Author + information
- Received July 19, 2014
- Revision received September 8, 2014
- Accepted September 16, 2014
- Published online December 30, 2014.
- Carla N. Holcomb, MD∗,
- Laura A. Graham, MPH†,
- Joshua S. Richman, MD, PhD∗,†,
- Robert R. Rhyne, BS∗,
- Kamal M.F. Itani, MD‡,
- Thomas M. Maddox, MD, MSc§,‖ and
- Mary T. Hawn, MD, MPH∗,†∗ ()
- ∗Section of Gastrointestinal Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama
- †The Center for Surgical, Medical Acute Care Research and Transitions (C-SMART), Birmingham Veterans Administration Hospital, Birmingham, Alabama
- ‡Department of Surgery, Veterans Affairs Boston Health Care System, Boston University and Harvard Medical School, Boston, Massachusetts
- §Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado
- ‖University of Colorado School of Medicine, Denver, Colorado
- ↵∗Reprint requests and correspondence:
Dr. Mary T. Hawn, Department of Surgery, Section of Gastrointestinal Surgery, University of Alabama, 1922 7th Avenue South, KB 428, Birmingham, Alabama 35294-0016.
Background Recent coronary stent placement and noncardiac surgery contribute to the risk of adverse cardiac events, but the relative contributions of these two factors have not been quantified.
Objectives This research was designed to determine the incremental risk of noncardiac surgery on myocardial infarction (MI) and coronary revascularization following coronary stenting.
Methods A U.S. retrospective cohort study of patients receiving coronary stents at Veterans Affairs medical centers between 2000 and 2010 was used to match patients undergoing noncardiac surgery within 24 months of stent placement to two patients with stents not undergoing surgery. Patients were matched on stent type and cardiac risk factors present at the time of stent placement. A composite endpoint of MI and/or cardiac revascularization for the 30-day interval post-surgery was calculated. Adjusted risk differences (RD) were compared across time periods following stent implantation, using generalized estimating equations.
Results We matched 20,590 surgical patients to 41,180 nonsurgical patients. During the 30-day interval following noncardiac surgery, the surgical cohort had higher rates of the composite cardiac endpoint (3.1% vs. 1.9%; RD: 1.3%; 95% confidence interval: 1.0% to 1.5%). The incremental risk of noncardiac surgery adjusted for surgical characteristics ranged from 3.5% immediately following stent implantation to 1% at 6 months, after which it remained stable out to 24 months. Factors associated with a significant reduction in risk following surgery more than 6 months post-stent included elective inpatient procedures (ΔRD: 1.8%; p = 0.01), high-risk surgery (ΔRD: 3.7%; p = 0.01), and drug-eluting stent (DES) (ΔRD: 1.3%; p = 0.01).
Conclusions The incremental risk of noncardiac surgery on adverse cardiac events among post-stent patients is highest in the initial 6 months following stent implantation and stabilizes at 1.0% after 6 months. Elective, high-risk, inpatient surgery, and patients with DES may benefit most from delay from a 6-month delay after stent placement.
The prevalence of surgical intervention within the 2 years following coronary stent implantation in the U.S. is estimated between 12% and 23% (1–3). Patients with recent coronary stent placement undergoing noncardiac surgery are at increased risk for adverse cardiac events (4–7). The adverse events are partly due to a combination of a patient’s cardiac disease and the body’s stress response to surgery. Important cardiac drivers of adverse event risk include a history of ischemic heart disease, congestive heart failure, and the time between coronary stent implantation and the surgery (2,8,9), while surgical factors implicated include urgency and complexity of the surgical procedure (4). However, the relative contribution of these cardiac and surgical factors to overall postoperative risk, and whether risk changes over time following stenting, are currently unknown. Understanding these contributions to risk would allow for more tailored, effective mitigation strategies, such as antiplatelet and statin therapies to minimize exacerbations of cardiac disease, as well as stable hemodynamic control and postoperative analgesia to minimize the stress of surgery (10). Additionally, the knowledge of which surgical characteristics are associated with the highest risk, especially in the early post-stent period, would improve pre-operative risk assessment and perioperative anesthesia management.
To estimate the relative contributions of surgical and cardiac factors to perioperative adverse cardiac events, we compared event rates in a cohort of post-stent patients undergoing noncardiac surgery to those in a matched cohort of post-stent patients not undergoing surgery to determine the incremental effect of surgery on perioperative events. In addition, we conducted analyses exploring the effect of time between coronary stent implantation and surgery on postoperative cardiac events and determined how this risk differs by surgical procedure type.
