antiplatelet therapy at hospital discharge. Patients with antiplatelet therapy had a significantly lower mortality at 1 year than those without antiplatelet therapy (7.5% vs 15.9%, adjusted HR 0.60, 95% CI 0.45 to 0.79, p<0.001). A risk of major bleeding at 1 year was not significantly different between the patients with and without antiplatelet therapy (6.6% vs 7.6%, adjusted HR 0.85, 95% CI 0.62 to 1.17, p=0.324). In propensity score-matched analysis of 886 pairs, patients with antiplatelet therapy had a significantly lower risk of 1-year mortality (adjusted HR 0.53, 95% CI 0.39 to 0.73, p<0.001) than those without antiplatelet therapy.

Conclusions In patients with MINS, antiplatelet therapy at discharge was associated with decreased 1-year mortality.

  • pharmacology, clinical
  • biomarkers
  • myocardial infarction

Data availability statement

Data are available upon reasonable request. Data of the present study will be provided by SHL upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/openhrt-2023-002318

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Myocardial injury after non-cardiac surgery (MINS), defined as a postoperative cardiac enzyme elevation, is a relatively common complication following non-cardiac surgery. However, little is known about the management of MINS.

    WHAT THIS STUDY ADDS

    • In this large observational study including 3818 patients with MINS, antiplatelet therapy at hospital discharge was associated with decreased 1-year mortality compared with no antiplatelet therapy.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Antiplatelet therapy might improve clinical outcomes of patients with MINS. A large randomised study is needed to confirm this finding.

    Introduction

    Myocardial injury after non-cardiac surgery (MINS) is a heterogeneous disorder that presents as an elevation of cardiac troponin (cTn), regardless of the presence of ischaemic symptoms. Prospective studies indicate that MINS is prevalent, with its incidence rate being as high as 18%.1 2 Moreover, patients with MINS have a sixfold to 10-fold increased risk of 30-day mortality when compared with those without MINS. With the increasing awareness of the high incidence of MINS and its association with poor prognosis following non-cardiac surgery, current guidelines and expert statement emphasise the importance of serial troponin measurements in at-risk patients, such as those aged 65 years or older, or those with known cardiovascular disease or risk factors.3–5 Given that there are over 200 million non-cardiac surgeries conducted annually worldwide,6 the optimal treatment of patients with MINS is crucial during perioperative management, but data are limited.

    Although ischaemic symptoms are present in only a minority of patients with MINS, myocardial ischaemia is suggested as a major cause of cTn elevation after non-cardiac surgery.2 7 Moreover, patients with MINS are known to have a higher prevalence of cardiovascular comorbidities and a greater risk of vascular complications.2 8 9 Recent research has suggested that early intervention with intensified cardiovascular therapies could have long-term benefits for patients with MINS,10 and dabigatran has been shown to reduce the risk of major vascular complications in these patients.11 Therefore, antiplatelet therapy, which is widely used in ischaemic heart disease, may be beneficial for patients with MINS. The substudy of the Perioperative Ischemic Evaluation trial demonstrated that in-hospital use of aspirin improved 30-day mortality in patients with perioperative myocardial infarction (MI).12 That analysis, however, only included a small subset of patients with MINS who had both cTn elevation and ischaemic features.1 2 To date, the association between antiplatelet therapy and long-term outcomes in patients with MINS is not known. Therefore, we sought to compare the 1-year mortality rate according to the presence of antiplatelet therapy at hospital discharge in patients with MINS.

    Methods

    Study population and data acquisition

    The entire data for this study were extracted from Samsung Medical Center Troponin in Noncardiac Operation (SMC-TINCO, KCT0004244) registry. The SMC-TINCO registry is a large single-centre deidentified cohort of 43 019 consecutive patients who had at least one measured high-sensitivity cTn I (hs-cTnI) before or within 30 days after non-cardiac surgery between January 2010 and June 2019 in Samsung Medical Center, Seoul, Republic of Korea. All data in the SMC-TINCO registry were extracted using the ‘Clinical Data Warehouse Darwin-C’, which was built for investigators to search and retrieve deidentified medical records from the electronic archive system. Samsung Medical Center operates a paperless electronic medical record system that contains data of more than 4 million patients with more than 2 million surgeries, 900 million laboratory findings and 200 million prescriptions. In addition, the death of patients in this system is consistently updated and confirmed by the National Population Registry of the Korea National Statistical Office using a unique personal identification number when available. Baseline characteristics of the patients were automatically extracted from preoperative evaluation sheets and organised into a standardised form by independent personnel.

