Predictive Ability of Cardiopulmonary Exercise Test Parameters in Heart Failure Patients with Cardiac Resynchronization Therapy

Abstract

Background

There is evidence suggesting that a peak oxygen uptake (pVO₂) cut-off of 10ml/kg/min provides a more precise risk stratification in cardiac resynchronization therapy (CRT) patients.

Objective

To compare the prognostic power of several cardiopulmonary exercise testing (CPET) parameters in this population and assess the discriminative ability of the guideline-recommended pVO₂cut-off values.

Methods

Prospective evaluation of consecutive heart failure (HF) patients with left ventricular ejection fraction ≤40%. The primary endpoint was a composite of cardiac death and urgent heart transplantation (HT) in the first 24 follow-up months, and was analysed by several CPET parameters for the highest area under the curve (AUC) in the CRT group. A survival analysis was performed to evaluate the risk stratification provided by several different cut-offs. p values <0.05 were considered significant.

Results

A total of 450 HF patients, of which 114 had a CRT device. These patients had a higher baseline risk profile, but there was no difference regarding the primary outcome (13.2% vs 11.6%, p =0.660). End-tidal carbon dioxide pressure at anaerobic threshold (P_ETCO_2AT)had the highest AUC value, which was significantly higher than that of pVO₂in the CRT group (0.951 vs 0.778, p =0.046). The currently recommended pVO₂cut-off provided accurate risk stratification in this setting (p <0.001), and the suggested cut-off value of 10 ml/min/kg did not improve risk discrimination in device patients (p =0.772).

Conclusion

P_ETCO_2ATmay outperform pVO₂’s prognostic power for adverse events in CRT patients. The current guideline-recommended pVO2 cut-off can precisely risk-stratify this population.

Heart Failure; Cardiac Resynchronization Therapy/methods; Exercise Test/methods; Oxygen Consumption; Heart Transplantation

Resumo

Fundamento

Há evidências sugerindo que um corte do pico de consumo de oxigênio (pVO₂) de 10ml/kg/min fornece uma estratificação de risco mais precisa em pacientes com Terapia de Ressincronização Cardíaca (TRC).

Objetivo

Comparar o poder prognóstico de vários parâmetros do teste cardiopulmonar de exercício (TCPE) nesta população e avaliar a capacidade discriminativa dos valores de corte de pVO₂ recomendados pelas diretrizes.

Métodos

Avaliação prospectiva de uma série consecutiva de pacientes com insuficiência cardíaca (IC) com fração de ejeção do ventrículo esquerdo ≤40%. O desfecho primário foi um composto de morte cardíaca e transplante cardíaco urgente (TC) nos primeiros 24 meses de acompanhamento, e foi analisado por vários parâmetros do TCPE para a maior área sob a curva (AUC) no grupo TRC. Uma análise de sobrevida foi realizada para avaliar a estratificação de risco fornecida por vários pontos de corte diferentes. Valores de p < 0,05 foram considerados significativos.

Resultados

Um total de 450 pacientes com IC, dos quais 114 possuíam aparelho de TRC. Esses pacientes apresentaram um perfil de risco basal mais alto, mas não houve diferença em relação ao desfecho primário (13,2% vs 11,6%, p = 0,660). A pressão expiratória de dióxido de carbono no limiar anaeróbico (P_ETCO_2AT) teve o maior valor de AUC, que foi significativamente maior do que o de pVO₂ no grupo TRC (0,951 vs 0,778, p = 0,046). O valor de corte de pVO2 atualmente recomendado forneceu uma estratificação de risco precisa nesse cenário (p <0,001), e o valor de corte sugerido de 10 ml/min/kg não melhorou a discriminação de risco em pacientes com dispositivos (p = 0,772).

Conclusão

A P_ETCO_2AT pode superar o poder prognóstico do pVO₂ para eventos adversos em pacientes com TRC. O ponto de corte de pVO₂ recomendado pelas diretrizes atuais pode estratificar precisamente o risco dessa população.

