Domenico Pagano

Queen Elizabeth Hospital Birmingham, Birmingham, England, United Kingdom

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Publications (93)474.41 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Various risk models exist to predict short-term risk-adjusted outcomes after cardiac surgery. Statistical models constructed using clinical registry data usually perform better than those based on administrative datasets. We constructed a procedure-specific risk prediction model based on administrative hospital data for England and we compared its performance with the EuroSCORE (ES) and its variants. Methods: The Hospital Episode Statistics (HES) risk prediction model was developed using administrative data linked to national mortality statistics register of patients undergoing CABG (35,115), valve surgery (18,353) and combined CABG and valve surgery (8392) from 2008 to 2011 in England and tested using an independent dataset sampled for the financial years 2011-2013. Specific models were constructed to predict mortality within 1-year post discharge. Comparisons with EuroSCORE models were performed on a local cohort of patients (2580) from 2008 to 2013. Results: The discrimination of the HES model demonstrates a good performance for early and up to 1-year following surgery (c-stats: CABG 81.6%, 78.4%; isolated valve 78.6%, 77.8%; CABG & valve 76.4%, 72.0%), respectively. Extended testing in subsequent financial years shows that the models maintained performance outside the development period. Calibration of the HES model demonstrates a small difference (CABG 0.15%; isolated valve 0.39%; CABG & valve 0.63%) between observed and expected mortality rates and delivers a good estimate of risk. Discrimination for the HES model for in-hospital deaths is similar for CABG (logistic ES 79.0%) and combined CABG and valve surgery (logistic ES 71.6%) patients and superior for valve patients (logistic ES 70.9%) compared to the EuroSCORE models. The C-statistics of the EuroSCORE models for longer periods are numerically lower than that of the HES model. Conclusion: The national administrative dataset has produced an accurate, stable and clinically useful early and 1-year mortality prediction after cardiac surgery.
    International journal of cardiology 10/2015; 203:196-203. DOI:10.1016/j.ijcard.2015.10.086 · 4.04 Impact Factor
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    ABSTRACT: Purpose: Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium. Method: Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses. Results: Myocardial uptake of both (+) and (-) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (-) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (-) perhexiline were the plasma concentrations [(+) perhexiline: β = -0.256, p = 0.015; (-) perhexiline: β = -0.347, p = 0.001] and patients' age [(+) perhexiline: β = 0.300, p = 0.004; (-) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (-) perhexiline varied inversely with simultaneous heart rate (β = -0.240, p = 0.015). Conclusion: (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (-) perhexiline may selectively modulate heart rate reduction.
    European Journal of Clinical Pharmacology 09/2015; DOI:10.1007/s00228-015-1934-8 · 2.97 Impact Factor
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    ABSTRACT: The goal of all clinical guidelines is to assist patients and practitioners in making healthcare decisions. However, clinical guidelines have been questioned about their quality, transparency and independence. Based on the revision of manuals by other scientific cardiothoracic organizations, this document provides instructions for the development of European Association for Cardio-Thoracic Surgery (EACTS) clinical guidelines and other types of evidence-based documents. Four key areas have been addressed: (i) selection of taskforce members and transparency of relations with the industry, (ii) methods for critical appraisal of medical evidence, (iii) rules for writing recommendations and (iv) review process. It is hoped that, by adopting this methodology, clinical guidelines produced by the EACTS will be well balanced, objective and, importantly, trusted by physicians and patients who benefit from their implementation.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 09/2015; 48(6). DOI:10.1093/ejcts/ezv309 · 3.30 Impact Factor
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    BMJ (online) 09/2015; 351. DOI:10.1136/bmj.h4596 · 17.45 Impact Factor
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    ABSTRACT: Chlorhexidine gluconate (CHG) is often recommended for skin antisepsis; however, the most efficacious concentration is currently unclear. Our objective was to compare the efficacy of 70% isopropyl alcohol (IPA) containing either 0.5% or 2% CHG for antiseptic skin preparation in patients undergoing coronary artery bypass grafting. One hundred patients were randomized to 1 of the 2 CHG concentrations. The designated antiseptic was applied to the skin of the operative site of patients before long saphenous vein harvest. Bacterial counts on the skin incision site were determined at various time points to assess any immediate and persistent antimicrobial activity. The number of patients developing surgical site infection was also determined. The total numbers of microorganisms on the skin 2 minutes after skin antisepsis and after wound closure was lower with 2% CHG/70% IPA compared with 0.5% CHG/70% IPA (P = .033 and P = .016, respectively). Six of 41 patients in the 0.5% CHG/70%IPA group developed a superficial surgical site infection compared with 2 of 44 patients in the 2% CHG/70% IPA group (relative risk, 3.22; 95% confidence interval, 0.63-22.75; P = .147). Isopropyl alcohol (70%) containing 2% CHG compared with 0.5% CHG reduces the number of microorganisms detectable on a surgical patient's skin perioperatively. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.
    American journal of infection control 05/2015; 43(8). DOI:10.1016/j.ajic.2015.03.034 · 2.21 Impact Factor

