Author + information
- Received August 22, 2018
- Revision received September 26, 2018
- Accepted September 29, 2018
- Published online November 5, 2018.
- Ravi B. Patel, MDa,∗ (, )@RBPatelMD,
- Muthiah Vaduganathan, MD, MPHb,
- Aruna Rikhi, MPHc,
- Hrishikesh Chakraborty, DrPHc,
- Stephen J. Greene, MDc,d,
- Adrian F. Hernandez, MDc,d,
- G. Michael Felker, MD, MHSc,d,
- Margaret M. Redfield, MDe,
- Javed Butler, MD, MPH, MBAf and
- Sanjiv J. Shah, MDa
- aDepartment of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- bHeart and Vascular Center, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- cDuke Clinical Research Institute, Durham, North Carolina
- dDivision of Cardiology, Duke University Medical Center, Durham, North Carolina
- eDepartment of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- fDepartment of Medicine, University of Mississippi School of Medicine, Jackson, Mississippi
- ↵∗Address for correspondence:
Ravi B. Patel, MD, Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 600, Chicago, Illinois 60611.
Objectives This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL).
Background AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding impact of AF/AFL on relief of congestion among patients who develop AHF.
Methods We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models.
Results Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro–brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (−5.7% vs. −6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (−18.7% vs. −31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17).
Conclusions More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF.
Atrial fibrillation (AF) and atrial flutter (AFL) and heart failure (HF) have evolved into global, contemporary cardiovascular epidemics. Worldwide, it is estimated that more than 30 million people are burdened by AF/AFL and that approximately 38 million individuals carry a diagnosis of HF (1,2). Chronic AF/AFL and HF (AF/AFL-HF) frequently coexist due to shared pathophysiology, and comorbid AF/AFL-HF carries a worse prognosis than either disease in isolation (3). Chronic AF/AFL serves as a risk factor for and a long-term consequence of both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) (4). Comorbid AF/AFL-HF is associated with both increased mortality and HF hospitalization among patients with chronic HF (5,6). The association between AF/AFL and adverse short-term clinical outcomes among those who develop acute HF (AHF) is inconsistent across multiple populations, which may lead to variability regarding management of AF in this setting (7–12). Although relief of congestion through aggressive diuresis remains the mainstay of therapy in AHF (13), the influence of AF/AFL on the clinical course of decongestion is unclear. As such, this study aimed to characterize the course of decongestion in patients hospitalized for AHF with a history of AF/AFL compared with those without a history of AF/AFL in a pooled, patient-level analysis of the National Heart, Lung, and Blood Institute-sponsored Heart Failure Network (HFN).
Dose, rose, and CARRESS-HF: study designs and patient selection
Patients from 3 trials conducted by the HFN were pooled for this analysis, including the DOSE (Diuretic Optimization Strategies Evaluation) trial (14), the ROSE (Renal Optimization Strategies Evaluation) trial (15), and the diuretic arm of the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial (16). The study designs, protocols, and results of these trials have been previously published (14–16). All 3 trials were prospective, randomized studies which enrolled patients with AHF, regardless of left ventricular ejection fraction (LVEF), and compared the following methods of decongestion with standard therapy methods: diuretic dosing and infusion strategies (DOSE), low-dose dopamine or nesiritide (ROSE), and ultrafiltration (CARRESS-HF). To reduce potential confounding by ultrafiltration on congestion parameters, only the diuresis (control) arm of the CARRESS-HF trial was used for this analysis. Nonduplicated patients among the 3 trials were included in the analysis. Patients were categorized based on history of AF/AFL as assessed at index examination on hospitalization.
