Substudy Of Trial Research Articles

Association between coagulation activity and clinical and imaging outcomes in acute ischemic stroke patients - A sub-study of the MR CLEAN NO-IV trial

BackgroundThe MR CLEAN NO-IV trial showed neither superiority nor noninferiority of endovascular treatment (EVT) alone compared to intravenous thrombolysis (IVT; Alteplase) before EVT in acute ischemic stroke (AIS) patients with large vessel occlusion of the anterior circulation. Although the treatment effect is largely attributable to EVT, IVT may affect hypercoagulability during AIS. AimsTo investigate the association between activated coagulation and final infarct volume and clinical outcomes (modified Rankin Scale 3–6 and mortality 90 days post-EVT), and whether this effect is modified by IVT administration. MethodsEnzyme-linked immunosorbent assays were used to quantify activated coagulation markers (activated coagulation factor (F) XIIa-C1 esterase inhibitor (C1inh); FXIIa-antithrombin (AT), FXIa-C1inh, FXIa-AT, FIXa-AT, FXa-AT, T-AT, FVIIa-AT) in plasma samples obtained on admission (T0), 1 h post-EVT (T1) and 24 h post-EVT (T2). Multivariable regressions were performed to investigate the associations and effect modification. ResultsIn the total cohort of 116 patients, a significant increase at T1 was seen in FIXa-AT (p = .001), FXa-AT (p < .001), T-AT (p < .001), and FVIIa-AT (p = .012), while there was a significant increase at T2 in FXIIa-C1inh (p < .001). Similar results were seen in the IVT+EVT subgroup. The EVT alone subgroup showed a significant temporary increase at T1 in FXa-AT (p < .001) and T-AT (p = .014). Neither the enzyme:inhibitor complexes nor the interaction with IVT were significantly associated with the outcome measures. ConclusionDespite temporary significant increases in enzyme:inhibitor complexes in the IVT+EVT group, but not in the EVT alone group, there were no significant associations with final infarct volume and clinical outcomes.

Virtual physiological analysis of non-culprit disease in patients with STEMI and multivessel disease: a substudy of the COMPLETE trial

Abstract Background In the Complete Revascularization with Multivessel PCI for Myocardial Infarction (COMPLETE) trial, patients with ST-segment-elevation myocardial infarction (MI) who underwent staged revascularization of non-culprit coronary stenoses experienced fewer major adverse cardiovascular events than those who underwent a culprit-only approach (1). Inclusion was, however, based on angiographic and not physiological criteria. Purpose To analyse, using computational modelling, the physiological significance of non-culprit lesions included in the COMPLETE trial, to compare these against angiographic measures of severity, and investigate interactions between physiology and the benefits of complete revascularization. Methods Angiograms with appropriate digital imaging and communications in medicine (DICOM) data from the COMPLETE trial (n=1327) underwent software-based 3-dimensional (3D) arterial reconstruction and analysis of 3D-quantitative coronary angiography (QCA) and virtual fractional flow reserve (vFFR) using computational fluid dynamics software. Physiological lesion significance was defined as vFFR ≤0.80 and was compared with operators’ visual angiographic analysis, core-laboratory 2D-QCA and 3D-QCA. Results vFFR was computed successfully in 635 patients (710 lesions). The median vFFR was 0.82 (interquartile range 0.73–0.91). 302 patients (48%) had at least one physiologically significant lesion and 333 (52%) had none. 321 (45%) lesions were physiologically significant and 389 (55%) were not. Physiologically significant lesions were angiographically more severe than non-significant lesions according to the operator’s visual angiographic assessment (mean stenosis 80% vs. 75%, P&amp;lt;0.0001), 2D-QCA (69% vs. 59%, p&amp;lt;0.0001), and 3D-QCA (56% vs. 43, P&amp;lt;0.0001). Percentage lesion stenosis was significantly different when measured visually, with 2D-QCA and with 3D-QCA (80% vs 62% vs 49%, P&amp;lt;0.0001). vFFR was weakly correlated with operators’ visual angiographic severity (Figure 1) and 2D-QCA, but more strongly with 3D-QCA (r=-0.21, -0.21, and -0.60, respectively; all p&amp;lt;0.0001). 3D-QCA predicted vFFR significance more accurately than visual and 2D-QCA (concordance 73% vs 49% vs 59%, respectively). There was no statistically significant interaction between physiological lesion significance and any of the trial coprimary or key secondary clinical outcomes, or on an exploratory outcome of ischaemia-driven revascularization without preceding MI (all interactions P&amp;gt;0.30) (Figure 2). Conclusions In this virtual physiological substudy of the COMPLETE trial, 52% of patients lacked any physiologically-significant lesions, 3D-QCA was a better predictor of physiological significance than either 2D-QCA or operator visual analysis, and the benefits of complete revascularization appeared to be independent of physiological lesion significance. Further research is warranted to compare angiography-guided and physiology-guided complete revascularization strategies.Figure 1.Figure 2.

