Association of systemic inflammation with shock severity, 30-day mortality, and therapy response in patients with cardiogenic shock.

BACKGROUND: Mortality in cardiogenic shock (CS) remains high even when mechanical circulatory support (MCS) restores adequate circulation. To detect a potential contribution of systemic inflammation to shock severity, this study determined associations between C-reactive protein (CRP) concentrations and outcomes in patients with CS. METHODS: Unselected, consecutive patients with CS and CRP measurements treated at a single large cardiovascular center between 2009 and 2019 were analyzed. Adjusted regression models were fitted to evaluate the association of CRP with shock severity, 30-day in-hospital mortality and treatment response to MCS. RESULTS: The analysis included 1116 patients [median age: 70 (IQR 58-79) years, 795 (71.3%) male, lactate 4.6 (IQR 2.2-9.5) mmol/l, CRP 17 (IQR 5-71) mg/l]. The cause of CS was acute myocardial infarction in 530 (48%) patients, 648 (58%) patients presented with cardiac arrest. Plasma CRP concentrations were equally distributed across shock severities (SCAI stage B-E). Higher CRP concentrations were associated with 30-day in-hospital mortality (8% relative risk increase per 50 mg/l increase in CRP, range 3-13%; p < 0.001), even after adjustment for CS severity and other potential confounders. Higher CRP concentrations were only associated with higher mortality in patients not treated with MCS [hazard ratio (HR) for CRP > median 1.50; 95%-CI 1.21-1.86; p < 0.001], but not in those treated with MCS (HR for CRP > median 0.92; 95%-CI 0.67-1.26; p = 0.59; p-interaction = 0.01). CONCLUSION: Elevated CRP concentrations are associated with increased 30-day in-hospital mortality in unselected patients with cardiogenic shock. The use of mechanical circulatory support attenuates this association.

Heart Rate Reduction and Outcomes in Heart Failure Outpatients.

Aim. Pharmacologic reduction in heart rate with beta-blockers (BB) or ivabradine is associated with improved survival in heart failure (HF) with sinus rhythm. We analyzed the association of different heart rate-reducing drug treatments on outcomes in HF outpatients. Methods. Consecutive patients with HF in sinus rhythm referred to a specialized tertiary service were prospectively enrolled from August 2015 until March 2018. Clinical characteristics were assessed at baseline. We performed Cox regression analyses to examine the effect of the resting heart rate and different heart rate-reducing drug regimens on all-cause mortality and a composite endpoint of "all-cause mortality or heart transplantation" over a mean follow-up of 3.1 years. Results. Of the 278 patients included, 213 (76.6%) were male, the median age was 57.0 years (IQR 49.0-66.1), and 185 (73.7%) had an ejection fraction <40%. Most patients received BB in submaximal [n = 118] or maximum dose [n = 136]. Patients on BB in maximum dose plus ivabradine [n = 24] were younger (53.0 vs. 58.0 years) and had a lower EF (25 vs. 31%). Higher resting heart rate was associated with an increased risk of death or transplantation (HR 1.03 [1.01, 1.06], p = 0.0072), even after adjusting for age and sex. There were no differences between the groups concerning all-cause mortality or the composite endpoint. Conclusion. Our prospective study confirms the association between low heart rate and survival in HF patients receiving various heart rate-reducing medications. We could not identify a specific effect of either regimen.

Sex differences in clinical characteristics and outcomes in patients undergoing heart transplantation.

AIMS: Whether sex affects selection for and outcomes after heart transplantation (HTx) remains unclear. We aimed to show sex differences in pre-transplant characteristics and outcomes after HTx. METHODS AND RESULTS: From 1995 to 2019, 49 200 HTx recipients were prospectively enrolled in the Organ Procurement and Transplantation Network. Logistic regression models were used to evaluate clinical characteristics by sex. Multivariable Cox regression models were fitted to assess sex differences in all-cause mortality, cardiovascular mortality, graft failure, cardiac allograft vasculopathy (CAV), and malignancy. In 49 200 patients (median age 55 years, interquartile range 46-62; 24.6% women), 49 732 events occurred during a median follow-up of 8.1 years. Men were older than women, had more often ischaemic cardiomyopathy (odds ratio [OR] 3.26, 95% confidence interval [CI] 3.11-3.42; P < 0.001), and a higher burden of cardiovascular risk factors, whereas women had less malignancies (OR 0.47, CI 0.44-0.51; P < 0.001). Men were more often treated in intensive care unit (OR 1.24, CI 1.12-1.37; P < 0.001) with a higher need for ventilatory (OR 1.24, CI 1.17-1.32; P < 0.001) or VAD (OR 1.53, CI 1.45-1.63; P < 0.001) support. After multivariable adjustment, men had a higher risk for CAV (hazard ratio [HR] 1.21, CI 1.13-1.29; P < 0.001) and malignancy (HR 1.80, CI 1.62-2.00; P < 0.001). There were no differences in all-cause mortality, cardiovascular mortality, and graft failure between sexes. CONCLUSIONS: In this US transplant registry, men and women differed in pre-transplant characteristics. Male sex was independently associated with incident CAV and malignancy even after multivariable adjustment. Our results underline the need for better personalized post-HTx management and care.

