C L I N I C A L F E AT U R E S
Perioperative Cardiovascular Medicine: An Update of the Literature 2013–2014
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DOI: 10.3810/hp.2014.10.1149
Barbara A. Slawski, MD, MS 1 Steven L. Cohn, MD 2 Kurt J. Pfeifer, MD 1 Suparna Dutta, MD, MBA 3 Amir K. Jaffer, MD 3 Gerald W. Smetana, MD 4 Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital Clinical Cancer Center, Milwaukee, WI; 2University of Miami Miller School of Medicine, Miami, FL; 3 Rush Medical College, Chicago, IL; 4 Harvard Medical School, Division of General Medicine and Primary Care, Boston, MA 1
Abstract: Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, cardiology, and hospital medicine. A multispecialty team approach that ensures the best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. Staying current in this multidisciplinary field is difficult, because physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, the authors performed a focused review of this literature published in 2013 and early 2014. In this update, key articles are reviewed that potentially impact clinical practice in perioperative cardiovascular risk prediction and risk management. Keywords: perioperative cardiovascular medicine; risk reduction; major adverse cardiac event; preoperative care; postoperative complications
Introduction
Cardiac complications are a frequent cause of postoperative morbidity and mortality.1,2 As the surgical population becomes older and more medically complex, reliable perioperative cardiac risk stratification continues to gain importance. Prediction of risk and opportunities to mitigate the risk of adverse perioperative cardiovascular events are key in the practice of perioperative medicine. Multiple recent studies have addressed perioperative cardiovascular evaluation and outcomes. Knowledge of this literature provides additional guidance to physicians in multiple specialties who provide care to the surgical patient. This article addresses recent advances in perioperative cardiovascular medicine. For a complete overview of general perioperative evaluation and management of patients undergoing noncardiac surgery, refer to the recently released 2014 American College of Cardiology/American Heart Association (ACC/ AHA) guidelines.3
Methods Correspondence: Barbara Slawski, MD, MS, FACP, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital Clinical Cancer Center, 9200 W Wisconsin Ave, Suite 5400, Milwaukee, WI 53226. Tel: 414-805-0840 E-mail: [email protected]
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This summary of recent literature is derived from the “Update in Perioperative Medicine” presented at the 9th Annual Perioperative Medicine Summit and the Society of General Internal Medicine 37th Annual Meeting.4,5 A Medline search of the relevant literature from January 2013 through April 2014 was performed using the medical subject heading (MeSH) terms preoperative care, intraoperative care, perioperative care, postoperative care, preoperative period, intraoperative period, intraoperative complications, postoperative complications, and noncardiac surgery. Pediatric and cardiac surgeries were excluded from the literature review.
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Perioperative Cardiovascular Medicine
Articles relevant to perioperative cardiovascular medicine were selected. Final articles were selected by expert consensus based on relevance to the clinical practice of perioperative medicine.
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Prediction of Perioperative Cardiovascular Risk
To assist with prediction of perioperative mortality and complications, multiple surgical risk calculators have been created.6–10 These tools are useful to physicians and patients when making decisions about the potential risks and benefits of an anticipated surgery. Several recent studies have also demonstrated the strong prognostic value of biomarkers when obtained before and/or after surgery. Furthermore, studies also show that these cardiac biomarkers allow for improved cardiac risk stratification when added to clinical risk assessment tools.
Perioperative Risk Indices
In a recent study using data from 1 414 006 patients at 393 hospitals in the American College of Surgeons National Surgical Quality Improvement Program database, Bilimoria et al11 developed a universal surgical risk estimation calculator and compared its performance with previous risk calculators. Twenty-one preoperative risk factors, including the type of procedure, patient demographics, and several specific comorbidities, were selected for inclusion in the risk calculator. There were no restrictions based on type of surgery. A surgeon risk adjustment score was also incorporated into the tool to permit individual providers to adjust for preoperative risks that may not be captured by the tool (ie, to adjust the risk up or down from the calculated estimate). A regression model had excellent performance at predicting mortality (C statistic = 0.94) and morbidity (C statistic = 0.82), and 6 additional complications. The performance was similar in procedure-specific risk calculators. The authors then developed a Web-based tool to calculate estimates of postoperative mortality, any complication, pneumonia, cardiac complications, surgical site infection, urinary tract infection, venous thromboembolism, renal failure, and serious complications. The online calculator (http:// riskcalculator.facs.org/) also provides an estimated hospital length of stay. This Web-based tool using high-quality clinical data and a large number of patients is easily accessible, functional, and provides practical information that can be used by physicians and patients for shared preoperative decision making.
The revised cardiac risk index (RCRI) score is another widely used tool that predicts rates of major cardiac complications for patients undergoing noncardiac surgery. The validated index includes 6 preoperative risk factors: highrisk surgery, history of ischemic heart disease, history of congestive heart failure (CHF), history of cerebrovascular disease, insulin treatment for diabetes, and serum creatinine level greater than 2 mg/dL. Although all 6 risk factors were included in the original model, insulin use for diabetes and creatinine level . 2 mg/dL were not significant risk factors in a subsequent validation cohort.12 In a new study, Davis et al13 sought to examine the importance of these 2 discordant predictors in the original RCRI criteria. Eligible subjects (n = 9519) were patients aged . 50 years who underwent elective noncardiac surgery with an expected length of stay of $ 2 days. The overall rate of cardiac complications was not significantly different between the original study by Lee et al12 and the new data set.13 When the original model was recalculated as a 4-factor model that eliminated insulin therapy for diabetes and preoperative creatinine level . 2 mg/dL, the rates of major cardiac complications were essentially unchanged. The authors created a revised 5-factor RCRI score that included high-risk surgery, ischemic heart disease, stroke history, CHF history, and estimated glomerular filtration rate , 30 mL/min. This score was a better predictor of postoperative major cardiac complications than the original RCRI score and improved calibration compared with the original model. Limitations of this study include lack of universal monitoring for postoperative myocardial infarction (MI) and differences between the original RCRI and current study data sets.
Cardiac Biomarkers
In addition to risk calculators, preoperative elevation of natriuretic peptides (NPs) strongly correlates with postoperative mortality and adverse cardiac events,14 but the value of measuring these biomarkers in the postoperative period is less clear. Rodseth et al15 performed a systematic review and individual patient data meta-analysis to clarify the prognostic utility of NPs obtained in the first week after noncardiac surgery. The authors identified 18 eligible studies (all prospective cohort studies) with a total of . 2000 patients for which they were able to obtain individual patient information on age, sex, postoperative brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) values, RCRI score, surgery characteristics, and 30-day and $ 180-day incidence of mortality and major adverse cardiac events (MACEs). The authors categorized
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Slawski et al
patients’ risk for 30-day mortality or nonfatal MI (, 5%, 5%–10%, . 10%–15%, . 15%) based on age, RCRI score, and type of surgery. Using cutoff values previously validated for acute heart failure diagnosis (BNP level # 250 or . 400 pg/mL and NT-proBNP level # 300 or . 900 pg/mL), they determined the adjusted odds ratio (AOR) for mortality and MI and reclassified patients’ estimated 30-day risk based on their measured NP levels. Results from this systematic review revealed a strong correlation between postoperative BNP and NT-proBNP levels and 30-day mortality and nonfatal MI.15 Patients with an NT-proBNP level of 901 to 3000 pg/mL had an AOR of 4.7 (95% CI, 1.62–13.37), and at a level of . 3000 pg/mL had an AOR of 12.5 (95% CI, 2.85–54.89). The AOR for a BNP level of 251 to 400 pg/mL was 2.5 (95% CI, 1.39–4.49), and for a BNP level of . 400 pg/mL it was 5.9 (95% CI, 3.71–9.26). When applied to clinical estimates, BNP levels with a high-risk cutoff value of $ 245 pg/mL and NT-proBNP levels with a high-risk cutoff value of $ 718 pg/mL also significantly improved risk categorization of patients, with a net reclassification index of 20% (P , 0.001). The improvement of risk classification was greatest among patients in intermediate-risk categories (5%–10% and . 10%–15%). In these groups, 46% of patients with 30-day mortality or nonfatal MI were reclassified as high risk because of an elevated postoperative BNP or NT-proBNP level, and 25% of patients without an adverse cardiac event were reclassified into a lower-risk category. This well-designed meta-analysis provides another piece to the puzzle of cardiovascular risk mitigation. Not only do postoperative NP levels predict 30-day mortality and cardiac events, they also seem to have greatest utility when used for most patients with intermediate risk based on clinical estimates. However, one of this study’s few limitations was its lack of adjustment for postoperative troponin and preoperative BNP levels, thus leaving the question unanswered of how correlation with these might alter risk assessment. Applying methodology similar to their earlier work with postoperative NPs, Rodseth et al16 sought to determine the additive benefit of postoperative (drawn , 8 days after surgery) and preoperative BNP or NT-proBNP measurements for predicting mortality and nonfatal MI at 30 and $ 180 days after noncardiac surgery. For this systematic review, 18 studies with individual patient data for 2179 patients were included in the meta-analysis. The authors estimated clinical risk using a model that incorporated age, RCRI score $ 3, and surgery characteristics (urgency and vascular vs nonvascular). High-risk cut-points for preoperative BNP and 128