Insuficiência Cardíaca; Terapia de Ressincronização Cardíaca/métodos; Teste de Esforço/métodos; Consumo de Oxigênio; Transplante do Coração

Introduction

The cardiopulmonary exercise test (CPET) is a powerful predictor of mortality in heart failure patients with reduced ejection fraction (HFrEF) and is used to guide patient referral for advanced therapies, such heart transplantation (HT) and mechanical circulatory support (MCS).¹ - ³

Peak oxygen uptake (pVO₂) and the VE/VCO₂slope are CPET-derived variables most commonly used as risk assessment tools; however, several other CPET variables have been shown to predict HF events and, some of them, can improve clinical stratification of HF patients when used together with the aforementioned variables (i.e., exercise oscillatory ventilation, end-tidal carbon dioxide variation during exercise testing, HR recovery, systolic blood pressure and the ECG response to exercise).

Cardiac resynchronization therapy (CRT) has emerged as a major therapeutic option in the management of HFrEF patients and, in selected patients, has shown to improve symptomatic burden and quality of life, as well to have a prognostic benefit regarding morbidity and mortality.⁴ - ⁸ A growing number of patients referred to HT already have a CRT device, either with or without defibrillator (CRT-D and CRT-P, respectively). Survival in HFrEF patients has improved significantly in recent years and some authors suggest the need for re-evaluation of the listing criteria for HT and prognostic thresholds of peak oxygen uptake (pVO₂) and VE/VCO2 slope.⁹ , ¹⁰

The 2016 International Society for Heart Lung Transplantation (ISHLT) listing criteria for heart transplantation defined pVO₂as a major criterion for listing patients for HT and that the presence of CRT device does not alter the recommended cut-off value of pVO_2.¹¹ This recommendation was based on a sub-analysis of the COMPANION trial which showed that CRT did not alter the predictability of pVO₂on adverse HFrEF events.¹² , ¹³ Conversely, Goda et al.¹⁴ showed that a cut-off value of 10 ml/kg/min rather than the traditional cut-off value of 14 ml/kg/min may be more useful for risk stratification in patients with CRT.¹⁴ Several other CPET variables were proven to be robust predictors of a worse clinical outcome in HFrEF populations, such as the VE/VCO₂slope, the O₂uptake efficiency slope (OUES) and the Cardiorespiratory Optimal Point (COP)¹⁵ , ¹⁶ .

The present study seeks to evaluate the predictive ability of the guideline recommended cut-off values in patients with CRT, to compare the prognostic power of several exercise parameters to that of pVO₂in this population and to compare their performance between patients with and without a CRT device.

Methods

Ethics

The investigation conforms to the principles outlined in the Declaration of Helsinki. The local institutional ethics committee approved the study protocol. All patients provided informed consent.

Study Sample

Single centre analysis of 450 consecutive HF patients referred to our institution from 2009 to 2018 with left ventricular ejection fraction (LVEF) ≤40% and New York Heart Association (NYHA) class II or III, who were submitted to CPET. All patients were referred for evaluation by the HF team with possible indication for HT or MCS.

Study Protocol

Patient follow-up included initial evaluation within a period of one month in each patient with: clinical data including aetiology of HF (ischemic vs non-ischemic), implanted cardiac devices (CIED), medication, comorbidities, NYHA class; laboratorial data; electrocardiographic data; echocardiographic data; CPET data; Heart Failure Survival Score (HFSS).

Patients were excluded if one of the following: age <18 years; planned percutaneous coronary revascularization or cardiac surgery; exercise-limiting comorbidities (cerebrovascular disease, musculoskeletal impairment, or severe peripheral vascular disease); previous HT.

Patients who underwent CRT implantation performed CPET and transthoracic echocardiogram at least 6 months after the procedure.

Patients with elective HT during the follow-up period (patients who had indication for HT and a heart become available in the first two year of follow-up) were censured from the analysis at the time of HT.

Cardiopulmonary exercise testing

A maximal symptom-limited treadmill CPET, defined by peak respiratory exchange rate (RER) >1.05, was performed using the modified Bruce protocol (GE Marquette Series 2000 treadmill). Gas analysis was preceded by calibration of the equipment. Minute ventilation, oxygen uptake and carbon dioxide production were acquired breath-by-breath, using a SensorMedics Vmax 229 gas analyser.

