Patterns of use of perioperative angiotensin-converting enzyme inhibitors in coronary artery bypass graft surgery with cardiopulmonary bypass: effects on in-hospital morbidity and mortality.

BACKGROUND: Despite proven benefit in ambulatory patients with ischemic heart disease, the pattern of use of angiotensin-converting enzyme inhibitors (ACEIs) in coronary artery bypass graft surgery has been erratic and controversial. METHODS AND RESULTS: This is a prospective observational study of 4224 patients undergoing coronary artery bypass graft surgery. The cohort included 1838 patients receiving ACEI therapy before surgery and 2386 (56.5%) without ACEI exposure. Postoperatively, the pattern of ACEI use yielded 4 groups: continuation, 915 (21.7%); withdrawal, 923 (21.8%); addition, 343 (8.1%); and no ACEI, 2043 (48.4%). Continuous treatment with ACEI versus no ACEI was associated with substantive reductions of risk of nonfatal events (adjusted odds ratio for the composite outcome, 0.69; 95% confidence interval, 0.52-0.91; P=0.009) and a cardiovascular event (odds ratio, 0.64; 95% confidence interval, 0.46-0.88; P=0.006). Addition of ACEI de novo postoperatively compared with no ACEI therapy was also associated with a significant reduction of risk of composite outcome (odds ratio, 0.56; 95% confidence interval, 0.38-0.84; P=0.004) and a cardiovascular event (odds ratio, 0.63; 95% confidence interval, 0.40-0.97; P=0.04). On the other hand, continuous treatment of ACEI versus withdrawal of ACEI was associated with decreased risk of the composite outcome (odds ratio, 0.50; 95% confidence interval, 0.38-0.66; P<0.001), as well as a decrease in cardiac and renal events (P<0.001 and P=0.005, respectively). No differences in in-hospital mortality and cerebral events were noted. CONCLUSIONS: Our study suggests that withdrawal of ACEI treatment after coronary artery bypass graft surgery is associated with nonfatal in-hospital ischemic events. Furthermore, continuation of ACEI or de novo ACEI therapy early after cardiac surgery is associated with improved in-hospital outcomes.

Lack of effectiveness of the pulmonary artery catheter in cardiac surgery.

BACKGROUND: The pulmonary artery catheter (PAC) continues to be used for monitoring of hemodynamics in patients undergoing coronary artery bypass graft (CABG) surgery despite concerns raised in other settings regarding both effectiveness and safety. Given the relative paucity of data regarding its use in CABG patients, and given entrenched practice patterns, we assessed the impact of PAC use on fatal and nonfatal CABG outcomes as practiced at a diverse set of medical centers. METHODS: Using a formal prospective observational study design, 5065 CABG patients from 70 centers were enrolled between November 1996 and June 2000 using a systemic sampling protocol. Propensity score matched-pair analysis was used to adjust for differences in likelihood of PAC insertion. The predefined composite endpoint was the occurrence of any of the following: death (any cause), cardiac dysfunction (myocardial infarction or congestive heart failure), cerebral dysfunction (stroke or encephalopathy), renal dysfunction (dysfunction or failure), or pulmonary dysfunction (acute respiratory distress syndrome). Secondary variables included treatment indices (inotrope use, fluid administration), duration of postoperative intubation, and intensive care unit length of stay. After categorization based on PAC and transesophageal echocardiography use (both, neither, PAC only, transesophageal echocardiography only), we performed the primary analysis contrasting PAC only and neither (total, 3321 patients), from which propensity paring yielded 1273 matched pairs. RESULTS: The primary endpoint occurred in 271 PAC patients versus 196 without PAC (21.3% vs.15.4%; adjusted odds ratio [AOR], 1.68; 95% confidence interval [CI], 1.24 to 2.26; P<0.001). The PAC group had an increased risk of all-cause mortality, 3.5% vs 1.7% (AOR, 2.08; 95% CI, 1.11 to 3.88; P=0.02) and an increased risk of cardiac (AOR, 1.58; 95% CI, 1.14 to 2.20; P=0.007), cerebral (AOR, 2.02; 95% CI, 1.08 to 3.77; P=0.03) and renal (AOR, 2.47; 95% CI, 1.68 to 3.62; P<0.001) morbid outcomes. PAC patients received inotropic drugs more frequently (57.8% vs 50.0%; P<0.001), had a larger positive IV fluid balance after surgery (3220 mL vs 3022 mL; P=0.003), and experienced longer time to tracheal extubation (15.40 hours [11.28/20.80] versus 13.18 hours [9.58/19.33], median plus Q1/Q3 interquartile range; P<0.0001). Use of PAC was also associated with prolonged intensive care unit stay (14.5% vs 10.1%; AOR, 1.55; 95% CI, 1.06 to 2.27; P=0.02). CONCLUSIONS: Use of a PAC during CABG surgery was associated with increased mortality and a higher risk of severe end-organ complications in this propensity-matched observational study. A randomized controlled trial with defined hemodynamic goals would be ideal to either confirm or refute our findings.

