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Relationship of Right- to Left-Ventricular Filling Pressures in Advanced Heart Failure:

Insights from the ESCAPE Trial

Drazner et al: Ratio of RAP to PCWP in Advanced Heart Failure

Mark H. Drazner*, MD, MSc; Mariella Velez-Martinez*, MD; Colby Ayers†, MS;

Sharon C. Reimold*, MD; Jennifer T. Thibodeau*, MD; Joseph D. Mishkin*, MD;

Pradeep P.A. Mammen*, MD; David W. Markham*, MD; Chetan B. Patel‡, MD

Division of Cardiology*, Department of Internal Medicine, and Department of Biostatistics†,

University of Texas Southwestern Medical Center, Dallas, TX

Division of Cardiology‡, Duke University Medical Center, Durham, NC

Correspondence to: Mark Drazner, MD, MSc University of Texas Southwestern Medical Center 5323 Harry Hines Blvd, Dallas, Texas, 75390-9047 E-mail: [email protected] Telephone: 214-645-7500 Fax: 214-645-7501

DOI: 10.1161/CIRCHEARTFAILURE.112.000204

Journal Subject Codes: Heart failure: [11] Other heart failure

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Abstract

Background—Although right atrial pressure (RAP) and pulmonary capillary wedge pressure

(PCWP) are correlated in heart failure, in a sizeable minority of patients the RAP and PCWP are not

tightly coupled. The basis of this variability in the RAP to PCWP ratio, and whether it conveys

prognostic value, is not known.

Methods and Results—We analyzed the Evaluation Study of Congestive Heart Failure and

Pulmonary Artery Catheterization Effectiveness (ESCAPE) database. Baseline characteristics

including echocardiographic assessment of right ventricular (RV) structure and function, and

invasively measured hemodynamic parameters, were compared among tertiles of the RAP/PCWP

ratio. Multivariable Cox proportional hazard models assessed the association of RAP/PCWP ratio

with the primary ESCAPE outcome [6-month death or hospitalization (days)] adjusting for systolic

blood pressure, BUN, six minute walk distance, and PCWP. The RAP/PCWP tertiles were: 0.27-0.4

(tertile 1); 0.41-0.615 (tertile 2), and 0.62-1.21(tertile 3). Increasing RAP/PCWP was associated with

increasing median right atrial area (23, 26, 29 cm2, respectively, p<0.005), RV area in diastole (21,

27, 27 cm2, respectively, p<0.005), and pulmonary vascular resistance (2.4, 2.9, 3.6 woods units,

respectively, p=0.003), and lower RV stroke work index (8.6, 8.4, 5.5 g-m/m2 per beat, respectively,

p<0.001). RAP/PCWP ratio was associated with death or hospitalization within 6 months [HR 1.16

(1, 1.4), p<0.05].

Conclusions—Increased RAP/PCWP ratio was associated with higher pulmonary vascular

resistance, reduced RV function (manifest as a larger right atrium and ventricle and lower RV stroke

work index), and an increased risk of adverse outcomes in patients with advanced heart failure.

Key Words: hemodynamics, heart failure, right ventricle, renal function, pulmonary hypertension

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Elevated right-ventricular and left-ventricular filling pressures contribute to many of the

symptoms of patients with advanced heart failure. In both systolic1 and diastolic2 heart failure,

right-ventricular filling pressure (i.e., right atrial pressure, RAP) is significantly correlated to

left-ventricular filling pressure (i.e., pulmonary capillary wedge pressure, PCWP). This

relationship is robust enough such that estimation of the PCWP is often based upon assessment

of the jugular venous pressure (JVP) in patients with heart failure.3 Further, the relationship of

the RAP and PCWP has been shown to be stable over a 14 year time period (1993 to 2007) in the

Cardiac Transplant Research Database (CTRD), a registry of patients with advanced heart failure

undergoing cardiac transplantation.4 However, in a sizeable minority of patients with heart

failure (25-30%), the RAP and PCWP are not tightly coupled.4, 5 The basis of the variability in

the relationship of right- to left-sided ventricular filling pressures (which can be expressed as the

ratio of the RAP to PCWP)4 is not well understood. Further, whether the ratio of the RAP to

PCWP is associated with outcome in the broader advanced heart failure population, as it is in

patients undergoing left ventricular assist device implantation6 or cardiac transplantation,4 has

not previously been assessed to our knowledge. The ESCAPE (Evaluation Study of Congestive

Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial, in which patients with

advanced heart failure underwent careful hemodynamic and echocardiographic assessment, as

well as longitudinal follow-up, afforded an excellent opportunity to further define the

physiologic basis and prognostic utility of the ratio of RAP to PCWP in this patient population.