NT-proBNP levels were derived from statistical analysis of the correlation of preoperative values to the combined postoperative outcome of death or nonfatal MI at 30 days after surgery. Using these and the postoperative high-risk cutoff values defined in their previous study (BNP $ 245 pg/mL and NT-proBNP $ 718 pg/mL),15 preoperative and postoperative NP values were added to the clinical risk estimation model to assess their impact on optimal risk classification. The threshold values for preoperative BNP and NTproBNP that were most predictive of 30-day mortality and nonfatal MI were 92 and 300 pg/mL, respectively. Using these cutoffs for high-risk classification, the addition of preoperative NP level to the clinical risk model significantly improved risk prediction, with a 31.6% net reclassification improvement. Adding postoperative NP levels to the model additionally improved classification of 20.2% of the patients; this was primarily due to reassignment to higher-risk categories because of elevated NP levels. The final model that combined clinical risk factors and preoperative and postoperative NP levels accurately predicted both 30- and $ 180-day mortality and nonfatal MI (P , 0.001 for both). Postoperative NP elevation, RCRI score $ 3, and preoperative NP elevation were the strongest independent predictors. The change in preoperative to postoperative NP levels did not correlate with death or MI at 30 days after surgery. This second rigorous meta-analysis by Rodseth et al16 adds to the evidence base supporting the benefit of adding BNP or NT-proBNP measurement to clinical risk estimation. This study does not address correlation of NP levels and cardiac outcomes with postoperative troponin levels, specifically troponin elevations not meeting diagnostic criteria for MI. A growing body of literature has demonstrated a strong association between postoperative troponin elevation, death, and adverse cardiovascular events. These findings include troponin elevations that do not meet the universal diagnostic criteria for MI: elevated troponin with either symptoms or electrocardiogram findings consistent with ischemia.17 The Vascular events In noncardiac Surgery patients cOhort evaluation (VISION) study previously published data showing that even small increases in troponin T (TnT) were independent predictors of 30-day mortality.18 However, this initial data analysis only followed troponin levels for 3 days after noncardiac surgery and did not account for the potential contribution of other postoperative complications or nonischemic causes of TnT elevation. By controlling for these factors, the current study by the VISION Writing Group aimed to define and characterize postoperative troponin elevations resulting
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Perioperative Cardiovascular Medicine
from myocardial ischemia, a condition termed myocardial injury after noncardiac surgery (MINS).19 The VISION study is an international, prospective cohort study of . 15 000 patients undergoing noncardiac surgery that assessed clinical outcomes and TnT levels on each of the first 3 postoperative days.19 Study personnel also tracked additional TnT levels obtained by providers in the first 30 days after surgery and determined whether troponin elevations were related to nonischemic causes, such as sepsis and pulmonary embolism. From these data, the authors of the VISION study determined that a peak TnT level of 0.03 ng/mL or higher, regardless of other ischemic findings, was a strong independent predictor of 30-day postoperative mortality and was designated as the diagnostic criterion for MINS. Among patients with MINS, 84.2% did not experience ischemic symptoms and 58.2% had no ischemic symptoms or electrocardiogram findings. Risk factors for developing MINS included age . 75 years, known cardiovascular disease, traditional cardiovascular risk factors (eg, hypertension and diabetes), and urgent or emergent surgery. Patients with MINS had significantly increased rates of heart failure (HF), stroke and cardiac arrest; the 30-day mortality rate was 9.8% compared with 1.1% in those without MINS. Perhaps most striking was the authors’ calculation of the proportion of all postoperative mortality potentially attributable to specific risk factors (ie, population-attributable risk). For all independent risk factors studied, MINS had the highest population-attributable risk at 34% (95% CI, 26.6–41.5), meaning that more than one-third of postoperative mortality was associated with elevated troponin levels. The VISION study has provided invaluable insight into the prognostic importance of postoperative troponin elevations. In this publication,19 the authors define the risk cutoff for TnT level at $ 0.03 ng/mL and confirm that the risks associated with MINS are significant and not dependent on concomitant ischemic findings. Most importantly, waiting for ischemic symptoms to trigger evaluation for myocardial injury misses . 80% of patients with MINS, a condition that may be attributable to one-third of postoperative deaths. Whether treatment based on the finding of MINS actually reduces mortality is unknown. Therefore, measurement of troponins before surgery (when interventions have the potential to prevent MINS) has gained increasing attention in the perioperative community. Elevations in newer, high-sensitivity troponin assays have been associated with increased mortality and adverse cardiac events, even in patients without apparent cardiovascular disease.20 However, few data are available on the
predictive value of preoperative troponin elevations. Nagele et al1 theorized that high-sensitivity troponin T (hs-TnT) obtained preoperatively may predict postoperative mortality and MI. To explore this question, the authors conducted a prospective cohort study within the VINO (Vitamins in Nitrous Oxide) trial.1 The VINO trial is a single-center, doubleblind, randomized, controlled trial investigating the impact of nitrous oxide on cardiac events in . 600 patients with coronary artery disease or multiple risk factors for coronary disease. In this study, electrocardiogram, troponin I (TnI), and hs-TnT were obtained within 2 hours before surgery, within 30 minutes of the end of surgery, and in the morning on postoperative days 1 through 3. Acute MI (defined as TnI elevation with ischemic symptoms and/or ischemic electrocardiogram changes) and TnI elevation within 72 hours after surgery were the primary outcomes; TnI elevation was classified as a peak level . 99th percentile ($ 0.07 mcg/L). Before surgery, 98.5% of patients had detectable levels of hs-TnT and 41% had levels . 99th percentile ($ 14 ng/L). When TnI was measured, only 13% of patients had detectable preoperative levels and only 4% had values . 99th percentile. In this higher risk study population, 13% had a postoperative TnI $ 0.07 mcg/L, and 5% met diagnostic criteria for MI. A preoperative hs-TnT . 14 ng/L was associated with a significantly increased probability of postoperative TnI elevation (odds ratio [OR], 3.33; 95% CI, 2.04–5.43; P , 0.001), postoperative MI (OR, 3.67; 95% CI, 1.65–8.15; P = 0.001), and 3-year mortality (adjusted hazard ratio [HR], 2.11; 95% CI, 1.26–3.53; P = 0.004). Preoperative hs-TnT $ 12 ng/L had a sensitivity of 73% and specificity of 52% for predicting postoperative MI, whereas detectable preoperative TnI (. 0.04 mcg/L) had a sensitivity of 20% and specificity of 92%. The work of Nagele et al1 provides useful insights into the perioperative utility of troponin levels. First, preoperative hs-TnT abnormalities are very common, and therefore if hsTnT levels are to be used to diagnose acute myocardial injury after surgery, preoperative and postoperative values must be compared to detect a change. Second, among patients with higher cardiovascular risk, a preoperative hs-TnT . 14 ng/L is associated with a 3.67-fold increased risk of postoperative MI and a 2-fold increased risk of 3-year mortality. Lastly, a preoperative hs-TnT cutoff of $ 12 ng/L provides a sensitive yet fairly specific assessment for postoperative cardiac complications. To determine the comparative and additive value of NTproBNP, hs-TnT, and the RCRI, Weber et al21 conducted
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a multicenter, observational study of 979 patients undergoing noncardiac surgery. Study patients were all aged . 55 years and had $ 1 cardiovascular risk factor (diabetes, hypertension, hyperlipidemia, smoking, or family history of heart disease). The primary endpoints of the study were mortality and a combined endpoint of mortality, acute MI, cardiac arrest, ventricular fibrillation, cardiopulmonary resuscitation, and acute HF. In this study, 24% of patients had a preoperative hsTnT . 14 ng/L, and 34% had an NT-pro-BNP $ 300 pg/mL. The median length of hospitalization was 11 days; 2.6% of patients died and 3.7% experienced the combined endpoint during their postoperative hospital stay. Revised cardiac risk index score, preoperative hs-TnT . 14 ng/L, and preoperative NT-proBNP $ 300 pg/mL all strongly correlated with postoperative cardiovascular events and mortality. In a regression analysis, hs-TnT . 14 ng/L was the strongest independent predictor for both in-hospital death and the combined endpoint, and when added to RCRI score provided improved prediction of both (although not statistically significant for the combined endpoint). The addition of NT-proBNP to RCRI score did not significantly improve risk estimation. For a given RCRI score, hs-TnT . 14 ng/L helped restratify patient risk. For instance, with an RCRI score of $ 2, approximately 4.7% of patients died during postoperative hospitalization. In this same group, those with a preoperative hs-TnT # 14 ng/L had 2.3% mortality, whereas those with an hs-TnT . 14 ng/L had 8.7% mortality.21 This study is the first to investigate the incremental value of both preoperative hs-TnT and NT-proBNP when added to the mainstay of cardiovascular risk assessment tools, the RCRI. Although the study was limited by the low number of observed outcomes and short follow-up, its findings that preoperative hs-TnT and NT-proBNP elevations are common and associated with increased morbidity and mortality are consistent with those of other literature discussed earlier, suggesting that the findings are valid. The biggest take away from this study is that hs-TnT seems to be superior to NTproBNP for cardiovascular risk prediction and significantly reclassifies risk assessment based on RCRI score alone. These studies provide powerful prediction tools that are limited to specific surgical groups and are noted to be validated risk-prediction tools in recent cardiovascular guidelines.3,22 The cardiac biomarker studies provide even more evidence that biomarkers are strong predictors of postoperative morbidity and mortality, and provide incremental prognostic value when combined with clinical risk prediction tools. Given the lack of data on how the results 130
of perioperative cardiac biomarker testing can influence outcomes, clinicians must use troponins and NPs with care, and, before ordering, have a clear plan for how the results will alter their management.23
Perioperative Cardiovascular Risk Reduction: β-Blockers and Clonidine
The effectiveness and safety of perioperative b-blockers for patients undergoing noncardiac surgery remain controversial. Early studies showed a benefit in reducing perioperative ischemia, myocardial infection, and mortality; however, subsequent larger studies showed no benefit. The largest trial, the PeriOperative Ischemic Evaluation study (POISE), found a reduction in MI, but at the expense of increased strokes and overall mortality.23 Some of these differences may be from the specific β-blocker used, whether the dose was titrated to control heart rate, and the timing of administration before surgery. More recently, the validity of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo (DECREASE) trials has been questioned because of concerns regarding academic integrity of the work.24 The articles discussed, although not randomized controlled trials (RCT), provide further insight into this controversy, highlighting outcome differences among the b-blockers based on their selectivity. The last article in this section is a RCT evaluating clonidine as an alternative to β-blockers. An observational study by Andersson et al25 investigated the association of perioperative β-blocker use with 30-day risk of MACEs and all-cause mortality in 28 263 patients with ischemic heart disease undergoing noncardiac surgery. β-Blocker use was defined as having filled an outpatient prescription within 4 months before surgery. In the 7990 patients with HF, β-blocker use was associated with a substantially reduced risk of MACE (HR, 0.78; 95% CI, 0.66–0.91) and all-cause mortality (HR, 0.82; 95% CI, 0.70–0.95). In patients without HF but with an MI in the past 2 years, β-blockers were also associated with a significant reduction in MACE (HR, 0.54; 95% CI, 0.37–0.78) and a nonstatistically significant trend toward lower mortality (HR, 0.80; 95% CI, 0.53–1.21). No benefit from b-blockers was seen in patients who had an MI . 2 years before, no prior MI, or no prior history of HF. Results were similar for propensity score–matched subgroups with HF. Patients without HF or with an MI , 2 years before only showed a nonstatistically significant trend toward a benefit. Limitations include not knowing when or whether a patient took the b-blocker perioperatively and not performing routine postoperative troponins or electrocardiograms.
