Usefulness of ventilatory inefficiency in predicting prognosis across the heart failure spectrum

Introduction

Cardiopulmonary exercise testing (CPET) measures cardiopulmonary reserve and provides an important prognostic tool in the management of heart failure (HF). In addition to peak oxygen consumption (peak VO2), the ratio of minute ventilation to carbon dioxide production (VE/VCO2 slope), a measure of ventilatory efficiency, strongly predicts adverse events in HF.1 In clinical practice, a single VE/VCO2 slope threshold defining abnormal, most commonly ≥36, is employed across the spectrum of HF categorized by left ventricular ejection fraction (LVEF).1-3 However, the predictive value of this VE/VCO2 slope threshold has largely been validated in patients with HF with reduced LVEF (HFrEF),4-7 and its application in patients with HF with mid-range LVEF (HFmrEF) and HF with preserved LVEF (HFpEF) requires additional validation.8-10

Moreover, a wide range of VE/VCO2 slope values are seen in clinical practice, and so risk stratification based on a single cut-point might underutilize the prognostic utility of VE/VCO2 slope. A multilevel categorization system developed in a small cohort (n = 448) of patients with HF, predominantly HFrEF (76%), correlated higher categories of VE/VCO2 slope cut-points with increasing risk of cardiac-related events.3 Whether a similar classification could refine prognostication and clinical decision-making warrants further evaluation in a larger cohort of patients with HF, especially those with HFmrEF or HFpEF. The objectives of this study were to evaluate and compare the prognostic utility of a multilevel VE/VCO2 slope classification system across categories of HF defined by LVEF.

Methods Study design

This was a single-centre, retrospective cohort study. Consecutive patients with a diagnosis of HF with known LVEF, who were clinically referred for CPET between June 2010 through December 2016 at Brigham and Women's Hospital, were considered for inclusion in this study. Patients were diagnosed as having HF if they had (i) a diagnosis of HF in the electronic medical record (EMR), (ii) documented use of loop diuretics/metolazone, or (iii) cardiomyopathy defined as LVEF < 40%. HF was then categorized into HFrEF (LVEF < 40%), HFmrEF (40% ≤ LVEF < 50%), and HFpEF (LVEF ≥ 50%) based on LVEF derived either by transthoracic echocardiography (n = 1309) or cardiac magnetic resonance imaging (n = 38) performed within a median of 1 day [interquartile range (IQR) 0, 76 days] of CPET.

Patients were excluded if they had incomplete CPET data, any history of a left-ventricular-assist device (LVAD) or cardiac transplantation prior to date of CPET, or where CPET did not follow a ramp protocol on an upright cycle ergometer. The final cohort consisted of 1347 patients (Supporting Information, Figure S1). This study was approved by the Partners Healthcare System Institutional Review Board.

Clinical information

Demographics, indications for exercise testing, and cardiovascular (CV) history and medications were prospectively recorded at the time of CPET by the exercise physiologist using a structured patient interview and EMR review. Ischaemic heart disease was defined as a history of myocardial infarction, coronary revascularization, or documented obstructive angiographic coronary artery disease. Hyperlipidaemia was defined as a known diagnosis of hyperlipidaemia or statin use at time of CPET. Diabetes mellitus was defined as a known diagnosis of diabetes mellitus or use of insulin or oral hypoglycaemic agents at time of CPET.

Cardiopulmonary exercise testing protocol

All CPETs were performed using a ramp protocol on an upright cycle ergometer (Lode Corival, Groningen, The Netherlands) with subjects breathing room air. Ventilatory expired gas analysis was performed using a metabolic cart (Breeze Suite 8.6.0.65 SP1, MGC Diagnostics, St. Paul, MN). Standard 12-lead electrocardiogram and blood pressures were obtained at rest, every 2 to 3 min during exercise, and for a period ≥4 min during the recovery phase. Baseline metabolic evaluation was performed during a 2- min rest period before exercise and during cool-down period for ≥1 min. VE, VO2, and VCO2 were acquired breath-by-breath and averaged for 10 s. Peak VO2 was defined as the highest 10 s averaged VO2 around the time of maximal effort. A set of previously published normative equations were used to estimate predicted peak VO2.11 VE/VCO2 slope was calculated by linear regression from the start of freewheel to the end of the test (peak exercise). All gas exchange calculations were performed automatically by the metabolic cart software and were manually verified by the exercise physiologist performing the test and subsequently by a cardiologist. Four ventilatory categories (VC) were defined based on previous work by Arena et al.3: VC-I, VE/VCO2 slope ≤ 29; VC-II, 29 < VE/VCO2 slope < 36; VC-III, 36 ≤ VE/VCO2 slope < 45; and VC-IV, VE/VCO2 slope ≥ 45.

