Abstract
Contemporary approaches to cardiovascular risk stratification prior to non-cardiac surgery focus on macrovascular atherosclerotic disease and risk factors. We sought to determine the prevalence of microvascular disease (MVD) and its associated perioperative outcomes. Adults ≥18 years old undergoing non-cardiac surgery between 2004–2014 were identified using the Nationwide Inpatient Sample (NIS). Prevalent MVD (retinopathy, neuropathy, and nephropathy) was identified by ICD-9 diagnosis codes. The primary outcomes were all-cause in-hospital mortality and the composite of major adverse cardiac events (MACE; death, myocardial infarction, and ischemic stroke). Multivariable logistic regression models were used to estimate associations between MVD and outcomes after adjusting for demographics and clinical covariates. Among 81,297,003 hospitalizations for non-cardiac surgery, 4,236,932 (5.0%) had a diagnosis of MVD. Patients with MVD were older and more likely to have traditional cardiovascular risk factors. In-hospital perioperative MACE (4.1% vs. 1.9%; adjusted OR [aOR] 1.15, 95% CI 1.13–1.17) and mortality (2.0% vs. 1.1%; aOR 1.15, 95% CI 1.12–1.17) were greater in hospitalizations with MVD compared to those without. Microvascular disease was associated with post-operative outcomes in when stratified by age, sex, and coronary artery disease (CAD). Compared to surgical hospitalizations without CAD or MVD, MVD alone (aOR 1.12; 95% CI 1.11–1.14), CAD alone (aOR 1.44; 95% CI 1.42–1.46), and MVD with CAD (aOR 2.01; 95% CI 1.96–2.06) were associated with perioperative MACE. In conclusion, microvascular disease was present in 1 in 20 hospitalizations for non-cardiac surgery, and was associated with perioperative mortality and MACE independent of macrovascular disease and traditional risk factors.
Keywords: Coronary artery disease, major adverse cardiovascular events, microvascular disease, non-cardiac surgery, perioperative, surgery
Background:
Hospital-based non-cardiac surgery is associated with a ~3% incidence of the composite of death, myocardial infarction (MI), and ischemic stroke, and a 16–20% risk of myocardial injury.1,2 Contemporary approaches to pre-operative cardiovascular risk stratification focus on the identification of macrovascular atherosclerotic disease and traditional cardiovascular risk factors.3–5 The relationship between microvascular disease (MVD) and cardiovascular outcomes of non-cardiac surgery is unknown. Observational data in non-surgical cohorts indicate that MVD is associated with lower extremity amputation and major adverse cardiovascular events independent of traditional cardiovascular risk factors.6–9 In the perioperative setting, MVD may underlie ischemic imbalances that predispose to post-operative tissue injury and myocardial injury after non-cardiac surgery.2,10 Two small studies evaluating associations between MVD and post-operative complications after abdominal surgery report discordant findings.11,12 The aim of the present study was to determine the prevalence of MVD and associated outcomes in a large, nationwide cohort of patients undergoing in-hospital non-cardiac surgery in the United States.
Methods:
Adults ≥18 years old hospitalized for non-cardiac surgery between 2004–2014 were identified from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample (NIS). The NIS includes data from a 20% stratified sample of discharges from all participating hospitals in the United States and represents the largest all-payer database in the United States. Hospitalizations with a principal International Classification of Diseases, Ninth Revision (ICD-9) procedure code for a major therapeutic operating room procedure (HCUP Procedure Class 4) were eligible for inclusion as previously described.1 Principal Clinical Classifications Software (CCS) procedure codes were used to stratify operating room procedures by surgical subtype. Hospitalizations for low risk procedures, such as ophthalmologic surgery and dental surgery, non-operating room procedures, such as radiation therapy, and interventional cardiology procedures and cardiac surgery were excluded. The remaining patients were clustered by major surgical subtype into the following groups: endocrine, general, genitourinary, gynecologic, neurosurgery, obstetric, orthopedic, otolaryngology, skin and breast, thoracic, transplant, and vascular surgery. Patients with prevalent MVD were identified by the presence of microvascular end organ damage, defined as retinopathy, neuropathy, or nephropathy, and identified by the presence of one or more of the following relevant ICD-9 diagnosis codes as previously described (Supplemental Table 1).8 Other clinical covariates were defined using ICD-9 codes and AHRQ comorbidity measures.
