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Barry Greenberg

Publications and source records attributed to Barry Greenberg.

16 recordsLinked to original sources
PubMed2026

Subgroups and Special Populations in Heart Failure Clinical Trials: Insights From the HFC-ARC Expert Consensus Panel.

In the evolving landscape of heart failure (HF) management, the identification and analysis of subgroups and special populations within clinical trials are crucial for enhancing clinical decision-making, guiding further research, and understanding heterogeneity in study outcomes. This expert consensus document results from the collaborative efforts of the Heart Failure Collaboratory and the Heart Failure Collaboratory Academic Research Consortium, which brought together stakeholders from academia, industry, the U.S. Food and Drug Administration, and patient representatives. The purpose of this assembly was to propose standardized definitions and critical endpoint considerations essential for shaping the design and conduct of clinical trials for drugs and devices in the field of HF. In this context, we propose definitions and endpoints for specific subgroups and special populations in the spectrum of HF. We enhanced the precision, efficacy, and applicability of clinical research and promote more "personalized" approaches to interpretation of clinical trials. Furthermore, we explore the burgeoning field of gene therapy as a promising avenue for addressing the genetic basis of certain cardiomyopathies within these specialized patient groups. We focus especially on methodological considerations for subgroup analyses in large-scale trials, highlighting the importance of proper interpretation of subgroups and best practices for identifying heterogeneity suggestive of differential treatment effects, including when these analyses should be considered hypothesis-generating and requiring subsequent validation. We advocate for a methodical approach to clinical trial design, one that prioritizes the strategic identification of subgroups and employs appropriate statistical methodologies to ensure the reliability and clinical relevance of findings. Through this lens, we envision a pathway toward more personalized and effective treatments for HF, ultimately aiming to improve patient outcomes by leveraging the insights garnered from meticulously designed and comprehensively analyzed clinical trials.

Humans↗
PubMed2006

Predictors of clinical outcomes in patients given carvedilol for heart failure.

Risk factors for outcomes in heart failure (HF) were derived from populations in clinical trials, at hospital discharge, or in localized geographic or socioeconomic strata before the widespread use of beta blockers. This study observed 4,280 patients in a community-based HF registry for 1 year after completing carvedilol titration. Independent risk factors for death, hospitalization for HF, or hospitalization for cardiovascular reasons other than HF were first identified by age-, gender-, and race-adjusted analyses, then by multivariate analysis adjusted simultaneously for all factors. Over this period, 7% of patients died, 11% were hospitalized for HF, 12% were hospitalized for other cardiovascular reasons, and 27% had > or =1 of these events. The most significant outcome predictors were New York Heart Association class III or IV, history of hospitalization for HF or other cardiovascular reasons, and angina pectoris, all associated with increased odds of having an adverse outcome (all p < or =0.001). The left ventricular ejection fraction was not a significant outcome predictor by multivariate analysis. The odds ratio for an adverse outcome was significantly reduced for patients with hypertensive or idiopathic causes of HF and for those whose physicians had graduated from medical school > or =24 years earlier compared with <14 years earlier (all p <0.005). In conclusion, easily obtained historical information predicts clinical outcomes in patients with HF in the year after initiating carvedilol. In this unselected community population, these historical factors were better predictors of risk than the left ventricular ejection fraction.

Adrenergic beta-Antagonists↗
PubMed2006

Role of aldosterone blockade for treatment of heart failure and post-acute myocardial infarction.

Heart failure continues to significantly impact morbidity and mortality after acute myocardial infarction (AMI), especially when associated with left ventricular systolic dysfunction (LVSD). Therefore, routine use of optimal therapy for patients with heart failure after AMI is needed in the future. Data from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) has demonstrated that addition of eplerenone to standard therapy in patients with LVSD and clinical heart failure post-AMI significantly improves outcomes in these patients, providing the basis for acceptance of aldosterone blockade as an integral component of therapy. However, further studies are needed to more broadly explore the usefulness of aldosterone blockade in heart failure therapy. As research clarifies the many complex pathophysiologic processes involved in post-AMI remodeling, treatment should continue to move beyond symptom-targeted therapies to disease- and mechanism-targeted therapies that will further improve outcomes in the setting of heart failure post-AMI and beyond.

Heart Failure↗
PubMed2006

Randomized comparison of pain perception during radial head subluxation reduction using supination-flexion or forced pronation.

