The results of this study showed that in patients who theoretical

The results of this study showed that in patients who theoretically would be most vulnerable to prolongation of the systolic ejection time (i.e., those with ischemic cardiomyopathy and a history of angina), treatment with omecamtiv mecarbil had no substantial deleterious effects on a broad range of safety assessments in the setting of symptom-limited exercise. Potential RG7204 supplier measures of cardiac ischemia such as the primary endpoint of this study (i.e., the proportion of patients

who stopped ETT3 because of angina and at a stage earlier than baseline) and the time to or appearance of ST-segment depression (which were assessable on ECG) were not adversely affected. Exercise time was also not adversely affected. This study was neither specifically designed nor powered to detect a potentially clinically significant improvement in exercise performance. Given the average baseline exercise time and variability in this study, it would have required >3 times the number of patients per treatment arm than were actually enrolled to detect a 15% improvement in exercise

time (80% power with a 2-sided alpha at 0.05). Finally, there were no consistent dose-related changes in the AE profile, and the majority of AEs VE-821 mouse were mild in severity. Troponin I levels were abnormal in 2 patients after exercise; in each case, the levels were just above the upper laboratory reference limit and occurred in the absence of other clinical signs or symptoms Monoiodotyrosine of cardiac ischemia. The background rate of detectable troponin after exercise testing in this patient population is not well established, but was approximately 10% in 2 small studies 13 and 14. Given the number of patients studied, our findings do not rule out the possibility that increases in troponin I might occur in some heart failure patients with coronary disease during exercise while receiving omecamtiv mecarbil treatment, but they do indicate that the occurrence of this event is likely to be low. The use of a high-sensitivity troponin assay in this study might have provided additional insights into the development

of ischemia in this population during exercise. Although the present study provides the first evaluation of omecamtiv mecarbil in heart failure patients under nonsedentary conditions, it has some important limitations. No hypothesis was formally tested, and the sample size was therefore empirically determined to be sufficient to provide an adequate assessment of the tolerability of the 2 target omecamtiv mecarbil plasma levels during symptom-limited exercise tolerance in patients with ischemic cardiomyopathy and angina. In addition, the sample size was too small to assess the effect on exercise time, and thus either a positive or negative effect on exercise duration could not be established.

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