Associations of Cardiac myosin binding protein C to Troponin I in patients with chronic heart failure during exercise. A substudy of the SMARTEX-HF trial

Abstract Aim Cardiac myosin binding protein C (cMyC) has shown promise being more sensitive than cardiac troponins, rising faster after myocardial infarction[i]. Its association to hs-cTnI in heart failure patients during physical activity is not known. The aim of this study was to assess the association between a novel biomarker: cMyC and the clinically used high sensitivity cardiac Troponin I (hs-cTnI) during a 12-week exercise training program in patients with chronic symptomatic heart failure with reduced ejection fraction (HFrEF). The changes of biomarkers in plasma levels in an intervention group, performing structured exercise programs, were compared to those in a control group, instructed to perform regular recommended exercise (RRE) according to current guidelines. Methods and results This was a post hoc analysis of the SMARTEX-HF trial in 215 patients with symptomatic heart failure (HF) with Left Ventricular Ejection Fraction (LVEF) &amp;lt;35% and NYHA II-III. The patients were randomly assigned to High Intensity Interval Training (HIIT, n=77), Moderate Continuous Training (MCT, n=65) or RRE, (n=73) for 12 weeks. Measurements and clinical data were acquired before and after the 12-week intervention. In 191 patients, plasma was available for hs-cTnI testing and in 189 patients plasma was available for cMyC testing. Due to the lack of a normal distribution, the values were log transformed. There was a significant association of change in log hs-cTnI and change in log cMyC (Pearson correlation R=0.52 (95% CI 0.37- 0.66) p&amp;lt;0.001) (Figure 1). For any 10% increase in cMyC level, the ratio of the hs-cTnI level increased with approximately 5% (Figure 2). There was no association between the levels of cMyC at baseline and change in hs-cTnI at 12 weeks. Conclusion Changes in levels of the novel biomarker cMyC was significantly associated with hs-cTnI plasma levels in patients with symptomatic chronic HFrEF during a structured 12 week exercise training program. Being more sensitive, it may indicate a role as a future marker of subclinical myocardial damage.Models with adjustmentsMarginal effect at the mean

The effects of targeting mild hypercapnia on right ventricular function after out-of-hospital cardiac arrest. A sub-study of the TAME trial.