The primary outcome was all cause mortality during the index hospital admission for non-cardiac surgery. Secondary outcomes included in-hospital major adverse cardiovascular events (MACE) defined as a composite of all-cause death, myocardial infarction (MI), and acute ischemic stroke. Myocardial infarction was defined based on ICD-9 diagnosis codes for acute ST-segment elevation myocardial infarction (ICD-9 diagnosis codes 410.01 to 410.61, 410.81, and 410.91) and non-ST-segment elevation myocardial infarction (ICD-9 diagnosis code 410.71), as previously described.1 Acute ischemic stroke was defined by ICD-9 diagnosis codes 433.x, 434.x, 436.x, 437.0, and 437.1.13
Continuous variables were reported as means with the standard error of measurement (SEM) and compared using linear regression. Categorical variables were reported as proportions and compared by Chi-square tests. Multivariable logistic regression models were used to estimate odds ratios adjusted for patient demographics, cardiovascular risk factors, comorbidities, and surgical characteristics. Covariates for adjustment included age, sex, race/ethnicity, tobacco use, obesity, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease (CAD), HIV/AIDS, liver disease, end stage renal disease, anemia, drug and alcohol abuse, pulmonary disease, year of surgery, elective hospital admission, and type of non-cardiac surgery. To confirm the validity of the overall study findings, we examined the associations between MVD and outcomes by sex, surgery subtype, and in patients with and without established CAD. We also performed sensitivity analyses in adults ≥45 years of age. Sampling weights were applied throughout the analysis to determine national incidence estimates, including pre-specified clustering and strata, unless otherwise noted. Statistical analyses were performed using SPSS 25 (IBM SPSS Statistics, Armonk, NY). Two-sided P-values <0.05 were considered to be statistically significant. The NIS is a publicly available, deidentified dataset, and the study was exempt from institutional board review.
Results:
A total of 85,533,934 hospitalizations for non-cardiac surgery were identified between 2004 and 2014, among which 4,236,932 (5.0%) had evidence of MVD. The prevalence of MVD among patients by subtype of non-cardiac surgery is shown in Supplemental Table 2. Patients who were hospitalized for non-cardiac surgery with MVD were older (66.4 vs. 53.0 years, p<0.001), less likely to be women (47.0% vs. 65.6%, p <0.001), and had a greater burden of cardiovascular risk factors and comorbidities compared with patients without MVD (Table 1). Patients with MVD were more likely to undergo vascular and orthopedic surgery during the index hospitalization than patients without MVD (Table 1).
Table 1.
Characteristics of adults with and without microvascular disease undergoing non-cardiac surgery.
| Microvascular Disease | ||||
|---|---|---|---|---|
| Variables | Total (n=85,533,934) | Yes (n=4,236,932) | No (n=81,297,003) | p-value |
| Age (Years) | 53.7 (0.11) | 66.4 (0.07) | 53.0 (0.11) | <0.001 |
| Women | 55240321 (64.7%) | 1991841 (47.0%) | 53248480 (65.6%) | <0.001 |
| White Non-Hispanic | 50794523 (59.4%) | 2718946 (64.2%) | 48075576 (59.1%) | <0.001 |
| Black Non-Hispanic | 8197580 (9.6%) | 493973 (11.7%) | 7703607 (9.5%) | <0.001 |
| Hispanic | 7899480 (9.2%) | 290947 (6.9%) | 7608533 (9.4%) | <0.001 |
| Other | 4273864 (5%) | 161158 (3.8%) | 4112706 (5.1%) | <0.001 |
| Unknown | 14368488 (16.8%) | 571907 (13.5%) | 13796581 (17%) | <0.001 |
