Christopher M. O’Connor

Clinical ResearchHeart FailureCharacteristics, Treatments, and Outcomes of Patients With Preserved Systolic Function Hospitalized for Heart Failure: A Report From the OPTIMIZE-HF Registry

OBJECTIVES We sought to evaluate the characteristics, treatments, and outcomes of patients with preserved and reduced systolic function heart failure (HF). BACKGROUND Heart failure with preserved systolic function (PSF) is common but not well understood. METHODS This analysis of the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry compared 20,118 patients with left ventricular systolic dysfunction (LVSD) and 21,149 patients with PSF (left ventricular ejection fraction [EF] > or =40%). Sixty- to 90-day follow-up was obtained in a pre-specified 10% sample of patients. Analyses of patients with PSF defined as EF >50% were also performed for comparison. RESULTS Patients with PSF (EF > or =40%) were more likely to be older, female, and Caucasian and to have a nonischemic etiology. Although length of hospital stay was the same in both groups, risk of in-hospital mortality was lower in patients with PSF (EF > or =40%) (2.9% vs. 3.9%; p < 0.0001). During 60- to 90-day post-discharge follow-up, patients with PSF (EF > or =40%) had a similar mortality risk (9.5% vs. 9.8%; p = 0.459) and rehospitalization rates (29.2% vs. 29.9%; p = 0.591) compared with patients with LVSD. Findings were comparable with those with PSF defined as EF >50%. In a risk- and propensity-adjusted model, there were no significant relationships between discharge use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or beta-blocker and 60- to 90-day mortality and rehospitalization rates in patients with PSF. CONCLUSIONS Data from the OPTIMIZE-HF registry reveal a high prevalence of HF with PSF, and these patients have a similar post-discharge mortality risk and equally high rates of rehospitalization as patients with HF and LVSD. Despite the burden to patients and health care systems, data are lacking on effective management strategies for patients with HF and PSF. (Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure [OPTIMIZE-HF]); http://www.clinicaltrials.gov/ct/show/NCT00344513?order=1; NCT00344513).

Relation of frequency and severity of mitral regurgitation to survival among patients with left ventricular systolic dysfunction and heart failure.

The goal of this study was to examine the frequency of mitral regurgitation (MR) in patients with left ventricular (LV) systolic dysfunction and to relate its presence and severity to long-term survival. Remodeling of the left ventricle after myocyte injury leads to a progressive change in LV size and shape, and it may lead to the development of MR. The frequency of MR and its relation to survival in patients with LV systolic dysfunction has not been completely characterized. We analyzed the histories, coronary anatomy, and degree of MR in patients with symptomatic heart failure and LV ejection fraction <40% who underwent cardiac catheterization between 1986 and 2000. Coxs proportional hazards modeling was used to assess the independent effect of MR on survival. Two thousand fifty-seven patients met study criteria; MR was common in this cohort (56.2%). Of patients with MR, 811 (70.1%) had mild (grades 1+ or 2+) and 345 (29.8%) had moderate or severe (grades 3+ or 4+) regurgitation. Survival rates at 1, 3, and 5 years were significantly lower in patients with moderate to severe MR versus those with mild or no MR (p <0.001). MR was found to be an independent predictor of mortality after multivariable analysis (hazards ratio 1.23, 95% confidence interval 1.13 to 1.34, p = 0.0001). This relation of MR and survival was present in those with ischemic and nonischemic cardiomyopathies. MR is common in patients with LV systolic dysfunction and heart failure. After adjusting for other clinical variables, the presence of MR independently predicted worsened survival.

Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study.

OBJECTIVES The goal of this study was to assess the interaction between heart failure (HF) etiology and response to milrinone in decompensated HF. BACKGROUND Etiology has prognostic and therapeutic implications in HF, but its relationship to response to inotropic therapy is unknown. METHODS The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study randomized 949 patients with systolic dysfunction and decompensated HF to receive 48 to 72 h of intravenous milrinone or placebo. The primary end point was days hospitalized from cardiovascular causes within 60 days. In a post-hoc analysis, we evaluated the interaction between response to milrinone and etiology of HF. RESULTS The primary end point was 13.0 days for ischemic patients and 11.7 days for nonischemic patients (p = 0.2). Sixty-day mortality was 11.6% for the ischemic group and 7.5% for the nonischemic group (p = 0.03). After adjustment for baseline differences, there was a significant interaction between etiology and the effect of milrinone. Milrinone-treated patients with ischemic etiology tended to have worse outcomes than those treated with placebo in terms of the primary end point (13.6 days for milrinone vs. 12.4 days for placebo, p = 0.055 for interaction) and the composite of death or rehospitalization (42% vs. 36% for placebo, p = 0.01 for interaction). In contrast, outcomes in nonischemic patients treated with milrinone tended to be improved in terms of the primary end point (10.9 vs. 12.6 days placebo) and the composite of death or rehospitalization (28% vs. 35% placebo). CONCLUSIONS Milrinone may have a bidirectional effect based on etiology in decompensated HF. Milrinone may be deleterious in ischemic HF, but neutral to beneficial in nonischemic cardiomyopathy.

