Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients With Systolic Heart Failure: The Henry Ford Hospital Cardiopulmonary Exercise Testing (FIT-CPX) Project

Accepted Manuscript Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients with Systolic Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) Project Clinton A. Brawner, PhD, Ali Shafiq, MD, Heather A. Aldred, PhD, Jonathan K. Ehrman, PhD, Eric S. Leifer, PhD, Yelena Selektor, MD, Christina Tita, MD, Mauricio Velez, MD, Celeste T. Williams, MD, John R. Schairer, DO, David E. Lanfear, MD, Steven J. Keteyian, PhD PII:

S1071-9164(15)00176-1

DOI:

10.1016/j.cardfail.2015.06.001

Reference:

YJCAF 3519

To appear in:

Journal of Cardiac Failure

Received Date: 21 October 2014 Revised Date:

1 June 2015

Accepted Date: 1 June 2015

Please cite this article as: Brawner CA, Shafiq A, Aldred HA, Ehrman JK, Leifer ES, Selektor Y, Tita C, Velez M, Williams CT, Schairer JR, Lanfear DE, Keteyian SJ, Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients with Systolic Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) Project, Journal of Cardiac Failure (2015), doi: 10.1016/j.cardfail.2015.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure | 1

Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients with

Project

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Systolic Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX)

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Brawner; Cardiopulmonary Exercise Testing in Heart Failure

Clinton A. Brawner, PhD1; Ali Shafiq, MD2; Heather A. Aldred, PhD1; Jonathan K. Ehrman, PhD1; Eric

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S. Leifer, PhD3; Yelena Selektor, MD1; Christina Tita, MD1; Mauricio Velez, MD1; Celeste T. Williams, MD1; John R. Schairer, DO1; David E. Lanfear, MD1; Steven J. Keteyian, PhD1

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Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, Michigan 2

Saint Luke’s Mid America Heart Institute, Kansas City, Missouri

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Office of Biostatistics Research, National Heart Lung, and Blood Institute, Bethesda, Maryland

Correspondence:

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Clinton A. Brawner, PhD

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Preventive Cardiology, Henry Ford Hospital 6525 Second Ave.

Detroit, MI, 48202 USA

W: 313.972.4108; F: 313.972.4138 [email protected]

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ABSTRACT Background: Many studies have shown a strong association between numerous variables from a

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cardiopulmonary exercise (CPX) test and prognosis in patients with heart failure with reduced ejection fraction (HFrEF). However, few studies have compared the prognostic value of a

majority of these variables simultaneously, thus controversy remains on optimal interpretation.

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Methods and Results: This was a retrospective analysis of patients with HFrEF (n = 1,201; 33% female; age = 55 ± 13 y) and a CPX test between 1997 and 2010. Thirty variables from a CPX

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test were considered in separate adjusted Cox regression analyses to describe the strength of the relation of each to a composite endpoint of all-cause mortality, left ventricular assist device implant, or heart transplant. During a median follow-up of 3.8 y there were 577 (48.0%) events. The majority of variables were highly significant (< 0.001). Among these, % predicted maximum

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VO2 (ppMV̇ O2; Wald= 203; P <0.001; C-index= 0.73) was comparable to VE-VCO2 slope (Wald= 201; P <0.001; C= 0.72) and peak VO2 (Wald= 161; P <0.001; C= 0.72). In addition, there was no significant interaction observed for peak respiratory exchange ratio <1 vs. ≥1.

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Conclusions: Consistent with prior studies, many CPX test variables are strongly associated with prognosis in patients with HFrEF. The choice of which variable to use is up to the clinician.

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Renewed attention should be given to ppMV̇ O2 as it appears highly predictive of survival in these patients.

Key words: cardiomyopathy, survival, prognosis, exercise test

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BACKGROUND Interest in the clinical utility of cardiopulmonary exercise (CPX) testing in patients with

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chronic heart failure (HF) may have started with Weber et al.1 following their 1982 publication in which they described hemodynamic and oxygen utilization responses during exercise by

categories (i.e., Weber classes) of peak oxygen uptake (V̇ O2). The earliest study to describe the

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association between peak V̇ O2 and mortality in HF was published by Szlachcic et al. in 1985.2 However, the most influential study in this field may be from Mancini et al.3 in which they

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reported that 1- and 2-y survival rates among patients with HF and a peak V̇ O2 < 14 mL•kg•min-1 were worse than patients who received a heart transplant (HT). Between 2000 and 2013 there have been over 1,200 studies published in indexed journals related to the combined topics of CPX testing, HF, and prognosis. The aim in many of these

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studies has been to evaluate the next novel CPX variable. As a result, today there are many variables from a CPX test that have been identified as significantly related to survival in patients with HF. However, few studies have simultaneously evaluated a majority of these variables. The

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most comprehensive study to date may be from Corra et al.4 in which they examined the relationship of 14 variables from a CPX test on survival in 749 patients with HF (88% male). In

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univariable analyses, all CPX variables were significantly related to survival. The strongest explanatory variables were: (1) the ratio of ventilatory efficiency to peak V̇ O2 (VES-O2), (2) percent of predicted maximum V̇ O2 (ppMV̇ O2), and (3) circulatory power.4 The next most comprehensive analysis may be from Woods et al.5 In a cohort of 132 patients with HF (67% male), they reported on 11 submaximal CPX variables, but did not include any from peak

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exercise.5 In spite of many studies of CPX testing and survival in HF, missing is a de novo analysis that considers a majority of the proposed variables from a CPX test.

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Therefore, we sought to build on prior work by performing a de novo analysis that

considered many of the CPX variables previously associated with survival. The purpose of this retrospective study was to identify the variable(s) from a maximal CPX test with the strongest

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relationship to a composite endpoint of all-cause mortality, left ventricular assist device (LVAD) implant, or HT among a large, demographically diverse group of patients with HF and reduced

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ejection fraction (HFrEF).

METHODS

Study Cohort

The study cohort included patients ≥ 18 y with HFrEF who underwent a CPX test at

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Henry Ford Hospital between January 1997 and December 2010 as part of an initial consultation or follow-up with a physician of the Henry Ford Heart & Vascular Institute. This study was approved by the Institutional Review Board of Henry Ford Health System.

