Baylor Heart and Vascular Institute

Packer, M., S. D. Anker, J. Butler, G. Filippatos and F. Zannad (2017). “Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: Proposal of a novel mechanism of action.” JAMA Cardiol: 2017 Aug [Epub ahead of print].

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Importance: Only 1 class of glucose-lowering agents-sodium-glucose cotransporter 2 (SGLT2) inhibitors-has been reported to decrease the risk of cardiovascular events primarily by reducing the risk of the development or progression of heart failure. In a landmark trial called Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes [EMPA-REG Outcomes], long-term treatment with empagliflozin prevented fatal and nonfatal heart failure events but did not reduce the risk of myocardial infarction or stroke in diabetic patients. Observations: The beneficial effect of SGLT2 inhibitors on heart failure cannot be explained by their actions on glycemic control or as osmotic diuretics. Instead, in the kidneys, SGLT2 functionally interacts with the sodium-hydrogen exchanger, which is responsible for the majority of sodium tubular reuptake following filtration. The activity of sodium-hydrogen exchanger is markedly increased in patients with heart failure and may be responsible for both resistance to diuretics and to endogenous natriuretic peptides. In addition, in the heart, empagliflozin appears to inhibit sodium-hydrogen exchange, which may in turn lead to a reduction in cardiac injury, hypertrophy, fibrosis, remodeling, and systolic dysfunction. Furthermore, the major pathophysiological derangements of heart failure and a preserved ejection fraction may be mitigated by the actions of SGLT2 inhibitors to reduce blood pressure, body weight, and fluid retention as well as to improve renal function. The benefits of spironolactone in patients with heart failure with either a reduced or a preserved ejection fraction may also be attributable to the actions of the drug to inhibit the sodium-hydrogen exchange mechanism. Conclusions and Relevance: The benefits of SGLT2 inhibitors in heart failure may be mediated by the inhibition of sodium-hydrogen exchange rather than the effect on glucose reabsorption. This hypothesis has important implications for the design and analysis of large-scale outcomes trials involving diabetic or nondiabetic patients with chronic heart failure.

Cedars, A., L. Benjamin, S. V. Burns, E. Novak and A. Amin (2017). “Clinical predictors of length of stay in adults with congenital heart disease.” Heart 103(16): 1258-1263.

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OBJECTIVE: Length of stay (LOS) is a major driver of inpatient care costs. To date, few studies have investigated risk factors associated with increased LOS in patients with adult congenital heart disease (ACHD). In the present work, we sought to address this knowledge gap. METHODS: We conducted an analysis of the State Inpatient Databases from Arkansas, California, Florida, Hawaii, Nebraska and New York. We analysed data on admissions in patients with ACHD and constructed a series of hierarchical regression models to identify the clinical factors having the greatest effects on LOS. RESULTS: We identified 99 103 inpatient hospitalisations meeting criteria for inclusion. Diagnoses associated with the longest LOS were septicaemia (LOS=14.2 days in patients atrial septal defect, and 11.7 days among all other ACHD) and pericarditis, endocarditis and myocarditis (LOS=13.6 days and 10.0 days, respectively). When separated by underlying anatomy, the variables most consistently associated with longer LOS were bacterial infection, complications of surgeries or medical care, acute renal disease and anaemia. CONCLUSIONS: In the present study, we identified risk factors associated with longer LOS in ACHD. These data may be used to identify at-risk patients for targeted intervention to decrease LOS and thereby cost.

Shen, L., P. S. Jhund, M. C. Petrie, B. L. Claggett, S. Barlera, J. G. F. Cleland, H. J. Dargie, C. B. Granger, J. Kjekshus, L. Kober, R. Latini, A. P. Maggioni, M. Packer, B. Pitt, S. D. Solomon, K. Swedberg, L. Tavazzi, J. Wikstrand, F. Zannad, M. R. Zile and J. J. V. McMurray (2017). “Declining risk of sudden death in heart failure.” N Engl J Med 377(1): 41-51.

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BACKGROUND: The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. METHODS: We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. RESULTS: Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis. CONCLUSIONS: Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death.

Lewis, E. F., B. L. Claggett, J. J. V. McMurray, M. Packer, M. P. Lefkowitz, J. L. Rouleau, J. Liu, V. C. Shi, M. R. Zile, A. S. Desai, S. D. Solomon and K. Swedberg (2017). “Health-related quality of life outcomes in paradigm-hf.” Circ Heart Fail 10(8): 1-16.

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BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (>/=5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure.

Rosenthal, R. L. (2017). “Revisiting the historical origins of clinically meaningful coronary artery obstruction.” Mayo Clin Proc 92(8): 1312.

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As part of a recent informative editorial on the significance of nonobstructive coronary artery disease, Rumberger1 reviewed the historical origins of the 50% coronary stenosis standard for the definition of myocardial ischemia and the relationship of percentage stenosis to coronary flow reserve and fractional flow reserve. I believe some corrections are warranted.