Prognostic Value of Cardiopulmonary Exercise Testing in Heart Failure With Reduced, Midrange, and Preserved Ejection Fraction
Background This study aimed to compare the independent and incremental prognostic value of peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) in heart failure (HF) with preserved (HFpEF), midrange (HFmEF), and reduced (HFrEF) ejection fraction (LVEF).
Methods and Results In 195 HFpEF (LVEF ≥50%), 144 HFmEF (LVEF 40–49%), and 630 HFrEF (LVEF <40%) patients, we assessed the association of cardiopulmonary exercise testing variables with the composite outcome of death, left ventricular assist device implantation, or heart transplantation (256 events; median follow‐up of 4.2 years), and 2‐year incident HF hospitalization (244 events). In multivariable Cox regression analysis, greater association with outcomes in HFpEF than HFrEF were noted with peak VO2 (HR [95% confidence interval]: 0.76 [0.67–0.87] versus 0.87 [0.83–0.90] for the composite outcome, Pinteraction=0.052; 0.77 [0.69–0.86] versus 0.92 [0.88–0.95], respectively for HF hospitalization, Pinteraction=0.003) and VE/VCO2 slope (1.11 [1.06–1.17] versus 1.04 [1.03–1.06], respectively for the composite outcome, Pinteraction=0.012; 1.10 [1.05–1.15] versus 1.04 [1.03–1.06], respectively for HF hospitalization, Pinteraction=0.019). In HFmEF, peak VO2 and VE/VCO2 slope were associated with the composite outcome (0.79 [0.70–0.90] and 1.12 [1.05–1.19], respectively), while only peak VO2 was related to HF hospitalization (0.81 [0.72–0.92]). In HFpEF and HFrEF, peak VO2 and VE/VCO2 slope provided incremental prognostic value beyond clinical variables based on the C‐statistic, net reclassification improvement, and integrated diagnostic improvement, with models containing both measures demonstrating the greatest incremental value.
Conclusions Both peak VO2 and VE/VCO2 slope provided incremental value beyond clinical characteristics and LVEF for predicting outcomes in HFpEF. Cardiopulmonary exercise testing variables provided greater risk discrimination in HFpEF than HFrEF.
- cardiopulmonary exercise testing
- ejection fraction
- heart failure
- oxygen consumption
- preserved ejection fraction
What Is New?
Peak oxygen consumption is robustly predictive of worse prognosis in heart failure with preserved ejection fraction, heart failure with midrange ejection fraction, and heart failure with reduced ejection fraction.
Among patients with heart failure with preserved ejection fraction, both peak oxygen consumption and minute ventilation/carbon dioxide production slope provided incremental prognostic value beyond relevant clinical covariates for long‐term adverse outcomes.
Cardiopulmonary exercise testing variables provided greater risk discrimination in heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction.
What Are the Clinical Implications?
These findings support the notion that cardiopulmonary exercise testing is a robust albeit underutilized tool for risk stratification in heart failure with preserved ejection fraction.
Further studies may be necessary to assess whether peak oxygen consumption and minute ventilation/carbon dioxide production slope are measures that should be systematically incorporated into decision algorithms for clinicians aiming to stratify risk and prognosis in heart failure patients across the left ventricular ejection fraction spectrum.