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Patients were identified through a query of the Henry Ford Preventive Cardiology

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Outcomes (PRECO) database which contains select data from all CPX tests performed in the Division of Cardiology. A manual review of the electronic medical record was performed on each prospective subject by physicians and clinical exercise physiologists to confirm a physician (i.e., cardiologist) diagnosis of cardiomyopathy; identify ischemic etiology; and to abstract ejection fraction (EF) and presence of an implanted pacemaker or cardioverter defibrillator. EF was obtained from echocardiography, cardiac catheterization, or myocardial perfusion imaging. To be included in this analysis an EF had to be measured ≤ 6 mo prior and ≤ 2 mo following the

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CPX test date. HFrEF was defined as an ejection fraction ≤ 40%. The cohort was not limited by other criteria. The identification of the study cohort is shown in Figure 1.

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Cardiopulmonary Exercise Testing

CPX tests were administered by clinical exercise physiologists based on guidelines

published by the American College of Cardiology and the American Heart Association.6 All tests

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were performed during an outpatient visit when patients were clinically stable and not exhibiting signs or symptoms suggestive of decompensated HF. All patients were verbally encouraged to

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exercise to a sign or symptom-limited maximum. Tests were not stopped due to achievement of a predicted maximum heart rate or a select respiratory exchange ratio. Resting heart rate and blood pressure were obtained after at least 2 min of standing rest. When possible, tests were performed on a treadmill using a low-level protocol (e.g., ~1 to 2

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metabolic equivalents [METs] per 2 or 3 min stage). Alternate exercise modes (e.g., leg ergometer) were used when clinically indicated. The electrocardiograph was monitored continuously starting at rest, through exercise, and for at least 6 min of post exercise recovery.

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Blood pressure was obtained via auscultation at rest, every 2 to 3 min during exercise, and regularly during recovery. Expired gases were analyzed using a metabolic cart from MGC

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Diagnostics (Ultima, CPX/D, or CPX Express; St. Paul, Minnesota, USA). The gas and flow analyzers were calibrated immediately prior to each test based on the manufacturer’s recommendations.

Gas Exchange Data Management Select CPX data were captured prospectively. Additional CPX variables were captured by re-analyzing test data using the system files (as available) imported into MGC Diagnostics’

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BreezeSuite 7.1 software. The response of minute ventilation to carbon dioxide production during exercise (VE-VCO2 slope) and the response of oxygen uptake to minute ventilation during

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exercise (oxygen uptake efficiency slope [OUES]) were calculated based on all exercise data using this software. Peak exercise gas exchange variables were identified as the highest interval value during the final minute of exercise based on 15 s averaged data. Exercise oscillatory

who are experienced reviewers of CPX data.

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ventilation (EOV) was identified based on published criteria7, 8 by clinical exercise physiologists

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Additional gas exchange variables were computed based on the literature. These included ppMV̇ O2,9 circulatory power (peak V̇ O2 [mL•kg-1•min-1] × peak systolic blood pressure),10 the ratio of peak systolic blood pressure to VE-VCO2 slope (SBP/VES; peak systolic blood pressure ÷ VE-VCO2 slope),11 peak oxygen uptake efficiency ratio (peak V̇ O2 ÷ log10[peakVE]),12 and VES-

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O2 (VE-VCO2 slope ÷ peak V̇ O2 [mL•kg-1•min-1]).13 The ratio of percent predicted heart rate reserve to percent predicted metabolic reserve14 was calculated using predicted maximum heart rate (based on Keteyian et al.15 and 220-age), measured resting (standing) heart rate, ppMV̇ O2,9

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and estimated resting V̇ O2 (3.5 mL•kg-1•min-1 × body mass [kg]). Chronotropic index16 was calculated based on measured resting (standing) heart rate, and predicted maximum heart rate

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(Keteyian et al.15 and 220-age). Percent predicted maximum heart rate was calculated for patients on beta-adrenergic blockade therapy who were tested on a treadmill based on the equation from Keteyian et al.15 Patients with atrial fibrillation were not included in any statistic that considered heart rate.

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Endpoint Data Mortality data were obtained from the US Centers for Disease Control and Prevention’s

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National Death Index through 2011. Social security numbers, name, date of birth, and gender were available on 100% of the cohort. Data from the National Death Index has been shown to accurately differentiate decedents from survivors when social security number is used in addition

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to other personal identifiers.17 Data on LVAD and HT were identified from the hospital’s clinic databases through 2011. A minimum of 1 y of follow-up was available on all subjects.

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Statistical Analysis

The primary outcome was the combined endpoint of all-cause mortality, LVAD implant, or HT. Only the first event from each patient was used for this primary outcome. The date of the CPX test served as the index date. Follow-up time was calculated as days between the CPX test

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date and the event date (when present) or December 31, 2011.

Life tables were used to identify the 1- and 3-y cumulative event rates. To facilitate comparisons to prior studies, the association with the outcome was evaluated separately for each

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of the CPX test variables with adjustment for age, gender, EF, and beta-adrenergic blockade therapy using Cox regression. Because many clinicians will consider the relevance of CPX

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variables without a risk calculator, we performed unadjusted Cox regression analyses among a subset of patients with complete data for the most significant variables from the adjusted analyses as well as EOV. We assessed the effect of test year (< 2005 vs. ≥ 2005) and peak respiratory exchange ratio (RER; < 1.0 vs. ≥ 1.0) using an interaction term in unadjusted Cox regression analyses in this subset. C-index was calculated based on Harrell et al. 18

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In order to provide more clinically meaningful results, unadjusted logistic regression was performed to predict the probability of an event by 1-y for select CPX test variables. These

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results were used to calculate the value for each variable that is associated with a 1-y event-free survival rate ≤ 86% (high risk) and ≥ 93% (low risk). These survival rates were chosen based on the 1-y (86.2%) and 3-y (79.4%) survival rates reported for patients who received a HT between

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April 1, 2009 and March 31, 2013 as reported by the International Society for Heart & Lung Transplant.19 Because our minimal follow-up was 1 y, we annualized the 3-y survival rate (79%;

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21% death rate at 3 y) to 93% (7% death rate at 1 y).

Alpha level was set at 0.05 for all analyses. IBM SPSS version 22 (IBM, Somers, New York, USA) was used for all statistical analyses.

RESULTS

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Identification of the study cohort is shown in Figure 1. Among 1,851 potential subjects that were identified in the PRECO database, manual query of the electronic medical record

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resulted in 1,201 patients with confirmed HFrEF. Demographic and clinical characteristics of these patients are shown in Table 1.

