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Omecamtiv mecarbil improves cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (EF). Consistency of drug benefit across race is a key public health topic.

Disease of the coronary arteries, the major blood vessels supplying the heart, frequently results in sudden death. Ventricular arrhythmias, or abnormal heart rhythms arising in the ventricles, are a common cause of sudden death, and may be the only symptom of coronary artery disease. Exposure to carbon monoxide, a common environmental pollutant, may cause ventricular arrhythmias and, thereby, contribute to the occurrence of sudden death in patients with coronary artery disease. Exposure to carbon monoxide leads to elevated blood levels of carboxyhemoglobin, the product of the interaction between carbon monoxide and hemoglobin, the oxygen-carrying pigment of the blood. Whether or not carbon monoxide-induced elevations in carboxyhemoglobin cause ventricular arrhythmias was assessed in 41 patients with coronary artery disease. Patients were exposed to room air, and to carbon monoxide levels which produced four and six percent carboxyhemoglobin. They were then required to perform exercise on a bicycle. The heart ventricles were X-rayed during exercise, and the electrical activity of the heart was recorded throughout the procedure to detect the occurrence of ventricular arrhythmias. During the exercise period, the frequency of single or multiple ventricular arrhythmias was greater after the patients were exposed to carbon monoxide producing six percent carboxyhemoglobin. This result did not occur at levels of four percent carboxyhemoglobin. The results also revealed that the patients who developed more frequent ventricular arrhythmias were older. In addition, patients who developed multiple or complex ventricular arrhythmias exercised longer and under greater workloads. These findings demonstrate that, during exercise, the number and complexity of ventricular arrhythmias increase in patients with coronary artery disease who achieve six percent carboxyhemoglobin after carbon monoxide exposure. (Consumer Summary produced by Reliance Medical Information, Inc.)

IMPORTANCE: Despite evidence that guideline-directed medical therapy (GDMT) improves outcomes in patients with heart failure (HF) and reduced ejection fraction, many patients are undertreated. The Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment (GUIDE-IT) trial tested whether a strategy of using target concentrations of N-terminal pro–brain natriuretic peptide (NT-proBNP) to guide optimization of GDMT could improve outcomes. OBJECTIVE: To examine medical therapy for HF in GUIDE-IT and potential reasons why the intervention did not produce improvements in medical therapy. DESIGN, SETTING, AND PARTICIPANTS: GUIDE-IT, a randomized clinical trial performed at 45 sites in the United States and Canada, was conducted from January 16, 2013, to September 20, 2016. A total of 894 patients with HF and reduced ejection fraction (≤40%) were randomized to NT-proBNP−guided treatment with a goal to suppress NT-proBNP concentrations to less than 1000 pg/mL vs usual care. This secondary analysis examined the medical therapy titration and reasons why the intervention did not produce improvements in care and outcomes. Data were analyzed March 27 to June 28, 2019. MAIN OUTCOMES AND MEASURES: For each encounter, medication titrations were captured. A reason was requested if a modification was not made. A Cox proportional hazards regression model was used to assess the independent association of drug class with outcomes. RESULTS: Among the 838 patients available for analysis (566 men [67.5%]; median age, 62.0 years), 6223 visits occurred during 24 months. Adjustments of HF medication were made during 2847 of 5218 qualified visits (54.6%) (all usual care visits and all guided care visits with NT-proBNP level ≥1000 pg/mL) in 862 patients (96.4%). Most adjustments occurred within the first 6 months, primarily within the first 6 weeks. The most common reasons for not adjusting were “clinically stable” and “already at maximally tolerated therapy.” Only 130 patients (15.5%) achieved optimal GDMT (≥50% of the target dose of β-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or any dose of mineralocorticoid antagonists) at 6 months, an increase from the baseline (79 of 891 [8.9%]) but not different by treatment arm. Higher doses of β-blockers were associated with reduced risk of the composite outcome of HF hospitalization and cardiovascular death (hazard ratio [HR], 0.98; 95% CI, 0.97-1.00; P = .008) and of all-cause death (HR, 0.97; 95% CI, 0.95-0.99; P = .01). Higher doses of angiotensin-converting enzyme inhibitors (HR, 0.84; 95% CI, 0.75-0.93; P < .001) and angiotensin receptor blockers (HR, 0.84; 95% CI, 0.71-0.99; P = .04) were associated with reduced risk of all-cause death. Increasing doses of mineralocorticoid antagonists did not appear to be associated with improved outcomes. CONCLUSIONS AND RELEVANCE: Despite a protocol-driven approach, many patients in GUIDE-IT did not receive medication adjustments and did not achieve optimal GDMT, including those with known elevated NT-proBNP concentrations. These results suggest that opportunities exist to titrate medications for maximal benefit in HF. GUIDE-IT may have failed to achieve treatment benefit because of therapeutic inertia in clinical practice, or current GDMT goals may be unrealistic. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01685840

This study aims to assess the association between biomarker-guided therapy and left ventricular (LV) remodeling.

