189 Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease

Aims Data regarding long-term prognosis of MINOCA are very limited and conflicting. Methods and results The Italian Genetic Study on early-onset MI enrolled 2000 patients who had a first MI before they were 45. The median follow-up was 19.9 years, the equivalent of 39 535 person-years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalization for coronary revascularization. MINOCA was experienced by 317 patients (15.9%). The risk of MACE was not significantly different between MINOCA patients and those with obstructive coronary artery disease (MICAD, 27.8% vs. 37.5%; adj. HR: 0.79, 95% CI: 0.57–1.09; P = 0.15, Figure 1). There was no between-group difference in the rate of non-fatal MI (17.3% vs. 25.4%; adj. HR: 0.76, 95% CI: 0.52–1.13; P = 0.18), non-fatal ischaemic stroke (9.5% vs. 3.7%; adj. HR: 1.79, 95% CI: 0.87–3.70; P = 0.12), or all-cause mortality (14.1% vs. 20.7%; adj. HR: 0.73, 95% CI: 0.43–1.25; P = 0.26), but the rates of CV death (6.2% vs. 8.4%; adj. HR: 0.26, 95% CI: 0.08–0.86; P = 0.03) and coronary revascularization (6.7% vs. 27.7%; HR: 0.27, 95% CI: 0.15–0.47; P < 0.001) were lower in the MINOCA group. Conclusions MINOCA is frequent in early-onset MI patients and is not benign with a long-term risk of MACE and overall mortality not significantly different from that of the MICAD patients. 189 Figure 1 Composite primary endpoint of CV death, non-fatal MI, and non-fatal stroke

How fragile are Mediterranean diet interventions? A research-on-research study of randomised controlled trials

IntroductionThe Mediterranean diet (MD) is a traditional regional dietary pattern and a healthy diet recommended for the primary and secondary prevention of various diseases and health conditions. Results from the higher level of primary evidence, namely randomised controlled trials (RCTs), are often used to produce dietary recommendations; however, the robustness of RCTs with MD interventions is unknown.MethodsA systematic search was conducted and all MD RCTs with dichotomous primary outcomes were extracted from PubMed. The fragility (FI) and the reverse fragility index (RFI) were calculated for the trials with significant and non-significant comparisons, respectively.ResultsOut of 27 RCTs of parallel design, the majority failed to present a significant primary outcome, exhibiting an FI equal to 0. The median FI of the significant comparisons was 5, ranging between 1 and 39. More than half of the comparisons had an FI <5, indicating that the addition of 1–4 events to the treatment arm eliminated the statistical significance. For the comparisons with an FI=0, the RFI ranged between 1 and 29 (Median RFI: 7). When the included RCTs were stratified according to masking, the use of a composite primary endpoint, sample size, outcome category, or dietary adherence assessment method, no differences were exhibited in the FI and RFI between groups, except for the RFI among different compliance assessment methods.ConclusionsIn essence, the present study shows that even in the top tiers of evidence hierarchy, research on the MD may lack robustness, setting concerns for the formulation of nutrition recommendations.

Conflicts of interest in randomized controlled trials reported in neurosurgical journals

OBJECTIVERandomized controlled trials (RCTs) form the basis of today’s evidence-based approach to medicine, and play a critical role in guidelines and the drug and device approval process. Conflicts of interest (COIs) are commonplace in medical research, but little is known about their influence. The authors aimed to evaluate the extent and influence of COIs in recent RCTs published in core neurosurgical journals using a cross-sectional analysis.METHODSThrough review of 6 general neurosurgical journals, all interventional RCTs published from January 2009 to January 2019 were identified. Because it is difficult to objectively assess study outcome, the authors opted for a strict rating approach based on the statistical significance of unambiguously reported primary endpoints, and the reported statistical protocol.RESULTSA total of 129 RCTs met the inclusion criteria. During the study period, the Journal of Neurosurgery published the largest number of RCTs (n = 40, 31%). Any potential COI was disclosed by 57%, and a mean of 12% of authors had a personal COI. Nonfinancial industry involvement was reported in 10%, while 31% and 20% received external support and sponsoring, respectively. Study registration was reported by 56%, while 51% of studies were blinded. Registration showed an increasing trend from 17% to 76% (p < 0.001). The median randomized sample size was 92 (interquartile range 50–153), and 8% were designed to investigate noninferiority or equality. Sixty-three RCTs (49%) unambiguously reported a primary endpoint, of which 13% were composite primary endpoints. In 43%, study outcome was positive, which was associated with a noninferiority design (31% vs 3%, p = 0.007) and a composite primary endpoint (46% vs 9%, p = 0.002). Potential COIs were not significantly associated with study positivity (69% vs 59%, p = 0.433). In the multivariate analysis, only a composite primary endpoint remained predictive of a positive study outcome (odds ratio 6.34, 95% confidence interval 1.51–33.61, p = 0.017).CONCLUSIONSThis analysis provides an overview of COIs and their potential influence on recent trials published in core neurosurgical journals. Reporting of primary endpoints, study registration, and uniform disclosure of COIs are crucial to ensure the quality of future neurosurgical randomized trials. COIs do not appear to significantly influence the outcome of randomized neurosurgical trials.

Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia

BackgroundIn hospitalized patients with COVID-19 pneumonia, progression to acute respiratory failure requiring invasive mechanical ventilation (MV) is associated with significant morbidity and mortality. Severe dysregulated systemic inflammation is the putative mechanism.Research QuestionWill early prolonged methylprednisolone (MP) treatment accelerate disease resolution, decreasing the need for ICU and mortality?Study Design and MethodsWe conducted a multicenter, observational study to explore the association between exposure to prolonged, low-dose, MP treatment and need for ICU referral, intubation or death within 28 days (composite primary endpoint) in patients with severe COVID-19 pneumonia admitted to Italian respiratory high-dependency units. Secondary outcomes were invasive MV-free days and changes in C-reactive protein (CRP) levels.ResultsFindings are reported as MP (n=83) vs. control (n=90). The composite primary endpoint was met by 19 vs. 40 [adjusted hazard ratio (HR) 0.41; 95% confidence interval (CI): 0.24-0.72]. Transfer to ICU and need for invasive MV was necessary in 15 vs. 27 (p=0.07) and 14 vs. 26 (p=0.10), respectively. By day 28, the MP group had fewer deaths (6 vs. 21, adjusted HR=0.29; 95% CI: 0.12-0.73) and more days off invasive MV (24.0 ± 9.0 vs. 17.5 ± 12.8; p=0.001). Study treatment was associated with rapid improvement in PaO2:FiO2 and CRP levels. The complication rate was similar for the two groups (p=0.84).InterpretationIn patients with severe COVID-19 pneumonia, early administration of prolonged MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Randomized controlled studies are needed to confirm these findings.Clinical trial registrationClinicalTrials.gov. Identifier: NCT04323592.

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalised for COVID-19 infection and requiring oxygen: results of a study using routinely collected data to emulate a target trial

BackgroundTreatments are urgently needed to prevent respiratory failure and deaths from coronavirus disease 2019 (COVID-19). Hydroxychloroquine (HCQ) has received worldwide attention because of positive results from small studies.MethodsWe used data collected from routine care of all adults in 4 French hospitals with documented SARS-CoV-2 pneumonia and requiring oxygen ≥ 2 L/min to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day. The composite primary endpoint was transfer to intensive care unit (ICU) within 7 days from inclusion and/or death from any cause. Analyses were adjusted for confounding factors by inverse probability of treatment weighting.ResultsThis study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21 events, relative risk [RR] 0.91, 95% CI 0.47–1.80). In the HCQ group, 2.8% of the patients died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13–2.89), and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7 days (24 vs 23 events, RR 1.14, 95% CI 0.65–2.00). Eight patients receiving HCQ (9.5%) experienced electrocardiogram modifications requiring HCQ discontinuation.InterpretationThese results do not support the use of HCQ in patients hospitalised for documented SARS-CoV-2-positive hypoxic pneumonia.

P2276Sudden cardiac death in non-ischemic systolic heart failure: do we only need LVEF to decide ICD implantation?