| Smoker | 15613692 (18.3%) | 964514 (22.8%) | 14649177 (18%) | <0.001 |
| Obesity † | 9258685 (10.8%) | 721179 (17%) | 8537506 (10.5%) | <0.001 |
| Hypertension † | 35051645 (41%) | 3253322 (76.8%) | 31798323 (39.1%) | <0.001 |
| Dyslipidemia † | 17064946 (20%) | 1722099 (40.6%) | 15342846 (18.9%) | <0.001 |
| Diabetes Mellitus | 14279372 (16.7%) | 2622062 (61.9%) | 11657309 (14.3%) | <0.001 |
| Chronic Pulmonary Disease | 11262583 (13.2%) | 869198 (20.5%) | 10393385 (12.8%) | <0.001 |
| End Stage Renal Disease | 1584292 (1.9%) | 289609 (6.8%) | 1294683 (1.6%) | <0.001 |
| Malignancy | 3295430 (3.9%) | 210748 (5.0%) | 3084682 (3.8%) | <0.001 |
| Liver Disease | 1420138 (1.7%) | 126970 (3.0%) | 1293168 (1.6%) | <0.001 |
| HIV/AIDS | 97379 (0.1%) | 9539 (0.2%) | 87840 (0.1%) | <0.001 |
| Anemia † | 12000463 (14%) | 1215288 (28.7%) | 10785175 (13.3%) | <0.001 |
| Drug Abuse | 1233030 (1.4%) | 70157 (1.7%) | 1162873 (1.4%) | <0.001 |
| Alcohol Abuse | 1612624 (1.9%) | 96525 (2.3%) | 1516100 (1.9%) | <0.001 |
| Admission Characteristics | ||||
| Elective Surgery | 48846167 (57.3%) | 1898067 (44.9%) | 46948100 (57.9%) | <0.001 |
| Surgery Type | <0.001 | |||
| General | 17031207 (19.9%) | 637217 (15%) | 16393990 (20.2%) | |
| Endocrine | 871629 (1%) | 23737 (0.6%) | 847892 (1%) | |
| Genitourinary | 5010313 (5.9%) | 246547 (5.8%) | 4763766 (5.9%) | |
| Gynecology | 6292696 (7.4%) | 57164 (1.3%) | 6235532 (7.7%) | |
| Neurosurgery | 4226007 (4.9%) | 182552 (4.3%) | 4043454 (5%) | |
| Obstetric | 14026920 (16.4%) | 15429 (0.4%) | 14011491 (17.2%) | |
| Orthopedic | 26158573 (30.6%) | 1912913 (45.1%) | 24245660 (29.8%) | |
| Otolaryngology | 794954 (0.9%) | 20340 (0.5%) | 774614 (1%) | |
| Skin/Breast | 3120471 (3.6%) | 343154 (8.1%) | 2777318 (3.4%) | |
| Thoracic | 1439441 (1.7%) | 69555 (1.6%) | 1369886 (1.7%) | |
| Transplant | 240253 (0.3%) | 33485 (0.8%) | 206768 (0.3%) | |
| Vascular | 6321470 (7.4%) | 694839 (16.4%) | 5626630 (6.9%) | |
Obesity was defined by ICD-9 codes 278.x. Hypertension was defined by CCS Classification codes 98 and 99. Dyslipidemia was defined by CCS Classification code 53. Anemia was defined according to the AHRQ comorbidity software definition for blood loss or deficiency anemia.
Overall, major adverse cardiovascular events occurred in 2.0% of surgical hospitalizations, and 1.1% of patients died during the surgical admission (Table 2). The incidence of major adverse cardiovascular events (4.1% vs. 1.9%, p<0.001; adjusted OR [aOR] 1.15, 95% CI 1.13–1.17) and in hospital mortality (2.0% vs. 1.1%, p<0.001; aOR 1.15, 95% CI 1.12–1.17) was greater among patients with a diagnosis of MVD compared with those without this diagnosis.
Table 2.
Perioperative major adverse cardiovascular events in adults with and without microvascular disease.
| Microvascular Disease | |||||
|---|---|---|---|---|---|
| Outcome | Total | Yes (n=4,236,932) | No (n=81,297,003) | Adjusted OR (95% CI)* | Adjusted OR (95% CI) † |
| MACE (Death/MI/Stroke) | 1710586 (2.0%) | 172453 (4.1%) | 1538133 (1.9%) | 1.51 (1.49-1.53) | 1.15 (1.13-1.17) |
| Mortality | 977427 (1.1%) | 83305 (2.0%) | 894122 (1.1%) | 1.19 (1.17–1.21) | 1.15 (1.12–1.17) |
| Acute Myocardial Infarction | 492116 (0.6%) | 63404 (1.5%) | 428712 (0.5%) | 2.52 (2.48–2.56) | 1.26 (1.23–1.29) |
| Ischemic Stroke | 405417 (0.5%) | 41417 (1%) | 364001 (0.4%) | 1.14 (1.14–1.14) | 0.97 (0.94–0.99) |
| Cardiac Arrest | 208726 (0.2%) | 20977 (0.5%) | 187749 (0.2%) | 1.29 (1.25–1.34) | 1.21 (1.16–1.25) |
Odds ratio adjusted for age, sex, and race/ethnicity, type of non-cardiac surgery.