A multinational study of the influence of health-related quality of life on in-hospital outcome after coronary artery bypass graft surgery.

BACKGROUND: The effect of health-related quality of life on in-hospital outcomes after coronary artery bypass grafting surgery has not been investigated in international multicenter studies. We hypothesized that poor preoperative health status is associated with mortality and length of hospital stay. METHODS: In the Multicenter Study of Perioperative Ischemia Epidemiology II, preoperative Short-Form 12, Mental Component Summary (MCS), and Physical Component Summary (PCS) scores were obtained prospectively from 4,811 patients (3,834 men, 977 women) undergoing coronary artery bypass grafting surgery at 72 centers in 17 countries. Primary outcome measures were in-hospital mortality and prolonged (>14 days) length of hospital stay. RESULTS: One hundred fifty-one patients (3.1%) died. After adjustment for regional differences, a 10-point reduction in MCS score was associated with higher mortality risk (odds ratio [OR] 1.17, 95% CI 1.004-1.37, P = .04) and prolonged hospital stay (OR 1.11, 95% CI 1.01-1.21, P = .03). The preoperative PCS score was not associated with mortality risk but significantly predicted prolonged length of hospital stay (OR 1.20, 95% CI 1.09-1.33, P < .001). There was no significant interaction between gender and either the MCS or the PCS score. DISCUSSION: The preoperative PCS predicted prolonged postoperative hospital stay, whereas the preoperative MCS score was an independent predictor of both prolonged length of hospital stay and mortality. Preoperative assessment of health-related quality of life factors with the Short-Form 12 might be a useful tool for risk stratification and planning for hospital discharge and rehabilitation.

Impact of hyperglycemia on perioperative mortality after coronary artery bypass graft surgery.

OBJECTIVE: The roles of perioperative hyperglycemia and diabetes in the risk stratification of patients undergoing coronary artery bypass graft surgery are unclear. The aim of this study is to explore the influence of perioperative hyperglycemia on postoperative mortality. METHOD: A prospective, observational study of 5050 patients undergoing cardiopulmonary bypass for coronary artery bypass graft surgery at 70 international centers was conducted, with 7500 measured variables per patient and outcomes adjudicated centrally. Postoperative blood glucose levels measured from the day of surgery to postoperative day 3 were available for 4799 patients. Multivariable logistic regression was used to determine the association of hyperglycemia with hospital mortality. RESULTS: A total of 164 patients died during hospitalization (3.2%). Mortality was significantly higher in the diabetic population compared with the nondiabetic population (4.2% vs 2.9%; P = .02). In nondiabetic patients, maximum postoperative blood glucose between 250 and 300 mg/dL (adjusted odds ratio, 2.56; 95% confidence interval, 1.18-5.57; P = .02) and maximum blood glucose of 300 mg/dL or greater (adjusted odds ratio, 2.74; 95% confidence interval, 1.22-6.16; P = .01), compared with maximum blood glucose less than 200 mg/dL, and postoperative insulin treatment (adjusted odds ratio, 2.04; 95% confidence interval, 1.12-3.70), were independent risk factors for an increased risk of in-hospital mortality. In diabetic patients, hyperglycemia was not associated with a higher mortality risk. CONCLUSIONS: Postoperative hyperglycemia is associated with increased in-hospital mortality in nondiabetic patients after coronary artery bypass graft surgery. In diabetic patients, hyperglycemia was not associated with mortality.

Postoperative red blood cell transfusion and morbid outcome in uncomplicated cardiac surgery patients.