The pVO₂was defined as the highest 30-second average achieved during exercise and was normalized for body mass. The anaerobic threshold was determined by combining the standard methods (V-slope preferentially and ventilatory equivalents). The VE/VCO₂slope was calculated by least squares linear regression, using data acquired throughout the whole exercise. COP was measured as the minimum value of the ventilatory equivalent for oxygen (VE/VO₂minimum). Partial pressure of end-tidal carbon dioxide (P_ETCO₂) was reported before exercise (P_ETCO_2AR), at anaerobic threshold (P_ETCO_2AT) and at peak exercise in mmHg units, and the increase during exercise until the anaerobic threshold is achieved (P_ETCO_2DIF) was also calculated. Peak oxygen pulse (PP) was calculated by dividing derived pVO₂by the maximum heart rate (HR) during exercise and was expressed in millilitres per beat. Circulatory power was calculated as the product of pVO₂and peak systolic blood pressure and the ventilatory power was calculated by dividing peak systolic blood pressure (BP) by the VE/VCO₂slope. Several composite parameters of CPET were also automatically calculated.

Follow-up and endpoint

All patients were followed-up for 24 months from the date of completion of the aforementioned complementary exams.

The primary endpoint was a composite of cardiac death and urgent HT occurring during an unplanned hospitalisation with dependency of inotropes for worsening HF. Data was obtained from the outpatient clinic visits (i.e., both unplanned visits for HF - clinical deterioration requiring iv diuretics - or planned visits for HF medication up-titration, diuretic therapy or routine clinical evaluation by the HF team) and was complemented with a standardised telephone interview to all patients at 24 months of follow-up.

Statistical analysis

All analyses compare patients with and without a CRT device (CRT and noCRT, respectively). Data was analysed using the software Statistical Package for the Social Science for Windows, version 24.0 (SPSS Inc, Chicago IL).

Baseline characteristics were summarised as frequencies (percentages) for categorical variables, as means and standard deviations for continuous variables when normality was verified and as median and interquartile range when normality was not verified by the Kolmogorov-Smirnov test. The Student’s t-test for independent samples or the Mann-Whitney test (when normality was not confirmed) were used for all comparisons. Chi-Square test or Fisher exact test were used to compare categorical variables.

Multivariate analysis for the prediction of the primary endpoint during two-years follow-up was performed using Cox regression, by including all statistically significant variables in the univariate analysis, in the total cohort and in each group.

The predictive power of several CPET parameters regarding the primary outcome in each group was analysed with Receiver Operating Characteristics (ROC) curve and area under the curve (AUC). Cut-off values for variables were determined from ROC curves so that the sum of sensitivity and specificity was maximised. Hanley and McNeil test was used to compare two correlated ROC curves.¹⁷

Event-free survival was determined using the Kaplan- Meier method and compared with log-rank analysis in order to evaluate the risk discriminative ability provided by the guideline-recommended cut-off values of pVO₂(pVO₂≤ 12 ml/kg/min or ≤ 14 ml/kg/min without beta-blocker - BB) and VE/VCO₂slope¹¹ and the suggested cut-off value of 10ml/kg/min.¹⁴ Statistical differences with a p value <0.05 were considered significant.

Results

Overview of CRT and noCRT groups

A total of 450 patients were enrolled in the study, of which 25.3% (n = 114) had a CRT device, mostly a CRT-D (98.2%). The overall population had a mean age of 56.2 years, with 78.7% being male and a mean LVEF of 28.6%. All CRT patients with atrial fibrillation underwent AV node ablation during the implantation procedure and the percentage of biventricular pacing was 96%. CPET was performed on average 8 months after CRT implantation. The baseline characteristics of both groups are presented in Table 1 .