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Methods

ESCAPE Trial

The ESCAPE trial assessed the effectiveness of right heart catheterization in hospitalized

patients with New York Heart Association (NYHA) IV symptomatic heart failure. Patients had

to have left ventricular ejection fraction 30%, 3 months of symptoms despite ACE-inhibitor

and diuretic therapy, a systolic blood pressure 125 mm Hg, and at least one sign and one

symptom of congestion. Of the 433 patients randomly assigned, 215 were assigned to the

pulmonary artery catheter arm. The trial was conducted in the United States and Canada between

2000 and 2003 at 26 sites. The primary results of the trial have been published.7 The protocols

were approved at each site and written informed consent was obtained from all patients prior to

randomization. This analysis was conducted with a public release of the ESCAPE database.

Right heart catheterization and hemodynamic classification

The sites participating in ESCAPE were selected for known expertise in invasive monitoring and

clinical management of patients with HF. Paper printouts were used for hemodynamic

measurements. Cardiac output was measured by thermodilution in triplicate. In this analysis, we

assessed both the initial hemodynamics and the final hemodynamics at right heart catheter

removal. The average length of time the right heart catheter was in place was 1.9 days. We

excluded three patients due to measurements that were extreme outliers possibly due to

erroneous data entry: two with baseline RAPs of 71 and 85 mm Hg, respectively, and one with

PCWP of 0 mm Hg. Subjects were classified into tertiles of the ratio of RAP to PCWP: 0.27 to

0.40 (tertile 1); 0.41 to 0.61 (tertile 2); and 0.62 to 1.21 (tertile 3).

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Echocardiography

Details of components of the echocardiographic examination in ESCAPE have been published.8

In brief, echocardiograms were performed within 24 hours of right heart catheterization.

Echocardiograms were analyzed at the core center at the University of Texas Southwestern

Medical Center. Measurements were performed offline by a single sonographer or physician in

accordance with the criteria of the American Society of Echocardiography, and were made in

triplicate and averaged. Measurements were obtained from the apical 4-chamber view (right

atrial area, RV area at end-diastole and end-systole, left atrial area, mitral regurgitant color jet

area, and left ventricular end-diastolic and end-systolic volumes by Simpson’s method of discs),

and subcostal view (inferior vena cava size in inspiration and expiration). Derived measures

included left ventricular ejection fraction, right ventricular fractional shortening [(RV area

diastole- RV area systole)/RV area diastole], and the ratio of the mitral regurgitant color jet area

to the left atrial area.

Variable definitions

Creatinine clearance was estimated by the Modification of Diet in Renal Disease equation.9

Transpulmonary gradient was calculated as mean pulmonary artery-PCWP. Pulmonary vascular

resistance was calculated as transpulmonary gradient/cardiac output. Right ventricular stroke

work index was calculated as (cardiac index/heart rate) x (mean pulmonary artery pressure-mean

RAP) x 13.6. Pulmonary compliance was calculated as stroke volume/(PA systolic pressure-PA

diastolic pressure).10

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Statistics

Data are presented as median (interquartile range) or number (percentage). To compare

characteristics across ordinal, increasing tertiles of baseline RAP/PCWP, we used the Cochran-

Armitage trend test for categorical variables and the Jonckheere-Terpstra trend test for

continuous data. The chi-squared statistic was used to assess any overall racial significance.

Spearman correlation coefficients were calculated between baseline RAP/PCWP and other

invasively measured hemodynamics. Outcome analysis was with the primary outcome of

ESCAPE, number of days alive outside the hospital at 180 days post randomization. In a

secondary analysis, we used overall morality as an outcome. Patients who underwent

LVAD/transplant were treated as dead in 1 analysis and were censored in another analysis. For

the outcomes analysis, we excluded patients who were lost to follow-up (N=5). After observing

no trends with time for the Schoenfeld residuals, Cox proportional hazards models were used to

assess hazard ratios for a 1 standard deviation increase in the RAP/PCWP ratio in both

unadjusted and adjusted analyses. For the adjusted analyses, model 1 adjusted for six minute

walk, BUN, Systolic blood pressure. Model 2 adjusted for the covariates in model 1 with the

addition of PCWP. Two-sided probability values (p-value) were used in all statistical analysis

with a p-value <0.05 considered statistically significant. All statistical analyses were performed

using SAS (v. 9.2; SAS Institute, Inc., Cary, North Carolina).

