Quality and transparency of evidence for implantable cardiovascular medical devices assessed by the CORE-MD consortium.

BACKGROUND AND AIMS: The European Union Medical Device Regulation 2017/745 challenges key stakeholders to follow transparent and rigorous approaches to the clinical evaluation of medical devices. The purpose of this study is a systematic evaluation of published clinical evidence underlying selected high-risk cardiovascular medical devices before and after market access in the European Union (CE-marking) between 2000 and 2021. METHODS: Pre-specified strategies were applied to identify published studies of prospective design evaluating 71 high-risk cardiovascular devices in seven different classes (bioresorbable coronary scaffolds, left atrial appendage occlusion devices, transcatheter aortic valve implantation systems, transcatheter mitral valve repair/replacement systems, surgical aortic and mitral heart valves, leadless pacemakers, subcutaneous implantable cardioverter-defibrillator). The search time span covered 20 years (2000-21). Details of study design, patient population, intervention(s), and primary outcome(s) were summarized and assessed with respect to timing of the corresponding CE-mark approval. RESULTS: At least one prospective clinical trial was identified for 70% (50/71) of the pre-specified devices. Overall, 473 reports of 308 prospectively designed studies (enrolling 97 886 individuals) were deemed eligible, including 81% (251/308) prospective non-randomized clinical trials (66 186 individuals) and 19% (57/308) randomized clinical trials (31 700 individuals). Pre-registration of the study protocol was available in 49% (150/308) studies, and 16% (48/308) had a peer-reviewed publicly available protocol. Device-related adverse events were evaluated in 82% (253/308) of studies. An outcome adjudication process was reported in 39% (120/308) of the studies. Sample size was larger for randomized in comparison to non-randomized trials (median of 304 vs. 100 individuals, P < .001). No randomized clinical trial published before CE-mark approval for any of the devices was identified. Non-randomized clinical trials were predominantly published after the corresponding CE-mark approval of the device under evaluation (89%, 224/251). Sample sizes were smaller for studies published before (median of 31 individuals) than after (median of 135 individuals) CE-mark approval (P < .001). Clinical trials with larger sample sizes (>50 individuals) and those with longer recruitment periods were more likely to be published after CE-mark approval, and were more frequent during the period 2016-21. CONCLUSIONS: The quantity and quality of publicly available data from prospective clinical investigations across selected categories of cardiovascular devices, before and after CE approval during the period 2000-21, were deemed insufficient. The majority of studies was non-randomized, with increased risk of bias, and performed in small populations without provision of power calculations, and none of the reviewed devices had randomized trial results published prior to CE-mark certification.

Sex Differences in 10-Year Outcomes After Percutaneous Coronary Intervention With Drug-Eluting Stents: Insights From the DECADE Cooperation.

BACKGROUND: Although some studies have investigated sex-related outcomes up to 5 years after percutaneous coronary intervention (PCI), analyses at longer follow-up (ie, to 10 years) in large cohorts treated exclusively with drug-eluting stent (DES) platforms are lacking. Therefore, this study aimed to define whether sex-related differences in long-term outcomes after PCI persist both in the DES era and at longer-term follow-up. METHODS: Individual data of patients treated with DES in 5 randomized controlled trials with 10-year follow-up were pooled. Patients were divided into 2 groups by sex. The analysis of individual participant data was performed using a 1-stage approach by entering a clustering effect by parent study in all univariable and multivariable models focusing on sex. The main outcomes of interest for this analysis included cardiovascular death, myocardial infarction, repeat revascularization, and definite stent thrombosis to 10 years after PCI. Survival was analyzed by the Kaplan-Meier method to estimate the time to first event, and differences between the 2 groups were tested with the log-rank test. Hazard ratios (HRs) and 95% CIs were calculated with a Cox proportional hazards model. Conventional multivariable analyses with adjustment for relevant variables were performed. RESULTS: Among 9700 patients undergoing PCI with DES implantation included in the present analysis, 2296 were women and 7404 were men. Through to 10 years, cardiovascular death occurred in 407 of the 2296 female patients and 1012 of the 7404 male patients (adjusted HR [HRadj], 0.94 [95% CI, 0.80-1.11]). Female sex was associated with a lower risk of repeat revascularization of the target lesion (HRadj, 0.80 [95% CI, 0.74-0.87]), target vessel (HRadj, 0.81 [95% CI, 0.76-0.87]), and nontarget vessels (HRadj, 0.69 [95% CI, 0.62-0.77]). Compared with male patients, female patients displayed an increased risk of myocardial infarction in the first 30 days after PCI with DES (HRadj, 1.65 [95% CI, 1.24-2.19]) but a comparable risk of myocardial infarction thereafter. The risk of definite stent thrombosis was not significantly different between female and male patients (HRadj, 1.14 [95% CI, 0.89-1.47]). CONCLUSIONS: Through to 10-year follow-up after PCI with DES, female patients are at increased risk of early myocardial infarction, receive fewer repeat revascularizations, and have no difference in cardiovascular mortality compared with male patients.