Table 1
Baseline Characteristics of CRT and no CRT groups

			Overall n 450	CRT n 114	no CRT n 336	p value
			CLINICAL DATA – CHARACTERISTICS
Age			56.2 ± 12.5	62.3 ± 11.5	54.2 ± 12.2	< 0.001
Male (%)			354 (78.7%)	85 (74.6%)	269 (80.1%)	0.216
BMI (kg/m2)			27.2 ± 4.3	27.2 ± 4.1	27.1 ± 4.4	0.829
Ischemic aetiology (%)			211 (46.9%)	42 (36.8%)	169 (50.6%)	0.011
ACEi/ARB/ARNI (%)			423 (94.0%)	104 (96.3%)	319 (96.1%)	1.000
BB (%)			388 (86.2%)	93 (85.3%)	295 (88.9%)	0.325
MRA (%)			340 (75.6%)	93 (84.5%)	247 (74.2%)	0.026
Diabetes (%)			98 (21.8%)	23 (22.3%)	75 (23.4%)	0.817
CKD (%)			140 (31.1%)	48 (46.6%)	92 (32.1%)	0.008
AF (%)			112 (24.9%)	43 (38.1%)	69 (20.6%)	< 0.001
ICD (%)			271 (60.2%)	112 (98.2%)	159 (47.3%)	< 0.001
NYHA Functional Class			2.2 ± 0.6	2.5 ± 0.5	2.1 ± 0.6	0.001
HFSS*			8.5 ± 1.0	8.14 ± 0.86	8.65 ± 1.04	< 0.001
			LABORATORIAL DATA
Creatinine (mg/dL)			1.4 ± 0.7	1.6 ± 0.4	1.0 ± 0.3	0.041
Sodium (mEq/L)			137.9 ± 3.1	137.5 ± 3.4	138.5 ± 2.9	0.138
NT-proBNP (pg/ml)			2224.2 ± 2764.0	2769.7 ± 2575.4	2034.3 ± 2808.1	0.045
			ECHOCARDIOGRAPHIC DATA
LVEDD (mm/m 2 )*			35.5 ± 5.9	37.9 ± 5.5	34.7 ± 5.9	0.032
LVEF (%)			28.6 ± 6.9	26.2 ± 7.2	29.6 ± 6.6	< 0.001
MR III-IV (%)			65 (14.7%)	16 (14.0%)	49 (14.5%)	0.935
			CPET DATA
CPET duration (min)			9.6 ± 4.4	7.4 ± 4.1	10.3 ± 4.3	< 0.001
Peak RER			1.07 ± 0.11	1.05 ± 0.11	1.08 ± 0.10	0.139
pVO 2 (ml/kg/min)			17.9 ± 6.1	15.2 ± 5.1	18.8 ± 6.1	< 0.001
VE/VCO 2 slope			33.8 ± 9.5	35.8 ± 10.9	33.2 ± 8.9	0.026
OUES			2.1 ± 1.8	2.2 ± 2.2	2.0 ± 1.6	0.645
pVO 2 (ml/kg/min) at AT			13.1 ± 4.5	10.3 ± 3.4	13.8 ± 4.5	0.001
O 2 Pulse (mL/kg/beat)			0.14 ± 0.06	0.12 ± 0.04	0.14 ± 0.07	0.028
Circulatory Power (mmHg.ml.kg-1 min-1)			2786.9 ± 1578.8	2262.3 ± 965.4	2963 ± 1702.4	< 0.001
Ventilatory Power (mmHg)			4.8 ± 1.7	4.4 ± 1.7	4.9 ± 1.7	0.020
Cardiorespiratory Optimal Point			29.6 ± 7.4	30.7 ± 7.5	29.3 ± 7.4	0.274
PETCO2at rest (mmHg)			33.4 ± 4.7	32.9 ± 4.8	33.6 ± 4.7	0.241
P ET CO 2AT (mmHg)			36.7 ± 5.9	35.3 ± 5.9	37.1 ± 5.9	0.010
P ET CO 2DIF (mmHg)			3.3 ± 3.7	2.3 ± 3.2	3.6 ± 3.8	0.004

• _{ET2ET2ATET2ET2DIFET22}

Primary endpoint

The primary endpoint occurred in 54 (12.0%) patients as represented in Table 2 , with 37 patients experiencing cardiac death and 16 patients undergoing urgent HT. A similar proportion of patients met the primary endpoint in both groups, which also applied to its individual components. Survival analysis revealed a similar event-free survival between groups during the follow-up period ( Figure 1 ).