Abstract Background The Targeted Therapeutic Mild Hypercapnia After Resuscitated Cardiac Arrest (TAME) trial found similar neurological outcomes between mild hypercapnia and normocapnia in resuscitated out-of- hospital cardiac arrest (OHCA) patients. Hypercapnic acidosis can cause pulmonary vasoconstriction and aggravate right ventricular dysfunction, which is common and associated with worsened outcomes after OHCA. Purpose We investigated the effects of targeting mild hypercapnia on right ventricular function. Methods Single-centre, pre-planned and prospective sub-study. Comatose OHCA patients were randomised to targeted mild hypercapnia (PaCO2 =6.7–7.3 kPa) or targeted normocapnia (PaCO 2 =4.7- 6.0 kPa) for 24 hours. Transthoracic echocardiography was performed at baseline, during intervention and 48 hours after randomisation. Serial right heart catherisation (RHC) was performed if available. Results A total of 137 patients were randomised, 111 were evaluated with echocardiography and 52 and 59 randomised to mild hypercapnia and normocapnia, respectively. 84 patients received RHC; 41 and 43 in the hypercapnia and normocapnia-group, respectively. Overall, the median age was 64 years, 80 % were male and median time to ROSC was 22 minutes. Baseline characteristics did not differ significantly between treatments groups (p &amp;gt;0.05). Targeting mild hypercapnia was associated with lower tidal volumes, respiratory frequencies and respiratory acidosis (P-group &amp;lt; 0.05). Positive end-expiratory pressure, right atrial pressure, pulmonary vascular resistance index and pulmonary capillary wedge pressure were similar between groups (P-group &amp;gt; 0.05). Median time to echocardiography after randomisation was 21 (IQR 14-23) and 17 (IQR 9-22) hours in the hypercapnia and normocapnia-group, respectively. Tricuspid annular plane systolic excursion (TAPSE) was similar between treatment-groups at baseline and higher in the hypercapnia-group during the intervention with a median of 21 mm (IQR 18-23) versus 16 mm (IQR 13-21), p = 0.002. S', fractional area change (FAC) and the ratio of TAPSE to the pulmonary artery systolic pressure (PASP) were all higher in the hypercapnia-group during the intervention. Overall, median left ventricular ejection fraction was 45 % (IQR 38-55) without treatment group differences (p=0.2). Both invasive and echocardiographic assessment found increased cardiac index and stroke volumes in the hypercapnia-group (p &amp;lt;0.05). Right ventricular stroke work index (RVSWI) was consistently higher in the hypercapnia-group throughout the intervention (P-group &amp;lt; 0.001), while the pulmonary artery pulsatility index did not differ (P-group &amp;gt;0.05). Conclusions In patients resuscitated from OHCA, targeting mild hypercapnia compared to normocapnia was associated with increased TAPSE, S', FAC, TAPSE:PASP, RVSWI and cardiac index. Contrary to our prior concern these results indicate improved right ventricular function while targeting mild hypercapnia.

Combining fractional flow reserve and the index of microcirculatory resistance for prognosis prediction in renal artery stenosis interventions: a feasibility sub-study of FAIR-pilot trial

Abstract Background Interventional therapies for renal artery stenosis (RAS) was debatable in previous randomized trials. Fractional flow reserve (FFR), while useful in coronary interventions, does not assess microcirculatory status, which may be critical in RAS. The index of microcirculatory resistance (IMR) provides additional microvascular information, which has not been used in RAS patients. Purpose To investigate the feasibility of IMR measurement in RAS patients and the association with the outcome. Methods FAIR-pilot study is a multicenter pilot randomized controlled trial exploring the application of FFR to guide the renal artery stenting in patients with renovascular hypertension (NCT05732077). A pressure-temperature sensor guidewire was used to measure the IMR. To derive mean transit time at rest, thermodilution curves were obtained by 3 injections of 4 mL of room temperature saline down the renal artery. Hyperemia was induced using dopamine 50μg/kg bolus to the renal artery. The IMR was calculated as distal arterial pressure (Pd) x mean transit time during hyperemia (TmnH) (Figure 1). Prognostic evaluation was based on improvements in postoperative blood pressure, which was assessed using both ambulatory blood pressure monitor (ABPM) and anti-hypertensive medication number, along with renal function, as determined by the estimated glomerular filtration rate (eGFR). Results The IMR was measured among five patients enrolled in FAIR-pilot study. As shown in Table 1 and 2, stent implantation was conducted on five lesions across patients 1 to 4 based on renal FFR &amp;lt; 0.8, with each experiencing varying degrees of improved blood pressure control subsequently. Patient 5 did not receive a stent and was lost to follow-up. At three-month, the recorded decrease in systolic blood pressure ranged from a maximum of 34 mmHg to a minimum decrease of -6 mmHg among the four patients. The antihypertensive medication number showed a maximum reduction of 2 and no change as the minimum. We observed a correlation between baseline IMR and baseline renal function. No significant change in IMR was noted after interventional procedures. Preliminary findings suggest that IMR measurement is feasible in patients with RAS, while the ∆T (temperature change time) was very small, which potentially increasing the measurement bias. Conclusion The study suggests measuring IMR in patients with RAS is feasible and can offer information into the renal microvasculature. However, the small ∆T encountered during measurement may introduce increased bias, which should be considered when interpreting results.