Results

The distribution of the ratio of the RAP/PCWP is shown (Figure 1). The median (interquartile

range) was 0.50 (0.37, 0.68). The RAP was significantly correlated with the PCWP (r=0.59,

p<0.001). The ratio RAP/PCWP measured on the initial hemodynamics was significantly

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correlated to that measured on the hemodynamics measured at the time of right heart catheter

removal (r=0.49, p<0.001). Of subjects with baseline RAP/PCWP tertile 1, 12% had shifted to

RAP/PCWP tertile 3 when hemodynamics were reassessed prior to right heart catheterization

removal. Similarly, 11% of subjects with baseline RAP/PCWP tertile 3 shifted to final

RAP/PCWP tertile 1 (Table 1).

Relationship of baseline characteristics and renal function to RAP/PCWP ratio

Baseline characteristics are shown by tertile of RAP/PCWP (Table 2). Increasing RAP/PCWP

was associated with impaired renal function as evidenced by a higher baseline creatinine and

BUN and a lower creatinine clearance. Increasing RAP/PCWP was also associated with the

maximum in-hospital BUN (28, 33, 40 mg/dl), discharge BUN (25, 34, 35 mg/dl), and discharge

creatinine (1.2, 1.5, 1.6 mg/dl), respectively (p 0.005 for all). Increasing RAP/PCWP was also

associated with signs of right sided heart failure including elevated jugular venous pressure,

ascites and peripheral edema. In contrast, there was no association of elevated RAP/PCWP with

orthopnea and other clinical predictors associated with worse outcomes such as NYHA class and

systolic blood pressure.

Relationship of invasively-measured hemodynamics to RAP/PCWP ratio

Invasively measured hemodynamics (Table 3) are shown by tertile RAP/PCWP. Increasing

RAP/PCWP was associated with a higher right atrial pressure but was not associated with

pulmonary capillary wedge pressure. Subjects with a higher RAP/PCWP also had a higher mean

PA pressure, transpulmonary gradient, and pulmonary vascular resistance than those with a

lower RAP/PCWP. Cardiac index and RV stroke work index were lower in those with higher

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RAP/PCWP. In correlation analysis, RAP/PCWP ratio correlated significantly with RAP

(r=0.78, p<0.001), transpulmonary gradient (r=0.24, p=0.001), pulmonary vascular resistance

(r=0.23, p=0.002), cardiac index (r=-0.15, p<0.05), and RV stroke work index (r=-0.43,

p<0.001), but not PCWP (r=0.01, p=0.9). In a subgroup analysis restricted to subjects with a

PCWP 22 mm Hg, similar associations of RAP/PCWP ratio with invasively measured

hemodynamics were found including increasing PVR among those with increasing RAP/PCWP:

2.4 (tertile 1); 3 (tertile 2); 4.3 Wood units (tertile 3), P<0.001 (other data not shown). There was

no difference in administration of milrinone (p=0.75), nitroprusside (p=0.15) or dobutamine

(p=0.6) among tertiles RAP/PCWP.

Relationship of echocardiographic parameters to RAP/PCWP ratio

Echocardiographic parameters are shown among tertile RAP/PCWP at baseline (Figure 2).

Subjects with a higher RAP/PCWP ratio had echocardiographic markers of right ventricular

dysfunction including a larger right atrial area, right ventricular area in both systole and diastole,

and a larger inferior vena cava both in inspiration and expiration. There was no significant

association of RAP/PCWP ratio with right ventricular fractional shortening (0.25 [0.2, 0.3] tertile

1; 0.2 [0.13, 0.29] tertile 2; 0.21 [0.15, 0.28] tertile 3, p=0.2). There was also no significant

association of the RAP/PCWP ratio with left atrial area, tricuspid regurgitation velocity, LV end-

diastolic or end-systolic volume, LV ejection fraction, or ratio of mitral regurgitation to left atrial

area (p 0.2 for all; data not shown).

