Transcatheter or surgical aortic valve implantation: 10-year outcomes of the NOTION trial.

BACKGROUND AND AIMS: Transcatheter aortic valve implantation (TAVI) has become a viable treatment option for patients with severe aortic valve stenosis across a broad range of surgical risk. The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize patients at lower surgical risk to TAVI or surgical aortic valve replacement (SAVR). The aim of the present study was to report clinical and bioprosthesis outcomes after 10 years. METHODS: The NOTION trial randomized 280 patients to TAVI with the self-expanding CoreValve (Medtronic Inc.) bioprosthesis (n = 145) or SAVR with a bioprosthesis (n = 135). The primary composite outcome was the risk of all-cause mortality, stroke, or myocardial infarction. Bioprosthetic valve dysfunction (BVD) was classified as structural valve deterioration (SVD), non-structural valve dysfunction (NSVD), clinical valve thrombosis, or endocarditis according to Valve Academic Research Consortium-3 criteria. Severe SVD was defined as (i) a transprosthetic gradient of 30 mmHg or more and an increase in transprosthetic gradient of 20 mmHg or more or (ii) severe new intraprosthetic regurgitation. Bioprosthetic valve failure (BVF) was defined as the composite rate of death from a valve-related cause or an unexplained death following the diagnosis of BVD, aortic valve re-intervention, or severe SVD. RESULTS: Baseline characteristics were similar between TAVI and SAVR: age 79.2 ± 4.9 years and 79.0 ± 4.7 years (P = .7), male 52.6% and 53.8% (P = .8), and Society of Thoracic Surgeons score < 4% of 83.4% and 80.0% (P = .5), respectively. After 10 years, the risk of the composite outcome all-cause mortality, stroke, or myocardial infarction was 65.5% after TAVI and 65.5% after SAVR [hazard ratio (HR) 1.0; 95% confidence interval (CI) 0.7-1.3; P = .9], with no difference for each individual outcome. Severe SVD had occurred in 1.5% and 10.0% (HR 0.2; 95% CI 0.04-0.7; P = .02) after TAVI and SAVR, respectively. The cumulative incidence for severe NSVD was 20.5% and 43.0% (P < .001) and for endocarditis 7.2% and 7.4% (P = 1.0) after TAVI and SAVR, respectively. No patients had clinical valve thrombosis. Bioprosthetic valve failure occurred in 9.7% of TAVI and 13.8% of SAVR patients (HR 0.7; 95% CI 0.4-1.5; P = .4). CONCLUSIONS: In patients with severe AS and lower surgical risk randomized to TAVI or SAVR, the risk of major clinical outcomes was not different 10 years after treatment. The risk of severe bioprosthesis SVD was lower after TAVR compared with SAVR, while the risk of BVF was similar.

Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release.

Effector-T-cell-mediated immunity depends on the efficient localization of antigen-primed lymphocytes to antigen-rich non-lymphoid tissue, which is facilitated by the expression of a unique set of "homing" receptors acquired by memory T cells. We report that engagement of the hepatocyte growth factor (HGF) receptor c-Met by heart-produced HGF during priming in the lymph nodes instructs T cell cardiotropism, which was associated with a specialized homing "signature" (c-Met(+)CCR4(+)CXCR3(+)). c-Met signals facilitated T cell recruitment to the heart via the chemokine receptor CCR5 by inducing autocrine CCR5 ligand release. c-Met triggering was sufficient to support cardiotropic T cell recirculation, while CCR4 and CXCR3 sustained recruitment during heart inflammation. Transient pharmacological blockade of c-Met during T cell priming led to enhanced survival of heart, but not skin, allografts associated with impaired localization of alloreactive T cells to heart grafts. These findings suggest c-Met as a target for development of organ-selective immunosuppressive therapies.

Eight-year outcomes for patients with aortic valve stenosis at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement.

AIMS: The aims of the study were to compare clinical outcomes and valve durability after 8 years of follow-up in patients with symptomatic severe aortic valve stenosis at low surgical risk treated with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). METHODS AND RESULTS: In the NOTION trial, patients with symptomatic severe aortic valve stenosis were randomized to TAVI or SAVR. Clinical status, echocardiography, structural valve deterioration, and failure were assessed using standardized definitions. In total, 280 patients were randomized to TAVI (n = 145) or SAVR (n = 135). Baseline characteristics were similar, including mean age of 79.1 ± 4.8 years and a mean STS score of 3.0 ± 1.7%. At 8-year follow-up, the estimated risk of the composite outcome of all-cause mortality, stroke, or myocardial infarction was 54.5% after TAVI and 54.8% after SAVR (P = 0.94). The estimated risks for all-cause mortality (51.8% vs. 52.6%; P = 0.90), stroke (8.3% vs. 9.1%; P = 0.90), or myocardial infarction (6.2% vs. 3.8%; P = 0.33) were similar after TAVI and SAVR. The risk of structural valve deterioration was lower after TAVI than after SAVR (13.9% vs. 28.3%; P = 0.0017), whereas the risk of bioprosthetic valve failure was similar (8.7% vs. 10.5%; P = 0.61). CONCLUSIONS: In patients with severe aortic valve stenosis at low surgical risk randomized to TAVI or SAVR, there were no significant differences in the risk for all-cause mortality, stroke, or myocardial infarction, as well as the risk of bioprosthetic valve failure after 8 years of follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01057173.