Effect of alirocumab on coronary plaque stratified by atherothrombotic risks

Abstract Background Previous clinical studies have shown that high-risk subgroups including patients with major atherosclerotic cardiovascular disease (ASCVD) events and multiple atherothrombotic risk factors derive enhanced cardiovascular benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. To date, the effect of alirocumab on coronary plaque regression stratified by the number of atherothrombotic risk factors remains unknown. Purpose To investigate the utility of atherothrombotic risk stratification to identify patients with acute myocardial infarction (AMI) who have the greatest potential for benefit on plaque regression as assessed by intracoronary imaging from the addition of alirocumab to high-intensity statin therapy. Methods This was a substudy of the PACMAN trial, a randomized, double-blind trial comparing biweekly alirocumab (150 mg) versus placebo in AMI patients undergoing percutaneous coronary intervention. Intravascular ultrasound (IVUS) was serially performed in non-infarct-related coronary arteries at baseline and after 52 weeks. Atherothrombotic risk factors defined in the 2018 ACC/AHA cholesterol guidelines include myocardial infarction, ischemic stroke, peripheral artery disease, age ≥65 years, familial hypercholesterolemia, coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, LDL-C ≥100 mg/dL despite maximum tolerated statin therapy, and history of heart failure. The key endpoint was the change in IVUS-derived percent atheroma volume (PAV) from baseline to 52 weeks. Results A total of 263 patients available for serial IVUS data were analyzed for the current study. The most prevalent atherothrombotic risk factors were current smoking (49%), hypertension (43%), and age ≥65 years (24%). Patients were divided into 3 groups according to the number of risk factors (0 risk factor: n=52, 1 risk factor: n=101, ≥2 risk factors: n=100). Patients with risk factors had greater PAV at baseline compared with those with 0 risk factor (39.0% vs. 42.6% vs. 42.8%, P=0.008). The addition of Alirocumab to high-intensity statin therapy demonstrated a significant reduction in PAV among patients with 0 risk factor (-2.66% vs. -1.02%, P=0.009) and those with 1 risk factor (-2.36% vs. -0.76%, P&amp;lt;0.001) (Figure 1). In contrast, patients with ≥2 risk factors had no significant PAV reduction by alirocumab (-1.72% vs. -1.12%, P=0.076, P for interaction=0.009). Conclusions Among AMI patients with no or 1 atherothrombotic risk factor, the addition of alirocumab to high-intensity statin therapy demonstrated greater coronary plaque regression. Patients with fewer risk factors thus appear to be more susceptible for atheroma regression.Change in PAV stratified by risk factors

Coronary stent edge segments as determinant of clinical outcomes: An OCTOBER Trial Substudy

Abstract Background Small lumen dimensions and high plaque burden in stent edge segments are known risk factors for subsequent clinical events after percutaneous coronary intervention (PCI). The evidence using intravascular optical coherence tomography is scarce. Purpose This study aimed to characterize edge segments after PCI and the relation to clinical outcomes in the randomized OCTOBER trial on bifurcation PCI optimized using optical coherence tomography. Methods This is a predefined substudy of the OCTOBER Trial. Edge segments were analysed in detail for degree of stenosis and plaque composition using a dedicated software. Data was planned to be analysed using multi-level cox regression analysis, but descriptive statistics was applied due to very low event rates after OCT-guided PCI. Main endpoints were OCT-detected edge residual stenosis, lipid plaque, calcification, and dissections. Post PCI coronary angiography was analysed for diameter stenosis, edge segment length and minimal lumen diameter. Patients with cardiac events were diagnosed with angiography duringt the two-year follow-up period. Results A total of 597 patients were treated with OCT-guided PCI. Analysable final OCT scans with no additional treatment was available for 505 patients in the main vessel and for the side branch in 289 cases. At deadline for abstract submission 242 scans with 474 edges were analysed and included in preliminary results.Lesions with ≥30% diameter stenosis was found in 20% of proximal edges, 24% of distal edges and 37% of side branch (SB) edges. A plaque burdenOCT ≥180° was found in 74% of proximal edges, 48% of distal edges, and 52% of SB edges. A lipid plaque wafound in 35%, 11% and 14%, dissections in 15%, 6% and 12%, and ≥180° calcium was found in 7%, 4% and 4% of edges respectively. Six patients (1%) of the total OCT-guided population had an edge-related event during the median two-year follow-up. Only two of these 6 patients had post-procedural OCT-scans of the event-related edge, thus 4 of the cases were effectively angiographic guided. Conclusion Only a small fraction of edge segments in the OCTOBER Trial were left with residual edge disease exceeding protocol thresholds. This resulted in historically very low rate of edge related events. No evaluation of a stent edge by OCT in otherwise OCT guided patients appeared to be the main predictor of edge related events. Final results are presented at ESC 2024.

