Combined Clinical Endpoint Research Articles

Early reduction of left atrial function predicts adverse clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement

AimsTo investigate the changes in left atrial strain (LAS) after correction of severe aortic stenosis (AS) with transcatheter aortic valve replacement (TAVR) and assess its prognostic impact.Methods and resultsOne hundred...

Impact of Anesthesia Strategy and Valve Type on Clinical Outcomes After Transcatheter Aortic Valve Replacement

BackgroundThe randomized SOLVE-TAVI (compariSon of secOnd-generation seLf-expandable vs. balloon-expandable Valves and gEneral vs. local anesthesia in Transcatheter Aortic Valve Implantation) trial compared newer-generation self-expanding valves (SEV) and balloon-expandable valves (BEV) as well as local anesthesia with conscious sedation (CS) and general anesthesia (GA) in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR). Both strategies showed similar outcomes at 30 days. ObjectivesThe purpose of this study was to compare clinical outcomes during 1-year follow-up in the randomized SOLVE-TAVI trial. MethodsUsing a 2 × 2 factorial design 447 intermediate- to high-risk patients with severe, symptomatic aortic stenosis were randomly assigned to transfemoral TAVR using either the SEV (Evolut R, Medtronic Inc., Minneapolis, Minnesota) or the BEV (Sapien 3, Edwards Lifesciences, Irvine, California) as well as CS or GA at 7 sites. ResultsIn the valve-comparison strategy, rates of the combined endpoint of all-cause mortality, stroke, moderate or severe paravalvular leakage, and permanent pacemaker implantation were similar between the BEV and SEV group (n = 84, 38.3% vs. n = 87, 40.4%; hazard ratio: 0.94; 95% confidence interval: 0.70 to 1.26; p = 0.66) at 1 year. Regarding the anesthesia comparison, the combined endpoint of all-cause mortality, stroke, myocardial infarction, and acute kidney injury occurred with similar rates in the GA and CS groups (n = 61, 25.7% vs. n = 54, 23.8%; hazard ratio: 1.09; 95% confidence interval: 0.76 to 1.57; p = 0.63). ConclusionsIn intermediate- to high-risk patients undergoing transfemoral TAVR, newer-generation SEV and BEV as well as CS and GA showed similar clinical outcomes at 1 year using a combined clinical endpoint. (SecOnd-generation seLf-expandable Versus Balloon-expandable Valves and gEneral Versus Local Anesthesia in TAVI [SOLVE-TAVI]; NCT02737150)

Endpoints for Perianal Crohn's Disease Trials: Past, Present and Future.

Since the 1980s, many studies have evaluated the efficacy of therapies to improve the outcomes of patients with perianal Crohn's disease. We performed a systematic review to describe the evolution of endpoints in perianal fistulizing Crohn's disease. Efficacy outcomes, definitions and measurement tools were assessed. Electronic databases were searched up to November 1, 2020. All published randomized placebo-controlled trials enrolling patients with perianal fistula and Crohn's disease were eligible for inclusion. Ongoing randomized clinical trials were also described. Nineteen randomized controlled trials were included. Clinical efficacy endpoints were reported in all trials. Clinical response was the most frequent primary endpoint [6/19 studies, 31.6%], followed by clinical remission in four studies [21%]. Clinical response was defined as closure of at least 50% of fistulas, while remission was defined as closure of all fistulas. A combined clinical and radiological primary endpoint was used to assess fistula healing in four studies [21%]. The Perianal Disease Activity Index was a primary endpoint in only one study [5.5%]. In addition, eight ongoing controlled trials were identified. Combined clinical and radiological remission was the most frequent primary endpoint in these studies [4/8, 50%]. In this systematic review, significant changes in outcomes used in randomized clinical trials of perianal Crohn's disease were observed. Radiological endpoints are increasingly used in perianal fistulizing Crohn's disease trials.

Prognostic Impact of Late Gadolinium Enhancement by Cardiovascular Magnetic Resonance in Myocarditis: A Systematic Review and Meta-Analysis.