    For this study, we initially identified adult patients who had MINS from the SMC-TINCO registry. MINS was defined as having an elevated hs-cTnI higher than the upper normal limit of 40 ng/L within 30 days after non-cardiac surgery. The exclusion criteria were as follows: (1) patients who had in-hospital mortality; (2) patients who had a history of coronary revascularisation before surgery or during the index hospitalisation; (3) patients who were prescribed warfarin or direct oral anticoagulants at hospital discharge; and (4) patients who did not have any follow-up visits to the hospital after discharge (online supplemental figure 1). Eligible patients were divided into two groups according to the presence of antiplatelet agent prescription at the time of hospital discharge.

    Perioperative management and measurement of troponin I

    Perioperative managements of patients at our institution followed an institutional protocol based on current guidelines. While measuring hs-cTnI levels for non-cardiac surgery is not a routine practice, it is generally recommended for patients undergoing intermediate-risk or high-risk surgery classified by the European Society of Cardiology and the European Society of Anaesthesiology (ESC/ESA) guidelines13 with one of the following: cardiovascular comorbidities, age ≥65 years or abnormal ECG or echocardiography. However, the measurement is at the discretion of attending clinicians. An automated analyser (Advia Centaur XP, Siemens Healthcare Diagnostics, Erlangen, Germany) with highly sensitive immunoassay was used for the hs-cTnI measurement. The lower limit of detection was 6 ng/L, and 40 ng/L of the 99th percentile upper normal limit was provided by the manufacturer.

    Study endpoints

    Study endpoints were compared between the patients with and without antiplatelet therapy at the time of hospital discharge. The primary endpoint was mortality at 1 year from hospital discharge. The secondary outcome was major bleeding at 1 year from hospital discharge. Major bleeding was defined as a bleeding that occurred at a critical site (intracranial, intraspinal, intra-articular, intraocular, pericardial, retroperitoneal or intramuscular with compartment syndrome) based on the International Classification of Diseases, 10th Revision codes (online supplemental table 1)14 15 or a transfusion of 3 or more units of red cells within 24 hours.16 Study endpoints were also evaluated at 30 days from hospital discharge to investigate short-term clinical outcomes.

    Statistical analysis

    Continuous variables were presented as mean±SD or median (IQR) according to normal distribution and analysed using Student’s t-test or the Mann-Whitney U test as appropriate. Categorical variables were analysed using the χ2 test. Event rates were calculated based on Kaplan-Meier censoring estimates and presented with the cumulative incidence, and the log-rank test was used to compare survival curves between groups. Multivariable Cox proportional hazards regression was used to calculate adjusted HR and 95% CI to compare between-group differences with adjustment for age, sex, hypertension, diabetes, current smoking, dialysis, previous stroke, previous heart failure, atrial fibrillation, peripheral artery disease, active cancer (defined as histological diagnosis of cancer within the previous 6 months before surgery),17 emergency operation, general anaesthesia, high-risk surgery by the ESC/ESA guideline,13 operation time, perioperative care in intensive care unit, peak hs-cTnI level, days from surgery to peak hs-cTnI level, days from surgery to discharge, haemoglobin level and presence of thrombocytopenia (platelet count <100 000×106/L) at discharge, and discharge medication of beta blocker, calcium channel blocker, ACE inhibitor (ACEi) or angiotensin II receptor blocker (ARB), or statins. Exploratory subgroup analysis for the primary endpoint using univariable Cox regression analysis was performed.