A standardized definition of ischemic cardiomyopathy for use in clinical research.

OBJECTIVES We sought to evaluate the association between the extent of coronary artery disease (CAD) and survival in patients with symptomatic heart failure (HF) and to create the most prognostically powerful clinical definition of ischemic cardiomyopathy. BACKGROUND An ischemic etiology of HF is known to be a predictor of adverse outcome; however, there is no uniform definition for ischemic cardiomyopathy. METHODS We assessed the clinical history and coronary anatomy of patients with symptomatic HF and ejection fraction < or = 40% undergoing diagnostic coronary angiography between 1986 and 1999 (n = 1,921). Five classification schemes were tested to identify the most prognostically powerful method for defining the extent of CAD and to develop the best definition of ischemic cardiomyopathy for prognostic purposes. RESULTS A more extensive CAD was independently associated with shorter survival. When the various classification schemes were compared, a modified number-of-diseased-vessels classification, in which patients with single-vessel disease and no prior history of revascularization or myocardial infarction (MI) were classified as nonischemic, provided the most prognostic power. A definition of ischemic cardiomyopathy that incorporated this definition had more prognostic power than the traditional definition. CONCLUSIONS Angiographically diagnosed ischemic HF is associated with shorter survival than nonischemic HF. A more extensive CAD is independently associated with shorter survival, and patients with single-vessel disease and no history of MI or revascularization should be classified as nonischemic for prognostic purposes. Standardization of the definition of ischemic cardiomyopathy will be useful in the conduct and interpretation of clinical research in HF.

Clinical Determinants of Mortality in Patients With Angiographically Diagnosed Ischemic or Nonischemic Cardiomyopathy

OBJECTIVES We sought to characterize the clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. BACKGROUND Patients with ischemic cardiomyopathy may have a worse prognosis than patients with nonischemic cardiomyopathy. Few studies have assessed the effect of ischemic versus nonischemic etiology on outcomes. METHODS We analyzed prospectively collected data on 3,787 patients with a left ventricular ejection fraction < or = 40% who underwent coronary angiography. Patients were considered to have ischemic cardiomyopathy (n = 3,112) if they had a history of myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery or at least one major epicardial coronary artery with > or = 75% stenosis; all others were considered to have nonischemic cardiomyopathy (n = 675). RESULTS The median age, ejection fraction and proportion of patients with New York Heart Association functional class III or IV symptoms for the nonischemic and ischemic groups were 55 years versus 63 years, 27% versus 32% and 57% versus 25%, respectively. After adjustment for baseline clinical risk factors and presenting characteristics, ischemic etiology remained an important independent predictor of 5-year mortality (p < 0.0001). The extent of coronary artery disease was a better predictor of survival than ischemic or nonischemic etiology (log likelihood chi-square 700 vs. 675, respectively). CONCLUSIONS Ischemic etiology is a significant independent predictor of mortality in patients with cardiomyopathy. However, the extent of coronary artery disease contributes more prognostic information than the clinical diagnosis of ischemic or nonischemic cardiomyopathy. Further research is needed to refine the clinical definition of ischemic cardiomyopathy so that physicians can appropriately prescribe treatment and accurately predict outcome.

Platelet/Endothelial Biomarkers in Depressed Patients Treated With the Selective Serotonin Reuptake Inhibitor Sertraline After Acute Coronary Events. The Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART) Platelet Substudy

Background—Depression after acute coronary syndromes (ACSs) has been identified as an independent risk factor for subsequent cardiac death. Enhanced platelet activation has been hypothesized to represent 1 of the mechanisms underlying this association. Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit platelet activity. Whether treatment of depressed post-ACS patients with SSRIs alters platelet function was not known. Accordingly, we serially assessed the release of established platelet/endothelial biomarkers in patients treated with sertraline vs placebo in the Sertraline AntiDepressant Heart Attack Randomized Trial (SADHART). Methods and Results—Plasma samples (baseline, week 6, and week 16) were collected from patients randomized to sertraline (n=28) or placebo (n=36). Anticoagulants, aspirin, and ADP-receptor inhibitors were permitted in this study. Platelet factor 4, &bgr;-thromboglobulin (&bgr;TG), platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane B2, 6-ketoprostaglandin F1a, vascular cell adhesion molecule-1, and E-selectin were measured by ELISA. Treatment with sertraline was associated with substantially less release of platelet/endothelial biomarkers than was treatment with placebo. These differences attained statistical significance for &bgr;TG (P =0.03) at weeks 6 and 16 and for P-selectin (P =0.04) at week 16. Repeated-measures ANOVA revealed a significant advantage for sertraline vs placebo for diminishing E-selectin and &bgr;TG concentrations across the entire treatment period. Conclusions—Treatment with sertraline in depressed post-ACS patients is associated with reductions in platelet/endothelial activation despite coadministration of widespread antiplatelet regimens including aspirin and clopidogrel. The antiplatelet and endothelium-protective properties of SSRIs might represent an attractive additional advantage in patients with depression and comorbid coronary artery and/or cerebrovascular disease.

