John C. Chen

Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: Results of the CABG surgery cohort of the GUARDIAN study

OBJECTIVESnTo evaluate the effects of cariporide on all-cause mortality or myocardial infarction at 36 days in patients at risk of myocardial necrosis after coronary artery bypass graft surgery.nnnMETHODSnIn the coronary artery bypass graft cohort of the GUARD During Ischemia Against Necrosis trial, patients > or =18 years who required urgent coronary artery bypass graft, repeat coronary artery bypass graft, or had a history of unstable angina and > or =2 risk factors (age >65 years, female gender, diabetes mellitus, ejection fraction <35%, or left main or 3-vessel disease) were randomized to placebo (n = 743) or cariporide 20 mg (n = 736), 80 mg (n = 705), or 120 mg (n = 734). A 1-hour intravenous infusion was initiated shortly before surgery and administered every 8 hours for 2 to 7 days. Patients were followed up for 6 months. A nonparametric covariance analysis was used to calculate the primary efficacy endpoint.nnnRESULTSnBaseline characteristics were similar between treatment groups. The cariporide 20- and 80-mg groups had event rates similar to placebo. The endpoint of all-cause mortality or myocardial infarction at day 36 was significant with cariporide 120 mg versus placebo (event rate 12.2% vs 16.2%; P =.027). The risk reduction was evident on postoperative day 1 (3.3% vs 6.5%; P =.005) and was maintained at 6 months (event rate 15.0% vs 18.6%; P =.033). Cariporide was well tolerated, and most adverse events were mild and transient in this high-risk population.nnnCONCLUSIONSnClinical benefit with cariporide 120 mg was observed early after treatment initiation and continued for 6 months postsurgery, suggesting that sodium-hydrogen exchange inhibition with cariporide is cardioprotective in patients undergoing high-risk coronary artery bypass graft surgery.

Effects of C5 complement inhibitor pexelizumab on outcome in high-risk coronary artery bypass grafting: combined results from the PRIMO-CABG I and II trials.

OBJECTIVEnThe previous Pexelizumab for Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery I (PRIMO-CABG I) trial (n = 3099) indicated that C5 complement inhibition with pexelizumab might reduce myocardial infarction (MI) and postoperative mortality. PRIMO-CABG II was designed to investigate the safety and efficacy of terminal complement inhibition in reducing perioperative MI and mortality in patients undergoing CABG surgery who have 2 or more predefined preoperative risk factors.nnnMETHODSnPRIMO-CABG II, a randomized, double-blind, placebo-controlled trial, enrolled 4254 patients undergoing CABG with or without valve surgery at 249 hospitals in North America and Western Europe from June 2004 to July 2005. The patients were randomly assigned to receive intravenous pexelizumab or placebo. The primary composite endpoint was the incidence of death or MI within 30 days of randomization.nnnRESULTSnThe PRIMO-CABG II trial did not meet its prespecified primary endpoint of death or MI at 30 days, the secondary endpoints of death at 30 days, or the development of new or worsening congestive heart failure (relative risk 0.91, 0.82, and 1.01, respectively; P > .05). However, in a combined analysis of both pivotal trials, PRIMO-CABG I and II (n = 7353), death at 30 days was significantly reduced for the greatest risk subset (n = 2156, pexelizumab 5.7% vs placebo 8.1%, P = .024). Furthermore, this mortality reduction persisted throughout the 180-day follow-up period (pexelizumab 11.1% vs placebo 14.4%, P = .036).nnnCONCLUSIONSnPexelizumab was associated with a nonsignificant 6.7% reduction in the primary composite endpoint of death or MI at postoperative day 30 in CABG patients enrolled in the PRIMO-CABG II trial, despite the suggestion of a more favorable treatment effect in the previous PRIMO-CABG I trial. However, an exploratory analysis of the combined PRIMO I and II data set using an established predictive risk model showed a mortality benefit for high-risk surgical patients.