  • 6th Annual Scientific Meeting of the; 03/2015
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    ABSTRACT: OBJECTIVES Patients undergoing cardiac surgery require adequate myocardial protection. Manipulating myocardial metabolism may improve the extent of myocardial protection. Perhexiline has been shown to be an effective anti-anginal agent due to its metabolic modulation properties by inhibiting the uptake of free fatty acids into the mitochondrion, and thereby promoting a more efficient carbohydrate-driven myocardial metabolism. Metabolic modulation may augment myocardial protection, particularly in patients with left ventricular hypertrophy (LVH) known to have a deranged metabolic state and are at risk of poor postoperative outcomes. This study aimed to evaluate the role of perhexiline as an adjunct in myocardial protection in patients with LVH secondary to aortic stenosis (AS), undergoing an aortic valve replacement (AVR).
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 12/2014; 48(3). DOI:10.1093/ejcts/ezu452 · 3.30 Impact Factor
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    ABSTRACT: Acute kidney injury (AKI) risk prediction scores are an objective and transparent means to enable cohort enrichment in clinical trials or to risk stratify patients preoperatively. Existing scores are limited in that they have been designed to predict only severe, or non-consensus AKI definitions and not less severe stages of AKI, which also have prognostic significance. The aim of this study was to develop and validate novel risk scores that could identify all patients at risk of AKI. Prospective routinely collected clinical data (n = 30,854) were obtained from 3 UK cardiac surgical centres (Bristol, Birmingham and Wolverhampton). AKI was defined as per the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines. The model was developed using the Bristol and Birmingham datasets, and externally validated using the Wolverhampton data. Model discrimination was estimated using the area under the ROC curve (AUC). Model calibration was assessed using the Hosmer-Lemeshow test and calibration plots. Diagnostic utility was also compared to existing scores. The risk prediction score for any stage AKI (AUC = 0.74 (95% confidence intervals (CI) 0.72, 0.76)) demonstrated better discrimination compared to the Euroscore and the Cleveland Clinic Score, and equivalent discrimination to the Mehta and Ng scores. The any stage AKI score demonstrated better calibration than the four comparison scores. A stage 3 AKI risk prediction score also demonstrated good discrimination (AUC = 0.78 (95% CI 0.75, 0.80)) as did the four comparison risk scores, but stage 3 AKI scores were less well calibrated. This is the first risk score that accurately identifies patients at risk of any stage AKI. This score will be useful in the perioperative management of high risk patients as well as in clinical trial design.
    Critical care (London, England) 11/2014; 18(6):606. DOI:10.1186/s13054-014-0606-x · 4.48 Impact Factor
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    ABSTRACT: Background Perhexiline is thought to modulate metabolism through the inhibition of mitochondrial carnitine palmitoyltransferase, reducing fatty acid uptake and increasing carbohydrate utilisation. Our group has shown that a glucose-insulin-potassium infusion enhances myocardial protection during coronary artery bypass graft (CABG) surgery through metabolic manipulation. This study assessed whether perhexiline improves clinical or biochemical markers of myocardial protection and analysed its effect on the myocardial metabolome.Methods In a prospective randomised double-blind placebo-controlled trial, patients undergoing CABG at two centres were randomised to receive oral perhexiline or placebo for at least 5 days before surgery. The primary outcome was a low cardiac output episode in the first 6 h after removal of the aortic cross-clamp. A low cardiac output episode was defined as a cardiac index of less than 2·2 L/min/m2 in the presence of adequate preload, afterload, and heart rate. All analyses were conducted according to the intention-to-treat principle with a 90% power to detect a relative risk of 0·5 with a one-sided α of 0·025. Left ventricular biopsy samples were taken before ischaemia, snap-frozen, and analysed with mass spectrometry-based (MS) metabolomics. This trial is registered with, number NCT00845364.FindingsOver a 3-year period, 286 patients were randomised, received the intervention, and included in the analysis. There were no important baseline differences between groups. The incidence of a low cardiac output episode in the perhexiline arm was 36·7% (51/139) versus 34·7% (51/147) in the control arm (odds ratio 0·92 [95% CI 0·56–1·50]; p=0·74). There were no significant differences in inotrope usage, myocardial injury with troponin-T or electrocardiogram, reoperation, renal dysfunction, or length of hospital stay. No difference in pre-ischaemia left ventricular metabolism was identified between groups.InterpretationPreoperative perhexiline does not improve myocardial protection in patients undergoing CABG. That perhexiline has no significant effect on the MS-visible polar myocardial metabolome in vivo in human beings supports the suggestion that it acts via a pathway that is independent of myocardial carnitine palmitoyltransferase inhibition.FundingBritish Heart Foundation and Sussex Heart Charity.
    The Lancet 06/2014; 381(3):S36. DOI:10.1016/S0140-6736(13)60476-6 · 45.22 Impact Factor
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    ABSTRACT: Late failure of bioprosthetic valves may limit their use in patients < 60 years. The superior hemodynamic performance offered by the Carbomedics Top Hat supraannular valve enables greater effective orifice areas to be achieved. The aim of this study was to assess the clinical outcomes of this valve, using a robust follow-up system. Patients who underwent aortic valve replacement with or without coronary artery bypass grafting between July 1997 and January 2010 with Carbomedics supraannular Top Hat valves were identified. Details of readmissions and late deaths were obtained from the National Hospital Episodes Statistics data and the Office of National Statistics, tracked by the Quality and Outcomes Research Unit. Late complications associated with this prosthesis were evaluated. Of 253 patients identified, 181 underwent isolated aortic valve replacement and 72 had aortic valve replacement with coronary artery bypass grafting. The 30-day mortality was 1.6%, and 5- and 10-year survival rates were 91.4% and 80.5%, respectively. Detailed readmission data were available after 2001 (n = 170). Two (1.2%) patients required reoperation for endocarditis and pannus formation. Of the 17 late deaths in this subset, 4 were attributable to cardiac causes. One patient was treated for heart failure, and 2 developed bleeding complications. Implantation of the Carbomedics Top Hat supraannular valve in our unit resulted in satisfactory in-hospital and midterm survival with low incidences of endocarditis and late heart failure.
    Asian cardiovascular & thoracic annals 04/2014; 23(1). DOI:10.1177/0218492314529954