Cardiopulmonary exercise testing (CPET) is routinely used in the prognostic evaluation of patients with heart failure (HF) with reduced ejection fraction (HFrEF), in whom the prognostic value of peak oxygen consumption (VO2) and the minute ventilation/carbon dioxide production (VE/VCO2) slope is powerful and well established.1, 2 However, it is well recognized that HF may occur with any ejection fraction (left ventricular ejection fraction [LVEF]). Indeed, HF with preserved ejection fraction (HFpEF) accounts for greater than half of HF cases, and is associated with a heightened risk of HF hospitalization and death similar to HFrEF.3, 4, 5 Pathophysiologic heterogeneity has frustrated efforts to develop efficacious interventions in HFpEF, highlighting the need for better approaches to identify relevant physiologic and prognostic subgroups.6, 7 Variability in the LVEF cutoff used for the definition of HFpEF contributes to this heterogeneity. Recent guidelines therefore introduced a novel classification schema for HF based on LVEF, adding HF with midrange LVEF (HFmEF; LVEF 40–49%) to HFpEF (≥50%) and HFrEF (LVEF <40%), with the expressed aim of fostering greater research into characteristics and pathophysiology of this understudied group.8
Exercise intolerance is a cardinal symptom of HF regardless of LVEF.9 Objective assessment of functional capacity by CPET has been increasingly used both as a diagnostic tool10 and as a surrogate efficacy end point in HFpEF therapeutic clinical trials.11, 12 However, the few studies that have assessed the relationship between peak VO2 and VE/VCO2 slope and prognosis in HFpEF have produced conflicting results, and none have evaluated their relevance for HF hospitalization—an important source of morbidity in HFpEF.13, 14, 15, 16 Furthermore, the prognostic value of CPET testing in HFmEF specifically has not been described. To evaluate the utility of CPET as a widely available diagnostic and prognostic tool in HFpEF and HFmEF, the present study aimed to define and compare the independent and incremental prognostic value of peak VO2 and VE/VCO2 slope for HF hospitalization and the composite of death, left ventricular assist device (LVAD) implantation or heart transplant in HFpEF, HFmEF, and HFrEF patients.
This study included 973 HF patients who underwent clinically indicated CPET at the Brigham and Women's Hospital between July 2007 and December 2012 as previously described.17 Participants with missing baseline LVEF data (n=4) were excluded, resulting in 969 subjects for the analysis. The study was approved by the Partners Human Research Committee, which waived the requirement for informed consent.
Classification of HF Patients
LVEF was assessed at the Brigham and Women's Hospital by quantitative echocardiography. Values of LVEF were obtained from echocardiography examinations that were most contemporary to the CPET dates (median time difference [25th, 75th percentiles]=0 [0, 10] days). For the primary analysis, participants were categorized based on LVEF as HFrEF if the LVEF was <40% (n=630), HFmEF if the LVEF was 40% to 49% (n=144), and HFpEF if the LVEF was ≥50% (n=195), as suggested by current guidelines.8
Clinical Variables Definition
Information regarding patients' demographics, body mass index, blood pressure, heart rate, current medications, presence of implantable cardioverter‐defibrillator, cardiac resynchronization therapy, or pacemaker, and gas‐exchange variables were collected at the time of CPET. Further clinical characteristics (comorbidities and New York Heart Association Classification) and laboratory values (hemoglobin and creatinine) most contemporary to CPET dates were obtained from chart review. Antiarrhythmic medications included digoxin and amiodarone. The Chronic Kidney Disease Epidemiology Collaboration formula was used to estimate glomerular filtration rate.18 Chronic kidney disease was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m2. Anemia was defined as hemoglobin <12 g/dL in women and <13 g/dL in men. Angiotensin‐converting‐enzyme inhibitors and angiotensin receptor blockers were coded into a single variable, while cardiac resynchronization therapy and implantable cardioverter‐defibrillator were coded as a single variable.
Exercise tests were performed in the Brigham and Women's Hospital cardiopulmonary exercise laboratory with the subjects breathing room‐air, using ramp protocols.17 Symptom‐limited CPET was performed on all subjects. Pharmacological therapy was continued before and through exercise testing. The equipment was calibrated daily as recommended by the manufacturer. VO2, carbon dioxide production (VCO2), and minute ventilation (VE) were acquired breath‐by‐breath and averaged over a 10‐second interval, using a ventilatory expired gas analysis system (MGC Diagnostics, St. Paul, MN). Peak VO2 was defined as the highest 10‐second averaged VO2 during the last stage of the symptom‐limited exercise test. The Wasserman formula was used to determine percent of predicted peak VO2.19 VE/VCO2 slope was calculated from rest to the gas exchange at peak exercise. Blood pressure was measured using a standard cuff sphygmomanometer. Resting and peak heart rate were obtained from the associated‐CPET ECGs. Age‐predicted maximal heart rate was estimated by Astrand's formula20: 220—age (years). Chronotropic index was calculated as: (peak heart rate−resting heart rate)/(age‐predicted maximal heart rate−resting heart rate).21
Clinical outcomes included the composite outcome of all‐cause death, LVAD implantation, or heart transplantation up to December 31, 2014, and incident and total HF hospitalization up to 2 years post‐CPET. LVAD implantations, heart transplantations, and HF hospitalizations were abstracted by chart review by individuals who were blinded to CPET data. HF hospitalizations were defined as any hospitalization for treatment or management of HF. All‐cause death was determined using the National Death Index.