OBJECTIVE: To evaluate postoperative red blood cell (RBC) transfusion and its association with postoperative cardiac events and multiorgan morbidity in uncomplicated cardiac surgery patients. METHODS: A cohort of 945 patients from the 5,436 coronary artery bypass grafting patients enrolled in the international Multicenter Study of Perioperative Ischemia (McSPI) Epidemiology II (EPI II) study was investigated. Inclusion criteria were low to moderate risk profile, postoperative hemoglobin level ≥ 10 g/dl, minimal postoperative blood loss, and no evidence of any morbid event on the day of surgery. RBC transfusion was assessed during the first 24 postoperative hours and cardiac as well as multiorgan outcomes from postoperative day 2 to hospital discharge. Multivariate analysis was applied to assess the effect of RBC transfusion on multiorgan outcomes. A secondary propensity score analysis was performed in 4,465 patients without early postoperative morbid outcomes. RESULTS: Transfused patients (193/945, 20.4%) were more likely to suffer cardiac events (P = 0.03), harvest-site infection (P = 0.002), and composite morbidity outcome (P = 0.04). RBC transfusion was associated with cardiac events on multivariate as well as on propensity score analysis (adjusted odds ratio, 1.39; 95% confidence interval, 1.01-1.92; P = 0.04), and with harvest-site infection on multivariate analysis. Additionally, propensity score analysis suggested possible associations of RBC transfusion with increased risks for composite morbidity outcome and in-hospital mortality, renal morbidity, pneumonia, and mediastinitis. CONCLUSIONS: The data suggest a potential association between postoperative RBC transfusion and increased morbidity for cardiac surgery patients with low to moderate mortality risk profiles, adequate hemoglobin levels, and low bleeding rates.

Predictive value of the National Institutes of Health Stroke Scale and the Mini-Mental State Examination for neurologic outcome after coronary artery bypass graft surgery.

OBJECTIVE: We intended to define the role of the National Institutes of Health Stroke Scale and the Mini-Mental State Examination in identifying adverse neurologic outcomes in a large international sample of patients undergoing cardiac surgery. METHODS: We evaluated 4707 patients undergoing cardiac surgery with cardiopulmonary bypass at 72 centers in 17 countries between November 1996 and June 2000. Prespecified overt neurologic outcomes were categorized as type I (clinically diagnosed stroke, transient ischemic attack, encephalopathy, or coma) or type II (deterioration of intellectual function). The National Institutes of Health Stroke Scale and Mini-Mental State Examination were administered preoperatively and on postoperative day 3, 4, or 5. Receiver operating characteristic curves were plotted to determine the predictive value of worsening in National Institutes of Health Stroke Scale and Mini-Mental State Examination scores with respect to type I and II outcomes. RESULTS: The receiver operating characteristic area under the curve for changes in National Institutes of Health Stroke Scale score (n = 4620) was 0.89 for type I outcomes and 0.66 for type II outcomes. A 1-point worsening in National Institutes of Health Stroke Scale score provided excellent discrimination (86% specificity; 84% sensitivity) of type I outcomes. The receiver operating characteristic area under the curve for changes in Mini-Mental State Examination score (n = 4707) was 0.75 for type I outcomes and 0.71 for type II outcomes. A 2-point worsening in Mini-Mental State Examination score provided only fair discrimination (73% specificity; 62% sensitivity) of type II outcomes. CONCLUSION: We used baseline controls and postoperative worsening in National Institutes of Health Stroke Scale and Mini-Mental State Examination scores to predict both serious adverse neurologic outcome and deterioration of intellectual function. Our findings provide the only reference for evaluating these tests that are used in cardiac surgical clinical trials.

Pulse pressure and risk of adverse outcome in coronary bypass surgery.

BACKGROUND: Among ambulatory patients, an increase in pulse pressure (PP) is a well-established determinant of vascular risk. The relationship of PP and acute perioperative vascular outcome among patients having coronary artery bypass graft (CABG) surgery is less well known. METHODS: We conducted a prospective observational study involving 5436 patients having elective CABG surgery requiring cardiopulmonary bypass. Of these, 4801 met final inclusion criteria. Comprehensive data were captured for medical history, intraoperative and postoperative physiologic and laboratory measures, diagnostic testing, and clinical events. The relationship between preoperative hypertension (systolic, diastolic, PP) and ischemic cardiac and cerebral outcomes and death was assessed using multivariable logistic regression; P<0.05 was considered significant. RESULTS: Nine hundred and seventeen patients (19.1%) had fatal and nonfatal vascular complications, including 146 patients (3.0%) with cerebral and 715 patients (14.9%) with cardiac events. In-hospital mortality occurred in 147 patients (3.1%). Among all blood pressure variables measured preoperatively, PP was most strongly associated with an increased risk of postoperative complications. PP increments of 10 mm Hg (above a threshold of 40 mm Hg) were associated with an increased risk of cerebral events (adjusted odds ratio: 1.12; 95% CI [1.002-1.28]; P=0.026). The incidence of a cerebral event and/or death from neurologic complications nearly doubled for patients with PP>80 mm Hg versus

The ongoing variability in blood transfusion practices in cardiac surgery.

