How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.

The Impact of Ferric Derisomaltose on Cardiovascular and Noncardiovascular Events in Patients With Anemia, Iron Deficiency, and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: In some countries, intravenous ferric derisomaltose (FDI) is only licensed for treating iron deficiency with anemia. Accordingly, we investigated the effects of intravenous FDI in a subgroup of patients with anemia in the IRONMAN (Effectiveness of Intravenous (IV) Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) trial. METHOD AND RESULTS: IRONMAN enrolled patients with heart failure, a left ventricular ejection fraction of ≤45%, and iron deficiency (ferritin <100 µg/L or transferrin saturation of <20%), 771 (68%) of whom had anemia (hemoglobin <12 g/dL for women and <13 g/dL for men). Patients were randomized, open label, to FDI (n = 397) or usual care (n = 374) and followed for a median of 2.6 years. The primary end point, recurrent hospitalization for heart failure and cardiovascular death, occurred less frequently for those assigned to FDI (rate ratio 0.78, 95% confidence interval 0.61-1.01; P = .063). First event analysis for cardiovascular death or hospitalization for heart failure, less affected by the coronavirus disease 2019 pandemic, gave similar results (hazard ratio 0.77, 95% confidence interval 0.62-0.96; P = .022). Patients randomized to FDI reported a better Minnesota Living with Heart Failure quality of life, for overall (P = .013) and physical domain (P = .00093) scores at 4 months. CONCLUSIONS: In patients with iron deficiency anemia and heart failure with reduced left ventricular ejection fraction, intravenous FDI improves quality of life and may decrease cardiovascular events.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

Treatment of myocardial ischaemia-reperfusion injury in patients with ST-segment elevation myocardial infarction: promise, disappointment, and hope.

Acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. Timely reperfusion with primary percutaneous coronary intervention (PPCI) remains the gold standard in patients presenting with ST-segment elevation myocardial infarction (STEMI), limiting infarct size, preserving left ventricular ejection fraction (LVEF), and improving clinical outcomes. Despite this, a significant proportion of STEMI patients develop post-infarct heart failure. We review the current understanding and up-to-date evidence base for therapeutic intervention of ischaemia-reperfusion injury (IRI), a combination of myocardial ischaemia secondary to acute coronary occlusion and reperfusion injury leading to further myocardial injury and cell death. Multiple treatment modalities have been shown to be cardioprotective and reduce IRI in experimental animal models. Recent phase II/III randomised controlled trials (RCT) have assessed multiple cardioprotective strategies ranging from ischaemic conditioning, therapeutic hypothermia and hyperoxaemia to pharmacological therapies. While several therapies have been shown to reduce infarct size in animal models or proof-of-concept studies, many larger scale trial results have proven inconsistent and disappointing. Hard clinical outcomes remain elusive. We discuss potential reasons for the difficulties in translation to clinical practice.

Clinical examination remains crucial to the correct diagnosis: a case of severe peripheral oedema referred for investigation of heart failure.

Hepatocellular carcinoma (HCC) uncommonly metastasises to the heart. We present a case of new onset bilateral leg swelling and suspected right heart failure in a previously fit and healthy man, which on further investigation revealed a new diagnosis of HCC with extension into the inferior vena cava and right atrium. This case highlights the importance of considering alternative possibilities when physical examination does not match the initial clinical diagnosis. The management approach was for best supportive care in view of extensive metastatic disease.

Cost-Effectiveness Analysis of Natriuretic Peptide Testing and Specialist Management in Patients with Suspected Acute Heart Failure.

OBJECTIVES: To determine the cost-effectiveness of natriuretic peptide (NP) testing and specialist outreach in patients with acute heart failure (AHF) residing off the cardiology ward. METHODS: We used a Markov model to estimate costs and quality-adjusted life-years (QALYs) for patients presenting to hospital with suspected AHF. We examined diagnostic workup with and without the NP test in suspected new cases, and we examined the impact of specialist heart failure outreach in all suspected cases. Inputs for the model were derived from systematic reviews, the UK national heart failure audit, randomized controlled trials, expert consensus from a National Institute for Health and Care Excellence guideline development group, and a national online survey. The main benefit from specialist care (cardiology ward and specialist outreach) was the increased likelihood of discharge on disease-modifying drugs for people with left ventricular systolic dysfunction, which improve mortality and reduce re-admissions due to worsened heart failure (associated with lower utility). Costs included diagnostic investigations, admissions, pharmacological therapy, and follow-up heart failure care. RESULTS: NP testing and specialist outreach are both higher cost, higher QALY, cost-effective strategies (incremental cost-effectiveness ratios of £11,656 and £2,883 per QALY gained, respectively). Combining NP and specialist outreach is the most cost-effective strategy. This result was robust to both univariate deterministic and probabilistic sensitivity analyses. CONCLUSIONS: NP testing for the diagnostic workup of new suspected AHF is cost-effective. The use of specialist heart failure outreach for inpatients with AHF residing off the cardiology ward is cost-effective. Both interventions will help improve outcomes for this high-risk group.