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Relationship of RAP/PCWP ratio and outcome

The association of the baseline and final RAP/PCWP with six-month outcome (Table 4) is

shown. In the whole cohort, increasing baseline RAP/PCWP was associated with death or

hospitalization (days) in a model adjusted for six minute walk, systolic blood pressure, BUN, and

pulmonary capillary wedge pressure. The correlation between RAP/PCWP and PCWP was

statistically insignificant, and thus multicollinearity was not an issue. In the subgroup of subjects

who had elevated PCWP ( 22 mm Hg), increasing baseline RAP/PCWP was associated with

death or hospitalization (days) both in univariate and multivariable analysis. In analyses in which

the final RAP/PCWP ratio was substituted for the baseline RAP/PCWP, qualitatively similar

associations with outcome were noted. In our secondary analysis using six-month mortality as

the outcome, the event rate in increasing baseline RAP/PCWP was 16% (tertile 1), 21% (tertile

2), 29% (tertile 3), p=0.09.

Discussion

Although right-ventricular and left-ventricular filling pressures are significantly correlated in

patients with advanced heart failure, there is a large distribution of the RAP/PCWP ratio. The

basis for the variability of this trait (RAP/PCWP ratio) is not well understood, nor is its

prognostic utility. In the ESCAPE trial which enrolled patients with advanced heart failure

selected for signs and symptoms of congestion, most of whom had elevated PCWPs, increasing

RAP/PCWP ratio resulted from increasing RAP. Subjects with a low RAP/PCWP ratio had

better right ventricular function as assessed by several echocardiographic measures (including

smaller right atrial and right ventricular area) and by the right ventricular stroke work index,

while those with a higher RAP/PCWP ratio had a higher pulmonary vascular resistance.

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Additionally, an elevated RAP/PCWP ratio was associated with a lower cardiac index and

impaired renal function at baseline and with a worse outcome at 6 months.

Whether the RAP/PCWP ratio is a stable and reproducible parameter in patients with

heart failure is not well known. In the CTRD, there was a significant correlation (r=0.33) of the

RAP/PCWP ratio when measured at least 1 day apart (median time 188 days).4 In the present

study, we confirmed this finding in patients with decompensated, advanced heart failure. In the

ESCAPE trial, the correlation between ratios of RAP/PCWP measured ~1.9 days apart was 0.49

(p<0.001). Additionally, there was relatively little shifting (11-12% of subjects) between tertiles

1 and 3 from baseline to final hemodynamic assessment. Together, these data suggest that the

RAP/PCWP ratio does, in part, reflect an underlying intrinsic trait in patients with advanced

heart failure.

The ratio RAP/PCWP can be influenced by changes in either the RAP or the PCWP. In

the ESCAPE trial, a high RAP/PCWP occurred on the basis of an elevated RAP rather than a

reduced PCWP (Table 3). In addition to a higher measured RAP, subjects in the highest tertile of

RAP/PCWP ratio also had clinical findings that provided confirmation of an elevated RAP

including more severe peripheral edema and ascites, and an elevated jugular venous pressure. In

contrast, in the CTRD, subjects in the highest quartile of RAP/PCWP ratio not only had the

highest RAP but they also had the lowest PCWP.4 This difference is likely due to the selection of

patients for the ESCAPE trial on the basis of signs and symptoms of congestion.

To our knowledge, only two prior studies have attempted to determine characteristics

associated with the relationship of the RAP to PCWP in patients with heart failure.4, 5 In a cohort

of patients with advanced heart failure undergoing cardiac transplant evaluation, female gender

was the only characteristic found to be associated with the RAP to PCWP relationship as

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assessed by 4 categories based on whether the RAP was 10 mm Hg and PCWP 22 mm Hg.5

In the present study, female gender was not associated with RAP/PCWP ratio. Also in contrast to

the present study, renal dysfunction, PVR, cardiac index, and echocardiographic assessment of

RV dysfunction were not significantly different among the four hemodynamic profiles in the

prior study.5 We postulate that this difference is in part based on the analytic approach used; i.e.,

a hemodynamic classification based on dichotomous values of RAP and PCWP or via the

RAP/PCWP ratio. Nevertheless, both studies demonstrated significant variability in the

relationship of right and left ventricular filling pressures in patients with advanced heart failure.

