Paul Guedeney

MD a ; Holger Thiele

MD b ; Mathieu Kerneis

MD a ; Olivier Barthélémy

MD c ; Stefan Baumann

MD Marcus Sandri

Suzanne De Waha-Thiele

MD d ; Georg Fuernau

MS e ; Stéphanie Rouanet

MD, PhD f ; Jan J Piek

MD d ; Suzanne De Waha- Thiele

MD g ; Ulf Landmesser

MD a ; Marie Hauguel-Moreau

MD a ; Michel Zeitouni

MD, PhD Johanne Silvain

MD a ; Benoit Lattuca

MD h ; Stephan Windecker

MD, PhD Jean-Philippe Collet

MD b ; Steffen Desch

MD i ; Uwe Zeymer

MD, PhD Gilles Montalescot #
email: gilles.montalescot@aphp.fr

MD Ibrahim Akin #

Gilles Pr

MD Montalescot

Radial versus femoral artery access for percutaneous coronary artery intervention in patients with acute myocardial infarction and multivessel disease complicated by cardiogenic shock: Subanalysis from the CULPRIT-SHOCK trial

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Structured abstract

Background The use and impact of transradial artery access (TRA) compared to transfemoral artery access (TFA) in patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) complicated by cardiogenic shock (CS) remains unclear.

Methods This is a post-hoc analysis of the CULPRIT-SHOCK trial where patients presenting with MI and multivessel disease complicated by CS were randomized to a strategy of culpritlesion-only or immediate multivessel PCI. Arterial access was left at operator's discretion. Adjudicated outcomes of interest were the composite of death or renal-replacement therapy (RRT) at 30-day and one-year. Multivariate logistic models were used to assess the association between the arterial access and outcomes. Results Among the 673 analyzed patients, TRA and TFA were successfully performed in 118 (17.5%) and 555 (82.5%) patients, respectively. TRA was associated with lower 30-day rate of death or RRT compared to TFA (37.3% vs. 53.2%, respectively, adjusted Odds Ratio [aOR]: 0.57; 95% confidence interval [CI] 0.34-0.96), lower 30-day rates of death (34.7% vs. 49.7%, respectively; aOR: 0.56; 95%CI 0.33-0.96) and RRT (5.9% vs. 15.9%; aOR: 0.40; 95%CI 0.16-0.97). No significant differences were observed regarding the 30-day risks of type 3 or 5 BARC bleeding and stroke. The observed reduction of death or RRT and death with TRA was no longer significant at one-year (44.9% vs 57.8%; aOR: 0.85; 95%CI 0.50-1.45 and 42.4% vs. 55.5%, aOR: 0.78; 95%CI 0.46-1.32, respectively).

Conclusions

In patients undergoing PCI for acute MI complicated by CS, TRA may be associated with improved early outcomes, while the reason for this finding needs further research.

Key words: myocardial infarction; cardiogenic shock; transradial artery access; percutaneous coronary intervention

