Cardiology

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.

Full text of this article.

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.

Busse, L. W., X. S. Wang, D. M. Chalikonda, K. W. Finkel, A. K. Khanna, H. M. Szerlip, D. Yoo, S. L. Dana and L. S. Chawla (2017). “Clinical experience with iv angiotensin ii administration: A systematic review of safety.” Crit Care Med 45(8): 1285-1294.

Full text of this article.

OBJECTIVE: Angiotensin II is an endogenous hormone with vasopressor and endocrine activities. This is a systematic review of the safety of IV angiotensin II. DATA SOURCES: PubMed, Medline, Scopus, and Cochrane. STUDY SELECTION: Studies in which human subjects received IV angiotensin II were selected whether or not safety was discussed. DATA EXTRACTION: In total, 18,468 studies were screened by two reviewers and one arbiter. One thousand one hundred twenty-four studies, in which 31,281 participants received angiotensin II (0.5-3,780 ng/kg/min), were selected. Data recorded included number of subjects, comorbidities, angiotensin II dose and duration, pressor effects, other physiologic and side effects, and adverse events. DATA SYNTHESIS: The most common nonpressor effects included changes in plasma aldosterone, renal function, cardiac variables, and electrolytes. Adverse events were infrequent and included headache, chest pressure, and orthostatic symptoms. The most serious side effects were exacerbation of left ventricular failure in patients with congestive heart failure and bronchoconstriction. One patient with congestive heart failure died from refractory left ventricular failure. Refractory hypotensive shock was fatal in 55 of 115 patients treated with angiotensin II in case studies, cohort studies, and one placebo-controlled study. One healthy subject died after a pressor dose of angiotensin II was infused continuously for 6 days. No other serious adverse events attributable to angiotensin II were reported. Heterogeneity in study design prevented meta-analysis. CONCLUSION: Adverse events associated with angiotensin II were infrequent; however, exacerbation of asthma and congestive heart failure and one fatal cerebral hemorrhage were reported. This systematic review supports the notion that angiotensin II has an acceptable safety profile for use in humans.

Goldberg, R. J. and H. L. Nguyen (2017). “Unlocking the keys to site activation and recruitment success in a randomized controlled trial.” Stroke: 2017 Aug [Epub ahead of print].

Full text of this article.

Two of the most crucial requirements for successfully carrying out and completing an RCT are the initial construction of different hypothetical scenarios to determine how many healthy individuals or patients with a specific disease or condition are needed to be enrolled in the trial and eventually followed on either a short- or long-term basis to find clinically meaningful differences in one’s principal study outcomes and, subsequently, to go out into the field, find, and recruit a sufficient number of patients to the proposed trial to satisfy one’s predetermined sample size requirements. Moreover, the logistical operations of an RCT need to be performed within the confines of a manageable budget and typically tight timeline for patient enrollment and follow-up in which all too often projected estimates of the number of patients to be enrolled and successfully retained in the trial greatly exceed reality.

McCullough, P. A. (2017). “How trialists and pharmaceutical sponsors have failed us by thinking that acute heart failure is a 48-hour illness.” Am J Cardiol 120(3): 505-508.

Full text of this article.

Trials of novel therapies for acute heart failure (HF) have followed a convention of short term, most commonly a 48-hour infusion of parenteral therapy compared with placebo or an active drug in a randomized, double-blind study design. Such trials include OPTIME-CHF, SURVIVE, VERITAS, PROTECT, ASCEND-HF, TRUE-HF, and RELAX-AHF-2. This article reviews how this practice in trials began and summarizes the reasons why such a brief exposure of any novel therapy has failed to reduce the end points of rehospitalization or death. Future trials should consider acute and extended use of novel agents to better match the pathophysiology of decompensation and recovery from acute HF.

Mooney, J., S. L. Sellers, P. Blanke, P. Pibarot, R. T. Hahn, D. Dvir, P. S. Douglas, N. J. Weissman, S. K. Kodali, V. H. Thourani, H. Jilaihawi, O. Khalique, C. R. Smith, S. H. Kueh, M. Ohana, R. Grover, C. Naoum, A. Crowley, W. A. Jaber, M. C. Alu, R. Parvataneni, M. Mack, J. G. Webb, M. B. Leon and J. A. Leipsic (2017). “Ct-defined prosthesis-patient mismatch downgrades frequency and severity, and demonstrates no association with adverse outcomes after tavr.” JACC Cardiovasc Interv: 2017 Jul [Epub ahead of print].

Full text of this article.

OBJECTIVES: This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis-patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). BACKGROUND: PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. METHODS: A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (>/=0.65 and