John L. Knight

Sodium-Hydrogen Exchange Inhibition by Cariporide to Reduce the Risk of Ischemic Cardiac Events in Patients Undergoing Coronary Artery Bypass Grafting: Results of the EXPEDITION Study

BACKGROUND The EXPEDITION study addressed the efficacy and safety of inhibiting the sodium hydrogen exchanger isoform-1 (NHE-1) by cariporide in the prevention of death or myocardial infarction (MI) in patients undergoing coronary artery bypass graft surgery. The premise was that inhibition of NHE-1 limits intracellcular Na accumulation and thereby limits Na/Ca-exchanger-mediated calcium overload to reduce infarct size. METHODS High-risk coronary artery bypass graft surgery patients (n = 5,761) were randomly allocated to receive either intravenous cariporide (180 mg in a 1-hour preoperative loading dose, then 40 mg per hour over 24 hours and 20 mg per hour over the subsequent 24 hours) or placebo. The primary composite endpoint of death or MI was assessed at 5 days, and patients were followed for as long as 6 months. RESULTS At 5 days, the incidence of death or MI was reduced from 20.3% in the placebo group to 16.6% in the treatment group (p = 0.0002). Paradoxically, MI alone declined from 18.9% in the placebo group to 14.4% in the treatment group (p = 0.000005), while mortality alone increased from 1.5% in the placebo group to 2.2% with cariporide (p = 0.02). The increase in mortality was associated with an increase in cerebrovascular events. Unlike the salutary effects that were maintained at 6 months, the difference in mortality at 6 months was not significant. CONCLUSIONS The EXPEDITION study is the first phase III myocardial protection trial in which the primary endpoint was achieved and proof of concept demonstrated. As a result of increased mortality associated with an increase in cerebrovascular events, it is unlikely that cariporide will be used clinically. The findings suggest that sodium hydrogen exchanger isoform-1 inhibition holds promise for a new class of drugs that could significantly reduce myocardial injury associated with ischemia-reperfusion injury.

Mood state as a predictor of neuropsychological deficits following cardiac surgery.

OBJECTIVES mood disorders and neuropsychological deficits are both commonly reported occurrences after cardiac surgery. We examined the relationship between mood state and postoperative cognitive deficits in this population. METHODS assessments of neuropsychological functions and mood state (depression, anxiety, stress scales; DASS) were performed preoperatively and postoperatively on 147 patients undergoing cardiac surgery. RESULTS the incidence of preoperative depression, anxiety, and stress symptomatology was 16%, 27%, and 16%, respectively. The incidence of postoperative anxiety symptomatology significantly increased to 45% (p<0.001), while the incidence of depression and stress symptomatology remained stable (19% and 15%, respectively; ns). Changes in mood state did not influence changes in neuropsychological performance. Preoperative mood was a strong predictor of postoperative mood, and was related to postoperative deficits on measures of attention and memory. CONCLUSIONS an assessment of preoperative mood is critical in identifying patients at risk of postoperative mood disorders and neuropsychological deficits. Measures assessing somatic manifestations of anxiety may not be suitable for a surgical population.

Preoperative depression and mortality in coronary artery bypass surgery: Preliminary findings

Background: There is convincing evidence to suggest that depression significantly increases the risk of mortality following myocardial infarction. There are few data concerning depression as a risk factor for mortality following cardiac surgery. The aim of the present observational study was to determine if preoperative depressive symptoms resulted in an increased risk of late mortality following cardiac surgery.

Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) Trial : Rationale and design

BACKGROUND Despite some concern that recent aspirin ingestion increases blood loss after coronary artery surgery, there is some evidence that this may reduce thrombotic complications. In contrast, antifibrinolytic drugs can reduce blood loss in this setting, but there is concern that they may increase thrombotic complications. Published guidelines are limited by a lack of large randomized trials addressing the risks and benefits of each of these commonly used therapies in cardiac surgery. The ATACAS Trial is a study comparing aspirin, tranexamic acid, or both, with placebo in patients undergoing on-pump or off-pump coronary artery surgery. METHODS We discuss the rationale for conducting ATACAS, a 4600-patient, multicenter randomized trial in at-risk coronary artery surgery, and the features of the ATACAS study design (objectives, end points, target population, allocation, treatments, patient follow-up, and analysis). CONCLUSIONS The ATACAS Trial will be the largest study yet conducted to ascertain the benefits and risks of aspirin and antifibrinolytic therapy in coronary artery surgery. Results of the trial will guide the routine clinical care of patients in this setting.

