Cardiology

Damman, K., M. Gori, B. Claggett, P. S. Jhund, M. Senni, M. P. Lefkowitz, M. F. Prescott, V. C. Shi, J. L. Rouleau, K. Swedberg, M. R. Zile, M. Packer, A. S. Desai, S. D. Solomon and J. J. V. McMurray (2018). “Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure.” JACC Heart Fail 6(6): 489-498.

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OBJECTIVES: The purpose of this study was to evaluate the renal effects of sacubitril/valsartan in patients with heart failure and reduced ejection fraction. BACKGROUND: Renal function is frequently impaired in patients with heart failure with reduced ejection fraction and may deteriorate further after blockade of the renin-angiotensin system. METHODS: In the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibition to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, 8,399 patients with heart failure with reduced ejection fraction were randomized to treatment with sacubitril/valsartan or enalapril. The estimated glomerular filtration rate (eGFR) was available for all patients, and the urinary albumin/creatinine ratio (UACR) was available in 1872 patients, at screening, randomization, and at fixed time intervals during follow-up. We evaluated the effect of study treatment on change in eGFR and UACR, and on renal and cardiovascular outcomes, according to eGFR and UACR. RESULTS: At screening, the eGFR was 70 +/- 20 ml/min/1.73 m(2) and 2,745 patients (33%) had chronic kidney disease; the median UACR was 1.0 mg/mmol (interquartile range [IQR]: 0.4 to 3.2 mg/mmol) and 24% had an increased UACR. The decrease in eGFR during follow-up was less with sacubitril/valsartan compared with enalapril (-1.61 ml/min/1.73 m(2)/year; [95% confidence interval: -1.77 to -1.44 ml/min/1.73 m(2)/year] vs. -2.04 ml/min/1.73 m(2)/year [95% CI: -2.21 to -1.88 ml/min/1.73 m(2)/year ]; p < 0.001) despite a greater increase in UACR with sacubitril/valsartan than with enalapril (1.20 mg/mmol [95% CI: 1.04 to 1.36 mg/mmol] vs. 0.90 mg/mmol [95% CI: 0.77 to 1.03 mg/mmol]; p < 0.001). The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38). CONCLUSIONS: Compared with enalapril, sacubitril/valsartan led to a slower rate of decrease in the eGFR and improved cardiovascular outcomes, even in patients with chronic kidney disease, despite causing a modest increase in UACR.

Lima, B., A. Bansal, J. Abraham, J. D. Rich, S. S. Lee, B. Soleimani, J. N. Katz, A. Kilic, J. S. Young, C. B. Patel and S. M. Joseph (2018). “Controversies and Challenges of Ventricular Assist Device Therapy.” Am J Cardiol 121(10): 1219-1224.

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Left ventricular assist device (LVAD) therapy has emerged as an increasingly vital facet of the treatment algorithm for advanced heart failure. Growing experience with LVAD support has led to substantial improvements in outcomes, with 1-year survival rates approaching that of cardiac transplantation. These therapeutic refinements have engendered growing interests in the potential for expanding the clinical indications for LVAD therapy to patients with less advanced heart failure. The primary obstacles to this evolution of care center largely on the prevention and/or management of the adverse events associated with LVAD therapy along with patient preference. Many programs also face the mounting difficulty of balancing quality outcomes with the increased volume of implants. During the recently assembled Users Meeting organized by St. Jude Medical, heart failure clinicians from nearly 50 LVAD implanting centers discussed these and other challenges and controversies impacting the field. The present review summarizes the key insights gleaned from this meeting.

Thourani, V. H., J. Forcillo, W. Y. Szeto, S. K. Kodali, E. H. Blackstone, A. M. Lowry, M. Semple, J. Rajeswaran, R. R. Makkar, M. R. Williams, J. E. Bavaria, H. C. Herrmann, H. S. Maniar, V. C. Babaliaros, C. R. Smith, A. Trento, P. J. Corso, A. D. Pichard, D. C. Miller, L. G. Svensson, S. Kapadia, G. Ailawadi, R. M. Suri, K. L. Greason, R. T. Hahn, W. A. Jaber, M. C. Alu, M. B. Leon and M. J. Mack (2018). “Outcomes in 937 Intermediate-Risk Patients Undergoing Surgical Aortic Valve Replacement in PARTNER-2A.” Ann Thorac Surg 105(5): 1322-1329.