Study endpoints

The primary endpoint was a composite of all-cause mortality or HF hospitalization (whichever occurred first) occurring within 2 years of CPET. Events were included through 1 July 2017. Mortality was determined using the Partners Health Care Research Patient Data Registry (linked to the Social Security Death Index, updated 30 July 2017). HF hospitalizations were abstracted by EMR review and were defined as unplanned admissions with clinical presentations consistent with HF exacerbations requiring escalation of existing HF treatment or initiation of new therapies (Table S1). Patients who received a LVAD or cardiac transplant after the CPET date were right-censored at the time of this event. Patients who were lost to follow-up were also right-censored.

Statistical analyses

Continuous variables with approximately normal distributions are reported as means ± standard deviation and compared using one-way ANOVA across all three HF cohorts. Continuous, non-normal data are presented as medians with IQR and compared using the Kruskal–Wallis test. Categorical variables are presented as counts with percentages and compared using Fisher's exact test. Median follow-up was estimated using the reverse Kaplan–Meier method.12 To examine the association between VE/VCO2 slope category and the composite outcome, cause-specific Cox proportional-hazards regression models were used. The VE/VCO2 slope category ≤ 29 (VC-I) was used as the reference group. A cause-specific approach was used for modelling, as LVAD and cardiac transplant (n = 34) were treated as competing risks; therefore, both events were right-censored. Unadjusted and adjusted (continuous age and gender) hazard ratios with 95% confidence intervals (CIs) were presented. Additionally, continuously measured VE/VCO2 slope was specified using restricted cubic splines with four knots in a model adjusting for age and gender. The number of knots was chosen using Akaike's information criterion. All models were assessed for overly influential patients, proportional hazards, and linearity. Cumulative incidence curves of the composite outcome were compared across VE/VCO2 slope categories for each LVEF cohort using Gray's test of equivalence.

Time-dependent receiver operating characteristic analysis was performed using the nearest neighbours approach to examine the performance of previously defined VE/VCO2 slope cut-offs (29 and 36)3 as predictors of the composite outcome at 2 year follow-up.3, 13 Sensitivity and specificity were calculated along with 95% CIs generated through bootstrapping using the percentile method.14 We independently determined VE/VCO2 slope cut-offs using Youden's index (maximizing sensitivity + specificity) and bootstrapped CIs to allow for comparison across LVEF.

Receiver operating characteristic analysis was also used to compare the performance of peak VO2, VE/VCO2 slope, and the combination of peak VO2 and VE/VCO2 slope as predictors of the 2 year composite outcome. All hypothesis testing was two-tailed, and P values less than 0.05 were considered statistically significant. Statistical analyses were performed using SAS Version 9.4 (SAS Institute, Cary, North Carolina, USA).

Results Baseline demographics

The entire cohort of 1347 patients had a mean age of 58.0 ± 14.6 years and was predominantly Caucasian (85.0%) and male (60.5%) (Table 1). Compared with HFmrEF and HFpEF cohorts, patients in the HFrEF cohort were more likely to be male, with a higher prevalence of diabetes, hypertension, hypercholesterolemia, ischaemic heart disease, and smoking (Table 1). All CV medications were more commonly prescribed in HFrEF compared with other cohorts (Table 1).