Defining left ventricular remodeling following acute ST-segment elevation myocardial infarction using cardiovascular magnetic resonance.

BACKGROUND: The assessment of post-myocardial infarction (MI) left ventricular (LV) remodeling by cardiovascular magnetic resonance (CMR) currently uses criteria defined by echocardiography. Our aim was to provide CMR criteria for assessing LV remodeling following acute MI. METHODS: Firstly, 40 reperfused ST-segment elevation myocardial infarction (STEMI) patients with paired acute (4 ± 2 days) and follow-up (5 ± 2 months) CMR scans were analyzed by 2 independent reviewers and the minimal detectable changes (MDCs) for percentage change in LV end-diastolic volume (%ΔLVEDV), LV end-systolic volume (%ΔLVESV), and LV ejection fraction (%ΔLVEF) between the acute and follow-up scans were determined. Secondly, in 146 reperfused STEMI patients, receiver operator characteristic curve analyses for predicting LVEF <50% at follow-up (as a surrogate for clinical poor clinical outcome) were undertaken to obtain cut-off values for %ΔLVEDV and %ΔLVESV. RESULTS: The MDCs for %ΔLVEDV, %ΔLVESV, and %ΔLVEF were similar at 12%, 12%, 13%, respectively. The cut-off values for predicting LVEF < 50% at follow-up were 11% for %ΔLVEDV on receiver operating characteristic curve analysis (area under the curve (AUC) 0.75, 95% CI 0.6 to 0.83, sensitivity 72% specificity 70%), and 5% for %ΔLVESV (AUC 0.83, 95% CI 0.77 to 0.90, sensitivity and specificity 78%). Using cut-off MDC values (higher than the clinically important cut-off values) of 12% for both %ΔLVEDV and %ΔLVESV, 4 main patterns of LV remodeling were identified in our cohort: reverse LV remodeling (LVEF predominantly improved); no LV remodeling (LVEF predominantly unchanged); adverse LV remodeling with compensation (LVEF predominantly improved); and adverse LV remodeling (LVEF unchanged or worsened). CONCLUSIONS: The MDCs for %ΔLVEDV and %ΔLVESV between the acute and follow-up CMR scans of 12% each may be used to define adverse or reverse LV remodeling post-STEMI. The MDC for %ΔLVEF of 13%, relative to baseline, provides the minimal effect size required for investigating treatments aimed at improving LVEF following acute STEMI.

Circadian variation in acute myocardial infarct size assessed by cardiovascular magnetic resonance in reperfused STEMI patients.

OBJECTIVE: Clinical studies using serum cardiac biomarkers to investigate a circadian variation in acute myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients reperfused by primary percutaneous coronary intervention (PPCI) have produced mixed results. We aimed to investigate this phenomenon using acute MI size measured by cardiovascular magnetic resonance (CMR). METHODS: Patient-level data was obtained from 4 randomized controlled trials investigating the MI-limiting effects of cardioprotective therapies in this pooled analysis. The primary analysis was performed in those patients with no pre-infarct angina; duration of ischemia >60min and <360min; Thrombolysis In Myocardial Infarction (TIMI) flow pre-PPCI ≤1; TIMI flow post-PPCI 3; and no collateral flow. RESULTS: 169 out of 376 patients with CMR data met the inclusion criteria for the primary analysis. A 24-hour circadian variation in acute MI size as a % of the area-at-risk (%AAR), after adjusting for confounders, was observed with a peak and nadir MI size in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively (difference from the average MI size 5.2%, 95%CI 1.1-9.4%; p=0.013). This was associated with a non-significant circadian variation in left ventricular ejection fraction (LVEF) (difference from the average LVEF 5.9%, 95%CI -0.6-2.2%, p=0.073). There was no circadian variation in MI size or LVEF in the whole cohort. CONCLUSIONS: We report a circadian variation in acute MI size assessed by CMR in a subset of STEMI patients treated by PPCI, with the largest and smallest MI size occurring in patients with symptom onset between 00:00 and 01:00 and between 12:00 and 13:00 respectively.