Thrombelastographic hypercoagulability and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): a randomized controlled trial.

A hypercoagulable state has, in observational studies, been associated with increased risk of thromboembolic events. The aim of this trial was to study whether dual antiplatelet therapy (DAPT) with clopidogrel in addition to aspirin could reduce the rate of graft occlusions, thromboembolic events, and death compared to aspirin monotherapy in hypercoagulable patients undergoing coronary artery bypass surgery. A total of 1683 patients were screened for eligibility, among which 165 patients were randomized and 133 patients underwent multislice computed tomography scan to evaluate their grafts. Thrombelastography (TEG) and multiplate aggregometry were performed before and after surgery, and again at three months follow up. TEG hypercoagulability was defined as the maximum amplitude above 69 mm. At three months follow up, 17 out of 66 (25.7%) DAPT patients and 15 of 67 (22.4%) aspirin patients had significant graft stenosis or occlusions (p = 0.839). Saphenous vein grafts (SVGs) were stenosed or occluded in 15 (22.7%) patients in the DAPT group and 7 (10.4%) in the aspirin group (p = 0.167). Thromboembolic events and death after the second postoperative day (when clopidogrel was started) were numerically, but not statistically, lower in the DAPT group, 3 (3.8%) vs. 8 (9.9%), p = 0.211. In univariate logistic regression analysis, only postoperative day 4 platelet response to aspirin measured with multiplate was correlated with graft occlusion, OR 1.020 [1.002-1.039], p = 0.033. This is the first trial to test the hypothesis of intensified antiplatelet therapy in hypercoagulable patients. Due to the low enrollment and high loss to follow up, our results can only be viewed as hypothesis generating. We found a high rate of graft occlusions in this patient population. Our results were not suggestive of that DAPT improved saphenous vein graft patency. A trend was observed in patients on DAPT toward fewer MI and deaths. Postoperative response to aspirin therapy was found to be associated with early SVG occlusion.

Heart Team therapeutic decision-making and treatment in severe aortic valve stenosis.

Objectives After transcatheter aortic valve implantation (TAVI) has been available for high-risk patients with severe aortic valve stenosis (AVS), the decision-making of the Heart Team (HT) has not been examined. Design All adult patients with severe AVS referred to a large tertiary medical centre in 2011 were prospectively included. Multivariate regression analysis identified independent factors associated with treatment decisions. Results A total of 487 patients were included (mean age: 75 years, NYHA class III-IV: 47%). The HT proposed medical therapy (MT) in 35 (7%), TAVI in 60 (12%), and surgical aortic valve replacement (SAVR) in 392 (81%) of patients. In patients referred to intervention, TAVI compared with SAVR patients were older (OR = 1.17 per year, 95% CI 1.09-1.26; p < 0.01) with more previous coronary artery bypass surgery (OR = 385, 79-2738; p < 0.01), obesity (OR = 4.69, 1.51-13.77; p < 0.01), and chronic obstructive pulmonary disease (COPD) (OR = 3.66, 1.21-10.75; p = 0.02). MT patients compared with patients referred to any intervention were older, had a higher prevalence of COPD, peripheral arterial disease, previous myocardial infarction, and cerebrovascular disease. Conclusions The HT proposed intervention in 93% of patients with severe AVS despite high age, advanced symptoms and a high burden of co-morbidity. TAVI was reserved for older patients particularly with previous CABG.

Preoperative hemostatic testing and the risk of postoperative bleeding in coronary artery bypass surgery patients.