OBJECTIVE: To determine if a difference exists in perceived pain between the forced pronation and supination-flexion methods of radial head subluxation (RHS) reduction. DESIGN AND METHODS: We developed a prospective randomized trial of children aged 6 months to 7 years who presented to the emergency department (ED) at Miami Children's Hospital with an immobile arm and physical findings suggestive of RHS. Children were randomized into 2 groups for RHS reduction: forced pronation and supination-flexion. Parents, physicians, and nurses were given a standard visual analog pain scale for pain assessment before, during, and at 1 minute after successful reduction. RESULTS: Seventy-five children presented to the ED with RHS; 3 children were excluded from the study because of nonadherence to the protocol and another 9 were excluded because of unsuccessful reduction during the first attempt. Of the remaining children, 32 children underwent forced pronation and 31 underwent supination-flexion. Physicians did not find a significant difference in gain scores between their perceptions of the premeasure and postmeasure of pain between those patients receiving supination-flexion and those receiving forced pronation. For nurses (P < 0.031) and parents (P < 0.043), there were statistically significant differences in gain scores. Nurses and parents perceived forced pronation as being less painful. The mean difference for parents was 1.7 cm, which exceeded the value of 1.3 cm identified as clinically significant. CONCLUSIONS: Forced pronation is perceived as less painful than the supination-flexion method by parents of children treated for RHS in our ED.

Arm Injuries↗
PubMed2005

Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST).

OBJECTIVES: The aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: Previous studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy. METHODS: Complete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates. RESULTS: On multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m(2). Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m(2), 150 ms, and 0.4 cm, respectively. CONCLUSIONS: Echocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.

Echocardiography, Doppler↗
PubMed2004

Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation.

It is anticipated that gamma-secretase inhibitors (gamma-Sec-I) that modulate Notch processing will alter differentiation in tissues whose architecture is governed by Notch signaling. To explore this hypothesis, Han Wistar rats were dosed for up to 5 days with 10-100 micromol/kg b.i.d. gamma-Sec-I from three chemical series that inhibit Notch processing in vitro at various potencies (Notch IC(50)). These included an arylsulfonamide (AS) (142 nM), a dibenzazepine (DBZ) (1.7 nM), and a benzodiazepine (BZ) (2.2 nM). The DBZ and BZ caused dose-dependent intestinal goblet cell metaplasia. In contrast, the AS produced no detectable in vivo toxicity, despite higher exposure to free drug. In a time course using BZ, small intestinal crypt cell and large intestinal glandular cell epithelial apoptosis was observed on days 1-5, followed by goblet cell metaplasia on days 2-5 and crypt epithelial and glandular epithelial regenerative hyperplasia on days 4-5. Gene expression profiling of duodenal samples from BZ-dosed animals revealed significant time-dependent deregulation of mRNAs for various panendocrine, hormonal, and transcription factor genes. Somatostatin, secretin, mucin, CCK, and gastrin mRNAs were elevated twofold or more by day 2, and a number of candidate "early-predictive" genes were altered on days 1-2, remaining changed for 4-5 days; these included Delta1, NeuroD, Hes1-regulated adipsin, and the Hes-regulated transcriptional activator of gut secretory lineage differentiation, the rat homolog of Drosophila atonal, Rath1. Western blotting of fecal protein from BZ-and DBZ-dosed animals exhibited increased levels of both anti-Rath1 reactive protein and anti-adipsin reactive proteins, confirming their potential value as noninvasive biomarkers of intestinal goblet metaplasia.

Amyloid Precursor Protein Secretases↗
PubMed2004

Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design.

Heart failure (HF) affects >5 million patients in the United States, and its prevalence is increasing every year. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors and beta-blockers reduce hospitalizations and mortality rates in patients with HF, these lifesaving therapies continue to be underused. Several studies in a variety of clinical settings have documented that a significant proportion of eligible patients with HF are not receiving treatment with these guideline-recommended, evidence-based therapies. In patients hospitalized with HF, who are at particularly high risk for re-hospitalization and death, the initiation of beta-blockers is often delayed because of concern that early initiation of these agents may exacerbate HF. Recent studies suggest that beta-blockers can be safely and effectively initiated in patients with HF before hospital discharge and that clinical outcomes are improved. The Initiation Management Predischarge Process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial demonstrated that pre-discharge initiation of carvedilol was associated with a higher rate of beta-blocker use after hospital discharge, with no increase in hospital length of stay. In addition, there was no increase in the risk of worsening of HF. Studies of hospital-based management systems that rely on early (pre-discharge) initiation of evidence-based therapies for patients with cardiovascular disease have also found increases in post-discharge use of therapy and a reduction in the rates of mortality and hospitalization. On the basis of these pivotal studies, the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) program is designed to improve medical care and education of hospitalized patients with HF and accelerate the initiation of evidence-based HF guideline recommended therapies by administering them before hospital discharge. A registry component, planned as the most comprehensive database of the hospitalized HF population focusing on admission to discharge and 60- to 90-day follow-up, is designed to evaluate the demographic, pathophysiologic, clinical, treatment, and outcome characteristics of patients hospitalized with HF. The ultimate aim of this program is to improve the standard of HF care in the hospital and outpatient settings and increase the use of evidence-based therapeutic strategies to save lives.