Ten-year clinical outcomes after drug-eluting stents implantation according to clinical presentation-Insights from the DECADE cooperation.

BACKGROUND: Investigations of very long-term outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) according to clinical presentation are scarce. Here, we investigated the 10-year clinical outcomes of patients undergoing DES-PCI according to clinical presentation. METHODS: Patient-level data from five randomized trials with 10-year follow-up after DES-PCI were pooled. Patients were dichotomized into acute coronary syndrome (ACS) or chronic coronary syndrome (CCS) groups as per clinical presentation. The primary outcome was all-cause death. Secondary outcomes were cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST) and repeat revascularization involving the target lesion (TLR), target vessel (TVR) or non-target vessel (nTVR). RESULTS: Of the 9700 patients included in this analysis, 4557 presented with ACS and 5143 with CCS. Compared with CCS patients, ACS patients had a higher risk of all-cause death and nTVR in the first year, but comparable risk thereafter. In addition, ACS patients had a higher risk of MI [adjusted hazard ratio 1.21, 95% confidence interval (1.04-1.41)] and definite ST [adjusted hazard ratio 1.48, 95% confidence interval (1.14-1.92)], while the risk of TLR and TVR was not significantly different up to 10-year follow-up. CONCLUSIONS: Compared to CCS patients, ACS patients treated with PCI and DES implantation have an increased risk of all-cause death and repeat revascularization of remote vessels up to 1 year, with no significant differences thereafter and up to 10-year follow-up. ACS patients have a consistently higher risk of MI and definite ST. Whether these differences persist with current antithrombotic and secondary prevention therapies requires further investigation.

Glu298Asp variant of the endothelial nitric oxide synthase gene and acute coronary syndrome or premature coronary artery disease: A systematic review and meta-analysis.

INTRODUCTION: Several published studies have reported an association between the Glu298Asp polymorphism (rs1799983), residing in the endothelial nitric oxide synthase (NOS3) gene, and lower levels of circulating nitric oxide, as well as an increased risk of coronary artery disease (CAD). However, association status of this genetic variant with acute coronary syndrome (ACS) or premature CAD (PCAD) is still unclear. Against this background, we conducted a systematic review and study level meta-analysis to assess the association of the NOS3 Glu298Asp polymorphism with ACS or PCAD. MATERIALS AND METHODS: A comprehensive online search to identify relevant studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science. The identified studies were stratified into two ancestral subgroups: 'European ancestry' and 'All other ancestries combined'. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random/fixed effects employing a Z test. RESULTS: Out of a total of 195 distinct records identified through online search, 37 articles with 39 different studies, with a total sample size of 27,441 (11,516 cases/15,925 controls) were included for quantitative synthesis. Pooled results suggested significant associations of the NOS3 Glu298Asp polymorphism with ACS or PCAD through dominant as well as allelic genetic models (p ≤ 0.002), primarily driven by the 'All other ancestries combined' subgroup. The 'All other ancestries combined' subgroup demonstrated an additional risk of 36% for ACS or PCAD, through both dominant and allelic genetic models (OR = 1.36, 95%CI = 1.13, 1.63, p = 0.001 and OR = 1.36, 95%CI = 1.14, 1.61, p = 0.0005 respectively). On the other hand, the 'European ancestry' subgroup did not show any significant associations. Sensitivity analysis and a sub-analysis for the myocardial infarction endpoint further supported these observed associations. CONCLUSIONS: This meta-analysis indicates towards an association between the NOS3 Glu298Asp polymorphism and ACS or PCAD, predominantly driven by 'All other ancestries combined' subgroup. In contrast, the 'European ancestry' subgroup did not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.

