# Prognosis of refractory cardiogenic shock in de-novo versus acute-on-chronic heart failure: Insights from the HYPO-ECMO trial

Guillaume Baudry, Bruno Levy, Kévin Duarte, Luca Monzo, Alain Combes, Antoine Kimmoun, Nicolas Girerd

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## To cite this version:

Guillaume Baudry, Bruno Levy, Kévin Duarte, Luca Monzo, Alain Combes, et al. Prognosis of refractory cardiogenic shock in de-novo versus acute-on-chronic heart failure: Insights from the HYPO-ECMO trial. Journal of Critical Care, 2025, 87, pp.155043. 10.1016/j.jcrc.2025.155043. hal-04974831

HAL Id: hal-04974831

https://hal.univ-lorraine.fr/hal-04974831v1

Submitted on 3 Mar 2025

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Distributed under a Creative Commons Attribution 4.0 International License
setting [11–14], occasionally in association with moderate hypothermia (MH) [14].

Indeed, MH has been associated with improved hemodynamic parameters in the context of cardiogenic shock, as well as enhanced neurological prognosis following cardiac arrest both in animal models and in humans [15–17]. However, results regarding MH are inconsistent [18]. The Hypothermia During ECMO (HYPO-ECMO) study aimed to assess whether MH could enhance survival in patients with cardiogenic shock [14,19]. In a recent French CS cohort study, acute-on-chronic HF (ACHF) patients were older and had more comorbidities with higher creatinine and total bilirubin levels at admission compared with de-novo HF (DNHF) patients [5]. Despite these differences at admission, the use of TCMS as salvage therapy was similar between groups. Nonetheless, prior HF history was associated with higher in-hospital mortality [5]. In contrast, prior HF history was associated with better prognosis in two other studies of 1414 and 1767 patients with CS, respectively [9,20]. In these studies, TMCS was used in a minority of patients. Its benefit is furthermore debated in patients with ACHF since they are at higher risk of death and weaning failure from TMCS [21]. Likewise, the effect of MH also remains to be clarified as preliminary data suggest that hypothermia may be harmful to an impaired myocardium [22,23].

In light of the above, this study aimed to assess the prognostic value of HF history in patients with refractory CS rescued by VA-ECMO as well as its impact on the effect of moderate hypothermia according to HF history.

# 2. Methods

## 2.1. Study design

The rationale, design and primary results of the HYPO-ECMO study have been reported previously [14,19,24]. Briefly, in the HYPO-ECMO trial, early application of MH (33–34 °C) for 24 h did not significantly increase 30-day survival compared with normothermia (36–37 °C) in patients with cardiogenic shock receiving VA-ECMO.

All consecutive adult patients admitted to ICU and treated with VA-ECMO were screened for enrollment. Patients were eligible for enrollment if they had been endotracheally intubated and were receiving VA-ECMO for less than 6 h for cardiogenic shock. The definition of cardiogenic shock was left to the investigator's discretion. After randomization, patients in the intervention group were exposed to moderate hypothermia, with their temperature maintained between 33 °C and 34 °C as early as possible following VA-ECMO implementation. This temperature was maintained for 24 h, followed by a gradual rewarming process. In the control group, their temperature was kept within the range of 36 °C to 37 °C during the initial 24 h and subsequently maintained at 37 °C (± 0.3 °C) for the following 72 h. Primary exclusion criteria consisted of individuals under 18 years of age, pregnant women, recipients of VA-ECMO after cardiac surgery for left ventricular assist device (LVAD) placement, heart transplant, or combined lung and heart transplant. Additionally, patients on VA-ECMO due to acute poisoning with cardiotoxic drugs, individuals with uncontrollable bleeding despite medical interventions such as surgery or medication, those requiring VA-ECMO after cardiopulmonary resuscitation lasting more than 45 min, and subjects who experienced an out-of-hospital refractory cardiac arrest were also excluded.

Consent from the patient's family was sought before inclusion in the trial, and patients were not included if the family declined consent. Written consent was requested from the patients as soon as they regained capacity. Per French law, the patient's data could not be analyzed if they did not provide consent at this latter stage. A total of 374 patients were ultimately randomized; however, 40 patients withdrew their consent, leaving 334 in the final analysis.

The trial was supported by the international ECMO Network (ECMONet) and was approved by the French health authorities (Agence Nationale de la Sécurité du Médicament et des Produits de Santé) and the

appropriate ethics committee (Comité de Protection des Personnes number: 2016-A00377-44, dated April 7, 2016).

## 2.2. Study endpoints

The primary outcome was mortality at day 30. Main secondary outcomes were 1) mortality at days 7, 60, and 180, 2) a composite outcome of death, heart transplant, escalation to left ventricular assist device implantation, or stroke at days 30, 60, and 180, and 3) need for renal replacement therapy (RRT).

## 2.3. Definition of heart failure history

The diagnosis of HF history was obtained by using any available method (e.g., medical record, patient-reported history) at the discretion of the local investigator. The ACHF and DNHF groups were not pre-specified as subgroups of interest in the HYPO-ECMO trial protocol.

## 2.4. Statistical analysis

Baseline characteristics are expressed as mean ± SD for continuous variables, median (IQR) for data with skewed distributions, and frequency (percentage) for categorical variables. Baseline characteristics were compared between ACHF and DNHF patients and between the four subgroups based on HF status and study intervention group (normothermia versus moderate hypothermia) by using *t*-test (ANOVA test for the 4 groups) or Wilcoxon test (Kruskal-Wallis test for the 4 groups) as appropriate for continuous variables and the Chi-square test or Fisher's exact test for categorical variables.

To assess the effect of ACHF on outcomes on an additive scale, risk differences (RDs) and 95 % confidence interval (CI) were calculated using a binomial regression model with an identity link function. In order to address the differences in characteristics between the two groups, a propensity score (PS)-based analysis was performed, using inverse probability weighting (IPW). This method allows balancing the distribution of baseline characteristics between the two groups by weighting each patient by the inverse probability of being in their group. Multiple imputation with chained equations (MICE) was used to impute missing values and preserve completeness of the data in the PS analysis. More details on multiple imputation and IPW method are given in Supplementary material.

Balance of covariates between the two groups was assessed before and after weighting by calculating the absolute standardized mean differences (ASMDs). As there is no definitive consensus on the threshold value indicating that a covariate is balanced, a covariate was considered balanced if ASMD was less than 0.25 [25,26].