BACKGROUND: Although blood utilization has been under considerable scrutiny for the past two decades, particularly for surgery, studies comparing perioperative blood transfusion practices between countries are rare, and the evolution of international standards remains unknown. Therefore, the objective of this evaluation was to compare the perioperative transfusion of blood components in cardiac surgery in multiple centers in different countries. STUDY DESIGN AND METHODS: Transfusion practice was investigated prospectively in 70 centers among 16 countries. A total of 5065 randomly selected cardiac surgery patients of the Multicenter Study of Perioperative Ischemia Epidemiology II (EPI II) Study were evaluated. Utilization of red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs) was assessed daily, before, during, and after surgery until hospital discharge. RESULTS: Intraoperative RBC transfusion varied from 9 to 100 percent among the 16 countries, and 25 to 87 percent postoperatively (percentage of transfused patients). Similarly, frequency of transfusion of FFP varied from 0 to 98 percent intraoperatively and 3 to 95 percent postoperatively, and PLT transfusion from 0 to 51 and 0 to 39 percent, respectively. Moreover, there were not only marked differences in transfusion rates between centers in different countries but also in interinstitutional comparison of multiple centers within countries. CONCLUSION: In cardiac surgical patients, marked variability in transfusion practice exists between centers in various countries and suggests differences in perioperative practice patterns as well as possible inappropriate use. International standardization of perioperative practice patterns as well as transfusion regimes appears necessary.

Impact of preoperative anemia on outcome in patients undergoing coronary artery bypass graft surgery.

BACKGROUND: The risk of preoperative anemia in patients undergoing heart surgery has not been described precisely. Specifically, the impact of low hemoglobin per se or combined with other risk factors on postoperative outcome is unknown. Thus, we determined the effects of low preoperative hemoglobin and comorbidities on postoperative adverse outcomes in patients with coronary artery bypass graft in a large comprehensive multicenter study. METHODS AND RESULTS: The Multicenter Study of Perioperative Ischemia investigated 5065 patients with coronary artery bypass graft at 70 institutions worldwide, collecting approximately 7500 data points per patient. In 4804 patients who received no preoperative transfusions, we determined the association between lowest preoperative hemoglobin levels and in-hospital cardiac and noncardiac morbidity and mortality and the impact of concomitant risk factors, assessed by EuroSCORE, on this effect. In patients with EuroSCORE < 4 (n=2054), only noncardiac outcomes were increased, whereas patients with EuroSCORE > or = 4 (n=2750) showed an increased incidence of all postoperative events, starting at hemoglobin < 11 g/dL. Low preoperative hemoglobin was an independent predictor for noncardiac (renal > cerebral; P<0.001) outcomes, whereas the increase in cardiac events was due to other factors associated with preoperative anemia. CONCLUSIONS: Anemic patients undergoing cardiac surgery have an increased risk of postoperative adverse events. Importantly, the extent of preexisting comorbidities substantially affects perioperative anemia tolerance. Therefore, preoperative risk assessment and subsequent therapeutic strategies, such as blood transfusion, should take into account both the individual level of preoperative hemoglobin and the extent of concomitant risk factors.

Coronary artery bypass graft surgery--care globalization: the impact of national care on fatal and nonfatal outcome.

OBJECTIVE: In an international, prospective, observational study, we contrasted adverse vascular outcomes among four countries and then assessed practice pattern differences that may have contributed to these outcomes. METHODS: A total of 5065 patients undergoing coronary artery bypass graft surgery were analyzed at 70 international medical centers, and from this pool, 3180 patients from the 4 highest enrolling countries were selected. Fatal and nonfatal postoperative ischemic complications related to the heart, brain, kidney, and gastrointestinal tract were assessed by blinded investigators. RESULTS: In-hospital mortality was 1.5% (9/619) in the United Kingdom, 2.0% (9/444) in Canada, 2.7% (34/1283) in the United States, and 3.8% (32/834) in Germany (P = .03). The rates of the composite outcome (morbidity and mortality) were 12% in the United Kingdom, 16% in Canada, 18% in the United States, and 24% in Germany (P < .001). After adjustment for difference in case-mix (using the European System for Cardiac Operative Risk Evaluation) and practice, country was not an independent predictor for mortality. However, there was an independent effect of country on composite outcome. The practices that were associated with adverse outcomes were the intraoperative use of aprotinin, intraoperative transfusion of fresh-frozen plasma or platelets, lack of use of early postoperative aspirin, and use of postoperative heparin. CONCLUSIONS: Significant between-country differences in perioperative outcome exist and appear to be related to hematologic practices, including administration of antifibrinolytics, fresh-frozen plasma, platelets, heparin, and aspirin. Understanding the mechanisms for these observations and selection of practices associated with improved outcomes may result in significant patient benefit.