Congestion and clinical endpoints
Study visits among the 3 trials were performed during index hospitalization at baseline, 24 h, and 48 h. The final assessment for in-hospital data collection was 72 h for the DOSE and ROSE trials and 96 h for the CARRESS-HF trial. During each timepoint, the following endpoints of congestion were obtained: weight (pounds [kg]), net fluid loss (calculated at 24 h and thereafter), and N-terminal pro–brain natriuretic peptide (NT-proBNP) concentration. In addition, patients completed 2 distinct self-assessments at each timepoint: the global visual analog scale(s) (VAS) and dyspnea VAS. To complete the global VAS, patients marked their global well-being on a 10-cm vertical line, the top of which was labeled “best you have ever felt” and the bottom of which was labeled “worst you have ever felt” (17). The dyspnea VAS used a similar vertical line and concept, with the top of the line labeled “I am not breathless at all” and the bottom labeled “I am as breathless as I have ever been.” Both the global and dyspnea VAS were tabulated from 0 to 100 based on the measurement (in millimeters) from the site marked by the patient to the bottom of the vertical line (higher scores reflected better symptoms). Finally, a 4-point “orthodema” congestion score was measured at each study assessment based on degree of orthopnea (≥2 pillows = 2 points, <2 pillows = 0 points) and peripheral edema (0 to 2 points) (18). For the DOSE and CARRESS-HF trials, edema was classified as none or trace (0 points), moderate (1 point), or severe (2 points). For the ROSE trial, edema was categorized as 0 or 1+ (0 points), 2+ or 3+ (1 point), or 4+ (2 points). The key clinical endpoint was the composite of all-cause mortality or any rehospitalization at 60 days post discharge.
Continuous variables were expressed as median (25th to 75th percentile), and categorical variables were expressed as numbers (%). Pearson chi-square analyses or Fischer exact tests and the Wilcoxon rank sum tests were used to compare categorical and continuous variables, respectively, by AF/AFL status. Congestion endpoints (weight, net fluid loss, NT-proBNP levels, dyspnea VAS results, global VAS results, and orthodema scores) were compared by history of AF/AFL at each time point (baseline, 24 h, 48 h, 72 or 96 h), using the Wilcoxon rank sum test. To account for relative (as opposed to absolute) changes in weight and NT-proBNP levels, relative changes in NT-proBNP and weight were defined by the following formula: [(72/96 h value − baseline value)/baseline value]. General linear regression models assessed the association between history of AF/AFL and change in all continuous congestion endpoints from baseline to 72 or 96 h. Ordinal logistic regression models assessed the association between history of AF/AFL and change in orthodema score at 72 or 96 h. Models were adjusted for the following covariates obtained at baseline and identified a priori by clinical relevance: age, sex, race, LVEF, heart rate, systolic blood pressure, serum creatinine concentration, trial, and loop diuretic dose equivalent. We also explored the relationship between history of AF/AFL and the primary marker of congestion (relative change in weight) in the following 3 prespecified subgroups: 1) LVEF, ≤40%, LVEF 41% to 49%, and LVEF ≥50%; 2) trial, DOSE, ROSE, and CARRESS-HF; and 3) baseline heart rate, above and below median values. Cox proportional hazards models were used to analyze the association between baseline history of AF/AFL and the key composite clinical endpoint at 60 days. Covariates included in the clinical endpoint analysis were the same as those used in the congestion endpoint analysis. All statistical analyses were performed using SAS software, version 9.1 (Cary, North Carolina).
Of the 762 patients from ROSE (n = 360), DOSE (n = 308), and the diuresis arm of CARRESS-HF (n = 94), 12 patients who participated in more than 1 trial were excluded. A total of 750 unique patients were thus identified and included in the analysis. More than half of patients had a history of AF/AFL (n = 418 [56%]). Patients with a history of AF/AFL tended to be older and carried higher rates of ischemic HF, whereas patients without history of AF/AFL had higher rates of diabetes mellitus and hypertension (p < 0.05 for all comparisons) (Table 1). In patients with a history of AF/AFL EF was higher (35% vs. 27%, respectively; p < 0.001), the rate of HFpEF (LVEF ≥50%) was higher (35.7% vs. 23.8%, respectively; p < 0.001), and NT-proBNP levels were not significantly different (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) than in patients without AF/AFL. HFpEF and HFrEF (LVEF ≤40%) patients with history of AF/AFL exhibited levels of NT-proBNP that were overall similar to those of their counterparts without AF/AFL (Online Table S1).