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CPX test data is presented in Tables 2 and 3. Total exercise time across the entire cohort was 8.1 ± 3.1 min. The majority of tests (n = 1,169, 98%) were performed on a treadmill, with 890 of these involving the same low-level, 3-min staged protocol. Total exercise time for this low-level protocol was 8.3 ± 3.0 min. The remaining non-treadmill tests (n = 30) were performed using a leg ergometer or a recumbent stepping ergometer. Exercise tests were stopped due to fatigue (81%), shortness of breath (9%), patient request (3%), chest pain (2%), and other reasons

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(5%). EOV was present in 10% of the cohort; 7% among patients who were event-free and 14% among those with an event (P < 0.05, event-free vs. event). There was a good level of cardio-

The lower 10th and 25th percentile was 1.00 and 1.06, respectively.

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metabolic stress based on a mean peak RER of 1.13 ± 0.11. Peak RER was normally distributed.

During a median follow-up of 3.8 y, there were 577 (48.0%) combined events which

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included 437 (36.3%) deaths, 58 (4.8%) LVADs, and 82 (6.8%) HTs. At 1 y and 3 y after the CPX test the cumulative composite event rate was 14% and 29%, respectively. Results from

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separate Cox regression analyses ordered by the Wald statistic are shown in Table 4. With just 5 exceptions, all CPX variables were significantly related (P < 0.05) to the composite endpoint. Unadjusted Cox regression analyses were performed among the subgroup of patients with complete data for the top 11 performing variables in Table 4 and EOV. As shown in Table 5,

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there were some variations in the relative ranking of each variable based on the Wald statistic, but each variable remained strongly related to the composite outcome with little change in the hazard ratio. Similar results were observed among the subset of patients who were tested on a

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treadmill (see Supplement Table 1). Also shown in Table 5 is the assessment of effect modification for peak RER < 1.0 vs. ≥ 1.0. Although the interaction of peak RER for two

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variables trended toward significance, no significant interaction was noted for any of the top performing variables. Effect modification was also assessed for test date year (< 2005 vs. ≥ 2005). Although a significant interaction (P < 0.05) for test year was noted for a few variables, all remained strongly related to prognosis with minor changes in the hazard ratio and C-index. Based on equations from a logistic regression, the values associated with 1-y event-free probability of 86% (high risk) and 93% (low risk) was calculated for three CPX test variables.

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This was calculated for ppMVO2 because it was consistently one of the top prognostic performers in the present analysis, as well as VE-VCO2 slope and peak VO2 (mL•kg-1•min-1)

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because of the extensive research on these variables (Table 6). Among women, peak VO2 was not significantly associated with risk for the combined outcome at 1 y (P = 0.210).

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DISCUSSION

In an analysis that simultaneously assessed over 30 variables from a CPX test among a

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large and diverse cohort of patients with HFrEF, tested as part of routine medical management, and followed-up for a median of 3.8 y, we showed that many CPX variables are strong predictors of a composite endpoint of mortality, LVAD implant, or HT. Two of these variables (ppMV̇ O2 and VE-VCO2 slope) were consistently among the strongest predictors. These results support

stratifying these patients.

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flexibility on the part of the clinician to focus on the CPX variables they prefer when risk

While many prior studies have included just a few of these variables, often in relatively small cohorts, the present study was the most comprehensive to date. Although a “best predictor”

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could be identified from a single cohort, applying this across different cohorts is difficult due to

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variations in sample sizes, cohort characteristics, measurement error, covariates, outcomes, and survival analysis methods. This challenge is observed in the present analysis with a few variables exchanging positions as the best predictor depending on the subgroup. Our results are consistent with Corra et al.4 and their evaluation of 14 CPX test variables;

the most comprehensive analysis that we are aware of. In univariable Cox regression analyses (N = 749), all 14 variables were strongly related to risk of cardiovascular mortality or urgent HT. Based on the Wald statistic, the top 5 predictors were (1) VES-O2, (2) ppMV̇ O2, (3) peak

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circulatory power, (4) peak V̇ O2 (mL•kg-1•min-1), and (5) peak SBP. VE-VCO2 slope ranked eighth and EOV was eleventh.

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The prognostic strength of ppMV̇ O2 was first reported by Aaronson and Mancini20 in 1995. Among 272 (79% male) patients with HF who were being considered for HT listing, the relationship to survival was not significantly different between ppMV̇ O2 and peak V̇ O2 (mL•kg•min-1). The authors concluded that a peak V̇ O2 < 14 mL•kg-1•min-1 remained the preferred

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criterion for HT candidacy because of its simplicity.20 In 1996, Stelken et al.21 reported that

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ppMV̇ O2 < 50% was superior to peak V̇ O2 < 14 mL•kg-1•min-1 in predicting survival among 181 patients with HF (81% male). At least 25 additional studies have considered ppMV̇ O2 as a potential predictor of survival in patients with HF. In spite of ppMV̇ O2 performing well in many of these studies, it is not among the preferred predictor variables in professional statements.22, 23

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Anecdotal evidence suggests this may be, in part, due to a perceived disconnect between a reported ppMV̇ O2 and peak V̇ O2 expressed in mL•kg-1•min-1; whereby a patient may have a relatively good ppMV̇ O2 (e.g., > 80%), but a low peak V̇ O2 (e.g., < 14 mL•kg-1•min-1). This most

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frequently occurs in patients who are obese and women. Regarding obesity, it is important to note that ppMV̇ O2 is a comparison to the predicted absolute maximum V̇ O2 (i.e., not normalized

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to body mass; e.g., mL•min-1). As for women, they have not been well represented in the development of current equations to predict maximum V̇ O2. Although these results may, at first glance, seem to contradict several studies that have

repeatedly shown that peak V̇ O2 (expressed in mL•kg-1•min-1) and VE-VCO2 slope are the best predictors of survival, we offer the following considerations. First, in the present analysis all traditional CPX variables were significantly related to the composite endpoint when tested in

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isolation (Table 4). Second, the purpose of many prior studies was to evaluate the significance of a previously untested CPX variable or to evaluate traditional CPX variables in a larger cohort;

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thus they were not intended to be comprehensive. This may be partly due to ongoing interest to identify the best predictor of survival in patients with HF. Third, we are aware of only isolated studies reporting SBP/VES,11 peak oxygen uptake efficiency ratio,12 and VES-O2.13 Each of these

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may deserve additional study. Finally, although the value of ppMV̇ O2 was first reported in 1995,20 peak V̇ O2 (mL•kg-1•min-1) and VE-VCO2 slope garner much more attention in the

