Keith B. Allen

Effect of an Investigational Vaccine for Preventing Staphylococcus aureus Infections After Cardiothoracic Surgery: A Randomized Trial

IMPORTANCEnInfections due to Staphylococcus aureus are serious complications of cardiothoracic surgery. A novel vaccine candidate (V710) containing the highly conserved S. aureus iron surface determinant B is immunogenic and generally well tolerated in volunteers.nnnOBJECTIVEnTo evaluate the efficacy and safety of preoperative vaccination in preventing serious postoperative S. aureus infection in patients undergoing cardiothoracic surgery.nnnDESIGN, SETTING, AND PARTICIPANTSnDouble-blind, randomized, event-driven trial conducted between December 2007 and August 2011 among 8031 patients aged 18 years or older who were scheduled for full median sternotomy within 14 to 60 days of vaccination at 165 sites in 26 countries.nnnINTERVENTIONnParticipants were randomly assigned to receive a single 0.5-mL intramuscular injection of either V710 vaccine, 60 μg (n = 4015), or placebo (n = 4016).nnnMAIN OUTCOME MEASURESnThe primary efficacy end point was prevention of S. aureus bacteremia and/or deep sternal wound infection (including mediastinitis) through postoperative day 90. Secondary end points included all S. aureus surgical site and invasive infections through postoperative day 90. Three interim analyses with futility assessments were planned.nnnRESULTSnThe independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. At the end of the study, the V710 vaccine was not significantly more efficacious than placebo in preventing either the primary end points (22/3528 V710 vaccine recipients [2.6 per 100 person-years] vs 27/3517 placebo recipients [3.2 per 100 person-years]; relative risk, 0.81; 95% CI, 0.44-1.48; P = .58) or secondary end points despite eliciting robust antibody responses. Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (1219/3958 vaccine recipients [30.8%; 95% CI, 29.4%-32.3%] and 866/3967 placebo recipients [21.8%; 95% CI, 20.6%-23.1%], including 797 [20.1%; 95% CI, 18.9%-21.4%] and 378 [9.5%; 95% CI, 8.6%-10.5%] with injection site reactions and 66 [1.7%; 95% CI, 1.3%-2.1%] and 51 [1.3%; 95% CI, 1.0%-1.7%] with serious adverse events, respectively) and a significantly higher rate of multiorgan failure during the entire study (31 vs 17 events; 0.9 [95% CI, 0.6-1.2] vs 0.5 [95% CI, 0.3-0.8] events per 100 person-years; P = .04). Although the overall incidence of vaccine-related serious adverse events (1 in each group) and the all-cause mortality rate (201/3958 vs 177/3967; 5.7 [95% CI, 4.9-6.5] vs 5.0 [95% CI, 4.3-5.7] deaths per 100 person-years; P = .20) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs 4/96; 23.0 [95% CI, 12.9-37.9] vs 4.2 [95% CI, 1.2-10.8] per 100 person-years; difference, 18.8 [95% CI, 8.0-34.1] per 100 person-years).nnnCONCLUSIONS AND RELEVANCEnAmong patients undergoing cardiothoracic surgery with median sternotomy, the use of a vaccine against S. aureus compared with placebo did not reduce the rate of serious postoperative S. aureus infections and was associated with increased mortality among patients who developed S. aureus infections. These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00518687.

Relationship Between Vein Graft Failure and Subsequent Clinical Outcomes After Coronary Artery Bypass Surgery

Background— Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes. Methods and Results— Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21–2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71–1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77–1.53; P=0.65). Conclusions— VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

Use of the Kansas City Cardiomyopathy Questionnaire for Monitoring Health Status in Patients With Aortic Stenosis

Background— Improving functional status and quality of life are important goals of treatment for patients with severe aortic stenosis. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a heart failure health status measure and has been used in studies of patients with aortic stenosis. However, its psychometric properties have not yet been evaluated in these patients. Methods and Results— We analyzed data from 955 patients, enrolled in the PARTNER trial of transcatheter aortic valve replacement, to evaluate the reliability, responsiveness, validity, and prognostic importance of the KCCQ in patients with severe aortic stenosis. The KCCQ was administered at baseline and at 1, 6, and 12 months after randomization to medical therapy, transcatheter aortic valve replacement, or surgical valve replacement. Among clinically stable patients, there were only small changes in the KCCQ domain scores over time (mean differences 0.1–4.2 points), and the intraclass correlation coefficients showed good agreement between paired assessments (0.65–0.76). However, the domain scores of patients who underwent transcatheter aortic valve replacement showed large changes after treatment (mean differences 13–30 points). Construct validity was demonstrated by comparing each domain against a relevant reference measure (Spearman correlations 0.46–0.69). Finally, among 157 patients randomized to medical management, lower KCCQ overall summary scores at baseline were strongly associated with an increased risk of mortality during the following 12 months. Conclusions— The KCCQ is a highly reliable, responsive, and valid measure of symptoms, functional status, and quality of life in patients with severe, symptomatic aortic stenosis.