In the CTRD, increasing quartile of RAP/PCWP was associated with younger age,

female gender, etiology of cardiomyopathy other than idiopathic or ischemic, increased number

of prior sternotomies, higher PVR, lower CI, and lower creatinine clearance.4 In the present

study, age was not associated with the RAP/PCWP ratio. This difference may be due to inclusion

of a broader range of patients in the CTRD (e.g., complex congenital heart disease) than in the

ESCAPE trial. In the ESCAPE database, the number of prior sternotomies was not captured. The

present study confirmed the association of increasing RAP/PCWP with declining renal function,

reduced cardiac index, and higher PVR first reported in the CTRD,4 indicating that these

associations warrant further discussion.

Increasingly, it is recognized that systemic venous congestion is an important contributor

to the cardiorenal syndrome.11, 12 In the ESCAPE trial, an elevated RAP previously was shown to

be weakly correlated with baseline renal function13 consistent with the findings of the present

study. Here we show that impaired renal function was prominent when right- and left-sided

ventricular filling pressures began to approximate one another. In such subjects, pericardial

constraint may lead to exaggerated diastolic ventricular interaction.14, 15 This pathophysiology

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may mediate the reduction in cardiac index associated with increasing RAP/PCWP ratio. A

disproportionately elevated RAP in relationship to the PCWP may therefore represent one

“hemodynamic signature” of patients with advanced systolic heart failure and cardiorenal

syndrome, and suggests that consideration of the right-left relationship may be important when

considering therapeutic strategies for treating congestion in heart.

The RAP/PCWP ratio also appears to have important relationships to the pulmonary

vasculature and the performance of the right ventricle. Increasing RAP/PCWP ratio was found to

be a marker for RV failure manifested by an enlarged right atrial area, enlarged right ventricular

area (both in systole and diastole) and a lower RV stroke work index. The RAP/PCWP ratio was

not associated with left ventricular volumes, ejection fraction, or severity of mitral regurgitation,

further emphasizing that this ratio reflected right ventricular performance. The hemodynamic

data also suggest that the RAP/PCWP ratio was related to changes in the pulmonary vasculature

because increasing RAP/PCWP ratio was associated with a higher PVR despite a similar PCWP

in each tertile. It is well known that there is variability in the increase of the pulmonary artery

pressure and PVR in response to an elevated PCWP in patients with heart failure. The basis of

this variability is not yet well understood16 but pulmonary hypertension is now being tested as a

therapeutic target in patients with heart failure.17 We hypothesize that an exaggerated response in

the pulmonary vasculature in response to an elevated PCWP (i.e., an increased PVR) is a

proximal pathophysiological event, leading to RV dysfunction and subsequently an increased

RAP/PCWP ratio. Studies with serial imaging and hemodynamic assessments are needed to test

this hypothesis.

Whether the ratio of RAP/PCWP is associated with outcome in patients with heart failure

has not previously been investigated to our knowledge. A high RAP/PCWP ratio was associated

ndex. The RAP/P/P/PP/PP P

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with worse outcomes in patients with advanced heart failure who undergo LVAD implantation6

or transplantation.4 An elevated jugular venous pressure, consistent with a high RAP, has been

shown to be an independent risk factor for outcome in patients with NYHA class II-III heart

failure.18 In the ESCAPE trial (Table 4), a high baseline RAP to PCWP ratio was associated

with adverse events at 6 months as assessed by the primary outcome of the ESCAPE trial

(number of days alive outside the hospital) but not with crude mortality. A lack of association

with mortality may represent limited power given that a higher RAP/PCWP ratio was associated

with markers of RV dysfunction and with impaired renal function, both well known risk factors

for adverse outcomes in heart failure.19-22 The final RAP/PCWP was similarly associated with

the primary ESCAPE outcome. The association of increasing RAP/PCWP ratio with outcome

was more consistent in those with a PCWP 22 mm Hg, highlighting the importance of assessing

this ratio in patients whom have elevated left-sided ventricular filling pressures. Overall, these

findings reinforce the importance of RV function in patients with advanced heart failure.