Odds ratio adjusted for age, sex, race/ethnicity, tobacco use, obesity, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, HIV/AIDS, liver disease, end stage renal disease, anemia, drug and alcohol abuse, pulmonary disease, year of surgery, elective hospital admission, and type of non-cardiac surgery
CAD: Coronary Artery Disease; MACE: Major adverse cardiovascular events; PAD: Peripheral Artery Disease
Microvascular disease was associated with mortality and MACE in patients with established epicardial CAD (Mortality: 2.2% vs. 2.0%, p<0.001; aOR 1.03, 95% CI 1.01–1.05; MACE: 5.6% vs. 4.7%, p<0.001; aOR 1.06, 95% CI 1.04 – 1.08) and without CAD (Mortality: 1.9 vs. 1.0%, p<0.001; aOR 1.11, 95% CI 1.09–1.13; MACE: 3.4% vs. 1.6%, p<0.001; aOR 1.15, 95% CI 1.13–1.17). Compared to patients without CAD or MVD, MVD alone (aOR 1.12; 95% CI 1.11–1.14), CAD alone (aOR 1.44; 95% CI 1.42–1.46), and MVD with CAD (aOR 2.01; 95% CI 1.96–2.06) were associated with perioperative MACE (Figure 1).
Figure 1.
Odds of perioperative MACE by epicardial coronary artery disease and microvascular disease status.
† Comparison versus MVD- / CAD-, adjusted for age, sex, race/ethnicity, surgical subtype and elective hospital admission.
* Crude unadjusted event rates.
Risks of perioperative MACE in patients with and without MVD are shown by subtype of non-cardiac surgery in Figure 2. Microvascular disease was associated with increased perioperative MACE in general surgery (aOR 1.83, 95% CI, 1.79 – 1.87), endocrine (aOR 1.39; 95% CI 1.12 – 1.73), genitourinary (aOR 1.40, 95% CI 1.32 – 1.49), gynecologic (aOR 1.45, 95% CI 1.19 – 1.78), orthopedic (aOR 1.21, 95% CI 1.18 – 1.24), otolaryngology (aOR 1.48, 95% CI 1.22 – 1.80), and thoracic surgery (aOR 1.25, 95% CI 1.17 – 1.34) after adjustment for demographics and clinical covariates. Associations between MVD and perioperative mortality and MACE were observed among women (mortality: 1.8% vs. 0.8%, aOR 1.17, 95% CI 1.15 – 1.20; MACE: 3.8% vs. 1.4%; aOR 1.21, 95% CI 1.19 – 1.23) and men (mortality: 2.1% vs. 1.7%, aOR 1.10, 95% CI 1.07–1.13; MACE: 4.3% vs. 2.8%; aOR 1.12, 95% CI 1.10–1.14). Finally, in a sensitivity analysis of patients ≥45 years of age, perioperative mortality (2.1% vs. 1.6%; aOR 1.09, 95% CI 1.08 – 1.10) and MACE (4.3% vs. 2.8%, aOR 1.15, 95% CI 1.13 – 1.16) was more common in patients with MVD versus those without MVD.
Figure 2.
Perioperative MACE in patients with and without microvascular disease by subtype of non-cardiac surgery.*
MACE: Major adverse cardiovascular events.
* Crude event rates, unadjusted for demographics and clinical covariates.
Discussion:
In a large United States database of hospital admissions, we identified a significant association between MVD and adverse perioperative outcomes, even after adjustment for traditional risk factors and demographics. The greater frequency of MACE in patients with MVD was observed across most non-cardiac surgical subtypes. In a sub-group analysis of patients with CAD, MVD was shown to be an independent risk factor, augmenting the risk of MACE and mortality post-operatively. These data suggest that MVD is a key non-traditional cardiovascular risk factor that accounts for residual risk in patients undergoing non-cardiac surgery, with the greatest impact among patients at lower baseline cardiovascular risk (i.e. without CAD).