Effects of a 6-month aerobic exercise intervention on brain morphology in women with breast cancer receiving aromatase inhibitor therapy: a sub-study of the EPICC trial.

Physical exercise may increase brain volume and cortical thickness in late adulthood. However, few studies have examined the possibility for exercise to influence brain morphology in women treated for breast cancer. We conducted a nested sub-study within a randomized clinical trial to examine whether 6 months of moderate-intensity aerobic exercise in postmenopausal women with early-stage breast cancer influences brain morphology. We included twenty-eight postmenopausal women newly diagnosed with Stage 0-IIIa breast cancer (M age = 62.96 ± 5.40) who were randomized to either 45-60 min of supervised aerobic exercise 3 days/week (n = 16) or usual care (n = 12). Before beginning aromatase inhibitor aromatase inhibitor therapy, and the exercise intervention, and again at 6-month follow-up, volumetric and cortical thickness measures were derived from magnetic resonance imaging scans. There were no significant intervention effects on brain volume and cortical thickness. However, greater average exercise intensity (%) during the intervention was associated with greater post-intervention cortical volume, mean cortical thickness, precentral gyrus thickness, and superior parietal thickness (all p < 0.05). Finally, total supervised exercise time was associated with higher precentral gyrus thickness after the intervention (p = 0.042, R 2 = 0.263). The exercise intervention did not significantly affect brain volumes and cortical thickness compared to the control group. However, positive associations were found between exercise intensity and brain morphology changes after the 6-month intervention, indicating that exercise may reduce the vulnerability of the brain to the deleterious effects of breast cancer and its treatment.

Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Impact of ticagrelor with or without aspirin on total and recurrent bleeding and ischemic events after percutaneous coronary intervention: A sub-study of the TWILIGHT trial.

In standard time-to-first event analysis, early aspirin discontinuation followed by ticagrelor monotherapy has been shown to reduce bleeding without increasing ischemic complications compared with ticagrelor plus aspirin after percutaneous coronary intervention (PCI). We evaluated whether these treatment effects are preserved when recurrent events are considered. In this TWILIGHT trial post hoc analysis, we assessed the effects of ticagrelor monotherapy on the total number of events that occurred over the 12-month follow-up among 7 119 high-risk patients randomized to aspirin or placebo in addition to ticagrelor at 3 months post-PCI if event-free and adherent to treatment. There were 391 patients with at least one Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (primary endpoint). Of those, 28 (7.2%) had a recurrent event. The total number of BARC 2, 3, or 5 bleeding events were 148 in the ticagrelor monotherapy arm compared with 278 with ticagrelor plus aspirin arm (p<0.001). Among 272 patients with at least one key secondary ischemic endpoint (all-cause death, myocardial infarction, or stroke), 37 (13.6%) sustained a recurrent event. Total ischemic events were similar (155vs 159) in the two groups. Among selected high-risk patients who underwent PCI and completed 3 months of dual antiplatelet therapy followed by ticagrelor with or without aspirin, recurrent bleeding was less common than recurrent ischemic events over 12 months. Analysis of total events indicates that ticagrelor monotherapy continues to be more effective than ticagrelor plus aspirin in reducing bleeding without a signal of ischemic harm.

