Gadi Cotter

Bio: Gadi Cotter is an academic researcher from Durham University. The author has contributed to research in topics: Heart failure & Tezosentan. The author has an hindex of 16, co-authored 27 publications receiving 1649 citations. Previous affiliations of Gadi Cotter include University Medical Center Groningen & Duke University.

Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure: The VERITAS Randomized Controlled Trials

Abstract: ContextPlasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure.ObjectiveTo determine if tezosentan improves outcomes in patients with acute heart failure.Design, Setting, and ParticipantsThe Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro–B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction.InterventionInfusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718).Main Outcome MeasuresThe coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined.ResultsOf the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of −12 (95% confidence interval [CI], −105 to 81) mm · h (P = .80) in the first trial and −25 (95% CI, −119 to 69) mm · h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95).ConclusionThe endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.Trial Registrationclinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).

Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance.

Abstract: Background: Renal function is a powerful prognostic variable in patients with heart failure (HF). Hospitalisations for acute HF (AHF) may be associated with further worsening of renal function (WRF). Methods and results: We analysed the clinical significance of WRF in 318 consecutive patients admitted at our institute for AHF. WRF was defined as the occurrence, at any time during the hospitalisation, of both a ≥25% and a ≥0.3 mg/dL increase in serum creatinine (s-Cr) from admission (WRF-Abs-%). Results: Patients were followed for 480±363 days. Fifty-three patients (17%) died and 132 (41%) were rehospitalised for HF. WRF-Abs-% occurred in 107 (34%) patients. At multivariable survival analysis, WRF-Abs-% was an independent predictor of death or HF rehospitalisation (adjusted HR, 1.47; 95%CI, 1.13–1.81; p=0.024). The independent predictors of WRF-Abs-%, evaluated using multivariable logistic regression, were history of chronic kidney disease (p=0.002), LV ejection fraction (p=0.012), furosemide daily dose (p=0.03) and NYHA class (p=0.05) on admission. Conclusion: WRF is a frequent finding in patients hospitalised for AHF and is associated with a poor prognosis. Severity of HF and daily furosemide dose are the most important predictors of the occurrence of WRF.

Signature of circulating microRNAs in patients with acute heart failure.

Abstract: Aims: Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF). Methods and results: Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs. Conclusions: Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies.

Early drop in systolic blood pressure and worsening renal function in acute heart failure: renal results of Pre-RELAX-AHF.

Abstract: Aims We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and results The Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality. Conclusions Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. Trial registration clinicaltrials.gov identifier NCT00520806.

Conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm: the effect of no treatment and high-dose amiodarone. A randomized, placebo-controlled study.

Abstract: Background Spontaneous conversion of recent onset paroxysmal atrial fibrillation to normal sinus rhythm occurs commonly and is not affected by low-dose amiodarone treatment. Methods In a randomized, placebo-controlled trial of 100 patients with paroxysmal atrial fibrillation of recent onset (<48h) we compared the effects of treatment with continuous intravenous amiodarone 125mg per hour (total 3g) and intravenous placebo. Patients in the placebo group who did not convert to normal sinus rhythm within 24h were started on amiodarone therapy. Results Conversion to normal sinus rhythm occurred within 24h in 32 of 50 patients (64%) in the placebo group, most of whom converted within 8h. Lower conversion rates were observed in patients with hypertension, ischaemic heart disease or congestive heart failure and in patients with echocardiographic findings of left atrial diameter above 45mm, ejection fraction below 45% or significant mitral regurgitation. However, in most patients these clinical or echocardiographic risk factors of decreases in conversion rate were not present. In such patients the spontaneous conversion rate was approximately 90%. The conversion rate during 24h of treatment in the amiodarone group was 92% ( P =0·0017, compared to the placebo group). In this group, the conversion rate was largely unaffected by baseline characteristics. Of the 18 patients who did not convert with placebo, 15 (85%) converted after being crossed over to amiodarone. All patients not responding to high-dose amiodarone were in chronic atrial fibrillation within 1 month. In patients still in atrial fibrillation after 8h of treatment, the pulse rate decreased significantly more in the amiodarone as compared to the placebo group (83±15 vs 114±20 beats.min−1, P =0·0014). Conclusion The spontaneous conversion of recent onset paroxysmal atrial fibrillation is high and approaches 90% in specific clinical and echocardiographically defined subgroups. Intravenous high-dose amiodarone safely facilitates conversion of paroxysmal atrial fibrillation. However, such treatment should be reserved for patients with unfavourable risk factor profiles, not converting during 8h of observation or requiring rate control.

A Systematic Review and Meta-analysis

Abstract: Methods: We conducted a systematic review of studies published from January 1, 1950, through November 31, 2008, using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews. Randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.

Narrative review: the management of acute decompensated heart failure.

Abstract: Acute decompensated heart failure (ADHF) is the most common reason for hospitalization in Western nations. The prognosis of patients admitted to hospital with ADHF is poor, with up to 64% being readmitted within the first 90 days after discharge and with a 1-year mortality approximating 20%. Epidemiological studies suggest that the majority of patients hospitalized with ADHF receive treatment that is inadequate and which is not based on scientific evidence. Furthermore, emerging data suggest that the "conventional" therapeutic interventions for ADHF including morphine, high-dose diuretics, and inotropic agents may be harmful. The goal of this review is to provide evidence-based recommendations for the diagnosis and management of ADHF.