INTRODUCTION

A growing body of evidence from large randomized trials and real-world observational studies has led to a generalization of transradial artery access (TRA) over transfemoral artery access (TFA) in patients undergoing percutaneous coronary intervention (PCI) for STsegment elevation myocardial infarction (STEMI) [START_REF] Beygui | Chapter 31: Transradial Approach for Diagnostic Coronary Angiography and Intervention[END_REF][START_REF] Bertrand | Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention[END_REF][START_REF] Valgimigli | Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial[END_REF][START_REF] Vranckx | Radial versus femoral access in patients with acute coronary syndromes with or without ST-segment elevation[END_REF][START_REF] Valgimigli | Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial[END_REF][START_REF] Ferrante | Radial Versus Femoral Access for Coronary Interventions Across the Entire Spectrum of Patients With Coronary Artery Disease: A Meta-Analysis of Randomized Trials[END_REF][START_REF] Feldman | Adoption of radial access and comparison of outcomes to femoral access in percutaneous coronary intervention: an updated report from the national cardiovascular data registry (2007-2012)[END_REF]. TRA has been associated with a lower risk of vascular complications, access site bleeding, acute kidney injury (AKI), and more remarkably, a survival benefit0 [START_REF] Valgimigli | Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial[END_REF][START_REF] Valgimigli | Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial[END_REF][START_REF] Ferrante | Radial Versus Femoral Access for Coronary Interventions Across the Entire Spectrum of Patients With Coronary Artery Disease: A Meta-Analysis of Randomized Trials[END_REF][START_REF] Andò | Acute Kidney Injury After Radial or Femoral Access for Invasive Acute Coronary Syndrome Management: AKI-MATRIX[END_REF][START_REF] Bernat | ST-segment elevation myocardial infarction treated by radial or femoral approach in a multicenter randomized clinical trial: the STEMI-RADIAL trial[END_REF][START_REF] Kinnaird | Access Site and Outcomes for Unprotected Left Main Stem Percutaneous Coronary Intervention: An Analysis of the British Cardiovascular Intervention Society Database[END_REF][START_REF] Porto | Impact of Access Site on Bleeding and Ischemic Events in Patients With Non-ST-Segment Elevation Myocardial Infarction Treated With Prasugrel: The ACCOAST Access Substudy[END_REF]. Therefore, international guidelines recommend TRA as the standard approach, if performed by an experienced operator and in the absence of overriding procedural considerations [START_REF] Roffi | ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC)[END_REF][START_REF] Van Diepen | Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association[END_REF][START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF][START_REF] Neumann | ESC/EACTS Guidelines on myocardial revascularization[END_REF][START_REF] Mason | An Update on Radial Artery Access and Best Practices for Transradial Coronary Angiography and Intervention in Acute Coronary Syndrome: A Scientific Statement From the American Heart Association[END_REF]. Whether the beneficial impact of TRA remains consistent in patients undergoing primary PCI for acute MI complicated by cardiogenic shock (CS) is less clear. CS represents a life-threatening situation, where the hemodynamic instability and the potential need for mechanical hemodynamic support may render TRA for primary PCI more challenging [START_REF] Dangas | Prediction, staging, and outcomes of ischaemic cardiogenic shock after STEMI: a complex clinical interplay[END_REF]. Although observational studies have suggested TRA to be associated with improved outcomes in this setting, there remains a dearth of data from randomized trials [START_REF] Bernat | Early and late outcomes after primary percutaneous coronary intervention by radial or femoral approach in patients presenting in acute STelevation myocardial infarction and cardiogenic shock[END_REF][START_REF] Mamas | Arterial access site utilization in cardiogenic shock in the United Kingdom: is radial access feasible?[END_REF][START_REF] Roule | Transradial versus transfemoral approach for percutaneous coronary intervention in cardiogenic shock: A radial-first centre experience and meta-analysis of published studies[END_REF][START_REF] Pancholy | Impact of access site choice on outcomes of patients with cardiogenic shock undergoing percutaneous coronary intervention: A systematic review and meta-analysis[END_REF][START_REF] Rodriguez-Leor | Transradial percutaneous coronary intervention in cardiogenic shock: a single-center experience[END_REF][START_REF] Romagnoli | Radial versus femoral approach comparison in percutaneous coronary intervention with intraaortic balloon pump support: the RADIAL PUMP UP registry[END_REF]. In fact, in previous randomized controlled trials comparing TRA to TFA, patients with CS were excluded [START_REF] Bernat | ST-segment elevation myocardial infarction treated by radial or femoral approach in a multicenter randomized clinical trial: the STEMI-RADIAL trial[END_REF][START_REF] Jolly | Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial[END_REF] or modestly represented [START_REF] Valgimigli | Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial[END_REF][START_REF] Romagnoli | Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study[END_REF][START_REF] May | The SAfety and Efficacy of Femoral Access vs RadIal Access in STEMI: The SAFARI-STEMI Trial[END_REF]. Our aim was to assess the use and association between the type of vascular route with early and late outcomes in patients randomized in the Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial.

METHODS

This is a post-hoc analysis of the CULPRIT-SHOCK trial, whose design and results have been previously described [START_REF] Thiele | Multivessel versus culprit lesion only percutaneous revascularization plus potential staged revascularization in patients with acute myocardial infarction complicated by cardiogenic shock: Design and rationale of CULPRIT-SHOCK trial[END_REF][START_REF] Thiele | PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock[END_REF][START_REF] Thiele | One-Year Outcomes after PCI Strategies in Cardiogenic Shock[END_REF]. Briefly, the CULPRIT-SHOCK trial was an investigatorinitiated, international, multicenter, open-label study where patients presenting with acute MI and multivessel coronary artery disease complicated by CS were randomized, in a 1:1 ratio, to a strategy of culprit-lesion-only PCI (with optional staged revascularization) or immediate multivessel PCI. In all patients, the culprit lesion was treated first, with the use of standard PCI techniques and with the recommended use of drug-eluting stents. In the culprit-lesiononly group, staged revascularization was performed according to the patient clinical status and the presence of residual ischemia. In the multivessel PCI group, any >70% stenosis of major coronary arteries (i.e. ≥ 2 mm diameter), including chronic total occlusion, were recommended to be treated with immediate PCI following the treatment of the culprit lesion, with a recommended maximum dose of contrast material of 300 mL. The indication for other therapy, including the use of mechanical circulatory support, was left to the discretion of the local physician, in accordance with generally accepted intensive care guidelines. The investigation was approved by the ethic committee or institutional review board of each participating center and written informed consent was obtained with the use of a prespecified process that varied slightly according to the country [START_REF] Thiele | PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock[END_REF]. The type of vascular access was left at the discretion of local operators. Patients undergoing brachial arterial access or concomitant TRA and TFA for the PCI procedures were excluded from this study. The CULPRIT-SHOCK trial was supported by a grant agreement (602202) from the European Union Seventh Framework Program and by the German Heart Research Foundation and the German Cardiac Society. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the papers and its final contents.