Continuous variables are expressed as mean±SD for normally distributed data or median [25th, 75th percentiles] for non‐normally distributed data. Categorical variables are expressed as number of subjects and proportion. Comparisons of clinical and CPET features among the studied groups were performed using 1‐way ANOVA for normally distributed variables, Kruskal–Wallis test for non‐normally distributed variables, and χ2 test for categorical variables. The rates of incident outcomes are expressed as events per 100 person‐years at risk.
Univariate and multivariable Cox regression models were used to assess the unadjusted and adjusted association between unit decrease of peak VO2 and unit increase of VE/VCO2 slope and the studied outcomes within each LVEF category. For the composite outcome of death, LVAD, or transplant, models used follow‐up through December 31, 2014 (median [interquartile range]=4.2 [2.8–5.6], 3.9 [2.5–5.5], 4.8 [3.2–5.8], and 4.5 [3.1–5.8] years for the total, HFrEF, HFmEF, and HFpEF samples, respectively). For incident HF hospitalization, models used follow‐up through 2 years post‐CPET (median [interquartile range]=2.0 [0.2–2.0], 1.6 [0.1–2.0], 2.0 [0.5–2.0], and 2.0 [1.2–2.0] years for the total, HFrEF, HFmEF, and HFpEF samples, respectively). The relationship between peak VO2 and VE/VCO2 slope and total HF hospitalization was evaluated using negative binomial models for recurrent events. For all Cox regression and negative binomial regression analyses, we used an overall model including LVEF as a categorical variable. However, we noted a violation of the proportionality assumption when including all patients in the same Cox regression model. We therefore used stratified Cox models using LVEF category as a stratification factor. Multivariable models adjusted for the following established prognostic variables in HF: age, sex, LVEF, chronic kidney disease, resting heart rate, resting systolic blood pressure, and coronary artery disease. The interaction between CPET variables and HF categories for the studied outcomes was assessed using interaction terms. The incremental value of peak VO2 and VE/VCO2 slope when added to clinical covariates either individually or together was evaluated using C‐statistic, continuous net reclassification improvement (NRI), and integrated diagnostic improvement (IDI) with time‐to‐event data.22 All C‐statistics values were obtained via leave‐1‐out cross validation. The clinical covariates included age, sex, LVEF, chronic kidney disease, resting heart rate, resting systolic blood pressure, and coronary artery disease. In secondary analysis, we categorized the HFpEF, HFmEF, and HFrEF groups using cutoff points for CPET variables that are reported to be of prognostic significance (14 mL/min per kg for peak VO2 and 30 for VE/VCO2 slope),1 and compared incidence rates of the studied outcomes between high and low peak VO2 and VE/VCO2 slope within each LVEF group. We also performed the following sensitivity analyses, which consisted of repeating the primary analysis after (1) considering the composite of incident HF hospitalization, death, transplant, or LVAD implantation at 2 years post‐CPET as the outcome; and (2) substituting percent of peak VO2 based on the Wasserman formula19 for peak VO2.
Statistical analysis was performed using Stata software Version 13.1 (Stata Corp LP, College Station, TX, USA). NRI and IDI analyses were performed using R software version 3.2.3. P<0.05 was considered significant.