Risk differences were calculated both in unadjusted and IPW-adjusted models. The effect of moderate hypothermia according to history of heart failure was also assessed for each outcome by introducing an interaction term within the binomial regression model with identity link.

Survival rates are illustrated using IPW-adjusted Kaplan-Meier analyses and differences between survival curves were analyzed using the robust log-rank test.

A subgroup analysis was performed for the primary outcome of mortality at 30 days using the following variables: age, prior myocardial infarction, after cardiac surgery, vasopressor dose (patients who did not receive vasopressor therapy were coded as having a dose of 0 µg/kg/min), lactate level, and SOFA score at baseline. For each continuous variable, subgroups were defined by dichotomizing the variable according to the median. Interactions between history of HF and the subgroups were assessed by introducing an interaction term within the binomial regression models with identity link.

All analyses were performed using R software version 4.1.2 (R Foundation for Statistical Computing). The two-tailed significance level was set at *P* < 0.05. Given the low power of interaction tests [27,28], a
significance level of 0.10 was used for interaction *p*-values.

# 3. Results

## 3.1. Baseline analyses

Of the 334 patients included in the final analysis of HYPO-ECMO, 321 (96.1 %) patients had available information on HF history (Fig. 1). Table 1 lists the baseline characteristics of the patients included in the final analysis. Sixty-five patients (20 %) had a history of heart failure and were considered as “Acute-on-chronic HF” (ACHF) while 256 patients (80 %) with no history of HF were considered as “de-novo HF”. Before IPW adjustment, the mean age was 57 and 60 years ($p = 0.067$) and the proportion of women was 26 % and 17 % ($p = 0.16$) in the DNHF and ACHF groups, respectively. ACHF patients were more likely to have a history of myocardial infarction ($p < 0.0001$), ischemic cardiomyopathy ($p < 0.0001$) or valvular heart disease ($p = 0.039$). There was no significant difference between groups in terms of cardiac arrest during hospitalization before inclusion, left ventricular ejection fraction (LVEF), lactate level, total SOFA score or vasopressor use at baseline although pH was slightly higher in the ACHF group ($p = 0.037$). Of note, creatinine and total bilirubin were significantly higher in the ACHF group ($p = 0.04$ and $< 0.0001$, respectively). There was no significant difference between groups after IPW adjustment.

## 3.2. Association of ACHF and DNHF with outcome

### 3.2.1. Primary outcomes

For the primary outcome of all-cause mortality at 30 days, 26/65 patients (40.0 %) in the ACHF group died compared to 122/256 patients (47.7 %) in the DNHF group. 30-day mortality tended to be lower in the ACHF group (IPW RD, -11.6 % [-24.8 to 1.6] $p = 0.084$) (Table 2). Fig. 2 shows the mortality curves according to prior HF history (IPW-adjusted, log-rank test, $p = 0.37$). The association between ACHF/DNHF with the primary outcome was consistent across all subgroups (*p*-value for interaction >0.10), except when considering prior cardiac arrest (IPW-adjusted RD in ACHF versus DNHF patients, -24.8 % [-44.5 to -5.1], IPW-adjusted RD in the absence of CA, -1.6 % [-19.1 to 16.0], *p* for interaction = 0.084, Fig. 3).

### 3.2.2. Secondary outcomes

All-cause mortality at days 60 and 180 was 46.2 % and 49.2 % in the ACHF group versus 53.1 % and 56.6 % in the DNHF group. Mortality was numerically lower in the ACHF group at 60 (IPW RD, -12.2 % [-25.7 to 1.2], $p = 0.075$) and 180 days (IPW RD, -13.7 % [-27.1 to -0.2], $p = 0.047$).

ACHF patients experienced significantly better outcomes (IPW RD, -20.0 % [-33.4 to -6.6], $p = 0.003$, -18.5 % [-31.9 to -5.0], $p = 0.007$ and -19.5 % [-32.9 to -6.1], $p = 0.004$) at 30, 60 and 180 days respectively) (Table 2).

Details relative to the composite endpoints are presented in Table 3. Briefly, strokes were significantly more frequent in DNHF patients in unadjusted analysis and after IPW at 30 (12.6 % vs. 0.8 %), 60 (13.7 % vs. 1.6 %) and 180 days (14.1 % vs. 1.6 %), $p < 0.0001$ for all. There was no significant difference in the number of heart transplants or LVAD implantation between the 2 groups ($p > 0.2$ at all time points).

## 3.3. Benefit of MH according to ACHF and DNHF status

### 3.3.1. Primary outcome

Moderate hypothermia tended to be associated with a lower risk for the primary outcome in the DNHF group (-10.9 % [-23.1 to 1.2] $p = 0.078$) whereas it did not in the ACHF group (IPW RD, 1.2 % [-22.6 to 25.1], $p = 0.92$; *p* for interaction = 0.37). Unadjusted all-cause mortality Kaplan-Meier curves at 30 days according to HF status and intervention group are presented in Fig. 4A (log-rank test, $p = 0.048$ in DNHF and $p = 0.88$ in ACHF).

### 3.3.2. Secondary outcomes

Moderate hypothermia was associated with non-significant lower mortality at 60 (IPW RD, -9.4 % [-21.5 to 2.8], $p = 0.13$) and 180 days (IPW RD, -10.2 [-22.2 to 1.9], $p = 0.099$) in the DNHF group but not in the ACHF group (*p* for interaction = 0.22 and 0.081, respectively) (Table 4). The Kaplan-Meier curves for unadjusted all-cause mortality at 180 days are depicted in Fig. 4B (log-rank test, $p = 0.051$ in DNHF and $p = 0.36$ in ACHF).