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literature. For peak V̇ O2 this might be explained by the longer history in the literature, its relevance to activities of daily living, and its frequent use as an endpoint in clinical trials. Peak V̇ O2 represents functional (exercise) capacity; the integration of the pulmonary, circulatory, and skeletal muscle systems; and is surrogate of the ability to increase cardiac

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output.24, 25 Compared to peak V̇ O2, the benefit of ppMV̇ O2 is that it quantifies functional capacity relative to age, gender, and anthropometrics.21 For instance, although a peak V̇ O2 = 14 mL•kg-1•min-1 represents reduced functional capacity at any age, the severity of the impairment

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is more significant for a patient who is 25 y compared to someone who is 75 y. Although not a measure of functional capacity, elevated VE-VCO2 slope has been shown to be an important

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marker of the physiologic sequelae of HF, such as ventilation/perfusion mismatching and autonomic dysfunction, with higher values associated with worse prognosis.22, 26, 27 While low peak RER (< 1.0) was significantly related to survival in our cohort, an

important secondary finding is that it did not significantly alter the association with survival of top performing variables in our analysis (Table 5). These results are consistent with Chase et al. 28

who reported that peak VO2 and VE-VCO2 slope were significantly related to prognosis among

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a range of peak RER subgroups with little variation in the adjusted hazard ratios. This is important because patients with a low peak RER have been excluded in several recent studies 29and it has been recommended that it may be advisable to repeats tests when a low peak RER is

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observed.35 However, considering that peak RER in our cohort followed a normal distribution, excluding patients with a low RER may limit the generalizability and clinical application of CPX

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test data.

In order to put our results into a clinically useful context, we calculated thresholds for

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ppMV̇ O2, VE-VCO2 slope, and peak VO2 associated with a high (≤ 86% event-free survival) and low (≥ 93% event-free survival) event risk at 1 y (Table 6). These values may be useful when risk stratifying patients for potential referral to an advanced HF program or need for advanced HF therapies (i.e., LVAD or HT). It is important to note that we observed differences by gender.

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Differences in CPX values and their indication of risk by gender have been reported in a few studies.30, 36, 37 As noted by Corra et al.30, this remains an underdeveloped area. Limitations

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This analysis has certain limitations that should be noted when interpreting the results. As a result of the retrospective design, all candidate CPX variables were not available for the entire

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cohort. As shown in Tables 2 and 3, candidate variables were available on more than 85% of the cohort with the exception of heart rate recovery and percent predicted maximum heart rate. In addition, there may be unmeasured confounders that could be related to a CPX variable and the endpoint that, if available, would have modified the results. Although we considered over 30 variables from a CPX test, additional variables reported in the literature were not available, such as ventilatory-derived anaerobic threshold and oxygen kinetics. However, we feel we included

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those variables from a CPX test that have been shown to have the strongest association with prognosis.

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Finally, many of patients included in this analysis were referred for a CPX test because they were being seen in a specialized HF clinic. It is unknown whether the medical management and outcomes of these patients represent patients who are not seen by similar specialists.

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Possibly as a result of our cohort’s referral source, in spite of being younger (55 y) and including a larger proportion of women (33%), we observed a higher crude annual event rate (12.6% for

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death, LVAD, or HT) and higher crude annual mortality (9.5%) than several previous studies of CPX testing and prognosis. For instance, among 2,716 patients (60 y; 16% women) with HFrEF, Agostoni et al.38 reported a 22% event rate (death or urgent HT) over 2.9 y for a crude annual rate of 7.6% (6.6% for death only). Among 2,625 patients (56 y; 25% women) with HF (reduced

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and preserved EF), Myers et al.39 reported a 16% event rate (death, LVAD, or HT) during 2.4 y of follow-up for a crude annual rate of 6.5% (4.6% for death only). Conclusions

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This study represents one of the largest and most comprehensive analyses of CPX test data and prognosis in patients with HFrEF. Consistent with prior studies, we showed that many

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CPX test variables are strong predictors of a clinically important composite endpoint of death, LVAD implant, or HT in these patients. We also provided data supporting the utility of CPX test in spite of a low peak RER. The choice of which variable to use is up to the clinician. Renewed attention should be given to ppMV̇ O2 as it appears highly predictive of survival in patients with HFrEF.

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Acknowledgements: We are grateful for the contributions of Dr. Raakesh Hassan, Dr. Stephanie Vasko, and Mr. Matthew A. Saval, MS.

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Funding Sources: None.

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Disclosures: None.

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cardiopulmonary exercise test in risk stratification of elderly patients with chronic heart failure.

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Cardiology. 2006;47:2237-42.

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cardiology. 2006;113:395-400.

Agostoni P, Corra U, Cattadori G, Veglia F, La Gioia R, Scardovi AB, Emdin M, Metra

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M, Sinagra G, Limongelli G, Raimondo R, Re F, Guazzi M, Belardinelli R, Parati G, Magri D, Fiorentini C, Mezzani A, Salvioni E, Scrutinio D, Ricci R, Bettari L, Di Lenarda A, Pastormerlo LE, Pacileo G, Vaninetti R, Apostolo A, Iorio A, Paolillo S, Palermo P, Contini M, Confalonieri M, Giannuzzi P, Passantino A, Cas LD, Piepoli MF, Passino C and Group MSR. Metabolic

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exercise test data combined with cardiac and kidney indexes, the MECKI score: a multiparametric approach to heart failure prognosis. International journal of cardiology. 2013;167:2710-8.

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test score in heart failure. Circulation Heart failure. 2013;6:211-8.

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Figure Legends

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exercise test; PRECO, Preventive Cardiology Outcomes database.

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Figure 1. Flow chart showing the identification of the study cohort. CPX, cardiopulmonary

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Event-Free

Event

(n = 1,201)

(n = 624)

(n = 577)

Age (y)

55 ± 13

54 ± 13

55 ± 13

Female gender, n (%)

396 (33)

224 (36)

172 (30)*

White

471 (39)

233 (37)

238 (41)*

Black

664 (55)

347 (56)

317 (55)

Characteristic

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Race, n (%)

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All Subjects

SC

Table 1. Demographic and clinical characteristics of the study cohort.