BACKGROUND: We sought to assess predictability of excessive bleeding using thrombelastography (TEG), multiplate impedance aggregometry, and conventional coagulation tests including fibrinogen in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: A total of 170 patients were enrolled in this prospective observational study. TEG, Multiplate aggregometry, and coagulation tests were sampled on the day before surgery. Excessive bleeding was defined as >1000 mL over 18 hours. RESULTS: Multiplate-adenosine diphosphate (ADP) measurements were significantly lower in patients with excessive bleeding, 85.5AU ± 32.8 versus 108.5AU ± 30.0, p = 0.012. Bivariate analysis revealed body mass index, myocardial infarction, and multiplate-ADP as predictors of bleeding. In multivariable linear regression analysis, multiplate-ADP remained a significant predictor of bleeding (ß: -6.2 [confidence interval: -12.0 to -0.3], p = 0.035). The lowest interval of multiplate-ADP (<50 AUC) was associated with significantly more bleeding and need for platelet concentrate transfusion. Fibrinogen levels <2.5 g/L were also found to be associated with excess bleeding (p = 0.020). CONCLUSIONS: Multiplate impedance aggregometry identified patients at risk for excessive bleeding after CABG. Low fibrinogen levels were associated with increased bleeding. Neither routine TEG parameters nor conventional coagulation tests were correlated with bleeding.

Transit-time flow measurement as a predictor of coronary bypass graft failure at one year angiographic follow-up.

BACKGROUND: Transit-time flow measurement (TTFM) is a commonly used intraoperative method for evaluation of coronary artery bypass graft (CABG) anastomoses. This study was undertaken to determine whether TTFM can also be used to predict graft patency at one year postsurgery. METHODS: Three hundred forty-five CABG patients with intraoperative graft flow measurements and one year angiographic follow-up were analyzed. Graft failure was defined as more than 50% stenosis including the "string sign." Logistic regression analysis was used to analyze the risk of graft failure after one year based on graft vessel type, anastomatic configuration, and coronary artery size. RESULTS: Nine hundred eighty-two coronary anastomoses were performed of which 12% had signs of graft failure at one year angiographic follow-up. In internal mammary arteries (IMAs), analysis showed a 4% decrease in graft failure odds for every 1 mL/min increase in TTFM (OR = 0.96, CI = [0.93; 0.99], p = 0.005). ROC analysis showed good discriminative ability for TTFM alone AUC = 69.5% in IMA grafts. For single-vein grafts the decrease in graft failure odds was 2% for every 1 mL/min increase in TTFM (OR = 0.98; CI = [0.97; 1.00], p = 0.059) and AUC of 59.9%. There were no significant relationships between TTFM and graft failure in other graft types or graft configurations. CONCLUSION: The TTFM method has good discriminative ability for assessing the risk of graft failure in certain graft types within the first year after CABG surgery and is a valuable instrument for intraoperative quality assessment of bypass grafts.

Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients.

BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell antibody induction for preventing rejection after liver transplantation. OBJECTIVES: To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2013. SELECTION CRITERIA: Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)). DATA COLLECTION AND ANALYSIS: We used RevMan analysis for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table. MAIN RESULTS: We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 µmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes - infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension - when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life. AUTHORS' CONCLUSIONS: The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).

Antibody induction versus corticosteroid induction for liver transplant recipients.

BACKGROUND: Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell specific antibody induction compared with corticosteroid induction of immunosuppression after liver transplantation. OBJECTIVES: To assess the benefits and harms of T-cell specific antibody induction versus corticosteroid induction for prevention of acute rejection in liver transplant recipients. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 30 September 2013 together with reference checking, citation searching, contact with trial authors and pharmaceutical companies to identify additional trials. SELECTION CRITERIA: We included all randomised clinical trials assessing immunosuppression with T-cell specific antibody induction versus corticosteroid induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. DATA COLLECTION AND ANALYSIS: We used RevMan for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). MAIN RESULTS: We included 10 randomised trials with a total of 1589 liver transplant recipients, which studied the use of T-cell specific antibody induction versus corticosteroid induction. All trials were with high risk of bias. We compared any kind of T-cell specific antibody induction versus corticosteroid induction in 10 trials with 1589 participants, including interleukin-2 receptor antagonist induction versus corticosteroid induction in nine trials with 1470 participants, and polyclonal T-cell specific antibody induction versus corticosteroid induction in one trial with 119 participants.Our analyses showed no significant differences regarding mortality (RR 1.01, 95% CI 0.72 to 1.43), graft loss (RR 1.12, 95% CI 0.82 to 1.53) and acute rejection (RR 0.84, 95% CI 0.70 to 1.00), infection (RR 0.96, 95% CI 0.85 to 1.09), hepatitis C virus recurrence (RR 0.89, 95% CI 0.79 to 1.00), malignancy (RR 0.59, 95% CI 0.13 to 2.73), and post-transplantation lymphoproliferative disorder (RR 1.00, 95% CI 0.07 to 15.38) when any kind of T-cell specific antibody induction was compared with corticosteroid induction (all low-quality evidence). Cytomegalovirus infection was less frequent in patients receiving any kind of T-cell specific antibody induction compared with corticosteroid induction (RR 0.50, 95% CI 0.33 to 0.75; low-quality evidence). This was also observed when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.55, 95% CI 0.37 to 0.83; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.21, 95% CI 0.06 to 0.70; low-quality evidence). However, when trial sequential analysis regarding cytomegalovirus infection was applied, the required information size was not reached. Furthermore, diabetes mellitus occurred less frequently when T-cell specific antibody induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.34 to 0.60; low-quality evidence), when interleukin-2 receptor antagonist induction was compared with corticosteroid induction (RR 0.45, 95% CI 0.35 to 0.61; low-quality evidence), and when polyclonal T-cell specific antibody induction was compared with corticosteroid induction (RR 0.12, 95% CI 0.02 to 0.95; low-quality evidence). When trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed. We found no subgroup differences for type of interleukin-2 receptor antagonist (basiliximab versus daclizumab). Four trials reported on adverse events. However, no differences between trial groups were noted. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were available on quality of life. AUTHORS' CONCLUSIONS: Because of the low quality of the evidence, the effects of T-cell antibody induction remain uncertain. T-cell specific antibody induction seems to reduce diabetes mellitus and may reduce cytomegalovirus infection when compared with corticosteroid induction. No other clear benefits or harms were associated with the use of T-cell specific antibody induction compared with corticosteroid induction. For some analyses, the number of trials investigating the use of T-cell specific antibody induction after liver transplantation is small, and the numbers of participants and outcomes in these randomised trials are limited. Furthermore, the included trials are heterogeneous in nature and have applied different types of T-cell specific antibody induction therapy. All trials were at high risk of bias. Hence, additional randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with corticosteroid induction for liver transplant recipients. Such trials ought to be conducted with low risks of systematic error and of random error.

