Cardiology

Roberts, W. C., P. A. Grayburn, J. M. Guileyardo and R. C. Stoler (2017). “Full development of consequences of congenital pulmonic stenosis in eighty-four years.” Am J Cardiol 119(8): 1284-1287.

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Described herein is an 84-year-old woman, the oldest reported, with severe pulmonic stenosis who underwent a highly successful pulmonic valvotomy at age 77 and highly unsuccessfully attempted percutaneous pulmonic valve implantation at age 84. During the 84 years she developed nearly all clinical and morphologic consequences of pulmonic stenosis, including heavy calcification of the pulmonic valve, heavy calcification of the tricuspid valve annulus, severe right ventricular wall thickening without ventricular cavity dilation, aneurysm of the pulmonary truck, multiple focal ventricular wall scars without narrowing of the epicardial coronary arteries, wall thickening and luminal narrowing of the intramural coronary arteries, and extremely low 12-lead QRS electrocardiographic voltage.

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: 2017 Mar [Epub ahead of print].

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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. (2017). “Let Us Not Forget the Long-term Safety Concerns of Sacubitril/Valsartan-Reply.” JAMA Cardiol: 2017 Mar [Epub ahead of print].

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The letter by McCarthy and McEvoy illustrates the distinctive process that permeates the thinking of physicians who treat heart failure in contrast to those who treat cancer. Oncologists enthusiastically use drugs in high doses in the hope that they might prolong life, knowing with certainty that the drugs cause serious adverse effects. In contrast, cardiologists hesitate to use a drug that has been demonstrated (beyond a reasonable doubt) to prolong life simply because someone raises the hypothetical concern about an unobserved adverse effect that might occur 10 to 20 years later. McCarthy and McEvoy make reference to the concerns of the US Food and Drug Administration about the risk of dementia with sacubitril/valsartan; fortunately, their position is far more reassuring than the authors of the letter have conveyed. A comprehensive summary of the regulatory position on the safety of the drug has recently been published.

Seferovic, J. P., B. Claggett, S. B. Seidelmann, E. W. Seely, M. Packer, M. R. Zile, J. L. Rouleau, K. Swedberg, M. Lefkowitz, V. C. Shi, A. S. Desai, J. J. McMurray and S. D. Solomon (2017). “Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.” Lancet Diabetes Endocrinol: 2017 Mar [Epub ahead of print].

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BACKGROUND: Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. METHODS: In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c >/=6.5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. FINDINGS: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0.16% (SD 1.40) in the enalapril group and 0.26% (SD 1.25) in the sacubitril/valsartan group (between-group reduction 0.13%, 95% CI 0.05-0.22, p=0.0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0.14%, 95% CI 0.06-0.23, p=0.0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0.71, 95% CI 0.56-0.90, p=0.0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0.77, 0.58-1.02, p=0.073) in the sacubitril/valsartan group. INTERPRETATION: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Fendler, T. J., M. E. Nassif, K. F. Kennedy, S. M. Joseph, S. C. Silvestry, G. A. Ewald, S. J. LaRue, J. M. Vader, J. A. Spertus and S. V. Arnold (2017). “Global outcome in patients with left ventricular assist devices.” Am J Cardiol 119(7): 1069-1073.

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Left ventricular assist devices (LVADs) improve survival and quality of life (QOL) for most, but not all, patients with advanced heart failure. We described a broader definition of poor outcomes after LVAD, using a novel composite of death, QOL, and other major adverse events. We evaluated the frequency of poor global outcome at 1 year after LVAD among 164 patients (86% Interagency Registry for Mechanically Assisted Circulatory Support profile 1 to 2; shock or declining despite inotropes) at a high-volume center. Poor global outcome (comprising death, poor QOL [Kansas City Cardiomyopathy Questionnaire <45], recurrent heart failure [>/=2 heart failure readmissions], or severe stroke) occurred in 58 patients (35%): 37 died, 17 had poor QOL, 3 had recurrent heart failure, and 1 had a severe stroke. Patients with poor global outcomes were more likely designated for destination therapy (46% vs 24%, p = 0.01), spent more days hospitalized per month alive (median [interquartile range] 18.6 [5.0 to 31.0] vs 3.7 [1.8 to 8.3], p <0.001), and had higher intracranial (12% vs 2%, p = 0.031) and gastrointestinal (44% vs 28%, p = 0.056) hemorrhage rates over the year after implant. Although LVADs often improve survival and QOL, approximately 1/3 of high-acuity patients experienced a poor global outcome over the year after LVAD. In conclusion, composite outcomes may better capture events that matter to patients with LVADs and thus support informed decisions about pursuing LVAD therapy.