B. Massie

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Dipyridamole thallium-201 scintigraphy as a preoperative screening test. A reexamination of its predictive potential. Study of Perioperative Ischemia Research Group.

BACKGROUND We examined the value of dipyridamole thallium-201 (201Tl) scintigraphy as a preoperative screening test for perioperative myocardial ischemia and infarction. METHODS AND RESULTS We prospectively studied 60 patients undergoing elective vascular surgery. We performed 201Tl scintigraphy preoperatively and blinded all treating physicians to the results. Historical, clinical, laboratory, and physiological data were gathered throughout hospitalization. Myocardial ischemia was assessed during the intraoperative period using continuous 12-lead electrocardiography (ECG) and transesophageal echocardiography (TEE) and during the postoperative period using continuous two-lead ambulatory ECG. Adverse cardiac outcomes (cardiac death, myocardial infarction, unstable angina, severe ischemia, or congestive heart failure) were assessed daily throughout hospitalization. Twenty-two patients (37%) had defects that improved or reversed on delayed scintigrams (redistribution defects), 18 (30%) had persistent defects, and 20 (33%) had no defects on 201Tl scintigraphy. There was no association between redistribution defects and adverse cardiac outcomes: 54% (seven of 13) of adverse outcomes occurred in patients without redistribution defects, and the risk of an adverse outcome was not significantly increased in patients with redistribution defects (relative risk 1.5, 95% confidence interval 0.6-3.9, p = 0.43). Consistent with these findings, there was also no association between redistribution defects and perioperative ischemia: 54% (19 of all 35) of perioperative ECG and TEE ischemic episodes and 58% (14 of 24) of severe ischemic episodes occurred in patients without redistribution defects. The sensitivity of 201Tl scintigraphy for perioperative ischemia and adverse outcomes ranged from 40% to 54%, specificity from 65% to 71%, positive predictive value from 27% to 47% and negative predictive value from 61% to 82%. CONCLUSIONS These results differ from those of previous studies and suggest that the routine use of 201Tl scintigraphy for preoperative screening of patients undergoing vascular surgery may not be warranted.

Mode of death in heart failure: findings from the ATLAS trial

Objective: To investigate markers that predict modes of death in patients with chronic heart failure. Design: Randomised, double blind, three period, comparative, parallel group study (ATLAS, assessment of treatment with lisinopril and survival). Patients: 3164 patients with mild, moderate, or severe chronic heart failure (New York Heart Association functional class II–IV). Interventions: High dose (32.5 or 35 mg) or low dose (2.5 or 5 mg) lisinopril once daily for a median of 46 months. Main outcome measures: All cause mortality, cardiovascular mortality, sudden death, and chronic heart failure death related to prognostic factors using competing risks analysis. Mode of death was classified by trialists and by an independent end point committee. Results: Age, male sex, pre-existing ischaemic heart disease, increasing heart rate, creatinine concentration, and certain drugs taken at randomisation were markers of increased risk of all cause mortality and cardiovascular death. There were risk markers for sudden death that were different from the risk markers for death from chronic heart failure. Low systolic blood pressure at baseline, raised creatinine, reduced serum sodium or haemoglobin, and increased heart rate were associated with chronic heart failure death. Use of β blockers or antiarrhythmic agents (mainly amiodarone) was associated with a reduced risk of sudden death, whereas long acting nitrates and previous use of angiotensin converting enzyme inhibitors were markers for increased risk. Conclusions: The use of competing risks analysis on the data from the ATLAS study has identified variables associated with certain modes of death in heart failure patients. This approach to analysing outcomes may make it possible to predict which patients might benefit most from particular therapeutic interventions.

Diuretic response in acute heart failure : clinical characteristics and prognostic significance

AIM Diminished diuretic response is common in patients with acute heart failure, although a clinically useful definition is lacking. Our aim was to investigate a practical, workable metric for diuretic response, examine associated patient characteristics and relationships with outcome. METHODS AND RESULTS We examined diuretic response (defined as Δ weight kg/40 mg furosemide) in 1745 hospitalized acute heart failure patients from the PROTECT trial. Day 4 response was used to allow maximum differentiation in responsiveness and tailoring of diuretic doses to clinical response, following sensitivity analyses. We investigated predictors of diuretic response and relationships with outcome. The median diuretic response was -0.38 (-0.80 to -0.13) kg/40 mg furosemide. Poor diuretic response was independently associated with low systolic blood pressure, high blood urea nitrogen, diabetes, and atherosclerotic disease (all P < 0.05). Worse diuretic response independently predicted 180-day mortality (HR: 1.42; 95% CI: 1.11-1.81, P = 0.005), 60-day death or renal or cardiovascular rehospitalization (HR: 1.34; 95% CI: 1.14-1.59, P < 0.001) and 60-day HF rehospitalization (HR: 1.57; 95% CI: 1.24-2.01, P < 0.001) in multivariable models. The proposed metric-weight loss indexed to diuretic dose-better captures a dose-response relationship. Model diagnostics showed diuretic response provided essentially the same or slightly better prognostic information compared with its individual components (weight loss and diuretic dose) in this population, while providing a less biased, more easily interpreted signal. CONCLUSIONS Worse diuretic response was associated with more advanced heart failure, renal impairment, diabetes, atherosclerotic disease and in-hospital worsening heart failure, and predicts mortality and heart failure rehospitalization in this post hoc, hypothesis-generating study.

Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure.

BackgroundRecent research has demonstrated that patients with congestive heart failure (CHF) exhibit significant functional impairment of skeletal muscle and that these changes may be important determinants of exercise capacity. Although muscle strength may be mildly reduced, the most significant abnormality is markedly enhanced muscle fatigue. The goal of the present study is to determine whether accelerated fatigue is caused by impaired muscle activation, as a result of inadequate central motor drive or neuromuscular transmission, or by a change in the muscle itself. Methods and ResultsThe study population consisted of nine patients with New York Heart Association class I-III CHF and eight sedentary, age- and sex-matched control subjects. Maximal voluntary contraction force of the foot dorsiflexors (primarily the tibialis anterior) was quantified as a measure of muscle strength, isometric endurance was quantified by the time required for force to decline to 60% of maximal during a sustained maximal contraction, and dynamic endurance was defined as the number of maximal contractions required for force to decline to 60% of maximal under a protocol of six repetitions per minute with an incremental duty cycle. The degree of central motor drive failure was quantified by the degree of force augmentation produced by a superimposed tetanic stimulus delivered to the peroneal nerve during the initial maximal voluntary contraction and at the time when force during the sustained isometric contraction declined to 60% of maximal. Neuromuscular junction transmission was examined by quantifying the amplitude of the compound muscle action potential (M wave) in response to a single nerve stimulus during fatiguing exercise. Muscle strength was relatively preserved in the CHF patients versus the control subjects (93±41 versus 105±34 lb;p=NS), but isometric endurance (time to decline to 60%, 34±15 versus 54±19 seconds;p<0.02) and dynamic endurance (number of repetitions before decline to 60%, 30±6 versus 43±7 contractions; p<0.001) were both impaired. Tetanic nerve stimulation increased force by similar degrees in the two groups, and the amplitude of the M wave did not decline in either group during exercise. ConclusionsThese findings indicate that enhanced muscle fatigue in patients with CHF is not caused by impaired central motor drive or an abnormality of neuromuscular junction transmission but rather by an abnormality in the muscle itself.

Losing ALTITUDE? How should ASTRONAUT launch into ATMOSPHERE.

Centre of Cardiovascular Research & Education in Therapeutics, Monash University, Melbourne, Australia; University of California, San Francisco, San Francisco, CA, USA; Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute, The Ohio State University, USA; Stavanger University Hospital, Stavanger, Norway; Institute of Internal Medicine, University of Bergen, Bergen, Norway; Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark; and University of Glasgow, Glasgow, UK

653 Atrial fibrillation is associated with increased risk of fatal and non-fatal cardiovascular events in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial

653 Atrial fibrillation is associated with increased risk of fatal and non-fatal cardiovascular events in patients with heart failure and preserved ejection fraction: findings from the I-PRESERVE trial M.R. Zile1, M. Komajda2, R. Mckelvie3, J. McMurray4, M. Donovan5, A.A. Ptaszynska5, B. Massie6, P. Carson7 1Medical Univ of South Carolina, cardiology, Charleston Sc, France; 2Pitie-Salpetriere Hosp., cardiology, Paris, France; 3McMaster Univ, cardiology, Hamilton On, Canada; 4Western Infirmary Glasgow, cardiology, Glasgow, United Kingdom; 5Bristol-Myers Squibb Pharmaceutical Research, biostatistics, Princeton Nj, United States of America; 6VA Medical Ctr, cardiology, San Francisco Ca, United States of America; 7VA Medical Ctr, cardiology, Washington Dc, United States of America

326 Anaemia is associated with poor outcome in patients with heart failure and preserved ejection fraction (HF‐PEF). Findings from the I‐PRESERVE trial

325 Renal dysfunction is associated with increased risk of fatal and non-fatal cardiovascular events in patients with heart failure and preserved ejection fraction findings from the I-PRESERVE trial J. McMurray1, M. Komajda2, R. Mckelvie3, M. Zile4, A. Ptaszynska5, M. Donovan6, B. Massie7, P. Carson8 1Western Infirmary Glasgow, Cardiology, Glasgow, United Kingdom; 2Pitie-Salpetriere Hosp., Cardiology, Paris, France; 3Hamilton Health Sciences McMaster University, Cardiology, Hamilton On, Canada; 4Medical University of South Carolina, Cardiology, Charleston Sc, United States of America; 5Bristol-Myers Squibb Company, Director CV& Immunology Clininal Design & Ev., Princeton, United States of America; 6Bristol-Myers Squibb Pharmaceutical Research, biostatistics, Princeton Nj, United States of America; 7VA Medical Ctr, cardiology, San Francisco Ca, United States of America; 8VA Medical Ctr, cardiology, Washington Dc, United States of America