BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

The relation between induced increases in cardiac work and phosphate metabolites was investigated in the canine heart in vivo to evaluate the role of ATP hydrolysis products, ADP and inorganic phosphate (Pi), in the control of myocardial oxygen consumption (MVO2). In these studies, myocardial blood flow and oxygen consumption were simultaneously measured with the 31P-nuclear magnetic resonance (NMR)-detected phosphate metabolites. Three protocols were used to increase myocardial work: pacing, epinephrine, and phenylephrine infusions. When these protocols were used, no or only slight changes in myocardial ATP, Pi, and creatine phosphate were observed with a greater than threefold increase in MVO2. The calculated intracellular free Mg concentration, ADP, and pH were also only slightly affected by these increases in work. These data indicate that a simple model involving the feedback of cytosolic ADP and Pi to the mitochondria regulating respiration is inadequate to explain respiratory control in vivo. These data suggest that some other parameters or cooperativity effects involving the phosphate metabolites must play a role in the feedback between respiration and work in the heart in vivo.

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Studies were performed to determine the contribution of red blood cells to the 31P-nuclear magnetic resonance (NMR) spectrum of the canine heart in vivo and the feasibility of measuring myocardial intracellular phosphate and pH. This was accomplished by replacing whole blood with a perfluorochemical perfusion emulsion blood substitute, Oxypherol, and noting the difference in the 31P-NMR spectrum of the heart. NMR data were collected with a NMR transmitter-receiver coil on the surface of the distal portion of the left ventricle. These studies demonstrated that a small (approximately 10%) contribution from 2,3-diphosphoglycerate (2,3-DPG) and phosphodiesters in the blood could be detected. The magnitude and shift of these blood-borne signals permitted the relative quantification of intracellular inorganic phosphate (Pi) content as well as intracellular pH. Under resting conditions, the intracellular ATP/Pi was 7.0 +/- 0.8 (n = 19). This corresponds to a free intracellular Pi content of approximately 0.8 mumol/g wet wt. The intracellular pH was 7.10 +/- 0.01 (n = 19). Acute respiratory alkalosis and acidosis, with the arterial pH ranging from approximately 7.0 to 7.7, resulted in only small changes in the intracellular pH (approximately 0.1 pH unit). These latter results demonstrate an effective myocardial intracellular proton-buffering mechanism in vivo.