TABLE 1. Baseline demographics of the study cohorts Entire cohort (n = 1347) HFrEF (n = 598) HFmrEF (n = 164) HFpEF (n = 585) P value Gender, male 815 (60.5%) 430 (71.9%) 98 (56.8%) 287 (49.1%) <0.0001 Age, years 58.0 ± 14.6 58.3 ± 13.1 55.8 ± 14.6 58.1 ± 16.0 0.12 Body mass index (kg/m2) 29.0 ± 6.3 28.2 ± 5.4 28.8 ± 6.2 29.9 ± 7.1 <0.0001 Racea Caucasian 1076 (85.0%) 475 (83.3%) 130 (83.3%) 471 (87.2%) 0.59 African American 90 (7.1%) 46 (8.1%) 15 (9.6%) 29 (5.4%) Hispanic/Latino 35 (2.8%) 20 (3.5%) 5 (3.2%) 10 (1.9%) Asian 20 (1.6%) 11 (1.9%) 2 (1.3%) 7 (1.3%) American Indian 2 (0.2%) 1 (0.2%) 0 (0.0%) 1 (0.2%) Others 10 (0.8%) 4 (0.7%) 1 (0.6%) 5 (0.9%) Missing/Unknown 33 (2.6%) 13 (2.3%) 3 (1.9%) 17 (3.2%) Left ventricular ejection fraction (%) 42 ± 17 25 ± 7 42 ± 2 59 ± 6 <0.0001 Diabetes mellitus 309 (22.9%) 167 (27.9%) 29 (17.7%) 113 (19.3%) <0.001 Hypertension 912 (67.7%) 425 (71.1%) 111 (67.7%) 376 (64.3%) 0.044 Peripheral vascular disease 21 (1.6%) 13 (2.2%) 3 (1.8%) 5 (0.9%) 0.18 Hypercholesterolemia 757 (56.2%) 372 (62.2%) 91 (55.5%) 294 (50.3%) <0.001 Ischaemic heart disease 388 (28.8%) 244 (40.8%) 37 (22.6%) 107 (18.3%) <0.0001 Active smoking 89 (6.6%) 55 (9.2%) 8 (4.9%) 26 (4.4%) 0.003 ACEi/ARB 772 (57.3%) 422 (70.6%) 108 (65.9%) 242 (41.4%) <0.0001 Beta-blocker 1030 (76.5%) 527 (88.1%) 138 (84.2%) 365 (62.4%) <0.0001 Aspirin 617 (45.8%) 303(50.7%) 69 (42.1%) 245 (41.9%) 0.006 Statin 655 (48.6%) 323 (54.0%) 80 (48.8%) 252 (43.1%) <0.001 Digoxin 54 (4.0%) 40 (6.7%) 5 (3.1%) 9 (1.5%) <0.0001 Loop diuretics/Metolazone 849 (63.0%) 403 (67.4%) 89 (54.3%) 357 (61.0%) 0.004 MRA 327 (24.3%) 214 (35.8%) 45 (27.4%) 68 (11.6%) <0.0001 ACEi/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist. Values are mean ± SD or n (%). Cardiopulmonary exercise testing results

The mean peak VO2 for the entire cohort was 15.0 ± 6.6 mL/kg/min with a mean peak respiratory exchange ratio of 1.16 ± 0.14; more than half the cohort had peak VO2 < 14 mL/kg/min (Table 2). The median VE/VCO2 slope for the entire cohort was 32.0 (IQR 27.9, 38.4). Compared with patients with HFmrEF or HFpEF, patients with HFrEF had a higher proportion with peak VO2 below 14 mL/kg/min (60.9% vs. 45.1% vs. 49.0%, P < 0.001) and achieved a statistically significantly lower peak VO2 (13.8 ± 5.3 vs. 16.0 ± 6.8 vs. 16.2 ± 7.5, P < 0.001; Table 2). Patients with HFrEF also had higher median VE/VCO2 slope [33.8 (IQR 29.2, 41.8) vs. 30.0 (IQR 26.4, 44.5) vs. 31.0 (27.2, 36.8), P < 0.001; Table 2). In addition, patients with HFrEF had higher resting heart rate, lower peak heart rate, and lower systolic and diastolic blood pressures at rest and at peak exercise (Table 2). Compared with HFmrEF patients, patients with HFpEF had significantly higher resting and peak systolic blood pressures (Table 2).