The goal of this study was to test the effects of long-chain omega-3 fatty acid supplementation on omega-3 levels, depressive symptoms, and other psychosocial factors, as well as other chronic heart failure (CHF)-related functional measures.

This study sought to determine the relationship between growth differentiation factor (GDF)-15 and clinical outcomes in ambulatory patients with heart failure and reduced ejection fraction (HFrEF).

Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil.

This study aimed to compare whether reduced heart rate (HR) or higher beta-blocker (BB) dose affected outcomes to a greater extent in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial population.

Congestion is a primary reason for hospitalization in patients with acute heart failure (AHF). Despite inpatient diuretics and vasodilators targeting decongestion, persistent congestion is present in many AHF patients at discharge and more severe congestion is associated with increased morbidity and mortality. Moreover, hospitalized AHF patients may have renal insufficiency, hyponatremia, or an inadequate response to traditional diuretic therapy despite dose escalation. Current alternative treatment strategies to relieve congestion, such as ultrafiltration, may also result in renal dysfunction to a greater extent than medical therapy in certain AHF populations. Truly novel approaches to volume management would be advantageous to improve dyspnea and clinical outcomes while minimizing the risks of worsening renal function and electrolyte abnormalities. One effective new strategy may be utilization of aquaretic vasopressin antagonists. A member of this class, the oral vasopressin-2 receptor antagonist tolvaptan, provides benefits related to decongestion and symptom relief in AHF patients. Tolvaptan may allow for less intensification of loop diuretic therapy and a lower incidence of worsening renal function during decongestion. In this article, we summarize evidence for decongestion benefits with tolvaptan in AHF and describe the design of the Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure Study (TACTICS) and Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) trials.

Optimizing management of patients with heart failure remains quite challenging despite many significant advances in drug and device therapy for this syndrome. Although a large body of evidence from robust clinical trials supports multiple therapies, utilization of these well-established treatments remains inconsistent and outcomes suboptimal in “real-world” patients with heart failure. Disease management programs may be effective, but are difficult to implement due to cost and logistical issues. Another approach to optimizing therapy is to utilize biomarkers to guide therapeutic choices. Natriuretic peptides provide additional information of significant clinical value in the diagnosis and estimation of risk inpatients with heart failure. Ongoing research suggests a potential important added role for natriuretic peptides in heart failure. Guiding therapy based on serial changes in these biomarkers may be an effective strategy to optimize treatment and achieve better outcomes in this syndrome. Initial, innovative, proof-of-concept studies have provided encouraging results and important insights into key aspects of this strategy, but well designed, large-scale, multicenter, randomized, outcome trials are needed to definitively establish this novel approach to management. Given the immense and growing public health burden of heart failure, identification of cost-effective ways to decrease the morbidity and mortality due to this syndrome is critical.

The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of <1,000 pg/ml compared with usual care in high-risk patients with systolic heart failure (HF).

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers.

Hyponatremia is a known complication in patients with heart failure (HF). HF patients with severe congestion, hyponatremia, and renal insufficiency are difficult to manage and may have worse outcomes. A main cause of hyponatremia is inappropriately elevated level of plasma arginine vasopressin (AVP), which causes water retention at the collecting duct. AVP antagonists have thus been developed to increase aquaresis and serum sodium levels in patients with euvolemic and hypervolemic hyponatremia. Although tolvaptan, an AVP-2 receptor antagonist, did not show outcomes benefit in patients with decompensated HF, prospective studies are ongoing to evaluate its optimal role in targeted HF patients.

The aim of this study was to determine whether biomarkers of myocardial stress and fibrosis improve prediction of the mode of death in patients with chronic heart failure.

ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study—a multicenter, randomized study of exercise training in HF.

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

The Arg389Gly polymorphism (Arg389Gly) in the 1-adrenergic receptor gene (ADRB1) has been associated with improvement in left-ventricular remodeling with -blocker treatment. One study of risk for heart failure suggested a synergistic effect of ADRB1Arg389Gly with the insertiondeletion polymorphism in the 2C-adrenergic receptor gene (ADRA2C). We tested whether the ADRA2Cinsertiondeletion polymorphism was associated with -blocker response in heart failure, either alone or in combination with the ADRB1Arg389Gly polymorphism.