Clinical decongestion by AF/AFL status and clinical outcomes
Comprehensive trends in markers of congestion over the course of HF hospitalization are displayed in Figure 1. Creatinine trend did not differ between the 2 groups by 72 or 96 h (median increases: +0.02 mg/dl in AF/AFL subjects, +0.01 mg/dl in no-AF/AFL subjects; p = 0.95). There were no significant differences in median baseline weight values (AF/AFL group = 200 lbs [90.7 kg], no-AF/AFL subjects = 208 lbs [94.3 kg]; p = 0.17), which decreased by 7 lbs (3.2 kg) in both groups by 72 or 96 h (Figure 1A). Patients with history of AF/AFL had lower overall net fluid loss by 72 or 96 h than those with no history of AF/AFL (4,018 ml vs. 4,466 ml, respectively; p = 0.02). Similarly, although NT-proBNP levels were comparable in the 2 groups at baseline (AF/AFL subjects = 4,210 pg/ml vs. no-AF/AFL subjects = 5,037 pg/ml; p = 0.27), the overall in-hospital decrease in NT-proBNP concentration was blunted in the patients with a history of AF/AFL at 72/96 h (−732 vs. −1,409 pg/ml, respectively; p < 0.001) (Figure 1C). Dyspnea VAS scores were similar in both groups at baseline (AF/AFL = 54, no-AF/AFL = 52; p = 0.69). There was a trend toward more appreciable increases in dyspnea VAS scores by 72/96 h in those without AF/AFL (median change in 25th to 75th percentiles: +18 [1 to 40] vs. +15 [0 to 32], respectively; p = 0.06) (Figure 1D). Likewise, global VAS scores were similar at baseline (AF/AFL = 50, no-AF/AFL = 49; p = 0.13) but increased more substantially by 72/96 h in the cohort without history of AF/AFL (median change in 25th to 75th percentiles: +21 [5.5 to 41.5] vs. +16.5 [0 to 34], respectively; p = 0.003) (Figure 1E). The median orthodema congestion score was 3 at baseline in both groups (p = 0.20) and decreased similarly in both groups by 72 or 96 h (median change in 25th to 75th percentiles: −1 [−2 to 0] vs. −1 [−2 to 0], respectively; p = 0.54).
After covariate adjustment, baseline history of AF/AFL was associated with less substantial loss of relative weight (−5.7% vs. −6.5%, respectively; p = 0.02) and decrease in relative NT-proBNP levels (−18.7% vs. −31.3%, respectively; p = 0.003) at 72 or 96 h (Table 2). The association between history of AF/AFL and blunted average net fluid loss was attenuated after covariate adjustment (adjusted average net fluid loss: 9,655.5 ml vs. 10,079.6 ml; adjusted p = 0.12). History of AF/AFL was associated with a blunted increase in global VAS score at 72 or 96 h (mean increase: +31.0 vs +35.9; p = 0.04). After multivariate adjustments, there was no significant association between history of AF/AFL and change in orthodema congestion score or dyspnea VAS score at 72 or 96 h (Table 2). In subgroup analyses, the association between history of AF/AFL and change in relative weight did not differ significantly by LVEF, clinical trial, or median heart rate (Table 3). At 60-day follow-up, 167 patients (40%) with history of AF/AFL and 121 patients (36%) without history of AF/AFL had experienced the key composite clinical endpoint (Figure 2, schematic). After covariate adjustment, history of AF/AFL was not significantly associated with the key composite clinical endpoint (hazard ratio: 1.21: 95% confidence interval: 0.92 to 1.59; p = 0.17).
In a pooled, patient-level analysis of 3 HFN trials of patients hospitalized for AHF, we defined the relationship between history of AF/AFL, course of decongestion, and short-term post-discharge clinical outcomes. History of AF/AFL was present in >50% of patients hospitalized for AHF, and these patients represented an older cohort with higher prevalence of ischemic heart disease. History of AF/AFL was associated with blunted decongestion as shown by diminished changes in weight and natriuretic peptides during hospitalization in both HFrEF and HFpEF. History of AF/AFL was not independently associated with adverse clinical outcomes at 60 days after hospital discharge.
Comorbid AF/AFL and acute HF
History of AF/AFL was present in most patients with AHF in this pooled trial population, and rates were slightly higher than those observed in other trials and registries of AHF (7,19). Similar to other AHF populations, these AF/AFL patients tended to be older and carry higher rates of ischemic heart disease. Consistent with prior studies (7,19), this AF/AFL cohort was more likely to have HFpEF than HFrEF, which may partially account for lower NT-proBNP levels at the time of presentation for AHF. Natriuretic peptides are lower in HFpEF during periods of stability and acute decompensation than in HFrEF (20).
AF/AFL and in-hospital decongestion
Although multiple prior studies have explored the association between AF/AFL and clinical outcomes among patients hospitalized for HF (7,9), the implications of AF/AFL for the in-hospital trajectory of decongestion has been poorly characterized. In the present study, the cohort of patients with a history of AF/AFL experienced significantly less in-hospital reduction in 2 markers of congestion (relative weight and NT-proBNP levels). Furthermore, differences in the rate of decongestion between the 2 groups became more apparent after the initial 24 h of diuresis. Thus, history of AF/AFL appears to be associated with a reduction in sustained decongestion over the course of the latter 48 to 96 h of hospitalization. Diminished rates of decongestion in those with a history of AF/AFL may be associated with lower overall well-being and quality of life, as shown by decreased global VAS scores among the AF/AFL cohort.