Prognostic Value of Anxiety and Depression in Patients With Chronic Heart Failure

Background—Anxiety is often present with depression and may be one of its manifestations. Although the adverse effects of depression in patients with chronic heart failure (CHF) have been well studied, the relation between anxiety and CHF prognosis has not been addressed. In a secondary analysis of data collected for a published study of depression and prognosis in patients with CHF, we examined the relations among anxiety, depression, and prognosis. Methods and Results—We measured symptoms of anxiety with the Spielberger State-Trait Anxiety Inventory (STAI) scale and symptoms of depression with the Beck Depression Inventory (BDI) scale in 291 patients with CHF hospitalized as a result of cardiac events. We followed up these patients for all-cause mortality over 1 year. The mean scores for state anxiety (State-A) and trait anxiety (Trait-A) were identical at 33.5; the mean BDI score was 8.7±7.6. State-A and Trait-A scores correlated highly with each other (r=0.85; P<0.01) and with BDI score (State-A, r=0.52; Trait-A, r=0.59; P<0.01). Cox proportional-hazards model with and without confounding variables showed no relation between State-A or Trait-A and 1-year mortality. BDI scores, however, significantly predicted increased mortality during 1-year follow-up (hazard ratio, 1.04 for each 1-unit increase; P<0.01). Conclusions—Although anxiety and depression are highly correlated in CHF patients, depression alone predicts a significantly worse prognosis for these patients.

Vasopressin: a new target for the treatment of heart failure.

BACKGROUND Arginine vasopressin is a peptide hormone that modulates a number of processes implicated in the pathogenesis of heart failure. Numerous vasopressin antagonists are currently under development for the treatment of this syndrome. METHODS Preclinical and clinical data describing the effects of vasopressin and the vasopressin antagonists on both normal physiology and heart failure were reviewed. RESULTS Through activation of V(1a) and V(2) receptors, vasopressin regulates various physiological processes including body fluid regulation, vascular tone regulation, and cardiovascular contractility. Vasopressin synthesis is significantly and chronically elevated in patients with heart failure despite the volume overload and reductions in plasma osmolality often observed in these patients. Vasopressin also appears to adversely effect hemodynamics and cardiac remodeling, while potentiating the effects of norepinephrine and angiotensin II. The selective V(2) and dual V(1a)/V(2) receptor antagonists tolvaptan and conivaptan, respectively, substantially increase free water excretion and plasma osmolality, reduce body weight, improve symptoms of congestion, and moderately increase serum sodium concentrations in patients with heart failure who present with symptoms of fluid overload. Tolvaptan effectively normalizes serum sodium concentrations in hyponatremic heart failure patients. Conivaptan significantly reduces pulmonary capillary wedge pressure without affecting systemic vascular resistance or cardiac output. The clinical significance of V(1a) receptor antagonism requires further investigation. CONCLUSIONS Current preclinical and clinical findings with the vasopressin antagonists appear promising, however further evaluation in phase III clinical trials is necessary to define the role of vasopressin antagonism in the treatment of heart failure.

Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia∗ ☆

We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.

Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction - The VALsartan In Acute myocardial iNfarcTion (VALIANT) trial

Background—A prior diagnosis of diabetes mellitus is associated with adverse outcomes after acute myocardial infarction (MI), but the risk associated with a new diagnosis of diabetes in this setting has not been well defined. Methods and Results—We assessed the risk of death and major cardiovascular events associated with previously known and newly diagnosed diabetes by studying 14 703 patients with acute MI enrolled in the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Patients were grouped by diabetic status: previously known diabetes (insulin use or diagnosis of diabetes before MI, n=3400, 23%); newly diagnosed diabetes (use of diabetic therapy or diabetes diagnosed at randomization [median 4.9 d after infarction], but no known diabetes at presentation, n=580, 4%); or no diabetes (n=10 719). Patients with newly diagnosed diabetes were younger and had fewer comorbid conditions than did patients with previously known diabetes. At 1 year after enrollment, patients with previously known and newly diagnosed diabetes had similarly increased adjusted risks of mortality (hazard ratio [HR] 1.43; 95% confidence interval [CI], 1.29 to 1.59 and HR, 1.50; 95% CI, 1.21 to 1.85, respectively) and cardiovascular events (HR, 1.37; 95% CI, 1.27 to 1.48 and HR, 1.34; 95% CI, 1.14 to 1.56). Conclusions—Diabetes mellitus, whether newly diagnosed or previously known, is associated with poorer long-term outcomes after MI in high-risk patients. The poor prognosis of patients with newly diagnosed diabetes, despite having baseline characteristics similar to those of patients without diabetes, supports the idea that metabolic abnormalities contribute to their adverse outcomes.