Similarly, MH was associated with significantly lower composite outcome at 30 (IPW RD, -14.8 %, $p = 0.013$), 60 (IPW RD, -11.7 %, $p = 0.046$), and 180 days (IPW RD, -12.5 %, $p = 0.029$) in the DNHF group

<figure><img src="image_3.png" /><figcaption>Fig. 1. Flowchart of patients included in the post-hoc analysis.</figcaption></figure>
<table><caption>**Table 1**
Baseline characteristics of the study patients.</caption><thead><tr><th rowspan="2">Variable</th><th colspan="4">Unadjusted</th><th colspan="4">IPW-adjusted</th></tr><tr><th>De-novo HF (n = 256)</th><th>Acute-on-chronic HF (n = 65)</th><th>p-value*</th><th>ASMD</th><th>De-novo HF (n = 256)</th><th>Acute-on-chronic HF (n = 65)</th><th>p-value**</th><th>ASMD</th></tr></thead><tbody><tr><td>Intervention group</td><td></td><td></td><td>1.00</td><td>0.015</td><td></td><td></td><td>0.89</td><td>0.028</td></tr><tr><td>Normothermia</td><td>128 (50.0 %)</td><td>33 (50.8 %)</td><td></td><td></td><td>128.1 (50.0 %)</td><td>33.4 (51.4 %)</td><td></td><td></td></tr><tr><td>Moderate hypothermia</td><td>128 (50.0 %)</td><td>32 (49.2 %)</td><td></td><td></td><td>127.9 (50.0 %)</td><td>31.6 (48.6 %)</td><td></td><td></td></tr><tr><td>Demographics</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Age (years)</td><td>57 ± 12</td><td>60 ± 11</td><td>0.067</td><td>0.266</td><td>58 ± 12</td><td>61 ± 13</td><td>0.36</td><td>0.209</td></tr><tr><td>Sex</td><td></td><td></td><td>0.16</td><td>0.226</td><td></td><td></td><td>0.14</td><td>0.254</td></tr><tr><td>Male</td><td>189 (73.8 %)</td><td>54 (83.1 %)</td><td></td><td></td><td>194.0 (75.8 %)</td><td>55.7 (85.7 %)</td><td></td><td></td></tr><tr><td>Female</td><td>67 (26.2 %)</td><td>11 (16.9 %)</td><td></td><td></td><td>62.0 (24.2 %)</td><td>9.3 (14.3 %)</td><td></td><td></td></tr><tr><td>Body mass index (kg/m<sup>2</sup>)<sup>a</sup></td><td>26.8 ± 5.6</td><td>27.3 ± 5.2</td><td>0.50</td><td>0.097</td><td>26.9 ± 5.7</td><td>27.5 ± 4.5</td><td>0.47</td><td>0.112</td></tr><tr><td>Cardiovascular history<sup>b</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cardiac arrest during hospitalization before inclusion</td><td>122 (47.7 %)</td><td>29 (44.6 %)</td><td>0.76</td><td>0.061</td><td>122.1 (47.7 %)</td><td>25.6 (39.4 %)</td><td>0.40</td><td>0.168</td></tr><tr><td>Hypertension</td><td>92 (36.1 %)</td><td>26 (41.3 %)</td><td>0.54</td><td>0.107</td><td>92.7 (36.3 %)</td><td>23.4 (37.2 %)</td><td>0.93</td><td>0.017</td></tr><tr><td>Ischemic cardiopathy</td><td>40 (15.6 %)</td><td>30 (47.6 %)</td><td>&lt;0.0001</td><td>0.733</td><td>53.0 (20.7 %)</td><td>19.6 (31.1 %)</td><td>0.20</td><td>0.239</td></tr><tr><td>Myocardial infarction</td><td>25 (9.8 %)</td><td>22 (35.5 %)</td><td>&lt;0.0001</td><td>0.646</td><td>36.3 (14.2 %)</td><td>10.7 (17.0 %)</td><td>0.60</td><td>0.077</td></tr><tr><td>Valvular cardiopathy</td><td>29 (11.3 %)</td><td>14 (22.2 %)</td><td>0.039</td><td>0.295</td><td>31.9 (12.5 %)</td><td>12.0 (19.0 %)</td><td>0.32</td><td>0.181</td></tr><tr><td>Etiologies of cardiogenic shock<sup>c</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acute coronary syndrome</td><td>102 (39.8 %)</td><td>9 (13.8 %)</td><td>0.0002</td><td>0.614</td><td>91.1 (35.6 %)</td><td>11.6 (17.8 %)</td><td>0.072</td><td>0.411</td></tr><tr><td>Valvular cardiopathy</td><td>22 (8.6 %)</td><td>5 (7.7 %)</td><td>1.00</td><td>0.033</td><td>22.4 (8.7 %)</td><td>9.9 (15.2 %)</td><td>0.33</td><td>0.200</td></tr><tr><td>Ischemic cardiomyopathy</td><td>47 (18.4 %)</td><td>21 (32.3 %)</td><td>0.022</td><td>0.325</td><td>55.0 (21.5 %)</td><td>17.0 (26.1 %)</td><td>0.56</td><td>0.110</td></tr><tr><td>Rhythmic cardiopathy</td><td>25 (9.8 %)</td><td>16 (24.6 %)</td><td>0.003</td><td>0.401</td><td>32.7 (12.8 %)</td><td>12.5 (19.2 %)</td><td>0.32</td><td>0.176</td></tr><tr><td>Post cardiac surgery</td><td>37 (14.5 %)</td><td>11 (16.9 %)</td><td>0.76</td><td>0.068</td><td>36.1 (14.1 %)</td><td>9.8 (15.0 %)</td><td>0.89</td><td>0.026</td></tr><tr><td>Acute myocarditis</td><td>29 (11.3 %)</td><td>1 (1.5 %)</td><td>0.029</td><td>0.407</td><td>24.8 (9.7 %)</td><td>4.8 (7.5 %)</td><td>0.78</td><td>0.080</td></tr><tr><td>Echocardiogram and laboratory results</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>LVEF before VA-ECMO implantation (%)</td><td>20 (15–35)</td><td>20 (15–30)</td><td>0.17</td><td>0.307</td><td>20 (15–30)</td><td>20 (15–30)</td><td>0.70</td><td>0.032</td></tr><tr><td>pH at baseline<sup>d</sup></td><td>7.31 ± 0.15</td><td>7.35 ± 0.14</td><td>0.037</td><td>0.296</td><td>7.31 ± 0.15</td><td>7.33 ± 0.14</td><td>0.53</td><td>0.121</td></tr><tr><td>Lactate at baseline (mmol/L)<sup>e</sup></td><td>4.8 (2.7–8.1)</td><td>4.0 (2.1–7.5)</td><td>0.27</td><td>0.014</td><td>4.8 (2.6–8.2)</td><td>3.4 (2.1–6.5)</td><td>0.100</td><td>0.209</td></tr><tr><td>SOFA total at baseline<sup>f</sup></td><td>10 (7–13)</td><td>9 (7–12)</td><td>0.44</td><td>0.053</td><td>10 (8–13)</td><td>10 (8–12)</td><td>0.62</td><td>0.038</td></tr><tr><td>Creatinine (µmol/L) at baseline</td><td>127 (92–178)</td><td>144 (105–219)</td><td>0.040</td><td>0.249</td><td>130 (96–192)</td><td>155 (108–228)</td><td>0.13</td><td>0.221</td></tr><tr><td>Total bilirubin (µmol/L) at baseline</td><td>13.0 (8.0–22.0)</td><td>23.0 (14.0–49.0)</td><td>&lt;0.0001</td><td>0.452</td><td>14.0 (8.9–25.0)</td><td>15.5 (10.0–26.7)</td><td>0.83</td><td>0.115</td></tr><tr><td>Medications</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Vasopressor use at baseline</td><td>205 (82.7 %)</td><td>55 (84.6 %)</td><td>0.85</td><td>0.053</td><td>207.0 (83.3 %)</td><td>58.2 (89.6 %)</td><td>0.21</td><td>0.186</td></tr><tr><td>Vasopressor dose at baseline (µg/kg/min)<sup>g</sup></td><td>0.41 (0.10–1.10)</td><td>0.35 (0.08–0.79)</td><td>0.48</td><td>0.100</td><td>0.42 (0.10–1.17)</td><td>0.43 (0.17–1.66)</td><td>0.64</td><td>0.155</td></tr><tr><td>Norepinephrine use at baseline</td><td>190 (76.6 %)</td><td>48 (73.8 %)</td><td>0.76</td><td>0.064</td><td>192.5 (77.4 %)</td><td>52.8 (81.2 %)</td><td>0.55</td><td>0.092</td></tr><tr><td>Norepinephrine dose at baseline (µg/kg/min) - only in patients who received this treatment</td><td>0.50 (0.20–1.30)</td><td>0.51 (0.22–1.00)</td><td>0.72</td><td>0.087</td><td>0.50 (0.18–1.28)</td><td>0.57 (0.22–1.86)</td><td>0.78</td><td>0.083</td></tr><tr><td>Epinephrine use at baseline</td><td>59 (23.8 %)</td><td>19 (29.2 %)</td><td>0.46</td><td>0.123</td><td>58.2 (23.4 %)</td><td>23.1 (35.5 %)</td><td>0.18</td><td>0.268</td></tr><tr><td>Epinephrine dose at baseline (µg/kg/min) - only in patients who received this treatment</td><td>0.30 (0.17–0.80)</td><td>0.22 (0.10–0.30)</td><td>0.19</td><td>0.298</td><td>0.40 (0.20–1.00)</td><td>0.27 (0.21–1.38)</td><td>0.96</td><td>0.105</td></tr><tr><td>Dobutamine use at baseline</td><td>149 (60.1 %)</td><td>46 (70.8 %)</td><td>0.15</td><td>0.226</td><td>148.1 (59.6 %)</td><td>45.0 (69.2 %)</td><td>0.31</td><td>0.201</td></tr><tr><td>Dobutamine dose at baseline (µg/kg/min) - only in patients who received this treatment</td><td>7.50 (4.80–10.25)</td><td>5.00 (4.40–11.00)</td><td>0.50</td><td>0.028</td><td>7.56 (4.99–10.93)</td><td>5.00 (4.68–11.29)</td><td>0.41</td><td>0.093</td></tr></tbody></table>