    To minimise selection bias and control for potential confounding variables, we performed an adjusted analysis using propensity score matching. The propensity score was estimated using a multivariable logistic regression analysis that included all baseline variables and represented the probability of receiving antiplatelet therapy. A 1:1 matching process without replacement was performed using a greedy algorithm with nearest neighbour matching, resulting in 886 matched pairs. Variables were considered balanced between patients with and without antiplatelet therapy after propensity score matching if the absolute value of the standardised mean difference of each variable was <10%.

    All probability values were two tailed, and p values <0.05 were considered statistically significant. R software V.3.6 (R Foundation for Statistical Computing) was used for all statistical analyses.

    Results

    Baseline characteristics

    Of the 35 269 patients who underwent non-cardiac surgery and had postoperative hs-cTnI value, 5875 were diagnosed with MINS (16.7%). Among them, 3818 were eligible for analysis (online supplemental figure 1). Of these 3818 eligible patients, 940 (24.6%) received antiplatelet therapy at the time of hospital discharge. Patients who received antiplatelet therapy were older and more likely to be male and have cardiovascular comorbidities, but had a lower rate of active cancer compared with those who did not receive antiplatelet therapy (table 1). In terms of surgery, patients who received antiplatelet therapy more frequently underwent ESC/ESA high-risk surgery and had longer operation times than those who did not. On the other hand, the rate of emergency surgery was higher in patients who did not receive antiplatelet therapy. Online supplemental table 2 provides details on the types of surgery.

    View this table:
    Table 1

    Baseline characteristics according to antiplatelet therapy at hospital discharge

    The peak hs-cTnI level was not significantly different between the groups (median 115 vs 105 ng/L, p=0.584). At the time of hospital discharge, the prescription rates of beta blocker, calcium channel blocker, ACEi or ARB, and statin were higher in patients who received antiplatelet therapy compared with those who did not.

    After propensity score matching, all variables in baseline characteristics were well balanced between the two groups (table 1).

    Mortality at 1 year after hospital discharge

    Patients who received antiplatelet therapy had a significantly lower risk of mortality at 1 year than those who did not (7.5% vs 15.9%, adjusted HR 0.60, 95% CI 0.45 to 0.79, p<0.001, table 2 and figure 1). Also, in the matched population, the risk of mortality at 1 year was significantly lower in patients who received antiplatelet therapy (7.4% vs 13.4%, adjusted HR 0.53, 95% CI 0.39 to 0.73, p<0.001).

    Figure 1
    Figure 1

    Clinical outcomes at 1 year after hospital discharge. (A) Death in overall population. (B) Major bleeding in overall population. (C) Death in matched population. (D) Major bleeding in matched population.

    View this table:
    Table 2

    Risk of death or major bleeding according to antiplatelet therapy at hospital discharge

    Major bleeding at 1 year after hospital discharge

    The risk of major bleeding at 1 year was not significantly different between patients who received antiplatelet therapy and those who did not (6.6% vs 7.6%, adjusted HR 0.85, 95% CI 0.62 to 1.17, p=0.324, table 2 and figure 1). In the matched population, the risk of major bleeding at 1 year was also not significantly different between the two groups (6.6% vs 5.4%, adjusted HR 1.17, 95% CI 0.78 to 1.74, p=0.447).

    Independent predictors of 1-year mortality and major bleeding in matched population

    In the multivariable Cox model, statin, ACEi or ARB therapy and a higher haemoglobin level at discharge were independently associated with a reduced risk of mortality at 1 year (table 3). Older age, history of active cancer, low platelet count (<100 000×106/L) and longer duration from surgery to peak cTnI and from surgery to discharge were associated with an increased risk of mortality at 1 year.

    View this table:
    Table 3

    Independent predictors for risk of death and major bleeding by multivariable Cox model in matched population

    Emergency surgery, previous stroke and longer duration from surgery to peak cTnI were associated with an increased risk of major bleeding at 1 year.

    Exploratory subgroup analysis

    A lower risk of 1-year mortality associated with antiplatelet therapy was observed consistently across the various subgroups except statin therapy at discharge (p value for interaction=0.033, figure 2).

    Figure 2
    Figure 2

    Subgroup analysis for mortality at 1 year in matched population. ACEi, ACE inhibitor; ARB, angiotensin II receptor blocker.