Large variability exists in the improvement in eft ventricular (LV) function from -blocker treatment. We hypothesized that polymorphisms at codon 389 (Arg389Gly) and 49 (Ser49Gly) in the 1-adrenergic receptor (AR) gene were associated with LV reverse remodeling changes in response to -blocker therapy among heart failure patients.

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Despite its high prevalence and significant rates of associated morbidity and mortality, the syndrome of decompensated heart failure remains poorly defined and vastly understudied. Few high-quality epidemiologic studies, randomized controlled trials, or published guidelines are available to guide the management of this complex disease. In addition, there is no consensus definition of the clinical problem that it presents, no agreed upon nomenclature to describe its clinical features, and no recognized classification scheme for its patient population; all of which has contributed to the lack of therapeutic development in this critical arena of cardiovascular disease. This review outlines the scope of the problem and proposes a system of nomenclature and classification sufficiently simple for general acceptance among clinicians while still encompassing the heterogeneity of the patient population. It also defines the current understanding of strategies for risk stratification in the setting of decompensated heart failure. (Am Heart J 2003;145:S18-25.)

OBJECTIVE: To describe the potential utility of a true surrogate marker of heart failure outcomes, historically investigate the validity of surrogates most commonly evaluated in heart failure, and identify specific end points offering the most potential for future use.DATA SOURCES: A MEDLINE search (1966–June 2001) was completed to identify relevant literature. Additional references were also retrieved from selected articles. Search terms included b-type natriuretic peptide, cardiac remodeling, end-diastolic volume, heart failure, and surrogate end points.DATA SYNTHESIS: By definition, true surrogate end points must predict outcomes associated with disease progression and response to therapy. A validated surrogate measure of mortality would render significant utility in both heart failure drug development and clinical practice. Improvements in traditional functional markers of heart failure, including ejection fraction and exercise capacity, have produced inconsistent results in regard to mortality in a number of clinical trials. Numerous measures of cardiac remodeling and neurohormonal activation, however, have proven to be reliable predictors of disease progression and therapeutic response. These findings have contributed significantly to the current understanding of heart failure pathophysiology and approach to treatment. Specifically, measures such as left-ventricular end-diastolic volume (LVEDV) and, potentially, b-type natriuretic peptide (BNP) concentrations may correlate with disease progression and parallel the mortality reductions observed with angiotensin-converting enzyme inhibitor and β-blocker therapy.CONCLUSIONS: Currently, LVEDV and plasma BNP offer the greatest potential as surrogate end points in heart failure. Further investigation of these measures is required before routine implementation in drug development and clinical practice can be justified.

BackgroundHemodynamics often are used as surrogate end points in phase II trials of acute heart failure (HF). We reviewed the Flolan International Randomized Survival Trial (FIRST) database to identify the hemodynamic variables that best predict survival in patients with advanced HF receiving epoprostenol therapy and to determine whether hemodynamics could predict the overall effect of a drug. MethodsThe trial enrolled 471 patients with class IIIb/IV HF and ejection fraction ≤25% for ≥3 months, all of whom underwent screening pulmonary artery catheter insertion. Patients were randomly assigned to receive either epoprostenol (n = 201) or placebo (n = 235); epoprostenol therapy was guided by pulmonary artery catheter measures, and standard treatment was guided by clinical findings. Multivariable modeling was used to identify and quantify the demographic, clinical, and hemodynamic variables most associated with 1-year survival. ResultsIn multivariable modeling, HF class, decreased pulmonary capillary wedge pressure (PCWP), and age best predicted 1-year survival. After adjustment for age and HF class, decreased PCWP still significantly predicted survival (hazard ratio, 0.96 for every 1–mm Hg decrease; 95% confidence interval, 0.94 to 0.99; P= .003). Survival was significantly higher with decreases in PCWP ≥9 versus <9 mm Hg, even after adjustment for age and HF class. Survival of patients in the PCWP ≥9 group was comparable with, and that of the PCWP <9 group was significantly higher than, survival of patients in the control group (hazard ratio, 1.44; 95% confidence interval, 1.05 to 1.99; P= .024). ConclusionsThe reduction in PCWP was the hemodynamic measure most predictive of survival in patients with advanced HF. However, patients with a ≥9–mm Hg decrease had no better survival than patients in the control group, who had limited changes in hemodynamics. Thus, improvement in hemodynamics may not predict the overall effect of a drug. (Am Heart J 2001;141:908-14.)