Mortality associated with aprotinin during 5 years following coronary artery bypass graft surgery.

CONTEXT: Acute safety concerns have been raised recently regarding certain hemorrhage-sparing medications commonly used in cardiac surgery. However, no comprehensive data exist regarding their associations with long-term mortality. OBJECTIVE: To contrast long-term all-cause mortality in patients undergoing coronary artery bypass graft (CABG) surgery according to use of 2 lysine analog antifibrinolytics (aminocaproic acid and tranexamic acid), the serine protease inhibitor aprotinin, or no antibleeding agent. DESIGN, SETTING, AND PARTICIPANTS: Observational study of mortality conducted between November 11, 1996, and December 7, 2006. Following index hospitalization (4374 patients; 69 medical centers), survival was prospectively assessed at 6 weeks, 6 months, and annually for 5 years after CABG surgery among 3876 patients enrolled in a 62-center international cohort study. The associations of survival with hemorrhage-sparing medications were compared using multivariable analyses including propensity adjustments. MAIN OUTCOME MEASURE: Death (all-cause) over 5 years. RESULTS: Aprotinin treatment (223 deaths among 1072 patients [20.8% 5-year mortality]) was associated with significantly increased mortality compared with control (128 deaths among 1009 patients [12.7%]; covariate adjusted hazard ratio for death, 1.48; 95% confidence interval, 1.19-1.85), whereas neither aminocaproic acid (132 deaths among 834 patients [15.8%]; adjusted hazard ratio for death, 1.03; 95% confidence interval, 0.80-1.33) nor tranexamic acid (65 deaths among 442 patients [14.7%]; adjusted hazard ratio for death, 1.07; 95% confidence interval, 0.80-1.45) was associated with increased mortality. In multivariable logistic regression, either with propensity adjustment or without, aprotinin was independently predictive of 5-year mortality (adjusted odds ratio with propensity adjustment, 1.48; 95% confidence interval, 1.13-1.93; P = .005) among patients with diverse risk profiles, as well as among those surviving their index hospitalization. Neither aminocaproic nor tranexamic acid was associated with increased risk of death. CONCLUSIONS: These findings indicate that in addition to the previously reported acute renal and vascular safety concerns, aprotinin use is associated with an increased risk of long-term mortality following CABG surgery. Use of aprotinin among patients undergoing CABG surgery does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.

Risk index for perioperative renal dysfunction/failure: critical dependence on pulse pressure hypertension.

BACKGROUND: An acute renal event after coronary bypass graft surgery is associated with high mortality and substantial additive cost. METHODS AND RESULTS: This prospective and descriptive study of 4801 patients having coronary bypass graft surgery with cardiopulmonary bypass from November 1996 to June 2000 at 70 centers in 16 countries established associations between predictor variables and postoperative renal composite (renal dysfunction and/or renal failure) from a cohort of 2381 patients and developed a risk index assessed in a validation cohort of 2420 patients. Postoperative renal composite occurred in 231 patients (4.8%). Independent and significant risk factors were age >75 years (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.23 to 3.37; P=0.006), preoperative congestive heart failure (OR, 2.38; CI, 1.55 to 3.64; P<0.001), prior myocardial infarction (OR, 1.75; CI, 1.08 to 2.83; P=0.023), preexisting renal disease (OR, 3.71; CI, 2.41 to 5.70; P<0.001), intraoperative multiple inotrope use (OR, 2.75; CI, 1.75 to 4.31; P<0.001), intraoperative intra-aortic balloon pump insertion (OR, 4.41; CI, 2.21 to 8.80; P<0.001), cardiopulmonary bypass >2 hours (OR, 1.78; CI, 1.15 to 2.74; P=0.01), and preoperative pulse pressure such that for every additional 20-mm Hg increment in pulse pressure >40 mm Hg, there was an OR of 1.49 (CI, 1.17 to 1.89; P=0.001). Patients with pulse pressure hypertension >80 mm Hg were 3 times more likely to die a renal-related death compared with those without (3.7% versus 1.1%). CONCLUSIONS: Beside established risk factors, pulse pressure is independently and significantly associated with increased renal composite.

Preoperative statin therapy is associated with reduced cardiac mortality after coronary artery bypass graft surgery.

