Peter A. McCullough M.D.

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.

Tecson, K. M., E. Erhardtsen, P. M. Eriksen, A. O. Gaber, M. Germain, L. Golestaneh, M. L. A. Lavoria, L. W. Moore and P. A. McCullough (2017). “Optimal cut points of plasma and urine neutrophil gelatinase-associated lipocalin for the prediction of acute kidney injury among critically ill adults: Retrospective determination and clinical validation of a prospective multicentre study.” BMJ Open 7(7): 1-9.

Full text of this article.

OBJECTIVES: To determine the optimal threshold of blood and urine neutrophil gelatinase-associated lipocalin (NGAL) to predict moderate to severe acute kidney injury (AKI) and persistent moderate to severe AKI lasting at least 48 consecutive hours, as defined by an adjudication panel. METHODS: A multicentre prospective observational study enrolled intensive care unit (ICU) patients and recorded daily ethylenediaminetetraacetic acid (EDTA) plasma, heparin plasma and urine NGAL. We used natural log-transformed NGAL in a logistic regression model to predict stage 2/3 AKI (defined by Kidney Disease International Global Organization). We performed the same analysis using the NGAL value at the start of persistent stage 2/3 AKI. RESULTS: Of 245 subjects, 33 (13.5%) developed stage 2/3 AKI and 25 (10.2%) developed persistent stage 2/3 AKI. Predicting stage 2/3 AKI revealed the optimal NGAL cutoffs in EDTA plasma (142.0 ng/mL), heparin plasma (148.3 ng/mL) and urine (78.0 ng/mL) and yielded the following decision statistics: sensitivity (SN)=78.8%, specificity (SP)=73.0%, positive predictive value (PPV)=31.3%, negative predictive value (NPV)=95.7%, diagnostic accuracy (DA)=73.8% (EDTA plasma); SN=72.7%, SP=73.8%, PPV=30.4%, NPV=94.5%, DA=73.7% (heparin plasma); SN=69.7%, SP=76.8%, PPV=32.9%, NPV=94%, DA=75.8% (urine). The optimal NGAL cutoffs to predict persistent stage 2/3 AKI were similar: 148.3 ng/mL (EDTA plasma), 169.6 ng/mL (heparin plasma) and 79.0 ng/mL (urine) yielding: SN=84.0%, SP=73.5%, PPV=26.6%, NPV=97.6, DA=74.6% (EDTA plasma), SN=84%, SP=76.1%, PPV=26.8%, NPV=96.5%, DA=76.1% (heparin plasma) and SN=75%, SP=75.8%, PPV=26.1, NPV=96.4%, DA=75.7% (urine). CONCLUSION: Blood and urine NGAL predicted stage 2/3 AKI, as well as persistent 2/3 AKI in the ICU with acceptable decision statistics using a single cut point in each type of specimen.

K, C. B., E. Mejia-Lopez, P. McCullough, K. Breathett, J. L. Kennedy, J. Tallaj, J. Bergin, S. Pamboukian, M. Abuannadi and S. Mazimba (2017). “Clinical impact of changes in hemodynamic indices of contractile function during treatment of acute decompensated heart failure.” J Card Fail: 2017 Jul [Epub ahead of print].

Full text of this article.

BACKGROUND: The objective was to determine the impact of improving right ventricular versus left ventricular stroke work indices (RVSWI v. LVSWI) during therapy for acute decompensated heart failure (ADHF). METHODS AND RESULTS: Cox proportional hazards regression and logistic regression was used to analyze key factors associated with outcomes in 175 patients (age 56.7 +/- 13.6 years, 29.1% female) with hemodynamic data from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. In this cohort, 28.6% and 69.7%, respectively, experienced the outcomes of death, transplant, or ventricular assist device (DVADTX) and DVADTX or HF rehospitalization (DVADTXHF) during 6 months of follow-up. Increasing RVSWI (DeltaRVSWI) from baseline to discharge was associated with a decrease in DVADTXHF (HR 0.923 [95% CI 0.871-0.979] per 0.1 mmHg*L/m2 increase); however, increasing LVSWI (DeltaLVSWI) only had a non-significant association with decreased DVADTXHF (P=0.11) In a multivariable model, patients with DeltaRVSWI

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2017). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis 28(4): 287-293.

Full text of this article.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

Howard, C. E. and P. A. McCullough (2017). “Decoding acute myocardial infarction among patients on dialysis.” J Am Soc Nephrol 28(5): 1337-1339.

Full text of this article.

In this issue of the Journal of the American Society of Nephrology, Shroff et al. utilized hospital billing records from patients on HD in the United States.3 In brief, professional coding specialists determine the principal diagnosis as that condition, established after study, which resulted in the patient’s admission to the hospital. Secondary diagnoses include comorbidities, complications, and other diagnoses that are documented by the attending physician on the inpatient face sheet, discharge summary, history and physical, consultation reports, operative reports, and other ancillary reports. Age, sex, discharge destination, principal diagnosis, up to 24 secondary diagnoses, and up to 25 procedure codes are entered into a computerized algorithm to generate the Medicare diagnosis-related group that determines payment to the hospital.4 The authors demonstrated that although the overall AMI claims in patients on dialysis have increased, the proportion of those in the principal position decreased, whereas those in the secondary position increased.3 In particular, the overall and proportional increase of NSTEMI claims increased dramatically in both the principal and secondary coding positions. These data are consistent with the general population, where several studies have shown a sharp decline in ST-segment elevation myocardial infarction (STEMI) and a lesser decline or increase in NSTEMI.5,6 Interestingly, other data sources suggest that unstable angina is ever less frequent because more sensitive troponin assays clinch a diagnosis of NSTEMI over unstable angina in about 98% of cases.7