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Perioperative Cardiovascular Medicine
London et al26 evaluated b-blocker exposure on the day of or after major noncardiac surgery in 136 745 patients in Veterans Administration Medical Centers from 2005 to 2010. Propensity-matched patients (37 805 pairs) were evaluated for 30-day total mortality, cardiac arrest, and Q-wave MI. Overall, b-blocker exposure was greater in patients undergoing vascular surgery and in those with higher RCRI scores. Although exposure in the overall group was associated with a higher mortality and stroke risk, in the propensity-matched cohort it was associated with a lower mortality (relative risk [RR], 0.73; 95% CI, 0.65–0.83; P , 0.001; number needed to treat [NNT], 241); a lower rate of MI and cardiac arrest (RR, 0.67; 95% CI, 0.57–0.79; P , 0.001; NNT, 339), but only in those undergoing nonvascular surgery; and no difference in stroke risk (0.35% vs 0.32%). When stratified by RCRI score, patients with $ 2 risk factors had a lower mortality (RR, 0.63, 0.54, and 0.40 with 2, 3, or 4 or more factors, respectively, all with P , 0.001). Metoprolol seemed to have a stronger association with mortality and stroke than did atenolol, although the metoprolol group was more likely to have ischemic heart disease and prior cerebrovascular disease. Limitations include not performing routine postoperative surveillance with troponins and electrocardiograms and only including Q-wave MIs. A retrospective cohort study of 44 092 patients undergoing noncardiac, nonneurologic surgery at the University Health Network in Toronto from 2003 to 2010 by Ashes et al27 compared stroke risk for patients taking bisoprolol versus less selective b-blockers (metoprolol, atenolol). The primary outcome was stroke within 7 days of surgery; a secondary outcome was a composite of all-cause mortality, postoperative myocardial injury, and stroke. The authors classified b-blocker use based on databases from the preoperative assessment and the in-patient pharmacy, and it represented in-patient exposure that was predominantly chronic. Stroke occurred in 88 of 10 756 patients (0.2%); in a matched cohort of 2462 patients, bisoprolol was associated with fewer strokes than the less selective agents (OR, 0.20; 95% CI, 0.04–0.91). The incidence of stroke in patients on no b-blocker, bisoprolol, atenolol, and metoprolol was 0.10%, 0.16%, 0.35%, and 0.62%, respectively. Two-thirds of the strokes occurred in the first 72 hours. Similar to the POISE trial, independent risk factors for stroke included a history of cerebrovascular disease and perioperative transfusion. In the setting of acute anemia with a hemoglobin , 9 gm/dL, all b-blockers were associated with an increased risk of stroke. The authors postulated that inhibition of β2-mediated cerebral vasodilation, which occurs at all hemoglobin levels with the nonselective
β-blockers, may be responsible for the increased stroke risk with metoprolol. β1-selective antagonists may better preserve peripheral circulation and vital organ perfusion in the setting of anemia and hypotension. Metoprolol was also associated with a higher rate of secondary outcome events. Limitations include lack of complete hemodynamic data to assess the effect of intraoperative hypotension, incomplete capture of β-blocker use by the databases, and a secular shift to more use of bisoprolol for unclear reasons during the study period. To assess the association of perioperative stroke and β-blocker use, Mashour et al28 retrospectively reviewed neuroimaging records of 57 218 patients who underwent noncardiac nonneurologic surgery in the University of Michigan Health System from 2003 to 2009. Perioperative stroke (within 30 days) occurred in 55 patients (0.09%) and was associated with increased short-term and long-term mortality (OR, 17.8 and 5.4, respectively). Most strokes (71%) occurred within 9 days of surgery. Metoprolol was associated with a 4.2-fold increase in risk of stroke (95% CI, 2.2–8.1; P , 0.001), whereas other β-blockers did not influence stroke rates. Intraoperative intravenous metoprolol use was also associated with a 3.3-fold increased risk (95% CI, 1.4–7.8; P = 0.003). No similar association existed with intravenous esmolol and labetalol. Matched cohort analysis revealed an increased stroke risk in those taking metoprolol compared with atenolol (0.3% vs 0; P = 0.016), but not in the overall (unmatched) population, possibly because it was a large diverse group. Independent predictors of postoperative stroke in the entire population included history of atrial fibrillation and prior stroke or transient ischemic attack. Limitations include a low event rate and relatively low use of β-blockers; use of in-hospital imaging records, which might miss strokes after discharge; and lack of compliance and dosing data. Dai et al29 assessed the effects of various β-blockers and the timing of treatment on postoperative outcomes. The authors performed a meta-analysis of 8 trials including 11 180 patients undergoing noncardiac surgery, of whom 5547 received β-blockers perioperatively. Perioperative β-blocker therapy was associated with a significant decrease in risk of developing postoperative MI (RR, 0.73; 95% CI, 0.61–0.86) but a significant increase in risk of developing stroke (RR, 2.17; 95% CI, 1.35–3.50) versus placebo. A nonsignificant decrease was seen in overall mortality (RR, 0.91; 95% CI, 0.60–1.36). This was driven by the large number of subjects in the POISE trial. Although no head-to-head trials were performed with different β-blockers, indirect comparisons demonstrated that perioperative atenolol therapy
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was associated with lower mortality and incidence of MI. Additionally, the authors noted that β-blocker therapy initiated . 1 week (vs , 1 week) before surgery was associated with improved postoperative mortality. In view of the uncertainties surrounding perioperative β-blockers, Devereaux et al and the POISE-2 Investigators30 aimed to determine if clonidine, which blunts the activity of the sympathetic nervous system, could reduce the risk of perioperative MI and death within 30 days of surgery. POISE-2 was a blinded 2x2 factorial randomized clinical trial evaluating the use of clonidine, aspirin, both, or neither in 10 010 patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. At 2 to 4 hours before surgery, patients received either 0.2 mg of clonidine orally and a transdermal patch (0.2 mg/d) or placebos, and also received aspirin or placebo. Vital signs were monitored every 4 hours for 96 hours postoperatively, and troponins were drawn 6 to 12 hours after surgery and daily for 3 days. Electrocardiograms were ordered if troponins were elevated. Clonidine did not decrease the composite outcome of death or nonfatal MI (7.3% vs 6.8%; HR, 1.08; 95% CI, 0.93–1.26; P = 0.29), but more patients in the clonidine group experienced a nonfatal cardiac arrest (15 vs 9; HR, 3.2; 95% CI, 1.17–8.73; P = 0.02). Clinically significant hypotension and bradycardia occurred significantly more often in the clonidine group, but no difference in strokes was seen. In contrast to a previous systematic review of alpha-2 adrenergic agonists,31 the authors of POISE-2 found no overall benefit among patients undergoing vascular surgery (n = 605). Because hypotension was a predictor of MI, the authors postulated that the potential benefit of lowering heart rate and blocking sympathetic outflow was offset by excess hypotension. Together these studies provide new insight as to why perioperative use of b-blockers may not benefit all patients with ischemic heart disease, and identify specific subgroups whose outcome was improved by b-blocker use. Patients with histories of HF or MI , 2 years before surgery seem to benefit from b-blocker administration. Findings were consistent with several prior meta-analyses that perioperative b-blockers are associated with a lower risk of MI and higher risk of strokes.32–34 Although some studies found no difference in stroke risk with β-blockers, this may be due to failure to evaluate specific β-blockers rather than the class overall. These studies also support previous findings that b-blockers reduce mortality only in high-risk patients, as defined by high RCRI score,35 and suggest that outcomes may differ based on the specific b-blocker used. Metoprolol, which was used in POISE, was associated with an increased risk of 132
stroke compared to the more selective β-blockers, atenolol and bisoprolol. Similar to several other reports, lower mortality was noted with β-blocker initiation $ 1 week before surgery, consistent with the European Society of Cardiology and ACC/AHA recommendations to start days to weeks in advance of surgery.3,22 In addition, low-dose clonidine did not reduce mortality or nonfatal MI but did increase clinically significant hypotension and cardiac arrests. New strategies are needed to reduce postoperative cardiovascular complications after noncardiac surgery.