Patients with acute myocarditis (AM) are at increased risk of adverse cardiac events after the index episode. Late gadolinium enhancement (LGE) detected by cardiovascular magnetic resonance in patients with AM plays an important diagnostic role, but its prognostic significance remains unresolved. This systematic review and meta-analysis sought to assess the prognostic implications of cardiovascular magnetic resonance-derived LGE in patients with AM. Data search was conducted from inception through February 28, 2020, using the following Medical Subject Heading terms: Myocarditis, CMR, Magnetic Resonance Imaging, Magnetic Resonance. From 2422 articles retrieved, we selected 11 studies reporting baseline cardiovascular magnetic resonance assessment and long-term clinical follow-up in patients with AM. Hazard ratios and CIs for a combined clinical end point were recorded for LGE presence, extent (>2 segments or >10% of left ventricular [LV] mass or >17g) and location (anteroseptal versus non-anteroseptal). A combined end point comprised all-cause mortality, cardiac mortality, and major adverse cardiovascular events. Hartung and Knapp correction improved robustness of the results. Prespecified sensitivity analyses explored potential sources of heterogeneity. The meta-analysis was conducted according to the Meta-analysis of Observational Studies in Epidemiology guidelines. LGE presence (pooled hazard ratios, 3.28 [95% CIs, 1.69-6.39], P<0.001 [95% CIs, 1.33-8.11] after Hartung and Knapp correction) and anteroseptal LGE (pooled-hazard ratios, 2.58 [95% CIs, 1.87-3.55], P<0.001 [95% CIs, 1.64-4.06] after Hartung and Knapp correction) were associated with an increased risk of the combined end point. Extensive LGE was associated with worse outcomes (pooled-hazard ratios, 1.96 [95% CIs, 1.08-3.56], P=0.027), but this association was not confirmed after Hartung and Knapp correction (95% CIs, 0.843-4.57). LGE presence and anteroseptal location at baseline cardiovascular magnetic resonance are important independent prognostic markers that herald an increased risk of adverse cardiac outcomes in patients with AM. Registration: https://www.crd.york.ac.uk/PROSPERO/ Unique identifier: CRD42019146619.

Prognostic value of multiparametric magnetic resonance imaging, transient elastography and blood-based fibrosis markers in patients with chronic liver disease.

Liver cT1 , liver T1 , transient elastography (TE) and blood-based biomarkers have independently been shown to predict clinical outcomes but have not been directly compared in a single cohort of patients. Our aim was to compare these tests' prognostic value in a cohort of patients with compensated chronic liver disease. Patients with unselected compensated liver disease aetiologies had baseline assessments and were followed up for development of clinical outcomes, blinded to the imaging results. The prognostic value of non-invasive liver tests at prespecified thresholds was assessed for a combined clinical endpoint comprising ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, liver transplantation and mortality. One hundred and ninety-seven patients (61% male) with median age of 54years were followed up for 693 patient-years (median (IQR) 43 (26-58) months). The main diagnoses were NAFLD (41%), viral hepatitis (VH, 25%) and alcohol-related liver disease (ArLD; 14%). During follow-up 14 new clinical events, and 11 deaths occurred. Clinical outcomes were predicted by liver cT1 >825ms with HR 9.9 (95% CI: 1.29-76.4, P=.007), TE>8kPa with HR 7.8 (95% CI: 0.97-62.3, P=.02) and FIB-4>1.45 with HR 4.09 (95% CI: 0.90-18.4, P=.05). In analysis taking into account technical failure and unreliability, liver cT1 >825ms could predict clinical outcomes (P=.03), but TE>8kPa could not (P=.4). We provide further evidence that liver cT1 , TE and serum-based biomarkers can predict clinical outcomes, but when taking into account technical failure/unreliability, TE cut-offs perform worse than those of cT1 and blood biomarkers.

Abstract 15815: Left Atrial Strain Characterizes the Atrio-ventricular Substrate Responsive to Cardiac Resynchronization Therapy in Patients With Intermediate Electrocardiographic Criteria