Study objective

Our objective was to evaluate the association between the type of vascular approach and early and late outcomes. Early outcomes of interest were the primary endpoint of the CULPRIT SHOCK trial, defined as the composite of all-cause death or severe renal failure leading to renal-replacement therapy within 30 days after randomization, as well as each individual component, the 30-day composite of type 3 or 5 bleeding academic research consortium (BARC) bleeding and the 30-day risk of stroke. Late outcomes of interest were the one-year risk of all-cause death or renal-replacement therapy and all-cause death. Events were defined as previously reported and adjudicated by an independent clinical event committee [START_REF] Thiele | Multivessel versus culprit lesion only percutaneous revascularization plus potential staged revascularization in patients with acute myocardial infarction complicated by cardiogenic shock: Design and rationale of CULPRIT-SHOCK trial[END_REF][START_REF] Thiele | PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock[END_REF][START_REF] Thiele | One-Year Outcomes after PCI Strategies in Cardiogenic Shock[END_REF]. Specific follow-up was performed at 30 days, 6 months and one year by means of structured telephone interviews, with any potential endpoint events verified by review of original records. Death registries were searched to identify or confirm all deaths.

Statistical analysis

Categorical variables were described as proportion and compared with Chi-square test or Fisher's exact test. Continuous variables were described as mean ± standard deviation or median (Q1; Q3) and compared using Student's t-test or Wilcoxon rank-sum test. As previously published, event rates were compared using Chi-square test [START_REF] Thiele | PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock[END_REF][START_REF] Thiele | One-Year Outcomes after PCI Strategies in Cardiogenic Shock[END_REF]. Kaplan-Meier curves were also used to show event rates over time with classification according to the arterial access and compared using log-rank test. Patients without event were censored at 30 days or one-year (for renal-replacement therapy or BARC type 2, 3 or 5 bleeding, deceased patients without event were censored at the date of death). A multivariate logistic regression model was used to evaluate the independent association between vascular access and outcomes. For each outcome, vascular access was adjusted on baseline clinical and procedural characteristics possibly associated with outcomes in univariate analysis (p<0.2) or significantly different between the two vascular accesses and clinically relevant (see Online Tables 1 and2). Several sensitivity analyses were performed. A dedicated multivariate logistic regression model (stepwise method with entry level of 0.2 and stay level of 0.05) was performed to determine the independent predictors of the vascular access among baseline characteristics. A model adjusted on consistent covariates as well as the effective revascularization strategy undergone by the patients was performed to account for cross-overs among the groups of randomization. In another sensitivity analysis, the association between arterial accesses and outcomes was evaluated using a marginal logistic regression adjusted on consistent covariates to account for the correlation among patients managed in the same center (cluster analysis per center). Finally, the bleeding risk according to the arterial access was also evaluated in the subgroups of patients with whom a mechanical circulatory support was not used. Results were interpreted in term of adjusted odd ratios with their associated 95% confidence intervals. A p-value <0.05 was considered significant unless otherwise specified. All statistical analyses were performed with SAS release 9.4 (SAS Institute Inc, Cary, NC) statistical software package.

RESULTS

Population characteristics

Of the 686 randomized patients with available informed consent, a total of 673 (98.1%) patients were included in this analysis, among whom TRA and TFA were performed in 118 (17.5%) and 555 (82.5%) patients, respectively (Figure 1). Baseline and procedural characteristics are detailed in Table 1 and Table 2. TFA patients came with more frequent history of arterial hypertension and TRA patients more frequently presented with STEMI.

Mild hypothermia, mechanical ventilation and catecholamine therapy were more frequently used among TFA patients although time until hemodynamic stabilization was significantly longer with TRA patients. In a dedicated multivariate logistic regression model, a medical history of systemic hypertension, the presence of left bundle branch block, and mechanical ventilation prior to percutaneous coronary intervention were significantly associated with lower use of TRA (Online Table 3 and4).

Arterial access and early outcomes

The univariate association of TRA with outcomes at 30 days is detailed in the Figure 2. After adjustments for baseline and procedural characteristics, TRA was significantly associated with a reduced risk of the composite of all-cause death or renal replacement therapy, as well as each individual endpoint (Table 3 and Graphical abstract). Results remained consistent in the sensitivity analysis adjusted on the revascularization strategy (Online Figure 1), and the sensitivity cluster analysis per center (Online Figure 2). There was no significant difference in the risk of stroke at 30 days between TRA and TFA (5.9% vs. 2.9%, respectively, p=0.16).