CAR links hypoxia signaling to improved survival after myocardial infarction.

The coxsackievirus and adenovirus receptor (CAR) mediates homo- and heterotopic interactions between neighboring cardiomyocytes at the intercalated disc. CAR is upregulated in the hypoxic areas surrounding myocardial infarction (MI). To elucidate whether CAR contributes to hypoxia signaling and MI pathology, we used a gain- and loss-of-function approach in transfected HEK293 cells, H9c2 cardiomyocytes and CAR knockout mice. CAR overexpression increased RhoA activity, HIF-1α expression and cell death in response to chemical and physical hypoxia. In vivo, we subjected cardiomyocyte-specific CAR knockout (KO) and wild-type mice (WT) to coronary artery ligation. Survival was drastically improved in KO mice with largely preserved cardiac function as determined by echocardiography. Histological analysis revealed a less fibrotic, more compact lesion. Thirty days after MI, there was no compensatory hypertrophy or reduced cardiac output in hearts from CAR KO mice, in contrast to control mice with increased heart weight and reduced ejection fraction as signs of the underlying pathology. Based on these findings, we suggest CAR as a therapeutic target for the improved future treatment or prevention of myocardial infarction.

SARS-CoV-2 Vaccination-Induced Immunogenicity in Heart Transplant Recipients.

Among heart transplant (HT) recipients, a reduced immunological response to SARS-CoV-2 vaccination has been reported. We aimed to assess the humoral and T-cell response to SARS-CoV-2 vaccination in HT recipients to understand determinants of immunogenicity. HT recipients were prospectively enrolled from January 2021 until March 2022. Anti-SARS-CoV-2-Spike IgG levels were quantified after two and three doses of a SARS-CoV-2 vaccine (BNT162b2, mRNA1273, or AZD1222). Spike-specific T-cell responses were assessed using flow cytometry. Ninety-one patients were included in the study (69% male, median age 55 years, median time from HT to first vaccination 6.1 years). Seroconversion rates were 34% after two and 63% after three doses. Older patient age (p = 0.003) and shorter time since HT (p = 0.001) were associated with lower antibody concentrations after three vaccinations. There were no associations between vaccine types or immunosuppressive regimens and humoral response, except for prednisolone, which was predictive of a reduced response after two (p = 0.001), but not after three doses (p = 0.434). A T-cell response was observed in 50% after two and in 74% after three doses. Despite three vaccine doses, a large proportion of HT recipients exhibits a reduced immune response. Additional strategies are desirable to improve vaccine immunogenicity in this vulnerable group of patients.

[Interventional treatment of heart failure : Stents and valves]. / Interventionelle Therapie der Herzinsuffizienz : Stents und Klappen.

The pharmacotherapy of heart failure has evolved in recent years and with the aid of new classes of drugs symptomatic and prognostic improvements can be achieved in patients with heart failure. Heart failure is particularly frequently associated with coronary artery disease or higher grade, often functional valve defects. In the context of the underlying disease, the operative risk is often increased, so that interventional treatment is preferred over surgical treatment options in interdisciplinary heart teams. Promising approaches with very different challenges are emerging for interventional myocardial revascularization and percutaneous correction of high-grade aortic valve stenosis or functional mitral or tricuspid valve regurgitation. It has consistently been shown that an elaborate diagnostic work-up and differentiated patient selection are decisive to achieve a prognostic or symptomatic benefit in these patients using interventional treatment. While awaiting further study data on this topic, the integration of a multidisciplinary heart team is essential to ensure a complementary and balanced therapeutic approach for patient-centered care in this complex patient population.

Eligibility for sotagliflozin in a real-world heart failure population based on the SOLOIST-WHF trial enrolment criteria: data from the Swedish heart failure registry.