OBJECTIVE: Statin therapy in ambulatory populations is associated with a significant reduction in adverse cardiovascular events, including death and myocardial infarction. Much less is known about the beneficial effects of statins on acute perioperative cardiovascular events. The purpose of this study was to determine whether preoperative statin therapy is associated with a reduced risk of early cardiac death or nonfatal, in-hospital postoperative myocardial infarction after primary, elective coronary artery bypass graft surgery requiring cardiopulmonary bypass. METHODS: The Multicenter Study of Perioperative Ischemia (McSPI) Epidemiology II Study was a prospective, longitudinal study of 5436 patients undergoing coronary artery bypass graft surgery between November 1996 and June 2000 at 70 centers in 17 countries. The present study consisted of a pre-specified subset of these subjects divided into patients receiving (n = 1352) and not receiving (n = 1314) preoperative statin therapy. To control for potential bias related to use of statin therapy, the study estimated propensity scores by logistic regression to determine the predicted probability of inclusion in the "statin" group. Multivariate, stepwise logistic regression was then performed, controlling for patient demographics, medical history, operative characteristics, and propensity score to determine whether preoperative statin therapy was independently associated with a reduction in the risk of early (DOS-POD3) cardiac death and/or nonfatal, in-hospital postoperative myocardial infarction. RESULTS: Preoperative statin therapy was independently associated with a significant reduction (adjusted odds ratio [OR] 0.25; 95% confidence intervals [CI] 0.07-0.87) in the risk of early cardiac death after primary, elective coronary bypass surgery (0.3% vs 1.4%; P < .03), but was not associated with a reduced risk of postoperative nonfatal, in-hospital myocardial infarction (7.9% vs 6.2%; P = not significant). Discontinuation of statin therapy after surgery was independently associated with a significant increase in late (POD4-discharge) all-cause mortality (adjusted OR 2.64; 95% CI 1.32-5.26) compared with continuation of statin therapy (2.64% vs 0.60%; P < .01). This was true even when controlling for the postoperative discontinuation of aspirin, beta-blocker, or angiotensin-converting enzyme inhibitor therapy. Discontinuation of statin therapy after surgery was also independently associated with a significant increase in late cardiac mortality (adjusted OR 2.95; 95% CI 1.31-6.66) compared with continuation of statin therapy (1.91% vs 0.45%; P < 0.01). CONCLUSIONS: Preoperative statin use is associated with reduced cardiac mortality after primary, elective coronary artery bypass grafting. Postoperative statin discontinuation is associated with increased in-hospital mortality. Although further randomized trials are needed to confirm these findings, these data suggest the importance of perioperative statin administration.

Post-reperfusion myocardial infarction: long-term survival improvement using adenosine regulation with acadesine.

OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the adenosine regulating agent (ARA) acadesine for reducing long-term mortality among patients with post-reperfusion myocardial infarction (MI). BACKGROUND: No prospectively applied therapy exists that improves long-term survival after MI associated with coronary artery bypass graft (CABG) surgery-a robust model of ischemia/reperfusion injury. Pretreatment with the purine nucleoside autocoid adenosine mitigates the extent of post-ischemic reperfusion injury in animal models. Therefore, we questioned whether use of the ARA acadesine-by increasing interstitial adenosine concentrations in ischemic tissue-would improve long-term survival after post-reperfusion MI. METHODS: At 54 institutions, 2,698 patients undergoing CABG surgery were randomized to receive placebo (n = 1,346) or acadesine (n = 1,352) by intravenous infusion (0.1 mg/kg/min; 7 h) and in cardioplegia solution (placebo or acadesine; 5 microg/ml). Myocardial infarction was prospectively defined as: 1) new Q-wave and MB isoform of creatine kinase (CK-MB) elevation (daily electrocardiography; 16 serial CK-MB measurements); or 2) autopsy evidence. Vital status was assessed over 2 years, and outcomes were adjudicated centrally. RESULTS: Perioperative MI occurred in 100 patients (3.7%), conferring a 4.2-fold increase in 2-year mortality (p < 0.001) compared with those not suffering MI. Acadesine treatment, however, reduced that mortality by 4.3-fold, from 27.8% (15 of 54; placebo) to 6.5% (3 of 46; acadesine) (p = 0.006), with the principal benefit occurring over the first 30 days after MI. The acadesine benefit was similar among diverse subsets, and multivariable analysis confirmed these findings. CONCLUSIONS: Acadesine is the first therapy proven to be effective for reducing the severity of acute post-reperfusion MI, substantially reducing the risk of dying over the 2 years after infarction.