There was no significant difference in the risk of BARC type 3 or 5 bleeding associated with the use of TRA or TFA (13.6% vs. 13.7%, respectively, p=0.97), in the overall population (Online Figure 3). In a sensitivity analyses only including patients with whom mechanical circulatory support was not used, the risk of BARC type 3 or 5 bleeding at 30 days was numerically lower with TRA compared to TFA (6.9% vs. 10.6%, respectively), albeit not reaching statistical significance (p=0.30).

Arterial access and late outcomes

The univariate association of TRA with outcomes at one year is detailed in the Figure 2 and Online Figure 4. After adjustments for baseline and procedural characteristics, use of TRA was not significantly associated with the composite of all-cause death or renal replacement therapy as well as all-cause death. Of note, no significant interactions between the coronary revascularization strategies (i.e. culprit-lesion-only or multivessel PCI) and arterial accesses were observed for any early and late outcomes.

DISCUSSION

The main findings of the present analysis are as follows: in patients undergoing PCI for acute myocardial infarction with multivessel coronary artery disease complicated by CS, TRA is used in less than 20% of the cases and is associated with a significant reduction of all-cause mortality and renal-replacement therapy at 30 days compared to TFA. This difference is no longer significant after adjustment for baseline and procedural characteristics at one-year follow-up.

Despite being the most frequently used arterial route for PCI in Western European countries, where the recruiting sites of the present study were located, TRA was only used in a minority of patients in this trial. There may be several reasons for this finding. Hemodynamic instability may result in weaker or even absent radial pulse, thus hindering the achievement of swift radial arterial access. In fact, CS has been previously reported as an independent risk factor for TRA failure [START_REF] Abdelaal | Risk score, causes, and clinical impact of failure of transradial approach for percutaneous coronary interventions[END_REF]. This technical impediment may have been one of the reasons, for otherwise TRA-experienced operators, to perform PCI with TFA in order to avoid any delay in achieving coronary reperfusion. Moreover, a TFA approach may be subsequently used for percutaneous mechanical circulatory support concomitant to PCI or following the procedure. Notwithstanding these considerations, TRA was associated with improved early outcomes, including a 30-day survival benefit, which is consistent with the results of previous large randomized trials as well as meta-analyses, in patients with or without CS [START_REF] Valgimigli | Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial[END_REF][START_REF] Ferrante | Radial Versus Femoral Access for Coronary Interventions Across the Entire Spectrum of Patients With Coronary Artery Disease: A Meta-Analysis of Randomized Trials[END_REF][START_REF] Bernat | Early and late outcomes after primary percutaneous coronary intervention by radial or femoral approach in patients presenting in acute STelevation myocardial infarction and cardiogenic shock[END_REF][START_REF] Pancholy | Impact of access site choice on outcomes of patients with cardiogenic shock undergoing percutaneous coronary intervention: A systematic review and meta-analysis[END_REF][START_REF] Rodriguez-Leor | Transradial percutaneous coronary intervention in cardiogenic shock: a single-center experience[END_REF][START_REF] Romagnoli | Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study[END_REF].

Nonetheless, the previously reported survival improvement with TRA over TFA has been most frequently credited to a reduction of major bleeding, which was not present in our study [START_REF] Valgimigli | Radial versus femoral access and bivalirudin versus unfractionated heparin in invasively managed patients with acute coronary syndrome (MATRIX): final 1-year results of a multicentre, randomised controlled trial[END_REF][START_REF] Bernat | ST-segment elevation myocardial infarction treated by radial or femoral approach in a multicenter randomized clinical trial: the STEMI-RADIAL trial[END_REF][START_REF] Kinnaird | Access Site and Outcomes for Unprotected Left Main Stem Percutaneous Coronary Intervention: An Analysis of the British Cardiovascular Intervention Society Database[END_REF]. The absence of significant difference in the rates of bleeding between TRA and TFA may be partially explained by a reduced effect of oral P2Y12 inhibitors in the setting of CS which may be associated with impaired intestinal absorption [START_REF] Orban | Prasugrel vs clopidogrel in cardiogenic shock patients undergoing primary PCI for acute myocardial infarction. Results of the ISAR-SHOCK registry[END_REF]. Moreover, there was a large use of mechanical circulatory support devices in both groups of patients, which may further increase the risk of vascular complications and bleeding, not related to the PCI access site [START_REF] Thiele | Management of cardiogenic shock[END_REF]. In this study, the localization of the bleeding (i.e. access site related or non-access site related) was not considered in the adjudication process and the impact of TRA on access site related bleeding in patients undergoing PCI for acute MI complicated with CS remains therefore unclear. This would warrant further investigation as a previous study reported nonaccess site related bleeding to be predominant in the setting of acute MI managed in radial centers [START_REF] Barthélémy | Bleeding complications in primary percutaneous coronary intervention of ST-elevation myocardial infarction in a radial center[END_REF]. Another interesting finding of the study was the significant reduction of severe renal failure leading to renal-replacement therapy associated with TRA. There exists a growing body of evidence linking TRA to a reduction of AKI following PCI [START_REF] Kooiman | Risk of acute kidney injury after percutaneous coronary interventions using radial versus femoral vascular access: insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium[END_REF][START_REF] Andò | Benefit of radial approach in reducing the incidence of acute kidney injury after percutaneous coronary intervention: a meta-analysis of 22,108 patients[END_REF][START_REF] Guedeney | Assessing and minimizing the risk of percutaneous coronary intervention in patients with chronic kidney disease[END_REF].

