Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure

    Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure Jennifer T. Thibodeau MD, MSc, Benjamin E. Jenny MD, Jeomi O. Maduka MD, Punag H. Divanji MD, Colby R. Ayers MS, Faris Araj MD, Alpesh A. Amin MD, Robert M. Morlend MD, Pradeep P.A. Mammen MD, Mark H. Drazner MD, MSc PII: DOI: Reference:

S0002-8703(16)30207-1 doi: 10.1016/j.ahj.2016.09.011 YMHJ 5288

To appear in:

American Heart Journal

Received date: Accepted date:

19 May 2016 8 September 2016

Please cite this article as: Thibodeau Jennifer T., Jenny Benjamin E., Maduka Jeomi O., Divanji Punag H., Ayers Colby R., Araj Faris, Amin Alpesh A., Morlend Robert M., Mammen Pradeep P.A., Drazner Mark H., Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure, American Heart Journal (2016), doi: 10.1016/j.ahj.2016.09.011

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ACCEPTED MANUSCRIPT Intended section: Clinical investigations

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Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure

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Jennifer T. Thibodeau, MD, MSc; Benjamin E. Jenny, MD; Jeomi O. Maduka, MD; Punag H. Divanji, MD; Colby R. Ayers, MS; Faris Araj, MD; Alpesh A. Amin, MD; Robert M. Morlend, MD; Pradeep P.A.

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Mammen, MD; Mark H. Drazner, MD, MSc

Author affiliations: Division of Cardiology, Department of Internal Medicine, University of

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Texas Southwestern Medical Center, Dallas, Texas

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Brief title: Bendopnea and adverse outcomes

Funding/Support: Dr. Drazner acknowledges support from the James M. Wooten Chair in

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Cardiology. No authors have a conflict of interest.

Corresponding author:

Mark Drazner, MD, MSc University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, TX 75390-9047 Phone: 214-645-7500 Fax: 214-645-7501 Email address: [email protected]

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ACCEPTED MANUSCRIPT Keywords Bendopnea

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Heart failure

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Outcomes

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Dyspnea

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Background: Recently, the symptom of bendopnea, i.e., shortness of breath when bending forwards such

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as when putting on shoes, has been described in heart failure patients and found to be associated with

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known whether bendopnea is associated with clinical outcomes.

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higher ventricular filling pressures, particularly in the setting of low cardiac index. However, it is not

Methods: In a prospective convenience sample of 179 patients followed in our heart failure disease

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management clinic, we determined the presence of bendopnea at the time of enrollment and ascertained clinical outcomes through 1 year of follow-up. We performed univariate and stepwise multivariable

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modeling to test the association of bendopnea with clinical outcomes.

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Results: Bendopnea was present in 32/179 (18%) subjects. At 1 year, those with versus without

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bendopnea were at increased risk of the composite endpoint of death, heart failure admission, inotrope initiation, left ventricular assist device implantation, or cardiac transplantation in univariate (hazard ratio

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1.9, p<0.05) but not multivariable (HR 1.9, p =0.11) analysis. Bendopnea was more strongly associated with short term outcomes including heart failure admission at 3 months, both in univariate (HR 3.1,

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p<0.004), and multivariable (HR 2.5, p=0.04) analysis.

Conclusions: Bendopnea was associated with an increased risk of adverse outcomes in ambulatory patients with heart failure, particularly heart failure admission at 3 months.

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ACCEPTED MANUSCRIPT INTRODUCTION We recently described a novel symptom of heart failure, bendopnea, or dyspnea when bending

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forward. Patients with versus without bendopnea had higher supine ventricular filling pressures,

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particularly in the presence of a low cardiac index.1 Bendopnea has also been shown to be associated with a higher VE/VCO2 on cardiopulmonary stress testing, a validated marker of heart failure disease severity.2

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To our knowledge, whether bendopnea is associated with increased rates of adverse outcomes in heart failure patients is not known. Thus, we conducted the present prospective observational study to

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determine risk of adverse outcomes in ambulatory heart failure patients with versus without bendopnea.

Study design and subject selection

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METHODS

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We conducted a single-center prospective observational study between January 2014 and April 2015 of a convenience sample of 179 patients with systolic heart failure who were followed in the heart

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failure disease management clinic at the University of Texas Southwestern Medical Center. Patients 18

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years of age or older with systolic heart failure, defined as a left ventricular ejection fraction < 45%, within 3 months of enrollment, were eligible for participation. Subjects were excluded if they had an

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active pulmonary infection, severe restrictive, obstructive or interstitial pulmonary process, were on inotropic therapy, non-English speaking, or unable or unwilling to bend forward to assess for bendopnea. The study protocol was reviewed and approved by the Institutional Review board. All subjects gave written informed consent. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents. Clinical and laboratory assessment An investigator obtained clinical data during the clinic visit by examination, interview, and review of medical records. Data collected included demographic data, cardiac medications, etiology of

