Type of evidence supporting ACC/AHA and ESC clinical practice guidelines for acute coronary syndrome.

AIM: The aim of clinical practice guidelines for ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS) is to assist healthcare professionals in clinical decision-making. We evaluated the type of studies supporting these guidelines and their recommendations. METHODS: All references and recommendations in the 2013 and 2014 ACC/AHA and 2017 and 2020 (ESC clinical guidelines for STEMI and NSTE-ACS were reviewed. References were classified into meta-analyses, randomised, non-randomised, and other types (e.g., position papers, reviews). Recommendations were classified according to class and their level of evidence (LOE). RESULTS: We retrieved 2128 non-duplicated references: 8.4% were meta-analyses, 26.2% randomised studies, 44.7% non-randomised studies, and 20.7% 'other' papers. Meta-analyses were based on randomised data in 78% of cases and used individual-patient data in 20.2%. Compared to non-randomised studies, randomised studies were more frequently multicentre (85.5% vs. 65.5%) and international (58.2% vs. 28.5%). The type of studies supporting recommendations varied as per the LOE of the recommendation. For LOE-A recommendations, the breakdown of supporting recommendations was: 18.5% meta-analyses, 56.6% randomised studies, 16.6% non-randomised studies and 8.3% 'other' papers; for LOE-B this breakdown was 9%, 39.8%, 38.2%, and 12.9%; and for LOE-C; 4.6%, 19.3%, 30.3%, and 45.9%. CONCLUSIONS: The references supporting the ACC/AHA and ESC guidelines on STEMI and NSTE-ACS consisted of non-randomised studies in ~ 45% of cases, with less than a third of the references consisting of meta-analyses and randomised studies. The type of studies supporting guideline recommendations varied widely by the LOE of the recommendation.

A systematic assessment of the characteristics of randomized controlled trials cited by acute coronary syndrome clinical practice guidelines.

AIMS: The aim of this study was to describe the methodological features of the randomized 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 American College of Cardiology/American Heart Association and 2017 and 2020 European Society of Cardiology 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%), had a 2-arm (82.6%), and 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%). Among 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.

The fragility index in randomized clinical trials supporting clinical practice guidelines for acute coronary syndrome: measuring robustness from a different perspective.

AIMS: In randomized 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 American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) clinical practice guidelines (CPGs) for ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndrome (NSTE-ACS) using the FI. METHODS AND RESULTS: 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 (two-arm RCT, 1:1 allocation, binary outcome, P < 0.05). 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 a 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). CONCLUSION: The 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.

Representativeness in randomised clinical trials supporting acute coronary syndrome guidelines.

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 under-represented (e.g. 25.3% RCTs recruited in Asia). There was 68.6% RCTs enrolling patient with ACS, whereas the remaining 31.4% did not enrol any patient with ACS. There was under-representation 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: Randomised clinical trials 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.