The mean age of the population was 55±14 years and was not significantly different between LVEF categories. While 33% overall were women, the prevalence was lowest in HFrEF and highest in HFpEF, with an intermediate prevalence in HFmEF. HFrEF had a higher prevalence of diabetes mellitus and coronary artery disease, and lower prevalence of postchemotherapy status and New York Heart Association Class I, while HFmEF had lower prevalence of chronic kidney disease than the other LVEF groups (Table 1). Use of angiotensin‐converting‐enzyme inhibitors/angiotensin receptor blockers, β‐blockers, aldosterone antagonists, diuretics, pacemakers, and cardiac resynchronization therapy/implantable cardioverter‐defibrillator were all most common in HFrEF, while use of calcium channel blockers was most common in HFpEF. Use of these medical therapies tended to be intermediate in HFmEF when compared with HFrEF and HFpEF.
Cardiopulmonary Exercise Performance
HFpEF and HFmEF patients had a lower resting heart rate and higher resting systolic blood pressure than HFrEF patients. Mean peak respiratory exchange ratio, a measure of exercise effort, was similar in all LVEF categories. With exercise, HFpEF and HFmEF patients showed higher peak heart rate, chronotropic index, and systolic and diastolic blood pressures than HFrEF patients. HFpEF and HFmEF participants had higher absolute and percent of predicted peak VO2, and lower VE/VCO2 slope compared with HFrEF participants (Table 2).
During a median follow‐up of 4.2 [2.8–5.6] years, 256 patients (26% of the study sample) experienced the composite outcome (164 all‐cause deaths, 37 LVAD implantations, and 55 heart transplantations). Annualized event rates were similar between the HFmEF and HFpEF groups, and considerably higher in the HFrEF group (Table 3). In multivariable Cox models containing clinical predictors, peak VO2, and VE/VCO2 slope, both peak VO2 and VE/VCO2 slope were independently associated with the composite outcome in HFpEF, HFmEF, and HFrEF (Table 3). Notably, the relative risk associated with peak VO2 increased in a graded pattern from HFrEF to HFpEF, with intermediate values in HFmEF. Interactions were noted between HFpEF/HFrEF and peak VO2 (Pinteraction=0.052) and VE/VCO2 slope (Pinteraction=0.012) with respect to the composite outcome. Although the absolute event rates of the composite outcome associated with any given value of peak VO2 and VE/VCO2 slope were consistently lower in HFpEF compared with HFrEF, the relative risk associated with a unit change in each CPET variable was greater in HFpEF compared with HFrEF (Table 3 and Figure 1). Similar findings were noted when modeling CPET variables as dichotomous variables (Figure 2 and Table S1).
By 2 years post‐CPET, 244 patients (25% of the study sample) experienced an incident HF hospitalization, and 475 total HF hospitalizations occurred. Similar to the composite end point, rates of HF hospitalization were similar between the HFmEF and HFpEF groups, and considerably higher in the HFrEF group (Table 3). In multivariable analysis, both peak VO2 and VE/VCO2 slope were independently associated with incident HF hospitalization in HFpEF and HFrEF. In contrast, only peak VO2 was associated with incident HF hospitalization in HFmEF (Table 3). Similar findings were noted for the composite of incident HF hospitalization, death, transplant, or LVAD implantation at 2 years post‐CPET (Table S2). Interactions between HFpEF/HFrEF and peak VO2 (Pinteraction=0.003) and VE/VCO2 slope (Pinteraction=0.019) were noted with respect to the risk of incident HF hospitalization. In addition, the relative risk of incident HF hospitalization associated with a unit change in each CPET variable was greater in HFpEF compared with HFrEF (Table 3 and Figure 1), with similar findings when modeling peak VO2 and VE/VCO2 as dichotomous variables (Figure 2 and Table S1). Peak VO2 was independently associated with total number of HF hospitalizations in all LVEF categories, while VE/VCO2 was independently associated with total number of HF hospitalizations only in HFrEF (Table 3).
In the HFpEF and HFrEF groups, both peak VO2 and VE/VCO2 individually provided incremental prognostic value beyond clinical variables in predicting the composite end point and incident HF hospitalization based on the cross‐validated C‐statistic, NRI, and IDI (Table 4). The largest improvement in C‐statistic and changes in NRI and IDI were observed with the addition of both peak VO2 and VE/VCO2 to clinical covariates in the HFpEF and HFrEF groups. In HFmEF patients, CPET variables did not provide incremental prognostic value when assessed by C‐statistic, even though there was a trend toward improvement in NRI and IDI when adding peak VO2 to clinical variables, particularly for incident HF hospitalization.