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ACCEPTED MANUSCRIPT cardiomyopathy, left ventricular ejection fraction within 3 months of enrollment, and assessment of the New York Heart Association (NYHA) classification system. “High-dose diuretics” was defined as

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furosemide dose > 160mg/day, torsemide dose > 80mg/day, bumetadine dose > 4mg/day, or any use of

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metolazone. Physical examination included blood pressure, pulse pressure, body mass index (BMI), hemodynamic profile as determined by the primary clinician caring for the patient, and assessment of

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bendopnea. The hemodynamic profiles were defined as follows, as advocated by others:3 profile A: warm/dry: well perfused, not volume overloaded; profile B: warm/wet: well perfused, volume

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overloaded; profile C: cold/wet: poorly perfused, volume overloaded; and profile L: cold/dry: poorly

collected within 1 week of enrollment.

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perfused, not volume overloaded. Pertinent laboratory values were included in the study if they were

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In order to determine the presence of bendopnea, each subject sat in a chair and bent forward at the waist as if putting on their shoes or socks, while an investigator timed the duration to the onset of

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shortness of breath as stated to the patient “tell me when you feel short of breath.” Before the bendopnea test was performed, subjects were instructed to not hold their breath during bending. The subject was

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classified as having bendopnea if they reported shortness of breath within 30 seconds of bending. If there

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was no shortness of breath at 30 seconds, the bendopnea test was concluded and the patient was classified as not having bendopnea.1 Outcome assessment

Patients were followed for one-year after enrollment. Outcomes included: heart failure (HF) admission, inotrope initiation, left ventricular assist device (LVAD) implantation, cardiac transplantation, and death. Patients were censored after cardiac transplantation or death. We evaluated 2 composite outcomes: one included death and HF admission, and the other was an overall composite which included all outcomes listed above. In order to assess whether outcomes were met, electronic medical records of our institution were reviewed. Additionally, subjects were contacted via telephone and asked about each of the outcomes after one-year of follow-up to capture any events that occurred outside of our institution.

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ACCEPTED MANUSCRIPT Statistical analysis Descriptive statistics are reported as mean (standard deviation), median (25th, 75th percentile) or No. (%)

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as appropriate. The Chi square test (categorical variables) and Wilcoxon rank sum test (continuous

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variables) were used to compare the clinical characteristics of the bendopnea and no bendopnea groups. In cases of low cell counts, the Fisher’s exact test was used for comparison of the categorical variables.

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Kaplan-Meier survival curves were generated for the outcomes of HF admissions, composite of HF

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admission and death, as well as the overall composite outcome. Univariate Cox regression models were performed testing the association of bendopnea with each outcome and with the two composite outcomes.

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Stepwise multivariable Cox regression models were then performed including the following candidate variables: bendopnea, variables that were different between bendopnea vs. no bendopnea on univariate

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analysis including: gender, high dose diuretic use, digoxin, amiodarone and statin use; as well as variables we thought to be clinically relevant: sodium concentration, creatinine level, NT-proBNP level, and

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systolic blood pressure. The Cox proportional hazards assumptions were tested by looking at Schoenfeld residuals and their correlation with time. There was no correlation, which indicated that the assumptions

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were valid. After review of the Kaplan-Meier curves, it appeared that bendopnea was a marker of a poor

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early prognosis. Thus, we looked at outcomes at 1, 3 and 6 months in addition to 1 year. Statistical significance was set at 0.05 and all tests were two-tailed. Statistical analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC). RESULTS Clinical characteristics Bendopnea was present in 32/179 (18%) subjects with median (25th, 75th percentile) time to onset of 13 (9, 18) seconds. The clinical characteristics of subjects with and without bendopnea are summarized in Table 1. Most patients were white, middle-aged men. Those with bendopnea were more likely to be NYHA class IV, to be on any diuretic, and to be on high dose diuretics. There was also a difference in estimated hemodynamic profiles between those with and without bendopnea. Specifically, those without

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ACCEPTED MANUSCRIPT bendopnea were more likely to be profile A while those with bendopnea were more likely to be profile B. There was no difference in age, ethnicity, Beta blocker or Angiotensin converting enzyme inhibitor use,

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left ventricular ejection fraction, blood pressure, body mass index, sodium, BUN, creatinine, or NT-

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proBNP between these two groups.