Other

66 (6)

44 (7)

22 (4)

31 ± 7

31 ± 7

30 ± 7*

397 (33)

169 (27)

228 (40)*

22 ± 9

24 ± 9

20 ± 8*

245 (32)

118 (30)

127 (34)

394 (33)

214 (34)

180 (31)

57 (5)

25 (4)

32 (6)

74 (6)

30 (5)

44 (8)

714 (59)

383 (61)

331 (57)

Diabetes (type 1 or 2)

316 (26)

157 (25)

159 (28)

Tobacco use within last 2 y

212 (18)

110 (18)

102 (18)

Beta-adrenergic blockade

938 (78)

542 (87)

396 (69)*

ACE or ARB

952 (79)

498 (80)

454 (79)

1,003 (84)

495 (79)

508 (88)*

Body mass index (kg•m-2) Ischemic etiology, n (%) Ejection fraction, n (%)

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Implanted pacemaker, n (%) Implanted cardioverter-defibrillator, n (%) Atrial fibrillation, n (%)

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Chronic obstructive pulmonary disease, n (%) Cardiovascular Risk Factors, n (%)

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Hypertension

Medications, n (%)

Diuretic

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Data are mean ± standard deviation or n (%). ACE, angiotensin converting enzyme inhibitor;

ARB, angiotensin receptor blocker.

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EP

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SC

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* P < 0.05, event-free vs. event.

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Table 2. Cardiopulmonary exercise test data: hemodynamics Variable

n (% events)

All Subjects

Event-Free

Event

HR (beats•min-1)

1,033 (49%)

79 ± 14

79 ± 13

80 ± 15

SBP (mmHg)

1,043 (49%)

112 ± 19

113 ± 19

110 ± 20*

DBP (mmHg)

1,043 (49%)

72 ± 12

72 ± 12

72 ± 12

MAP (mmHg)

1,043 (49%)

85 ± 13

86 ± 13

85 ± 13

1,195 (48%)

126 ± 24

129 ± 23

123 ± 24*

1,031 (49%)

47 ± 21

51 ± 21

43 ± 20*

739 (42%)

78 ± 14

81 ± 13

75 ± 14*

-1

HR reserve (beats•min )† % predicted maximum HR‡

M AN U

HR (beats•min-1)

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Peak Exercise Data

RI PT

Rest Data

SBP (mmHg)

1,194 (48%)

144 ± 40

150 ± 27

138 ± 50*

DBP (mmHg)

1,192 (48%)

77 ± 14

77 ± 13

76 ± 14

1,192 (48%)

99 ± 19

101 ± 16

100 ± 22*

1,190 (48%)

183 ± 63

195 ± 54

171 ± 69*

388 (32%)

18 ± 14

18 ± 13

16 ± 14

31 ± 17

33 ± 16

27 ± 17*

MAP (mmHg)

RPP ×10 (beats•mmHg•min ) -2

-1

Recovery Data

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HR recovery at 1 min (beats) HR recovery at 2 min (beats)

377 (32%)

Data are mean ± standard deviation. HR, heart rate; DBP, diastolic blood pressure; MAP, mean

arterial pressure; RPP, rate-pressure product; SBP, systolic blood pressure. * P < 0.05, event-free vs. event.

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†Reserve = measured peak – measured rest. ‡Predicted maximum heart rate calculated from Keteyian et al.15 in patients on beta-adrenergic

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blockade therapy and tested on a treadmill.

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Table 3. Cardiopulmonary exercise test data: ventilatory gas analysis. Variable

n (% events) All Subjects Event-Free

Event

RI PT

Peak Oxygen Uptake L•min-1

1,201 (48%) 1.40 ± 0.55

% predicted maximum

1,200 (48%)

59 ± 18

mL•kg-1•min-1

1,201 (48%)

15.3 ± 5.0

Peak oxygen pulse (mL•beat-1)

1,195 (48%)

11.1 ± 3.8

12.1 ± 3.8

10.1 ± 3.5*

Peak VE (l•min-1)

1,118 (47%)

54 ± 17

57 ± 18

51 ± 17*

Peak PETCO2 (mmHg)

1,057 (46%)

39 ± 6

35 ± 6*

Peak respiratory exchange ratio

1,199 (48%) 1.13 ± 0.11

Peak VE/VCO2 ratio

1,110 (47%)

VE-VCO2 slope

OUE slope ×10-2

Circulatory power ×10-2

Ratio of HR reserve to MET reserve†

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SBP/VES VES-O2

51 ± 15*

16.9 ± 5.1

13.6 ± 4.3*

SC

M AN U 37 ± 6

37 ± 9

1.12 ± 0.10 1.14 ± 0.12* 41 ± 10*

1,116 (47%) 35.1 ± 10.6

31.9 ± 7.2

38.6 ± 12.5*

1,116 (47%)

16.7 ± 6.7

18.7 ± 6.6

14.5 ± 6.2*

739 (42%)

0.58 ± 0.26

0.63 ± 0.25 0.51 ± 0.25*

1,194 (48%)

23 ± 11

1,115 (47%) 0.80 ± 0.26

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Peak OUE ratio

66 ± 17

34 ± 7

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Chronotropic index†

1.56 ± 0.57 1.22 ± 0.48*

26 ± 10

19 ± 11*

0.88 ± 0.27 0.71 ± 0.23*

739 (42%)

1.2 ± 1.2

1.1 ± 0.5

1.3 ± 1.8*

1,110 (47%)

4.5 ± 1.8

5.0 ± 1.5

3.9 ± 1.9*

1,116 (47%)

2.7 ± 2.0

2.1 ± 1.1

3.3 ± 2.5*

Data are mean ± standard deviation. HR, heart rate; MET, metabolic equivalents; MAP, mean

arterial pressure; PETCO2, partial pressure of end-tidal CO2; ppMET, % predicted METs; ppMHR, % predicted maximum HR; ppMVO2, % predicted maximum VO2; RER, respiratory exchange ratio; SBP, systolic blood pressure; SBP/VES, ratio of peak SBP to VE-VCO2 slope; VCO2, volume

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of carbon dioxide produced; VE, minute ventilation; VES-O2, ratio of VE-VCO2 slope to peak V̇ O2;

V̇ O2, volume of oxygen uptake.

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* P < 0.05, event-free vs. event. †Predicted maximum HR calculated from Keteyian et al.15 in patients on beta-adrenergic blockade

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therapy and tested on a treadmill.