Our analysis of the prognostic value of peak VO2 and VE/VCO2 slope in HFpEF, HFmEF, and HFrEF is one of the first, to our knowledge, to specifically assess the prognostic relevance of functional capacity and ventilatory efficiency in HFmEF and to quantify their incremental value in HFpEF. Our study has 3 major novel findings. First, both peak VO2 and VE/VCO2 slope provide independent and incremental prognostic value for the composite of all‐cause death, LVAD implantation or heart transplant, and for incident HF hospitalization in HFpEF. Second, the magnitude of association between peak VO2 and VE/VCO2 slope and adverse outcomes was greater in HFpEF compared with HFrEF, such that these CPET variables provided greater risk discrimination in HFpEF compared with HFrEF. Third, the relative risk associated with peak VO2 for all studied outcomes had intermediate values in HFmEF when compared with HFrEF and HFpEF. These findings support the use CPET as a robust tool for prognostic stratification of HFpEF patients.
Existing studies regarding the prognostic relevance of CPET in HFpEF have demonstrated conflicting results. In 46 patients with LVEF ≥50%, Guazzi et al reported that VE/VCO2 slope, but not peak VO2, was associated with all‐cause mortality and hospitalization at 1 year.13 The same group subsequently reported that VE/VCO2 slope, but not peak VO2, was associated with cardiac‐related death in a sample of 151 HFpEF patients with an average LVEF value of 47.8% and a median follow‐up of 13 months.14 Notably, multivariable adjustment for clinical risk factors was not included in these 2 reports. In a study including 224 HFpEF (LVEF ≥50%) patients with a mean follow‐up of 30 months, Yan et al found that VE/VCO2 slope, but not peak VO2, was associated with all‐cause mortality after adjusting for clinical variables and brain natriuretic peptide levels.15 In contrast, Shafiq et al found that peak VO2, but not VE/VCO2 slope, was associated with all‐cause mortality or cardiac transplant after adjusting for age, sex, and β‐blockade therapy in their study of 173 HFpEF (LVEF ≥50%) patients followed up for a median of 5.2 years.16 Our study had more diverse outcomes than previous reports and a larger sample size than most of the former studies.13, 14, 15, 16 In multivariable analysis including a greater number of relevant clinical covariates than previous studies,15, 16 both VE/VCO2 slope and peak VO2 (absolute or percent of predicted) were independently prognostic in HFpEF patients. Beyond demonstrating an independent association with HF morbidity and mortality, VE/VCO2 slope and peak VO2 provided incremental prognostic value beyond relevant clinical covariates, as assessed by C‐statistic, NRI and IDI, demonstrating that both measures provide complementary prognostic information in HFpEF.
Consistent with prior reports,13 at any given value of peak VO2 or VE/VCO2 slope, HFrEF patients demonstrated higher event rates than HFpEF patients for all study outcomes. However, in Cox regression analysis, the magnitude of association between peak VO2 and VE/VCO2 slope and outcomes is greater in HFpEF compared with HFrEF, suggesting that peak VO2 and VE/VCO2 slope may offer greater prognostic discrimination in HFpEF than HFrEF. The reasons for these differences are not certain, but may relate to the greater clinical and pathophysiologic heterogeneity characterizing the HFpEF syndrome relative to HFrEF.6 Conversely, the lower event rates in HFpEF participants than in HFrEF participants, particularly at the highest peak VO2 and the lowest VE/VCO2 slope values, may contribute to the greater relative risk associated with these measures in HFpEF compared with HFrEF. Indeed, the absolute difference in event rates was higher in HFrEF than in HFpEF when comparing high versus low peak VO2 and VE/VCO2 slope modeled dichotomously. However, these findings demonstrate the ability of peak VO2 and VE/VCO2 slope to identify patients with HFpEF with very low risk (composite outcome in 0.0% annually and HF hospitalization in 1.4% annually with peak VO2 >14 mL/min per kg and VE/VCO2 slope <30) and very high risk (composite outcome in 8.7% annually and HF hospitalization in 20.6% annually with both CPET measures abnormal). This degree of risk discrimination is particularly impressive when compared with other routinely used approaches to risk stratification in HFpEF. For example, echocardiographic abnormalities of left ventricular hypertrophy, left atrial enlargement and pulmonary hypertension, or elevated circulating natriuretic peptide levels (NT‐proBNP >339 pg/mL) have been associated with 1.5‐ to 2.5‐fold higher risk of adverse outcomes in HFpEF populations,23, 24, 25 strengthening the notion that CPET measures are a robust tool for prognostic stratification in HFpEF. Further studies may be necessary to assess whether peak VO2 and VE/VCO2 slope are CPET measures that should be systematically incorporated into decision algorithms for clinicians aiming to stratify risk and prognosis in HF patients across the LVEF spectrum.