    Clinical outcome at 30 days after hospital discharge

    The result of 30-day outcomes after hospital discharge was similar to that of 1-year outcomes. Both in overall and matched population, patients who received antiplatelet therapy had a significantly lower mortality at 30 days than those who did not (table 2). The risk of major bleeding at 30 days was not significantly different between the groups.

    Discussion

    The main findings of this study were as follows. First, in patients with MINS, antiplatelet therapy at the time of hospital discharge was independently associated with a decreased risk of mortality at 1 year. Second, there was no significant difference in the incidence of major bleeding between patients with and without antiplatelet therapy. Last, other cardiovascular drugs, such as statins and ACEi or ARB, were also associated with a lower risk of mortality in patients with MINS.

    Antiplatelet therapy is a cornerstone in the prevention and management of ischaemic cardiovascular diseases. Current guidelines recommend antiplatelet therapy as a class I indication in patients with coronary artery disease, unless contraindicated.18 In patients with acute MI, antiplatelet therapy reduces vascular events up to 30% and mortality by 20%.19 Although standard management is also recommended for patients with perioperative MI after non-cardiac surgery,20 there is a lack of evidence for an association between antiplatelet therapy and long-term outcomes. Moreover, the diagnostic criteria of MINS cover a broader pathological area than MI which, by the definition, requires symptoms or objective findings suggestive of actual myocardial loss.21 The diagnostic criteria of MINS only require elevation in cTn as a prognostic indicator.2 8 22 The Vascular Events in Noncardiac Surgery Patients Cohort Evaluation study proposed a sole cTn elevation without a definite non-ischaemic aetiology as a diagnostic criterion of MINS,9 as only 6% of patients with MINS presented typical chest pain.2 Our study demonstrated that despite different clinical presentation from non-operative MI, antiplatelet therapy was associated with improved survival after MINS.

    The beneficial effects of antiplatelet therapy may depend on the aetiology of MINS. Although most patients with MINS do not present ischaemic symptoms, the evidence suggests that myocardial ischaemia remains a main aetiology of MINS, with non-ischaemic causes contributing to 11–14% of cTn elevation after non-cardiac surgery.1 2 9 This explanation becomes clearer when considering the types of MI. Previous studies have demonstrated that antiplatelet therapy has maximal benefit in type 1 MI, which is closely related with fatal perioperative cases. The angiographic registry study suggests that nearly 50% of patients with acute coronary syndrome after non-cardiac surgery showed markers of plaque disruption indicating a type 1 MI.23 Additionally, nearly half of the fatal perioperative MIs were associated with coronary plaque rupture, as shown in the two autopsy studies.24 Furthermore, Ellis et al found that patients with in-hospital death or MI after vascular surgery had more severe and complex coronary artery disease in preoperative coronary angiogram compared with matched patients without death or infarction.25 Based on the aforementioned studies, antiplatelet therapy can be specifically effective on MINS related with coronary plaque disruption and can still lead to improved survival through this mechanism.

    However, robust evidence has shown that type 2 MI, a mismatch between myocardial oxygen supply and demand, is considered as a major mechanism of MINS.7 26 Nevertheless, antiplatelet therapy is thought to play a role in type 2 MI because obstructive coronary artery disease appears to be related also with this type of MI. Multivessel coronary artery disease is generally found in 30–40% of patients with type 2 MI, a rate similar to that in type 1 MI.27 28 In a prospective study where coronary CT was performed before non-cardiac surgery, normal coronary arteries were found in only 4% of the patients who had a perioperative MI, while obstructive or extensive coronary artery diseases were present in 72% of patients.29 Although patients with perioperative MI in the Optical Coherence Tomographic Imaging of Thrombus study had a low incidence of intracoronary thrombus in optical coherence tomographic images, obstructive coronary artery disease was present in 70% and chronic total occlusion in 20% of the study patients.26 Due to the risk of postoperative bleeding, the majority of the patients with MINS may not be suitable for routine coronary catheterisation and subsequent revascularisation requiring dual antiplatelet therapy.30 Therefore, medical treatments such as antiplatelet therapy may play an important role in preventing subsequent adverse events in these patients.1 22

    Subgroup analysis identified a positive interaction between statins and antiplatelet therapy for the risk of mortality at 1 year. This interaction may be due to the strong prognostic implication of statins since statin therapy has been shown to be a protective predictor of mortality.12 In patients receiving statins, which are well-established drugs for improved outcomes in cardiovascular diseases, it is likely that the beneficial effects of antiplatelet therapy could be diluted compared with those not receiving statins. However, this requires further evaluation.