Values are mean ± SD or median (Q1 - Q3) for continuous variables, n (%) for categorical variables.

ASMD: absolute standardized mean difference; HF: heart failure; IPW: inverse probability weighting; n: number.

ECMO: extracorporeal membrane oxygenation; LVEF: left ventricular ejection fraction. SI conversion factor: to convert lactate to mg/dL, divide by 0.111.

* p-value from t-test or Wilcoxon test for continuous variables, chi-square test or Fisher's exact test for categorical variables.

** p-value from weighted t-test or weighted Wilcoxon test for continuous variables, weighted chi-square test for categorical variables.

a Calculated as weight in kilograms divided by height in meters squared.

b Determined by the clinician in charge of the patient and based on chart review.

c May have 1 or more cardiogenic shock etiologies.

d Normal range is 7.35 to 7.45.

e A normal level is less than 2 mmol/L.

f Mortality prediction score based on the degree of dysfunction in 6 organ systems. Scores range from 0 to 24. The score was quantified by the clinicians in charge of the patients during the trial.

g Only considered in treated patients with available data.

whereas it was not in the ACHF group ($p > 0.7$ for all and $p$ for interaction $>0.2$ for all).

In contrast, moderate hypothermia was associated with a significantly lower rate of RRT in the ACHF group (IPW RD, -28.7 %, $p = 0.014$) but not in the DNHF group ($p = 0.34$) ($p$ for interaction $=0.088$).

## 4. Discussion

The Hypo-ECMO trial is the largest randomized study to date on refractory cardiogenic shock rescued by VA-ECMO. This trial assessed