Particularly, the recent AKI-Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox (AKI-MATRIX) substudy reported a lower rate of post-PCI in-hospital AKI in patients randomized to TRA compared to TFA [START_REF] Andò | Acute Kidney Injury After Radial or Femoral Access for Invasive Acute Coronary Syndrome Management: AKI-MATRIX[END_REF].

Of note, a quantitative positive interaction testing was reported in patients with Killip class III or IV, suggesting that the benefit of TRA was greater in this high-risk population. The mechanisms by which TRA could prevent AKI may not be limited to the reduction of periprocedural bleeding. TFA may result in scraping of the descending aorta atherosclerotic debris, leading to potential atheroembolic renal complications, with the worst clinical manifestation being the cholesterol embolization syndrome [START_REF] Keeley | Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases[END_REF][START_REF] Itzhak | Cholesterol Embolization Syndrome[END_REF]. Rothenbüler et al., in a post-hoc, hypothesis-generating analysis of the MATRIX trial, provided a mechanistic explanation for the mortality benefit associated with TRA, predominantly involving the prevention of AKI rather than bleeding [START_REF] Rothenbühler | Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasive management: secondary analysis of a randomized clinical trial[END_REF][START_REF] Kerneis | Kidney in the transformation matrix[END_REF]. A retrospective analysis of a large database reported that although bleeding was a risk factor of AKI, the lower odds of AKI with TRA was not mediated by a reduction in bleeding [START_REF] Kooiman | Risk of acute kidney injury after percutaneous coronary interventions using radial versus femoral vascular access: insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium[END_REF]. The present study adds to the current knowledge by showing an association between TRA use and a lower need for renal-replacement therapy in hemodynamically unstable patients. This may have led to the reduced all-cause mortality, independently of a reduction of bleeding. Of note, there was no significant difference between the two arterial accesses in the amount of contrast dye used.

There exists a dearth of data evaluating the impact of arterial routes on long-term outcomes in patients undergoing PCI for acute MI in the setting of CS [START_REF] Bernat | Early and late outcomes after primary percutaneous coronary intervention by radial or femoral approach in patients presenting in acute STelevation myocardial infarction and cardiogenic shock[END_REF]. Although TRA was associated with an absolute reduction of all-cause death or renal-replacement therapy and all-cause death at one year of 12.9% and 13.1%, respectively, compared to TFA, this difference was no longer significant after adjustment for baseline and procedural characteristics. However, as mortality as well as the need for renal-replacement therapy in patients with CS mainly occurred within the first 30 days, it is likely that the present analysis lacks the necessary statistical power to comprehensively evaluate the impact of TRA on one-year outcomes [START_REF] Thiele | One-Year Outcomes after PCI Strategies in Cardiogenic Shock[END_REF].

Study limitations

This is a post-hoc analysis of a randomized trial where the type of arterial route was left at the local operator's discretion. Thus, unmeasured confounding variables may have persisted, despite adjustment for baseline and procedural covariates. Particularly, one cannot exclude a potential geographic or center bias regarding the choice of vascular access in patients with CS, although the sensitivity cluster analysis per center reported consistent results. There may also have been a selection bias in the choice of the vascular access as suggested by the multivariate analysis showing that the presence of left bundle branch block and mechanical ventilation prior to randomization, reflecting more serious cases in general, related positively with TFA. Use of percutaneous closure device in case of TFA as well as the impact of the timing and type of all mechanical circulatory support devices were not available and could therefore not be included in the multivariate model. The level of expertise of recruiting sites and individual operators with respect to TRA technique was not collected, nor were the use of ultrasound or palpability of the radial artery pulse. Incidence of access site related vascular complications was not evaluated. Finally, there was a sample size imbalance in the groups of analyzed patients with a smaller number of patients undergoing TRA compared to TFA, potentially resulting in underpowered analyses. Consequently, the present study should be considered as hypothesis-generating and only a dedicated randomized trial comparing vascular access for PCI in patients presenting with acute MI complicated by CS could provide a definitive answer.

CONCLUSION

In patients undergoing PCI for an acute MI with multivessel coronary artery disease complicated by CS, a TRA approach may be associated with improved early outcomes.