Study design and data sources
We performed a matched retrospective cohort study to assess the incremental risk of surgery on postoperative adverse cardiac events following coronary stent implantation. Patients with a coronary stent implanted at Veterans Affairs (VA) medical centers between October 1, 1999, and September 30, 2009, were identified in the VA Patient Treatment Files by International Classification of Diseases-Ninth Edition (ICD-9) procedure codes of 36.06 for bare-metal stent (BMS) or 36.07 for drug-eluting stent (DES). Following the identification of the study cohort, information on noncardiac procedures in the 24 months following coronary stent implantation was obtained from the VA National Surgery Office and the Centers for Medicaid & Medicare Services. Noncardiac surgery was defined by CPT codes, and detailed information on the construction of the study cohort and study variables has been previously published (4). Admission status was defined as elective if a patient was admitted to the hospital from home, and all other admission sources were considered nonelective.
We compared all patients with coronary stents undergoing noncardiac surgery in the 24 months following stent implantation to patients with coronary stents not undergoing subsequent surgery. Each patient undergoing surgery was matched to two patients who did not undergo surgery. Matching was on the basis of patient age, race, stent type (BMS or DES), year of stent placement, each of the six variables included in the revised Cardiac Risk Index (RCRI) (9), and those identified in our previous analyses as significant predictors of major adverse cardiac events, including myocardial infarction (MI) 6 months prior to stent implantation and peripheral vascular disease (4). Patients in the nonsurgical cohort were required to be alive during the time interval following stent placement when their matched counterpart underwent surgery. That is, if a surgical patient had surgery 200 days following stent placement, their two matched nonsurgical patients had to be alive for at least 200 days following their stent placements.
Our primary outcome was a composite endpoint of acute MI and/or coronary revascularization by percutaneous coronary intervention or coronary artery bypass grafting within 30 days following surgery in the surgical cohort or the equivalent post-stent time period for the nonsurgical cohort. We did not include all-cause mortality in our composite endpoint as the cohorts were not matched on probability of death at the time of stent placement. We excluded patients from the study who underwent surgery within 2 weeks following coronary stent placement as it was difficult to attribute an MI to surgery versus an MI associated with receiving a coronary stent on the basis of administrative data.
Assessment of the matched cohort
The matched cohort was compared by univariate and bivariate frequencies to describe patient characteristics and the composite outcome of adverse cardiac events. Bivariate frequencies were compared using chi-square tests and continuous variables were compared using Wilcoxon rank-sum tests. To ensure effective matching on cardiac event outcomes, we calculated the cumulative risk of the composite cardiac endpoint using Kaplan-Meier survival curves comparing time to first outcome by cohort and by stent type.
Assessment of the incremental risk of noncardiac surgery
To determine the incremental risk of surgery on adverse cardiac events, we estimated the risk difference for adverse events in the 30 days following procedure by calculating the rate for the nonsurgical patients during the same 30-day time interval following stent as their matched surgery. For example, in a nonsurgical cohort patient matched to a surgical cohort patient at 370 days post-stent, we only examined adverse cardiac events during the time period of 370 to 400 days post-stent. Unadjusted risk differences and 95% confidence intervals (CI) for all outcomes were determined both overall and stratified by time since coronary stent placement using binomial regression models and incorporating generalized estimating equations (GEE).
Contribution of time post-stent to incremental risk of surgery
We sought to determine how surgical risk for adverse cardiac events changes over time since stent placement. Examination of unadjusted plots strongly suggested that the relationship between cardiac risk and time from stent is nonlinear. To fully understand this, we considered time as a continuous variable in the main analyses. Additional analyses considered timing intervals to simplify clinical interpretation.
To plot changes in risk difference across time as a continuous variable, adjusted risk differences for adverse cardiac events were first determined by calculating a baseline risk of events across time since stent using a generalized additive model. Covariates in the baseline risk model included history of ischemic heart disease, congestive heart failure, cerebral vascular disease, chronic kidney disease, and insulin-dependent diabetes mellitus. Next, the predicted probability of adverse cardiac events for each surgical patient was calculated using a second generalized additive model that adjusted for surgery type, surgery admission status, and work relative value unit as a measure of surgical complexity. The final adjusted risk difference for each surgical case was determined by taking the difference between the baseline risk of the matched nonsurgical patient and the predicted probability of adverse cardiac events following surgery for the surgical patient.
