Research from JAMA — Effects of Tolvaptan, a Vasopressin Antagonist, in Patients Hospitalized With Worsening Heart Failure — A Randomized Controlled Trial — ContextNearly 1 million hospitalizations for chronic heart failure occur yearly in the United States, with most related to worsening systemic congestion. Diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function.ObjectiveTo evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized with heart failure.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy.InterventionAfter admission, patients were randomized to receive 30, 60, or 90 mg/d of oral tolvaptan or placebo in addition to standard therapy, including diuretics. The study drug was continued for up to 60 days.Main Outcome MeasuresIn-hospital outcome was change in body weight at 24 hours after randomization; outpatient outcome was worsening heart failure (defined as death, hospitalization, or unscheduled visits for heart failure) at 60 days after randomization.ResultsMedian (interquartile range) body weight at 24 hours after randomization decreased by −1.80 (−3.85 to −0.50), −2.10 (−3.10 to −0.85), −2.05 (−2.80 to −0.60), and −0.60 (−1.60 to 0.00) kg in the groups receiving tolvaptan 30, 60, and 90 mg/d, and placebo, respectively (P≤.008 for all tolvaptan groups vs placebo). The decrease in body weight with tolvaptan was not associated with changes in heart rate or blood pressure, nor did it result in hypokalemia or worsening renal function. There were no differences in worsening heart failure at 60 days between the tolvaptan and placebo groups (P = .88 for trend). In post hoc analysis, 60-day mortality was lower in tolvaptan-treated patients with renal dysfunction or severe systemic congestion.ConclusionTolvaptan administered in addition to standard therapy may hold promise for management of systemic congestion in patients hospitalized for heart failure.

The presence of left bundle-branch block on the electrocardiogram may conceal the changes of acute myocardial infarction, which can delay both its recognition and treatment. We tested electrocardiographic criteria for the diagnosis of acute infarction in the presence of left bundle-branch block. Methods The base-line electrocardiograms of patients enrolled in the GUSTO-1 (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial who had left bundle-branch block and acute myocardial infarction confirmed by enzyme studies were blindly compared with the electrocardiograms of control patients who had chronic coronary artery disease and left bundle-branch block. The electrocardiographic criteria for the diagnosis of infarction were then tested in an independent sample of patients presenting with acute chest pain and left bundle-branch block. Results Of 26,003 North American patients, 131 (0.5 percent) with acute myocardial infarction had left bundle-branch block. The three electrocardiographic criteria with independent value in the diagnosis of acute infarction in these patients were ST-segment elevation of 1 mm or more that was concordant with (in the same direction as) the QRS complex; ST-segment depression of 1 mm or more in lead V1, V2, or V3; and ST-segment elevation of 5 mm or more that was discordant with (in the opposite direction from) the QRS complex. We used these three criteria to develop a scoring system (0 to 5), which allowed a highly specific diagnosis of acute myocardial infarction to be made. Conclusions We developed and validated a clinical prediction rule based on a set of electrocardiographic criteria for the diagnosis of acute myocardial infarction in patients with chest pain and left bundle-branch block. The use of these criteria, which are based on simple ST-segment changes, may help identify patients with acute myocardial infarction, who can then receive appropriate treatment.

Background —Unstable angina and non–Q-wave myocardial infarction involve coronary arterial plaque rupture, platelet activation, and thrombus formation. This study tested the benefit of different doses of lamifiban (a platelet IIb/IIIa antagonist) alone and in combination with heparin in patients with these conditions to select the most promising lamifiban regimen for subsequent evaluation. Methods and Results —At 273 hospitals in 20 countries, 2282 patients were randomly assigned to lamifiban (2×2 factorial design: low-dose [1 μg/min] with and without heparin versus high-dose [5 μg/min] with and without heparin) or to standard therapy (placebo and heparin). All patients received aspirin. The composite primary end point of death or nonfatal myocardial infarction at 30 days occurred in 11.7% of those receiving standard therapy, 10.6% receiving low-dose lamifiban, and 12.0% receiving high-dose lamifiban ( P =0.668). By 6 months, this composite was lowest for those assigned to low-dose lamifiban ( P =0.027) and intermediate for those assigned to high-dose lamifiban ( P =0.450) compared with control (13.7%, 16.4%, and 17.9%, respectively). Compared with control, the combination of high-dose lamifiban and heparin resulted in more intermediate or major bleeding (12.1% versus 5.5%; P =0.002) and a similar rate of ischemic events. Conversely, low-dose lamifiban and heparin yielded similar bleeding rates as in the control group but fewer ischemic events at 6 months (12.6% versus 17.9%; P =0.025). Conclusions —In unstable angina and non–Q-wave infarction, platelet IIb/IIIa antagonism with lamifiban reduces adverse ischemic events at 6 months beyond that of aspirin and heparin therapy. The role of conjunctive heparin remains uncertain but appears more favorable with low-dose IIb/IIIa antagonism. Larger-scale study is needed to more reliably estimate these effects.