Association of haemodynamic changes measured by serial central venous saturation during ultrafiltration for acutely decompensated heart failure with diuretic resistance and change in renal function.

BACKGROUND: Patients with acute decompensated heart failure with diuretic resistance (ADHF-DR) have a poor prognosis. The aim of this study was to assess in patients with ADHF-DR, whether haemodynamic changes during ultrafiltration (UF) are associated with changes in renal function (Δcreatinine) and whether Δcreatinine post UF is associated with mortality. METHODS: Seventeen patients with ADHF-DR underwent 20 treatments with UF. Serial bloods (4-6 hourly) from the onset of UF treatment were measured for renal function, electrolytes and central venous saturation (CVO2). Univariate and multivariate analysis were performed to assess the relationship between changes in markers of haemodynamics [heart rate (HR), systolic blood pressure (SBP), packed cell volume (PCV) and CVO2] and Δcreatinine. Patients were followed up and mortality recorded. Cox-regression survival analysis was performed to determine covariates associated with mortality. RESULTS: Renal function worsened after UF in 17 of the 20 UF treatments (baseline vs. post UF creatinine: 164±58 vs. 185±69µmol/l, P<0.01). ΔCVO2 was significantly associated with Δcreatinine [ß-coefficient of -1.3 95%CI (-1.8 to -0.7), P<0.001] and remained significantly associated with Δcreatinine after considering changes in SBP, HR and PCV [P<0.001]. Ten (59%) patients died at 1-year and 15(88%) by 2-years. Δcreatinine was independently associated with mortality (adjusted-hazard ratio 1.03 (1.01 to 1.07) per 1µmol/l increase in creatinine; P=0.02). CONCLUSIONS: Haemodynamic changes during UF as measured by the surrogate of cardiac output was associated with Δcreatinine. Worsening renal function at end of UF treatment occurred in the majority of patients and was associated with mortality.

Cor triatriatum and hypertrophic cardiomyopathy.

: Cor triatriatum is a rare congenital anomaly known to be associated with other inherited heart diseases. We present a nonrestrictive cor triatriatum sinistrum associated with hypertrophic cardiomyopathy to illustrate how different multimodality noninvasive imaging techniques complement each other and can help with the diagnosis. To the best of our knowledge, this coexistence has not been previously reported.

The diagnostic accuracy of the natriuretic peptides in heart failure: systematic review and diagnostic meta-analysis in the acute care setting.

OBJECTIVES: To determine and compare the diagnostic accuracy of serum natriuretic peptide levels (B type natriuretic peptide, N terminal probrain natriuretic peptide (NTproBNP), and mid-regional proatrial natriuretic peptide (MRproANP)) in people presenting with acute heart failure to acute care settings using thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure. DESIGN: Systematic review and diagnostic meta-analysis. DATA SOURCES: Medline, Embase, Cochrane central register of controlled trials, Cochrane database of systematic reviews, database of abstracts of reviews of effects, NHS economic evaluation database, and Health Technology Assessment up to 28 January 2014, using combinations of subject headings and terms relating to heart failure and natriuretic peptides. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible studies evaluated one or more natriuretic peptides (B type natriuretic peptide, NTproBNP, or MRproANP) in the diagnosis of acute heart failure against an acceptable reference standard in consecutive or randomly selected adults in an acute care setting. Studies were excluded if they did not present sufficient data to extract or calculate true positives, false positives, false negatives, and true negatives, or report age independent natriuretic peptide thresholds. Studies not available in English were also excluded. RESULTS: 37 unique study cohorts described in 42 study reports were included, with a total of 48 test evaluations reporting 15 263 test results. At the lower recommended thresholds of 100 ng/L for B type natriuretic peptide and 300 ng/L for NTproBNP, the natriuretic peptides have sensitivities of 0.95 (95% confidence interval 0.93 to 0.96) and 0.99 (0.97 to 1.00) and negative predictive values of 0.94 (0.90 to 0.96) and 0.98 (0.89 to 1.0), respectively, for a diagnosis of acute heart failure. At the lower recommended threshold of 120 pmol/L, MRproANP has a sensitivity ranging from 0.95 (range 0.90-0.98) to 0.97 (0.95-0.98) and a negative predictive value ranging from 0.90 (0.80-0.96) to 0.97 (0.96-0.98). At higher thresholds the sensitivity declined progressively and specificity remained variable across the range of values. There was no statistically significant difference in diagnostic accuracy between plasma B type natriuretic peptide and NTproBNP. CONCLUSIONS: At the rule-out thresholds recommended in the 2012 European Society of Cardiology guidelines for heart failure, plasma B type natriuretic peptide, NTproBNP, and MRproANP have excellent ability to exclude acute heart failure. Specificity is variable, and so imaging to confirm a diagnosis of heart failure is required. There is no statistical difference between the diagnostic accuracy of plasma B type natriuretic peptide and NTproBNP. Introduction of natriuretic peptide measurement in the investigation of patients with suspected acute heart failure has the potential to allow rapid and accurate exclusion of the diagnosis.

