A wide variety of predictors of adverse outcome in heart failure (HF) have been described and it can be difficult to choose the most appropriate tools in clinical practice.1,2 Risk stratification should be as accurate as possible, particularly when selecting patients for heart transplantation (HTX), as procedure-related morbidity and mortality are non-negligible and it cannot be offered to all candidates due to the shortage of donors.3 For ambulatory patients, both the American Heart Association and the International Society for Heart and Lung Transplantation (ISHLT) recommend the use of peak oxygen consumption (VO2 max) achieved in cardiopulmonary exercise testing (CPET), with optional use of risk scores in gray zones; VO2 max <10-12 ml/kg/min is considered a listing criterion for HTX.4,5 We believe that risk stratification and referral criteria for HTX can be improved using simple parameters. Additional CPET variables have shown to be accurate for risk stratification, particularly the ventilatory efficiency (VE/VCO2) slope.6–8 However, most studies that highlight the value of ergospirometric parameters have focused mainly on clinical and CPET data, without comprehensive assessment of other parameters, and few had long-term follow-up.6–9 Identifying robust criteria for selecting patients for HTX should be based on a comprehensive prospective clinical and complementary assessment.

Our aims were to identify the most accurate predictors of adverse events in non-transplanted patients with HF and an approach to optimize the selection of patients for HTX.

The investigation conforms to the principles outlined in the Declaration of Helsinki. The institutional ethics committee approved the study protocol.

A total of 263 patients were included. The combined endpoint occurred in 54 patients (20.5%) within 36 months and in 69 (26.2%) within 60 months. The main baseline data are presented in Table 1, in which patients with and without events up to 36 months of follow-up are compared and the most important risk predictors identified in univariate Cox regression are presented. Complete data on baseline characteristics and univariate Cox regression are presented in Supplementary Tables 1 and 2, respectively.

Cumulative adverse events occurring in different follow-up periods are presented in Table 2. The independent predictors of adverse events identified in multivariate Cox regression with follow-up times of 12, 36 and 60 months are presented in Table 3. At 36 months of follow-up, VE/VCO2 slope, creatinine levels and LVEF were independent predictors of adverse events. The VE/VCO2 slope had the highest Wald chi-square value in univariate and multivariate analysis at 36 months and was the parameter with the highest AUC in all multivariate models, considering 12, 36 and 60 months of follow-up. Specifically for the 36-month follow-up period, the AUC of the overall model including all predictors of adverse outcome did not differ significantly from the AUC of the model with VE/VCO2 slope alone (DeLong test p=0.103). In addition, the overall NRI was 63.4% (95% CI 33.5-93.4%) and the IDI was 0.019 (95% CI [-0.01]-[0.046]), when creatinine levels and LVEF were added to VE/VCO2 slope; as the 95% CI of IDI includes the null value, the improvement in model performance is negligible. Since the other predictors included in the model (creatinine levels and LVEF) did not add significantly to VE/VCO2 slope for risk prediction, only VE/VCO2 slope was selected to obtain a cut-off value for clinical use.

Based on the martingale residuals, the best estimated cut-off value for VE/VCO2 slope to identify patients at higher risk at 36 months of follow-up was 32.0 (specificity 80%, sensitivity 83%) (Supplementary Figure 1). However, a threshold of 39.0 provided higher specificity (97%), with 52% sensitivity. The estimated 36-month survival for high-risk (VE/VCO2 slope ≥39.0) and low-risk (VE/VCO2 slope <39.0) patients was significantly different (Figure 1).

ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.'> ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.' title='Event-free survival up to 36 months of follow-up according to VE/VCO2 slope threshold of 39.0, and 95% CI of estimated survival for each subgroup. CI: 95% confidence interval; ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.'/>

Figure 1.

Event-free survival up to 36 months of follow-up according to VE/VCO2 slope threshold of 39.0, and 95% CI of estimated survival for each subgroup. CI: 95% confidence interval; ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.