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double‐blind, two‐period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12‐hour carvedilol dosing interval, and the concentrations of the R(+) and S(−) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (± SD) R(+) enantiomer AUC0–12(522 ± 413 vs. 927 ± 506 ng•h/mL, p = 0.01) and a nonsignificant increase in S(−) enantiomer AUC (244 ± 185 vs. 330 ±179 ng•h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 ± 7.2 vs. 4.5 ± 2.2 mL/min/kg; S(−): 22.5 ± 12.3 vs. 12.6 ± 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(−) enantiomer. However, this interaction was of little clinical significance in our sample population.

The rapid growth of medical knowledge has created many advances in therapeutics related to chronic disease. Translation of these advances into everyday care of patients with chronic disease has proven problematic. Guideline development offers a principal strategy to improve use of new and existing therapeutic modalities of proven benefit. To be effective, practice guidelines must not only deal with which therapies are efficacious but attempt to consider the many practical aspects necessary in the actual care of patients. In this way both the art and science of medicine can be employed to obtain optimal patient outcomes in many chronic diseases that have been associated with severe mortality, morbidity, and poor quality of life. The logical process of guideline development and its use in one specific chronic disease, heart failure, is examined.

OBJECTIVES

OBJECTIVE: To review the Agency for Health Care Policy and Research (AHCPR) clinical practice guideline for heart failure and comment on the guideline regarding pharmacotherapy from the perspective of the latest clinical trial data and the authors' clinical experience.DATA SOURCES: A MEDLINE search (1966 to June 1997) of English-language literature pertaining to the pharmacotherapy of heart failure was performed. Special emphasis was placed on literature published in the last 5 years. Additional literature was obtained from reference lists of key articles identified through the search.DATA SYNTHESIS: Pertinent clinical trials were reviewed and considered along with information from the authors' database of over 800 patients with heart failure. Evidence concerning the use of angiotensin-converting enzyme inhibitors at appropriate dosages in all New York Heart Association classes of heart failure and the inclusion of digoxin as part of triple therapy in all symptomatic patients with left ventricular systolic dysfunction are reviewed. Strategies to circumvent clinical problems that may limit the proper application of standard therapeutic agents are considered, and the possible future role of β-blockers as therapeutic agents in patients with heart failure is discussed.CONCLUSIONS: The AHCPR guideline provides the clinician with an excellent framework for treating the patient with heart failure. Building on the fundamentals of the guideline, the clinician can carefully apply current therapy at appropriate dosages and in the best combinations to individualize and thereby optimize pharmacologic therapy for this patient population.

Background: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174.Objective and Methods: Ten healthy volunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pharmacokinetics were determined.Results: Rifampin decreased the area under the concentration-time curve from time zero to 24 hours after the dose (AUC[0–24]) of losartan by 35% (349 ± 246 versus 225 ± 130; p = 0.0001) and decreased the AUC(0–24) of E3174 by 40% (1336 ± 445 versus 792 ± 302; p < 0.005). Losartan oral clearance was increased by 44% (p = 0.0001). The half-life values of both compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not significantly affect the AUC(0–24) or half-life of either losartan or E3174.Conclusions: Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.

This study investigated the relation between gender, etiology and survival in patients with symptomatic heart failure.

Objective: To review the clinical pharmacology of torsemide and to compare it with currently available loop diuretics, particularly furosemide.Data Sources: An English-language MEDLINE search, 1985 to October 1994, was used to identify pertinent literature, including review articles.Data Extraction: Data from scientific literature were extracted, evaluated, and summarized for presentation. Pivotal and representative studies are discussed relating to the pharmacology, pharmacokinetics, and use of torsemide in patients with congestive heart failure, renal disease, hepatic disease, and hypertension.Data Synthesis: Torsemide is a loop diuretic of the pyridine-sulfonylurea class. The bioavailability of torsemide is approximately 80%, with little first-pass metabolism, and torsemide can be given without regard to meals. The serum concentration reaches its peak within 1 hour after oral administration and diuresis lasts approximately 6—8 hours. Torsemide is eliminated both hepatically (80%) and renally (20%) as unchanged drug with an elimination half-life of about 3.5 hours. Because of the high bioavailability, oral and intravenous doses are therapeutically equivalent. Torsemide, and other loop diuretics such as furosemide, are indicated for the treatment of edema associated with congestive heart failure, renal disease, and hepatic disease. They also are indicated for the treatment of hypertension alone or in combination with other antihypertensive agents. Depending on the indication, the recommended initial adult dosage of torsemide is between 5 and 20 mg once daily orally or intravenously. Special dosage adjustments in the elderly are not necessary.Conclusions: Torsemide is a loop diuretic similar to furosemide, with similar indications. Torsemide is characterized by good bioavailability and once-daily dosing and, compared with furosemide, provides generally equivalent therapeutic efficacy.