Background Implantable cardioverter defibrillator (ICD) is recommended in patients (pts) with non-ischaemic heart failure with left ventricular systolic dysfunction who receive optimal medical therapy (OMT) in order to prevent sudden cardiac death (SCD). However, the results of the DANISH study have recently shown the limits of these recommendations. It is therefore mandatory to reconsider the risk stratification of SCD in this population. Purpose The purpose of our study is to determine independent predictors of severe arrhythmic events (AE in pts with non-ischemic systolic heart failure. Methods Between January 1998 and December 2014, all consecutive outpatients with non-ischemic systolic heart failure, receiving OMT and without a history of significant arrhythmic events, were included. We performed to all the pts a clinical and biological evaluation, an echocardiography, a cardiopulmonary exercise test, a radionuclide angiography and a Holter-ECG. Follow-up was performed either by direct examination, by contact with the general practitioner or the cardiologist and by remote monitoring if available. The composite primary endpoint was the occurrence of SCD, recovered cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by the ICD. Results We included 910 pts with a mean age of 53±12 years, 244 (27%) were women, LVEF was 36±10%. Most of the pts received renin-angiotensin blockers (97%) and betablockers (84%), 77% received diuretics and 41% spironolactone. During a median follow-up period of 6.33 [3.29–10.18] years, 160 (17.6%) pts presented the composite primary endpoint. The median time between the assessment and the occurrence of AE was 4.05 [1.68–7.85] years. The most powerful independent predictor of AE was non-sustained ventricular tachycardia (≥3 ectopic beats) (HR: 2.8 [1.66–4.72], p<0.0001). The other independent factors of AE were left atrial diameter (HR: 1.03 [1.01–1.06], p<0.0001); gender (HR: 0.71 [0.55–0.92], p=0.010); digoxin intake (HR: 1.63 [1.10–2.44], p=0.016); QRS duration (HR: 1.01 [1.00–1.01], p=0.022), sinus rhythm (HR: 0.70 [0.56–0.87], p=0.001). LVEF, as a quantitative parameter, was not an independent predictor of AE. However, LVEF dichotomized with a value of 35% was a modest predictor of AE (HR =1.38 [1.12–1.70], p=0.002). Neither the NYHA classification nor the parameters of the cardiopulmonary exercise test were independent factors of AE occurrence. Conclusion LVEF is not the most powerful predictor of severe arrhythmic events in outpatients with non-ischemic systolic heart failure receiving optimal medical therapy. New risk scores are required. We found that in addition to LVEF, gender, QRS duration, sinus rhythm, left atrial diameter and more particularly non-sustained ventricular tachycardia were independent predictors of AE. This score needs to be validated in an independent population. Acknowledgement/Funding None

Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study

SummaryDyspnoea may be induced by some reversibly-binding P2Y12 inhibitors, including cangrelor and ticagrelor. Dyspnoea was not associated with any compromise to the efficacy of ticagrelor in the PLATO study. The CHAMPION PHOENIX study (NCT01156571) compared initial treatment with cangrelor versus initial treatment with clopidogrel in patients undergoing PCI. We investigated the incidence, characteristics, and associated clinical outcomes in patients with dyspnoea in CHAMPION PHOENIX. Adverse events (AEs) of dyspnoea to 48 hours were recorded in patients randomised to cangrelor or clopidogrel in CHAMPION PHOENIX. The composite primary endpoint of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis as well its individual components were assessed in patients who did or did not report dyspnoea. A total of 68 (1.2 %) cangrelor-treated patients and 18 (0.3 %) clopidogrel-treated patients reported dyspnoea (p<0.001). Most dyspnoea events in cangrelor-treated patients were considered mild (71 %) or moderate (28 %) and only one event was considered severe and led to discontinuation of cangrelor. The dyspnoea events in the clopidogrel-treated patients were mild (78 %) or moderate (22 %). Characteristics of dyspnoea were consistent with those seen in the CHAMPION programme as a whole. In the modified intention-to-treat population, rates of the composite primary outcome and its individual components were not affected by the presence of dyspnoea in cangrelor-treated patients. Cangrelor-related dyspnoea is transient, usually mild or moderate, and unlikely to lead to discontinuation of therapy. The occurrence of dyspnoea does not seem to be associated with any reduction in the efficacy of cangrelor compared with clopidogrel as initial therapy in PCI patients.Supplementary Material to this article is available online at www.thrombosis-online.com.