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A threshold of 39.0 for VE/VCO2 slope was assessed as a potential listing criterion for HTX. Firstly, the 95% CIs of estimated survival (considering all-cause death) for high- and low-risk subgroups did not overlap with those of post-HTX reported by the ISHLT.15 Secondly, the VE/VCO2 slope had a higher AUC than VO2 max, considering both as continuous variables (AUC of VO2 max 0.79, 95% CI 0.72-0.87; DeLong test for comparison p=0.009). Moreover, there was a significant improvement in the percentage of correct classification using the VE/VCO2 slope threshold of 39.0, in comparison to discretized VO2 max (Table 4): considering the VO2 max threshold of 10.0 ml/kg/min, the overall NRI and IDI were 82.2% (95% CI 52.3-112.1%) and 0.278 (95% CI 0.182-0.373), respectively; considering the VO2 max threshold of 12.0 ml/kg/min, the overall NRI and IDI were 93.3% (95% CI 63.4-123.2%) and 0.226 (95% CI 0.141-0.311), respectively. Since the data consistently favored the use of VE/VCO2 slope as an indication for HTX, high-risk patients (VE/VCO2 slope ≥39.0) were excluded from subsequent analysis. In the other 229 patients, 27 (11.8%) events occurred during 36 months of follow-up. Sodium and creatinine levels, LVEF, and variation achieved in CPET (anaerobic threshold minus baseline) of the end-tidal carbon dioxide partial pressure (Δ PetCO2) were independent predictors of adverse events at 36 months of follow-up (Table 3). The AUC was similar for these predictors. For LVEF, the flatness of the martingale residuals smoother did not enable a suitable cut-off point to be identified that discriminated high- and low-risk patients (Supplementary Figure 2); sodium ≤136.0 mEq/l, creatinine ≥1.0 mg/dl and Δ PetCO2 ≤0.45 kPa (3.4 mmHg) were associated with higher risk of adverse events (specificity 63%, 61% and 63%, sensitivity 77%, 74% and 74%, respectively). Eight subgroups were created according to the three mentioned cut-off values (Supplementary Figure 3). Prognosis was similar for patients with up to one variable (sodium, creatinine or Δ PetCO2) with abnormal values (classified according to the thresholds identified); prognosis was similar for patients with two variables with abnormal values, and event-free survival was worst when the three variables were classified as abnormal. Three groups were created accordingly (Figure 2); prognosis was significantly different for the three categories.

ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.'> ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.' title='Event-free survival up to 36 months of follow-up (excluding patients with VE/VCO2 slope ≥39.0) and 95% CI of estimated survival for each subgroup, according to the combination of sodium (136.0 mEq/l), creatinine (1.0 mg/dl) and variation of end-tidal carbon dioxide partial pressure (0.45 kPa) cut-off values. Group 1: up to one abnormal parameter; group 2: two abnormal parameters; group 3: three abnormal parameters. CI: 95% confidence interval; ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.'/>

Figure 2.

Event-free survival up to 36 months of follow-up (excluding patients with VE/VCO2 slope ≥39.0) and 95% CI of estimated survival for each subgroup, according to the combination of sodium (136.0 mEq/l), creatinine (1.0 mg/dl) and variation of end-tidal carbon dioxide partial pressure (0.45 kPa) cut-off values. Group 1: up to one abnormal parameter; group 2: two abnormal parameters; group 3: three abnormal parameters. CI: 95% confidence interval; ISHLT: International Society for Heart and Lung Transplantation; VCO2: carbon dioxide production; VE: minute ventilation.

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The most accurate predictor of adverse outcome in patients with HF with reduced LVEF was VE/VCO2 slope and the best threshold for identifying patients who may benefit from HTX was 39.0. Sodium levels, creatinine levels and Δ PetCO2 were able to identify low-risk patients with excellent outcome.

Risk stratification in HF and selecting patients for HTX are challenging. Mancini et al.18 showed in an ancillary study that VO2 max is a valuable parameter for selecting patients for HTX, and subsequently refined their cut-off values.11,19 Currently, the American Heart Association recommends listing ambulatory patients for HTX when VO2 max is <10 ml/kg/min with achievement of anaerobic metabolism, and to defer when VO2 max is >14 ml/kg/min.4 Mancini et al.19 proposed a similar decision algorithm, also recommending assessment using the Heart Failure Survival Score (HFSS). The ISHLT recommends listing when VO2 max is <12 ml/kg/min on beta-blockers, deferring when it is >14 ml/kg/min, and using the HFSS in the gray zone.5 Only in the presence of a submaximal CPET should VE/VCO2 slope be considered as a listing criterion, according to the ISHLT guidelines.5 Risk stratification and patient selection for HTX could probably be improved.7 However, the use of randomized controlled trials to address the issue of listing criteria is hindered by ethical and social considerations. In this context, data from robust registries on non-transplanted HF patients receiving contemporary pharmacological and device therapy are of great value.