Notably, history of AF/AFL was not associated with changes in the 4-point orthodema congestion score. This score has proved useful in stratifying patients' risk for AHF for post-discharge events (18). In our population, orthodema scores, although initially elevated, dropped significantly in the first 24 h from baseline and remained relatively low in most patients, regardless of history or not of AF/AFL.
The finding of numerically lower NT-proBNP levels among patients with a history of AF/AFL on admission for AHF was not consistent with that of the chronic HF population and requires further attention. Higher rates of HFpEF in the AF/AFL cohort may only partially explain diminished natriuretic peptide levels, as history of AF/AFL was associated with numerically lower NT-proBNP levels, even compared across similar EF subtypes (i.e., HFrEF and HFpEF). This paradoxical finding has been noted in prior AHF trials of HFrEF populations (21). Among patients with AF/AFL, less myocardial stretch may be required to promote congestive symptoms that ultimately “tip over” such patients into AHF than those without AF/AFL, leading to paradoxically lower natriuretic peptides on admission. Additionally, symptoms of AF/AFL and AHF are often overlapping, posing a clinical challenge to discern the primary cause of dyspnea among patients with comorbid AF/AFL and HF. Given numerically lower baseline weight and natriuretic peptide levels, it is possible that arrhythmia is the primary cause of symptoms in the AF/AFL cohort, as opposed to progressive volume overload. Further investigation using invasive or non-invasive (e.g., echocardiographic) hemodynamic data on hospital presentation is required to understand the true congestive status of patients with AF/AFL-HF who present with dyspnea.
Mechanisms of blunted decongestion in AF/AFL
Mechanisms driving blunted decongestion in AF/AFL are not well understood. AF/AFL resulting in rapid ventricular rate leads to decreased diastolic left ventricular filling time and may ultimately limit diuresis (22). However, the baseline heart rates among patients with and without AF/AFL were similar in our study. In addition, there were no differences in association of AF/AFL and relative change in weight when patients were categorized based on resting heart rate. Abnormal left ventricular myocardial mechanics in AF/AFL may also predispose patients to decreased overall systemic circulatory flow and impaired diuresis. Finally, left atrial mechanical dysfunction may hinder decongestion in HF. Marked anatomic and physiologic changes occur to the left atrium in the setting of AF/AFL, particularly among patients with HF (23,24). Progressive left atrial fibrosis, abnormalities in calcium handling, and increased sympathetic tone through upregulation of the renin-angiotensin-aldosterone system lead to mechanical dysfunction of the left atrium and are associated with poor clinical outcomes (25–27). Specifically, AF/AFL perturbs left atrial contraction (booster function) (28) and filling (reservoir function) (29,30), which together may promote the development of AHF and hinder the efficacy of traditional strategies to achieve decongestion.
AF/AFL in acute HF: a target for therapy?
Therapeutic management of AF/AFL in AHF remains challenging. Aside from limiting aggressive rate controlling and negative inotropic therapies, current guidelines do not provide clear management suggestions in AHF (31). In this study, the presenting rhythm of patients was not captured at the time of trial inclusion and randomization; thus, it is likely that a proportion of patients with a history of AF/AFL were in sinus rhythm during hospitalization for AHF. However, previous trial and registry data of AHF have revealed that 84% to 86% of HF patients with history of AF/AFL present with AF/AFL at the time of hospitalization (8,32). Rhythm control with antiarrhythmic drugs yielded neutral outcomes compared with rate-controlling therapies in the chronic HF population (33). Recently, in a modestly sized trial of patients with chronic HFrEF, catheter ablation of AF was associated with improved clinical outcomes compared with standard medical therapy (34). Indeed, an additional trial of catheter ablation of AF is currently underway (RAFT-AF [Rhythm Control–Catheter Ablation With or Without Anti-arrhythmic Drug Control of Maintaining Sinus Rhythm Versus Rate Control With Medical Therapy and/or Atrio-ventricular Junction Ablation and Pacemaker Treatment for Atrial Fibrillation]; NCT01420393), which includes patients with chronic HF, and results are expected shortly. It is not known whether the various strategies of rhythm control (cardioversion, antiarrhythmic drugs, catheter ablation, or a combination) of AF/AFL would yield benefits in promoting decongestion during hospitalization for AHF. Further research is required to address the utility of rhythm control of AF/AFL in the setting of AHF.