Introduction: Guidelines favor patient selection by left bundle branch block (LBBB) with QRS width ≥150 ms for cardiac resynchronization therapy (CRT). Predicting CRT response in patients with QRS width 120 to 149 ms or non-LBBB remains difficult. Left ventricular (LV) global longitudinal strain (GLS) and systolic stretch index (SSI) have shown to characterize the ventricular substrate responsive to CRT. However, the potential application of longitudinal left atrial (LA) strain remains unclear. Hypothesis: Baseline LA strain has prognostic value in CRT patients with intermediate ECG criteria. Methods: We studied 195 patients who underwent CRT based on routine indications: ejection fraction ≤35% and QRS width ≥120 ms. GLS was assessed using the 3 standard apical views. Radial SSI was derived from the mid LV short axis view. Peak longitudinal LA strain was derived from the 2 and 4-chamber apical view. The predefined combined clinical endpoint was death, heart transplant or left ventricular assist device over 4 years after CRT. Results: LA strain was feasible in 162 (83%) of the CRT candidates: QRS duration 156 ± 26 ms, 39.5% had LBBB with QRS ≥ 150ms, 60.5% had intermediate ECG criteria. High peak longitudinal strain (&gt;median, 10.1%) was associated with favorable event-free survival (p&lt;0.001). Patients with intermediate ECG criteria for CRT and both high peak longitudinal LA strain and high GLS (&gt;median, 8.4%) had similar outcome to those with Class I indications for CRT. Multivariable analysis revealed that LA strain had independent prognostic value (hazard ratio 0.9 per LA strain %, p &lt; 0.001) even after adjusted for other clinical, electrophysiological and echocardiographic covariates including QRS morphology and duration, GLS and SSI. Conclusions: Peak LA strain had important prognostic value in candidates for CRT. Prognostic value of LA strain was additive to LV strain characteristics and most significant in CRT patients with intermediate ECG criteria for CRT.

Impact of the dynamics of ejection fraction on risk stratification in a large multicenter registry of STEMI patients using sequential CMR

Abstract Background Left ventricular ejection fraction (LVEF) has traditionally been used as the cornerstone for risk stratification after ST-segment elevation myocardial infarction (STEMI) and it can be accurately quantified by cine cardiovascular magnetic resonance (CMR). In recent years, the additional prognostic value of contrast CMR-derived infarct size (IS) and microvascular obstruction (MVO) has been demonstrated. Purpose We explored the impact of sequential assessment of CMR-derived LVEF on dynamic risk stratification after STEMI. Methods Data were obtained from three prospective registries of reperfused STEMI patients (n=1036) in whom LVEF, IS and MVO were sequentially quantified by CMR (at least at 1 week and at 6 months). Major adverse cardiac events (MACE) were defined as a combined clinical end-point: death or re-admission for acute heart failure (HF), whichever occurred first. Late events were regarded as those occurring after the 6-month CMR. Results During a mean and median follow-up of 5 years, 105 first MACE (10%, 36 deaths and 69 HF) and 82 late MACE (8%, 35 deaths and 47 HF) were registered. From 1-week to 6-month CMR, LVEF improved (49±12 vs. 53±12%), IS decreased (21±14 vs 17±12% of LV mass) and MVO vanished (1.3±1.9 vs. 0.1±0.7% of LV mass), p&amp;lt;0.001 for all comparisons. At 1-week CMR, 207 patients (20%) displayed reduced LVEF (r-LVEF, &amp;lt;40%), 328 (32%) mid-range LVEF (mr-LVEF, 40–50%) and 501 (48%) preserved LVEF (p-LVEF, &amp;gt;50%). At 6-month CMR, 144 patients (14%) displayed r-LVEF, 247 (24%) mr-LVEF and 645 (62%) p-LVEF. The total MACE rate was higher (p&amp;lt;0.001) only in patients with r-LVEF at 1 week (22%) vs. 7% in those with mr-LVEF and 7% in those with p-LVEF. Similarly, the late MACE rate was higher (p&amp;lt;0.001) only in patients with r-LVEF at 6 months (20%) vs. 7% in those with mr-LVEF and 5% in those with p-LVEF. The late MACE rate was very low in patients with sustained mr- or p-LVEF (41/794, 5%), intermediate in those with improved LVEF from r-LVEF at 1 week to mr- or p-LVEF at 6 months (12/98, 12%) and high in patients with sustained r-LVEF (22/109, 20%) or worsened LVEF from mr- or p-LVEF at 1 week to r-LVEF at 6 months (7/35, 20%), p&amp;lt;0.001 for the trend. Using a Markov approach, only r-LVEF (at any time assessed) significantly related to a higher MACE rate. Conclusions Of available CMR parameters, LVEF persists as the pivotal index for simple post-STEMI risk stratification. Mid-range or preserved LVEF in acute phase associates with excellent long-term outcome. Changes in LVEF provide valuable dynamic prognostic information. Maintenance of mid-range or preserved LVEF in chronic phase occurs in the majority of patients and associates with a very low risk of late clinical events. Whereas late improvement reaching at least mid-range LVEF exerts salutary effects, detection of reduced LVEF at this point identifies the small subset of patients at high risk in the long term. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (PIE15/00013, PI17/01836, and CIBERCV16/11/00486 grants).

