Aims Clinical practice guidelines (CPGs) are published to guide the management of acute coronary syndrome (ACS). We aimed to critically appraise the representativeness and standard of care of randomised clinical trials (RCTs) supporting CPGs for ACS. Methods and Results American and European CPGs for ST- and non-ST-elevation ACS were screened to extract all references (n = 2128) and recommendations (n = 600). Among the 407 primary publications of RCTs (19.1%), there were 52.6% and 73.2% recruiting patients in North America and Europe, respectively, whereas other regions were largely underrepresented (e.g., 25.3% RCTs recruited in Asia). There was 68.6% RCTs enrolling patient with ACS, whereas the remaining 31.4% did not enroll any patient with ACS. There was underrepresentation of some important subgroups, including elderly, female (29.9%) and non-white patients (<20%). The incidence and type of reperfusion reported in these RCTs were not reflective of current clinical practice (the percentage of patients who underwent percutaneous coronary intervention (PCI) among all RCTs was 42.7%; whereas for ST-Elevation Myocardial Infarction patients, the number of participants who underwent fibrinolysis was 3.3-fold higher than those who underwent primary PCI). All-cause mortality in these RCTs was 11.9% in RCTs with a follow-up ≤1 year. Conclusion RCTs supporting CPGs for ACS are not fully representative of the diversity of the ACS population and their current standard of care. While some of these issues with representativeness may be explained by how evidence has been accrued over time, efforts should be made by trialists to ensure that the evidence supporting CPGs is representative of the wider ACS population.

In patients with infective endocarditis and neurological complications, the optimal timing for cardiac surgery is unclear due to the varied risk of clinical deterioration when early surgery is performed. The aim of this review is to summarize the best evidence on the optimal timing for cardiac surgery in the presence of each type of neurological complication. An English literature search was carried out from June 2018 through July 2022. The resulting selection, comprising observational studies, clinical trials, systematic reviews and society guidelines, was organized into four sections according to the four groups of neurological complications: ischemic, hemorrhagic, infectious, and asymptomatic complications. Cardiac surgery could be performed without delay in cases of ischemic vascular neurological complication (provided the absence of severe damage, which can be avoided with the performance of mechanical thrombectomy in cases of major stroke), as well as infectious or asymptomatic complications. In the presence of intracranial hemorrhage, a delay of four weeks is recommended for most cases, although recent studies have suggested that performing cardiac surgery within four weeks could be a suitable option for selected cases. The findings of this review are mostly in line with the recommendations of the current European and American infective endocarditis guidelines.

Background In randomised clinical trials (RCTs) rejecting the null hypothesis, the fragility index (FI) yields the minimum number of participants who would need to have had a different outcome for the results of the trial to become non-significant. We evaluated the robustness of RCTs supporting ACC/AHA and ESC clinical practice guidelines (CPGs) for ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS) using the FI. Methods There were 407 RCTs among the 2128 studies cited in the 2013 and 2014 ACC/AHA and 2017 and 2020 ESC CPGs for STEMI and NSTE-ACS, respectively. The FI could be calculated in 132 RCTs (32.4%) meeting the needed criteria for its estimation (2-arm RCT, 1:1 allocation, binary outcome, p < 0.05). Results The median FI was 12 (interquartile range: 4-29). Hence, a change in the outcome status of 12 patients would be needed to reverse the statistical significance of the primary endpoint in 50% of the RCTs. The FI was ≤1% than their sample size in 55.7% RCTs, whereas in 47% of RCTs, the FI was lower than the number of patients lost to follow-up. Some study design features were associated with higher FI (international, multicentre, private funding; all p < 0.05), whilst baseline patient characteristics were not substantially different by FI (e.g., age, female sex, white study participants; all p > 0.05), except for geographic enrolment (p = 0.042). Conclusions FI might be useful to evaluate the robustness of those RCTs with statistically significant findings for the primary endpoint that have an impact on key guideline recommendations.

Aims The aim of this study was to describe the methodological features of the randomised controlled trials (RCTs) cited in American and European clinical practice guidelines (CPGs) for ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS). Methods and results Out of 2128 non-duplicated references cited in the 2013 and 2014 ACC/AHA and 2017 and 2020 ESC CPGs for STEMI and NSTE-ACS, we extracted data for 407 RCTs (19.1% of total references). The majority were multicenter studies (81.8%), evaluated pharmacological interventions (63.1%), and had a 2-arm (82.6%), superiority (90.4%) design. Most RCTs (60.2%) had an active comparator, and 46.2% were funded by industry. The median observed sample size was 1001 patients (84.2% of RCTs achieved ≥80% of the intended sample size). Most RCTs had a single primary outcome (90.9%), which was a composite in just over half (51.9%). Amongst the RCTs testing for superiority, 44.0% reported a p-value of ≥0.05 for the primary outcome and 61.9% observed a risk reduction of >15%. The observed treatment effect was lower-than-expected in 67.6% of RCTs, with 34.4% having at least a 20% lower-than-expected treatment effect. The calculated post hoc statistical power was ≥80% for 33.9% of cited RCTs. Conclusions This analysis demonstrates that RCTs cited by CPGs can still have significant methodological issues and limitations, highlighting that a better understanding of the methodological aspects of RCTs is crucial in order to formulate recommendations relevant to clinical practice.

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