Table 2
Adverse events at 24 months follow-up

Adverse events at 24 months follow-up	Overal n (%)	CRT Group n (%)	No CRT n (%)	p value
Combined primary endpoint	54 (12.0%)	15 (13.2%)	39 (11.6%)	0.660
Total mortality	38 (8.4%)	11 (9.6%)	27 (8.0%)	0.592
Cardiac mortality	37 (8.2%)	11 (9.6%)	26 (7.7%)	0.521
Sudden cardiac death	14 (3.1%)	3 (2.6%)	11 (3.3%)	0.977
Death for worsening HF	23 (5.1%)	8 (7.0%)	15 (4.5%)	0.285
Urgent HT	16 (3.6%)	4 (3.5%)	12 (3.6%)	0.991

• CRT: cardiac resynchronization therapy; HF: heart failure; HT: heart transplantation.

Figure 1
Survival curves by cardiac resynchronization therapy.

CRT: cardiac resynchronization therapy.

Relationship between CPET prognostic parameters and primary outcome

Both in patients with CRT and in the total cohort, pVO₂, VE/VCO₂slope and P_ETCO_2ATwere independent predictors of the primary endpoint – Table 3 .

Table 3
CPET Predictors of adverse events at 24 months follow-up

Total Cohort	Univariate, OR (CI 95%)	p value	Multivariate analysis, OR (CI 95%)		p value
pVO2(ml/kg/min)	0.851 (0.799-0.906)	<0.001		0.867 (0.812-0.921)	0.004
VE/VCO2slope	1.092 (1.061-1.124)	0.005		1.104 (1.020-1.196)	0.015
Cardiorespiratory Optimal Point	1.128 (1.050-1.212)	0.010			0.250
OUES	0.357 (0.179-0.713)	<0.001			0.284
Circulatory Power (mmHg.ml.kg-1 min-1)	0.996 (0.994-0.999)	0.040			0.540
Ventilatory Power (mmHg)	0.471(0.367-0.605)	0.017			0.287
Peak O2Pulse (mL/kg/beat)	0.769 (0.573-1.031)	0.079			0.357
PETCO2at rest (mmHg)	0.871 (0.814-0.931)	0.012			0.135
PETCO2AT(mmHg)	0.814 (0.763-0.868)	<0.001		0.713 (0.577-0.880)	0.002
PETCO2DIF(mmHg)	0.734 (0.660-0.815)	<0.001			0.110
CRT Group	Univariate, OR (CI 95%)	p value		Multivariate analysis, OR (CI 95%)	p value
pVO2(ml/kg/min)	0.794 (0.688-0.916)	0.002		0.821 (0.647-0.905)	0.005
VE/VCO2slope	1.162 (1.077-1.253)	<0.001		1.109 (1.053-1.165)	0.008
Cardiorespiratory Optimal Point	1.101 (0.982-1.235)	0.090			0.319
OUES	0.974 (0.702-1.353)	0.470			0.657
Circulatory Power (mmHg.ml.kg-1 min-1)	0.997 (0.998-0.999)	0.047			0.470
Ventilatory Power (mmHg)	0.313 (0.157-0.624)	0.001			0.314
Peak O2Pulse (mL/kg/beat)	0.751 (0.371-1.063)	0.097			0.490
PETCO2at rest (mmHg)	0.779 (0.668-0.910)	0.002			0.197
PETCO2AT(mmHg)	0.564 (0.413-0.771)	<0.001		0.527 (0.309-0.898)	0.001
PETCO2DIF(mmHg)	0.595 (0.451-0.786)	<0.001			0.097
No CRT Group
pVO2(ml/kg/min)	0.860 (0.801-0.924)	<0.001		0.819 (0.668-0.930)	0.007
VE/VCO2slope	1.075 (1.040-1.110)	<0.001		1.109 (1.015-1.210)	0.012
Cardiorespiratory Optimal Point	1.143 (1.040-1.257)	0.005			0.154
OUES	0.088 (0.030-0.253)	<0.001			0.454
Circulatory Power (mmHg.ml.kg-1 min-1)	0.095 (0.091-0.097)	0.039			0.564
Ventilatory Power (mmHg)	0.513 (0.391-0.674)	<0.001			0.309
Peak O2Pulse (mL/kg/beat)	0.783 (0.453-1.021)	0.070			0.410
PETCO2at rest (mmHg)	0.900 (0.834-0.972)	0.007			0.229
PETCO2AT(mmHg)	0.849 (0.794-0.907)	0.001			0.080
PETCO2DIF(mmHg)	0.765 (0.682-0.858)	<0.001		0.689 (0.532-0.893)	0.005