Perioperative Risk Management: Antiplatelet Agents
Recommendations by different professional societies regarding the perioperative management of antiplatelet agents vary;2,36 evidence that perioperative antiplatelet therapy reduces MACEs is mixed.37,38 Several new studies reevaluate the role of perioperative antiplatelet therapy in patients with cardiovascular disease and cardiovascular risk. Hawn et al39 performed a retrospective cohort study of . 28 000 patients in the Veterans Affairs National Patient Care and Centers for Medicaid and Medicare Services databases who had noncardiac surgery within 24 months after coronary stent placement. A multivariate regression model was used to evaluate the association of MACEs with (1) additional risk factors, (2) stent type, (3) time between stent placement to surgery, and (4) preoperative antiplatelet cessation. Of patients who underwent noncardiac surgery within 24 months after stent implantation, 4.7% had MACEs. Major adverse cardiac event rates were higher among patients who had stents placed , 6 months before surgery than among those with a longer time between stent placement and surgery. Stent type (bare metal stent vs drug-eluting stent [DES]) was not an independent predictor of MACE rates. Other independent risk factors of MACE were inpatient and nonelective surgery, MI within 6 months, RCRI score . 2, invasiveness of the surgery, and CHF within the last 6 months. A matched case-control cohort was used to demonstrate the association of perioperative antiplatelet cessation and MACE. Among matched pairs, no association was seen between cessation of dual antiplatelet therapy and MACE (OR, 0.86; 95% CI, 0.57–1.29; P = 0.49). The POISE-2 trial also examined the effect of aspirin and clonidine on outcomes in patients undergoing noncardiac surgery.40 More than 10 000 patients aged $ 45 years and at risk of vascular complications because of underlying medical comorbidities were included in the study. This study included
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Perioperative Cardiovascular Medicine
2 aspirin study groups: the initiation stratum (n = 5628) and the continuation stratum (n = 4382). In the initiation group, 200 mg of aspirin or placebo was started before surgery and continued at 100 mg/d for 30 days. In the continuation stratum, patients already on an aspirin regimen stopped taking aspirin for $ 72 hours before surgery and then followed the same regimen as the initiation patients for 7 days. After this, they resumed their chronic aspirin dose.40 The primary outcome was a composite of death or nonfatal MI within 30 days of surgery. Outcomes were similar in both the initiation and continuation aspirin strata. No difference was seen between aspirin or placebo in the primary outcome of death or MI within 30 days (7.0% vs 7.1%; HR, 0.86; 95% CI, 0.86–1.15; P = 0.92). No difference was also seen in rates of multiple tertiary outcomes, including MI, venous thromboembolism, or stroke. Major bleeding occurred more often in aspirin-treated patients than placebo patients (4.6% vs 3.8%; HR, 1.23; 95% CI, 1.01–1.49; P = 0.04). Limitations of the study include the fact that most of the patients in the trial received aspirin for primary prevention, only 23% had known coronary artery disease and only 5% had cardiac stents, and subgroup analysis was not performed. Together the study by Hawn et al39 and the POISE 2 trial provide some additional guidance when managing antiplatelet agents in the perioperative period. Aspirin did not seem to provide significant perioperative cardiovascular benefit in these trials, but did increase rates of major bleeding. This evidence suggests that surgery may be considered 6 months after DES placement. Additional patient and surgical risk factors may impact perioperative cardiovascular outcomes more than stent type, and should be carefully considered during the preoperative evaluation. Based on the net risks and benefits of perioperative antiplatelet therapy in the context of available literature, the recent ACC/AHA guidelines recommend that elective surgery should optimally be delayed for 365 days after DES placement and that elective noncardiac surgery may be considered 180 days after DES implantation if the risk of delay is greater than the expected risks of ischemia and stent thrombosis.3 If patients who have stents undergo surgical procedures that mandate dual antiplatelet therapy discontinuation, aspirin should be continued if possible and the management of perioperative antiplatelet therapy should be based on consensus between the treating physicians and the patient. These guidelines also emphasize balancing risk and benefit of perioperative aspirin therapy in patients without previous coronary stenting.
Conclusion
This new body of literature in perioperative cardiovascular medicine provides powerful risk prediction tools that, when used appropriately, can assist the physician and patient with preoperative decision-making. For patients who proceed to surgery, β-blockers may reduce the risk of MACEs, and new findings have shown that more cardioselective β-blockers may provide better risk reduction than less selective ones. Stroke risk also must be considered when managing preoperative β-blockers. In addition, the newest studies have created additional uncertainty about the role of aspirin in perioperative prevention of MACEs. These studies clearly show that a careful risk/benefit analysis should be undertaken when managing cardiovascular medications in the perioperative period.
Conflict of Interest Statement
Steven L. Cohn, MD, Kurt J. Pfeifer, MD, and Gerald W. Smetana, MD, disclose no conflicts of interest. Suparna Dutta, MD, MBA, is a member of the advisory committee for Otsuka Pharmaceuticals. Barbara A. Slawski, MD, MS, and Amir K. Jaffer, MD, have been on a scientific advisory board for Marathon Pharmaceuticals. Dr Jaffer also reports consulting activities for Boehringer-Ingelheim, Janssen Pharmaceuticals, Pfizer, and Astra-Zeneca; research and grant funding from NHLBI and Astra-Zeneca; and board membership in the Society of Perioperative Assessment and Quality Improvement (SPAQI).
References 1. Nagele P, Brown F, Gage BF, et al. High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and longterm mortality after noncardiac surgery. Am Heart J. 2013;166(2): 325–332. 2. Grines CL, Bonow RO, Casey DE, et al. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation. 2007;115:813–818. 3. Fleischer LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guidelines on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published online ahead of print July 29, 2014]. J Am Coll Cardiol. doi:10.1016/j.jacc.2014.07.944. 4. Cohn S, Pfeifer K, Dutta S. Update in Perioperative Medicine. Perioperative Medicine Summit. http://periopmedicine.org/2014/02/ download-pdf-handouts-from-2014-summit.html. Accessed September 22, 2014. 5. Cohn S, Jaffer A, Slawski B, Smetana G. Update in Perioperative Medicine 2014. Society of General Internal Medicine Annual Meeting. San Diego, CA. http://www.sgim.org/meetings/annual-meeting/ handouts-and-presentations. Accessed September 22, 2014.
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Slawski et al 6. Parikh P, Shiloach M, Cohen ME, et al. Pancreatectomy risk calculator: an ACS-NSQIP resource. HPB (Oxford). 2010;12(7):488–497. 7. Gupta PK, Franck C, Miller WJ, Gupta H, Forse RA. Development and validation of a bariatric surgery morbidity risk calculator using the prospective, multicenter NSQIP dataset. J Am Coll Surg. 2011;212(3):301–309. 8. Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation. 2011;124:381–387. 9. Cohen ME, Bilimoria KY, Ko CY, Hall BL. Development of an American College of Surgeons National Surgery Quality Improvement Program: morbidity and mortality risk calculator for colorectal surgery. J Am Coll Surg. 2009;208:1009–1016. 10. Arozullah AM, Khuri SF, Henderson WG, Daley J; Participants in the National Veterans Affairs Surgical Quality Improvement Program. Development and validation of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med. 2001;135(10):847–857. 11. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am Coll Surg. 2013;217(5):833–842.e1–e3. 12. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100(10):1043–1049. 13. Davis C, Tait G, Carroll J, Wijeysundera DN, Beattie WS. The Revised Cardiac Risk Index in the new millennium: a single-centre prospective cohort re-evaluation of the original variables in 9,519 consecutive elective surgical patients. Can J Anaesth. 2013;60(9):855–863. 14. Rodseth RN, Lurati Buse GA, Bolliger D, et al. The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol. 2011;58(5):522–529. 15. Rodseth RN, Biccard BM, Chu R, et al. Postoperative B-type natriuretic peptide for prediction of major cardiac events in patients undergoing noncardiac surgery: systematic review and individual patient metaanalysis. Anesthesiology. 2013;119(2):270–283. 16. Rodseth RN, Biccard BM, Le Manach Y, et al. The prognostic value of preoperative and postoperative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: a systematic review and individual patient data meta-analysis. J Am Coll Cardiol. 2014;63(2):170–180. 17. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(26):2020–2035. 18. Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators ; Devereaux PJ, Chan MT, AlonsoCoelle P, et al. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307(21):2295–2304. 19. Botto F, Alonso-Coello P, Chan MT, et al; The Vascular events In noncardiac Surgery patients cOhort evaluatioN (VISION) Writing Group. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors and 30-day outcomes. Anesthesiology. 2014;120(3):564–578. 20. de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304(22):2503–2512. 21. Weber M, Luchner A, Seeberger M, et al. Incremental value of high-sensitive troponin T in addition to the revised cardiac index for peri-operative risk stratification in non-cardiac surgery. Eur Heart J. 2013;34(11):853–862. 22. Kristensen SD, Knuuti J, Saraste A. 2014 ESC/ESA Guidelines on noncardiac surgery: cardiovascular assessment and management [published online ahead of print August 11, 2014]. Eur Heart J. doi:10.1093/ eurheartj/ehu282.