Adrenergic beta-Antagonists↗
PubMed2004

Beta-blocker therapy for heart failure outside the clinical trial setting: findings of a community-based registry.

BACKGROUND: beta-Blockers reduce morbidity and mortality rates in heart failure (HF) clinical trials, but it is unknown whether these findings persist in the community setting. METHODS: A registry was created to survey tolerability and outcomes during initiation and 1-year follow-up of beta-blocker treatment with carvedilol in patients with HF treated by cardiologists (CARD) and primary care physicians (PCP) in the community. RESULTS: A total 4280 patients were enrolled (3121 by 259 CARD, 1159 by 129 PCP). Patient age averaged 67 +/- 13 years; 35% were women and 12% were black. The left ventricular ejection fraction averaged 31 +/- 12; New York Heart Association class was II-III in 86% and IV in 3%. Patients of PCP had higher left ventricular ejection fraction, were older, and more frequently were female, black, diabetic, hypertensive, and in New York Heart Association class III/IV. Minimal difficulty titrating carvedilol was noted by >80% of CARD and PCP. Significantly more CARD-treated patients reached carvedilol doses of 25 mg twice daily (49% vs 27%). Kaplan-Meier all-cause mortality rate was 8.5% at 1 year and did not differ between CARD-treated and PCP-treated patients (8.2% vs 9.3%, P =.254). At least one HF hospitalization occurred in 11% of patients during follow-up, compared with 28% in the preceding year. CONCLUSIONS: Community-based physicians use carvedilol with success approaching that of clinical trials. Overall mortality rates and HF hospitalizations were in the same low range as in clinical trials. Thus, it appears that results of clinical trials with carvedilol for HF can be translated to the community setting.

Adrenergic beta-Antagonists↗
PubMed2004

Nonselective versus selective beta-blockers in the management of chronic heart failure: clinical implications of the carvedilol or Metoprolol European Trial.

The abundance of evidence supporting beta-blocker therapy has resulted in the widespread acceptance of these drugs in the treatment of heart-failure patients. However, beta-blockers are not a homogeneous class of drugs, and important differences in efficacy have been noted between different members of the class. Thus, practicing physicians are faced with a choice when selecting a particular beta-blocker for treating heart failure. One of the considerations is whether to choose a selective or a nonselective beta-blocker. The results of the Carvedilol or Metoprolol European Trial indicate that carvedilol, a third-generation, nonselective beta-blocker with additional a-blocking, antioxidant, and other properties, is clearly superior to a beta1-blocking drug, metoprolol tartrate. The choice between these drugs is therefore unambiguously in favor of carvedilol.

Adrenergic alpha-Antagonists↗
PubMed2003

Myocardial contractile reserve by dobutamine stress echocardiography predicts improvement in ejection fraction with beta-blockade in patients with heart failure: the Beta-Blocker Evaluation of Survival Trial (BEST).

BACKGROUND: beta-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. METHODS AND RESULTS: Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol (r=-0.72, P<0.0001) and was the most significant multivariate predictor of change in LVEF (P=0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687+/-333 versus 420+/-246 pg/mL, P<0.05) and greater decrease in plasma norepinephrine in response to bucindolol (-249+/-171 versus -35+/-277 pg/mL, P<0.05). CONCLUSIONS: This study suggests a direct relationship between contractile reserve and improvement in LVEF with beta-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.

Adrenergic beta-Antagonists↗
PubMed2003

Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials.

OBJECTIVES: This study sought to assess the effect of angiotensin-converting enzyme (ACE) inhibitors and beta-blockers on all-cause mortality in patients with left ventricular (LV) systolic dysfunction according to gender, race, and the presence of diabetes. BACKGROUND: Major randomized clinical trials have established that ACE inhibitors and beta-blockers have life-saving benefits in patients with LV systolic dysfunction. Most patients enrolled in these trials were Caucasian men. Whether an equal effect is achieved in women, non-Caucasians, and patients with major comorbidities has not been established. METHODS: The authors performed a meta-analysis of published and individual patient data from the 12 largest randomized clinical trials of ACE inhibitors and beta-blockers to produce random effects estimates of mortality for subgroups. RESULTS: Data support beneficial reductions in all-cause mortality for the use of beta-blockers in men and women, the use of ACE inhibitors and some beta-blockers in black and white patients, and the use of ACE inhibitors and beta-blockers in patients with or without diabetes. Women with symptomatic LV systolic dysfunction probably benefit from ACE inhibitors, but women with asymptomatic LV systolic dysfunction may not have reduced mortality when treated with ACE inhibitors (pooled relative risk = 0.96; 95% confidence interval: 0.75 to 1.22). The pooled estimate of three beta-blocker studies supports a beneficial effect in black patients with heart failure, but one study assessing bucindolol reported a nonsignificant increase in mortality. CONCLUSIONS: Angiotensin-converting enzyme inhibitors and beta-blockers provide life-saving benefits in most of the subpopulations assessed. Women with asymptomatic LV systolic dysfunction may not achieve a mortality benefit when treated with ACE inhibitors.