• _{ET2ET2ATET2ET2DIFET22}

In the CRT group, P_ETCO_2AThad the highest AUC value followed by P_ETCO_2DIFand VE/VCO₂slope – Table 4 . COP presented the lowest predictive power in this group. The Hanley & McNeil test revealed that P_ETCO_2ATwas the only variable presenting a significantly higher predictive power than that of pVO₂– Table 5 .

Table 4
AUC analysis for the Primary Endpoint

Characteristics	CRT Group		No CRT Group		Hanley and McNeil for ROC curve comparison between groups (p value)
	AUC	CI 95%	AUC	CI 95%
pVO2(ml/kg/min)	0.778	0.683-0.873	0.723	0.643-0.804	0.531
VE/VCO2slope	0.868	0.782-0.954	0.757	0.693-0.822	0.159
Cardiorespiratory Optimal Point	0.668	0.355-0.980	0.739	0.487-0.991	0.699
OUES	0.775	0.591-0.960	0.800	0.710-0.890	0.808
Circulatory Power (mmHg.ml.kg-1 min-1)	0.777	0.679-0.876	0.743	0.668-0.819	0.697
Ventilatory Power (mmHg)	0.830	0.729-0.930	0.759	0.687-0.830	0.398
Peak O2Pulse (mL/kg/beat)	0.659	0.486-0.831	0.716	0.642-0.761	0.546
PETCO2at rest (mmHg)	0.797	0.518-0.713	0.615	0.518-0.713	0.042
PETCO2AT(mmHg)	0.951	0.900-0.980	0.741	0.662-0.8220	0.002
PETCO2DIF(mmHg)	0.889	0.819-0.960	0.776	0.712-0.841	0.121

• _{ET2ET2ATET2ET2DIFET22}

Table 5
Hanley and McNeil for ROC curve comparison between each variable and pVO2 (p value

Characteristics	CRT Group	No CRT Group
VE/VCO2slope	0.353	0.613
Cardiorespiratory Optimal Point	0.487	0.900
OUES	0.979	0.261
Circulatory Power (mmHg.ml.kg-1 min-1)	0.992	0.766
Ventilatory Power (mmHg)	0.607	0.592
Peak O2Pulse (mL/kg/beat)	0.277	0.918
PETCO2at rest (mmHg)	0.855	0.123
PETCO2AT(mmHg)	0.046	0.794
PETCO2DIF(mmHg)	0.213	0.431

• _{ET2ET2ATET2ET2DIFET22}

In the noCRT group, OUES and P_ETCO_2DIFpresented the highest AUC values, both higher than the one of pVO₂and VE/VCO₂slope, but no statistically significant difference was found.

P_ETCO_2ARand P_ETCO_2ATwere the only parameters revealing a better performance in patients with CRT than in patients without device – Table 4 . A P_ETCO_2ATof 33mmHg had a sensitivity of 90% and a specificity of 78% for the primary outcome in the CRT group and below this value, patients had a significantly lower 24 months survival free of events, not only in the total cohort, but also in the two study groups – Figure 2 .

Figure 2
Survival curves according to a PETCO2AT cut-off of 33mmHg in the general cohort, CRT group and no CRT group.

Cut-off value for HT selection

In the overall cohort, as well as in each group, patients with a pVO₂> 12ml/kg/min (or > 14ml/kg/min if under BB)¹¹ had a better prognosis in comparison to pVO₂≤ 10ml/kg/min and 10 < pVO₂≤ 12ml/kg/min strata, whereas a cut-off of 10ml/kg/min did not provide a proper risk stratification – Figure 3 . A VE/VCO₂slope cut-off of 35 significantly discriminated the risk for HF events in all cohorts – Figure 3 .