Effect of tocilizumab on endothelial and platelet-derived CXC-chemokines and their association with inflammation and myocardial injury in STEMI patients undergoing primary PCI

BackgroundTocilizumab improves myocardial salvage in ST-elevation myocardial infarction (STEMI) patients when administered before percutaneous coronary intervention (PCI). The mechanisms underlying ischemia-reperfusion injury remain unclear. In this sub-study, we investigated whether endothelial and platelet-derived CXC chemokines are involved, as they represent inflammatory mediators from two cell types relevant to myocardial infarction. Associations between these chemokines and neutrophils, C-reactive protein (CRP), troponin T (TnT), myocardial salvage index (MSI), microvascular obstruction (MVO), and infarct size. MethodsThis is a sub-study of the ASSAIL-MI trial, a double-blind clinical trial that randomized 199 STEMI patients to receive either 280 mg tocilizumab (n = 101) or placebo (n = 98) intravenously before PCI. Blood samples were collected prior to infusion, at day 1–2, 3–7, and at 3 and 6 months. Heparin was administered before baseline in 150 patients, while 49 received it after. We measured CXC-chemokines CXCL4, CXCL5, CXCL6, CXCL7, and CXCL12 using immunoassays. Cardiac MRI was performed in the first week and at 6 months. ResultsTocilizumab did not significantly affect CXC-chemokines levels. Although some correlations were observed between chemokine levels and neutrophil counts and CRP, none of the CXC chemokines were associated with infarct size, MSI, MVO, or TnT levels. Notably, CXCL 12 levels increased in patients who received heparin before baseline, while other CXC-chemokines decreased significantly. ConclusionThis study suggests that the beneficial effects of tocilizumab in STEMI patients are not due to changes in circulating endothelial or platelet-derived CXC-chemokines, compared to placebo. However, heparin significantly influences the levels of these chemokines.

Systemic pro-inflammatory response following bronchoscopic lung volume reduction using endobronchial valves

RationaleBronchoscopic lung volume reduction treatment using endobronchial valves (EBV) is an effective treatment for severe COPD patients by improving lung function and quality of life. However, little is known about its effects on systemic inflammation. Therefore, the aim of our study was to investigate whether EBV treatment impacts the inflammatory cytokine profile.MethodsThis study was a predefined substudy of the SoLVE trial (NCT03474471) that investigated the combination of EBV treatment with pulmonary rehabilitation (PR). The substudy included the collection of blood samples with assessment of 10 inflammatory markers prior to EBV treatment and 6 months after EBV or EBV+PR treatment.ResultsIn 66 patients, six months after treatment a pro-inflammatory cytokine profile was observed, with an increase in all pro-inflammatory markers and a decrease in the anti-inflammatory cytokine IL-10. The changes in plasma cytokine profile were not associated with changes in clinical outcomes such as lung function or exercise capacity.DiscussionIn conclusion, our study demonstrated an elevation in systemic pro-inflammatory cytokine levels following successful EBV-treatment, which was not associated with adverse clinical outcomes. It would be interesting to further explore, whether this increase is attributed to a foreign body response or if other factors contribute to this phenomenon.

A sub-study of the POISE-3 randomized trial examined effects of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of acute kidney injury

In this pre-specified sub-study of the POISE-3 trial, we examined the effect of a perioperative hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of postoperative acute kidney injury (AKI). Altogether, 7307 patients were included from 110 hospitals in 22 countries. Patients were 45 years and older, had or were at risk of atherosclerotic disease, took at least one antihypertensive medication, and were scheduled for noncardiac surgery. Hypotension-avoidance strategy: (i) target intraoperative mean arterial pressure (MAP) 80 mmHg or over, (ii) on day of surgery and for two days after, hold renin-angiotensin-aldosterone system inhibitors and use other antihypertensives in stepwise fashion if systolic blood pressure (SBP) 130 mmHg or more. Hypertension-avoidance strategy: (i) target intraoperative MAP 60 mmHg or more, (ii) continue all antihypertensives before and after surgery. Primary outcome: postoperative AKI, an increase in serum creatinine concentration of either 26.5 μmol/L or more (0.3 mg/dL or more) within 48 hours of randomization or 50% or more within seven days of randomization. The hypotension-avoidance group (3654 patients) used fewer antihypertensive medications than the hypertension-avoidance group (3653 patients); specifically, 6% vs. 38% used an ACEI or ARB on the day of surgery, and 6% vs. 47% and 7% vs. 50% one and two days after surgery, respectively. Patients also spent about half as much intraoperative time with a MAP under 80 mmHg (27 vs. 60 minutes, respectively), but had little difference in average BP before or after surgery. There was no significant difference in AKI risk (15.1% vs. 14.4%). Results were consistent with other definitions of AKI and in patients with preexisting chronic kidney disease. Thus, a hypotension-avoidance strategy targeting a MAP greater than 80 mmHg in the operating room and discontinued blood pressure medication during the perioperative period did not confer a lower risk of AKI compared to a hypertension avoidance strategy. Clinical trial registration number: NCT03505723.