Preliminary Report of the Effects of Complement Suppression With Pexelizumab on Neurocognitive Decline After Coronary Artery Bypass Graft Surgery

Background and Purpose— Pharmacological modulation of complement activation recently has been postulated as a therapeutic target in the treatment of neurological injury. We hypothesized that pexelizumab, a humanized scFv monoclonal antibody directed against the C5 complement component, would limit deficits in patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass. Methods— The Phase II Pexelizumab study was a 914-patient, double-blind, placebo-controlled, 65-center study of patients undergoing coronary artery bypass graft surgery. Patients were randomized to pexelizumab bolus, bolus plus infusion, or placebo. Neurological and neurocognitive functions were assessed as secondary endpoints at baseline and on postoperative days (POD) 4 and 30. Cognitive deficits were assessed with multivariable tests accounting for baseline cognition, age, diabetes, years of education, sex, elevated creatinine, history of myocardial infarction, neurological disorder or congestive heart failure, and cardiopulmonary bypass time. Results— Pexelizumab had no statistically significant effect on the primary composite endpoint or on overall cognition. When domain specific effects were examined, a decline of at least 10% in the visuo-spatial domain was observed on POD 4 in 56% of patients receiving placebo compared with 40% receiving pexelizumab by bolus and infusion (P=0.003). Similarly, on POD 30, a 10% decline was present in 21% of patients in the placebo group versus only 12% of the drug bolus plus infusion group (P=0.016). No differences were seen between treatment groups in any of the other domains. Conclusions— Pexelizumab administration for 24 hours perioperatively had no effect on global measures of cognition but may reduce dysfunction in the visuo-spatial domain.

Myocardial infarction following coronary artery bypass graft surgery increases healthcare resource utilization.

Objective:To assess the health economic impact of perioperative myocardial infarction in a cohort of patients undergoing coronary artery bypass graft surgery. Design:Retrospective cohort analysis using data from hospital bills and uniform billing forms. Setting:A total of 147 geographically diverse hospitals in the United States. Patients:The study population consisted of 2,102 coronary artery bypass graft surgery patients enrolled in the PRIMO-CABG trial at U.S. sites between January 2002 and February 2003. Interventions:None. Measurements and Main Results:Resource utilization and costs during the index hospitalization and during a 6-month follow-up period were compared between patients who had a myocardial infarction by postoperative day 4 and those who did not. Linear regression was used to examine whether myocardial infarction by day 4 was associated with index hospitalization costs, after adjusting for baseline characteristics. Myocardial infarction occurred in 191 (9.1%) patients undergoing coronary artery bypass graft surgery. Myocardial infarction was associated with a doubling of intensive care unit time (3.5 days among patients with no myocardial infarction and 7.1 days among patients with myocardial infarction, p < .01) and a 48% increase in hospital length of stay. Myocardial infarction by day 4 was associated with a 43% increase in hospital costs, a 29% increase in physician service costs, a 41% increase in total costs during the index hospitalization, and a 38% increase in cumulative 6-month costs. After baseline adjustment, myocardial infarction continued to be associated with higher index hospitalization costs. Conclusions:Myocardial infarction following coronary artery bypass graft surgery was associated with a significant increase in intensive care unit time, hospital length of stay, and overall costs, which contributed to greater hospital and physician service costs. Healthcare resource utilization is increased in patients sustaining a myocardial infarction following coronary artery bypass graft surgery.

Pharmacologic C5‐Complement Suppression Reduces Blood Loss During On‐Pump Cardiac Surgery

Abstractu2003 Background: Inflammation contributes to morbidity following on‐pump cardiac surgery. Complement activation during cardiopulmonary bypass has been associated with the postoperative bleeding and tissue injury. This study examines the pharmacology and impact on blood loss of complement C5 suppression with pexelizumab in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Pexelizumab, a humanized monoclonal antibody single‐chain fragment that binds to the human C5 complement component, was studied in a Phase II multicentered clinical trial. CABG (n = 800) and CABG with concomitant valve surgery (n = 114) patients were evaluated. Patients were randomized to either: pexelizumab bolus (2.0 mg/kg) + placebo infusion; pexelizumab bolus (2.0 mg/kg) + pexelizumab infusion (0.05 mg/kg/hour for 24 hours); or placebo bolus + placebo infusion. Pharmacology, chest tube drainage, and transfusion requirements were assessed. Results: Mean maximum pexelizumab serum concentration was similar for bolus and bolus + infusion‐treated patients. Complement‐dependent serum hemolytic activity was completely suppressed within 1 hour following pexelizumab bolus, however, suppression was maintained for a longer duration in the bolus + infusion compared to the bolus‐only treated patients. A reduction in chest tube drainage was observed for all pexelizumab‐treated patients, although transfusion of blood products was similar across all study groups. Conclusion: Pexelizumab administration inhibits complement‐dependent hemolytic activity and is associated with a reduction in postoperative chest tube drainage in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Further, clinical studies are needed to assess the value of complement attenuation in this setting.