Conditioning techniques and ischemic reperfusion injury in relation to on-pump cardiac surgery.

OBJECTIVES: The objective was to investigate the potential protective effects of two conditioning methods, on myocardial ischemic and reperfusion injury in relation to cardiac surgery. DESIGN: Totally 68 patients were randomly assigned to either a control group (n = 23), a remote ischemic preconditioning (RIPC) group (n = 23) or a glucagon-like peptide-1 (GLP-1) analogue group (n = 22). The RIPC protocol consisted of three cycles of upper limb ischemia. The GLP-1 analogue protocol consisted of intravenous infusion with exenatide. The primary endpoint was postoperative cardiac enzyme release. The other secondary endpoints were metabolic parameters related to myocardial ischemia, measured using microdialysis technique, as well as other operative- and postoperative data. RESULTS: Postoperative cardiac enzyme release indicated a possible beneficial effect of the interventions, but the difference did not reach statistical significance. RIPC showed a trend toward lower levels (p = 0.07). We managed to establish a functional myocardial microdialysis model, but we were unable to demonstrate clear protective effects. CONCLUSIONS: We were in this prospective randomized proof-of-concept trial, unable to show distinct protective effects of the studied conditioning methods. However, this trial can hopefully contribute to generate a productive discussion concerning limitations and future use of cardiac conditioning as well as microdialysis technique.

Acute kidney injury is independently associated with higher mortality after cardiac surgery.

OBJECTIVES: To investigate the incidence of acute kidney injury after cardiac surgery and its association with mortality in a patient population receiving ibuprofen and gentamicin perioperatively. DESIGN: Retrospective study with Cox regression analysis to control for possible preoperative, intraoperative and postoperative confounders. SETTING: University hospital-based single-center study. PARTICIPANTS: All patients who underwent coronary artery bypass grafting ± valve surgery during 2012. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Acute surgery within 24 hours of coronary angiography, previous nephrectomy, preoperative sCr >2.26 mg/dL and selective cerebral perfusion during cardiopulmonary bypass were used as exclusion criteria. Acute kidney injury was defined, using the Acute Kidney Injury Network (AKIN) criteria. Six hundred eight patients were included in the study. Mean age was 68.2 ± 9.7 years, and 81% were males. Acute kidney injury was seen in 28.1% of the patients. Overall mortality at one year was 7% and 3% in the no-AKI group. At one year, mortality was 15% in patients with AKIN stage 1 and AKIN stage 2 compared to 70% in AKIN stage 3. A hazard ratio of 2.34 (95% CI: 1.21-4.51, p = 0.011) and 5.62 (95% CI: 2.42-13.06), p<0.0001) were found for AKIN stage 1 and 2/3 combined, respectively. CONCLUSIONS: More than 28% of the patients undergoing elective or subacute cardiac surgery developed AKI in this contemporary cohort. Furthermore, acute kidney injury was an independent predictor of increased mortality irrespective of the perioperative risk factors.

Off-pump versus on-pump coronary artery bypass grafting.