  • 03/2014; 9(1):e77. DOI:10.1016/j.gheart.2014.03.1484
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    ABSTRACT: OBJECTIVES Perhexiline is thought to modulate metabolism by inhibiting mitochondrial carnitine palmitoyltransferase-1, reducing fatty acid uptake and increasing carbohydrate utilization. This study assessed whether preoperative perhexiline improves markers of myocardial protection in patients undergoing coronary artery bypass graft surgery and analysed its effect on the myocardial metabolome.
    European Journal of Cardio-Thoracic Surgery 01/2014; 47(3). DOI:10.1093/ejcts/ezu238 · 3.30 Impact Factor
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    ABSTRACT: Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomised controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24mg/L (IQR 0.12-0.44), the median atrial concentration was 6.02mg/Kg (IQR 2.70-9.06) and median ventricular concentration was 10.0mg/Kg (IQR 5.76-13.1). Atrial (R(2) 0.76) and ventricular (R(2) 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both p<0.001). The median atrial:plasma ratio was 21.5 (IQR 18.1-27.1), ventricular:plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular:atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (R(2) 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (R(2) 0.84). This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.
    British Journal of Clinical Pharmacology 10/2013; 77(5). DOI:10.1111/bcp.12254 · 3.88 Impact Factor
  • Will Lester · Nick Freemantle · Irena Begaj · Daniel Ray · John Wood · Domenico Pagano ·
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    ABSTRACT: In 2010, the Department of Health in England introduced an incentivised national target for National Health Service (NHS) hospitals aiming to increase the number of patients assessed for the risk of developing venous thromboembolism (VTE) associated with hospital admission. We assessed the impact of this initiative on VTE mortality and subsequent readmission with non-fatal VTE. Observational cohort study. All patients admitted to NHS hospitals in England between July 2010 and March 2012. An NHS hospital which assessed at least 90% of patient admissions achieved the quality standard. The principal outcome measured was death from VTE up till 90 days after hospital discharge using linked Office of National Statistics and Hospital Episode Statistics data. In the principal analyses of patients admitted to hospital for more than 3 days, there was a statistically significant reduction in VTE deaths in hospitals achieving 90% VTE risk assessment: relative risk (RR) 0.85 (95% CI 0.75 to 0.96; p=0.011) for VTE as the primary cause of death. In supportive analyses of postdischarge deaths after index admissions of up to 3 days, there was also a reduction in fatal VTE RR 0.61 (0.48 to 0.79; p=0.0002). This effect was seen for both surgical and non-surgical patients. No effect was seen in day case admissions. There was no change in non-fatal VTE readmissions up to 90 days after discharge. A national quality initiative to increase the number of hospitalised patients assessed for risk of VTE has resulted in a reduction in VTE mortality.
    Heart (British Cardiac Society) 09/2013; 99(23). DOI:10.1136/heartjnl-2013-304479 · 5.60 Impact Factor
  • Domenico Pagano · Nick Freemantle ·