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Outcomes

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There were a total of 80 events in 53 patients after one-year follow-up. Most (n=45) of these events were HF admissions. In addition, there were 12 deaths, 8 patients had inotropes initiated, 9

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underwent LVAD implantation, and 6 cardiac transplant. Kaplan-Meier curves are shown stratified by bendopnea status (Figure 1). The presence of bendopnea was associated with a trend toward increased

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risk of HF admission (Fig 1A, p=0.07) and the composite of death and HF admission (Fig 1B, p=0.08), and a significantly higher risk of the overall composite endpoint (Figure 1C, p=0.04). Noting that there

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appeared to be early divergence in outcomes between the two groups, we conducted a series of univariate Cox regression analyses at various time points (Table 2). Bendopnea was associated with an increased

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risk of HF admission, the composite of death or HF admission, and the overall composite endpoint at 1

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month, 3 months and 6 months. At 1 year, those with versus without bendopnea were at increased risk of the composite endpoint of death, heart failure admission, inotrope initiation, left ventricular assist device implantation, or cardiac transplantation in univariate (hazard ratio 1.9, p<0.05) but not multivariable (HR 1.9, p =0.11) analysis. In multivariable Cox regression models, bendopnea remained associated with an increased risk of HF admission (bendopnea HR 2.5, p=0.04) at 3 months. The other variables associated with risk of HF admission at 3 months were systolic blood pressure (HR 0.97, p=0.01) and creatinine (HR 1.3, p = 0.05). DISCUSSION This study is the first, to our knowledge, to demonstrate that bendopnea was associated with adverse clinical outcomes in patients with heart failure. We found that bendopnea was present in a

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ACCEPTED MANUSCRIPT sizeable minority (18%) of ambulatory patients followed in a heart failure disease management clinic. Patients with bendopnea were at an increased risk at one year of the composite endpoint of death, HF

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admission, inotrope initiation, LVAD implantation, and cardiac transplantation, with a strong trend

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towards increased risk of HF admission. Notably, on Kaplan-Meier analysis, bendopnea was associated more robustly with risk of short term adverse clinical outcomes. Indeed, the association of bendopnea and

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heart failure admission at 3 months persisted both in univariate and multivariable Cox regression modeling. The associations of bendopnea with adverse outcomes was driven by HF admission, rather than

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death, possibly due to the difference in numbers who reached these endpoints. In total, these data suggest

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that bendopnea is a marker of severity of illness in ambulatory heart failure patients. It may not be surprising that bendopnea is associated with adverse clinical events in patients with

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heart failure. First, bendopnea was shown to be associated with elevated ventricular filling pressures, particularly in those with a low cardiac index, and both elevated LV filling pressures,1 and the

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combination of low filling pressures with low cardiac index3 has been associated with adverse outcomes. Indeed, it is now well established that the congested state in heart failure is associated with adverse

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clinical outcomes.3-11 The mechanism behind this increased risk is not clear, but it may be that increased

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congestion leads to enhanced activation of the sympathetic nervous system12, 13 or apoptosis due to myocardial stretch.14 Additionally, bendopnea has been shown to be associated with elevated VE/VCO2,2 itself a risk factor for adverse outcomes in heart failure patients.15-18 Interestingly, many other markers of disease severity19-30 did not differ between those with and without bendopnea (Table 1) including serum sodium concentration, renal function, natriuretic peptide concentration, LVEF, blood pressure, and pulse pressure. These data suggest that bendopnea may provide additive prognostic information to previously established risk factors. It is important to consider the role of obesity in bendopnea. In our initial publication, we reported a higher BMI in those with bendopnea, but no difference in waist or hip circumference, suggesting that increased abdominal girth was not the primary cause of bendopnea.1 Subsequently, in a study from Spain,

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ACCEPTED MANUSCRIPT BMI was not associated with bendopnea.2 In the current study of ambulatory heart failure patients, we found no difference in BMI between those with and without bendopnea (Table 1). In addition, the

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demonstration that bendopnea was associated with adverse clinical outcomes provides further support that

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obesity is unlikely to be the major cause of bendopnea, for a higher BMI is associated with improved clinical outcomes in heart failure patients (the “obesity paradox”).31-37

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Our study has limitations. This was a single-center study, thus results may not be generalizable.

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The cohort was a convenience sample recruited from the heart failure clinic due to investigator availability. However, bendopnea status was not used to decide whom to recruit. Routine

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electrocardiograms were not obtained so we cannot determine differences in heart rhythm between those with and without bendopnea. Additionally, the assessment of bendopnea by some clinicians may have

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influenced their assignment of NYHA class or hemodynamic profile. In addition, our sample size was relatively small, which may have impacted the robustness of the associations with clinical events.

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Nevertheless, we were able to demonstrate that bendopnea was a marker of early adverse outcomes in

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patients with CHF.

In conclusion, we have found that bendopnea was present in a sizeable minority of ambulatory

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patients followed in a heart failure disease management clinic. Further, bendopnea was associated with increased risk of adverse outcomes in patients with heart failure, particularly subsequent admissions for decompensated heart failure within 3 months. This increased risk occurred despite similar findings of other markers of disease severity, suggesting that bendopnea may provide additive prognostic information to previously identified risk factors.