TCT-455 Quantitative Coronary Dissection Volume After Sirolimus or Paclitaxel Coated Balloon and Lumen Changes at 6 Months: Serial OCT Sub-study of TRANSFORM-I Trial

TCT-455 Quantitative Coronary Dissection Volume After Sirolimus or Paclitaxel Coated Balloon and Lumen Changes at 6 Months: Serial OCT Sub-study of TRANSFORM-I Trial

Effects of a single oral dose of azithromycin in laboring women on antimicrobial resistance (AMR) and the microbiome: a protocol for the Antimicrobial Resistance Sub-Study of the A-PLUS trial

Background The Azithromycin Prevention in Labor Use Study (A-PLUS), a large, multi-national randomized trial, was performed to evaluate the improvement of maternal and newborn outcomes following a single dose of azithromycin (AZ) given during labor. However, the immediate and long-term impact of this single dose on the microbiome and the development or prevalence of antimicrobial resistance are unknown. We designed a sub-study to assess AZ resistance of bacterial isolates from clinical infections and of three target bacteria (Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli) from the serial surveillance of the nasopharynx and rectum. Additionally, the serially surveilled samples will be evaluated for changes to the microbiome and the resistome of the nasopharynx and rectum. Methods and Analysis As part of the large, randomized APLUS trial, maternal and neonatal clinical infections were monitored for up to 42 days postpartum, and samples collected for culture using site-specific routine methods. For this sub-study, cultured bacterial isolates will be assessed for AZ resistance using an antibiotic susceptibility method. Additionally, a random subset of maternal-neonatal dyads from the main trial will be selected for serial surveillance with aseptic swab collections of the nasopharynx and the rectum at baseline, and subsequently at 1-week, 6-weeks, 3-months, 6-months, and 12-months postpartum. The serial samples will undergo selective culturing of sentinel bacterial species and screened for AZ resistance. An additional set of serial samples will be stored for future microbiome and resistome analyses. Ethics and Dissemination The study protocol was reviewed, and ethics approval obtained from all the relevant ethical review boards at each research site. All participants will provide informed written consent prior to their enrollment. Results of the trial will be disseminated through peer-reviewed publications, presentations at relevant conferences, and at dissemination meetings with the ministries of health and local stakeholders at each research site. Trial Registration NCT03871491.

Exploring the Relationships Between Clinical Examination Findings, Subjective Reported Symptoms and Objective Nasal Patency Measures in Nasal Obstruction: A Baseline NAIROS Sub-Study Analysis.

The role of objective nasal airflow measures using peak nasal inspiratory flow (PNIF) and rhinospirometry in supporting clinical examination findings when offering patients septoplasty remain undefined. To explore the baseline relationships between clinical examination findings, subjective reported symptoms and objective nasal patency measures in nasal obstruction. This is a sub-study of the NAIROS trial. Participants with nasal obstruction secondary to septal deviation were included in this NAIROS sub-study. The side of septal deviation, enlargement of inferior turbinate (IT), the need for IT reduction if septoplasty was being performed, the area of septum deflecting into the airway and observer rated airway block (ORAB-arbitrarily divided by <50% and >50% blockage) were assessed by clinicians. The subjective score of nasal obstruction was assessed using the Double Ordinal Assessed Subjective Scale (DOASS). Objective nasal patency measures (e.g., nasal partitioning ratio, [NPR] and PNIF) were measured using PNIF and rhinospirometry. The mean NPR for left-sided, both-sided and right-sided septal deviation was -0.35, -0.02 and 0.51, respectively (p < 0.001). There was very weak correlation between the requirement for IT reduction and PNIF change (0.13, p < 0.01). There was no difference in mean PNIF (94 L/min vs. 93 L/min) and mean DOASS (0.33 vs. 0.38) for participants with ORAB rated <50% and >50%. The mean NPR for participants with ORAB >50% was higher than for those with ORAB <50% (0.51 vs. 0.41, p = 0.002). There was strong correlation between the DOASS and NPR (+0.737, p < 0.001). The mean DOASS score for right-sided, both-sided and left-sided septal deviation was 0.32, 0.05 and -0.29, respectively (p < 0.001). This study identified strong relationships between the clinician rated side of septal deflection, the patient reported DOASS and the objective NPR measurements. NPR and the clinician rated degree of airway blockage were concordant.