Survival After Isolated Coronary Artery Bypass Grafting in Patients With Severe Left Ventricular Dysfunction

BACKGROUND The number of patients with severe left ventricular dysfunction referred for coronary artery bypass graft surgery (CABG) continues to increase. The aim of this study was to document the long-term survival in this group. METHODS The 30-day mortality and long-term survival outcome of 162 patients with severely depressed left ventricular ejection fraction (LVEF [< or = 30%]) who had consecutive isolated CABG between 1996 and 2005 were compared with 661 patients who had impaired LVEF (31% to 59%) and 1,231 patients with normal LVEF (> or = 60%). RESULTS The 30-day mortality for patients with severely depressed LVEF was 5.6%. The median survival for deceased patients was 3.4 years (interquartile range, 1.3 to 5.9). The risk of all-cause mortality attributable to severe left ventricular dysfunction was increased twofold compared with having normal LVEF (hazard ratio = 2.28; 95% confidence interval: 1.64 to 3.18; p < 0.001). Among the covariates, older age, emergency surgery, mitral incompetence, smoking history, respiratory disease, diabetes mellitus, cerebrovascular disease, intensive care unit intubation for 24 hours or more, postoperative renal failure, postoperative pleural effusion, and nonuse of left internal mammary artery were detected as significant predictors of increased mortality risk. CONCLUSIONS The mortality rate among CABG patients with severely depressed LVEF was comparable to that reported in other series. Severe left ventricular dysfunction carried more than a twofold increased mortality risk compared with patients who had an impaired LVEF, adjusted for traditional risk factors. These data suggest that LVEF has an impact on long-term patient survival even after preoperative covariates and postoperative morbidity outcomes are considered.

Neuropsychologic and Quality-of-Life Outcomes After Coronary Artery Bypass Surgery With and Without Cardiopulmonary Bypass: A Prospective Randomized Trial

OBJECTIVES The objective of this study was to compare neuropsychologic and quality-of-life outcomes of patients undergoing off-pump coronary artery bypass surgery to those undergoing coronary artery bypass graft surgery using conventional cardiopulmonary bypass. DESIGN A prospective randomized trial of coronary artery bypass graft surgery with and without the use of cardiopulmonary bypass. SETTING A cardiothoracic surgery unit at a tertiary hospital. PARTICIPANTS Sixty-six patients undergoing coronary artery bypass graft surgery and a control group of 50 participants not undergoing cardiac surgery. INTERVENTIONS Patients were randomized to receive coronary artery bypass graft surgery with cardiopulmonary bypass or randomized to coronary artery bypass graft surgery without the use of cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS The proportions of neuropsychologic deficits and improvement in quality-of-life were comparable regardless of whether patients were randomized to receive off-pump coronary artery bypass graft surgery or conventional coronary artery graft surgery with cardiopulmonary bypass. CONCLUSIONS Patients receiving coronary artery bypass grafts without cardiopulmonary bypass did not show fewer cognitive deficits or greater improvement in quality of life.

Neuropsychological dysfunction after minimally invasive direct coronary artery bypass grafting