Environmental Sustainability in the Cardiac Catheter Laboratory.

The health care sector contributes to nearly 5% of global carbon emissions with the exponential growth of medical waste posing a significant challenge to environmental sustainability. As the impact of climate change on individuals and population health becomes increasingly more apparent, the health care system's significant impact on the environment is also raising concerns. Hospitals contribute disproportionately to health care waste with the majority arising from resource intensive areas such as operating theatres and cardiac catheter labs (CCLs). Despite the growing volume of cardiac procedures worldwide, initiatives to reduce waste from CCLs have received limited attention, overlooking opportunities for significant reduction in operational costs and carbon footprint. We aim to raise awareness of the current landscape of waste management in CCLs. We identify areas of resource optimisation and highlight practical strategies and frameworks employed elsewhere in health care to reduce waste. Importantly, we hope to empower health care workers in CCLs to make a meaningful change to their practice and contribute towards a more sustainable future.

Long-term clinical outcomes after drug eluting stent implantation with and without stent overlap.

OBJECTIVE: The aim of this study was to investigate the impact of drug eluting stent (DES) overlap on clinical outcomes after percutaneous coronary intervention (PCI). BACKGROUND: While the use of overlapping bare metal stent has been associated with an increased risk of adverse clinical events, the long-term impact of DES overlap on clinical outcomes is not certain at present. Similarly, the effect of different DES generations and polymer types on DES overlap associated clinical outcomes has not previously been comprehensively elucidated. METHODS: We analyzed the angiographic and clinical outcomes of 5605 patients treated with DES in the setting of the ISAR-TEST 4 and ISAR-TEST 5 randomized control trials according to the presence or absence of stent overlap. The clinical endpoints assessed in this study were all-cause death, myocardial infarction (MI), target lesion revascularization (TLR), and definite or probable stent thrombosis at 10-years. We also compared rates of binary angiographic restenosis (BAR) at 6-8 months. RESULTS: At 10 years, all-cause mortality (Hazard ratios [HR] = 1.05 [0.95-1.16]; p = 0.348) did not differ between the stent overlap and no stent overlap groups. MI (8.4% vs. 5.2%; HR = 1.67 [1.35-2.07], p < 0.001) and TLR (23.7% vs. 16.3%; HR = 1.54 [1.36-1.74], p < 0.001) occurred more frequently in the stent overlap group. For MI, landmark analysis demonstrated that this increase in risk was primarily in the first 30 days post PCI. BAR at 6-8 months was also more frequent in the stent overlap group (16.0% vs. 10.3%; HR = 1.65 [1.41-1.92], p < 0.001). CONCLUSION: DES overlap is associated with an increased risk of adverse clinical events post PCI.

Pre-Percutaneous Coronary Intervention TIMI Flow Grade in STEMI Patients Treated with Pre-Hospital Ticagrelor Loading.

Aim We hypothesised that pre-hospital ticagrelor loading would result in a higher proportion of STEMI patients presenting with pre percutaneous coronary intervention TIMI flow grade (ppTFG) 3 than had previously been reported in the clopidogrel era. Methods Retrospective observational analysis of all STEMI patients attending our centre from 01/01/2016 to 31/12/2019. Patients presenting with STEMI were required to have received pre-hospital load-ing with 180 mg ticagrelor. The coronary angiography images were assessed for each patient to determine the ppTFG in the infarct related artery. Results 590 patients met the inclusion criteria. 125 patients (21.2%) presented with ppTFG 3 on pre-PCI angiography with the remaining 465 patients (78.8%) presenting with ppTFG ≤ 2. In-hospital mor-tality was comparable between the two groups (4% vs 5.6%, p=0.48). Conclusion In STEMI patients loaded with ticagrelor in the field, over one-fifth present with ppTFG 3 on angi-ography pre-PCI. This data is comparable to data from the clopidogrel era.

The diagnostic yield of transthoracic echocardiography in the intensive care unit: A retrospective observational analysis.