Coronary artery bypass grafting (CABG) remains the preferred treatment in patients with complex coronary artery disease. However, whether the procedure should be performed with or without the use of cardiopulmonary bypass, referred to as off-pump and on-pump CABG, is still up for debate. Intuitively, avoidance of cardiopulmonary bypass seems beneficial as the systemic inflammatory response from extracorporeal circulation is omitted, but no single randomized trial has been able to prove off-pump CABG superior to on-pump CABG as regards the hard outcomes death, stroke or myocardial infarction. In contrast, off-pump CABG is technically more challenging and may be associated with increased risk of incomplete revascularization. The purpose of the review is to summarize the current literature comparing outcomes of off-pump versus on-pump coronary artery bypass surgery.

Impaired mitochondrial function in chronically ischemic human heart.

Chronic ischemic heart disease is associated with myocardial hypoperfusion. The resulting hypoxia potentially inflicts damage upon the mitochondria, leading to a compromised energetic state. Furthermore, ischemic damage may cause excessive production of reactive oxygen species (ROS), producing mitochondrial damage, hereby reinforcing a vicious circle. Ischemic preconditioning has been proven protective in acute ischemia, but the subject of chronic ischemic preconditioning has not been explored in humans. We hypothesized that mitochondrial respiratory capacity would be diminished in chronic ischemic regions of human myocardium but that these mitochondria would be more resistant to ex vivo ischemia and, second, that ROS generation would be higher in ischemic myocardium. The aim of this study was to test mitochondrial respiratory capacity during hyperoxia and hypoxia, to investigate ROS production, and finally to assess myocardial antioxidant levels. Mitochondrial respiration in biopsies from ischemic and nonischemic regions from the left ventricle of the same heart was compared in nine human subjects. Maximal oxidative phosphorylation capacity in fresh muscle fibers was lower in ischemic compared with nonischemic myocardium (P < 0.05), but the degree of coupling (respiratory control ratio) did not differ (P > 0.05). The presence of ex vivo hypoxia did not reveal any chronic ischemic preconditioning of the ischemic myocardial regions (P > 0.05). ROS production was higher in ischemic myocardium (P < 0.05), and the levels of antioxidant protein expression was lower. Diminished mitochondrial respiration capacity and excessive ROS production demonstrate an impaired mitochondrial function in ischemic human heart muscle. No chronic ischemic preconditioning effect was found.

Immunosuppressive T-cell antibody induction for heart transplant recipients.

BACKGROUND: Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation. OBJECTIVES: To review the benefits, harms, feasibility and tolerability of immunosuppressive T-cell antibody induction versus placebo, or no antibody induction, or another kind of antibody induction for heart transplant recipients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2012), MEDLINE (Ovid) (1946 to November Week 1 2012), EMBASE (Ovid) (1946 to 2012 Week 45), ISI Web of Science (14 November 2012); we also searched two clinical trial registers and checked reference lists in November 2012. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) assessing immunosuppressive T-cell antibody induction for heart transplant recipients. Within individual trials, we required all participants to receive the same maintenance immunosuppressive therapy. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. RevMan analysis was used for statistical analysis of dichotomous data with risk ratio (RR), and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Methodological components were used to assess risks of systematic errors (bias). Trial sequential analysis was used to assess the risks of random errors (play of chance). We assessed mortality, acute rejection, infection, Cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, and hyperlipidaemia. MAIN RESULTS: In this review, we included 22 RCTs that investigated the use of T-cell antibody induction, with a total of 1427 heart-transplant recipients. All trials were judged to be at a high risk of bias. Five trials, with a total of 606 participants, compared any kind of T-cell antibody induction versus no antibody induction; four trials, with a total of 576 participants, compared interleukin-2 receptor antagonist (IL-2 RA) versus no induction; one trial, with 30 participants, compared monoclonal antibody (other than IL-2 RA) versus no antibody induction; two trials, with a total of 159 participants, compared IL-2 RA versus monoclonal antibody (other than IL-2 RA) induction; four trials, with a total of 185 participants, compared IL-2 RA versus polyclonal antibody induction; seven trials, with a total of 315 participants, compared monoclonal antibody (other than IL-2 RA) versus polyclonal antibody induction; and four trials, with a total of 162 participants, compared polyclonal antibody induction versus another kind, or dose of polyclonal antibodies.No significant differences were found for any of the comparisons for the outcomes of mortality, infection, CMV infection, post-transplantation lymphoproliferative disorder, cancer, adverse events, chronic allograft vasculopathy, renal function, hypertension, diabetes mellitus, or hyperlipidaemia. Acute rejection occurred significantly less frequently when IL-2 RA induction was compared with no induction (93/284 (33%) versus 132/292 (45%); RR 0.73; 95% CI 0.59 to 0.90; I(2) 57%) applying the fixed-effect model. No significant difference was found when the random-effects model was applied (RR 0.73; 95% CI 0.46 to 1.17; I(2) 57%). In addition, acute rejection occurred more often statistically when IL-2 RA induction was compared with polyclonal antibody induction (24/90 (27%) versus 10/95 (11%); RR 2.43; 95% CI 1.01 to 5.86; I(2) 28%). For all of these differences in acute rejection, trial sequential alpha-spending boundaries were not crossed and the required information sizes were not reached when trial sequential analysis was performed, indicating that we cannot exclude random errors.We observed some occasional significant differences in adverse events in some of the comparisons, however definitions of adverse events varied between trials, and numbers of participants and events in these outcomes were too small to allow definitive conclusions to be drawn. AUTHORS' CONCLUSIONS: This review shows that acute rejection might be reduced by IL-2 RA compared with no induction, and by polyclonal antibody induction compared with IL-2 RA, though trial sequential analyses cannot exclude random errors, and the significance of our observations depended on the statistical model used. Furthermore, this review does not show other clear benefits or harms associated with the use of any kind of T-cell antibody induction compared with no induction, or when one type of T-cell antibody is compared with another type of antibody. The number of trials investigating the use of antibodies against T-cells for induction after heart transplantation is small, and the number of participants and outcomes in these RCTs is limited. Furthermore, the included trials are at a high risk of bias. Hence, more RCTs are needed to assess the benefits and harms of T-cell antibody induction for heart-transplant recipients. Such trials ought to be conducted with low risks of systematic and random error.

