Tariq Ahmad

Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C

Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)‐based therapy to direct‐acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off‐target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS‐986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty‐four patients received IFN‐free BMS‐986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%‐50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T‐wave inversions were the most sensitive predictor of LVEF dysfunction. B‐type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS‐986094 toxicity. Conclusion: A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease. (Hepatology 2015;62:409–416

Reduced Cardiac Index Is Not the Dominant Driver of Renal Dysfunction in Heart Failure

BACKGROUNDnIt is widely believed that a reduced cardiac index (CI) is a significant contributor to renal dysfunction in patients with heart failure (HF). However, recent data have challenged this paradigm.nnnOBJECTIVESnThis study sought to determine the relationship between CI and renal function in a multicenter population of HF patients undergoing pulmonary artery catheterization (PAC).nnnMETHODSnPatients undergoing PAC in either the randomized or registry portions of the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial were included (nxa0= 575). We evaluated associations between CI and renal function across multiple subgroups and assessed for nonlinear, threshold, and longitudinal relationships.nnnRESULTSnThere was a weak but significant inverse correlation between CI and estimated glomerular filtration rate (eGFR), such that higher CI was paradoxically associated with worse eGFR (rxa0= -0.12; pxa0= 0.02). CI was not associated with blood urea nitrogen (BUN) or the BUN to creatinine ratio. Similarly, no associations were observed between CI and better renal function across multiple subgroups defined by indications for PAC or hemodynamic, laboratory, or demographic parameters. A nonlinear or threshold effect could not be identified. In patients with serial assessments of renal function and CI, we were unable to find within-subject associations between change in CI and eGFR using linear mixed modeling. Neither CI nor change in CI was lower in patients developing worsening renal function (pxa0≥ 0.28).nnnCONCLUSIONSnThese results reinforce evidence that reduced CI is not the primary driver for renal dysfunction in patients hospitalized for HF, irrespective of the degree of CI impairment or patient subgroup analyzed.

Subcutaneous B-type natriuretic peptide for treatment of heart failure: a dying therapy reborn?

“Yet none of them died, they only changed, were always reborn, continually had a new face: only time stood between one face and another.” —Hermann Hesse ([1][1])nnHeart failure (HF) is among the leading causes of death and morbidity worldwide ([2][2]). The development of efficacious new

Worsening Renal Function in Patients With Acute Heart Failure Undergoing Aggressive Diuresis Is Not Associated With Tubular Injury

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-&bgr;-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation–Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis. Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C. Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300–815 mg), which induced a urine output of 8425 mL (interquartile range, 6341–10u2009528 mL) over the 72-hour intervention period. Levels of N-acetyl-&bgr;-D-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (−8.7 ng/mg; interquartile range, −169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-&bgr;-D-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-&bgr;-D-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69–0.91; P=0.001). Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

The Role of Sodium and Chloride in Heart Failure: Does It Take Two to Tango?

The cardiac retains salt and water because the kidneys do not excrete sodium normally. —Eugene Stead, Jr. [(1)][1]nnThe last century saw some of the giants in medicine meticulously unearth key mechanisms of cardiorenal connections in heart failure (HF); nonetheless, the precise role of the heart

Clinical Implications of Cluster Analysis-Based Classification of Acute Decompensated Heart Failure and Correlation with Bedside Hemodynamic Profiles