Recent recommendations have defined a third HF category, HFmEF, comprising patients with LVEF ranging from 40% to 49%.8 Our analysis, one of the first to our knowledge to specifically interrogate HFmEF relative to HFpEF and HFrEF, demonstrates that clinical features of this group are generally intermediate between those of HFpEF and HFrEF, while CPET performance metrics of HFmEF more closely approximate to HFpEF patients. Notably, the relative risk associated with peak VO2 for all studied outcomes had intermediate values in HFmEF when compared with HFrEF and HFpEF. In contrast, VE/VCO2 slope—which was robustly associated with the composite outcome and incident HF hospitalization in both HFrEF and HFpEF—was associated with the composite outcome, but tended to show a neutral association with incident HF hospitalization in HFmEF in fully adjusted analysis. The reasons for this are unclear, but our midrange LVEF sample size was relatively small, and our power may therefore have been limited. However, for recurrent HF hospitalization, effect estimates were clearly neutral in HFmEF, making power alone an unlikely explanation. Further studies in larger samples are required to confirm and further clarify these observations.
This study has several limitations. First, this is an observational study, and thus we cannot exclude the possibility of residual confounding of the observed associations between peak VO2, VE/VCO2 slope, and clinical outcomes. Second, our study population consisted of patients referred for CPET at a tertiary medical center, who may not be representative of the overall HF population, potentially limiting the generalizability of our results. However, the average values of peak VO2 and VE/VCO2 slope in our population were similar to those reported in other HFrEF and HFpEF populations of comparable age,13, 16, 26, 27 suggesting that our HF sample had functional capacity measures that reflected those commonly seen in standard practice. Additionally, the rates of both mortality and HF hospitalization in our sample of HFpEF subjects were similar to those reported in HFpEF clinical trials.28, 29 Third, LVAD implantation, heart transplantation, and HF hospitalization data were obtained by review of Brigham and Women's Hospital charts, which could have led to underestimation of these outcomes. However, the frequency of these events occurring at a referral institution different from where they are being longitudinally followed is usually low. Fourth, natriuretic peptides levels, which have known prognostic relevance in HF, were not available or uniformly assessed in our population. Fifth, we did not routinely collect measures of subjective effort in our CPET database. However, we objectively measured subject effort by peak respiratory exchange ratio, which is considered both accurate and reliable.1 Sixth, LVEF was included as a covariate in all multivariate models, which might raise the possibility of multicollinearity, given that HF categories were derived based on LVEF. We included LVEF as a covariate because this variable showed an inverse relationship with the studied outcomes even within HF categories (Figure S1). This approach is concordant with other reports that also included LVEF in multivariate models when evaluating outcomes in HF patients stratified by LVEF categories.30, 31 Importantly, the exclusion of LVEF from our multivariate models did not change the observed associations between CPET variables and the studied outcomes (Table S5).