    In our study, the risk of major bleeding was not significantly different between patients with and without antiplatelet therapy. Aspirin, which has the lowest risk of bleeding among antithrombotic agents in patients with MI, was the most frequently prescribed antiplatelet agent in our study.31 Although administration of aspirin before and during non-cardiac surgery is associated with an elevated risk of bleeding at 30 days,32 the risk of bleeding is likely to be lower in patients taking aspirin at the time of hospital discharge when most patients are expected to be recovered from surgical wounds. For example, in the MANAGE (Dabigatran in patients with myocardial injury after non-cardiac surgery) trial, dabigatran, which has a higher potential risk of bleeding than aspirin,33 did not elevate the incidence of life-threatening or major bleeding.11 However, the decision to prescribe antiplatelet agents in patients undergoing non-cardiac surgery should be based on underlying diseases and bleeding risk. A prospective randomised trial is needed to address this issue in postoperative patients.

    We observed the peak troponin levels on average 0.9 days after surgery. These findings are in line with the current consensus that MINS typically occurs within the first three postoperative days.1 4 8

    Our study has several limitations. First, it has the inherent limitations of a non-randomised study. Although the baseline variables were well balanced between patients with and without antiplatelet therapy after propensity score matching, the results could still be affected by unmeasured confounders. Patients who did not receive antiplatelet therapy might have had contraindications for it, such as higher bleeding tendency. However, we presented haemoglobin level and prevalence of thrombocytopenia, which were similar between the two groups. Also, the fact that patients who received antiplatelet therapy were older age and had a higher prevalence of cardiovascular comorbidities favoured the beneficial effects of antiplatelet therapy in our study. Second, cTn measurements were not routinely performed but were at the discretion of clinicians. Detailed information on ischaemic or non-ischaemic features was not accessed due to the lack of information on symptoms, ECG and imaging modalities in patients with cTn elevation. Although the incidence of MINS in the SMC-TINCO registry was similar to previous prospective registries systematically collecting cardiac enzymes,1 2 the application of our results to general practice should be based on the underlying cause and clinical judgement. Last, the types of non-cardiac surgery were described but were not adjusted for analysis. Given the numerous types of surgeries, such as those involving different location, organ, unilateral or bilateral procedures and causes of surgery, we classified non-cardiac surgeries based on their ESC/ESA risk category, use of general anaesthesia, emergency status and operation time. Therefore, our results should be interpreted based on the individualised characteristics of the surgery.

    Despite its limitations, our study has the largest sample size of patients with elevated cTn after non-cardiac surgery and suggests a potential benefit and clinical safety of antiplatelet therapy in this population. Future well-designed randomised studies are needed to confirm our results.

    Conclusions

    Among patients presenting elevated hs-cTnI after non-cardiac surgery, antiplatelet therapy at hospital discharge was associated with a decreased risk of 1-year mortality without a significant increase in major bleeding. Large randomised trials are needed to confirm this finding.

    Data availability statement

    Data are available upon reasonable request. Data of the present study will be provided by SHL upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The Samsung Medical Center Institutional Review Board approved this study and waived the requirement for written informed consent for access to the registry.

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    Footnotes

    • JK and JP contributed equally.

    • Contributors JK and SHL designed the study. JP collected the data. JK, JP and SHL verified the analytical methods and wrote the manuscript. J-hK, JHL, KY, JJM, S-CL and SWP supervised the findings of this work. All authors discussed the results and contributed to the final manuscript. SHL is responsible for the overall content as the guarantor.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.