Safety and clinical outcome of erythropoiesis-stimulating agents in patients with ST-elevation myocardial infarction: a meta-analysis of individual patient data.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. METHODS: A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. RESULTS: Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). CONCLUSIONS: Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

AIMS: The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. METHOD AND RESULTS: A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. CONCLUSION: This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.

Clinical features of myocardial infarction and myocarditis in young adults: a retrospective study.

OBJECTIVES: To evaluate the prevalence and clinical presentation of myocardial infarction (MI) and myocarditis in young adults presenting with chest pain (CP) and an elevated serum troponin I (TnI) to the emergency department (ED). DESIGN: Retrospective, observational, single-centre study. PARTICIPANTS: All consecutive patients 18-40 years old admitted to the ED for CP with an elevated TnI concentration. PRIMARY OUTCOME MEASURES: Prevalence of MI, myocarditis and the characterisation of clinical presentation. RESULTS: 1588 patients between 18 and 40 years old were admitted to the ED with CP during 30 consecutive months. 49 (3.1%) patients with an elevated TnI (>0.09 µg/l) were included. 32.7% (16/49) were diagnosed with MI (11 ST-elevation myocardial infarction (STEMI) and 5 non-ST-elevation myocardial infarction (NSTEMI)) and 59.2% (29/49) with myocarditis. Compared with patients with myocarditis, MI patients were older (34.1±3.8 vs 26.9±6.4, p=0.0002) with more cardiovascular risk factors (mean 2.06 vs 0.69). Diabetes (18.8% vs 0%, p=0.0039), dyslipidaemia (56.2% vs 3.4%, p<0.0001) and family history of coronary artery disease (CAD) (37.5% vs 10.3% p=0.050) were associated with MI. Fever or recent viral illness were present in 75.9% (22/29) of patients with myocarditis, and in 0% of MI patients (p<0.0001). During follow-up, two patients with myocarditis were re-admitted for CP. CONCLUSIONS: In this study, 32.7% of patients <40-year-old admitted to an ED with CP and elevated TnI had a diagnosis of MI. Key distinctive clinical factors include diabetes, dyslipidaemia, family history of CAD and fever or recent viral illness.

Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial.

OBJECTIVE: The acute administration of high-dose erythropoietin (EPO) on reperfusing ischaemic myocardium has been reported to halve myocardial infarct (MI) size in preclinical studies, but its effect in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PPCI) remains unknown. We investigated whether high-dose EPO administered as an adjunct to PPCI reduces MI size. DESIGN: Double-blinded, randomised, placebo-controlled. SETTING: Single tertiary cardiac centre. PATIENTS: Fifty-one ST elevation myocardial infarction patients undergoing PPCI. INTERVENTIONS: Patients were randomly assigned to receive either a single intravenous bolus of EPO (50,000 IU) prior to PPCI with a further bolus given 24 h later (n=26) or placebo (n=25). MAIN OUTCOME MEASURES: MI size measured by 24 h area under the curve troponin T and cardiac magnetic resonance imaging performed on day 2 and at 4 months. RESULTS: EPO treatment failed to reduce MI size (troponin T area under the curve: 114.6±78 µg/ml EPO vs 100.8±68 µg/ml placebo; infarct mass by cardiac magnetic resonance: 33±16 g EPO vs 25±16 g placebo; both p>0.05). Unexpectedly, EPO treatment doubled the incidence of microvascular obstruction (82% EPO vs 47% placebo; p=0.02) and significantly increased indexed left ventricular (LV) end-diastolic volumes (84±10 ml/m(2) EPO vs 73±13 ml/m(2) placebo; p=0.003), indexed LV end-systolic volumes (41±9 ml/m(2) EPO vs 35±11 ml/m(2) placebo; p=0.035) and indexed myocardial mass (89±16 g/m(2) EPO vs 79±11 g/m(2) placebo; p=0.03). At 4 months, there were no significant differences between groups. CONCLUSIONS: High-dose EPO administered as an adjunct to PPCI failed to reduce MI size. In fact, EPO treatment was associated with an increased incidence of microvascular obstruction, LV dilatation and increased LV mass. Clinical Trial Registration Information http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=4058 Unique Identifier=Study ID 4058.