Peak VO2 is robustly predictive of worse prognosis in HFpEF, HFmEF, and HFrEF. Among patients with HFpEF, both peak VO2 and VE/VCO2 slope provided incremental prognostic value beyond relevant clinical covariates for the composite of all‐cause death, LVAD implantation or heart transplant, and for incident HF hospitalization. Notably, the magnitude of association between peak VO2 and VE/VCO2 slope and adverse outcomes was greater in HFpEF compared with HFrEF, such that these CPET variables provided greater risk discrimination in HFpEF compared with HFrEF. Together these findings support the notion that CPET is a robust albeit underutilized tool for risk stratification in HFpEF.
Sources of Funding
This work was supported by NHLBI grant K08HL116792 (Shah), AHA grant 14CRP20380422 (Shah), a Watkins Discovery Award from the Brigham and Women's Heart and Vascular Center (Shah), and the Brazilian National Council for Scientific and Technological Development grant 249481/2013‐8 (Nadruz).
Dr Shah reports receiving research support from Novartis and Gilead, and consulting fees from Myocardia. The other authors have nothing to disclose.
Table S1. Unadjusted Incidence Rates, Rate Differences, and Adjusted Hazard Ratios of the Studied Outcomes in HFpEF and HFrEF Patients Categorized According to Presence of Abnormalities in CPET Measures
Table S2. Univariate and Multivariable Cox Regression Analyses of CPET Variables for the Composite of Incident HF Hospitalization or Composite Outcome Up to 2 Y Post‐CPET in HFrEF, HFmEF, and HFpEF Patients
Table S3. Univariate and Multivariable Cox Regression Analyses of CPET Variables (% of Predicted Peak VO2 and VE/VCO2 Slope) for the Composite Outcome (Death, Left Ventricular Assist Device Implantation or Transplant), Incident HF Hospitalization, and Total HF Hospitalization in Patients With HFrEF, HFmEF, and HFpEF
Table S4. Incremental Value of CPET Variables (% of Predicted Peak VO2 and VE/VCO2 Slope) in Predicting the Composite Outcome (Death, Left Ventricular Assist Device Implantation or Transplant) or Incident HF Hospitalization Beyond Clinical Variables in Patients With HFrEF, HFmEF, and HFpEF
Table S5. Multivariable Cox Regression Analyses of CPET Variables for the Composite Outcome (Death, Left Ventricular Assist Device Implantation or Transplant), Incident HF Hospitalization and Total HF Hospitalization in Patients With HFrEF, HFmEF, and HFpEF Including or Not LVEF as a Covariate
Figure S1. Unadjusted relationship between incidence of studied outcomes and LVEF assessed by restricted cubic splines.
- ↵Balady GJ, Arena R, Sietsema K, Myers J, Coke L, Fletcher GF, Forman D, Franklin B, Guazzi M, Gulati M, Keteyian SJ, Lavie CJ, Macko R, Mancini D, Milani RV; American Heart Association Exercise, Cardiac Rehabilitation, and Prevention Committee of the Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Interdisciplinary Council on Quality of Care and Outcomes Research . Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation. 2010;122:191–225.
- ↵Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol. 2003;41:1510–1518.
- ↵Samson R, Jaiswal A, Ennezat PV, Cassidy M, Le Jemtel TH. Clinical phenotypes in heart failure with preserved ejection fraction. J Am Heart Assoc. 2016;5:e002477. DOI: 10.1161/JAHA.115.002477.
- ↵Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González‐Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members . 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
- ↵Guazzi M. Cardiopulmonary exercise testing in heart failure preserved ejection fraction: time to expand the paradigm in the prognostic algorithm. Am Heart J. 2016;174:164–166.
- ↵Nedeljkovic I, Banovic M, Stepanovic J, Giga V, Djordjevic‐Dikic A, Trifunovic D, Nedeljkovic M, Petrovic M, Dobric M, Dikic N, Zlatar M, Beleslin B. The combined exercise stress echocardiography and cardiopulmonary exercise test for identification of masked heart failure with preserved ejection fraction in patients with hypertension. Eur J Prev Cardiol. 2016;23:71–77.
- ↵Edelmann F, Wachter R, Schmidt AG, Kraigher‐Krainer E, Colantonio C, Kamke W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen HD, Tschöpe C, Herrmann‐Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B; Aldo‐DHF Investigators . Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo‐DHF randomized controlled trial. JAMA. 2013;309:781–791.