Limitations

This was a retrospective analysis. The associations of RAP/PCWP with death and hospitalization

did not reach conventional levels of statistical significance in all models, perhaps because the

overall size of the cohort in ESCAPE who underwent right heart catheterization was relatively

small. As such, the prognostic utility of the RAP/PCWP ratio needs to be validated in other,

larger datasets.

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Conclusions

In patients with advanced heart failure selected for signs and symptoms of congestion, there was

a wide distribution in the ratio of RAP to PCWP. A high RAP/PCWP ratio was associated with a

high RAP, underlying RV dysfunction in the setting of an elevated pulmonary vascular

resistance, and was an adverse prognostic finding associated with impaired renal function and a

worse 6-month outcome.

Sources of Funding

Dr. Drazner is supported by the James M. Wooten Chair in Cardiology at UT Southwestern

Medical Center.

Disclosures

None.

References

1. Drazner MH, Hamilton MA, Fonarow G, Creaser J, Flavell C, Stevenson LW. Relationship between right and left-sided filling pressures in 1000 patients with advanced heart failure. J Heart Lung Transplant. 1999;18:1126-32. 2. Drazner MH, Prasad A, Ayers C, Markham DW, Hastings J, Bhella PS, Shibata S, Levine BD. The relationship of right- and left-sided filling pressures in patients with heart failure and a preserved ejection fraction. Circulation: Heart Fail. 2010;3:202-6. 3. Drazner MH, Hellkamp AS, Leier CV, Shah MR, Miller LW, Russell SD, Young JB, Califf RM, Nohria A. Value of clinician assessment of hemodynamics in advanced heart failure: the ESCAPE trial. Circulation: Heart Fail. 2008;1:170-7. 4. Drazner MH, Brown RN, Kaiser PA, Cabuay B, Lewis NP, Semigran MJ, Torre-Amione G, Naftel DC, Kirklin JK. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. The J Heart Lung Transplant. 2012;31:67-72. 5. Campbell P, Drazner MH, Kato M, Lakdawala N, Palardy M, Nohria A, Stevenson LW. Mismatch of right- and left-sided filling pressures in chronic heart failure. J Card Fail. 2011;17:561-8.

iology at UT SSSSSSSooooo

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6. Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, Massey T, Milano CA, Moazami N, Sundareswaran KS, Farrar DJ. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thor Cardiovasc Surg. 2010;139:1316-24. 7. Binanay C, Califf RM, Hasselblad V, O'Connor CM, Shah MR, Sopko G, Stevenson LW, Francis GS, Leier CV, Miller LW. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294:1625-33. 8. Palardy M, Stevenson LW, Tasissa G, Hamilton MA, Bourge RC, Disalvo TG, Elkayam U, Hill JA, Reimold SC. Reduction in mitral regurgitation during therapy guided by measured filling pressures in the ESCAPE trial. Circulation: Heart Fail. 2009;2:181-8. 9. O'Meara E, Chong KS, Gardner RS, Jardine AG, Neilly JB, McDonagh TA. The Modification of Diet in Renal Disease (MDRD) equations provide valid estimations of glomerular filtration rates in patients with advanced heart failure. Eur J Heart Fail. 2006;8:63-7. 10. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125:289-97. 11. Tedford RJ, Hassoun PM, Mathai SC, Girgis RE, Russell SD, Thiemann DR, Cingolani OH, Mudd JO, Borlaug BA, Redfield MM, Lederer DJ, Kass DA. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53:589-96. 12. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol. 2009;53:582-8. 13. Nohria A, Hasselblad V, Stebbins A, Pauly DF, Fonarow GC, Shah M, Yancy CW, Califf RM, Stevenson LW, Hill JA. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51:1268-74. 14. Applegate RJ, Johnston WE, Vinten-Johansen J, Klopfenstein HS, Little WC. Restraining effect of intact pericardium during acute volume loading. Am J Physiol. 1992;262:H1725-33. 15. Atherton JJ, Moore TD, Lele SS, Thomson HL, Galbraith AJ, Belenkie I, Tyberg JV, Frenneaux MP. Diastolic ventricular interaction in chronic heart failure. Lancet. 1997;349:1720-4. 16. Guazzi M, Arena R. Pulmonary hypertension with left-sided heart disease. Nature Rev Cardiol. 2010;7:648-59. 17. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study. Circulation. 2011;124:164-74. 18. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. N Engl J Med. 2001;345:574-81. 19. Fonarow GC, Adams KF, Jr., Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA. 2005;293:572-80. 20. Di Salvo TG, Mathier M, Semigran MJ, Dec GW. Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure. J Am Coll Cardiol. 1995;25:1143-53.

