Kevin J. Anstrom

Prednisone, Azathioprine, and N-Acetylcysteine for Pulmonary Fibrosis

BACKGROUND A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) has been widely used as a treatment for idiopathic pulmonary fibrosis. The safety and efficacy of this three-drug regimen is unknown. METHODS In this randomized, double-blind, placebo-controlled trial, we assigned patients with idiopathic pulmonary fibrosis who had mild-to-moderate lung-function impairment to one of three groups -- receiving a combination of prednisone, azathioprine, and NAC (combination therapy), NAC alone, or placebo -- in a 1:1:1 ratio. The primary outcome was the change in longitudinal measurements of forced vital capacity during a 60-week treatment period. RESULTS When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P=0.01) and hospitalization (23 vs. 7, P<0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks. Data from the ongoing comparison of the NAC-only group and the placebo group are not reported here. CONCLUSIONS Increased risks of death and hospitalization were observed in patients with idiopathic pulmonary fibrosis who were treated with a combination of prednisone, azathioprine, and NAC, as compared with placebo. These findings provide evidence against the use of this combination in such patients. (Funded by the National Heart, Lung, and Blood Institute and the Cowlin Family Fund; ClinicalTrials.gov number, NCT00650091.).

Outcomes of cardiac surgery in patients age ≥80 years: results from the National Cardiovascular Network☆

OBJECTIVES The purpose of this study was to evaluate characteristics and outcomes of patients age > or =80 undergoing cardiac surgery. BACKGROUND Prior single-institution series have found high mortality rates in octogenarians after cardiac surgery. However, the major preoperative risk factors in this age group have not been identified. In addition, the additive risks in the elderly of valve replacement surgery at the time of bypass are unknown. METHODS We report in-hospital morbidity and mortality in 67,764 patients (4,743 octogenarians) undergoing cardiac surgery at 22 centers in the National Cardiovascular Network. We examine the predictors of in-hospital mortality in octogenarians compared with those predictors in younger patients. RESULTS Octogenarians undergoing cardiac surgery had fewer comorbid illnesses but higher disease severity and surgical urgency than younger patients. Octogenarians had significantly higher in-hospital mortality after cardiac surgery than younger patients: coronary artery bypass grafting (CABG) only (8.1% vs. 3.0%), CABG/aortic valve (10.1% vs. 7.9%), CABG/mitral valve (19.6% vs. 12.2%). In addition, they had twice the incidence of postoperative stroke and renal failure. The preoperative clinical factors predicting CABG mortality in the very elderly were quite similar to those for younger patients with age, emergency surgery and prior CABG being the powerful predictors of outcome in both age categories. Of note, elderly patients without significant comorbidity had in-hospital mortality rates of 4.2% after CABG, 7% after CABG with aortic valve replacement (CABG/AVR), and 18.2% after CABG with mitral valve replacement (CABG/MVR). CONCLUSIONS Risks for octogenarians undergoing cardiac surgery are less than previously reported, especially for CABG only or CABG/AVR. In selected octogenarians without significant comorbidity, mortality approaches that seen in younger patients.

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Contemporary outcome trends in the elderly undergoing percutaneous coronary interventions: Results in 7,472 octogenarians

OBJECTIVES We sought to define the risks facing octogenarians undergoing contemporary percutaneous coronary interventions (PCIs). BACKGROUND The procedural risks of PCI for octogenarians have not been well established. METHODS We compared the clinical characteristics and in-hospital outcomes of 7,472 octogenarians (mean age 83 years) with those of 102,236 younger patients (mean age 62 years) who underwent PCI at 22 National Cardiovascular Network (NCN) hospitals from 1994 through 1997. RESULTS Octogenarians had more comorbidities, more extensive coronary disease and a two- to fourfold increased risk of complications, including death (3.8% vs. 1.1%), Qwave myocardial infarction (1.9% vs. 1.3%), stroke (0.58% vs. 0.23%), renal failure (3.2% vs. 1.0%) and vascular complications (6.7% vs. 3.3%) (p < 0.001 for all comparisons). Independent predictors of procedural mortality in octogenarians included shock (odds ratio [OR] 5.4, 95% confidence interval [CI] 3.3 to 8.8), acute myocardial infarction (OR 3.2, 95% CI 2.3 to 4.4), left ventricular ejection fraction (LVEF) <35% (OR 2.9, 95% CI 2.1 to 3.9), renal insufficiency (OR 2.8, 95% CI 2.0 to 3.8), first PCI (OR 2.3, 95% CI 1.7 to 3.3), age >85 years (OR 2.1, 95% CI 1.5 to 2.7) and diabetes mellitus (OR 1.5, 95% CI 1.1 to 2.0). For elective procedures, octogenarian mortality varied nearly 10-fold, and was strongly influenced by comorbidities (0.79% mortality with no risk factors vs. 7.2% with renal insufficiency or LVEF <35%). Despite similar case-mix, PCI outcomes in octogenarians improved significantly over the four years of observation (OR of 0.61 for death/myocardial infarction/stroke in 1997 vs. 1994; 95% CI 0.45 to 0.85). CONCLUSIONS Risks to octogenarians undergoing PCI are two- to fourfold higher than those of younger patients, strongly influenced by comorbidities, and have decreased in the stent era.