Changes in incremental risk of surgery by time intervals
To test whether specific factors contributed to the reduction in risk by time intervals, we used an interaction term within the GEE model to determine significant changes in risk difference by stent type, procedure type, surgical complexity, and case status across time of coronary stent placement (<6 weeks, 6 weeks to 6 months, and >6 months). Bivariate frequencies and GEE models were completed using SAS version 9.2 (SAS Institute Inc., Cary, North Carolina). Adjusted risk differences were calculated and plotted using R packages MGCV and GGPLOT (11,12).
Matched variables and characteristics of the surgical and nonsurgical cohorts
Of 41,989 surgeries, we matched 49% to two patients in the nonsurgical cohort on the basis of stent type and cardiac risk factors. Differences between the matched and nonmatched surgeries are presented in Online Table 1. On the basis of available VA Clinical Assessment, Reporting, and Tracking Program information, the majority of stents in both cohorts during the study period were first-generation DES (58.0%), with 58.4% sirolimus-eluting and 42.9% paclitaxel-eluting in the surgical cohort versus 55.9% and 44.8% in the nonsurgical cohort, respectively (Online Table 2). Demographics and comorbidities of the surgical and nonsurgical cohort after matching are presented in Table 1. Approximately two-thirds of stents in both cohorts were placed for acute coronary syndromes. The surgical cohort had higher rates of elective stent placement compared with the nonsurgical cohort (33.9% vs. 31.4%). The matched surgical procedures included a broad representation of surgical procedure types and most surgeries were performed at a VA hospital (Table 2). To examine secular trends and evolving stent technology over the study period, we determined the rates of the composite cardiac endpoint by the fiscal year of stent placement (Online Figure 1). Postoperative adverse cardiac event rates remained relatively stable over time for both surgical and nonsurgical cohorts and by stent type. The cumulative incidence of adverse cardiac events over the 24 months following coronary stent placement was similar in both the surgical and nonsurgical cohorts when stratified by stent type indicating that both cohorts were evenly matched on risk for adverse cardiac events (Figure 1). When stratified by stent type, the surgical cohort had lower adverse cardiac event rates compared to the nonsurgical cohort following BMS placement (18.6% vs. 19.0%) but higher rates were observed with DES (16.2% vs. 15.1%) over the 24-month time period.
Thirty-day post-surgical outcomes of the surgical cohort compared to nonsurgical cohort
To better refine the incremental risk associated with surgery, we restricted the comparison to adverse cardiac events occurring in the 30-day interval following surgery for the surgical cohort and the same post-stent period for the matched nonsurgical cohort. We observed higher rates of the composite cardiac endpoint (3.1% vs. 1.9%), MI (2.5% vs. 1.1%), and all-cause mortality (1.4% vs. 0.4%) (all p <0.001) in the surgical population compared with those who did not undergo surgery. There was no difference in revascularization rates (1.1% vs. 1.0%; p = 0.37). The RD for the surgical cohort during the 30-day period following surgery for MI was 1.4% (95% CI: 1.2% to 1.7%) and 1.0% (95% CI: 0.9% to 1.2%) for all-cause mortality compared to the nonsurgical cohort (Table 3).
Incremental risk of noncardiac surgery for adverse cardiac events across time from coronary stent
The 30-day adverse cardiac event rates for both the surgical cohort and nonsurgical cohorts decrease over time as time from stent placement increases (Figure 2A). Rates for both cohorts were highest immediately post-stent and decreased rapidly in the first 6 months regardless of stent type. The risk difference, adjusted for surgical characteristics associated with adverse cardiac events, is plotted in Figure 2B. The adjusted risk difference is highest in the first 6 weeks following stent implantation, decreasing sharply in the first 6 months, and leveling off to 1% for the remainder of the 24 months. This pattern is similar for surgery following DES or BMS implantation.
Incremental risk of noncardiac surgery stratified by <6 weeks, 6 weeks to 6 months, and >6 months
To quantify the incremental risk of surgery over time following stent placement, we stratified 30-day adverse cardiac events post-procedure into three time intervals of <6 weeks, 6 weeks to 6 months, and >6 months from time of stent placement (Table 4). When surgeries were performed in the first 6 weeks following stent placement, the overall rates and associated RDs of the composite cardiac endpoint (9.0%; RD: 2.8%; 95% CI: 0.8% to 4.8%), MI (7.5%; RD: 3.6%; 95% CI: 1.8% to 5.4%), and death (3.2%; RD: 2.5%; 95% CI: 1.4% to 3.6%) were markedly higher compared to the later time intervals. Across the three time intervals, a decreasing trend in the rates and associated RDs was observed for all of the adverse event endpoints, excepting revascularization.