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89-96. H

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21. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001;37:183-8. 22. O'Connor CM, Hasselblad V, Mehta RH, Tasissa G, Califf RM, Fiuzat M, Rogers JG, Leier CV, Stevenson LW. Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score. J Am Coll Cardiol. 2010;55:872-8.


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Table 1. Relationship of the baseline to final RAP/PCWP tertile

Final RAP/PCWP tertile

T1 T2 T3

Baseline

RAP/PCWP

tertile

T1 27 (54%) 17 (34%) 6 (12%)

T2 16 (34%) 15 (32%) 16 (34%)

T3 5 (11%) 16 (35%) 25 (54%)

Data are presented as number (% of subjects within baseline RAP/PCWP tertile who were within

denoted final RAP/PCWP tertile).


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Table 2. Baseline characteristics by baseline ratio of RAP to PCWP

Tertile RAP/PCWP P

1 2 3

N=63 N=62 N=63

Age, y 57 [47, 63] 58 [50, 66] 59 [48, 70] 0.14

Ethnicity: White 35 (56%) 39 (63%) 36 (57%) 0.7

Male 42 (67%) 48 (77%) 49 (78%) 0.16

Ischemic etiology 35 (56%) 31 (50%) 33 (52%) 0.7

Idiopathic etiology 21 (33%) 22 (36%) 23 (37%) 0.7

Hypertension 32 (51%) 28 (45%) 32 (51%) 1.000

Diabetes 14 (24%) 25 (40%) 22 (36%) 0.2

NYHA class IV 60 (95%) 54 (87%) 55 (87%) 0.1

JVP 8 cm 47 (77%) 59 (98%) 59 (97%) 0.0002

Ascites moderate 1 (2%) 11 (18%) 16 (25%) 0.0002

Peripheral edema 2+ 9 (14%) 28 (45%) 39 (62%) <.0001

Orthopnea 2 pillows 54 (86%) 50 (81%) 51 (82%) 0.6

Systolic blood pressure, mm Hg 111 [97, 120] 108 [98, 116] 109 [98, 120] 0.7

Heart rate, bpm 81 [71, 91] 79 [67, 91] 81 [69, 91] 0.8

Body mass index, kg/m2 25 [22, 30] 27 [24, 32] 29 [24, 35] 0.03

Creatinine, mg/dL 1.3 [0.9, 1.6] 1.5 [1.1, 1.8] 1.5 [1.2, 2] 0.004

CrCl, ml/min 62 [41, 91] 52 [44, 67] 52 [37, 68] 0.010

BUN, mg/dL 26 [16, 33] 33 [22, 51] 30 [22, 49] 0.003

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Table 3. Association of baseline RAP to PCWP ratio with invasively measured hemodynamics

Tertile RAP/PCWP P

1 2 3

Right atrial pressure, mm Hg 6 [4, 8] 13.5 [11, 17] 20 [13, 23] <.0001

Pulmonary capillary wedge pressure, mm Hg 23 [18, 30] 25 [22, 32] 24 [19, 30] 0.7

Pulmonary artery systolic, mm Hg 50 [40, 60] 58 [50, 70] 52 [42, 67] 0.08

Pulmonary artery diastolic, mm Hg 24 [18, 29] 29 [25, 36] 25 [20, 35] 0.02

Mean pulmonary artery pressure, mm Hg 42 [33, 49] 49 [42, 56] 45 [35, 57] 0.049

Transpulmonary gradient, mm Hg 9 [7, 12] 12 [8, 15] 13 [9, 17] 0.001

Pulmonary vascular resistance, WU 2.4 [1.8, 3.4] 2.9 [2, 4.1] 3.6 [2, 4.7] 0.003

Cardiac output, liters/min 3.9 [3, 4.5] 3.9 [3.2, 4.6] 3.3 [2.8, 4.9] 0.2

Cardiac index, liters/min/m2 2.1 [1.7, 2.3] 1.9 [1.7, 2.3] 1.8 [1.5, 2.2] 0.049

Mixed venous saturation, % 60 [44, 67] 54 [41, 62] 55 [44, 68] 0.45

Stroke volume, ml 47 [39, 56] 51 [41, 63] 44 [33, 60] 0.6

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Systemic vascular resistance, dyne-sec-cm-5 1387 [1042, 1664] 1310 [1089, 1596.5] 1322 [848, 1987] 0.9