Edifoligide and long-term outcomes after coronary artery bypass grafting: PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) 5-year results

BACKGROUNDnEdifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes.nnnMETHODSnA total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.nnnRESULTSnFive-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 [95% CI 0.89-1.18], P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure.nnnCONCLUSIONSnUp to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG.

Epidemiology and outcome of major postoperative infections following cardiac surgery: Risk factors and impact of pathogen type

BACKGROUNDnMajor postoperative infections (MPIs) are poorly understood complications of cardiac surgery. We examined the epidemiology, microbiology, and outcome of MPIs occurring after cardiac surgery.nnnMETHODSnThe study cohort was drawn from the Society of Thoracic Surgeon National Cardiac Database and comprised adults who underwent cardiac surgery at 5 tertiary hospitals between 2000 and 2004. We studied the incidence, microbiology, and risk factors of MPI (bloodstream or chest wound infections within 30 days after surgery), as well as 30-day mortality. We used multivariate regression analyses to evaluate the risk of MPI and mortality.nnnRESULTSnMPI was identified in 341 of 10,522 patients (3.2%). Staphylococci were found in 52.5% of these patients, gram-negative bacilli (GNB) in 24.3%, and other pathogens in 23.2%. High body mass index, previous coronary bypass surgery, emergency surgery, renal impairment, immunosuppression, cardiac failure, and peripheral/cerebrovascular disease were associated with the development of MPI. Median postoperative duration of hospitalization (15 days vs 6 days) and mortality (8.5% vs 2.2%) were higher in patients with MPIs. Compared with uninfected individuals, odds of mortality were higher in patients with S aureus MPIs (adjusted odds ratio, 3.7) and GNB MPIs (adjusted odds ratio, 3.0).nnnCONCLUSIONSnStaphylococci accounted for the majority of MPIs after cardiac surgery. Mortality was higher in patients with Staphylococcus aureus- and GNB-related MPIs than in patients with MPIs caused by other pathogens and uninfected patients. Preventive strategies should target likely pathogens and high-risk patients undergoing cardiac surgery.

Incidence of and Preoperative Risk Factors for Staphylococcus aureus Bacteremia and Chest Wound Infection After Cardiac Surgery

OBJECTIVEnStaphylococcus aureus infections after cardiac surgery result in significant morbidity and mortality. Identifying patients at elevated risk for these infections preoperatively could facilitate efforts to reduce infection rates. The objectives of this study were to estimate the incidence of postoperative S. aureus infections in cardiac surgery patients, to identify preoperative risk factors for these infections, and to establish a patient risk profile by means of data available to clinicians prior to surgery.nnnDESIGNnCohort study.nnnSETTINGnEight medical centers that participate in the Society of Thoracic Surgeons National Cardiac Database.nnnPATIENTSnPatients who were undergoing elective cardiac surgery during the period January 1, 2000 through December 31, 2004.nnnMETHODSnClinical and microbiological data from 16,386 patients were combined. Multivariable stepwise logistic regression analysis was performed to predict S. aureus infection, which was defined by culture results.nnnRESULTSnOf the 16,386 patients, 205 (1.3%) developed S. aureus bloodstream or chest wound infection within 90 days after surgery. On multivariable analysis, bootstrap-validated preoperative risk factors for S. aureus bloodstream or chest wound infection included a body mass index greater than 40 (adjusted odds ratio [aOR], 1.9 [95% confidence interval {CI}, 1.1-3.2]), chronic renal failure (aOR, 1.8 [95% CI, 1.1-2.9]), and chronic lung disease (aOR, 1.4 [95% CI, 1.0-2.0]). Only 8 patients had all 3 risk factors.nnnCONCLUSIONSnAlthough preoperative risk factors can be easily identified, the majority of patients who developed S. aureus infections after cardiac surgery did not have any risk factors. Preventive measures should not be restricted to a select group of cardiac surgery patients and should rather address the entire patient population.

Transmyocardial laser revascularization: from randomized trials to clinical practice. A review of techniques, evidence-based outcomes, and future directions.

Cardiac surgeons are increasingly faced with a more complex patient who has developed a pattern of diffuse coronary artery disease that cannot be completely revascularized by CAGB alone. Considering the increased operative and long-term cardiac risks predicted by incomplete revascularization, and the documented operative and long-term benefits associated with sole therapy and adjunctive TMR in randomized patients with diffuse coronary artery disease, increased use of sole therapy and adjunctive TMR therapy is warranted.