Antibody induction therapy for lung transplant recipients.

BACKGROUND: Lung transplantation has become a valuable and well-accepted treatment option for most end-stage lung diseases. Lung transplant recipients are at risk of transplanted organ rejection, and life-long immunosuppression is necessary. Clear evidence is essential to identify an optimal, safe and effective immunosuppressive treatment strategy for lung transplant recipients. Consensus has not yet been achieved concerning use of immunosuppressive antibodies against T-cells for induction following lung transplantation. OBJECTIVES: We aimed to assess the benefits and harms of immunosuppressive T-cell antibody induction with ATG, ALG, IL-2RA, alemtuzumab, or muromonab-CD3 for lung transplant recipients. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 4 March 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared immunosuppressive monoclonal and polyclonal T-cell antibody induction for lung transplant recipients. An inclusion criterion was that all participants must have received the same maintenance immunosuppressive therapy within each study. DATA COLLECTION AND ANALYSIS: Three authors extracted data. We derived risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data with 95% confidence intervals (CI). Methodological risk of bias was assessed using the Cochrane risk of bias tool and trial sequential analyses were undertaken to assess the risk of random errors (play of chance). MAIN RESULTS: Our review included six RCTs (representing a total of 278 adult lung transplant recipients) that assessed the use of T-cell antibody induction. Evaluation of the included studies found all to be at high risk of bias.We conducted comparisons of polyclonal or monoclonal T-cell antibody induction versus no induction (3 studies, 140 participants); polyclonal T-cell antibody versus no induction (3 studies, 125 participants); interleukin-2 receptor antagonists (IL-2RA) versus no induction (1 study, 25 participants); polyclonal T-cell antibody versus muromonab-CD3 (1 study, 64 participants); and polyclonal T-cell antibody versus IL-2RA (3 studies, 100 participants). Overall we found no significant differences among interventions in terms of mortality, acute rejection, adverse effects, infection, pneumonia, cytomegalovirus infection, bronchiolitis obliterans syndrome, post-transplantation lymphoproliferative disease, or cancer.We found a significant outcome difference in one study that compared antithymocyte globulin versus muromonab-CD3 relating to adverse events (25/34 (74%) versus 12/30 (40%); RR 1.84, 95% CI 1.13 to 2.98). This suggested that antithymocyte globulin increased occurrence of adverse events. However, trial sequential analysis found that the required information size had not been reached, and the cumulative Z-curve did not cross the trial sequential alpha-spending monitoring boundaries.None of the studies reported quality of life or kidney injury. Trial sequential analyses indicated that none of the meta-analyses achieved required information sizes and the cumulative Z-curves did not cross the trial sequential alpha-spending monitoring boundaries, nor reached the area of futility. AUTHORS' CONCLUSIONS: No clear benefits or harms associated with the use of T-cell antibody induction compared with no induction, or when different types of T-cell antibodies were compared were identified in this review. Few studies were identified that investigated use of antibodies against T-cells for induction after lung transplantation, and numbers of participants and outcomes were also limited. Assessment of the included studies found that all were at high risk of methodological bias.Further RCTs are needed to perform robust assessment of the benefits and harms of T-cell antibody induction for lung transplant recipients. Future studies should be designed and conducted according to methodologies to reduce risks of systematic error (bias) and random error (play of chance).

Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients.

BACKGROUND: Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects. OBJECTIVES: To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013. SELECTION CRITERIA: We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study. DATA COLLECTION AND ANALYSIS: Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance). MAIN RESULTS: We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures. AUTHORS' CONCLUSIONS: Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance).

Renal replacement therapy after cardiac surgery; renal function recovers.

OBJECTIVES: To assess renal outcome in patients discharged from hospital following cardiac surgery-associated acute kidney injury (CSA-AKI) with need for renal replacement therapy. DESIGN: In April 2012 we conducted a cross-sectional study of patients treated with renal replacement therapy following cardiac surgery during 2008-2010. We included all adult patients with a pre-operative serum creatinine (sCr) < 200 µM, surviving to discharge. Primary endpoint was use of renal replacement therapy after hospital discharge; secondary endpoint was a sCr > 200 µM at the time of follow-up. RESULTS: We reviewed the records of 3828 patients receiving cardiac surgery in the defined period. A total of 107 adult patients with sCr concentrations < 200 µM were treated with post-operative renal replacement therapy of whom 70 survived to discharge. Fifty-six patients were alive at follow-up and none had required renal replacement therapy after initial discharge. Median sCr concentration at follow-up was 111 [56-257] µM and two patients had sCr above 200 µM. CONCLUSIONS: In this study, renal function recovered in patients discharged from hospital following renal replacement therapy after CSA-AKI. No patients needed further renal replacement therapy and only two (4%) had a sCr > 200 µM at follow-up.

Hypercoagulability in relation to coronary artery bypass graft patency and clinical outcome.

OBJECTIVE: Hypercoagulability evaluated with thrombelastography (TEG) has been reported to be associated to thrombembolic events in patients undergoing coronary artery bypass graft surgery (CABG). The objective of this study was to test the hypothesis that graft patency and post-CABG thrombembolic events are related to the pre-surgical TEG status. DESIGN: 124 patients scheduled for CABG were matched according to mean age, gender and mean left ventricular ejection fraction in two groups defined by their pre-surgical TEG status (TEG-hypercoagulable and TEG-normocoagulable). Three months after the operation graft patency was assessed with multidetector computed tomography (MDCT). Major adverse cardiovascular and cerebral events (MACCE) were recorded for a median period of 7 months (range 3 to 37 months) after CABG. RESULTS: A total of 359 grafts were analyzed, 186 in TEG-hypercoagulable and 173 in TEG-normocoagulable patients. Frequency of bypass graft occlusion was not significantly different between the two groups (TEG-hypercoagulable = 21 and TEG-normocoagulable = 18, p = 0.9). The number of MACCE was significantly higher in the TEG-hypercoagulable compared to the TEG-normocoagulable group (TEG-hypercoagulable = 30% and TEG-normocoagulable = 9% p = 0.004). CONCLUSIONS: Hypercoagulability, as evaluated by TEG in patients undergoing CABG is associated with an increased risk of post-surgical thrombembolic events, however not accompanied by augmented coronary bypass graft failure.

Off-pump versus on-pump coronary artery bypass grafting for ischaemic heart disease.

BACKGROUND: Coronary artery bypass grafting (CABG) is performed both without and with cardiopulmonary bypass, referred to as off-pump and on-pump CABG respectively. However, the preferable technique is unclear. OBJECTIVES: To assess the benefits and harms of off-pump versus on-pump CABG in patients with ischaemic heart disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 1, 2011), MEDLINE (OVID, 1950 to February 2011), EMBASE (OVID, 1980 to February 2011), Science Citation Index Expanded on ISI Web of Science (1970 to February 2011) and CINAHL (EBSCOhost, 1981 to February 2011) on 2 February 2011. No language restrictions were applied. SELECTION CRITERIA: Randomised clinical trials of off-pump versus on-pump CABG irrespective of language, publication status and blinding were selected for inclusion. DATA COLLECTION AND ANALYSIS: For statistical analysis of dichotomous data risk ratio (RR) and for continuous data mean difference (MD) with 95% confidence intervals (CI) were used. Trial sequential analysis (TSA) was used for analysis to assess the risk of random error due to sparse data and to multiple updating of accumulating data. MAIN RESULTS: Eighty-six trials (10,716 participants) were included. Ten trials (4,950 participants) were considered to be low risk of bias. Pooled analysis of all trials showed that off-pump CABG increased all-cause mortality compared with on-pump CABG (189/5,180 (3.7%) versus 160/5144 (3.1%); RR 1.24, 95% CI 1.01 to 1.53; P =.04). In the trials at low risk of bias the effect was more pronounced (154/2,485 (6.2%) versus 113/2,465 (4.6%), RR 1.35,95% CI 1.07 to 1.70; P =.01). TSA showed that the risk of random error on the result was unlikely. Off-pump CABG resulted in fewer distal anastomoses (MD -0.28; 95% CI -0.40 to -0.16, P <.00001). No significant differences in myocardial infarction, stroke, renal insufficiency, or coronary re-intervention were observed. Off-pump CABG reduced post-operative atrial fibrillation compared with on-pump CABG, however, in trials at low risk of bias, the estimated effect was not significantly different. AUTHORS' CONCLUSIONS: Our systematic review did not demonstrate any significant benefit of off-pump compared with on-pump CABG regarding mortality, stroke, or myocardial infarction. In contrast, we observed better long-term survival in the group of patients undergoing on-pump CABG with the use of cardiopulmonary bypass and cardioplegic arrest. Based on the current evidence, on-pump CABG should continue to be the standard surgical treatment. However, off-pump CABG may be acceptable when there are contraindications for cannulation of the aorta and cardiopulmonary bypass. Further randomised clinical trials should address the optimal treatment in such patients.