A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.

BACKGROUND Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value. METHODS We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil. RESULTS A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P=0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups. CONCLUSIONS This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00517933.)

Using Inverse Probability-Weighted Estimators in Comparative Effectiveness Analyses With Observational Databases

Inverse probability-weighted estimation is a powerful tool for use with observational data. In this article, we describe how this propensity score-based method can be used to compare the effectiveness of 2 or more treatments. First, we discuss the inherent problems in using observational data to assess comparative effectiveness. Next, we provide a conceptual explanation of inverse probability-weighted estimation and point readers to sources that address the method in more formal, technical terms. Finally, we offer detailed guidance about how to implement the estimators in comparative effectiveness analyses.

A Placebo-Controlled Randomized Trial of Warfarin in Idiopathic Pulmonary Fibrosis

RATIONALE Animal and human studies support the importance of the coagulation cascade in pulmonary fibrosis. OBJECTIVES In a cohort of subjects with progressive idiopathic pulmonary fibrosis (IPF), we tested the hypothesis that treatment with warfarin at recognized therapeutic doses would reduce rates of mortality, hospitalization, and declines in FVC. METHODS This was a double-blind, randomized, placebo-controlled trial of warfarin targeting an international normalized ratio of 2.0 to 3.0 in patients with IPF. Subjects were randomized in a 1:1 ratio to warfarin or matching placebo for a planned treatment period of 48 weeks. International normalized ratios were monitored using encrypted home point-of-care devices that allowed blinding of study therapy. MEASUREMENTS AND MAIN RESULTS The primary outcome measure was the composite outcome of time to death, hospitalization (nonbleeding, nonelective), or a 10% or greater absolute decline in FVC. Due to a low probability of benefit and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin versus 3 placebo deaths; P = 0.005) an independent Data and Safety Monitoring Board recommended stopping the study after 145 of the planned 256 subjects were enrolled (72 warfarin, 73 placebo). The mean follow-up was 28 weeks. CONCLUSIONS This study did not show a benefit for warfarin in the treatment of patients with progressive IPF. Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation.

Incidence and Prevalence of Heart Failure in Elderly Persons, 1994-2003

BACKGROUND Recent analyses have presented conflicting evidence regarding the incidence and prevalence of heart failure in the United States. We sought to estimate the annual incidence and prevalence of heart failure and associated survival in elderly persons from January 1, 1994, through December 31, 2003. METHODS We conducted a retrospective cohort study of 622,789 Medicare beneficiaries 65 years or older who were diagnosed as having heart failure between 1994 and 2003. The main outcome measures were incidence and prevalence of heart failure and survival following a heart failure diagnosis. RESULTS The incidence of heart failure declined from 32 per 1000 person-years in 1994 to 29 per 1000 person-years in 2003 (P < .01). Incidence declined most sharply among beneficiaries aged 80 to 84 years (from 57.5 to 48.4 per 1000 person-years, P < .01) and increased slightly among beneficiaries aged 65 to 69 years (from 17.5 to 19.3 per 1000 person-years, P < .01). Although risk-adjusted mortality declined slightly from 1994 to 2003, the prognosis for patients diagnosed as having heart failure remains poor. In 2002, risk-adjusted 1-year mortality was 27.5%, more than 3 times higher than for age- and sex-matched patients. CONCLUSIONS Although the incidence of heart failure has declined somewhat during the past decade, modest survival gains have resulted in an increase in the number of patients living with heart failure. Identifying optimal strategies for the treatment and management of heart failure will become increasingly important as the size of the Medicare population grows.

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

Cost-Effectiveness of Defibrillator Therapy or Amiodarone in Chronic Stable Heart Failure: Results From the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)

Background— In the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), implantable cardioverter-defibrillator (ICD) therapy significantly reduced all-cause mortality rates compared with medical therapy alone in patients with stable, moderately symptomatic heart failure, whereas amiodarone had no benefit on mortality rates. We examined long-term economic implications of these results. Methods and Results— Medical costs were estimated by using hospital billing data and the Medicare Fee Schedule. Our base case cost-effectiveness analysis used empirical clinical and cost data to estimate the lifetime incremental cost of saving an extra life-year with ICD therapy relative to medical therapy alone. At 5 years, the amiodarone arm had a survival rate equivalent to that of the placebo arm and higher costs than the placebo arm. For ICD relative to medical therapy alone, the base case lifetime cost-effectiveness and cost-utility ratios (discounted at 3%) were