We describe the results of two placebo-controlled trials (MIL-1077 and MIL-1078) designed to evaluate the clinical efficacy of oral milrinone administered together with converting enzyme inhibitors to patients with congestive heart failure. Although these trials were terminated prematurely, they provide the only controlled data regarding the effect of oral milrinone on exercise capacity in patients receiving converting enzyme inhibitors. Of the 254 patients randomized, 140 completed one of the trials or reached an end point and are the basis of this report. In both trials, there was a clear trend for an increase in exercise capacity in the milrinone-treated patients (+ 26 ± 8% vs. +5 ± 7% in MIL-1077 and + 11 ± 5% vs. + 2 ± 4% in MIL-1078). Symptoms of congestive heart failure were decreased in one trial but not the other. Quality of life, as assessed by a questionnaire, was not effected in either trial. There was an increased incidence of adverse events in milrinone-treated patients. Adverse events related primarily to hypotension and vasodilation led to discontinuation of drug in 18 milrinone-treated patients vs. 1 placebo-treated patient. Milrinone had little or no proarrhythmic effect and cardiovascular deaths were distributed equally between the milrinone and placebo groups. These data suggest that when used in combination with a converting enzyme inhibitor, oral milrinone improves exercise capacity but is associated with a high incidence of adverse events that appear to be related to excessive vasodilation.

Objectives. We sought to study the efficacy of “triple” therapy with digoxin, diuretic and angiotensin-converting enzyme inhibitor (ACEI) compared to other combinations of these drugs in patients with symptomatic left ventricular systolic dysfunction.

The evolution of segmental wall motion in Q and non-Q wave acute myocardial infarction was studied in detall in 15 patients without known prior ischemic events. Serial two-dimensional echocardiographic studies were performed beginning early after the onset of chest pain and continuing until 10 to 14 days after admission. An area of apparent infarction was identified on each initial study based on later correlation of ECG and echocardiographic findings. Wall motion of infarct-and noninfarct-related areas was graded in a semiquantitative fashion based on the scoring of a visual analysis. Sequential image data demonstrated significant spontaneous improvement in wall motion of the infarct area in non-Q but not in Q wave events. Patients with non-Q wave infarction and improvement in regional function were at high risk for recurrent infarction within 6 months. Improvement in wall motion inside or outside the area of infarction in Q wave events was related to future risk. We concluded that in patients with initial acute myocardial infarction, fallure to develop Q waves correlated with return of function in the apparent area of infarction. Improvement in regional wall motion after the initial study suggested risk for future ischemic events in both ECG types of myocardial infarction. Serial echocardiographic imaging may be a means to identify patients at risk for infarct extension in both non-Q and Q wave events.

This prospective study investigated whether pretreatment with intravenously administered calcium would influence the effect of nifedipine on rest hemodynamics and treadmill performance in patients with ischemic heart disease. Seventeen patients were studied after undergoing a qualifying treadmill exercise test that revealed ST segment depression indicative of ischemic heart disease. Study subjects performed three additional treadmill tests as part of the protocol. One treadmill test was obtained from each patient to provide baseline measurements without a preceding intravenous infusion and in the absence of all antianginal drugs including nifedipine; two additional exercise tests were preceded by an infusion and 10 mg of bite-and-swallow nifedipine. The infusions, administered in a randomized, double-blind, crossover fashion, consisted of either 10 ml of 10% calcium chloride (13.6 mEq) in 50 ml of 5% dextrose in water or 5% dextrose in water alone.

Acute exposure to carbon monoxide has the potential to impair exercise capacity in patients with ischemic heart disease. The effect of sufficient inhalation of this compound to gradually produce a level of 6% carboxyhemoglobin was studied in 30 nonsmoking patients with obstructive coronary artery disease and evidence of exercise-induced ischemia. After an initial training session, subjects were exposed to air or carbon monoxide on successive days in a randomized double-blind crossover fashion. Cardiac function and exercise capacity were assessed during symptomlimited supine radionuclide ventriculography. On the carbon monoxide day, mean postexposure carboxyhemoglobin was 5.9 ± 0.1% compared with 1.6 ± 0.1% (p < 0.01) after air exposure.

Objectives. We investigated whether patients with mild heart failure due to left ventricular systolic dysfunction were at risk of worsening during digoxin withdrawal.

Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).

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