Mid term results after bone marrow laser revascularization for treating refractory angina

BackgroundTo evaluate the midterm results of patients with angina and diffuse coronary artery disease treated with transmyocardial revascularization in combination with autologous stem cell therapy.MethodsNineteen patients with diffuse coronary artery disease and medically refractory class III/IV angina were evaluated between June 2007 and December 2009 for sole therapy TMR combined with intramyocardial injection of concentrated stem cells. At the time of surgery, autologous bone marrow (120cc) was aspirated from the iliac crest. A cardiac MRI and an isotopic test were performed before and after the procedure. Follow-up was performed by personal interview.ResultsThere were no perioperative adverse events including no arrhythmias. Mean number of laser channels was 20 and the mean total number of intramyocardially injected cells per milliliter were: total mononuclear cells(83.6 × 106), CD34+ cells(0.6 × 106), and CD133+ cells(0.34 × 106). At 12 months mean follow-up average angina class was significantly improved (3.4 ± 0.5 vs 1.4 ± 0.6; p = 0.004). In addition, monthly cardiovascular medication usage was significantly decreased (348 ± 118 vs. 201 ± 92; p = 0.001). At six months follow up there was a reduction in the number of cardiac hospital readmissions (2.9 ± 2.3 vs. 0.5 ± 0.8; p < 0.001). MRI showed no alterations regarding LV volumes and a 3% improvement regarding ejection fraction.ConclusionsThe stem cell isolator efficiently concentrated autologous bone marrow derived stem cells while the TMR/stem cell combination delivery device worked uneventfully. An improvement in clinical status was noticed in the midterm follow-up. Images test showed no morphological alterations in the left ventricle after the procedure.

Staphylococcus aureus Infections after Elective Cardiothoracic Surgery: Observations from an International Randomized Placebo-Controlled Trial of an Investigational S. aureus Vaccine

Background u2003An unmet need to prevent Staphylococcus aureus (SA) infections after cardiothoracic surgery persists despite current practices. Cost-effective implementation of preventive strategies requires contemporary knowledge about modifiable risk factors. Methods u2003From 2007 to 2011, an international, double-blind, randomized placebo-controlled trial of a novel SA vaccine (V710) was conducted in 7664 adults scheduled for median sternotomy at 164 sites. We analyzed SA infections developing up to 360 days postoperatively in 3832 placebo recipients. Results u2003Coronary artery bypass grafting was performed in 80.8% (3096 of 3832) of placebo recipients. The overall incidence of any postoperative SA infection was 3.1% (120 of 3832). Invasive SA infections (including bacteremia and deep sternal-wound infections) developed in 1.0%. Methicillin-resistant SA (MRSA) accounted for 19% (23 of 120) of SA infections, with 57% (13 of 23) of the MRSA infections occurring in diabetic patients. All-cause mortality was 4.1% (153 of 3712) in patients without SA infection, 7.2% (7 of 97) in methicillin-susceptible SA (MSSA) infections, and 17.3% (4 of 23) in MRSA infections (P < .01). Staphylococcus aureus nasal carriage was detected preoperatively in 18.3% (701 of 3096) patients, including 1.6% colonized with MRSA. Postoperative SA infections occurred in 7.0% (49 of 701) of colonized patients versus 2.3% (71 of 3131) of patients without colonization (relative risk = 3.1 [95% confidence interval, 2.2–4.4]). Conclusions u2003In this large international cohort of patients undergoing cardiac surgery and observed prospectively, invasive postoperative SA infections occurred in 1% of adult patients despite modern perioperative management. The attributable mortality rates were 3% for MSSA and 13% for MRSA infections. Preoperative nasal colonization with SA increased the risk of postoperative infection threefold. The utility of strategies to reduce this incidence warrants continued investigation.

Bone marrow laser revascularisation for treating refractory angina due to diffuse coronary heart disease

To increase the angiogenic response and clinical efficacy of TMR, the potential synergy and safety of combining TMR with concentrated autologous bone marrow derived stem cells was evaluated. Fourteen patients with diffuse coronary artery disease and medically refractory class III/IV angina who were not candidates for conventional therapies were treated using TMR in combination with intramyocardial injection of concentrated stem cells. At the time of surgery, autologous bone marrow (120 cc) was aspirated from the iliac crest and processed over 15 min into 20 cc of concentrated mononuclear cells using a centrifugal system (HARVEST, Boston, MA). A single device performed holmium: YAG:TMR (CardioGenesis, Irvine, CA) with injection of 1 cc of concentrated stem cells through three multi-holed needles into the border zone around each laser channel. There were no perioperative adverse events including no arrhythmias. Mean number of injected cells per milliliter were: total mononuclear cells (81.3 x 10(6)), CD34(+) cells (0.6 x 10(6)), and CD133(+) cells (0.37 x 10(6)). At 7 months mean follow-up average angina class was significantly improved (3.5+/-0.5 vs 1.4+/-0.5; p=0.004). There was no death during the follow-up. Efficient delivery of stem cells combined with TMR in a single device seems to be safe and effective for treating unmanageable angina.