Background Classification of acute decompensated heart failure (ADHF) is based on subjective criteria that crudely capture disease heterogeneity. Improved phenotyping of the syndrome may help improve therapeutic strategies. Objective To derive cluster analysis-based groupings for patients hospitalized with ADHF, and compare their prognostic performance to hemodynamic classifications derived at the bedside. Methods We performed a cluster analysis on baseline clinical variables and PAC measurements of 172 ADHF patients from the ESCAPE trial. Employing regression techniques, we examined associations between clusters and clinically determined hemodynamic profiles (warm/cold/wet/dry). We assessed association with clinical outcomes using Cox proportional hazards models. Likelihood ratio tests were used to compare the prognostic value of cluster data to that of hemodynamic data. Results We identified four advanced HF clusters: 1) male Caucasians with ischemic cardiomyopathy, multiple comorbidities, lowest B-type natriuretic peptide (BNP) levels; 2) females with non-ischemic cardiomyopathy, few comorbidities, most favorable hemodynamics; 3) young African American males with non-ischemic cardiomyopathy, most adverse hemodynamics, advanced disease; and 4) older Caucasians with ischemic cardiomyopathy, concomitant renal insufficiency, highest BNP levels. There was no association between clusters and bedside-derived hemodynamic profiles (p = 0.70). For all adverse clinical outcomes, Cluster 4 had the highest risk, and Cluster 2, the lowest. Compared to Cluster 4, Clusters 1–3 had 45–70% lower risk of all-cause mortality. Clusters were significantly associated with clinical outcomes, whereas hemodynamic profiles were not. Conclusions By clustering patients with similar objective variables, we identified four clinically relevant phenotypes of ADHF patients, with no discernable relationship to hemodynamic profiles, but distinct associations with adverse outcomes. Our analysis suggests that ADHF classification using simultaneous considerations of etiology, comorbid conditions, and biomarker levels, may be superior to bedside classifications.

Disentangling the Association between Statins, Cholesterol, and Colorectal Cancer: A Nested Case-Control Study.

Background Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration. Methods and Findings 22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91–0.99; short-term: OR, 0.92; 95% CI, 0.85–0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79–1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87–0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (<6 mo: OR, 0.76; 95% CI, 0.47–0.61; >24 mo: OR, 0.98; 95% CI, 0.93–1.03). Decreases in serum total cholesterol >1 mmol/L ≥1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03–1.53; nonusers: OR, 2.36; 95 CI%, 1.78–3.12). As an observational study, limitations included incomplete data and residual confounding. Conclusions Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy.

Evaluation of the Incremental Prognostic Utility of Increasingly Complex Testing in Chronic Heart Failure

Background—Current heart failure (HF) risk prediction models do not consider how individual patient assessments occur in incremental steps; furthermore, each additional diagnostic evaluation may add cost, complexity, and potential morbidity. Methods and Results—Using a cohort of well-treated ambulatory HF patients with reduced ejection fraction who had complete clinical, laboratory, health-related quality of life, imaging, and exercise testing data, we estimated incremental prognostic information provided by 5 assessment categories, performing an additional analysis on those with available N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels. We compared the incremental value of each additional assessment (quality of life screen, laboratory testing, echocardiography, and exercise testing) to baseline clinical assessment for predicting clinical outcomes (all-cause mortality, all-cause mortality/hospitalization, and cardiovascular death/HF hospitalizations), gauging incremental improvements in prognostic ability with more information using area under the curve and reclassification improvement (net reclassification index), with and without NT-proBNP availability. Of 2331 participants, 1631 patients had complete clinical data; of these, 1023 had baseline NT-proBNP. For prediction of all-cause mortality, models with incremental assessments sans NT-proBNP showed improvements in C-indices (0.72 [clinical model alone]−0.77 [complete model]). Compared with baseline clinical assessment alone, net reclassification index improved from 0.035 (w/laboratory data) to 0.085 (complete model). These improvements were significantly attenuated for models in the subset with measured NT-proBNP data (c-indices: 0.80 [w/laboratory data]−0.81 [full model]); net reclassification index improvements were similarly marginal (0.091→0.096); prediction of other clinical outcomes had similar findings. Conclusions—In chronic HF patients with reduced ejection fraction, the marginal benefit of complex prognostic evaluations should be weighed against potential patient discomfort and cost escalation. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Can Big Data Simplify the Complexity of Modern Medicine?: Prediction of Right Ventricular Failure After Left Ventricular Assist Device Support as a Test Case.

Everything should be made as simple as possible, but not simpler. —Albert Einstein [(1)][1]The delivery of high-quality and patient-centered care relies on accurate risk prediction and phenotyping of disease [(2)][2]. Cardiologists pride themselves on being particularly data-driven; appropriate

Hypochloremia and Diuretic Resistance in Heart Failure Mechanistic Insights

Background—Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature. Methods and Results—Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving ≥80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride ⩽96 mmol/L). Plasma renin concentration correlated with serum chloride (r=−0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343±101 mOsm/kg versus 475±136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3–16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2±2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio. Conclusions—Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354.