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23. POISE Study Group; Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing noncardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371(9627):1839–1847. 24. Erasmus MC, Follow-up Investigation Committee 2012. Report on the 2012 follow-up investigation of possible breaches of academic integrity. http://cardiobrief.files.wordpress.com/2012/10/integrity-report2012–10-english-translation.pdf. Accessed September 10, 2014. 25. Andersson C, Mérie C, Jørgensen M, et al. Association of β-blocker therapy with risks of adverse cardiovascular events and deaths in patients with ischemic heart disease undergoing noncardiac surgery: a Danish nationwide cohort study. JAMA Intern Med. 2014;174(3):336–344. 26. London MJ, Hur K, Schwartz GG, Henderson WG. Association of perioperative β-blockade with mortality and cardiovascular morbidity following major noncardiac surgery. JAMA. 2013;309(16):1704–1713. 27. Ashes C, Judelman S, Wijeysundera DN, et al. Selective β1-antagonism with bisoprolol is associated with fewer postoperative strokes than atenolol or metoprolol: a single-center cohort study of 44,092 consecutive patients. Anesthesiology. 2013;119(4):777–787. 28. Mashour GA, Sharifpour M, Freundlich RE, et al. Perioperative metoprolol and risk of stroke after noncardiac surgery. Anesthesiology. 2013;119(6):1340–1346. 29. Dai N, Xu D, Zhang J, et al. Different β-blockers and initiation time in patients undergoing noncardiac surgery: a meta-analysis. Am J Med Sci. 2014;347(3):235–244. 30. Devereaux PJ, Sessler DI, Leslie K, et al; POISE-2 Investigators. Clonidine in patients undergoing noncardiac surgery. N Engl J Med. 2014;370(16):1504–1513. 31. Wijeysundera DN, Bender JS, Beattie WS. Alpha-2 adrenergic agonists for the prevention of cardiac complications among patients undergoing surgery. Cochrane Database Syst Rev. 2009;(4):CD004126. 32. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008;372(9654):1962–1976. 33. Talati R, Reinhart KM, White CM, et al. Outcomes of perioperative betablockade in patients undergoing noncardiac surgery: a meta-analysis. Ann Pharmacother. 2009;43(7):1181–1188. 34. Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2014;100(6):456–464. 35. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. 2005;353(4):349–361. 36. Douketis, JD, Spyropoulos, AC, Spencer FA, et al; American College of Chest Physicians. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e326S–e350S. 37. Assali A, Vaknin-Assa H, Lev E, et al. The risk of cardiac complications following noncardiac surgery in patients with drug eluting stents implanted at least six months before surgery. Catheter Cardiovasc Interv. 2009;74(6):837–843. 38. van Kuijk JP, Flu WJ, Schouten O, et al. Timing of noncardiac surgery after coronary artery stenting with bare metal or drug-eluting stents. Am J Cardiol. 2009;104(9):1229–1234. 39. Hawn MT, Graham LA, Richman JS, Itani KM, Henderson WG, Maddox TM. Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents. JAMA. 2013;310(14):1462–1472. 40. Devereaux PJ, Mrkobrada M, Sessler DI, et al; POISE-2 Investigators. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014;370(16):1494–1503.
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Perioperative Cardiovascular Medicine: An Update of the Literature 2013–2014
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DOI: 10.3810/hp.2014.10.1149
Barbara A. Slawski, MD, MS 1 Steven L. Cohn, MD 2 Kurt J. Pfeifer, MD 1 Suparna Dutta, MD, MBA 3 Amir K. Jaffer, MD 3 Gerald W. Smetana, MD 4 Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital Clinical Cancer Center, Milwaukee, WI; 2University of Miami Miller School of Medicine, Miami, FL; 3 Rush Medical College, Chicago, IL; 4 Harvard Medical School, Division of General Medicine and Primary Care, Boston, MA 1
Abstract: Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, cardiology, and hospital medicine. A multispecialty team approach that ensures the best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. Staying current in this multidisciplinary field is difficult, because physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, the authors performed a focused review of this literature published in 2013 and early 2014. In this update, key articles are reviewed that potentially impact clinical practice in perioperative cardiovascular risk prediction and risk management. Keywords: perioperative cardiovascular medicine; risk reduction; major adverse cardiac event; preoperative care; postoperative complications
Introduction
Cardiac complications are a frequent cause of postoperative morbidity and mortality.1,2 As the surgical population becomes older and more medically complex, reliable perioperative cardiac risk stratification continues to gain importance. Prediction of risk and opportunities to mitigate the risk of adverse perioperative cardiovascular events are key in the practice of perioperative medicine. Multiple recent studies have addressed perioperative cardiovascular evaluation and outcomes. Knowledge of this literature provides additional guidance to physicians in multiple specialties who provide care to the surgical patient. This article addresses recent advances in perioperative cardiovascular medicine. For a complete overview of general perioperative evaluation and management of patients undergoing noncardiac surgery, refer to the recently released 2014 American College of Cardiology/American Heart Association (ACC/ AHA) guidelines.3
Methods Correspondence: Barbara Slawski, MD, MS, FACP, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital Clinical Cancer Center, 9200 W Wisconsin Ave, Suite 5400, Milwaukee, WI 53226. Tel: 414-805-0840 E-mail: [email protected]
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This summary of recent literature is derived from the “Update in Perioperative Medicine” presented at the 9th Annual Perioperative Medicine Summit and the Society of General Internal Medicine 37th Annual Meeting.4,5 A Medline search of the relevant literature from January 2013 through April 2014 was performed using the medical subject heading (MeSH) terms preoperative care, intraoperative care, perioperative care, postoperative care, preoperative period, intraoperative period, intraoperative complications, postoperative complications, and noncardiac surgery. Pediatric and cardiac surgeries were excluded from the literature review.
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Perioperative Cardiovascular Medicine
Articles relevant to perioperative cardiovascular medicine were selected. Final articles were selected by expert consensus based on relevance to the clinical practice of perioperative medicine.
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Prediction of Perioperative Cardiovascular Risk
To assist with prediction of perioperative mortality and complications, multiple surgical risk calculators have been created.6–10 These tools are useful to physicians and patients when making decisions about the potential risks and benefits of an anticipated surgery. Several recent studies have also demonstrated the strong prognostic value of biomarkers when obtained before and/or after surgery. Furthermore, studies also show that these cardiac biomarkers allow for improved cardiac risk stratification when added to clinical risk assessment tools.
Perioperative Risk Indices
In a recent study using data from 1 414 006 patients at 393 hospitals in the American College of Surgeons National Surgical Quality Improvement Program database, Bilimoria et al11 developed a universal surgical risk estimation calculator and compared its performance with previous risk calculators. Twenty-one preoperative risk factors, including the type of procedure, patient demographics, and several specific comorbidities, were selected for inclusion in the risk calculator. There were no restrictions based on type of surgery. A surgeon risk adjustment score was also incorporated into the tool to permit individual providers to adjust for preoperative risks that may not be captured by the tool (ie, to adjust the risk up or down from the calculated estimate). A regression model had excellent performance at predicting mortality (C statistic = 0.94) and morbidity (C statistic = 0.82), and 6 additional complications. The performance was similar in procedure-specific risk calculators. The authors then developed a Web-based tool to calculate estimates of postoperative mortality, any complication, pneumonia, cardiac complications, surgical site infection, urinary tract infection, venous thromboembolism, renal failure, and serious complications. The online calculator (http:// riskcalculator.facs.org/) also provides an estimated hospital length of stay. This Web-based tool using high-quality clinical data and a large number of patients is easily accessible, functional, and provides practical information that can be used by physicians and patients for shared preoperative decision making.
The revised cardiac risk index (RCRI) score is another widely used tool that predicts rates of major cardiac complications for patients undergoing noncardiac surgery. The validated index includes 6 preoperative risk factors: highrisk surgery, history of ischemic heart disease, history of congestive heart failure (CHF), history of cerebrovascular disease, insulin treatment for diabetes, and serum creatinine level greater than 2 mg/dL. Although all 6 risk factors were included in the original model, insulin use for diabetes and creatinine level . 2 mg/dL were not significant risk factors in a subsequent validation cohort.12 In a new study, Davis et al13 sought to examine the importance of these 2 discordant predictors in the original RCRI criteria. Eligible subjects (n = 9519) were patients aged . 50 years who underwent elective noncardiac surgery with an expected length of stay of $ 2 days. The overall rate of cardiac complications was not significantly different between the original study by Lee et al12 and the new data set.13 When the original model was recalculated as a 4-factor model that eliminated insulin therapy for diabetes and preoperative creatinine level . 2 mg/dL, the rates of major cardiac complications were essentially unchanged. The authors created a revised 5-factor RCRI score that included high-risk surgery, ischemic heart disease, stroke history, CHF history, and estimated glomerular filtration rate , 30 mL/min. This score was a better predictor of postoperative major cardiac complications than the original RCRI score and improved calibration compared with the original model. Limitations of this study include lack of universal monitoring for postoperative myocardial infarction (MI) and differences between the original RCRI and current study data sets.