the effect of moderate hypothermia versus normothermia and enrolled 20 % of patients with a prior history of HF. In the present post-hoc analysis, without adjustment on clinical differences, we show that prognosis did not significantly differ between ACHF and DNHF in all-cause mortality or the combined endpoint. However, we found a significant improvement in 180-day survival as well as in the composite outcome at 30, 60, and 180 days. Second, a heterogeneous effect of MH on mortality was also found based on ACHF/DNHF status. In effect, MH showed a tendency to be associated with reduced mortality and was significantly linked to a lower risk of the composite outcome at 30, 60,
<table><caption>**Table 2**
Effect of acute-on-chronic heart failure (vs. de-novo heart failure) on primary and secondary outcomes and adverse events.</caption><thead><tr><th rowspan="2"></th><th colspan="4">Unadjusted</th><th colspan="4">IPW-adjusted</th></tr><tr><th>De-novo HF (n = 256)</th><th>Acute-on-chronic HF (n = 65)</th><th>RD (CI 95 %)</th><th>p-value</th><th>De-novo HF (n = 256)</th><th>Acute-on-chronic HF (n = 65)</th><th>RD (CI 95 %)</th><th>p-value</th></tr></thead><tbody><tr><td>Primary endpoint</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>All-cause mortality at 30 days</td><td>122/256 (47.7 %)</td><td>26/65 (40.0 %)</td><td>-7.7 (-21.0 to 5.7)</td><td>0.26</td><td>123.1/256.0 (48.1 %)</td><td>23.7/65.0 (36.5 %)</td><td>-11.6 (-24.8 to 1.6)</td><td>0.084</td></tr><tr><td>Secondary endpoints</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>All-cause mortality at 60 days</td><td>136/256 (53.1 %)</td><td>30/65 (46.2 %)</td><td>-7.0 (-20.5 to 6.6)</td><td>0.31</td><td>136.8/256.0 (53.5 %)</td><td>26.8/65.0 (41.2 %)</td><td>-12.2 (-25.7 to 1.2)</td><td>0.075</td></tr><tr><td>All-cause mortality at 180 days</td><td>145/256 (56.6 %)</td><td>32/65 (49.2 %)</td><td>-7.4 (-21.0 to 6.2)</td><td>0.29</td><td>145.7/256.0 (56.9 %)</td><td>28.1/65.0 (43.2 %)</td><td>-13.7 (-27.1 to -0.2)</td><td>0.047</td></tr><tr><td>Composite endpoint at day 30</td><td>159/256 (62.1 %)</td><td>36/65 (55.4 %)</td><td>-6.7 (-20.2 to 6.7)</td><td>0.33</td><td>160.9/256.0 (62.9 %)</td><td>27.8/65.0 (42.8 %)</td><td>-20.0 (-33.4 to -6.6)</td><td>0.003</td></tr><tr><td>Composite endpoint at day 60</td><td>169/256 (66.0 %)</td><td>41/65 (63.1 %)</td><td>-2.9 (-16.0 to 10.1)</td><td>0.66</td><td>171.6/256.0 (67.0 %)</td><td>31.5/65.0 (48.5 %)</td><td>-18.5 (-31.9 to -5.0)</td><td>0.007</td></tr><tr><td>Composite endpoint at day 180</td><td>176/256 (68.8 %)</td><td>42/65 (64.6 %)</td><td>-4.1 (-17.1 to 8.8)</td><td>0.53</td><td>178.1/256.0 (69.6 %)</td><td>32.5/65.0 (50.0 %)</td><td>-19.5 (-32.9 to -6.1)</td><td>0.004</td></tr><tr><td>Renal replacement therapy during the study</td><td>109/253 (43.1 %)</td><td>26/64 (40.6 %)</td><td>-2.5 (-15.9 to 11.0)</td><td>0.72</td><td>108.7/253.5 (42.9 %)</td><td>19.5/64.0 (30.4 %)</td><td>-12.5 (-25.3 to 0.4)</td><td>0.057</td></tr></tbody></table>

HF: heart failure; IPW: inverse probability weighting; n: number; RD: risk difference.

<figure><img src="image_4.png" /><figcaption>**Fig. 2.** Kaplan–Meier curves for all-cause mortality at day 30 according to HF status. KM = Kaplan–Meier.</figcaption></figure>

and 180 days specifically in the DNHF group. Third, moderate hypothermia was associated with a lower rate of RRT in patients with treated ACHF as opposed to unchanged in the DNHF group.

Chronic heart failure is often associated with a decrease in both cardiac output and blood pressure together with an increase in pulmonary and systemic congestion [29]. Progressive adaptation allows the kidneys and liver to tolerate low flow and high venous pressure values that would otherwise be intolerable in an acute setting, albeit at the cost of a progressive dysfunction of both organs. In addition, chronic activation of the neurohormonal and sympathetic nervous systems is treated by the introduction of HF therapy, such as beta-blockers and renin-angiotensin system antagonists, resulting in a decrease in systemic vascular resistance. These profound modifications induced by heart failure and its management explain the varying pathophysiology of cardiogenic shock according to HF history. ACHF patients included in heart failure or cardiogenic shock studies have been found to be older, have more comorbidities, and sicker compared to DNHF patients [5,30]. In the present analysis comprised of a selected population of CS rescued by VA-ECMO, nearly one out of 3 patients was alive at 180 days without

stroke or escalation to LVAD or HT, with a similar proportion in both groups. This proportion is higher compared with that reported in the literature [6]. Specifically, in a retrospective single-center study which included 105 patients receiving ECMO for ACHF, only one patient was weaned from ECMO, 33 patients were transplanted, and 12 patients were bridged to LVAD or total artificial heart [21].

As anticipated, patients with ACHF in this study exhibited higher creatinine and bilirubin levels at admission, likely indicative of chronic low cardiac output syndromes Despite a higher severity at inclusion of patients with ACHF, all-cause mortality or composite endpoint were not significantly different between groups at all studied time points before IPW. When adjusting for IPW, ACHF patients had a better prognosis, with higher 180-day survival and a reduction in the composite endpoint at all assessment times. This difference in composite outcome is explained by a lower risk of stroke, mainly in the first 30 days in the ACHF group compared with the DNHF group (1.5 % versus 12 %). Interestingly, the rate of LVAD implantation or heart transplant was broadly similar across groups. Taken together, these data suggest that the prognosis of selected patients (according to HYPO-ECMO inclusion
<table><caption>Fig. 3. Effect of acute-on-chronic HF (vs. de-novo HF) in subgroups for the primary endpoint (IPW-adjusted).</caption><thead><tr><th>Subgroup</th><th>De-novo HF</th><th>Acute-on-chronic HF</th><th>IPW-adjusted<br>Risk Difference (CI 95%)</th><th>P Value for<br>Interaction</th></tr></thead><tbody><tr><td>Overall effect</td><td>48.1 %</td><td>36.5 %</td><td>-11.6 (-24.8 to 1.6)</td><td></td></tr><tr><td>Age</td><td></td><td></td><td></td><td>0.12</td></tr><tr><td>≤60 years</td><td>39.0 %</td><td>17.2 %</td><td>-21.8 (-37.2 to -6.5)</td><td></td></tr><tr><td>>60 years</td><td>58.1 %</td><td>55.9 %</td><td>-2.2 (-21.4 to 17.0)</td><td></td></tr><tr><td>Previous MI</td><td></td><td></td><td></td><td>0.38</td></tr><tr><td>No</td><td>46.2 %</td><td>36.9 %</td><td>-9.3 (-24.0 to 5.4)</td><td></td></tr><tr><td>Yes</td><td>59.6 %</td><td>34.6 %</td><td>-25.0 (-56.3 to 6.4)</td><td></td></tr><tr><td>Prior cardiac arrest</td><td></td><td></td><td></td><td>0.084</td></tr><tr><td>No</td><td>42.7 %</td><td>41.2 %</td><td>-1.6 (-19.1 to 16.0)</td><td></td></tr><tr><td>Yes</td><td>54.0 %</td><td>29.2 %</td><td>-24.8 (-44.5 to -5.1)</td><td></td></tr><tr><td>Post cardiac surgery</td><td></td><td></td><td></td><td>0.28</td></tr><tr><td>No</td><td>46.9 %</td><td>38.1 %</td><td>-8.8 (-23.2 to 5.6)</td><td></td></tr><tr><td>Yes</td><td>55.4 %</td><td>27.2 %</td><td>-28.2 (-60.5 to 4.0)</td><td></td></tr><tr><td>Vasopressor dose</td><td></td><td></td><td></td><td>0.91</td></tr><tr><td>&lt;0.4 µg/kg/min</td><td>42.1 %</td><td>31.4 %</td><td>-10.7 (-29.1 to 7.6)</td><td></td></tr><tr><td>≥0.4 µg/kg/min</td><td>53.7 %</td><td>41.5 %</td><td>-12.2 (-31.4 to 6.9)</td><td></td></tr><tr><td>Lactate</td><td></td><td></td><td></td><td>0.79</td></tr><tr><td>≤4.8 mmol/L</td><td>42.0 %</td><td>30.1 %</td><td>-11.9 (-28.6 to 4.8)</td><td></td></tr><tr><td>>4.8 mmol/L</td><td>54.7 %</td><td>46.3 %</td><td>-8.3 (-29.7 to 13.1)</td><td></td></tr><tr><td>SOFA score</td><td></td><td></td><td></td><td>0.95</td></tr><tr><td>≤10</td><td>43.0 %</td><td>30.4 %</td><td>-12.6 (-31.1 to 5.9)</td><td></td></tr><tr><td>>10</td><td>54.3 %</td><td>42.5 %</td><td>-11.7 (-31.7 to 8.2)</td><td></td></tr></tbody></table>