Analysis of mitral valve replacement outcomes is enhanced by meaningful clinical use of electronic health records.

OBJECTIVEnCardiac surgical mortality has improved during the last decade despite the aging of the population. An integrated US health plan developed a heart valve registry to track outcomes and complications of heart valve operations. This database was used for longitudinal evaluation of mitral valve (MV) outcomes from 1999 to 2008 at four affiliated hospitals.nnnMETHODSnWe identified 3130 patients in the Apollo database who underwent 3180 initial MV procedures. Internal administrative and Social Security Administration databases were merged to determine survival rates. Electronic health records were searched to ascertain demographics, comorbidities, and postoperative complications. Cox regression was used to evaluate mean survival and identify risk factors.nnnRESULTSnThe procedures included 1160 mechanical valve replacements, 1159 tissue valve replacements, and 861 annuloplasties. The mean age of patients undergoing these procedures was 58 ± 11 years, 69 ± 12 years, and 62 ± 12 years, respectively. Mean survival was 8.9 ± 0.1 years for mechanical valve replacement, 7.0 ± 0.1 years for tissue valve replacement, and 7.7 ± 0.1 years for annuloplasty. Early in the study, there was a preference for implanting mechanical MVs. Beginning in 2003, more patients received tissue valve replacements rather than mechanical valves. Over time, there was an increasing trend of annuloplasty. Cox regression analysis identified the following risk factors for increased ten-year mortality: tissue valve implantation; advanced age; female sex; nonelective, nonisolated procedure; diabetes; postoperative use of banked blood products; previous cardiovascular intervention; dialysis; and longer perfusion time. Hospital location, reoperation, preoperative anticoagulation, and cardiogenic shock were not statistically significant risk factors.nnnCONCLUSIONSnWhen controlling for other risk factors, we observed a lower long-term survival rate for tissue valve replacement compared with mechanical valve replacement. Integrating electronic health records with existing electronic databases provided near-real-time analysis of longitudinal cardiac surgical outcomes.

Western Thoracic Surgical Association 2013 presidential address: winning the HITECH challenge.

It is heartwarming for me to be presented to you by Tom Burdon, a distinguished colleague and sincere friend. A ‘‘thank you’’ to Bobby, our immediate past president for his leading our strategic planning. I want to thank you all for joining us as we celebrate a wonderful tradition: the address of a new president. Your presence honors the Western Thoracic Surgical Association (WTSA), which members affectionately refer to as the Western. WTSA is an association that has been strengthened throughout its history by upholding the highest values of science, integrity, collegiality, and openness to people from around the world. By being here today, you are stating your desire for us to continue embodying everything that is good and principled about self-learning. I humbly recognize that I am just the guardian of something much larger than myself and much larger than all of us. I am the temporary guardian of an organization that means so much to so many, and, in that capacity, I sincerely thank you all for being here. I want to offer a special greeting to those families present, which are among WTSA’s friends—you are the great force who lives out our dreams. I am deeply grateful for the company of our many distinguished colleagues from all over the world. We need you here, of course, to make the day seem properly serious. It is good to confirm that the presidents of theWTSAdo look presidential in their roles as I am trying in mine. I must express how honored I am to have been so chosen: As a simple, community cardiothoracic surgeon. Fifteen years ago, I became a member, and like most initiates, I knew surprising little about the ‘‘Western’’ culture. I distinctly recall wearing a suit and tie at my first scientific session, and I believe I have not sported another at our annual meeting until today. You might wonder why I dressed the way I did: As a new member attending his first ever Western meeting, I erroneously assumed STS (Society of Thoracic Surgeons) etiquette! Let me again welcome our 19 newmembers of 2013 and invite them to participate in the discussions throughout our stay in Coeur D’Alene.