TABLE 2. Cardiopulmonary exercise testing results, overall, and by left ventricular ejection fraction category Entire cohort (n = 1347) HFrEF (n = 598) HFmrEF (n = 164) HFpEF (n = 585) P value VE/VCO2 slope 32.0 (27.9, 38.4) 33.8 (29.2, 41.8) 30.0 (26.4, 44.5) 31.0 (27.2, 36.8) <0.001 Peak VO2 (mL/kg/min) 15.0 ± 6.6 13.8 ± 5.3 16.0 ± 6.8 16.0 ± 7.5 <0.001 Peak VO2 < 14 mL/kg/min 721 (53.8%) 363 (60.9%) 73 (45.1%) 285 (49.0%) <0.001 Peak RER 1.16 ± 0.14 1.17 ± 0.14 1.16 ± 10.13 1.15 ± 0.14 0.005 Resting heart rate (bpm) 72.2 ± 14.0 73.8 ± 14.6 70.9 ± 12.5 70.8 ± 13.5 <0.001 Peak heart rate (bpm) 120.4 ± 28.0 117.5 ± 26.6 123.1 ± 27.9 122.7 ± 29.2 0.003 Resting SBP (mmHg) 121.5 ± 21.9 114.1 ± 19.7 121.3 ± 17.9 128.7 ± 22.8 <0.001 Resting DBP (mmHg) 73.3 ± 11.0 72.4 ± 10.4 73.3 ± 11.2 74.1 ± 11.4 0.040 Peak SBP (mmHg) 145.3 ± 31.5 132.7 ± 28.0 145.6 ± 25.2 158.2 ± 31.3 <0.001 Peak DBP (mmHg) 73.6 ± 12.5 71.6 ± 11.9 74.6 ± 12.5 75.3 ± 12.8 <0.001 Exercise duration (min) 7.4 ± 2.9 7.3 ± 2.8 7.9 ± 3.1 7.3 ± 2.9 0.05 bpm, beats per minute; DBP, diastolic blood pressure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection; HFrEF, heart failure with reduced ejection fraction; METs, metabolic equivalents; RER, respiratory exchange ratio; SBP, systolic blood pressure; VE/VCO2, minute ventilation to carbon dioxide production ratio; VO2, oxygen uptake. Values are mean ± SD, median (interquartile range) or n (%). VE/VCO2 slope category as a predictor of the 2 year composite endpoint

There were 201 composite events (65 deaths and 136 HF hospitalizations) over a median follow-up of 2.0 (IQR: 1.9, 2.0) years (range: 6–730 days) from CPET (Table 3). Higher VE/VCO2 slope categories were associated with incremental 2 year cumulative incidences of the composite outcome within each HF category (Figure 1). Across the entire study cohort, compared with patients in VC-I, those in VC-II, III, and IV had over three-fold, five-fold, and eight-fold increased hazards of the primary composite endpoint [hazard ratio (HR) 3.12, 95% CI 1.86 to 5.26, P < 0.001; HR 5.47, 95% CI 3.20 to 9.35, P < 0.001; HR 8.21, 95% CI 4.75 to 14.18, P < 0.001, respectively; Table 4].

TABLE 3. Study outcome for the entire cohort and left ventricular ejection fraction subgroups Entire cohort (n = 1347) HFrEF (n = 598) HFmrEF (n = 164) HFpEF (n = 585)

Follow-up timea (years)

Range, days

2.0 (1.9, 2.0)

6–730

2.0 (2.0, 2.0)

6–730

2.0 (2.0, 2.0)

13–730

2.0 (1.8, 2.0)

8–730

Deaths + HF hospitalizations, n 201 128 19 54 Deaths, n 65 41 6 18 HF hospitalizations, n 136 87 13 36 HF, heart failure; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection; HFrEF, heart failure with reduced ejection fraction. image

Cumulative incidence of 2 year composite outcome (death and HF admissions) across VE/VCO2 slope categories for (A) all cohorts, (B) HFrEF cohort over time, (C) HFmrEF cohort over time, and (D) HFpEF cohort over time. HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; VC, ventilatory efficiency category.

TABLE 4. Association between VE/VCO2 slope categories and death + HF hospitalization across HF LVEF categories Entire cohort (n = 1347) HFrEF (n = 598) HFmrEF (n = 164) HFpEF (n = 585) Adjusted HRa (95% CI) P value Adjusted HRa (95% CI) P value Adjusted HRa (95% CI) P value Adjusted HRa (95% CI) P value VC-I 1.0 1.0 1.0 1.0 VC-II 3.12 (1.86, 5.26) <0.0001 2.82 (1.40, 5.68) 0.004 3.98 (0.82, 19.23) 0.09 2.67 (1.11, 6.40) 0.028 VC-III 5.47 (3.20, 9.35) <0.0001 5.09 (2.55, 10.19) <0.0001 8.72 (1.67, 45.60) 0.010 2.96 (1.13, 7.78) 0.027 VC-IV 8.21 (4.75, 14.18) <0.0001 6.02 (2.93, 12.38) <0.0001 10.55 (2.03, 54.79) 0.005 8.68 (3.52, 12.40) <0.0001 CI, confidence interval; HF, heart failure; HFmrEF, HF with mid-range ejection fraction; HFpEF, HF with preserved ejection; HFrEF, HF with reduced ejection fraction; HR, hazard ratio, VC, ventilatory category; VE/VCO2, minute ventilation to carbon dioxide production ratio. VC-I: VE/VCO2 slope ≤ 29, VC-II: 29 < VE/VCO2 slope < 36, VC-III: 36 ≤ VE/VCO2 slope < 45, VC-IV: VE/VCO2 slope ≥ 45.