Cardiac Biomarkers
In addition to risk calculators, preoperative elevation of natriuretic peptides (NPs) strongly correlates with postoperative mortality and adverse cardiac events,14 but the value of measuring these biomarkers in the postoperative period is less clear. Rodseth et al15 performed a systematic review and individual patient data meta-analysis to clarify the prognostic utility of NPs obtained in the first week after noncardiac surgery. The authors identified 18 eligible studies (all prospective cohort studies) with a total of . 2000 patients for which they were able to obtain individual patient information on age, sex, postoperative brain natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) values, RCRI score, surgery characteristics, and 30-day and $ 180-day incidence of mortality and major adverse cardiac events (MACEs). The authors categorized
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Slawski et al
patients’ risk for 30-day mortality or nonfatal MI (, 5%, 5%–10%, . 10%–15%, . 15%) based on age, RCRI score, and type of surgery. Using cutoff values previously validated for acute heart failure diagnosis (BNP level # 250 or . 400 pg/mL and NT-proBNP level # 300 or . 900 pg/mL), they determined the adjusted odds ratio (AOR) for mortality and MI and reclassified patients’ estimated 30-day risk based on their measured NP levels. Results from this systematic review revealed a strong correlation between postoperative BNP and NT-proBNP levels and 30-day mortality and nonfatal MI.15 Patients with an NT-proBNP level of 901 to 3000 pg/mL had an AOR of 4.7 (95% CI, 1.62–13.37), and at a level of . 3000 pg/mL had an AOR of 12.5 (95% CI, 2.85–54.89). The AOR for a BNP level of 251 to 400 pg/mL was 2.5 (95% CI, 1.39–4.49), and for a BNP level of . 400 pg/mL it was 5.9 (95% CI, 3.71–9.26). When applied to clinical estimates, BNP levels with a high-risk cutoff value of $ 245 pg/mL and NT-proBNP levels with a high-risk cutoff value of $ 718 pg/mL also significantly improved risk categorization of patients, with a net reclassification index of 20% (P , 0.001). The improvement of risk classification was greatest among patients in intermediate-risk categories (5%–10% and . 10%–15%). In these groups, 46% of patients with 30-day mortality or nonfatal MI were reclassified as high risk because of an elevated postoperative BNP or NT-proBNP level, and 25% of patients without an adverse cardiac event were reclassified into a lower-risk category. This well-designed meta-analysis provides another piece to the puzzle of cardiovascular risk mitigation. Not only do postoperative NP levels predict 30-day mortality and cardiac events, they also seem to have greatest utility when used for most patients with intermediate risk based on clinical estimates. However, one of this study’s few limitations was its lack of adjustment for postoperative troponin and preoperative BNP levels, thus leaving the question unanswered of how correlation with these might alter risk assessment. Applying methodology similar to their earlier work with postoperative NPs, Rodseth et al16 sought to determine the additive benefit of postoperative (drawn , 8 days after surgery) and preoperative BNP or NT-proBNP measurements for predicting mortality and nonfatal MI at 30 and $ 180 days after noncardiac surgery. For this systematic review, 18 studies with individual patient data for 2179 patients were included in the meta-analysis. The authors estimated clinical risk using a model that incorporated age, RCRI score $ 3, and surgery characteristics (urgency and vascular vs nonvascular). High-risk cut-points for preoperative BNP and 128
NT-proBNP levels were derived from statistical analysis of the correlation of preoperative values to the combined postoperative outcome of death or nonfatal MI at 30 days after surgery. Using these and the postoperative high-risk cutoff values defined in their previous study (BNP $ 245 pg/mL and NT-proBNP $ 718 pg/mL),15 preoperative and postoperative NP values were added to the clinical risk estimation model to assess their impact on optimal risk classification. The threshold values for preoperative BNP and NTproBNP that were most predictive of 30-day mortality and nonfatal MI were 92 and 300 pg/mL, respectively. Using these cutoffs for high-risk classification, the addition of preoperative NP level to the clinical risk model significantly improved risk prediction, with a 31.6% net reclassification improvement. Adding postoperative NP levels to the model additionally improved classification of 20.2% of the patients; this was primarily due to reassignment to higher-risk categories because of elevated NP levels. The final model that combined clinical risk factors and preoperative and postoperative NP levels accurately predicted both 30- and $ 180-day mortality and nonfatal MI (P , 0.001 for both). Postoperative NP elevation, RCRI score $ 3, and preoperative NP elevation were the strongest independent predictors. The change in preoperative to postoperative NP levels did not correlate with death or MI at 30 days after surgery. This second rigorous meta-analysis by Rodseth et al16 adds to the evidence base supporting the benefit of adding BNP or NT-proBNP measurement to clinical risk estimation. This study does not address correlation of NP levels and cardiac outcomes with postoperative troponin levels, specifically troponin elevations not meeting diagnostic criteria for MI. A growing body of literature has demonstrated a strong association between postoperative troponin elevation, death, and adverse cardiovascular events. These findings include troponin elevations that do not meet the universal diagnostic criteria for MI: elevated troponin with either symptoms or electrocardiogram findings consistent with ischemia.17 The Vascular events In noncardiac Surgery patients cOhort evaluation (VISION) study previously published data showing that even small increases in troponin T (TnT) were independent predictors of 30-day mortality.18 However, this initial data analysis only followed troponin levels for 3 days after noncardiac surgery and did not account for the potential contribution of other postoperative complications or nonischemic causes of TnT elevation. By controlling for these factors, the current study by the VISION Writing Group aimed to define and characterize postoperative troponin elevations resulting
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Perioperative Cardiovascular Medicine
from myocardial ischemia, a condition termed myocardial injury after noncardiac surgery (MINS).19 The VISION study is an international, prospective cohort study of . 15 000 patients undergoing noncardiac surgery that assessed clinical outcomes and TnT levels on each of the first 3 postoperative days.19 Study personnel also tracked additional TnT levels obtained by providers in the first 30 days after surgery and determined whether troponin elevations were related to nonischemic causes, such as sepsis and pulmonary embolism. From these data, the authors of the VISION study determined that a peak TnT level of 0.03 ng/mL or higher, regardless of other ischemic findings, was a strong independent predictor of 30-day postoperative mortality and was designated as the diagnostic criterion for MINS. Among patients with MINS, 84.2% did not experience ischemic symptoms and 58.2% had no ischemic symptoms or electrocardiogram findings. Risk factors for developing MINS included age . 75 years, known cardiovascular disease, traditional cardiovascular risk factors (eg, hypertension and diabetes), and urgent or emergent surgery. Patients with MINS had significantly increased rates of heart failure (HF), stroke and cardiac arrest; the 30-day mortality rate was 9.8% compared with 1.1% in those without MINS. Perhaps most striking was the authors’ calculation of the proportion of all postoperative mortality potentially attributable to specific risk factors (ie, population-attributable risk). For all independent risk factors studied, MINS had the highest population-attributable risk at 34% (95% CI, 26.6–41.5), meaning that more than one-third of postoperative mortality was associated with elevated troponin levels. The VISION study has provided invaluable insight into the prognostic importance of postoperative troponin elevations. In this publication,19 the authors define the risk cutoff for TnT level at $ 0.03 ng/mL and confirm that the risks associated with MINS are significant and not dependent on concomitant ischemic findings. Most importantly, waiting for ischemic symptoms to trigger evaluation for myocardial injury misses . 80% of patients with MINS, a condition that may be attributable to one-third of postoperative deaths. Whether treatment based on the finding of MINS actually reduces mortality is unknown. Therefore, measurement of troponins before surgery (when interventions have the potential to prevent MINS) has gained increasing attention in the perioperative community. Elevations in newer, high-sensitivity troponin assays have been associated with increased mortality and adverse cardiac events, even in patients without apparent cardiovascular disease.20 However, few data are available on the
predictive value of preoperative troponin elevations. Nagele et al1 theorized that high-sensitivity troponin T (hs-TnT) obtained preoperatively may predict postoperative mortality and MI. To explore this question, the authors conducted a prospective cohort study within the VINO (Vitamins in Nitrous Oxide) trial.1 The VINO trial is a single-center, doubleblind, randomized, controlled trial investigating the impact of nitrous oxide on cardiac events in . 600 patients with coronary artery disease or multiple risk factors for coronary disease. In this study, electrocardiogram, troponin I (TnI), and hs-TnT were obtained within 2 hours before surgery, within 30 minutes of the end of surgery, and in the morning on postoperative days 1 through 3. Acute MI (defined as TnI elevation with ischemic symptoms and/or ischemic electrocardiogram changes) and TnI elevation within 72 hours after surgery were the primary outcomes; TnI elevation was classified as a peak level . 99th percentile ($ 0.07 mcg/L). Before surgery, 98.5% of patients had detectable levels of hs-TnT and 41% had levels . 99th percentile ($ 14 ng/L). When TnI was measured, only 13% of patients had detectable preoperative levels and only 4% had values . 99th percentile. In this higher risk study population, 13% had a postoperative TnI $ 0.07 mcg/L, and 5% met diagnostic criteria for MI. A preoperative hs-TnT . 14 ng/L was associated with a significantly increased probability of postoperative TnI elevation (odds ratio [OR], 3.33; 95% CI, 2.04–5.43; P , 0.001), postoperative MI (OR, 3.67; 95% CI, 1.65–8.15; P = 0.001), and 3-year mortality (adjusted hazard ratio [HR], 2.11; 95% CI, 1.26–3.53; P = 0.004). Preoperative hs-TnT $ 12 ng/L had a sensitivity of 73% and specificity of 52% for predicting postoperative MI, whereas detectable preoperative TnI (. 0.04 mcg/L) had a sensitivity of 20% and specificity of 92%. The work of Nagele et al1 provides useful insights into the perioperative utility of troponin levels. First, preoperative hs-TnT abnormalities are very common, and therefore if hsTnT levels are to be used to diagnose acute myocardial injury after surgery, preoperative and postoperative values must be compared to detect a change. Second, among patients with higher cardiovascular risk, a preoperative hs-TnT . 14 ng/L is associated with a 3.67-fold increased risk of postoperative MI and a 2-fold increased risk of 3-year mortality. Lastly, a preoperative hs-TnT cutoff of $ 12 ng/L provides a sensitive yet fairly specific assessment for postoperative cardiac complications. To determine the comparative and additive value of NTproBNP, hs-TnT, and the RCRI, Weber et al21 conducted