    The Journal of thoracic and cardiovascular surgery 09/2013; 146(3):732. DOI:10.1016/j.jtcvs.2013.04.024 · 4.17 Impact Factor
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    ABSTRACT: Continuous monitoring of surgical outcomes through benchmarking and the identification of best practices has become increasingly important. A structured approach to data collection, coupled with validation, analysis and reporting, is a powerful tool in these endeavours. However, inconsistencies in standards and practices have made comparisons within and between European countries cumbersome. The European Association for Cardio-Thoracic Surgery (EACTS) has established a large international database with the goals of (i) working with other organizations towards universal data collection and creating a European-wide repository of information on the practice of cardio-thoracic surgery, and (ii) disseminating that information in scientific, peer-reviewed articles. We report on the process of data collection, as well as on an overview of the data in the database. The EACTS Database Committee met for the first time in Monaco, September 2002, to establish the ground rules for the process of setting up the database. Subsequently, data have been collected and merged by Dendrite Clinical Systems Ltd. As of December 2008, the database included 1 074 168 patient records from 366 hospitals located in 29 countries. The latest submission from the years 2006-08 included 404 721 records. The largest contributors were the UK (32.0%), Germany (20.9%) and Belgium (7.3%). Isolated coronary bypass surgery was the most frequently performed operation; the proportion of surgical workload that comprised isolated coronary artery bypass grafting varied from country to country: 30% in Spain and almost 70% in Denmark. Isolated valve procedures constituted 12% of all procedures in Norway and 32% in Spain. Baseline demographics showed an increase in the mean age and the percentage of patients that were female over time. Remarkably, the mortality rates for all procedures declined over the period analysed, to 2.2% (95% confidence interval [CI] 2.2-2.3%) for isolated coronary bypass, 3.4% (95% CI 3.3-3.5%) for isolated valve and 6.2% (95% CI 6.0-6.5%) for bypass + valve procedures. The EACTS database has proven to be an important step forward in providing opportunities for monitoring cardiac surgical care across Europe. As the database continues to expand, it will facilitate research projects, establish benchmarking standards and identify potential areas for quality improvements.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 06/2013; 44(3). DOI:10.1093/ejcts/ezt303 · 3.30 Impact Factor
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    ABSTRACT: Objectives: Prediction of operative risk in adult patients undergoing cardiac surgery remains a challenge, particularly in high-risk patients. In Europe, the EuroSCORE is the most commonly used risk-prediction model, but is no longer accurately calibrated to be used in contemporary practice. The new EuroSCORE II was recently published in an attempt to improve risk prediction. We sought to assess the predictive value of EuroSCORE II compared with the original EuroSCOREs in high-risk patients. Methods: Patients who underwent surgery between 1 April 2006 and 31 March 2011 with a preoperative logistic EuroSCORE ≥ 10 were identified from prospective cardiac surgical databases at two European institutions. Additional variables included in EuroSCORE II, but not in the original EuroSCORE, were retrospectively collected through patient chart review. The C-statistic to predict in-hospital mortality was calculated for the additive EuroSCORE, logistic EuroSCORE and EuroSCORE II models. The Hosmer-Lemeshow test was used to assess model calibration by comparing observed and expected mortality in a number of risk strata. The fit of EuroSCORE II was compared with the original EuroSCOREs using Akaike's Information Criterion (AIC). Results: A total of 933 patients were identified; the median additive EuroSCORE was 10 (interquartile range [IQR] 9-11), median logistic EuroSCORE 15.3 (IQR 12.0-24.1) and median EuroSCORE II 