We evaluated an extensive range of clinical, laboratory, electrocardiographic, echocardiographic, and CPET parameters as potential predictors of adverse outcome. The single best parameter of all those studied was VE/VCO2 slope, yielding the highest Wald chi-square value and the highest AUC at 12, 36 and 60 months of follow-up, and with even more discriminative power than the HFSS, which combines different variables. Of note, VO2 max did not remain in any multivariate model in our cohort. The 60-month follow-up period was not used to identify an approach for selecting patients for HTX, since prognostic reassessment should be undertaken earlier.7,8 Nevertheless, the long-term follow-up carried out confirmed the consistently higher accuracy of VE/VCO2 slope over a long period, in comparison to other parameters. This finding has not been properly addressed in previous studies.6–8 Arena et al.6 showed that the risk of adverse events increases continuously over different categories of VE/VCO2 slope. However, thresholds are useful for clinical practice, and VE/VCO2 slope values of 34.0 and 35.0 have been proposed as optimal criteria for classifying patients with HF as high- and low-risk.5,14 In line with these thresholds, the risk of adverse events began to rise for values above 32.0 in our cohort, as shown by analysis of the martingale residuals. Although the specificity for this threshold was not low (80%), a non-negligible proportion of patients would be classified as high-risk even though they would not experience an adverse outcome. If this was considered a listing criterion for HTX, issues related to the shortage of donors and to the morbidity and mortality following HTX might arise, by listing patients who were at a less severe stage of HF. Therefore, the threshold of 39.0, which provides very high specificity with reasonable sensitivity, may be more appropriate for selecting patients for HTX than lower cut-off values.5,14 Freedom from the combined endpoint at 36 months of follow-up was very low (19.3%) for patients with VE/VCO2 slope ≥39.0. Even though this threshold was not primarily identified to predict total mortality, the 95% CI of estimated overall survival of high- and low-risk subgroups did not overlap with those of post-HTX reported by the ISHLT.15 This finding suggests that, for our cohort, survival of hypothetically transplanted patients would be better than survival of non-transplanted high-risk patients and worse than survival of non-transplanted low-risk patients. In addition, the threshold of 39.0 for VE/VCO2 slope was more accurate than the cut-off values of 10 or 12 ml/kg/min for VO2 max, which are recommended as listing criteria.4,5 VE/VCO2 slope has previously been reported as providing a discriminative power at least as good as VO2 max for predicting adverse events.6,9 Nevertheless, the majority of studies that highlighted the value of VE/VCO2 slope did not assess this parameter in the light of a comprehensive assessment of clinical, laboratory, electrocardiographic, echocardiographic and CPET parameters, and few had a long-term follow-up.6–8 Compared to previous studies, we carried out a more comprehensive (and prospective) baseline assessment, with a long-term follow-up, and employing a robust statistical analysis with consistent results. Based on our results, patients with VE/VCO2 slope ≥39.0 may benefit from HTX.

For low-risk non-transplanted patients with sodium levels >136.0 mEq/l, creatinine levels <1.0 mg/dl and Δ PetCO2 >0.45 kPa (3.4 mmHg), or patients with up to one of these variables classified as abnormal, the prognosis was excellent and total mortality was lower than that reported for post-HTX.15 Sodium and creatinine levels are known independent predictors of adverse events in HF and are included in risk scores such as the HFSS and the Meta-Analysis Global Group in Chronic Heart Failure score.1,2 PetCO2 at rest and at the anaerobic threshold were shown to stratify risk beyond the VE/VCO2 slope, and combining them into a single parameter (Δ PetCO2) may be more practical and accurate.20,21 We suggest that particular attention should be paid to sodium levels, creatinine levels and Δ PetCO2, in addition to VE/VCO2 slope, particularly for identifying low-risk patients in clinical practice.

Some limitations of the study should be acknowledged. Firstly, the analyzed cohort was not large. However, it was possible to identify the most important independent predictors of adverse outcome in HF and a strategy for optimizing the selection of patients for HTX, and the results were consistent using different statistical analyses. The sample size is similar to those of other studies that highlighted the value of CPET parameters, including for the selection of patients for HTX.6,14,18,20,21 Secondly, this was a single-center study. Nevertheless, this meant that the CPET protocol was consistent in all cases, and may have reduced the number of physicians responsible for the interpretation of the exam, reducing interobserver variability. Thirdly, listing for HTX is a complex and multidisciplinary decision and should not rely solely on ‘magic numbers’ of specific parameters from complementary exams; however, thresholds are useful in clinical practice, as pointed out above. In addition, the aim was not to replace but to potentially optimize current listing criteria for HTX. The decision threshold we propose is in line with current practice in different centers, where clinical decisions are supported by VE/VCO2 slope data in addition to VO2 max, even though current guidelines do not address this approach.4,5,7 A further validation study would certainly be useful.

Among a large variety of predictors of adverse outcome in ambulatory patients with HF with reduced LVEF, the most accurate was VE/VCO2 slope. Patients with VE/VCO2 slope of 39.0 or higher may benefit from HTX. Beyond the VE/VCO2 slope, sodium levels, creatinine levels and Δ PetCO2 were able to identify patients with excellent outcome.

None.

The authors have no conflicts of interest to declare.