The risk associated with aprotinin in cardiac surgery.

BACKGROUND: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition--namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken. METHODS: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.) RESULTS: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss. CONCLUSIONS: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

Hormone replacement therapy is safe in women undergoing coronary artery bypass grafting.

In postmenopausal women, hormone replacement therapy (HRT) does not substantially reduce the incidence of cardiovascular disease and may produce a short-term increase in risk. Therefore, we investigated whether HRT increased risk in patients with severe coronary artery disease necessitating surgery We prospectively studied 4,782 patients undergoing coronary artery bypass grafting at 70 centers in 17 countries from November 1996 through June 2000. Patients were selected using a systematic sampling technique. Mortality, major morbidity, and transfusion requirements were compared among 3 groups: men (n=3,840), women receiving HRT (n= 144), and women not receiving HRT (n=798). Women actively receiving HRT, compared with women not receiving HRT or with men, were at no greater risk of developing the following fatal or non-fatal complications: death (2.8% vs 4.4% vs 2.8%, respectively; P=0.05), myocardial infarction (6.3% vs 7.0% vs 7.7%; P=0.67), central nervous system complication (2.1% vs 2.8% vs 2.9%; P=0.85), or renal dysfunction (0.7% vs 5.3% vs 4.8%; P=0.06). Incidence of postoperative congestive heart failure was significantly lower in men (7.7%) than in women receiving HRT (12.5%; P=0.04) and in women without HRT (12.8%; P <0.0001). Fewer men (61%) needed red blood cell transfusion than did women receiving HRT (79%) and women without HRT (88%) (P <0.0001 compared with both other groups). However, the need for fresh frozen plasma transfusions was significantly less in women receiving HRT (16%) than in women not receiving HRT (25%; P=0.01). We conclude that HRT administration before coronary artery bypass grafting does not increase women's risk of any adverse outcome.

Adverse gastrointestinal complications after cardiopulmonary bypass: can outcome be predicted from preoperative risk factors?

UNLABELLED: Adverse gastrointestinal (GI) outcome after cardiac surgery is an infrequent event but is a clinically important health care problem because of associated increased morbidity and mortality. The ability to identify patients at greatest risk before surgery may be helpful in planning appropriate perioperative management strategies. We examined the pre- and intraoperative characteristics of 2417 patients from 24 diverse United States medical centers enrolled in the Multicenter Study of Perioperative Ischemia Study who were undergoing cardiac surgery using cardiopulmonary bypass as predictors for adverse GI outcome. Resource utilization was evaluated for patients with and without adverse GI outcomes. Adverse GI outcomes occurred in 5.5% of patients (133 of 2417), increased in-hospital mortality 6.5-fold, prolonged the mean intensive care unit length of stay by 1 wk, and more than doubled the mean postoperative hospital stay (P < 0.0001). Predictors of adverse GI outcome included decreased left ventricular function, hyperbilirubinemia, thrombocytopenia, prolonged partial thromboplastin time, prior cardiovascular surgery, combined coronary artery bypass graft surgery and intracardiac or proximal aortic surgery, pharmacological cardiovascular support, and intraoperative transfusion. The literature suggests that adverse GI outcome after cardiac surgery is secondary to poor splanchnic perfusion, which many of these risk factors may predict. Therefore, patients deemed to be at risk before surgery may benefit from tightly controlled hemodynamic management and other strategies that optimize perioperative organ perfusion. IMPLICATIONS: We identified the preoperative and intraoperative predictors associated with an increased incidence of postoperative gastrointestinal complications after cardiac surgery using cardiopulmonary bypass. Because these complications are associated with frequent morbidity and mortality, these predictors may be helpful in identifying patients at increased risk so that risk stratification can be modified and perioperative management can be appropriately adjusted.

A multicenter risk index for atrial fibrillation after cardiac surgery.