9.3 (5.8-15.6). There were 90 (9.7%) in-hospital deaths. None of the EuroSCORE models performed well with a C-statistic of 0.67 for the additive EuroSCORE and EuroSCORE II, and 0.66 for the logistic EuroSCORE. Model calibration was poor for the EuroSCORE II (chi-square 16.5; P = 0.035). Both the additive EuroSCORE and logistic EuroSCORE had a numerically better model fit, the additive EuroSCORE statistically significantly so (difference in AIC was -5.66; P = 0.017). Conclusions: The new EuroSCORE II does not improve risk prediction in high-risk patients undergoing adult cardiac surgery when compared with original additive and logistic EuroSCOREs. The key problem of risk stratification in high-risk patients has not been addressed by this new model. Future iterations of the score should explore more advanced statistical methods and focus on developing procedure-specific algorithms. Moreover, models that predict complications in addition to mortality may prove to be of increasing value.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 03/2013; 44(6). DOI:10.1093/ejcts/ezt174 · 3.30 Impact Factor
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    ABSTRACT: Objectives: Risk prediction in adult patients undergoing cardiac surgery remains inaccurate and should be further improved. Therefore, we aimed to identify risk factors that are predictive of mortality, stroke, renal failure and/or length of stay after adult cardiac surgery in contemporary practice. Methods: We searched the Medline database for English-language original contributions from January 2000 to December 2011 to identify preoperative independent risk factors of one of the following outcomes after adult cardiac surgery: death, stroke, renal failure and/or length of stay. Two investigators independently screened the studies. Inclusion criteria were (i) the study described an adult cardiac patient population; (ii) the study was an original contribution; (iii) multivariable analyses were performed to identify independent predictors; (iv) ≥ 1 of the predefined outcomes was analysed; (v) at least one variable was an independent predictor, or a variable was included in a risk model that was developed. Results: The search yielded 5768 studies. After the initial title screening, a second screening of the full texts of 1234 studies was performed. Ultimately, 844 studies were included in the systematic review. In these studies, we identified a large number of independent predictors of mortality, stroke, renal failure and length of stay, which could be categorized into variables related to: disease pathology, planned surgical procedure, patient demographics, patient history, patient comorbidities, patient status, blood values, urine values, medication use and gene mutations. Many of these variables are frequently not considered as predictive of outcomes. Conclusions: Risk estimates of mortality, stroke, renal failure and length of stay may be improved by the inclusion of additional (non-traditional) innovative risk factors. Current and future databases should consider collecting these variables.
    European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 02/2013; 43(5). DOI:10.1093/ejcts/ezt044 · 3.30 Impact Factor
  • Domenico Pagano · Neil Howell · Eshan Senanayake · Nick Freemantle ·

    The Journal of thoracic and cardiovascular surgery 02/2013; 145(2):610-1. DOI:10.1016/j.jtcvs.2012.11.003 · 4.17 Impact Factor
  • W. Lester · I. Begaj · D. Ray · D. Pagano ·

    Thrombosis Research 01/2013; 131:S75. DOI:10.1016/S0049-3848(13)70041-0 · 2.45 Impact Factor

Publication Stats

2k Citations
474.41 Total Impact Points


  • 1995-2015
    • Queen Elizabeth Hospital Birmingham
      Birmingham, England, United Kingdom
  • 2008-2014
    • University of Birmingham
      • School of Clinical and Experimental Medicine
      Birmingham, England, United Kingdom
  • 2010-2013
    • University Hospitals Birmingham NHS Foundation Trust
      • Department of Cardiothoracic Surgery
      Birmingham, England, United Kingdom
  • 1995-2013
    • The Queen Elizabeth Hospital
      • Department of Cardiac and Thoracic Surgery
      Tarndarnya, South Australia, Australia