Cardiology

Mehta, R. H., J. D. Leimberger, S. van Diepen, J. Meza, A. Wang, R. Jankowich, R. W. Harrison, D. Hay, S. Fremes, A. Duncan, E. G. Soltesz, J. Luber, S. Park, M. Argenziano, E. Murphy, R. Marcel, D. Kalavrouziotis, D. Nagpal, J. Bozinovski, W. Toller, M. Heringlake, S. G. Goodman, J. H. Levy, R. A. Harrington, K. J. Anstrom and J. H. Alexander (2017). “Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery.” N Engl J Med 376(21): 2032-2042.

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BACKGROUND: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 mug per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 mug per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass.

Packer, M., C. O’Connor, J. J. V. McMurray, J. Wittes, W. T. Abraham, S. D. Anker, K. Dickstein, G. Filippatos, R. Holcomb, H. Krum, A. P. Maggioni, A. Mebazaa, W. F. Peacock, M. C. Petrie, P. Ponikowski, F. Ruschitzka, D. J. van Veldhuisen, L. S. Kowarski, M. Schactman and J. Holzmeister (2017). “Effect of ularitide on cardiovascular mortality in acute heart failure.” N Engl J Med 376(20): 1956-1964.

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BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients’ long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality.

Mumtaz, M., H. Gada, M. J. Mack and M. J. Reardon (2017). “Who’s afraid of the big bad wolf?” J Thorac Cardiovasc Surg 153(6): 1287-1289.

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Surgical aortic valve replacement (SAVR) for the treatment of symptomatic severe aortic stenosis is arguably one of the most successful cardiac procedures ever developed. Since the introduction of SAVR in 1960, millions of lives have been saved and improved. Although never tested against the previous standard of care, medical therapy, we as surgeons knew it was the right choice because without SAVR these patients were resigned to heart failure and death. We did track our outcomes both individually and nationally by the creation of the Society of Thoracic Surgery Adult Cardiac Surgery database, which now encompasses more than 6.1 million patients contributed by more than 95% of cardiac surgeons in the United States.

Packer, M. (2017). “Tetralogy of fallow: Four trials and tribulations.” JACC Heart Fail 5(6): 408-410.

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When Chris O’Connor became the Founding Editor of JACC: Heart Failure, he opened a dead letter office (1) to welcome old trials that had been completed and reported years before but had never been published. Their results had been fully analyzed and presented at scientific meetings, and often drafts of the primary papers had been written…Once the papers were sidelined, it was easy to fantasize that they would eventually be published. Yet, despite the overwhelming ethical mandate to place the results in print, there was always a reason to pursue different priorities and to follow other paths of immediate interest. The papers were left fallow; they were plots of land that had been plowed and harrowed but remained unsown, presumably under the premise that doing so would restore their fertility. It was this false premise that allowed time to pass…

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2017). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis 28(4): 287-293.

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BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.