CONTEXT: Atrial fibrillation is a common, but potentially preventable, complication following coronary artery bypass graft (CABG) surgery. OBJECTIVES: To assess the nature and consequences of atrial fibrillation after CABG surgery and to develop a comprehensive risk index that can better identify patients at risk for atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study of 4657 patients undergoing CABG surgery between November 1996 and June 2000 at 70 centers located within 17 countries, selected using a systematic sampling technique. From a derivation cohort of 3093 patients, associations between predictor variables and postoperative atrial fibrillation were identified to develop a risk model, which was assessed in a validation cohort of 1564 patients. MAIN OUTCOME MEASURE: New-onset atrial fibrillation after CABG surgery. RESULTS: A total of 1503 patients (32.3%) developed atrial fibrillation after CABG surgery. Postoperative atrial fibrillation was associated with subsequent greater resource use as well as with cognitive changes, renal dysfunction, and infection. Among patients in the derivation cohort, risk factors associated with atrial fibrillation were advanced age (odds ratio [OR] for 10-year increase, 1.75; 95% confidence interval [CI], 1.59-1.93); history of atrial fibrillation (OR, 2.11; 95% CI, 1.57-2.85) or chronic obstructive pulmonary disease (OR, 1.43; 95% CI, 1.09-1.87); valve surgery (OR, 1.74; 95% CI, 1.31-2.32); and postoperative withdrawal of a beta-blocker (OR, 1.91; 95% CI, 1.52-2.40) or an angiotensin-converting enzyme (ACE) inhibitor (OR 1.69; 95% CI, 1.38-2.08). Conversely, reduced risk was associated with postoperative administration of beta-blockers (OR, 0.32; 95% CI, 0.22-0.46), ACE inhibitors (OR, 0.62; 95% CI, 0.48-0.79), potassium supplementation (OR, 0.53; 95% CI, 0.42-0.68), and nonsteroidal anti-inflammatory drugs (OR, 0.49; 95% CI, 0.40-0.60). The resulting multivariable risk index had adequate discriminative power with an area under the receiver operating characteristic (ROC) curve of 0.77 in the validation sample. Forty-three percent (640/1503) of patients who had atrial fibrillation after CABG surgery experienced more than 1 episode of atrial fibrillation. Predictors of recurrent atrial fibrillation included older age, history of congestive heart failure, left ventricular hypertrophy, aortic atherosclerosis, bicaval venous cannulation, withdrawal of ACE inhibitor or beta-blocker therapy, and use of amiodarone or digoxin (area under the ROC curve of 0.66). Patients with recurrent atrial fibrillation had longer hospital stays and experienced greater infectious, renal, and neurological complications than those with a single episode. CONCLUSIONS: We have developed and validated models predicting the occurrence of atrial fibrillation after CABG surgery based on an analysis of a large multicenter international cohort. Our findings suggest that treatment with beta-blockers, ACE inhibitors, and/or nonsteroidal anti-inflammatory drugs may offer protection. Atrial fibrillation after CABG surgery is associated with important complications.

Impact of pexelizumab, an anti-C5 complement antibody, on total mortality and adverse cardiovascular outcomes in cardiac surgical patients undergoing cardiopulmonary bypass.

BACKGROUND: During cardiac surgery requiring cardiopulmonary bypass, pro-inflammatory complement pathways are activated by exposure of blood to bio-incompatible surfaces of the extracorporeal circuit and reperfusion of ischemic organs. Complement activation promotes the generation of additional inflammatory mediators thereby exacerbating tissue injury. We examined the safety and efficacy of a C5 complement inhibitor for attenuating inflammation-mediated cardiovascular dysfunction in cardiac surgical patients undergoing cardiopulmonary bypass. METHODS: Pexelizumab (Alexion Pharmaceuticals, Inc, Cheshire, CT), a recombinant, single-chain, anti-C5 monoclonal antibody, was evaluated in a randomized, double-blinded, placebo-controlled, multicenter trial that involved 914 patients undergoing coronary artery bypass grafting with or without valve surgery requiring cardiopulmonary bypass. RESULTS: Pexelizumab was administered intravenously as a bolus (2.0 mg/kg) or bolus plus infusion (2.0 mg/kg plus 0.05 mg/kg/h for 24 hours), and inhibited complement activation. There were no statistically significant differences between placebo-treated and pexelizumab-treated patients in the primary endpoint (composite of death, or new Q-wave, or non-Q-wave [myocardial-specific isoform of creatine kinase > 60 ng/mL] myocardial infarction, or left ventricular dysfunction, or new central nervous system deficit). However, post hoc analysis revealed a reduction in the composite of death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) for the isolated coronary artery bypass grafting, bolus plus infusion subgroup on POD 4 (p = 0.007) and on POD 30 (p = 0.004). CONCLUSIONS: Pexelizumab had no statistically significant effect on the primary endpoint. However, the reduction in death or myocardial infarction (myocardial-specific isoform of creatine kinase >/= 100 ng/mL) as revealed in the post hoc analysis in the isolated coronary artery bypass grafting bolus plus infusion subpopulation, suggests that further investigation of anti-C5 therapy for ameliorating complement-mediated inflammation and myocardial injury is warranted.