BACKGROUND: Transthoracic echocardiography (TTE) is a commonly requested ICU investigation. Despite this, limited data exist regarding the diagnostic yield of unselected TTEs in a heterogenous ICU population. METHODS: A retrospective, cross-sectional, single-center study was performed. All ICU patients admitted from January 2018 to February 2019 were included. AIMS: The primary aim was to define the indications for, and diagnostic yield of, TTEs performed in the ICU. We also investigated the association between major abnormalities identified on TTE and mortality. RESULTS: There were 358 patients admitted to the ICU during the study period. Of these patients, 115 (32%) had a TTE performed during their ICU stay. The primary indication was to assess left ventricular function. Just under two-thirds of TTEs (65%) were normal or had minor abnormalities. Compared to the rest of the ICU population in our study (including both patients without a TTE performed and patients with a normal TTE), patients with an abnormal TTE had higher ICU (35.9% vs 21.3%, Odds Ratio [OR], 2.06; 95% CI, 1.02-4.19, P = .04) and in-hospital (43.6% vs 30.3%, OR, 2.64; 95% CI, 1.33-5.25, P = .01) mortality. CONCLUSIONS: A formal TTE was performed in one-third of patients during their ICU admission. Major abnormalities were identified in over one-third of these TTEs. ICU and in-hospital mortality were higher in patients with an abnormal TTE.

Diagnosing, fast and slow.

Diagnostic error is increasingly recognised as a source of significant morbidity and mortality in medicine. In this article, we will attempt to address several questions relating to clinical decision making; How do we decide on a diagnosis? Why do we so often get it wrong? Can we improve our critical faculties?We begin by describing a clinical vignette in which a medical error occurred and resulted in an adverse outcome for a patient. This case leads us to the concepts of heuristic thinking and cognitive bias. We then discuss how this is relevant to our current clinical paradigm, examples of heuristic thinking and potential mechanisms to mitigate bias.The aim of this article is to increase awareness of the role that cognitive bias and heuristic thinking play in medical decision making. We hope to motivate clinicians to reflect on their own patterns of thinking with an overall aim of improving patient care.

Widespread generalist clones are associated with range and niche expansion in allopolyploids of Pacific Northwest Hawthorns (Crataegus L.).

Range and niche expansion are commonly associated with transitions to asexuality, polyploidy and hybridity (allopolyploidy) in plants. The ability of asexual polyploids to colonize novel habitats may be due to widespread generalist clones, multiple ecologically specialized clones, or may be a neutral by-product of multiple, independent origins of asexual polyploids throughout the range. We have quantified niche size and divergence for hawthorns of the Pacific Northwest using data from herbarium vouchers with known cytotypes. We find that all polyploid niches diverge from that of the diploid range, and allopolyploids have the broadest niches. Allotetraploids have the largest niche and the widest geographic distribution. We then assessed the genetic mechanism of range expansion by surveying the ecological and geographic distribution of genotypes within each cytotype from sites in which fine-scale habitat assessments were completed. We find no isolation by either geographic or ecological distance in allopolyploids, suggesting high dispersal and colonization ability. In contrast, autotriploids and diploids show patterns of isolation by geographic distance. We also compared the geographic and ecological distributions of clonal genotypes with those of randomly drawn sites of the most widespread cytotype. We found that most clones are geographically widespread and occur in a variety of habitats. We interpret these findings to suggest that patterns of range and niche expansion in Pacific Northwest Hawthorns may stem from these widespread, ecologically generalist clones of hybrid origin.

Trophic flexibility and opportunism in pike Esox lucius.

The first comprehensive investigation of pike Esox lucius trophic ecology in a region (Ireland) where they have long been thought to be a non-native species is presented. Diet was investigated across habitat types (lake, river and canal) through the combined methods of stable-isotope and stomach content analyses. Variations in niche size, specialization and the timing of the ontogenetic dietary switch were examined, revealing pronounced opportunism and feeding plasticity in E. lucius, along with a high occurrence of invertivory (up to 60 cm fork length, LF ) and a concomitant delayed switch to piscivory. Furthermore, E. lucius were found to primarily prey upon the highly available non-native roach Rutilus rutilus, which may alleviate predation pressure on brown trout Salmo trutta, highlighting the complexity of dynamic systems and the essential role of research in informing effective management.

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.