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a multicenter, observational study of 979 patients undergoing noncardiac surgery. Study patients were all aged . 55 years and had $ 1 cardiovascular risk factor (diabetes, hypertension, hyperlipidemia, smoking, or family history of heart disease). The primary endpoints of the study were mortality and a combined endpoint of mortality, acute MI, cardiac arrest, ventricular fibrillation, cardiopulmonary resuscitation, and acute HF. In this study, 24% of patients had a preoperative hsTnT . 14 ng/L, and 34% had an NT-pro-BNP $ 300 pg/mL. The median length of hospitalization was 11 days; 2.6% of patients died and 3.7% experienced the combined endpoint during their postoperative hospital stay. Revised cardiac risk index score, preoperative hs-TnT . 14 ng/L, and preoperative NT-proBNP $ 300 pg/mL all strongly correlated with postoperative cardiovascular events and mortality. In a regression analysis, hs-TnT . 14 ng/L was the strongest independent predictor for both in-hospital death and the combined endpoint, and when added to RCRI score provided improved prediction of both (although not statistically significant for the combined endpoint). The addition of NT-proBNP to RCRI score did not significantly improve risk estimation. For a given RCRI score, hs-TnT . 14 ng/L helped restratify patient risk. For instance, with an RCRI score of $ 2, approximately 4.7% of patients died during postoperative hospitalization. In this same group, those with a preoperative hs-TnT # 14 ng/L had 2.3% mortality, whereas those with an hs-TnT . 14 ng/L had 8.7% mortality.21 This study is the first to investigate the incremental value of both preoperative hs-TnT and NT-proBNP when added to the mainstay of cardiovascular risk assessment tools, the RCRI. Although the study was limited by the low number of observed outcomes and short follow-up, its findings that preoperative hs-TnT and NT-proBNP elevations are common and associated with increased morbidity and mortality are consistent with those of other literature discussed earlier, suggesting that the findings are valid. The biggest take away from this study is that hs-TnT seems to be superior to NTproBNP for cardiovascular risk prediction and significantly reclassifies risk assessment based on RCRI score alone. These studies provide powerful prediction tools that are limited to specific surgical groups and are noted to be validated risk-prediction tools in recent cardiovascular guidelines.3,22 The cardiac biomarker studies provide even more evidence that biomarkers are strong predictors of postoperative morbidity and mortality, and provide incremental prognostic value when combined with clinical risk prediction tools. Given the lack of data on how the results 130
of perioperative cardiac biomarker testing can influence outcomes, clinicians must use troponins and NPs with care, and, before ordering, have a clear plan for how the results will alter their management.23
Perioperative Cardiovascular Risk Reduction: β-Blockers and Clonidine
The effectiveness and safety of perioperative b-blockers for patients undergoing noncardiac surgery remain controversial. Early studies showed a benefit in reducing perioperative ischemia, myocardial infection, and mortality; however, subsequent larger studies showed no benefit. The largest trial, the PeriOperative Ischemic Evaluation study (POISE), found a reduction in MI, but at the expense of increased strokes and overall mortality.23 Some of these differences may be from the specific β-blocker used, whether the dose was titrated to control heart rate, and the timing of administration before surgery. More recently, the validity of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo (DECREASE) trials has been questioned because of concerns regarding academic integrity of the work.24 The articles discussed, although not randomized controlled trials (RCT), provide further insight into this controversy, highlighting outcome differences among the b-blockers based on their selectivity. The last article in this section is a RCT evaluating clonidine as an alternative to β-blockers. An observational study by Andersson et al25 investigated the association of perioperative β-blocker use with 30-day risk of MACEs and all-cause mortality in 28 263 patients with ischemic heart disease undergoing noncardiac surgery. β-Blocker use was defined as having filled an outpatient prescription within 4 months before surgery. In the 7990 patients with HF, β-blocker use was associated with a substantially reduced risk of MACE (HR, 0.78; 95% CI, 0.66–0.91) and all-cause mortality (HR, 0.82; 95% CI, 0.70–0.95). In patients without HF but with an MI in the past 2 years, β-blockers were also associated with a significant reduction in MACE (HR, 0.54; 95% CI, 0.37–0.78) and a nonstatistically significant trend toward lower mortality (HR, 0.80; 95% CI, 0.53–1.21). No benefit from b-blockers was seen in patients who had an MI . 2 years before, no prior MI, or no prior history of HF. Results were similar for propensity score–matched subgroups with HF. Patients without HF or with an MI , 2 years before only showed a nonstatistically significant trend toward a benefit. Limitations include not knowing when or whether a patient took the b-blocker perioperatively and not performing routine postoperative troponins or electrocardiograms.
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Perioperative Cardiovascular Medicine
London et al26 evaluated b-blocker exposure on the day of or after major noncardiac surgery in 136 745 patients in Veterans Administration Medical Centers from 2005 to 2010. Propensity-matched patients (37 805 pairs) were evaluated for 30-day total mortality, cardiac arrest, and Q-wave MI. Overall, b-blocker exposure was greater in patients undergoing vascular surgery and in those with higher RCRI scores. Although exposure in the overall group was associated with a higher mortality and stroke risk, in the propensity-matched cohort it was associated with a lower mortality (relative risk [RR], 0.73; 95% CI, 0.65–0.83; P , 0.001; number needed to treat [NNT], 241); a lower rate of MI and cardiac arrest (RR, 0.67; 95% CI, 0.57–0.79; P , 0.001; NNT, 339), but only in those undergoing nonvascular surgery; and no difference in stroke risk (0.35% vs 0.32%). When stratified by RCRI score, patients with $ 2 risk factors had a lower mortality (RR, 0.63, 0.54, and 0.40 with 2, 3, or 4 or more factors, respectively, all with P , 0.001). Metoprolol seemed to have a stronger association with mortality and stroke than did atenolol, although the metoprolol group was more likely to have ischemic heart disease and prior cerebrovascular disease. Limitations include not performing routine postoperative surveillance with troponins and electrocardiograms and only including Q-wave MIs. A retrospective cohort study of 44 092 patients undergoing noncardiac, nonneurologic surgery at the University Health Network in Toronto from 2003 to 2010 by Ashes et al27 compared stroke risk for patients taking bisoprolol versus less selective b-blockers (metoprolol, atenolol). The primary outcome was stroke within 7 days of surgery; a secondary outcome was a composite of all-cause mortality, postoperative myocardial injury, and stroke. The authors classified b-blocker use based on databases from the preoperative assessment and the in-patient pharmacy, and it represented in-patient exposure that was predominantly chronic. Stroke occurred in 88 of 10 756 patients (0.2%); in a matched cohort of 2462 patients, bisoprolol was associated with fewer strokes than the less selective agents (OR, 0.20; 95% CI, 0.04–0.91). The incidence of stroke in patients on no b-blocker, bisoprolol, atenolol, and metoprolol was 0.10%, 0.16%, 0.35%, and 0.62%, respectively. Two-thirds of the strokes occurred in the first 72 hours. Similar to the POISE trial, independent risk factors for stroke included a history of cerebrovascular disease and perioperative transfusion. In the setting of acute anemia with a hemoglobin , 9 gm/dL, all b-blockers were associated with an increased risk of stroke. The authors postulated that inhibition of β2-mediated cerebral vasodilation, which occurs at all hemoglobin levels with the nonselective
β-blockers, may be responsible for the increased stroke risk with metoprolol. β1-selective antagonists may better preserve peripheral circulation and vital organ perfusion in the setting of anemia and hypotension. Metoprolol was also associated with a higher rate of secondary outcome events. Limitations include lack of complete hemodynamic data to assess the effect of intraoperative hypotension, incomplete capture of β-blocker use by the databases, and a secular shift to more use of bisoprolol for unclear reasons during the study period. To assess the association of perioperative stroke and β-blocker use, Mashour et al28 retrospectively reviewed neuroimaging records of 57 218 patients who underwent noncardiac nonneurologic surgery in the University of Michigan Health System from 2003 to 2009. Perioperative stroke (within 30 days) occurred in 55 patients (0.09%) and was associated with increased short-term and long-term mortality (OR, 17.8 and 5.4, respectively). Most strokes (71%) occurred within 9 days of surgery. Metoprolol was associated with a 4.2-fold increase in risk of stroke (95% CI, 2.2–8.1; P , 0.001), whereas other β-blockers did not influence stroke rates. Intraoperative intravenous metoprolol use was also associated with a 3.3-fold increased risk (95% CI, 1.4–7.8; P = 0.003). No similar association existed with intravenous esmolol and labetalol. Matched cohort analysis revealed an increased stroke risk in those taking metoprolol compared with atenolol (0.3% vs 0; P = 0.016), but not in the overall (unmatched) population, possibly because it was a large diverse group. Independent predictors of postoperative stroke in the entire population included history of atrial fibrillation and prior stroke or transient ischemic attack. Limitations include a low event rate and relatively low use of β-blockers; use of in-hospital imaging records, which might miss strokes after discharge; and lack of compliance and dosing data. Dai et al29 assessed the effects of various β-blockers and the timing of treatment on postoperative outcomes. The authors performed a meta-analysis of 8 trials including 11 180 patients undergoing noncardiac surgery, of whom 5547 received β-blockers perioperatively. Perioperative β-blocker therapy was associated with a significant decrease in risk of developing postoperative MI (RR, 0.73; 95% CI, 0.61–0.86) but a significant increase in risk of developing stroke (RR, 2.17; 95% CI, 1.35–3.50) versus placebo. A nonsignificant decrease was seen in overall mortality (RR, 0.91; 95% CI, 0.60–1.36). This was driven by the large number of subjects in the POISE trial. Although no head-to-head trials were performed with different β-blockers, indirect comparisons demonstrated that perioperative atenolol therapy