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ACCEPTED MANUSCRIPT FIGURE LEGENDS Figure 1. Freedom from (A) HF admission (B) composite of death or HF admission or (C)

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composite of death, HF admission, inotrope initiation, LVAD implantation, or cardiac transplant,

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each stratified by bendopnea status.

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ACCEPTED MANUSCRIPT TABLE 1.

Clinical characteristics of subjects with and without bendopnea

Characteristic

Bendopnea (n=32)

No bendopnea

P-value

57 (12)

Male

17 (53%)

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Race

15 (47%)

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Caucasian Black

Ischemic etiology of cardiomyopathy

Angiotensin converting enzyme

100 (68%)

0.05 0.41

92 (63%) 38 (26%)

4 (13%)

14 (10%)

14 (44%)

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Current medications

0.36

13 (41%)

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Hispanic

58 (15)

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Age, yrs

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(n=147)

50 (34%)

0.09

22 (69%)

99 (67%)

0.16

7 (22%)

30 (21%)

0.18

Aldosterone antagonist

17 (53%)

61 (42%)

0.08

Beta blocker

30 (94%)

138 (94%)

0.3

9 (28%)

63 (43%)

0.05

31 (97%)

117 (80%)

0.01

13 (41%)

40 (27%)

0.05

Sodium, mmol/L

138.3 (3.7)

138.4 (3.3)

0.79

BUN, mg/dL

22 (17, 26)

22 (17, 33)

0.96

1.2 (1.0, 1.6)

1.2 (0.9, 1.5)

0.58

64 (42, 80)

62 (46, 86)

0.64

1502 (585, 4180)

1276 (556, 4155)

0.75

30 (20, 36)

25 (20, 31)

0.29

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inhibitor

Diuretic

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Digoxin

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Angiotensin receptor antagonist

High-dose diuretic

Creatinine, mg/dL Estimated GFR, mL/min NT-proBNP, pg/mL Left ventricular ejection fraction, %

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Systolic blood pressure, mmHg

117.5 (16.7)

118.2 (18.5)

0.69

Diastolic blood pressure, mmHg

67.9 (13.8)

68.7 (12.1)

0.67

Pulse Pressure

49.9 (14.2)

48.7 (12.8)

0.44

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0.13

13 (41%)

Body mass index, kg/m2

31.2 (7.7)

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Estimated hemodynamic profile

68 (46%)

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Systolic blood pressure <115 mmHg

30.3 (8.1)

14 (44%)

103 (70%)

B

15 (47%)

36 (24%)

C

1 (3%)

1 (1%)

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A

L

2 (6%)

New York Heart Association

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Classification

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NYHA class I

NYHA class III NYHA class IV

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NYHA class II

0.49 0.03

7 (5%) <0.0001

0 (0%)

22 (15%)

0 (0%)

48 (33%)

9 (28%)

56 (38%)

23 (72%)

21 (14%)

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Data are presented as mean (SD), median (IQR) or number (%). ADL = activities of daily living; GFR = glomerular filtration rate; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association Classification.

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ACCEPTED MANUSCRIPT Univariate regression models of bendopnea and outcomes

Outcome

Number of events

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1 month

Hazard ratio

Death

P-value

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TABLE 2.

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N/A

N/A

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3.1 (1.2, 8.1)

0.02

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3.1 (1.2, 8.1)

0.02

18

3.1 (1.2, 8.1)

0.02

5

3.2 (0.5, 19.2)

0.21

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3.1 (1.4, 6.8)

0.004

Composite of death and HF admission

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3.1 (1.5, 6.6)

0.003

Composite of death, HF admission, inotrope initiation,

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3.1 (1.5, 6.6)

0.003

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2.4 (0.4, 13.1)

0.31

30

2.7 (1.3, 5.8)

0.01

Composite of death and HF admission

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2.7 (1.3, 5.7)

0.007

Composite of death, HF admission, inotrope initiation,

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2.7 (1.3, 5.7)

0.007

Death

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2.5 (0.7, 8.4)

0.13

HF admission

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1.9 (0.9, 3.7)

0.07

Composite of death and HF admission

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1.8 (0.9, 3.4)

0.08

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HF admission

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Composite of death and HF admission Composite of death, HF admission, inotrope initiation,

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LVAD, transplant 3 months

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Death

LVAD, transplant

Death HF admission

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6 months

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HF admission

LVAD, transplant 1 year

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ACCEPTED MANUSCRIPT Composite of death, HF admission, inotrope initiation,

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1.9 (1.01, 3.5)

0.046

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LVAD, transplant

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ACCEPTED MANUSCRIPT FIGURE 1A. HF Admission

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FIGURE 1B. Composite of death or HF admission

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FIGURE 1C. Composite of death, HF admission, inotrope initiation, LVAD implantation, cardiac transplant

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