Figure 3
Survival curves stratified by pVO2 and VE/VCO2 for the total cohort, CRT group and no CRT group. CRT: cardiac resynchronization therapy.

For the traditional pVO₂cut-off for HT selection, the PPV for the primary outcome was 98.4% in the CRT group and 93.3% in the no CRT group ( Table 5 ), with a NPV of 27.5% and 27.2%, respectively. A pVO₂cut-off of 10 ml/kg/min revealed a lower PPV in both groups, despite a similar NPV, with no significant differences between groups – Table 6 .

Table 6
PPV and NPV of several variables’ cut-offs for the primary endpoint

Characteristics	CRT Group		No CRT Group
	NPV	PPV	NPV	PPV
pVO2≤ 10 ml/kg/min	89.0%	30.8%	89.1%	26.7%
pVO2≤ 12 ml/kg/min1	98.4%	27.5%	93.3%	27.2%
VE/VCO2slope ≥ 35	96.4%	26.1%	93.1%	21.7%
PETCO2AT≤ 33 mmHg	98.4%	35.7%	91.9%	27.4%

• ¹_2ET2AT2

In the CRT group, P_ETCO_2AT≤ 33 mmHg had slightly higher PPV and NPV values than the recommended pVO₂cut-off.

Discussion

Previous trial have shown that the addition of CRT to optimal medical therapy or defibrillator therapy significantly reduces mortality among patients with HFrEF⁴ , ⁷ and improves exercise capacity, leading to an increase in pVO₂and a reduction of VE/VCO₂slope, thereby safely delaying HT.¹⁸ , ¹⁹ It has been recognized the need to review HT selection cut-offs due to the improvement in HF therapies.⁹ , ¹⁰ Based on the survival benefit conferred by CRT, and its effect on pVO₂, it is unclear whether this is still a valid tool for HT selection. A work from 2011 suggested that the HFSS outperformed pVO₂in risk stratification in the presence of a CIED and that a pVO₂cut-off of 10 ml/kg/min would be more suitable.¹⁴ Our analysis tried to address this unmet need in contemporary cardiology.

There were crucial baseline differences between groups, as patients in CRT group were significantly older, more symptomatic, had a lower LVEF, higher mean natriuretic peptides levels, higher prevalence of AF and CKD, and a poorer exercise performance – lower baseline pVO₂and higher VE/VCO₂slope. However, this did not translate into a worse prognosis, as a similar proportion of patients met the primary endpoint in both groups (12.0% vs 13.2%, p = 0.660), with no significant difference in event-free survival (p = 0.856).

As expected, pVO₂presented an acceptable prognostic power, irrespective of the presence of a CRT device (p = 0.531). The VE/VCO₂slope has been suggested to be more accurate than the current listing criteria for HT.²⁰ There was no difference between groups regarding its predictive power (p = 0.159), and its predictive ability, despite being numerically higher than that of pVO₂, this difference did not reach statistical significance in any group.

P_ETCO₂correlates with cardiac output in HF patients and can reflect disease severity, having a prognostic value independent of that of pVO_2.²¹ - ²⁴ A P_ETCO_2AR< 33.0 mmHg or an increase < 3 mmHg during exercise test were associated with a worse prognosis.³ In CRT patients, P_ETCO_2AR, P_ETCO_2ATand P_ETCO_2DIFpresented higher AUC values than pVO₂, but this difference only reached statistical significance for P_ETCO_2AT(p = 0.046). Patients with a P_ETCO_2AT≤ 33.0 mmHg had a significantly lower 24-months survival free of events, not only in the CRT arm, but also in the overall cohort and in the no CRT group (p < 0.001).

A pVO₂cut-off value of 10 ml/kg/min did not improve risk stratification in the CRT group, since it has a markedly lower NPV than the traditional cut-offs. There was no discrimination between the high-risk (pVO₂≤10 ml/min/kg) and the medium risk strata (10 < pVO₂≤ 12 ml/min/kg) regarding event-free survival during the first 24 months of follow-up in neither of the groups. The low-risk strata (pVO₂≥12 ml/min/kg) had a significantly better prognosis than the remainder strata, in both groups. The recommended cut-off value for VE/VCO₂provided accurate 2 years-risk discrimination in the CRT group (72.6% vs 96.6%, p = 0.001).