Right ventricular stroke work index, g-m/m2 per beat 8.6 [6.9, 12] 8.4 [6.1, 11] 5.5 [4, 7.6] <.0001

Pulmonary arterial compliance, ml/mm Hg 1.83 [1.33, 2.58] 1.61 [1.3, 2.47] 1.65 [1.14, 2.27] 0.25


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Table 4. Association of the RAP to PCWP ratio with death or hospitalization (days) at 6 months

Whole cohort* Subgroup PCWP 22 mm Hg*

Transplant/LVAD

count as dead

Transplant/LVAD

count as alive

Transplant/LVAD

count as dead

Transplant/LVAD

count as alive

HR (95% CI) P Value HR (95% CI) P value HR (95% CI) P Value HR (95% CI) P value

Baseline RAP/PCWP

Unadjusted 1.1 (0.97, 1.3) 0.14 1.12 (0.97, 1.3) 0.14 1.18 (1, 1.4) <0.05 1.2 (1.01, 1.4) 0.04

Adjusted

Model 1

1.13 (0.97, 1.3) 0.12 1.14 (0.99, 1.3) 0.08 1.18 (0.98, 1.4) 0.08 1.2 (1, 1.5) <0.05

Adjusted

Model 2

1.16 (1, 1.4) <0.05 1.19 (1.02, 1.4) 0.03 1.2 (1.02, 1.5) 0.03 1.3 (1.04, 1.5) 0.02

Final RAP/PCWP

Unadjusted 1.2 (1.1, 1.5) 0.001 1.3 (1.1, 1.5) 0.009 1.8 (1.2, 2.8) 0.009 1.8 (1.1, 2.7) 0.01

Adjusted 1.17 (0.99, 1.3) 0.07 1.17 (0.99, 1.4) 0.07 1.8 (1.1, 3.1) 0.03 1.8 (1.05, 3.1) 0.03

PP

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Model 1

Adjusted

Model 2

1.19 (.99, 1.4) 0.06 1.19 (0.99, 1.4) 0.06 1.7 (1.01, 3) 0.04 1.7 (0.99, 3) 0.05

*Whole cohort: N=183 for baseline RAP/PCWP; N=137 for final RAP/PCWP; Subgroup PCWP 22 mm Hg: N=137 for baseline

RAP/PCWP; N=35 for final RAP/PCWP.

Model 1 adjusted for six minute walk, BUN, Systolic blood pressure.

Model 2 adjusted for six minute walk, BUN, systolic blood pressure, PCWP.

Hazard ratios in whole cohort shown are for unit ratio change (1 standard deviation) baseline RAP/PCWP=0.235; for final

RAP/PCWP=0.306. Hazard ratios for subgroup PCWP 22 mm Hg are for unit ratio change (1 standard deviation) baseline

RAP/PCWP 0.235; for final RAP/PCWP 0.20.

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Figure Legends

Figure 1. The distribution of the RAP/PCWP ratio in the study cohort. RAP = right atrial

pressure; PCWP = pulmonary capillary wedge pressure

Figure 2. Association of echocardiographic measures of right ventricular dysfunction with

RAP/PCWP ratio (tertiles).

A. Right atrial area

B. Right ventricular area (diastole)

C. Right ventricular area (systole)

D. Inferior vena cava size (expiration)

E. Inferior vena cava size (inspiration).

Data are presented as box-and-whisker plots.

RAP/PCWP ratios were Tertile 1 (T1): 0.27-0.4; Tertile 2 (T2): 0.41-0.61; Tertile 3 (T3): 0.62 –

1.21.

*P<0.005 † P<0.01

area (systole)

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Joseph D. Mishkin, Pradeep P.A. Mammen, David W. Markham and Chetan B. PatelMark H. Drazner, Mariella Velez-Martinez, Colby Ayers, Sharon C. Reimold, Jennifer T. Thibodeau,

from the ESCAPE TrialRelationship of Right- to Left-Ventricular Filling Pressures in Advanced Heart Failure: Insights

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online February 7, 2013;Circ Heart Fail.

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