AIMS: The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population. METHODS AND RESULTS: SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to (i) literal scenario (all inclusion/exclusion criteria) or (ii) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration <3 months, eGFR <30 ml/min/1.73 m2, age >85 years, acute coronary syndrome <3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0). CONCLUSION: In this large, real-world HF cohort with T2DM, ∼1/3 of patients were eligible for sotagliflozin in the literal and ∼2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events.

Global burden of heart failure: a comprehensive and updated review of epidemiology.

Heart Failure (HF) is a multi-faceted and life-threatening syndrome characterized by significant morbidity and mortality, poor functional capacity and quality of life, and high costs. HF affects more than 64 million people worldwide. Therefore, attempts to decrease its social and economic burden have become a major global public health priority. While the incidence of HF has stabilized and seems to be declining in industrialized countries, the prevalence is increasing due to the ageing of the population, improved treatment of and survival with ischaemic heart disease, and the availability of effective evidence-based therapies prolonging life in patients with HF. There are geographical variations in HF epidemiology. There is substantial lack of data from developing countries, where HF exhibits different features compared with that observed in the Western world. In this review, we provide a contemporary overview on the global burden of HF, providing updated estimates on prevalence, incidence, outcomes, and costs worldwide.

Clinical characteristics, causes and predictors of outcomes in patients with in-hospital cardiac arrest: results from the SURVIVE-ARREST study.

INTRODUCTION: In-hospital cardiac arrest (IHCA) is acutely life-threatening and remains associated with high mortality and morbidity. Identifying predictors of mortality after IHCA would help to guide acute therapy. METHODS: We determined patient characteristics and independent predictors of 30-day in-hospital mortality, neurological outcome, and discharge/referral pathways in patients experiencing IHCA in a large tertiary care hospital between January 2014 and April 2017. Multivariable Cox regression model was fitted to assess predictors of outcomes. RESULTS: A total of 368 patients with IHCA were analysed (median age 73 years (interquartile range 65-78), 123 (33.4%) women). Most patients (45.9%) had an initial non-shockable rhythm and shockable rhythms were found in 20.9%; 23.6% of patients suffered from a recurrent episode of cardiac arrest. 172/368 patients died within 30 days (46.7%). Of 196/368 patients discharged alive after IHCA, the majority (72.9%, n = 143) had a good functional neurological outcome (modified Rankin Scale ≤ 3 points). In the multivariable analysis, return of spontaneous circulation without mechanical circulatory support (hazard ratio (HR) 0.36, 95% confidence interval (CI) 0.21-0.64), invasive coronary angiography and/or percutaneous intervention (HR 0.56, 95% CI 0.34-0.92), and antibiotic therapy (HR 0.87, 95% CI 0.83-0.92) were associated with a lower risk of 30-day in hospital mortality. CONCLUSION: In the present study, IHCA was survived in ~ 50% in a tertiary care hospital, although only a minority of patients presented with shockable rhythms. The majority of IHCA survivors (~ 70%) had a good neurological outcome. Recovery of spontaneous circulation and presence of treatable acute causes of the arrest are associated with better survival. Clinical Characteristics, Causes and Predictors of Outcomes in Patients with In-Hospital Cardiac Arrest: Results from the SURVIVE-ARREST Study. ABBREVIATIONS: CPR, cardiopulmonary resuscitation; IHCA, In-hospital cardiac arrest; MCS, mechanical circulatory support; PCI, percutaneous coronary intervention; ROSC, return of spontaneous circulation; SBP, systolic blood pressure.

Temporal trends in incidence, patient characteristics, microbiology and in-hospital mortality in patients with infective endocarditis: a contemporary analysis of 86,469 cases between 2007 and 2019.

BACKGROUND: Infective endocarditis (IE) is characterized by high morbidity and mortality rates, despite recent improvements in diagnostics and treatment. We aimed to investigate incidence, clinical characteristics, and in-hospital mortality in a large-scale nationwide cohort. METHODS: Using data from the German Federal Bureau of Statistics, all IE cases in Germany between 2007 and 2019 were analyzed. Logistic regression models were fitted to assess associations between clinical factors and in-hospital mortality. RESULTS: In total, 86,469 patients were hospitalized with IE between 2007 and 2019. The mean age was 66.5 ± 14.7 years and 31.8% (n = 27,534/86,469) were female. Cardiovascular (CV) comorbidities were common. The incidence of IE in the German population increased from 6.3/100,000 to 10.2/100,000 between 2007 and 2019. Staphylococcus (n = 17,673/86,469; 20.4%) and streptococcus (n = 17,618/86,469; 20.4%) were the most common IE-causing bacteria. The prevalence of staphylococcus gradually increased over time, whereas blood culture-negative IE (BCNIE) cases decreased. In-hospital mortality in patients with IE was 14.9%. Compared to BCNIE, staphylococcus and Gram-negative pathogens were associated with higher in-hospital mortality. In multivariable analysis, factors associated with higher likelihood of in-hospital mortality were advanced age, female sex, CV comorbidities (e.g., heart failure, COPD, diabetes, stroke), need for dialysis or invasive ventilation, and sepsis. CONCLUSIONS: In this contemporary cohort, incidence of IE increased over time and in-hospital mortality remained high (~ 15%). While staphylococcus and streptococcus were the predominant microorganisms, bacteremia with staphylococcus and Gram-negative pathogens were associated with higher likelihood of in-hospital mortality. Our results highlight the need for new preventive strategies and interventions in patients with IE. Infective endocarditis in Germany. BCNIE blood culture-negative infective endocarditis, IE infective endocarditis.

