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1.  Randomized Trial of N-acetylcysteine in Idiopathic Pulmonary Fibrosis 
The New England journal of medicine  2014;370(22):2093-2101.
N-acetylcysteine (NAC) has been suggested as a beneficial treatment for idiopathic pulmonary fibrosis (IPF). A placebo-controlled study of this agent administrated orally alone in an IPF population has not been conducted.
An initially designed three-arm randomized, double-blind, placebo-controlled trial of prednisone plus azathioprine plus NAC (three-drug regimen) versus NAC versus placebo in IPF patients with mild-moderate impairment in pulmonary function was interrupted due to safety concerns associated with the three-drug regimen. The trial continued as a two-arm design (NAC vs. placebo) without other changes and enrolled 133 and 131 patients in the NAC and placebo arms, respectively. The primary outcome measure was the change in forced vital capacity (FVC) over a 60-week period.
Over the 60-week treatment period, there was no difference between the NAC and placebo groups in the decline of FVC (60-week change of −0.18 liters for NAC vs. −0.19 liters for placebo, p=0.77). In addition, there were no significant differences between NAC and placebo for mortality (6 [4.9%] vs. 3 [2.5%] events, p=0.50) or acute exacerbation (3 [2.3%] vs. 3 [2.3%] events, p>0.99).
Compared to placebo NAC offered no benefit for the preservation of FVC in IPF patients with mild-to-moderate physiological abnormalities.
PMCID: PMC4116664  PMID: 24836309
2.  Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome 
The New England journal of medicine  2012;367(24):2296-2304.
Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function.
We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days.
Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was −0.04±0.53 mg per deciliter (−3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03).
In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events.
PMCID: PMC3690472  PMID: 23131078
3.  Diuretic Strategies in Patients with Acute Decompensated Heart Failure 
The New England journal of medicine  2011;364(9):797-805.
Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use.
In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.
In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P = 0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5μmol per liter], respectively; P = 0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P = 0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 μmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 μmol per liter] with the low-dose strategy, P = 0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function.
Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; number, NCT00577135.)
PMCID: PMC3412356  PMID: 21366472
4.  Quality of Life and Cost Following Late Invasive Therapy for Occluded Infarct Arteries 
The New England journal of medicine  2009;360(8):774-783.
The open artery hypothesis postulates that late opening of an infarct-related artery after myocardial infarction (MI) will improve clinical outcomes. The quality of life (QOL) and economic outcomes associated with this strategy have not been described.
The Occluded Artery Trial (OAT) compared percutaneous coronary intervention (PCI) plus stenting with medical therapy alone in stable, high-risk patients who had a totally occluded infarct-related artery at 3 to 28 days post-MI. In 951 patients (44% of those eligible), QOL was assessed by a battery that included two principal outcome measures, the Duke Activity Status Index (DASI) reflecting cardiac-related physical functioning, and the Rand Short-Form 36 Mental Health Inventory 5 reflecting psychological well-being. Structured QOL interviews were performed at baseline, 4, 12, and 24 months. Costs were measured in 458 of 469 U.S. patients (98%) and 2-year cost effectiveness was estimated.
At 4 months, the medical therapy group showed a clinically marginal 3.4-point decline in DASI relative to the PCI group (p=0.007). At 1 and 2 years, the differences were smaller. No significant differences in psychological well-being were observed. In the 469 US OAT patients, cumulative 2-year costs were about $7,000 higher in the PCI group (p<0.0001) while quality-adjusted survival was marginally higher in the medical therapy group.
In this trial, PCI was associated with a marginal advantage in cardiac physical functioning at 4 months but not thereafter. At 2 years, medical therapy remained significantly less expensive than routine PCI and had higher quality-adjusted survival.
PMCID: PMC2724193  PMID: 19228620
Percutaneous coronary intervention; quality of life; costs; coronary artery disease; myocardial infarction
5.  Quality of Life with Defibrillator Therapy or Amiodarone in Heart Failure 
The New England journal of medicine  2008;359(10):999-1008.
Implantable cardioverter defibrillator (ICD) therapy significantly prolongs life in patients at increased risk of sudden cardiac death from depressed left ventricular function. However, it is unclear whether this increased longevity is accompanied by deterioration in quality of life.
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) compared ICD therapy or amiodarone versus state-of-the-art medical therapy alone in 2521 stable heart failure patients with depressed left ventricular function. Quality of life, a secondary end point of the trial, was prospectively measured at baseline, 3, 12, and 30 months and was 93% to 98% complete. The Duke Activity Status Index (which measures cardiac physical functioning) and the SF-36 Mental Health Inventory (which measures psychological well-being or distress) were prespecified principal quality-of-life outcomes. Multiple additional quality-of-life outcomes were also examined.
Compared with medical therapy alone, psychological well-being in the ICD arm significantly improved at 3 months (p=0.01) and 12 months (p=0.004) but not at 30 months. No clinically or statistically significant differences in physical functioning by treatment were observed. Some other quality-of-life measures improved in the ICD arm at 3 and/or 12 months but none differed significantly at 30 months. ICD shocks within the month preceding a scheduled assessment were associated with decreased quality of life in multiple domains. Amiodarone had no significant effects on the principal quality-of-life outcomes.
In a large primary prevention population with moderately symptomatic heart failure, single lead ICD therapy was not associated with any detectable adverse quality-of-life effects over 30 months of follow-up.
PMCID: PMC2823628  PMID: 18768943
Sudden cardiac death; congestive heart failure; implantable cardioverter-defibrillator; quality of life

Results 1-5 (5)