Adrenergic beta-Antagonists↗
PubMed2003

Pharmacotherapeutic approaches for decompensated heart failure: a role for the calcium sensitiser, levosimendan?

Although no universal definition exists, decompensated heart failure may be regarded as either a worsening of chronic heart failure or new-onset heart failure precipitated by an acute incident. Haemodynamic management of patients hospitalised with decompensated heart failure may include the administration of diuretics, vasodilators and positive inotropic agents. Until recently, these latter agents constituted the only drug class to produce a direct increase in stroke volume via enhanced myocardial contractility. However, despite their short-term benefits, the clinical utility of inotropic agents is compromised by their potentially deleterious effects on calcium handling and oxygen consumption, resulting in an increased risk of serious ventricular arrhythmias and death. In contrast, calcium sensitisers enhance cardiac performance without affecting calcium movement and, therefore, are potentially associated with a reduced risk of rhythmic disturbances. These agents constitute a heterogeneous group of compounds with different affinities for calcium sensitisation. Levosimendan is a potent calcium sensitiser with vasodilating properties that has been shown to provide symptomatic and haemodynamic improvement with no increase in oxygen consumption. Calcium sensitisation is therefore emerging as a promising treatment approach in this challenging therapeutic area.

Calcium Channel Blockers↗
PubMed1993

Studies of Left Ventricular Dysfunction (SOLVD).

Given the increasing incidence and dismal prognosis in congestive heart failure, it is not surprising that strenuous efforts have been made to limit the morbidity and mortality that result from this syndrome. The National Institutes of Health designed and implemented the Studies of Left Ventricular Dysfunction (SOLVD) to assess the effect of therapy with enalapril, an angiotensin-converting enzyme inhibitor, on all cause mortality in a population with left ventricular dysfunction (i.e., ejection fraction at or below 35%). Important secondary objectives included the effects of this therapy on cause-specific mortality, development of heart failure, and hospitalization for congestive heart failure. Patients within each of two arms of the trial were randomized on the basis of the administration (treatment arm) or lack (prevention arm) of concomitant therapy for congestive heart failure. The trial was double blind and placebo controlled. The mean follow-up period for the combined arms was 39.2 months, during which time there was a 16% risk reduction in all-cause mortality in the treatment arm of the trial (P equals 0.008) and an 8% risk reduction in the prevention arm (P equals NS). In the prevention arm, however, there was a 12% reduction risk for cardiovascular mortality (P equals 0.12) and a 37% reduction in risk of progression to heart failure (P is less than 0.001). Thus, the results of SOLVD indicate that therapy with an angiotensin-converting enzyme inhibitor has beneficial effects on morbidity and mortality that are apparent in a broad spectrum of patients with left ventricular dysfunction.

Journal Article↗
PubMedDate not supplied

Heart failure in community practice: relationship to age and sex in a beta-blocker registry.

Women and the elderly are underrepresented in clinical trials of heart failure (HF). The authors analyzed, by sex and age groups, a registry of 4280 community patients initiating carvedilol for HF. Women (n=1485) were older than men (n=2793) and had worse functional class with higher left ventricular ejection fraction and blood pressure. Women also had more HF hospitalizations, less use of angiotensin-converting enzyme inhibitors, and lower doses of carvedilol. Nevertheless, during 1-year follow-up, both groups experienced greater than 40% reductions in HF hospitalizations (P<.001), with mortality of 7.3% in women vs 9.1% in men (P=.085). With increasing age, left ventricular ejection fraction, blood pressure, and functional class increased, whereas angiotensin-converting enzyme inhibitor use and carvedilol doses decreased. HF hospitalizations fell at least 40% in all age groups after starting carvedilol (P<.001). Characteristics of women and the elderly with HF in the community suggest increased risk, but both populations respond well after initiating carvedilol.

Adrenergic beta-Antagonists↗