Calcineurin inhibitor minimisation versus continuation of calcineurin inhibitor treatment for liver transplant recipients.

BACKGROUND: The therapeutic success of liver transplantation has been largely attributable to the development of effective immunosuppressive treatment regimens. In particular, calcineurin inhibitors were essential in reducing acute rejection and improving early survival. Currently, more than 90% of all liver transplant recipients are treated with the calcineurin inhibitor cyclosporine or tacrolimus. Unfortunately, calcineurin inhibitors cause adverse events, such as nephrotoxicity, and because of this, minimisation (reduction and withdrawal) regimens of calcineurin inhibitor have been developed and studied. However, the benefits and harms of these minimisation regimens are unclear. OBJECTIVES: To assess the benefits and harms of calcineurin inhibitor minimisation for liver transplant recipients without substitution by another immunosuppressive agent. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2010), Cochrane Central Register of Controlled Clinical Trials (CENTRAL) in The Cochrane Library, MEDLINE (OvidSP), EMBASE (OvidSP), Science Citation Index Expanded (Royle 2003), and the World Health Organization (WHO) international clinical trials registry platform (www.who.int/ictrp) until August 2011. In addition, we searched bibliographies of relevant articles as well as US Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug approval reviews for additional trials. SELECTION CRITERIA: We planned to select all randomised clinical trials investigating calcineurin inhibitor reduction or withdrawal in liver transplant recipients, irrespective of blinding, publication status, or language. Quasi-randomised clinical studies and cohort studies that were obtained through the searches were considered only for the reporting of harms. Trials investigating substitution of one calcineurin inhibitor by another calcineurin inhibitor were excluded. Trials investigating calcineurin inhibitor withdrawal concurrently with switching over to a mammalian target of rapamycin (mTOR) inhibitor-based regimen (everolimus or sirolimus) or mycophenolate mofetil-based regimen are the subject of a separate review. DATA COLLECTION AND ANALYSIS: Search strategies were used to obtain titles and abstracts of studies that were relevant for the review. Two authors independently scanned the references and assessed trial eligibility. MAIN RESULTS: A total of 1299 references were identified by the searches. After removal of duplicates, 794 references were left. Out of these, two abstract reports of one ongoing randomised trial fulfilled the inclusion criteria of the review. This ongoing trial studies total withdrawal of immunosuppression in patients who receive a calcineurin inhibitor (cyclosporine or tacrolimus) or mycophenolate mofetil as the only immunosuppressive agent. The trial compares withdrawal of calcineurin inhibitor or mycophenolate mofetil with continuation of calcineurin inhibitor or mycophenolate mofetil. However, no trial results on the outcomes of interest to this review were available. AUTHORS' CONCLUSIONS: This review shows that strategies regarding calcineurin inhibitor minimisation, that is, reduction or withdrawal, without substitution versus continuation of calcineurin inhibitor treatment lack evidence from randomised trials.More research with calcineurin inhibitor reduction and withdrawal regimens is needed to optimise dosing and timing of calcineurin inhibitor treatment in order to achieve optimal patient and graft survival with a minimum of adverse events.Specifically regarding calcineurin inhibitor reduction versus no reduction, we recommend that randomised trials evaluating calcineurin inhibitor reduction versus continuation of calcineurin inhibitor treatment are conducted.Regarding calcineurin inhibitor withdrawal, we recommend that mechanisms for tolerance and 'graft acceptance' are clarified, and patient groups likely to tolerate calcineurin inhibitor withdrawal are identified in order to select the right patients for total withdrawal of calcineurin inhibitors without substitution with another immunosuppressive drug. The randomised trials should only be performed in highly selected patients.