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BACKGROUND: The Placement of Aortic Transcatheter Valves 2A (PARTNER-2A) randomized trial compared outcomes of transfemoral transcatheter and surgical aortic valve replacement (SAVR) in intermediate-risk patients with severe aortic stenosis. The purpose of the present study was to perform an in-depth analysis of outcomes after SAVR in the PARTNER-2A trial. METHODS: From January 2012 to January 2014, 937 patients underwent SAVR at 57 centers. Mean age was 82 +/- 6.7 years and 55% were men. Less-invasive operations were performed in 140 patients (15%) and concomitant procedures in 198 patients (21%). Major outcomes and echocardiograms were adjudicated by an independent events committee. Follow-up was 94% complete to 2 years. RESULTS: Operative mortality was 4.1% (n = 38, Society of Thoracic Surgeons predicted risk of mortality: 5.2% +/- 2.3%), observed to expected ratio (O/E) was 0.8, and in-hospital stroke was 5.4% (n = 51), twice expected. Aortic clamp and bypass times were 75 +/- 30 minutes and 104 +/- 46 minutes, respectively. Patients having severe prosthesis-patient mismatch (n = 260, 33%) had similar survival to patients without (p > 0.9), as did patients undergoing less-invasive SAVR (p = 0.3). Risk factors for death included cachexia (p = 0.004), tricuspid regurgitation (p = 0.01), coronary artery disease (p = 0.02), preoperative atrial fibrillation (p = 0.001), higher white blood cell count (p < 0.0001), and lower hemoglobin (p = 0.0002). CONCLUSIONS: In this adjudicated prospective study, SAVR in intermediate-risk patients had excellent results at 2 years. However, there were more in-hospital strokes than expected, most likely attributable to mandatory neurologic assessment after the procedure. No pronounced structural valve deterioration was found during 2-year follow-up. Continued long-term surveillance remains important.

Packer, M., B. Claggett, M. P. Lefkowitz, J. J. V. McMurray, J. L. Rouleau, S. D. Solomon and M. R. Zile (2018). “Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial.” Lancet Diabetes Endocrinol. Apr 13. [Epub ahead of print].

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BACKGROUND: Neprilysin inhibition has favourable effects on experimental diabetic nephropathy. We sought to assess the effects of neprilysin inhibition on the course of renal function in patients with type 2 diabetes. METHODS: In the randomised, double-blind PARADIGM-HF trial, the effects of sacubitril/valsartan (97 mg/103 mg twice daily) were compared with enalapril (10 mg twice daily) in 8399 patients with mild-to-moderate chronic heart failure and systolic dysfunction. In this secondary intention-to-treat analysis, we assessed the change in estimated glomerular filtration rate (eGFR) over a 44-month follow-up period in patients with (n=3784) and those without (n=4615) diabetes. PARADIGM-HF is registered with ClinicalTrials.gov, number NCT01035255. FINDINGS: eGFR decreased by 1.1 mL/min per 1.73 m(2) per year (95% CI 1.0-1.2) in patients without diabetes, but by 2.0 mL/min per 1.73 m(2) per year (1.9-2.1) in those with diabetes (p<0.0001). Compared with patients treated with enalapril, those treated with sacubitril/valsartan had a slower rate of decline in eGFR (-1.3 vs -1.8 mL/min per 1.73 m(2) per year; p<0.0001), and the magnitude of the benefit was larger in patients with versus those without diabetes (difference 0.6 mL/min per 1.73 m(2) per year [95% CI 0.4-0.8] in patients with vs 0.3 mL/min per 1.73 m(2) per year [0.2-0.5] in those without diabetes; pinteraction=0.038). The greater effect of neprilysin inhibition in patients with diabetes could not be explained by the effects of treatment on the course of heart failure or on HbA1c. The incremental benefit of sacubitril/valsartan in patients with diabetes was no longer apparent when changes in eGFR were adjusted for urinary cyclic guanosine monophosphate (p=0.41). INTERPRETATION: In patients in whom the renin-angiotensin system is already maximally blocked, the addition of neprilysin inhibition attenuates the effect of diabetes to accelerate the deterioration of renal function that occurs in patients with chronic heart failure. FUNDING: Novartis.

Packer, M. (2018). “Why is the use of digitalis withering? Another reason that we need medical heart failure specialists.” Eur J Heart Fail 20(5): 851-852.

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The evolution of the use of digoxin in heart failure provides additional evidence that the treatment of chronic heart failure may have become too complex for most practitioners who are tasked with the long‐term management of patients with this disease. Optimal treatment now requires the expert orchestration of as many as seven different classes of drugs, together with the appropriate application of different devices. Neither primary care physicians nor cardiologists generally have the time, experience, motivation or supporting infrastructure to tackle the complexities of this progressively disabling and lethal disorder. As a result, the typical patient with heart failure is prescribed low doses of a diuretic, an inhibitor of the renin–angiotensin system, and (if they are fortunate) a β‐blocker. Most patients do not receive target doses of these drugs nor are they offered therapy with a mineralocorticoid receptor antagonist, a neprilysin inhibitor or digoxin. When digitalis – a drug that has been used by generalists for more than 200 years – is now recommended for use only by specialists, it is time to ask who these specialists might be. Those who currently regard themselves as heart failure specialists often focus on devices and cardiac transplantation and are not incentivized for optimizing drug therapy. If patients with cancer have dedicated specialists (i.e. medical oncologists) who devote their energies to optimizing drug therapy, patients with chronic heart failure also need dedicated practitioners who will do the same. Perhaps we can call them ‘medical heart failure specialists’. But we should ask: will national health services pay for physicians to think? (Excerpt from text, p. 852; no abstract available.)