Despite CRT patients having a higher risk baseline profile in our study, this did not translate into a higher rate of events during follow-up. The current cut-off of pVO₂for HT selection can stratify these high-risk patients more precisely than the suggested pVO₂cut-off of 10ml/kg/min,¹⁴ irrespective of the presence of a CRT device.

The low PPV and the high NPV of the analysed variables suggest that in the studied population all these parameters, when used individually, are best suited to identify patients who do not need HT.

Our results suggest that advanced HF therapies can be safely withheld in HF patients, with pVO₂> 12 ml/kg/min (or 14 ml/kg/min in the absence of beta-blocker), irrespective of the presence of CRT device, as the event-rate in these population is low. Patients below this cut-off should be managed accordingly, and their timely referral for HT or MCS should be considered. The low PPV of the recommended cut-offs suggests that pVO₂alone is insufficient to guide referral and other prognostic factors must be taken into account, such as, NYHA functional class, INTERMACS profile, LVEF, HFSS, recurrent planned and unplanned hospitalizations for HF or ventricular arrhythmias, persistent congestion/need for escalating diuretic doses or combining it with other CPET variables, such as P_ETCO_2AT. The surprisingly low PPV might be explained by the fact that a significant proportion of our cohort performed a submaximal CPET, a setting on which pVO₂may lose discriminative power.

P_ETCO_2ATmay increase the prognostic value of CPET in HFrEF, irrespective of the presence of a CRT device, and eventually refine the predictive ability of the current CPET parameters used for HT referral decision.

Study limitations

This was a single-centre experience, and therefore, the results can reflect our local practice and might not be applicable to other HF Centres.

Secondly, despite a high number of patients were receiving guideline-approved neurohormonal blockade therapies, several patients were included in this analysis before the advent of angiotensin receptor-neprilysin inhibitors – ARNI (<10% of patients under ARNI). So, it is unclear if our results can be extrapolated to the sacubitril-valsartan era, as this drug has shown to have an impact on exercise capacity.The vast majority of the patients in the CRT cohort had a CRT-D device (98.4%), so it is unknown whether P_ETCO_2ATand other CPET variables would retain their predictive ability in patients with

CRT-P devices. As patients in the CRT arm had a theoretical higher risk baseline clinical profile, it would be expected that in the absence of a defibrillator, a higher proportion of these patients would meet the primary endpoint, due to higher rates of arrhythmic death. Fourth, there are no data regarding CRT response and it would be useful to compare these variables’ performance between clinical/ echocardiographic responder and non-responders.Furthermore, pVO₂and other CPET variables may lose some of their prognostic value in a submaximal setting.²⁵ However, our total cohort presented a mean RER of 1.07 and the CRT group of 1.05, meaning that a substantial proportion of patients performed submaximal exercise, which may have an influence on each parameter’s performance.

Conclusions

The performance of risk stratification tools in HF patients referred for HT was defined before the widespread use of CRT devices and there is limited data regarding their prognostic accuracy in these patients. Our findings suggest that the recommended pVO₂and VE/VCO₂cut-off values retain their discriminative ability in this setting; however, P_ETCO_2ATmay provide a higher predictive ability for adverse events in a 24-months follow-up in CRT patients. This parameter was an independent prognostic predictor in CRT patients and had a better performance in this population than in patients without a CRT. Further studies are required to assess the reproducibility of our data and if P_ETCO_2ATcan improve risk stratification when combined with pVO₂.

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• Study Association
  This study is not associated with any thesis or dissertation work.
• Ethics approval and consent to participate
  This study was approved by the Ethics Committee of the Centro Hospitalar Central de Lisboa under the protocol number 1232. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013. Informed consent was obtained from all participants included in the study.

• Sources of Funding: There were no external funding sources for this study.

Publication Dates

• Publication in this collection
  18 July 2022
• Date of issue
  Sept 2022

History

• Received
  21 July 2021
• Reviewed
  16 Dec 2021
• Accepted
  26 Jan 2022