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Table 4. Results from separate Cox regression analyses to predict the composite endpoint of death, left

ventricular assist device implant, or heart transplant adjusted for age, gender, ejection fraction, and beta-

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adrenergic blockade therapy. Hazard Ratio

Wald

P

ppMV̇ O2 (per 10%)*

1,200 (48%)

203

< 0.001

VE-VCO2 slope

1,116 (47%)

201

Peak OUE ratio (per 10th)

1,115 (47%)

184

Peak VE/VCO2 ratio

1,110 (47%)

179

VES-O2

1,116 (47%)

Peak V̇ O2 (per 100 mL•min-1)

(95% CI)

C-Index

0.66 (0.62, 0.70)

0.73

SC

n (% events)

1.04 (1.03, 1.04)

0.72

< 0.001

0.74 (0.71, 0.77)

0.74

< 0.001

1.05 (1.05, 1.06)

0.72

168

< 0.001

1.12 (1.10, 1.14)

0.70

1,201 (48%)

166

< 0.001

0.87 (0.85, 0.89)

0.73

Peak V̇ O2 (mL•kg-1•min-1)

1,201 (48%)

161

< 0.001

0.87 (0.85, 0.89)

0.72

OUE slope (per 100 units)

1,116 (47%)

154

< 0.001

0.91 (0.89, 0.92)

0.73

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< 0.001

M AN U

Variable

Circulatory power (per 100 units)

1,194 (48%)

143

< 0.001

0.93 (0.92, 0.95)

0.73

SBP/VES

1,110 (47%)

140

< 0.001

0.67 (0.63, 0.72)

0.74

1,057 (46%)

111

< 0.001

0.92 (0.91, 0.94)

0.71

1,195 (48%)

97

< 0.001

0.86 (0.84, 0.89)

0.69

1,135 (48%)

92

< 0.001

0.92 (0.90, 0.93)

0.71

1,138 (48%)

66

< 0.001

0.98 (0.98, 0.99)

0.68

983 (49%)

61

< 0.001

0.98 (0.98, 0.99)

0.68

1,194 (48%)

60

< 0.001

0.89 (0.86, 0.91)

0.70

ppMHR (per 10%)‡

739 (42%)

52

< 0.001

0.71 (0.65, 0.78)

0.69

Chronotropic index (per 10th)‡

972 (48%)

51

< 0.001

0.86 (0.82, 0.90)

0.68

1,118 (47%)

47

< 0.001

0.98 (0.97, 0.99)

0.67

Peak O2-pulse

EP

Peak PETCO2

AC C

Peak RPP (per 1,000 units) Peak HR

HR reserve*

Peak SBP (per 10 mmHg)

Peak VE

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730 (42%)

43

< 0.001

0.85 (0.80, 0.89)

0.69

SBP reserve (per 10 mmHg)*

1,040 (49%)

42

< 0.001

0.87 (0.83, 0.91)

0.68

Peak MAP (per 10 mmHg)

1,192 (48%)

40

< 0.001

0.85 (0.81, 0.89)

0.68

MAP reserve (per 10 mmHg)*

1,038 (49%)

22

< 0.001

0.83 (0.77, 0.90)

0.67

Test limited by shortness of breath

1,044 (49%)

16

< 0.001

1.68 (1.30, 2.18)

0.65

Rest SBP < 100 mmHg

1,043 (49%)

16

< 0.001

1.44 (1.20, 1.71)

0.65

Exercise oscillatory ventilation

1,115 (48%)

13

HR recovery at 2 min (continuous)

367 (31%)

15

HR recovery at 2 min < 22 beats

362 (32%)

9

HR recovery at 1 min < 12 beats

378 (31%)

< 0.001

1.57 (1.23, 2.01)

0.65

< 0.001

0.98 (0.96, 0.99)

0.71

0.002

1.84 (1.24, 2.72)

0.71

7

0.009

1.65 (1.13, 2.41)

0.70

1,199 (48%)

5

0.021

1.40 (1.05, 1.85)

0.64

HR recovery at 1 min (continuous)

378 (31%)

4

0.038

0.98 (0.97, 1.00)

0.69

ppMHR reserve to ppMET reserve

M AN U

SC

RI PT

Chronotropic index (per 10th)†

982 (49%)

3

0.095

1.00 (1.00, 1.01)

NC

1,201 (48%)

2

0.115

1.38 (0.93, 2.05)

NC

1,199 (48%)

1

0.243

1.56 (0.74, 3.29)

NC

739 (42%)

1

0.247

1.00 (1.00, 1.01)

NC

1,201 (48%)

1

0.477

0.87 (0.60, 1.27)

NC

(per 10th)*‡ Angina during test

EP

Peak RER (continuous)

TE D

Peak RER< 1

ppMHR reserve to ppMET reserve

AC C

(per 10th)*†

Exercise ST-segment depression

CI, confidence interval; HR, heart rate; MET, metabolic equivalents; MAP, mean arterial pressure; NC,

not calculated. PETCO2, partial pressure of end-tidal CO2; ppMET, % predicted METs; ppMHR, % predicted maximum HR; ppMVO2, % predicted maximum VO2; RER, respiratory exchange ratio; SBP, systolic blood pressure; SBP/VES, ratio of peak SBP to VE-VCO2 slope; VCO2, volume of carbon dioxide produced; VE, minute ventilation; VES-O2, ratio of VE-VCO2 slope to peak V̇ O2; V̇ O2, volume of oxygen

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uptake.

*Reserve = measured peak – measured rest.

therapy and tested on a treadmill.

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‡Predicted maximum HR calculated from 220-age.

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†Predicted maximum HR calculated based on Keteyian et al.15 in patients on beta-adrenergic blockade

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Table 5. Results from separate unadjusted Cox regression analyses to predict the composite endpoint of

death, left ventricular assist device implant, or heart transplant and the interaction of low peak respiratory exchange ratio (RER) among patients with complete data. Peak RER < 1.0

Peak RER ≥ 1.0

n = 1,043, 479 events

n = 89, 47 events

n = 954, 432 events

241 (< 0.001)

25 (< 0.001)

213 (< 0.001)

1.30 (1.26, 1.35)

2.19 (1.61, 2.97)

0.69

0.69

204 (< 0.001)

20 (< 0.001)

Wald (P) HR (95% CI) C-index

Wald (P) HR (95% CI)

1.06 (1.05, 1.07)

1.06 (1.05, 1.07)

0.68

0.68

11 (0.001)

193 (< 0.001)

0.68 (0.54, 0.86)

0.64 (0.60, 0.68)

0.67

0.72

181 (< 0.001)

19 (< 0.001)

160 (< 0.001)

1.05 (1.05, 1.06)

1.09 (1.05, 1.13)

1.05 (1.05, 1.06)