criteria) receiving VA-ECMO for CS is not modified by HF status. Therefore, this criterion should not be a contraindication to the use of VA-ECMO when necessary. However, on the other hand, this does not imply that all patients with ACHF of varying severity should undergo VA-ECMO, as the HYPO-ECMO trial did not assess the benefit of VA-ECMO implantation compared to standard of care. Indeed, early ECMO implantation in the setting of CS of various etiology has recently been assessed in a small, randomized trial that included 24 % of ACHF patients, the result of which was neutral [31]. Notwithstanding, whether ACHF may derive greater benefit from early ECMO warrants further testing in a specific trial.

While nearly half of our population presented with CA, all-cause mortality at 30 days remained below 50 % in both the ACHF and DNHF groups. However, it is noteworthy that the prognosis appears more favorable in the ACHF group in cases of CA, with an interaction test approaching statistical significance. These data suggest that the association between CA and survival could be influenced by the history of HF.

In the present post-hoc analysis, MH was associated with a 13 % reduction in composite outcomes (including death, heart transplant, escalation to LVAD implantation, or stroke) at 180 days among patients in the DNHF group. In contrast, moderate hypothermia was neutrally associated with outcome in ACHF patients. These results are not surprising given that most animal and human studies having shown a benefit of hypothermia were largely focused on DNHF models by using ischemia-reperfusion (IR)-induced CS or cardiac arrest [32–35]. Current data are both scarce and debated in patients with a history of HF. Indeed, an in-vitro study in explanted human failing heart showed that hypothermia could induce diastolic dysfunction by decreasing the time to achieve ventricular filling during diastole [22]. Additionally, in a recent study, MH was associated with increased mortality among cardiac arrest survivors with known HF [36].

MH was associated with a reduction in RRT only in the ACHF population with a trend for interaction with HF history, likely due to the lack of statistical power of the interaction tests [37]. The significantly higher renal benefit of hypothermia in the ACHF group was unexpected, and we cannot rule out the possibility of a fortuitous finding. The possibility of a regression to the mean phenomenon in the ACHF group, which had poorer baseline renal function, cannot be excluded. The effect of MH on renal function in the setting of CS is practically nonexistent in the literature. However, hypothermia in organ donors has been found to reduce the rate of delayed graft function among kidney transplant recipients [38] as well as provide protection from acute and chronic renal ischemia-reperfusion injury in an animal study [39]. Likewise, recipients of organs from expanded-criteria donors experienced a greater benefit from hypothermia than recipients of organs from standard-criteria donors [38]. Taken together, these results may suggest that chronic low flow (which is more likely in patients with history of HF) could induce ischemic preconditioning which, in turn, translates into a favorable renal outcome when MH is used. Dedicated studies are needed to confirm this potentially fortuitous finding and to better understand the hypothetical mechanisms underlying the renal benefits of MH in CS, providing clarity on whether these effects are reproducible and clinically meaningful.