Funding acknowledgements

The CULPRIT-SHOCK trial was supported by a grant agreement (602202) from the European Union Seventh Framework Program and by the German Heart Research Foundation and the German Cardiac Society. hypercholesterolemia, diabetes mellitus, prior chronic kidney disease, prior PCI, arterial lactate>2mmol/L at baseline, need for mechanical ventilation before randomization, culprit left main or left anterior descending coronary artery, ≥ 1 chronic total coronary occlusion, mechanical circulatory support, mild hypothermia, mechanical ventilation, use of catecholamine therapy, pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 3 and randomized coronary revascularization strategy. † N=596 patients, covariates of adjustment are: body mass index, hypertension, diabetes mellitus, prior chronic kidney disease, anterior ST-segment elevation, ≥ 1 chronic total coronary occlusion, mechanical circulatory support, mild hypothermia, mechanical ventilation, use of catecholamine therapy, pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 3 and randomized coronary revascularization strategy. ‡ N=594, covariates of adjustment are: age, body mass index, smoking status, hypercholesterolemia, diabetes mellitus, previous stroke, prior chronic kidney disease, previous CABG, arterial lactate>2mmol/L at baseline, need for mechanical ventilation before randomization, fibrinolysis before randomization, culprit left main or left anterior descending coronary artery, ≥ 1 chronic total coronary occlusion, mechanical circulatory support, mild hypothermia, mechanical ventilation, use of catecholamine therapy, pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 3, periprocedural use of GP IIb/IIa inhibitors and randomized coronary revascularization strategy. § N=595, covariates of adjustment are: age, sex, body mass index, smoking status, hypercholesterolemia, diabetes mellitus, prior chronic kidney disease, prior stroke, previous CABG, arterial lactate>2mmol/L at baseline, need for mechanical ventilation before randomization, culprit left main or left anterior descending coronary artery, ≥ 1 chronic total coronary occlusion, mechanical circulatory support, mild hypothermia, mechanical ventilation, use of catecholamine therapy, pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 3, periprocedural use of GP IIb/IIa inhibitors and randomized coronary revascularization strategy. OR: Odds Ratio; CI: confidence interval.

Disclosures

Figure titles and legends

Figure 1 Figure 2

 12 Figure 1 Flow chart

  Dr. Zeymer reports personal fees from Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, Novartis, Sanofi, MSD, The Medicines Company, Pfizer, Daiichi Sankyo, Eli Lilly, Abiomed, outside the submitted work. Dr. Montalescot: reports the following disclosures during the past 2 years research Grants to the Institution or Consulting/Lecture Fees from ADIR, Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women's Hospital, Cardiovascular Research Foundation, Celladon, CME Resources, Daiichi-Sankyo, Eli-Lilly, Europa, Elsevier, Fédération Française de Cardiologie, Fondazione Anna Maria Sechi per il Cuore, Gilead, ICAN, Janssen, Lead-Up, Menarini, Medtronic, MSD, Pfizer, Sanofi-Aventis, The Medicines Company, TIMI Study Group, WebMD. Dr. Windecker has received research, educational, and training grants from Amgen, Abbott, Bayer, Bristol-Myers Squibb, Boston Scientific, Biotronik, Medtronic, Edwards Lifesciences, St. Jude, and Terumo. Dr. Silvain reports reports consulting fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, CSL Berhing, Gilead Science; and Sanofi Aventis; Speaker honoraria from AstraZeneca, Amgen, Bayer, Algorythm, and Sanofi-Aventis; and travel support from Amgen, Astra-Zeneca, Bayer, and Bristol-Myer Squibb. Dr. Kerneis has received research grants from Sanofi, Institut Servier and Fédération Française de Cardiologie; consultant fees from Bayer and AstraZeneca. Dr. Lattuca has received research grants from Biotronik, Daiichi-Sankyo and Fédération Française de Cardiologie; consultant fees from Daiichi-Sankyo and Eli Lilly; and lecture fees from AstraZeneca and Novartis. Dr. Michel Zeitouni has received research grants from Federation Française de Cardiologie and Institut Servier. Dr. Collet has received research grants or honorarium from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Eli-Lilly, Fédération Française de Cardiologie, Lead-Up, Medtronic, MSD, Sanofi-Aventis, and WebMD. All other authors do not report any disclosure relative to this study.

Table 3 . Early and late outcomes according to the arterial access

 3

	Radial access (n=118)	Femoral access (n=555)	Unadjusted OR (95%CI) p-value	Adjusted OR (95%CI)	p-value

*N=593 patients, covariates of adjustment are: age, sex, body mass index, smoking status,

Abbreviations


Hugo De Vries

Food science and technology contributes to sustainable food systems

 Food Science and Technologists jointly contribute to sustainable and circular food systems  Food Science is a unique science domain addressing all complex system elements  Evidence-based food science cases provide tasteful options for policy making, also in times of uncertainty.