Evaluation of procedure characteristics associated with reduced incremental risk for surgery >6 months post-stenting
Given that the risk for adverse cardiac events associated with surgery was stabilized at 6 months from stent placement, we sought to determine which procedure types would most benefit from delaying surgery until 6 months after stent deployment. Accordingly, we compared the RD between two different stent to surgery time periods: 6 weeks to 6 months and 6 months to 24 months following stent placement. Nonelective surgeries (RD6wk–6mo: 12.3%; RD6mo–24mo: 7.6%), vascular (RD6wk–6mo: 3.8%; RD6mo-24mo: 2.7%), and respiratory (RD6wk–6mo: 3.0%; RD6mo–24mo: 3.3%) procedures confer the highest RD for adverse cardiac events, but risk was not significantly decreased between the two time periods (Table 5). Compared to earlier surgery, digestive procedures (RD6wk–6mo: 4.6%; RD6mo–24mo: 0.9% [p = 0.003]), high-risk surgeries (RD6wk–6mo: 6.5%; RD6mo–24mo: 2.1% [p = 0.01]), and elective inpatient cases (RD6wk–6mo: 3.7%; RD6mo–24mo: 1.9% [p = 0.01]) are associated with a significant decrease in the RD when performed more than 6 months following stent. Surgery performed on patients with a DES more than 6 months from time of placement was associated with a significant decrease in risk difference (RD6wk–6mo: 2.1%; RD6mo–24mo: 0.9% [p = 0.01]), whereas the risk difference for patients with a BMS did not significantly change (RD6wk–6mo: 1.9%; RD6mo–24mo: 1.0% [p = 0.13]). This difference by stent type was still observed after adjusting for procedure characteristics during each time period (DES: p = 0.03; BMS: p = 0.14).
Among patients with coronary stents, both surgical and nonsurgical patients are at highest risk for adverse cardiac events in the early post-stent period. However, when examining discrete 30-day intervals post-surgery, a higher rate of composite cardiac events, MI, and all-cause mortality was observed for the surgical cohort. The incremental risk of surgery was greatest when surgery occurred in the first 6 weeks following stent deployment and decreased to approximately 1% after 6 months, where it remained stable out to 24 months. Procedure characteristics associated with significant reduction in incremental risk after 6 months post-stent included elective, inpatient procedures, and in the setting of a DES.
Previous large cohort studies have reported that rates of postoperative adverse cardiac events are elevated in the first 6 months following coronary stent placement (2,4,8). In the discrete 30-day post-stent time intervals, we observed that approximately 50% of the risk of adverse cardiac events was due to underlying cardiac risk factors and approximately 50% was due to surgical factors. When surgery occurred 6 months after stenting, there was a significant reduction in the incremental risk of surgery for: 1) elective inpatient surgery; 2) complex procedures (as determined by higher work RVU); and 3) high-risk cases as defined by RCRI. When appropriate, these circumstances may benefit most from delay until at least 6 months following stent, whereas minor outpatient procedures were associated with insignificant incremental risk (Central Illustration). Furthermore, although the incremental risk decreased for both BMS and DES, the change was significant only for DES when surgery was more than 6 months after stent placement. Underlying patient conditions inherent to decision-making for BMS placement, not necessarily stent characteristics, likely explain this. These results further refine the incremental risk of noncardiac surgery in patients with coronary stents and how the risk is modulated over time.
Specific risk factors associated with adverse cardiac events after coronary stent placement include age, diabetes, renal failure, congestive heart failure, and recent MI (13–17). These comorbid conditions are important components of the RCRI and used to predict the risk of adverse perioperative cardiac events in patients with coronary artery disease (9). After matching these cardiac risk factors, we found no significant difference in cumulative incidence of adverse cardiac event rates between the surgical population and their nonsurgical matches over the 24 months following stenting. However, mortality rates were significantly higher in the surgical population compared to the nonsurgical population. The similar rate of cardiac events during this time period among both cohorts implies that the difference in mortality is largely accounted for by noncardiac causes of death in the surgical population. The observed increased mortality risk among surgical patients likely reflects the underlying disease processes necessitating a surgery and other noncardiac postoperative complications (18).
