Cardiology

Mogensen, U. M., J. Gong, P. S. Jhund, L. Shen, L. Kober, A. S. Desai, M. P. Lefkowitz, M. Packer, J. L. Rouleau, S. D. Solomon, B. L. Claggett, K. Swedberg, M. R. Zile, G. Mueller-Velten and J. J. V. McMurray (2018). “Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).” Eur J Heart Fail. Feb 12. [Epub ahead of print].

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AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.E

Grayburn, P. A. (2018). “Evaluating Patients With Low-Flow, Low-Gradient Aortic Stenosis by Dobutamine Echocardiography: It’s Complicated.” J Am Coll Cardiol 71(5): 486-488.

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The concept of low-flow, low-gradient aortic stenosis (LF-LG AS) was first introduced in 1980 by Carabello, who described 4 patients with low left ventricular ejection fraction (LVEF) and severe AS by calculated aortic valve area (AVA), but mean transvalvular gradient <25 mm Hg. Those patients either died (n = 3) after aortic valve replacement (AVR) or continued to have intractable heart failure (n = 1). Subsequent articles on the topic have highlighted the poor prognosis of such patients relative to high-gradient AS and the difficulty in evaluating whether such patients have truly severe AS or “pseudo-severe” AS, a condition in which the calculated AVA is artificially low because there is not enough flow to open a mild or moderately diseased valve. deFilippi et al. introduced the concept of using dobutamine stress echocardiography (DSE) to evaluate the response of peak velocity, mean gradient, and calculated AVA at baseline and after a graded infusion of dobutamine to increase forward flow across the valve. Three general responses were identified: true AS (increased peak velocity and gradient with no significant change in AVA), pseudo-severe AS (increased AVA with minimal change in peak velocity or gradient), and uncertain resulting from failure of forward flow to increase with dobutamine. Although numerous articles have now been written on this topic, it can still be difficult to accurately classify some patients based on their response to DSE. Recent American College of Cardiology/American Heart Association guidelines have proposed that AVR is indicated (Class IIa) if the mean gradient is ≥40 mm Hg or AVA ≤1.0 cm2 during dobutamine challenge. (Excerpt from text, p. 486; no abstract available.)

Dehmer, G. J. (2018). “Seeking Quality Cardiac Care: Is Public Reporting the Answer?” JACC Cardiovasc Interv 11(4): 351-353.

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Letter to the Editor; no abstract available.

Velasco, C. E., H. Hashemi, C. P. Roullard, J. Machannaford and W. C. Roberts (2018). “Asymptomatic Ascending Aorta Aneurysm With Severe Aortic Regurgitation Caused by Multiple Intimal-Medial Tears Unassociated With Aortic Dissection.” Am J Cardiol 121(5): 668-669.

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A 62-year-old man was found to have an asymptomatic ascending aortic aneurysm (6.6 cm) associated with severe aortic regurgitation. Operative resection of the wall of the aneurysm disclosed its cause to be multiple healed intimal-medial tears without dissection involving a previously normal aorta. The concept of an intimal-medial tear unassociated with aortic dissection is a poorly recognized entity and these tears appear to be asymptomatic and after the aortic tearing lead to aneurysmal formation.

Vaduganathan, M., B. Claggett, M. Packer, J. J. V. McMurray, J. L. Rouleau, M. R. Zile, K. Swedberg and S. D. Solomon (2018). “Natriuretic Peptides as Biomarkers of Treatment Response in Clinical Trials of Heart Failure.” JACC Heart Fail. Mar 4. [Epub ahead of print].

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BACKGROUND: The lack of reliable predictors of the efficacy of drugs and devices in heart failure (HF) has presented a major hurdle to the development and evaluation of novel therapies. OBJECTIVES: To determine whether treatment-related changes in natriuretic peptides (NP) predict longer-term therapeutic effects in clinical trials of HF. METHODS: We conducted a trial-level analysis of 16 phase-3 chronic HF trials completed between 1987 and 2013 studying 18 therapeutic comparisons in 48,844 patients. We calculated weighted Pearson correlation coefficients between average control- or placebo-corrected changes in NPs and the longer-term treatment effects on clinical endpoints (expressed as log-transformed hazard ratios). RESULTS: Median follow-up for clinical endpoints was 28 (interquartile range: 18 to 36) months. NPs were available in a median of 748 (interquartile range: 270 to 1868) patients and measured at a median of 4 (interquartile range 3 to 6) months after randomization. Treatment-related changes in NPs were not correlated with longer-term treatment effects on all-cause mortality (r=0.12, P=0.63), but were correlated with HF hospitalization (r=0.63, P=0.008). Correlation with HF hospitalization improved when analyses were restricted to trials completed in the last decade (>2010; r=0.92, P=0.0095), employing NT-proBNP assays (r=0.65, P=0.06), and evaluating inhibitors of the renin-angiotensin-aldosterone-system (r=0.97, P=0.0002). CONCLUSIONS: When examining a broad range of interventions, therapy-related changes in NPs appeared modestly correlated with longer-term therapeutic effects on hospitalization for HF, but not with effects on all-cause mortality. These observations raise important caveats regarding the use of NPs in phase II trials for decision-making regarding phase III trials.