We relied on history of AF/AFL because presenting rhythm was not available at the time of AHF. As such, we were unable to determine whether atrial arrhythmia was the precipitant of AHF. Additionally, category of AF/AFL (paroxysmal, persistent, permanent) was also not recorded at randomization. Although invasive hemodynamic data (right heart catheterization) is considered the “gold standard” for congestive status, these data were not captured in our study cohort. Intensity of in-hospital decongestive therapy (i.e., diuretic dose) was not uniformly collected across all 3 trials and, thus, multivariate models adjusted for diuretic dose at the time of randomization. Given the retrospective nature of the analysis, the findings may be influenced by unmeasured confounders despite careful statistical accounting. Furthermore, AF/AFL is associated with elevated NT-proBNP levels in patients with chronic HF; thus, natriuretic peptides may not be truly reflective of degree of congestion in this cohort. For this reason, relative change in weight was chosen as the prespecified primary marker of congestion. Given higher levels of congestive markers in those without history of AF/AFL at baseline, our findings may be partially explained by regression to the mean. The lack of association between AF/AFL and short-term post-discharge clinical endpoints in our pooled cohort should be interpreted with caution, as the 3 trials were each powered to detect changes in symptoms and signs of congestion rather than clinical endpoints. This pooled analysis benefits from consistent data collection across 3 HFN trials, detailed accounting of congestion markers at multiple time-points during hospitalization for AHF, and robust representation of patients hospitalized for HFpEF.
In this pooled clinical trial cohort of patients hospitalized for AHF, more than half of patients had a history of AF/AFL, which was independently associated with blunted in-hospital decongestion in HFrEF and HFpEF. Further research is required to investigate the utility of rhythm-controlling therapies in promoting decongestion, relieving patient symptoms, and improving clinical outcomes in the setting of concomitant AF/AFL and AHF.
COMPETENCY IN MEDICAL KNOWLEDGE: History of AF/AFL is a common comorbidity among patients hospitalized for AHF, representing an elderly, frail cohort with high comorbidity burden.
TRANSLATIONAL OUTLOOK 1: History of AF/AFL is associated with a blunted course of decongestion among patients hospitalized for AHF. Further research is required to better understand the hemodynamic effects of AF/AFL in the setting of AHF and the mechanisms that may influence decongestion.
TRANSLATIONAL OUTLOOK 2: Despite its high prevalence in AHF, management strategies of AF/AFL in this setting are widely variable. Further research is needed to evaluate the utility of rhythm-controlling therapies in the setting of AHF with comorbid AF/AFL.
Supported by National Heart, Lung, and Blood Institute/National Institutes of Health awards U10 HL084904, U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr. Patel is supported by NHLBI T32 postdoctoral training grant T32HL069771. Dr. Vaduganathan is supported by KL2/Catalyst Medical Research Investigator Training award, Harvard Catalyst, Harvard Clinical and Translational Science Center, National Center for Advancing Translational Sciences, NIH award KL2 TR002542; and serves on advisory boards for Bayer AG and Baxter Healthcare. Dr. Greene is supported by NHLBI T32 postdoctoral training grant T32HL069749-14 and Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award, Novartis; and has received research support from Amgen and Novartis. Dr. Felker has received research support from NHLBI, the American Heart Association, Novartis, Cytokinetics, Amgen and Merck; and has consulted for Amgen, Novartis, Bristol-Myers Squibb, Stealth, SC Pharma, Innolife, Cytokinetics, VWave, EBR Systems, and Cardionomic. Dr. Butler has received research support from NIH and European Union; and has consulted for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Relypsa, Vifor Pharma, and ZS Pharma. Dr. Shah has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and is a compensated consultant for Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, and United Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Barry Greenberg, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- atrial fibrillation/atrial flutter
- acute heart failure
- heart failure
- heart failure with preserved ejection fraction
- heart failure with reduced ejection fraction
- left ventricular ejection fraction
- N-terminal pro–B-type natriuretic peptide
- visual analog scale
- Received August 22, 2018.
- Revision received September 26, 2018.
- Accepted September 29, 2018.
- 2018 American College of Cardiology Foundation
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