### 4.1. Implication for clinical practice

Our results highlight the importance of not unequivocally contraindicated patients with prior HF history from receiving ECMO in the setting of refractory cardiogenic shock. Indeed, the prognosis in this group was at least equivalent if not better in our analysis when patients were carefully selected according to HYPO-ECMO inclusion criteria. These findings may have a major impact since these patients can often be perceived as at too high risk to be referred to tertiary centers. In fact,
<table><caption>**Table 3**
Composite endpoints at 30, 60 and 180 days (death, heart transplant, stroke, escalation to LVAD) according to HF status.</caption><thead><tr><th rowspan="2">Variable</th><th colspan="4">Unadjusted</th><th colspan="4">IPW-adjusted</th></tr><tr><th>De-novo HF (n = 256)</th><th>Acute-on-chronic (n = 65)</th><th>RD (CI 95 %)</th><th>p-value</th><th>De-novo HF (n = 256)</th><th>Acute-on-chronic (n = 65)</th><th>RD (CI 95 %)</th><th>p-value</th></tr></thead><tbody><tr><td>Composite outcome of death, heart transplant, escalation to LVAD implantation or stroke at 30 days</td><td>159 (62.1 %)</td><td>36 (55.4 %)</td><td>-6.7 (-20.2 to 6.7)</td><td>0.33</td><td>160.9 (62.9 %)</td><td>27.8 (42.8 %)</td><td>-20.0 (-33.4 to -6.6)</td><td>0.003</td></tr><tr><td>Death at 30 days</td><td>122 (47.7 %)</td><td>26 (40.0 %)</td><td>-7.7 (-21.0 to 5.7)</td><td>0.26</td><td>123.1 (48.1 %)</td><td>23.7 (36.5 %)</td><td>-11.6 (-24.8 to 1.6)</td><td>0.084</td></tr><tr><td>Stroke at 30 days</td><td>31 (12.1 %)</td><td>1 (1.5 %)</td><td>-10.6 (-15.6 to -5.6)</td><td>&lt;0.0001</td><td>32.4 (12.6 %)</td><td>0.5 (0.8 %)</td><td>-11.9 (-16.5 to -7.3)</td><td>&lt;0.0001</td></tr><tr><td>Heart transplant at 30 days</td><td>8 (3.1 %)</td><td>4 (6.2 %)</td><td>3.0 (-3.2 to 9.2)</td><td>0.34</td><td>7.1 (2.8 %)</td><td>1.6 (2.4 %)</td><td>-0.4 (-4.6 to 3.9)</td><td>0.87</td></tr><tr><td>Escalation to LVAD implantation at 30 days</td><td>31 (12.1 %)</td><td>8 (12.3 %)</td><td>0.2 (-8.7 to 9.1)</td><td>0.97</td><td>29.5 (11.5 %)</td><td>4.6 (7.1 %)</td><td>-4.4 (-11.8 to 2.9)</td><td>0.24</td></tr><tr><td>Composite outcome of death, heart transplant, escalation to LVAD implantation or stroke at 60 days</td><td>169 (66.0 %)</td><td>41 (63.1 %)</td><td>-2.9 (-16.0 to 10.1)</td><td>0.66</td><td>171.6 (67.0 %)</td><td>31.5 (48.5 %)</td><td>-18.5 (-31.9 to -5.0)</td><td>0.007</td></tr><tr><td>Death at 60 days</td><td>136 (53.1 %)</td><td>30 (46.2 %)</td><td>-7.0 (-20.5 to 6.6)</td><td>0.31</td><td>136.8 (53.5 %)</td><td>26.8 (41.2 %)</td><td>-12.2 (-25.7 to 1.2)</td><td>0.075</td></tr><tr><td>Stroke at 60 days</td><td>33 (12.9 %)</td><td>2 (3.1 %)</td><td>-9.8 (-15.7 to -3.9)</td><td>0.001</td><td>35.1 (13.7 %)</td><td>1.0 (1.6 %)</td><td>-12.1 (-17.3 to -6.9)</td><td>&lt;0.0001</td></tr><tr><td>Heart transplant at 60 days</td><td>9 (3.5 %)</td><td>5 (7.7 %)</td><td>4.2 (-2.7 to 11.0)</td><td>0.23</td><td>8.7 (3.4 %)</td><td>2.2 (3.4 %)</td><td>-0.0 (-4.9 to 4.9)</td><td>1.00</td></tr><tr><td>Escalation to LVAD implantation at 60 days</td><td>32 (12.5 %)</td><td>9 (13.8 %)</td><td>1.3 (-8.0 to 10.7)</td><td>0.78</td><td>30.4 (11.9 %)</td><td>4.9 (7.5 %)</td><td>-4.3 (-11.9 to 3.2)</td><td>0.26</td></tr><tr><td>Composite outcome of death, heart transplant, escalation to LVAD implantation or stroke at 180 days</td><td>176 (68.8 %)</td><td>42 (64.6 %)</td><td>-4.1 (-17.1 to 8.8)</td><td>0.53</td><td>178.1 (69.6 %)</td><td>32.5 (50.0 %)</td><td>-19.5 (-32.9 to -6.1)</td><td>0.004</td></tr><tr><td>Death at 180 days</td><td>145 (56.6 %)</td><td>32 (49.2 %)</td><td>-7.4 (-21.0 to 6.2)</td><td>0.29</td><td>145.7 (56.9 %)</td><td>28.1 (43.2 %)</td><td>-13.7 (-27.1 to -0.2)</td><td>0.047</td></tr><tr><td>Stroke at 180 days</td><td>34 (13.3 %)</td><td>2 (3.1 %)</td><td>-10.2 (-16.1 to -4.3)</td><td>0.0007</td><td>36.0 (14.1 %)</td><td>1.0 (1.6 %)</td><td>-12.5 (-17.7 to -7.2)</td><td>&lt;0.0001</td></tr><tr><td>Heart transplant at 180 days</td><td>10 (3.9 %)</td><td>5 (7.7 %)</td><td>3.8 (-3.1 to 10.7)</td><td>0.28</td><td>9.5 (3.7 %)</td><td>2.2 (3.4 %)</td><td>-0.3 (-5.3 to 4.6)</td><td>0.89</td></tr><tr><td>Escalation to LVAD implantation at 180 days</td><td>32 (12.5 %)</td><td>9 (13.8 %)</td><td>1.3 (-8.0 to 10.7)</td><td>0.78</td><td>30.4 (11.9 %)</td><td>4.9 (7.5 %)</td><td>-4.3 (-11.9 to 3.2)</td><td>0.26</td></tr></tbody></table>

HF: heart failure; IPW: inverse probability weighting; n: number; RD: risk difference.