In patients with HFrEF (n = 598), there were 128 composite events within 2 years of CPET (Table 3). Compared with patients in VC-I, patients with HFrEF in VC-II, III, and IV demonstrated incremental risk of the primary composite endpoint (HR 2.82, 95% CI 1.40 to 5.68, P = 0.004; HR 5.09, 95% CI 2.55 to 10.19, P < 0.001; HR 6.02, 95% CI 2.93 to 12.38, P < 0.001, respectively; Table 4).

Among patients with HFmrEF (n = 164), there were 19 composite events within 2 years of CPET (Table 3). Among patients with HFmrEF, VC-III and IV demonstrated increased hazards of the primary composite endpoint compared with VC-I in both unadjusted and adjusted analyses (Tables 4 and S2). VC-II had a trend towards increased risk but did not achieve statistical significance in either unadjusted or adjusted analyses (Tables 4 and S2).

Fifty-four composite events occurred within 2 years of CPET in the HFpEF cohort (n = 585) (Table 3). As with HFrEF, each incremental VE/VCO2 slope category was associated with an increased hazard of the composite endpoint, even after adjusting for age and gender (Tables 4 and S2).

When examined as a continuous variable across the entire cohort, increasing VE/VCO2 slope was associated with a progressive increase in the risk of the 2 year composite outcome (Figure 2).

image

(A) A plot of continuously measured VE/VCO2 slope specified using restricted cubic splines by the hazard ratio for the 2 year composite outcome (death and HF admissions) (reference: VE/VCO2 slope = 29) is displayed for all HF strata (joint Wald test P value < 0.0001). (B) Incremental risk of the 2 year composite outcome across categories of increasing VE/VCO2 slope for the entire cohort and across the spectrum of HF defined by LVEF. HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Receiver operating characteristic analysis

Receiver operating characteristic analysis demonstrated that a threshold VE/VCO2 slope > 36, which is commonly employed in clinical practice, was more specific but less sensitive for the primary composite endpoint when applied to the HFmrEF and HFpEF cohorts compared with the HFrEF cohort (Table 5). Alternatively, a lower VE/VCO2 slope cut-point of 29 was associated with higher sensitivity (>85.0% in all three categories) at the cost of lower specificity across all HF categories (Table 5). These cut-points were then independently validated in our cohort (Figure 3). We compared the predictive value of peak VO2, VE/VCO2 slope, and the combination of peak VO2 and VE/VCO2 slope for each LVEF category. Our data showed overlapping C-statistics for all three variables for each LVEF subgroup, suggesting that they had comparable prognostic value for the 2 year composite outcome (Table 6 and Figure S2).

TABLE 5. Sensitivities and specificities of various VE/VCO2 slope cut-points among HF groups, defined by LVEF VE/VCO2 slope ≥ 36 Sensitivity (95% CI) Specificity (95% CI) HFrEF 61.1% (52.6%, 70.7%) 64.7% (60.5%, 69.2%) HFmrEF 41.6% (20.9%, 70.3%) 82.1% (75.7%, 88.2%) HFpEF 47.0% (33.2%, 62.9%) 74.2% (70.5%, 77.9%) VE/VCO2 slope ≥ 29 Sensitivity (95% CI) Specificity (95% CI) HFrEF 90.5% (86.0%, 95.0%) 28.4% (24.3%, 32.6%) HFmrEF 87.9% (67.1%, 100.0%) 46.1% (38.0%, 55.7%) HFpEF 85.0% (75.0%, 93.8%) 39.2% (34.9%, 43.3%) CI, confidence interval; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; VE/VCO2, minute ventilation to carbon dioxide production ratio. image

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