A number of studies have previously shown that inadequate tissue oxygenation, measured indirectly by central venous oxygen saturation, is an independent risk factor for post-operative complications following major surgery.14–16 Small randomized trials suggest that interventions targeting increases in global oxygen delivery reduce post-operative complications and mortality in high-risk surgical candidates.17 Yet, emerging evidence indicates that reassuring global measures of tissue oxygenation may not adequately reflect microvascular perfusion. A study of 25 patients undergoing high-risk abdominal surgeries reported that pre-operative measures of impaired microvascular flow were associated with poor post-operative outcomes, even in patients with preserved global oxygen delivery.12 However, in a similar study of 42 adults undergoing abdominal surgery, no relationship between direct measurements of microvascular circulation and post-operative complications were observed, although event rates in this study were low and no fatalities occurred.11 Adequately powered prospective studies to evaluate the relationship between microvascular function and perioperative outcomes have not been conducted. In larger cohorts of non-surgical patients hospitalized with sepsis, deranged microcirculatory function, measured by sublingual microcirculation, was an independent predictor of outcomes.18,19 Achievement of systemic resuscitation goals did not prevent development of microcirculatory derangements in patients with sepsis.
In the current analysis, we report that clinical evidence of MVD as documented by routine ICD-9 coding is common and associated with mortality and MACE after non-cardiac surgery. MVD was independently associated with adverse surgical outcomes in patients with and without established epicardial CAD. This is consistent with prior reports from non-surgical cohorts.7 This suggests that MVD confers increased perioperative risk independent of and additive to large vessel atherosclerosis. Since the presence of MVD may denote a surgical cohort at excess risk for adverse outcomes, microvascular circulatory diagnostics may aid perioperative risk stratification. Still, the optimal approach to MVD diagnosis and the utility of pre-operative assessment of microvascular function to improve cardiovascular risk-stratification prior to non-cardiac surgery warrants additional confirmation in a large prospective study.
Data from the present study are consistent with associations between ICD-9 coding for MVD and clinical outcomes reported in non-surgical cohorts. In a recent analysis of participants in the Veterans Aging Cohort Study, evidence of MVD was associated with MACE and lower extremity amputation.8 Synergistic effects of MVD and large-vessel peripheral artery disease on adverse outcomes were also reported.8 In a separate non-surgical, cross-sectional cohort study of adults in the Netherlands, albuminuria suggestive of renal MVD was associated with cardiovascular comorbidities, even among non-diabetic and non-hypertensive participants.20 Ultimately, additional efforts to develop therapeutics to improve microvascular function may improve perioperative cardiovascular outcomes.
There are notable limitations of the present analysis. First, data were obtained from a national administrative database of hospital admissions in the United States and may be subject to errors in miscoding and misclassification. Microvascular disease was defined based on an array of previously validated ICD-9 codes. Screening for and documentation of subclinical MVD was limited to that performed for routine clinical care. Second, potentially important clinical laboratory values (including proteinuria, hemoglobin A1c), results of cardiovascular imaging (left ventricular ejection fraction), and perioperative hemodynamic data are not captured in AHRQ administrative databases and could not be reported. Third, the sequence of diagnoses cannot be established in this analysis, although, major adverse cardiovascular events such as myocardial infarction and stroke are typically contraindications to major non-cardiac surgery. Fourth, medications are not documented in the NIS and could not be included in the current analysis. Finally, the NIS is limited to in-hospital outcomes and rates of out-of-hospital cardiovascular complications early after discharge are unknown. Given the inherent limitations of retrospective observational analyses of administrative data, prospective investigation is necessary to further evaluate the relationship between MVD and perioperative outcomes.
In conclusion, in an analysis of a large United States database, MVD was present in 1 in 20 non-cardiac surgical hospitalizations. Patients with MVD were at increased risk of death and perioperative thromboembolic complications independent of macrovascular disease and traditional risk factors. These findings highlight an underappreciated marker of perioperative cardiovascular risk that warrants confirmation in a prospective observational study.
Supplementary Material
Microvascular disease is found 1 in 20 pts undergoing non-cardiac surgery
Microvascular disease patients are older and have more cardiovascular risk factors
Perioperative adverse events are more common in patients with microvascular disease
Risks of microvascular disease are independent of macrovascular coronary disease
Acknowledgments
Disclosures: Dr. Smilowitz is supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number K23HL150315. Dr. Berger is funded, in part, by the National Heart and Lung Blood Institute of the National Institute of Health (R01HL139909 and R35HL144993). The remainder of the authors have no relevant conflicts of interest to disclosure.
Footnotes
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