Previous studies of post-operative adverse cardiac events have reported similar rates, on the basis of stent type with elevated rates for patients with BMS (2,19,20). A limitation of these observational studies is confounded by indication for stent selection that cannot be adequately controlled in a surgical cohort. In this analysis, we compared the incremental risk of surgery to nonsurgical control subjects matched by stent type. When examining incremental risk by stent type, we found that: 1) the overall adverse event rates were lower in patients with a DES regardless of whether they underwent surgery; 2) the incremental risk of surgery was similar for both stent types in the first 6 months; and 3) the incremental risk of surgery was significantly reduced when surgery occurred more than 6 months following stent placement in patients with DES, but not BMS. These observations provide further evidence that the higher rates of post-surgical adverse cardiac events in patients with BMS are more likely due to the underlying patient conditions that led to BMS selection than the interaction with stent type and surgery. Additionally, these data provide further reassurance that the incremental risk of surgery in patients with DES is minimal, especially when surgery occurred more than 6 months after stenting. The current guidelines for the timing of noncardiac surgery following stent are dictated by stent type. These findings and our previous work (4) suggest that focus should be shifted away from stent type and toward a patient’s cardiac and surgical risk factors when considering the optimal timing of surgery following coronary stent placement.
Several considerations need to be applied to our findings. First, the study sample is comprised primarily of older male patients, thus limiting the generalizability to women or younger men. Second, surgical procedures were distributed over a broad range of procedures, and although this increases generalizability, the overall findings may not apply equally to every subpopulation in this study. Third, patients were matched on the basis of clinical criteria and stent type, but we were not able to include important variables such as the number and length of stents placed at the time of cardiac catheterization (21). Although we did have information on whether stents were placed for acute versus nonacute coronary syndromes, a selection bias does exist for whether patients were chosen to receive BMS or DES. This is evident in our analysis, demonstrating that both the surgical and nonsurgical cohorts with BMS had higher overall adverse cardiac events over the study period. We also did not have information on cardiac function, limiting our ability to further discern important cardiac determinants of adverse postoperative events. These specific limitations mean that unmeasured confounding could explain timing from coronary stent and adverse cardiac events. Fourth, we relied on administrative data to determine our endpoints, which could result in misclassification bias. Fifth, we did not measure the effects of antiplatelet management, including duration or interruptions in therapy. Thus, we cannot infer what association, if any, antiplatelet therapy had on adverse cardiac events over the study period. However, our prior study and others did not find an association between temporary antiplatelet therapy cessation and major adverse cardiac events (4,22,23). Finally, a selection bias exists as we included in the analysis only patients who survived until the time of surgery in both the study and control groups to be able to directly compare 30-day postoperative outcomes. This bias may render lower estimated risks than exists in the entire population with coronary stents.
The incremental risk of noncardiac surgery on adverse cardiac events in patients with coronary stents is related to timing of surgery following stent with the highest risk early post-stent placement and stabilizes by approximately 1%, 6 months after stenting. Elective major inpatient procedures especially in patients with DES were associated with significant reductions in the incremental risk when performed more than 6 months following coronary stent. Accordingly, these surgeries may benefit most from delay beyond 6 months.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with coronary stents undergoing noncardiac surgery are at an increased risk for adverse cardiac events, especially during the first 6 months after stent placement.
TRANSLATIONAL OUTLOOK: Additional studies are needed to provide more granular information about outcomes associated with noncardiac surgery in relation to patient demographics, the number and types of stents deployed, and alternative perioperative strategies for managing antithrombotic therapy.
The VA National Surgery Office and the VA Clinical Assessment, Reporting, and Tracking Program approved the manuscript for adherence to the data use agreements. The opinions expressed are those of the authors and not necessarily those of the Department of Veterans Affairs or the U.S. Government.
This study was supported by Veterans Affairs Health Services Research & Development (grant IIR 09-347). Drs. Maddox and Richman are supported by Veterans Affairs Career Development awards. Dr. Holcomb is supported by the Agency for Healthcare Research and Quality, Rockville, Maryland (grant T32 HS013852-11). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- drug-eluting stent(s)
- myocardial infarction
- revised Cardiac Risk Index
- risk difference
- Received July 19, 2014.
- Revision received September 8, 2014.
- Accepted September 16, 2014.
- American College of Cardiology Foundation
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