Introduction

The year 2020 followed an extremely unexpected course, bringing sadness and difficult living and working conditions to many of us. With the hope that 2021 will rebalance our quality of life, I would like to share some reflections about the contribution of Food Science and Technology to create more sustainable food systems as the newly elected President of the European Federation of Food Science and Technology (EFFoST, 2021a).

At the past EFFoST conferences and in our affiliated journals, namely Trends in Food Science (TIFS), Innovative Food Science and Emerging Technologies (IFSET), Food Control, and Taste of Science, I am delighted to see your passion for food science and technology, your creative ideas and innovations, and willingness to collectively contribute to more sustainable food systems.

Perception, Criticism and Debates

This is highly appreciated since the general public's perception of food science and technology is not always positive (e.g. EUFIC, 2016; and references therein), witnessed in the discourses on ultraprocessing, unhealthy food products, food waste and spoilage, environmental impact of food packaging materials, some less-appreciated preservation means and so on. In some countries, the phrase 'novel technologies' is banned from strategic research agendas while others strongly support the development of these technologies. This then raises the question whether the criticism on food science and technology is based on scientific facts? Is the debate being constructive for example by providing realistic and accepted alternatives? Who is criticizing and what is her/his knowledge about our domain and what are their invested interests? What is apparent, is that we as experts need to be even more visible in these debates, hence the ambitions of Young EFFoST, some of our Standing Committees, Working Groups and our Special Interest Groups like the Global Harmonization Initiative. They welcome societally engaged colleagues willing to contribute to these debates.

Towards more sustainable food systems

Since constructive criticism is an essential driver of scientific progress, scientists need to be willing to have their work critiqued and review the work of their colleagues to raise the field of food science and technology to greater heights. If we do not learn from our experiences and from each other, we will stand still and not move towards more sustainable food systems. This is needed as a famous saying goes 'If you do not change direction, you may end up where you are heading' (Lao Tzu). It is therefore interesting to note that both young -like our highly dynamic Young EFFoST team -and 'many years young' scientists within the EFFoST community are continuously seeking solutions that are more sustainable. Examples include preserving biodiverse and healthy foods in a milder way; utilizing more environmentally friendly packaging; and developing tracking and tracing tools in order to care for the safety of food products and so on [START_REF] Knorr | Advancing the Role of Food Processing for Improved Integration in Sustainable Food Chains[END_REF]. Recently, three EFFoST Working Groups were initiated on Sustainable Food, Health & Food and Digital Food to further the discussion on these subject matters based on scientific evidence (EFFoST, 2021b).

Joint actions

Today, circular economy concepts are debated as one way of reaching more sustainable outcomes1 [START_REF] Korhonen | Circular economy: The concept and its limitations[END_REF], in particular acknowledged in the agri-food domain for closing nutrient cycles. During my mathematics courses, I learnt that a circle has neither a beginning nor an end with all points equally distanced to its centre. This implies that all actors at the arc of the circle are connected and, thus always confronted with the outputs of their own actions. In other words, citizens in their various roles both demand (consumers of goods and services) and supply (providers of goods, services and waste) inputs. Also as stated before, all actors are positioned at the same distance to the centre of the circle, thus having a fairly equal role to play, which could even be considered democratic; this may be questioned for linear (value) chains.

Collective, fair and respectful actions are needed to solve problems and end up with better solutions, I deem this the most sensible way forward. Joint projects representing different organizations in different countries provide good opportunities for collaboration, like in the European Horizon2020 projects, Bio-Based Industry Joint Undertakings projects (BBI, 2021), national and local projects. EFFoST is highly active in quite a number of these projects (EFFoST, 2021c). As a project partner we enable public and private partners to connect with food scientists at our events, to close cycles. We also intend to encourage them to join our Standing Committees, like the one on innovation, to provide their unique perspective. Collaboration is needed, because we all realize that we are both part of the problem and of the solution. This realisation, however, does not need to interfere with our credibility as independently thinking (public and private) researchers seeking well-founded knowledge.

Recognition of Food as a Science domain I am astounded that food science and technology is not a recognized 'scientific field' in many countries. This is hard to understand from a societal standpoint, if one realizes that (i) by far the majority of consumed foods are processed renewable resources (EC, 2021) -needed from e.g., a safety, swallowing or digestibility point of view; all non-trivial issues -and (ii) food is both a primary need, commons, and right for all [START_REF] Jackson | Food as a commodity, human right or common good[END_REF], which poses numerous questions.