0.68

0.69

0.68

0.68

ppMV̇ O2 (per 10%) Wald (P) HR (95% CI)

203 (< 0.001) 0.64 (0.60, 0.68)

Wald (P) HR (95% CI) C-index

0.72

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C-index Peak VE/VCO2 ratio

184 (< 0.001)

1.09 (1.05, 1.14)

C-index

0.070

0.69

M AN U

VE-VCO2 slope

1.29 (1.25, 1.34)

P*

SC

Ratio of VE-VCO2 slope to peak V̇ O2†

RI PT

Variable

All Subjects

0.071

0.557

0.207

Wald (P)

155 (< 0.001)

17 (< 0.001)

138 (< 0.001)

0.65 (0.61, 0.69)

0.58 (0.44, 0.75)

0.65 (0.61, 0.70)

0.70

0.72

138 (< 0.001)

18 (< 0.001)

120 (< 0.001)

0.91 (0.90, 0.93)

0.88 (0.84, 0.94)

0.92 (0.90, 0.93)

0.67

0.71

0.67

118 (< 0.001)

15 (< 0.001)

107 (< 0.001)

0.94 (0.92, 0.95)

0.90 (0.85, 0.95)

0.94 (0.92, 0.95)

AC C

HR (95% CI)

EP

Ratio of peak systolic blood pressure to VE-VCO2 slope

C-index

0.71

0.831

Peak partial pressure of end-tidal CO2 Wald (P)

HR (95% CI) C-index

0.762

Circulatory power (per 100 units) Wald (P) HR (95% CI)

0.163

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C-index

0.69

0.67

0.70

115 (< 0.001)

9 (0.003)

107 (< 0.001)

0.88 (0.86, 0.90)

0.85 (0.77, 0.95)

0.88 (0.86, 0.90)

0.66

0.62

0.67

96 (< 0.001)

5 (0.020)

0.90 (0.89, 0.92)

0.90 (0.83, 0.98)

0.65

0.59

98 (< 0.001)

7 (0.008)

Peak V̇ O2 (mL•kg •min ) -1

Wald (P) HR (95% CI) C-index

Peak V̇ O2 (per 100 mL•min ) -1

HR (95% CI) C-index

Wald (P) HR (95% CI)

0.92 (0.91, 0.94)

C-index

0.65

Exercise oscillatory ventilation Wald (P)

20 (< 0.001)

HR (95% CI)

1.80 (1.39, 2.34) 0.53

0.421

0.66

91 (< 0.001)

0.92 (0.87, 0.98)

0.92 (0.91, 0.94)

0.61

0.66

6 (0.014)

15 (< 0.001)

2.80 (1.24, 6.33)

1.74 (1.32, 2.29)

0.54

0.53

TE D

C-index

0.90 (0.88, 0.92)

M AN U

OUE slope (per 100 units)

91 (< 0.001)

SC

Wald (P)

0.253

RI PT

-1

0.589

0.180

CI, confidence interval; HR, hazard ratio; OUE, oxygen uptake efficiency ratio; ppMVO2, % predicted

maximum VO2; VCO2, volume of carbon dioxide produced; VE, minute ventilation; V̇ O2, volume of oxygen uptake. *P value for interaction.

AC C

EP

†Expressed in mL•kg-1•min-1

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Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure | 34

Table 6. Risk categories and associated estimates for percent predicted maximum VO2, VE-VCO2 slope,

and peak VO2 among patients with heart failure with reduced ejection fraction.

RI PT

Risk Categories (1-y Event-Free Survival)* High Risk

Intermediate Risk

Low Risk

(1-y survival ≤ 86%)

(1-y survival 87 – 92%)

(1-y survival ≥ 93%)

SC

Estimated % predicted maximum VO2 (95% confidence interval) ≤ 53 (35, 80)

54 – 63

≥ 64 (46, 97)

Men (n = 804)

≤ 52 (34, 81)

53 – 62

≥ 63 (43, 96)

Women (n = 396)

≤ 50 (8, 224)

M AN U

All Patients (n = 1,200)

51 – 72

≥ 73 (23, 283)

Estimated VE-VCO2 slope (95% confidence interval) ≥ 37.6 (23.1, 60.3)

37.5 – 26.8

≤ 26.7 (14.2, 46.3)

Men (n = 747)

≥ 36.0 (20.9, 60.6)

35.9 – 26.5

≤ 26.4 (13.3, 48.0)

Women (n = 369)

≥ 46.1 (7.5, 470.4)

46.0 – 26.9

≤ 26.8 (-3.1, 354.9)

≤ 14.0 (8.1, 24.4)

14.1 – 18.6

≥ 18.7 (11.8, 30.9)

≤ 15.0 (9.4, 14.2)

15.1 – 18.3

≥ 18.4 (12.1, 28.7)

Model NS

Model NS

Model NS

TE D

All Patients (n = 1,116)

Estimated peak V̇ O2 (95% confidence interval)†

Men (n = 805) Women (n = 396)

EP

All Patients (n = 1,201)

AC C

NS, not significant; VCO2, volume of carbon dioxide produced; VE, minute ventilation; V̇O2, volume of

oxygen uptake.

*Based on survival rates for patients who received a cardiac transplant between April 1, 2009 and March 31, 2013 as reported by the International Society for Heart & Lung Transplant.19 †Units = mL•kg-1•min-1

AC C

EP

TE D

M AN U

SC

RI PT

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ACCEPTED MANUSCRIPT Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure (Supplement)| 1

Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients with Systolic Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX)

Brawner et al. Highlights

RI PT

Project

Many cardiopulmonary exercise test variables are strong predictors of prognosis.

•

% predicted V̇ O2 and VE-VCO2 slope were consistently among the strongest predictors of

SC

•

prognosis.

Renewed attention should be given to % predicted V̇ O2 as an strong predictor of

M AN U

•

prognosis.

EP

TE D

Data from tests with low peak RER is useful for risk stratifying patients.

AC C

•

ACCEPTED MANUSCRIPT Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure (Supplement)| 1

Comprehensive Analysis of Cardiopulmonary Exercise Testing and Mortality in Patients with Systolic Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) Project Brawner et al.

RI PT

Supplemental Material

Supplement Table 1. Results from separate unadjusted Cox regression analyses to predict the composite

SC

endpoint of death, left ventricular assist device implant, or heart transplant among patients tested on a treadmill (n = 1,019; 465 events).