- ↵Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, LeWinter MM, Rouleau JL, Bull DA, Mann DL, Deswal A, Stevenson LW, Givertz MM, Ofili EO, O'Connor CM, Felker GM, Goldsmith SR, Bart BA, McNulty SE, Ibarra JC, Lin G, Oh JK, Patel MR, Kim RJ, Tracy RP, Velazquez EJ, Anstrom KJ, Hernandez AF, Mascette AM, Braunwald E; RELAX Trial . Effect of phosphodiesterase‐5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013;309:1268–1277.
- ↵Guazzi M, Myers J, Arena R. Cardiopulmonary exercise testing in the clinical and prognostic assessment of diastolic heart failure. J Am Coll Cardiol. 2005;46:1883–1890.
- ↵Shafiq A, Brawner CA, Aldred HA, Lewis B, Williams CT, Tita C, Schairer JR, Ehrman JK, Velez M, Selektor Y, Lanfear DE, Keteyian SJ. Prognostic value of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. The Henry Ford HospITal CardioPulmonary EXercise Testing (FIT‐CPX) project. Am Heart J. 2016;174:167–172.
- ↵Nadruz W Jr., West E, Santos M, Skali H, Groarke JD, Forman DE, Shah AM. Heart failure and midrange ejection fraction: implications of recovered ejection fraction for exercise tolerance and outcomes. Circ Heart Fail. 2016;9:e002826.
- ↵Brubaker PH, Kitzman DW. Chronotropic incompetence: causes, consequences, and management. Circulation. 2011;123:1010–1020.
- ↵Anand IS, Rector TS, Cleland JG, Kuskowski M, McKelvie RS, Persson H, McMurray JJ, Zile MR, Komajda M, Massie BM, Carson PE. Prognostic value of baseline plasma amino‐terminal pro‐brain natriuretic peptide and its interactions with irbesartan treatment effects in patients with heart failure and preserved ejection fraction: findings from the I‐PRESERVE trial. Circ Heart Fail. 2011;4:569–577.
- ↵Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu CF, Massie BM, Carson PE; I‐PRESERVE Investigators . Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011;124:2491–2501.
- ↵Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O'Meara E, Desai AS, Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial. Circ Heart Fail. 2014;7:740–751.
- ↵Chase PJ, Kenjale A, Cahalin LP, Arena R, Davis PG, Myers J, Guazzi M, Forman DE, Ashley E, Peberdy MA, West E, Kelly CT, Bensimhon DR. Effects of respiratory exchange ratio on the prognostic value of peak oxygen consumption and ventilatory efficiency in patients with systolic heart failure. JACC Heart Fail. 2013;1:427–432.
- ↵Keteyian SJ, Patel M, Kraus WE, Brawner CA, McConnell TR, Piña IL, Leifer ES, Fleg JL, Blackburn G, Fonarow GC, Chase PJ, Piner L, Vest M, O'Connor CM, Ehrman JK, Walsh MN, Ewald G, Bensimhon D, Russell SD; HF‐ACTION Investigators . Variables measured during cardiopulmonary exercise testing as predictors of mortality in chronic systolic heart failure. J Am Coll Cardiol. 2016;67:780–789.
- ↵Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees . Effects of candesartan in patients with chronic heart failure and preserved left‐ventricular ejection fraction: the CHARM‐Preserved Trial. Lancet. 2003;362:777–781.
- ↵Gupta DK, Shah AM, Castagno D, Takeuchi M, Loehr LR, Fox ER, Butler KR, Mosley TH, Kitzman DW, Solomon SD. Heart failure with preserved ejection fraction in African Americans: the ARIC (Atherosclerosis Risk In Communities) study. JACC Heart Fail. 2013;1:156–163.
- ↵Yanagihara K, Kinugasa Y, Sugihara S, Hirai M, Yamada K, Ishida K, Kato M, Yamamoto K. Discharge use of carvedilol is associated with higher survival in Japanese elderly patients with heart failure regardless of left ventricular ejection fraction. J Cardiovasc Pharmacol. 2013;62:485–490.