Evaluation of the analytical and clinical performance of a high-sensitivity troponin I point-of-care assay in the Mersey Acute Coronary Syndrome Rule Out Study (MACROS-2).

The objective of this study is to evaluate the analytical and diagnostic performance of a high-sensitivity point-of-care (POC) cardiac troponin I assay, the Quidel TriageTrue™ (QuidelOrtho Inc, San Diego, USA), compared to central laboratory testing (CLT) in accelerated diagnostic protocols (ADP) in real time in a clinical environment. In a nested sub-study of a pragmatic randomised control trial, consecutive patients with suspected acute coronary syndrome (ACS) and chest pain <12 h duration were randomised to the ESC 0/1 and 0/3-h ADP. Subjects underwent sampling for Quidel TriageTrue POC hs-TnI whole blood and plasma, CLT hs-TnT Roche Elecsys and a validated, NICE approved CLT High sensitivity cardiac troponin I (hs-TnI) (Siemens Attellica) at each time point. Assay imprecision was assessed by repeat analysis of whole blood samples at three levels (low, near 10 % CV 5-10 ng/L, medium, approximating 99th percentile 15-25 ng/L and high, 3-5 times the 99th percentile, 60-100 ng/L). Final diagnosis was adjudicated at 6weeks by Roche hs-TnT using the 4th universal definition of myocardial infarction (MI). A total of 1,157 patients consented and had both investigational POC whole blood and plasma and central lab hs-cTn available. The median age was 59, 47.2 % were female and 15 % had suffered a previous MI. Assay imprecision of whole blood POC TriageTrue revealed 10 % CV at 8.6 ng/L (>50 % lower than 99th percentile [20.5 ng/L]) and a 20 % CV at 1.2 ng/L. Receiver operator characteristics (ROC) curves were computed for each assay against adjudicated index type 1 MI to study clinical performance. At all-time points there were excellent performance for whole blood POC TriageTrue: area under the curve (AUC) 0.97 [95 % CI 0.94-098], 0.98 [95 % CI 0.97-1.00] and 0.95 [95 % CI 0.92-0.98] at time 0, 1 and 3 h respectively. There was statistical equivalence for performance of whole blood and plasma POC TriageTrue hs-TnI and laboratory Siemens Atellica hs-TnI. The whole blood POC TriageTrue hs-TnI assay demonstrates imprecision levels consistent with high sensitivity characteristics and has a clinical performance equivalent to an established, validated and NICE approved laboratory Siemens Atellica hs-TnI.

1764P Role of PIK3CA as a predictive biomarker in metastatic, imatinib-resistant GIST: A ct-DNA substudy of the VOYAGER trial

1764P Role of PIK3CA as a predictive biomarker in metastatic, imatinib-resistant GIST: A ct-DNA substudy of the VOYAGER trial

1880P Antiemetic prophylaxis during chemoradiation: Sub-study of the GAND-emesis trial identifying dosimetric predictors for vomiting

1880P Antiemetic prophylaxis during chemoradiation: Sub-study of the GAND-emesis trial identifying dosimetric predictors for vomiting

1219P Integrating artificial intelligence (AI)-based lymphocytic infiltration assessment in early stage NSCLC: A sub-study of the TNM-I trial

1219P Integrating artificial intelligence (AI)-based lymphocytic infiltration assessment in early stage NSCLC: A sub-study of the TNM-I trial