Ratio of VE-VCO2 slope to peak V̇ O2*

P

M AN U

Wald

HR (95% CI)

C-Index

260

< 0.001

1.31 (1.27, 1.36)

0.70

216

< 0.001

1.06 (1.05, 1.07)

0.68

203

< 0.001

0.63 (0.60, 0.68)

0.72

187

< 0.001

1.06 (1.05, 1.07)

0.68

155

< 0.001

0.64 (0.60, 0.69)

0.72

Peak partial pressure end-tidal CO2

143

< 0.001

0.91 (0.90, 0.92)

0.68

Circulatory power (per 100 units)

117

< 0.001

0.93 (0.92, 0.95)

0.70

Peak oxygen uptake efficiency ratio (per 10th)

115

< 0.001

0.79 (0.76, 0.82)

0.67

Peak V̇ O2 (mL•kg-1•min-1)

114

< 0.001

0.88 (0.86, 0.90)

0.67

Oxygen uptake efficiency slope (per 100 units)

98

< 0.001

0.92 (0.90, 0.93)

0.66

Peak V̇ O2 (per 100 mL•min-1)

94

< 0.001

0.90 (0.88, 0.92)

0.66

Exercise oscillatory ventilation

19

< 0.001

1.79 (1.38, 2.34)

0.53

VE-VCO2 slope Percent predicted maximum V̇ O2 (per 10%) Peak VE/VCO2 ratio

AC C

EP

TE D

Ratio of peak systolic blood pressure to VE-VCO2 slope

VCO2, volume of carbon dioxide produced; VE, minute ventilation; VO2, volume of oxygen uptake.

*Expressed in mL•kg-1•min-1

ACCEPTED MANUSCRIPT Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure (Supplement)| 2

Supplement Table 2. The interaction of tests performed before 2005 in separate unadjusted Cox

regression analyses to predict the composite endpoint of death, left ventricular assist device implant, or heart transplant among patients with complete data. Test Date ≥ 2005

n = 1,043, 479 events

n = 552, 344 events

n = 491, 135 events

203 (< 0.001)

110 (< 0.001)

97 (< 0.001)

0.64 (0.60, 0.68)

0.67 (0.63, 0.73)

0.58 (0.52, 0.64)

0.72

0.69

0.76

204 (< 0.001)

121 (< 0.001)

1.06 (1.05, 1.07)

1.05 (1.04, 1.06)

ppMV̇ O2 (per 10%) Wald (P) HR (95% CI) C-index

Wald (P) HR (95% CI) C-index

0.68

0.72

67 (< 0.001)

51 (< 0.001)

0.81 (0.77, 0.85)

0.74 (0.69, 0.81)

0.65

0.70

181 (< 0.001)

96 (< 0.001)

91 (< 0.001)

1.05 (1.05, 1.06)

1.05 (1.04, 1.06)

1.08 (1.06, 1.09)

0.68

0.65

0.72

241 (< 0.001)

136 (< 0.001)

89 (< 0.001)

1.30 (1.26, 1.35)

1.27 (1.22, 1.32)

1.48 (1.37, 1.61)

0.69

0.67

0.73

96 (< 0.001)

54 (< 0.001)

44 (< 0.001)

0.90 (0.89, 0.92)

0.92 (0.89, 0.94)

0.87 (0.84, 0.91)

0.65

0.63

0.69

115 (< 0.001)

67 (< 0.001)

50 (< 0.001)

0.88 (0.86, 0.90)

0.89 (0.87, 0.92)

0.86 (0.82, 0.89)

0.66

0.64

0.70

Peak OUE ratio (per 10 ) Wald (P)

117 (< 0.001)

HR (95% CI)

0.79 (0.76, 0.83)

C-index

0.67

Peak VE/VCO2 ratio

TE D

Wald (P) HR (95% CI)

1.07 (1.05, 1.08)

0.66

th

C-index

0.097

82 (< 0.001)

M AN U

VE-VCO2 slope

P*

RI PT

Test Date < 2005

SC

Variable

All Patients

0.363

0.065

0.874

Ratio of VE-VCO2 slope to peak V̇ O2†

EP

Wald (P) HR (95% CI) C-index

0.452

AC C

Peak V̇ O2 (per 100 mL•min-1) Wald (P)

HR (95% CI) C-index

0.038

Peak V̇ O2 (mL•kg •min ) -1

Wald (P) HR (95% CI) C-index

-1

0.042

ACCEPTED MANUSCRIPT Brawner; Cardiopulmonary Exercise Testing in Systolic Heart Failure (Supplement)| 3

OUE slope (per 100 units) Wald (P) HR (95% CI)

98 (< 0.001)

56 (< 0.001)

43 (< 0.001)

0.92 (0.91, 0.94)

0.93 (0.91, 0.95)

0.90 (0.87, 0.93)

0.65

0.64

0.68

118 (< 0.001)

74 (< 0.001)

47 (< 0.001)

0.94 (0.92, 0.95)

0.94 (0.93, 0.95)

0.92 (0.90, 0.94)

0.69

0.66

0.74

C-index

0.076

HR (95% CI) C-index

Ratio of peak SBP to VE-VCO2 slope HR (95% CI)

155 (< 0.001)

92 (< 0.001)

0.65 (0.61, 0.69)

0.68 (0.63, 0.74)

0.71

0.68

C-index Peak PETCO2 Wald (P) HR (95% CI)

138 (< 0.001)

0.92 (0.91, 0.94)

0.89 (0.86, 0.91)

0.65

0.70

12 (< 0.001)

7 (0.010)

1.80 (1.39, 2.34)

1.71 (1.27, 2.31)

1.99 (1.18, 3.35)

0.53

0.53

0.53

0.67

Exercise oscillatory ventilation 20 (< 0.001)

TE D

Wald (P)

C-index

0.006

0.76

61 (< 0.001)

C-index

HR (95% CI)

0.56 (0.49, 0.64)

81 (< 0.001)

0.91 (0.90, 0.93)

0.015

68 (< 0.001)

M AN U

Wald (P)

SC

Wald (P)

RI PT

Circulatory power (per 100 units)

0.013

0.912

CI, confidence interval; HR; hazard ratio; OUE, oxygen uptake efficiency; PETCO2, partial pressure of

end-tidal CO2; ppMVO2, % predicted maximum VO2; SBP, systolic blood pressure; VCO2, volume of

EP

carbon dioxide produced; VE, minute ventilation; V̇O2, volume of oxygen uptake. *P value for interaction.

AC C

†Expressed in mL•kg-1•min-1