BACKGROUND We compared postoperative neuropsychological dysfunction after minimally invasive direct coronary artery bypass grafting (MIDCAB) operation with coronary artery bypass graft operations using cardiopulmonary bypass. METHODS Neuropsychological assessment was performed preoperatively and before discharge on 7 patients undergoing MIDCAB procedures, 9 patients undergoing single-graft cardiopulmonary bypass operation, and 27 patients undergoing multiple-graft cardiopulmonary bypass operation. From a matched control group of 40 normal subjects reliable change indices were derived for each measure and used to determine the incidence of postoperative decline. RESULTS There was little difference between the MIDCAB and single-graft cardiopulmonary bypass groups on the incidence of neuropsychologic decline. However, the multiple-graft cardiopulmonary bypass group had a significantly higher incidence of decline than the MIDCAB and single-graft cardiopulmonary bypass groups on specific neuropsychologic measures, coupled with a significantly greater number of postoperative deteriorations per patient. CONCLUSIONS The elimination of cardiopulmonary bypass does not prevent neuropsychological dysfunction after cardiac operation as patients undergoing MIDCAB and single-graft cardiopulmonary bypass experience similar deteriorations in performance. However, the deterioration is markedly worsened when the number of surgical grafts is increased.

Neuropsychological function 5 years after cardiac surgery and the effect of psychological distress.

Research has shown conflicting results with regard to the influence of depression and anxiety on neuropsychological performance following coronary artery bypass graft (CABG) surgery. Notably, the independent effects of depression and anxiety have not been examined among CABG candidates in the longer term where it is has been suggested that these patients show marked cognitive deterioration. A neuropsychological test battery and measures of psychological distress were completed by 86 CABG patients and 50 nonsurgical control participants at baseline and 6 months, whereas 75 patients and 36 controls, respectively, completed a 5-year follow-up. In CABG patients, cognitive and affective depressive symptoms were independently associated with lower and worse performance on the Boston Naming Test, Purdue Peg Board, and Digit Symbol Coding 6 months after surgery, whereas at 5-year follow-up an effect for Digit Symbol persisted, and an association was also observed for the Trail Making Test (TMT). On average, CABG patients performed worse on TMT and Digit Symbol at 6 months, whereas at 5-year follow-up their performance was worse on short-term delayed verbal recall. The results among the CABG patients did not show a consistent pattern of association between psychological distress and those neuropsychological domains that were on average significantly lower than a nonsurgical control group. The results here also support the use of nonbiased statistical methodology to document dysfunction among heterogeneous cognitive domains after CABG surgery.

Female Sex as an Independent Predictor of Morbidity and Survival After Isolated Coronary Artery Bypass Grafting

BACKGROUND This study sought to determine whether female sex was an independent risk factor for combined in-hospital morbidity, mortality, and long-term survival after coronary artery bypass grafting (CABG). METHODS Data were collected prospectively for 1,114 (23.5%) women and 3,628 (76.5%) men operated on between January 1, 1996 and December 31, 2004 with median follow-up of 7.9 years (interquartile range 3.55 to 10.5). The combined morbidity end point was defined as in-hospital renal failure, stroke, ventilation for more than 24 hours, deep sternal wound infection, reoperation, myocardial infarction (MI), and mortality less than 30 days after discharge. The long-term all-cause and cardiac mortality outcomes were analyzed using multivariate proportional hazard regression. RESULTS Females were older, with lower body surface area, and generally had more significant comorbid conditions than did males (p<0.05). Female sex was associated with increased odds of the combined morbidity end point (adjusted odds ratio [OR]=1.29; 95% confidence interval, 1.04 to 1.59, p=0.02). There were 868 deaths (18.3% of total sample) during the follow-up period, and 305 deaths (n=305 [35.1%] of deaths) were deemed to be of cardiac causes. In adjusted survival models, female sex was associated with cardiac mortality (hazard ratio [HR]=1.28; 95% confidence interval, 0.96 to 1.73; p=0.10) but not with all-cause mortality (HR=0.92; 95% confidence interval, 0.77 to 1.11; p=0.38). CONCLUSIONS Female sex was associated with early combined morbidity and long-term cardiac mortality but not long-term all-cause mortality. A greater proportion of concomitant risk factors characterize female patients undergoing CABG.

Assessment of myocardial injury by troponin T in off‐pump coronary artery grafting and conventional coronary artery graft surgery

Purpose: The present study was undertaken to assess the degree of myocardial injury, using troponin T (TnT), in off‐pump coronary artery surgery (OPCAB) and in a comparable patient group undergoing conventional coronary artery graft surgery (CABG).