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was associated with lower mortality and incidence of MI. Additionally, the authors noted that β-blocker therapy initiated . 1 week (vs , 1 week) before surgery was associated with improved postoperative mortality. In view of the uncertainties surrounding perioperative β-blockers, Devereaux et al and the POISE-2 Investigators30 aimed to determine if clonidine, which blunts the activity of the sympathetic nervous system, could reduce the risk of perioperative MI and death within 30 days of surgery. POISE-2 was a blinded 2x2 factorial randomized clinical trial evaluating the use of clonidine, aspirin, both, or neither in 10 010 patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery. At 2 to 4 hours before surgery, patients received either 0.2 mg of clonidine orally and a transdermal patch (0.2 mg/d) or placebos, and also received aspirin or placebo. Vital signs were monitored every 4 hours for 96 hours postoperatively, and troponins were drawn 6 to 12 hours after surgery and daily for 3 days. Electrocardiograms were ordered if troponins were elevated. Clonidine did not decrease the composite outcome of death or nonfatal MI (7.3% vs 6.8%; HR, 1.08; 95% CI, 0.93–1.26; P = 0.29), but more patients in the clonidine group experienced a nonfatal cardiac arrest (15 vs 9; HR, 3.2; 95% CI, 1.17–8.73; P = 0.02). Clinically significant hypotension and bradycardia occurred significantly more often in the clonidine group, but no difference in strokes was seen. In contrast to a previous systematic review of alpha-2 adrenergic agonists,31 the authors of POISE-2 found no overall benefit among patients undergoing vascular surgery (n = 605). Because hypotension was a predictor of MI, the authors postulated that the potential benefit of lowering heart rate and blocking sympathetic outflow was offset by excess hypotension. Together these studies provide new insight as to why perioperative use of b-blockers may not benefit all patients with ischemic heart disease, and identify specific subgroups whose outcome was improved by b-blocker use. Patients with histories of HF or MI , 2 years before surgery seem to benefit from b-blocker administration. Findings were consistent with several prior meta-analyses that perioperative b-blockers are associated with a lower risk of MI and higher risk of strokes.32–34 Although some studies found no difference in stroke risk with β-blockers, this may be due to failure to evaluate specific β-blockers rather than the class overall. These studies also support previous findings that b-blockers reduce mortality only in high-risk patients, as defined by high RCRI score,35 and suggest that outcomes may differ based on the specific b-blocker used. Metoprolol, which was used in POISE, was associated with an increased risk of 132
stroke compared to the more selective β-blockers, atenolol and bisoprolol. Similar to several other reports, lower mortality was noted with β-blocker initiation $ 1 week before surgery, consistent with the European Society of Cardiology and ACC/AHA recommendations to start days to weeks in advance of surgery.3,22 In addition, low-dose clonidine did not reduce mortality or nonfatal MI but did increase clinically significant hypotension and cardiac arrests. New strategies are needed to reduce postoperative cardiovascular complications after noncardiac surgery.
Perioperative Risk Management: Antiplatelet Agents
Recommendations by different professional societies regarding the perioperative management of antiplatelet agents vary;2,36 evidence that perioperative antiplatelet therapy reduces MACEs is mixed.37,38 Several new studies reevaluate the role of perioperative antiplatelet therapy in patients with cardiovascular disease and cardiovascular risk. Hawn et al39 performed a retrospective cohort study of . 28 000 patients in the Veterans Affairs National Patient Care and Centers for Medicaid and Medicare Services databases who had noncardiac surgery within 24 months after coronary stent placement. A multivariate regression model was used to evaluate the association of MACEs with (1) additional risk factors, (2) stent type, (3) time between stent placement to surgery, and (4) preoperative antiplatelet cessation. Of patients who underwent noncardiac surgery within 24 months after stent implantation, 4.7% had MACEs. Major adverse cardiac event rates were higher among patients who had stents placed , 6 months before surgery than among those with a longer time between stent placement and surgery. Stent type (bare metal stent vs drug-eluting stent [DES]) was not an independent predictor of MACE rates. Other independent risk factors of MACE were inpatient and nonelective surgery, MI within 6 months, RCRI score . 2, invasiveness of the surgery, and CHF within the last 6 months. A matched case-control cohort was used to demonstrate the association of perioperative antiplatelet cessation and MACE. Among matched pairs, no association was seen between cessation of dual antiplatelet therapy and MACE (OR, 0.86; 95% CI, 0.57–1.29; P = 0.49). The POISE-2 trial also examined the effect of aspirin and clonidine on outcomes in patients undergoing noncardiac surgery.40 More than 10 000 patients aged $ 45 years and at risk of vascular complications because of underlying medical comorbidities were included in the study. This study included
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Perioperative Cardiovascular Medicine
2 aspirin study groups: the initiation stratum (n = 5628) and the continuation stratum (n = 4382). In the initiation group, 200 mg of aspirin or placebo was started before surgery and continued at 100 mg/d for 30 days. In the continuation stratum, patients already on an aspirin regimen stopped taking aspirin for $ 72 hours before surgery and then followed the same regimen as the initiation patients for 7 days. After this, they resumed their chronic aspirin dose.40 The primary outcome was a composite of death or nonfatal MI within 30 days of surgery. Outcomes were similar in both the initiation and continuation aspirin strata. No difference was seen between aspirin or placebo in the primary outcome of death or MI within 30 days (7.0% vs 7.1%; HR, 0.86; 95% CI, 0.86–1.15; P = 0.92). No difference was also seen in rates of multiple tertiary outcomes, including MI, venous thromboembolism, or stroke. Major bleeding occurred more often in aspirin-treated patients than placebo patients (4.6% vs 3.8%; HR, 1.23; 95% CI, 1.01–1.49; P = 0.04). Limitations of the study include the fact that most of the patients in the trial received aspirin for primary prevention, only 23% had known coronary artery disease and only 5% had cardiac stents, and subgroup analysis was not performed. Together the study by Hawn et al39 and the POISE 2 trial provide some additional guidance when managing antiplatelet agents in the perioperative period. Aspirin did not seem to provide significant perioperative cardiovascular benefit in these trials, but did increase rates of major bleeding. This evidence suggests that surgery may be considered 6 months after DES placement. Additional patient and surgical risk factors may impact perioperative cardiovascular outcomes more than stent type, and should be carefully considered during the preoperative evaluation. Based on the net risks and benefits of perioperative antiplatelet therapy in the context of available literature, the recent ACC/AHA guidelines recommend that elective surgery should optimally be delayed for 365 days after DES placement and that elective noncardiac surgery may be considered 180 days after DES implantation if the risk of delay is greater than the expected risks of ischemia and stent thrombosis.3 If patients who have stents undergo surgical procedures that mandate dual antiplatelet therapy discontinuation, aspirin should be continued if possible and the management of perioperative antiplatelet therapy should be based on consensus between the treating physicians and the patient. These guidelines also emphasize balancing risk and benefit of perioperative aspirin therapy in patients without previous coronary stenting.
Conclusion
This new body of literature in perioperative cardiovascular medicine provides powerful risk prediction tools that, when used appropriately, can assist the physician and patient with preoperative decision-making. For patients who proceed to surgery, β-blockers may reduce the risk of MACEs, and new findings have shown that more cardioselective β-blockers may provide better risk reduction than less selective ones. Stroke risk also must be considered when managing preoperative β-blockers. In addition, the newest studies have created additional uncertainty about the role of aspirin in perioperative prevention of MACEs. These studies clearly show that a careful risk/benefit analysis should be undertaken when managing cardiovascular medications in the perioperative period.
Conflict of Interest Statement
Steven L. Cohn, MD, Kurt J. Pfeifer, MD, and Gerald W. Smetana, MD, disclose no conflicts of interest. Suparna Dutta, MD, MBA, is a member of the advisory committee for Otsuka Pharmaceuticals. Barbara A. Slawski, MD, MS, and Amir K. Jaffer, MD, have been on a scientific advisory board for Marathon Pharmaceuticals. Dr Jaffer also reports consulting activities for Boehringer-Ingelheim, Janssen Pharmaceuticals, Pfizer, and Astra-Zeneca; research and grant funding from NHLBI and Astra-Zeneca; and board membership in the Society of Perioperative Assessment and Quality Improvement (SPAQI).
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