<figure><img src="image_5.png" /><figcaption>**Fig. 4.** IPW-adjusted Kaplan-Meier curves for all-cause mortality according to HF status and study group. A) at 30 days, B) at 180 days. KM = Kaplan-Meier.</figcaption></figure>
<table><caption>**Table 4**
Effect of moderate hypothermia (vs. normothermia) according to HF status on binary endpoints.</caption><thead><tr><th></th><th>Moderate hypothermia (n = 161)</th><th>Normothermia (n = 160)</th><th>RD (CI 95 %)</th><th>p-value</th><th>Interaction p-value</th></tr></thead><tbody><tr><td>All-cause mortality at 30 days</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>67/160 (41.9 %)</td><td>81/161 (50.3 %)</td><td>-8.4 (-19.3 to 2.4)</td><td>0.13</td><td>0.37</td></tr><tr><td>De-novo HF</td><td>54/128 (42.2 %)</td><td>68/128 (53.1 %)</td><td>-10.9 (-23.1 to 1.2)</td><td>0.078</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>13/32 (40.6 %)</td><td>13/33 (39.4 %)</td><td>1.2 (-22.6 to 25.1)</td><td>0.92</td><td></td></tr><tr><td>All-cause mortality at 60 days</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>78/160 (48.8 %)</td><td>88/161 (54.7 %)</td><td>-5.9 (-16.8 to 5.0)</td><td>0.29</td><td>0.22</td></tr><tr><td>De-novo HF</td><td>62/128 (48.4 %)</td><td>74/128 (57.8 %)</td><td>-9.4 (-21.5 to 2.8)</td><td>0.13</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>16/32 (50.0 %)</td><td>14/33 (42.4 %)</td><td>7.6 (-16.6 to 31.8)</td><td>0.54</td><td></td></tr><tr><td>All-cause mortality at 180 days</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>84/160 (52.5 %)</td><td>93/161 (57.8 %)</td><td>-5.3 (-16.1 to 5.6)</td><td>0.34</td><td>0.081</td></tr><tr><td>De-novo HF</td><td>66/128 (51.6 %)</td><td>79/128 (61.7 %)</td><td>-10.2 (-22.2 to 1.9)</td><td>0.099</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>18/32 (56.2 %)</td><td>14/33 (42.4 %)</td><td>13.8 (-10.3 to 37.9)</td><td>0.26</td><td></td></tr><tr><td>Composite endpoint at day 30</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>87/160 (54.4 %)</td><td>108/161 (67.1 %)</td><td>-12.7 (-23.3 to -2.1)</td><td>0.019</td><td>0.45</td></tr><tr><td>De-novo HF</td><td>70/128 (54.7 %)</td><td>89/128 (69.5 %)</td><td>-14.8 (-26.6 to -3.1)</td><td>0.013</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>17/32 (53.1 %)</td><td>19/33 (57.6 %)</td><td>-4.5 (-28.6 to 19.7)</td><td>0.72</td><td></td></tr><tr><td>Composite endpoint at day 60</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>97/160 (60.6 %)</td><td>113/161 (70.2 %)</td><td>-9.6 (-19.9 to 0.8)</td><td>0.070</td><td>0.43</td></tr><tr><td>De-novo HF</td><td>77/128 (60.2 %)</td><td>92/128 (71.9 %)</td><td>-11.7 (-23.2 to -0.2)</td><td>0.046</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>20/32 (62.5 %)</td><td>21/33 (63.6 %)</td><td>-1.1 (-24.6 to 22.3)</td><td>0.92</td><td></td></tr><tr><td>Composite endpoint at day 180</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>101/160 (63.1 %)</td><td>117/161 (72.7 %)</td><td>-9.5 (-19.7 to 0.6)</td><td>0.066</td><td>0.27</td></tr><tr><td>De-novo HF</td><td>80/128 (62.5 %)</td><td>96/128 (75.0 %)</td><td>-12.5 (-23.8 to -1.2)</td><td>0.029</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>21/32 (65.6 %)</td><td>21/33 (63.6 %)</td><td>2.0 (-21.3 to 25.2)</td><td>0.87</td><td></td></tr><tr><td>Renal replacement therapy during study</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Overall</td><td>59/158 (37.3 %)</td><td>76/159 (47.8 %)</td><td>-10.5 (-21.3 to 0.4)</td><td>0.058</td><td>0.084</td></tr><tr><td>De-novo HF</td><td>51/127 (40.2 %)</td><td>58/126 (46.0 %)</td><td>-5.9 (-18.1 to 6.3)</td><td>0.34</td><td></td></tr><tr><td>Acute-on-chronic HF</td><td>8/31 (25.8 %)</td><td>18/33 (54.5 %)</td><td>-28.7 (-51.7 to -5.8)</td><td>0.014</td><td></td></tr></tbody></table>

HF: heart failure; n: number; RD: risk difference.

patients with ACHF represented a fraction of patients included in the HYPO-ECMO trial (approximately 20 %) whereas ACHF is a leading cause of CS; this suggests that a number of patients with CS in the setting of ACHF may not have been referred to ECMO implantation.

Moderate hypothermia was associated with a sizeable (and often statistically significant) reduction in both mortality and composite outcome in DNHF patients. These findings suggest that excluding patients with a history of heart failure may be considered in the design of future randomized clinical trials on MH in CS. Furthermore, the routine use of hypothermia in this population does not appear to be recommended in the absence of demonstrated benefit.

## 4.2. Limitations

This study has several limitations. First, investigators coded HF history using only binary responses, which omitted crucial details such as the duration and severity of HF, prior HF hospitalizations, LVEF, and baseline natriuretic peptide levels. However, these details are often missing in the charts of patients admitted to the ICU for cardiogenic shock. Therefore, the data's granularity in this analysis likely reflects what is typically available in routine practice. The duration from cardiogenic shock onset to VA-ECMO implantation, as well as the proportion of successful VA-ECMO weaning, were unavailable and may have varied between groups.

IPW was used to reduce the baseline difference between groups, but we cannot rule out the persistence of bias or the incomplete correction for intrinsic differences across groups (e.g., acute coronary syndrome). Second, the small number of patients with a history of HF resulted in limited statistical power to assess between-group interactions.

## 5. Conclusion

Thirty-day survival of refractory cardiogenic shock rescued by VA-ECMO was not significantly different in acute-on-chronic and de-novo heart failure patients. In this exploratory post-hoc analysis, moderate hypothermia showed benefits exclusively for patients with de-novo

heart failure, emphasizing the need to refine target populations for future trials.

## Funding statement

The trial was sponsored and conducted by the Direction de la Recherche Clinique, CHU Nancy, with a grant from the French Ministry. The funder/sponsor had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

## CRediT authorship contribution statement

Guillaume Baudry: Writing – review & editing, Writing – original draft, Formal analysis, Conceptualization. Bruno Levy: Writing – review & editing, Supervision, Investigation, Conceptualization. Kevin Duarte: Methodology, Formal analysis. Luca Monzo: Writing – review & editing. Alain Combes: Writing – review & editing. Antoine Kimmoun: Writing – review & editing, Validation. Nicolas Girerd: Writing – review & editing, Supervision, Methodology, Conceptualization.

## Declaration of competing interest

Dr. Baudry reported receiving personal fees from Abbott, AstraZeneca, and Boehringer, outside the submitted work.

Pr Girerd reported receiving personal fees from Novartis, Bayer, AstraZeneca, Lilly, Boehringer, and Vifor, outside the submitted work.

Dr. Duarte reported no conflict of interest regarding this work.

Dr. Monzo reported receiving personal fees from AstraZeneca and Vifor, outside the submitted work.

Pr Combes reported receiving personal fees from Getinge, Baxter, and Fresenius-Xenios, outside the submitted work.

Pr Kimmoun reported no conflict of interest regarding this work.

Pr Levy reported receiving personal fees from Abiomed, Gettinge, Baxter, Novartis, Sanofi, Abiomed, and Orion, outside the submitted work.
work.

## Acknowledgments

None.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jcrc.2025.155043.

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