Failure to recapture cardioprotection with high-dose atorvastatin in coronary artery bypass surgery: a randomised controlled trial.

The acute administration of atorvastatin has been reported to reduce myocardial infarct size in animal studies. However, this cardioprotective effect is lost with the chronic administration of atorvastatin, although it can be recaptured by administering an acute high-dose of atorvastatin. We hypothesised that pre-treatment with high-dose atorvastatin, on a background of chronic standard 'statin' therapy, would reduce myocardial injury in patients undergoing elective coronary artery bypass graft (CABG) surgery. One hundred and one consenting patients undergoing elective CABG surgery at a single tertiary cardiac centre were recruited into two randomised controlled, single-blinded clinical studies. Study 1: 45 patients were randomised to receive either 160 mg of atorvastatin 2 h preoperatively and 24 h following surgery or their standard statin therapy. Study 2: 56 patients were randomised to receive either 160 mg of atorvastatin 12 h preoperatively and 24 h following surgery or their standard statin therapy. Blood samples for troponin T and creatine kinase were taken prior to surgery and then at 6, 12, 24, 48 and 72 h post-surgery. Cardiac enzyme levels at each time point and the total area-under curve (AUC) were calculated. The group characteristics and surgical methods were well matched. High-dose atorvastatin was not associated with any significant side effects. There was no significant difference in serum troponin T or creatine kinase in either study at each time point or over 72 h. Study 1: AUC, troponin T: atorvastatin 29.6 ± 34.8 µg/L versus control 25.0 ± 22.0 µg/L:P > 0.05. Creatine kinase: atorvastatin 33,544 ± 20,063 IU/L versus control 30,620 ± 10,776 IU/L:P > 0.05. Study 2: AUC, troponin T: atorvastatin 21.8 ± 14.3 µg/L versus control 20.9 ± 8.7 µg/L:P > 0.05. Creatine kinase: atorvastatin 36,262 ± 28,821 IU/L versus control 33,448 ± 14,984:P > 0.05. There were no differences in postoperative outcomes. We report that the administration of high-dose atorvastatin to low risk patients undergoing elective CABG surgery, who are already on standard dose 'statin' therapy is safe, but does not further reduce perioperative myocardial injury.

Effect of remote ischemic preconditioning on acute kidney injury in nondiabetic patients undergoing coronary artery bypass graft surgery: a secondary analysis of 2 small randomized trials.

BACKGROUND: Novel treatment strategies are required to reduce the development of acute kidney injury (AKI) in patients undergoing cardiac surgery. In this respect, remote ischemic preconditioning (RIPC), a phenomenon in which transient nonlethal ischemia applied to an organ or tissue protects another organ or tissue from subsequent lethal ischemic injury, is a potential renoprotective strategy. STUDY DESIGN: Secondary analysis of 2 randomized trials. SETTING & PARTICIPANTS: 78 consenting selected nondiabetic patients in a university teaching hospital undergoing elective coronary artery bypass graft (CABG) surgery recruited to 2 previously reported randomized studies. INTERVENTION: RIPC consisted of three 5-minute cycles of right forearm ischemia, induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg, with an intervening 5 minutes of reperfusion, during which time the cuff was deflated. The control consisted of placing an uninflated cuff on the arm for 30 minutes. OUTCOMES: AKI measured using Acute Kidney Injury Network (AKIN) criteria, duration of hospital stay, in-hospital and 30-day mortality. RESULTS: Numbers of participants with AKI stages 1, 2, and 3 were 1 (3%), 3 (8%), and 0 in the intervention group compared with 10 (25%), 0, and 0 in the control group, respectively (P = 0.005). The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times, which were distributed unevenly between the 2 groups. LIMITATIONS: Retrospective analysis of data. More patients in the RIPC group underwent concomitant aortic valve replacement with CABG; although we have corrected statistically for this imbalance, it remains an important confounding variable. CONCLUSIONS: RIPC induced using transient forearm ischemia decreased the incidence of AKI in nondiabetic patients undergoing elective CABG surgery in this retrospective analysis. A large prospective clinical trial is required to study this effect and clinical outcomes in patients undergoing cardiac surgery.