Use of evidence-based therapy in heart failure with reduced ejection fraction across age strata.

AIMS: In older patients, guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (<40%; HFrEF) is not contraindicated, but adherence to guidelines is limited. We investigated the implementation of GDMT in HFrEF across different age strata in a large nationwide cohort. METHODS AND RESULTS: Patients with HFrEF and HF duration ≥3 months registered in the Swedish HF Registry between 2000-2018 were analysed according to age. Multivariable logistic and multinomial regressions were fitted to investigate factors associated with underuse/underdosing. Of 27 430 patients, 31% were <70 years old, 34% 70-79 years old, and 35% ≥80 years old. Use of treatments progressively decreased with increasing age. Use of renin-angiotensin system/angiotensin receptor-neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists was 80%, 88% and 35% in age ≥80 years; 90%, 93% and 47% in age 70-79 years; and 95%, 95% and 54% in age <70 years, respectively. Among patients with an indication, use of implantable cardioverter defibrillator and cardiac resynchronization therapy (CRT) was 7% and 23% in age ≥ 80 years; 22% and 42% in age 70-79 years; and 29% and 50% in age <70 years, respectively. Older patients were less likely treated with target doses or combinations of HF medications. Except for CRT, after extensive adjustments, age was inversely associated with the likelihood of GDMT use and target dose achievement. CONCLUSION: In HFrEF, gaps persist in the use of medications and devices. In disagreement with current recommendations, older patients remain undertreated. Improving strategies and a more individualized approach for implementing use of GDMT in HFrEF are required, particularly in older patients.

Differences in the Treatment of Acute Coronary Syndrome in the Pre-COVID and COVID Era: An Analysis from Two German High-Volume Centers.

The COVID-19 pandemic is placing a heavy burden on healthcare systems worldwide with the risk that acute cardiovascular diseases are treated too late. The present study aims to analyze patients with acute coronary syndrome in the current pandemic. A total of 966 patients (2019 n = 463, 2020 n = 503) can be evaluated. A comparison of patient care during and before the COVID-19 pandemic was made in terms of patient characteristics and pre- and in-hospital processes. Another aim is to show how many patients seek clinical care at a late stage of the disease. After Lockdown in Germany at week 12, 2020, there was a significant decrease in patients with an acute coronary syndrome (ACS), significant for STEMI cases in the first weeks after Lockdown (calendar week 13-16 2019 n = 43, 2020 n = 30; p = 0.02). The time from pain to first medical contact (time to FMC) is significantly extended during Lockdown, while internal clinical processes are unchanged. The rate of subacute myocardial infarction is numerically, but not significantly increased in calendar weeks 15, 2020 (p = 0.40) and 16 (p = 0,19). In addition, elderly patients avoid treatment for multifactorial reasons, and the longer overall pain to FMC may impact long-term mortality.

Gender differences in characteristics and outcomes in heart failure patients referred for end-stage treatment.

