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.

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.

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.

Incidence and pattern of urgent revascularization in acute coronary syndromes treated with ticagrelor or prasugrel.

BACKGROUND: The ISAR-REACT 5 trial compared the efficacy and safety of ticagrelor and prasugrel in patients with ACS managed invasively. The present study sought to investigate the impact of ticagrelor and prasugrel on the incidence and pattern of urgent revascularization in acute coronary syndromes (ACS) patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: This post-hoc analysis of the ISAR-REACT 5 trial included all ACS patients who underwent PCI. The primary endpoint for this analysis was the incidence of urgent revascularization at 12-month follow-up. Secondary outcome was the pattern of urgent revascularization procedures (namely, urgent target vessel/non-target vessel revascularization - TVR/NTVR). Among 3,377 ACS patients who underwent PCI, 1,676 were assigned to ticagrelor and 1,701 to prasugrel before PCI. After 12 months, the incidence of urgent revascularization was higher among patients assigned to ticagrelor as compared to prasugrel (6.8% vs. 5.2%; hazard ratio [HR] = 1.32, 95% confidence interval [CI] 1.00-1.75; p = 0.051), mostly attributable to significantly more urgent NTVR in the ticagrelor group (3.8% vs. 2.4%; HR = 1.62 [1.09-2.41]; p = 0.017). The risk of urgent TVR did not differ between treatment groups (3.3% vs. 3.0%; HR = 1.13 [0.77-1.65]; p = 0.546). CONCLUSIONS: In ACS patients treated with PCI, the cumulative rate of urgent revascularizations after 12 months is higher with ticagrelor compared to prasugrel, due to a significant increase in urgent revascularizations involving remote coronary vessels.

Derivation and validation of the ISAR score to predict the risk of repeat percutaneous coronary intervention for recurrent drug-eluting stent restenosis.

BACKGROUND: The treatment of drug-eluting stent (DES) in-stent restenosis (ISR) is challenging as it has a high risk of recurrence. AIMS: The aim of this analysis was to develop and validate a model to predict the risk of repeat percutaneous coronary intervention (PCI) for recurrent DES-ISR. METHODS: A retrospective, observational analysis was performed including consecutive patients treated with PCI for DES-ISR at two centres in Germany. Included patients were randomly divided into training and validation cohorts. Two regression analyses identified factors associated with repeat PCI for recurrent DES-ISR up to 1 year. The discriminative ability of the resultant model was then compared to a benchmark ISR classification model using bootstrap resampling. A classification and regression tree analysis and a numerical scoring system (the ISAR score) were used to predict the risk of repeat PCI for recurrent DES-ISR based on the identified predictors. RESULTS: We included 1,986 patients in the current analysis, divided randomly into training (1,471 patients, 1,778 lesions) and validation (515 patients, 614 lesions) cohorts. Four factor variables (a non-focal ISR pattern, a time interval to ISR of <6 months, ISR of the left circumflex artery and ISR in a calcified vessel) were associated with repeat PCI for recurrent DES-ISR at 1-year follow-up. On bootstrap resampling analysis, the C-statistic for the model including these four variables was 0.60 (95% confidence interval [CI]: 0.57-0.63), whereas the C-statistic for the benchmark ISR classification model was 0.54 (95% CI: 0.52-0.57), a difference that was statistically significant (delta C-statistic 0.062; 95% CI: 0.035-0.094; p<0.001). The cumulative incidence of repeat PCI for recurrent DES-ISR was over three times higher in DES-ISR lesions with an ISAR score of ≥3 in comparison to lesions with an ISAR score of 0. CONCLUSIONS: This study developed and validated a risk prediction model for repeat PCI for recurrent DES-ISR at 1-year follow-up. This model served to generate the ISAR score, a standardised tool that can be used to predict the 1-year risk of repeat PCI for recurrent DES-ISR.

Ten-year clinical outcomes of drug-eluting stents with different polymer coating strategies by degree of coronary calcification: a pooled analysis of the ISAR-TEST 4 and 5 randomised trials.

BACKGROUND: Long-term data concerning the efficacy of different polymer-coating strategies of new-generation drug-eluting stents (DES) in patients with coronary artery calcification (CAC) are scant. AIMS: We aimed to investigate 10-year outcomes by degree of CAC after new-generation DES implantation with different polymer-coating strategies. METHODS: We analysed individual patient and lesion characteristics of patients randomised to treatment with polymer-free sirolimus-eluting, biodegradable-polymer sirolimus-eluting and permanent-polymer zotarolimus- or everolimus-eluting stents. Endpoints of interest at 10 years were all-cause mortality, myocardial infarction (MI), target lesion revascularisation (TLR) and definite or probable stent thrombosis (ST) according to the degree of CAC (no, mild, moderate or severe) and coating strategy (polymer-free vs biodegradable-polymer vs permanent-polymer). RESULTS: A total of 4,953 patients with 6,924 lesions were included. No, mild, moderate or severe CAC was present in 24.5%, 41.8%, 25.8% and 8.0% of patients, respectively. At 10-year follow-up, overall event rates were high, with an incremental increase according to the degree of CAC (all-cause mortality: no 25.3%, mild 32.1%, moderate 41.7%, severe CAC 46.5%; adjusted [adj.] p=0.004; TLR: no 17.4%, mild 16.5%, moderate 19.8%, severe CAC 28.7%; adj. p=0.001; MI: no 4.9%, mild 5.9%, moderate 6.0%, severe CAC 10.5%; adj. p=0.02; and ST: no 1.3%, mild 1.4%, moderate 1.8%, severe CAC 3.6%; adj. p=0.57). In patients with moderate-severe CAC, event rates were comparable, regardless of the DES polymer-coating strategy. CONCLUSIONS: At 10 years after PCI with new-generation DES, there was an incremental increase in adverse events by degree of coronary calcification. These detrimental effects do not seem to be impacted by different polymer-coating strategies.