From a scientific perspective it is also impossible to explain. Food systems are highly complex (de Vries et al., 2018), if one considers the seven elements of systems (or building blocks of game theory), namely playing fields (specific food areas), players (stakeholders), pieces (products), moves (transformation steps), rules (legislation and incentives), outcomes (win-lose like healthy or unhealthy, sustainable or unsustainable, etc.), and time (from start till outcome). In food science and technology, one is dealing with a wide range of dynamic 'playing fields' with a variety of transformative moves -from harvest, processing, preparation, consumption till digestion -resulting into diverse food products. These are subject to changing rules and constraints like safety measures or subsidies. Trajectories are explored by various 'players', like public and private stakeholders who seek knowledge to reach specific 'outcomes' e.g. functionalities, healthiness, desirability, affordability, accessibility, and availability. Consequently, our domain deals with complex processstructure-function relationships [START_REF] Fischer | Rheology of food materials[END_REF] spanning the lifetime of resources moving to and along the digestive tract [START_REF] Dupont | Can dynamic in vitro digestion systems mimic the physiological reality?[END_REF]. This is in essence not different from material science, ecology, economics, etc. that also deal with a high level of complexity in which objects or species face (extreme) conditions in their struggle for resilience, adaptability and emerging properties. If one considers sustainable food systems as a key priority to respond to climate change, biodiversity loss and food related diseases, then food science and technology logically deserves a place as a science domain on (inter)national agendas, like for example at the UN Food Summit 2021 (UN, 2021).

Science-Policy interfaces in times of uncertainties

Since we are frequently confronted with the science -policy interfaces in our work, food as a science domain is even more relevant today (SAPEA, 2020). Policy makers ask for precise and preferably quantified recommendations and indicators that can be immediately used and translated into policy measures. Moreover, we also need to contribute to a viable planet with complex adaptive (food) systems that are resilient, adaptive and socially fair. This challenge is characterized e.g. by highly nonlinear behaviour and subject to the Heisenberg principle of uncertainty as I have learnt as a physicist. Thus, in this new normal, we all, politicians, entrepreneurs and scientists alike have to live with the uncertainty and unpredictability of time and place. Consequently, scientists cannot propose 100% accurate recommendations; however, we still can come up with the most relevant options for policies based on state-of-the-art scientific outcomes. This is what we, as EFFoST, try to do by contributing to the Working Groups on Food Systems of the Standing Committee on Agricultural Research (SCAR and SCAR Foresight), the Science Advice for Policy making of European Academies (SAPEA, 2020), the EU Food2030 agenda, the ERANET SUSFood program, the Joint Programming Initiatives like A Healthy Diet for a Healthy Living, Foodforce network, ISEKI network, the European Technology Platforms like Food for Life, etc2 .

Contributions to policy options

Our contributions to policy options are evidence-based and often rely on cases, thoroughly tested and analysed for their outcomes (positive or negative; see for example the special issue edited by [START_REF] Taoukis | Editorial to the IFSET Special Issue on the 33rd EFFoST International Conference[END_REF]). An example is the search for specific alternative protein foods -preferably produced via agro-ecological practices -without fully stepping away from animal or marine proteins. Other examples include spoilage reduction, valorisation pathways for by-products and waste, and the assessment of environmental, social or economic trade-offs for healthier diets. The three dimensions of sustainability are particularly well represented in the solutions provided by food science and technology in projects namely: the eco-friendliness of all transformation steps (environmental); the preferences, acceptance and needs (social); and the creation of added value (economic). Remarkable projects, showing scientific creativity and societal relevance are awarded by EFFoST and our partners at the annual conference. Here, all interested stakeholders are warmly welcome including policy makers.

Ingredients of life

In our fascinating real and dynamic world, Food Science and Technology will continue to fuel us with diverse and challenging questions that require new knowledge and know-how, not only for experts in laboratories and production plants, but also at home. Anyone who cooks and consumes, or even stores food in their fridge, could be considered a food engineer. Therefore, we remain inspired by the surprisingly wonderful tastes that nature offers and potentially new food, drinks and diets consumed in beautiful green and blue environments, either urban, rural or marine. As EFFoST we collectively hope to provide a modest but scientifically passionate contribution to the challenges of today and tomorrow, not just for the happy few, but for all in a changing world.

On behalf of the EFFoST Board, our best wishes to all of you for 2021 and beyond, both in your private life and at work. Hugo de Vries, President of the European Federation of Food Science and Technology P.S. The 35th EFFoST International Conference: Healthy Individuals, Resilient Communities, and Global Food Security will held in the city of Lausanne in Switzerland from 1-4 November 2021. We would like to invite you to submit abstracts for oral and poster presentations on the conference topics via the abstract submission system. Submission deadline is 23 April 2021 (EFFoST, 2021d).

In real life, one can better speak about helices allowing systems to evolve in time.

For more information: https://scar-europe.org/index.php/food; https://ec.europa.eu/info/research-andinnovation/research-area/food-systems/food-2030_en; https://susfood-db-era.net/main; https://www.healthydietforhealthylife.eu/; https://www.foodforcenetwork.eu/; https://www.iseki-food.net/; https://etp.fooddrinkeurope.eu/

Acknowledgments

The author likes to express his sincere appreciation and gratitude for all colleagues contributing to research in the domain of food science and technology as well as to the activities of EFFoST and its office.

Funding sources: This short commentary did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest:

The author declares no conflict of interest.