AIMS: Despite signals from clinical trials and mechanistic studies implying different resilience to heart failure (HF) depending on gender, the impact of gender on presentation and outcomes in patients with HF remains unclear. This study assessed the impact of gender on clinical presentation and outcomes in patients with HF referred to a specialised tertiary HF service. METHODS AND RESULTS: Consecutive patients with HF referred to a specialised tertiary HF service offering advanced therapy options including left ventricular assist devices (LVAD) and heart transplantation were prospectively enrolled from August 2015 until March 2018. We assessed clinical characteristics at baseline and performed survival analyses and age-adjusted Cox regression analyses in men vs. women for all-cause death and a combined disease-related endpoint comprising death, heart transplantation, and LVAD implantation. Analyses were performed for the overall study population and for patients with HF with reduced ejection fraction (HFrEF). Of 356 patients included, 283 (79.5%) were male. The median age was 58 years (interquartile range 50-67). Two hundred and fifty-one (74.5%) patients had HFrEF. HF aetiology, ejection fraction, functional status measures, and most of the cardiac and non-cardiac comorbidities did not differ between men and women. In a median follow-up of 3.2 years, 50 patients died (45 men, 5 women), 15 patients underwent LVAD implantation, and 8 patients heart transplantation. While all-cause death was not significantly different between both genders in the overall population [16.9 vs. 6.0%, P = 0.065, hazard ratio (HR) 2.29 (95% confidence interval 0.91-5.78), P = 0.078], in the HFrEF subgroup, a significant difference between men and women was observed [20.7% vs. 3.9%, P = 0.017, HR 3.67 (95% confidence interval 1.13-11.91), P = 0.031]. The combined endpoint was more often reached in men than in women in both the overall population [21.6% vs. 9.0%, P = 0.053, HR 2.51 (1.08-5.82), P = 0.032] and the HFrEF subgroup [27.1% vs. 7.7%, P = 0.015, HR 3.58 (1.29-9.94), P = 0.014]. CONCLUSIONS: Patients referred to a specialised tertiary HF service showed a similar clinical profile without relevant gender differences. In the mid-term follow-up, more male than female patients died or underwent heart transplantation and LVAD implantation. These findings call for independent validation and for further research into gender-specific drivers of HF progression.

Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the Swedish Heart Failure Registry.

AIMS: Iron deficiency (ID) is associated with poor prognosis regardless of anaemia. Intravenous iron improves quality of life and outcomes in patients with ID and heart failure (HF) with reduced ejection fraction (HFrEF). In the Swedish HF registry, we assessed (i) frequency and predictors of ID testing; (ii) prevalence and outcomes of ID with/without anaemia; (iii) use of ferric carboxymaltose (FCM) and its predictors in patients with ID. METHODS AND RESULTS: We used multivariable logistic regressions to assess patient characteristics independently associated with ID testing/FCM use, and Cox regressions to assess risk of outcomes associated with ID. Of 21 496 patients with HF and any ejection fraction enrolled in 2017-2018, ID testing was performed in 27%. Of these, 49% had ID and more specifically 36% had ID-/anaemia-, 15% ID-/anaemia+, 29% ID+/anaemia-, and 20% ID+/anaemia+ (48%, 39%, 13%, 30% and 18% in HFrEF, respectively). Risk of recurrent all-cause hospitalizations was higher in patients with ID regardless of anaemia. Of 1959 patients with ID, 19% received FCM (24% in HFrEF). Important independent predictors of ID testing and FCM use were anaemia, higher New York Heart Association class, having HFrEF, and referral to HF specialty care. CONCLUSION: In this nationwide HF registry, ID testing occurred in only about a quarter of the patients. Among tested patients, ID was present in one half, but only one in five patients received FCM indicating low adherence to current guidelines on screening and treatment.

Study design and rationale of the pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R).

AIM: Due to improved therapy in childhood, many patients with congenital heart disease reach adulthood and are termed adults with congenital heart disease (ACHD). ACHD often develop heart failure (HF) as a consequence of initial palliative surgery or complex anatomy and subsequently require advanced HF therapy. ACHD are usually excluded from trials evaluating heart failure therapies, and in this context, more data about heart failure trajectories in ACHD are needed to guide the management of ACHD suffering from HF. METHODS AND RESULTS: The pAtients pResenTing with cOngenital heaRt dIseAse Register (ARTORIA-R) will collect data from ACHD evaluated or listed for heart or heart-combined organ transplantation from 16 countries in Europe and the Asia/Pacific region. We plan retrospective collection of data from 1989-2020 and will include patients prospectively. Additional organizations and hospitals in charge of transplantation of ACHD will be asked in the future to contribute data to the register. The primary outcome is the combined endpoint of delisting due to clinical worsening or death on the waiting list. The secondary outcome is delisting due to clinical improvement while on the waiting list. All-cause mortality following transplantation will also be assessed. The data will be entered into an electronic database with access to the investigators participating in the register. All variables of the register reflect key components important for listing of the patients or assessing current HF treatment. CONCLUSION: The ARTORIA-R will provide robust information on current management and outcomes of adults with congenital heart disease suffering from advanced heart failure.

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

AIMS: Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials. METHODS AND RESULTS: Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility. CONCLUSION: The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.