Strict compliance with ESC therapeutic guidelines after myocardial infarction treated with invasive strategy correlates with improved 18-month outcomes

Abstract Background Despite improved early outcomes in patients (pts) with acute myocardial infarction (MI) in Poland with prevalent strategy of primary angioplasty by radial access, mid- and long-term outcomes are unsatisfactory. Objective We hypothesized that strict implementation of secondary prevention ESC guidelines in post-infarction management may be related with improved mid-term clinical outcomes Methods We compared 18-month outcomes of pts treated for MI with primary invasive strategy in a tertiary university hospital (NSTEMI 470/47%, or STEMI 535/53%; N=1005; Gr-L) with similar subset from national databases AMI-PL and PL-ACS (N=117307; NSTEMI 50966/43%, STEMI 64078/57%; Gr-Pol). Females represented 38.5% / 35.7% of Gr-L/Gr-Pol and mean age was 66.1±11.5 vs 65.8±11.9% (NS). The center implemented a strict policy of optimization prognosis-modifying prescriptions at discharge according to ESC guidelines. Endpoints over 18-month follow-up were defined as total mortality and combined clinical endpoint (death, stroke, recurrent MI, recurrent revascularization). Results 30-days survival was comparable between Gr-L and national cohort. Key medicationrates were significantly higher for Gr-L vs most recent national estimates: renin-angiotensin blockers: 94% vs 79%, statins: 98% vs 75%, beta-blockers 95% vs 85%; ASA: 99% vs 94.5%, P2Y12 inhibitors 100% vs 83%. Rehabilitation was completed in 32% and 51% (after NSTEMI/STEMI) with national average around 20% - all differences p&amp;lt;0.05. Long-term mortality rate (overall 10.6% vs 14.5%, p=0.0005) and composite outcome rate was significantly improved in Gr-L – details shown in the table. Conclusions Outcomes of MI patients in primary PCI era are related to optimized medical therapy and rehabilitation planned at discharge. Our study does not prove causality but indicates on strong association of strict compliance with ESC guidelines and improved 18-month outcomes including overall survival. Funding Acknowledgement Type of funding source: None

Baseline left atrial strain is associated with clinical outcomes following cardiac resynchronization therapy in patients with intermediate electrocardiographic criteria

Abstract Background Guidelines favor patient selection by left bundle branch block (LBBB) with QRS width ≥150 ms for cardiac resynchronization therapy (CRT). However, predicting response to CRT patients with QRS width 120 to 149 ms or non-LBBB remains difficult. Speckle tracking left atrial (LA) strain is a novel means to assess cardiac function, however its applications to CRT patients remains unclear. Purpose To test the hypothesis that baseline LA strain has prognostic value in CRT patients with intermediate ECG criteria. Methods We studied 195 patients with heart failure (HF) who underwent CRT based on routine indications: ejection fraction ≤35% and QRS width ≥120 ms. GLS was assessed using the 3 standard apical views. LA longitudinal strain was based on 12 segments from the 2 and 4-chamber apical view. Peak LA strain, a measure associated with the reservoir function of the LA, was defined as the average of peak longitudinal strain from all segments. The predefined combined clinical endpoint was death, heart transplant or left ventricular assist device (LVAD) over 4 years after CRT. Results LA strain was feasible in 162 (83%) of the candidates for CRT: age 64±11 years, 72% male, QRS duration 156±26 ms, 39.5% had LBBB with QRS ≥150ms, 60.5% had intermediate ECG criteria. Median LA strain was 11.0% [1.3% - 36.8%]. High LA peak strain was associated with more favorable event-free survival and Low LA Peak strain was associated with worse clinical outcome following CRT (FIGURE, p&amp;lt;0.001). Patients with intermediate ECG criteria for CRT (non-LBBB or QRS width 120 to 149 ms) and high peak LA strain had similar outcome to those with Class I indications for CRT (LBBB and QRS≥150 ms). Multivariable analysis revealed that LA strain had independent prognostic value (hazard ratio 0.98 per LA strain %, p&amp;lt;0.01) even after adjusted for other clinical, electrophysiological and echocardiographic covariates including QRS morphology and duration, ischemic cardiomyopathy, LVEF and global longitudinal strain. Conclusions Baseline peak LA strain had important prognostic value in HF patients who are candidates for CRT. Prognostic value of LA strain was most significant in CRT patients with intermediate ECG criteria (QRS 120 to 149ms or non-LBBB) and has promise for clinical applications. LA strain and clinical outcome after CRT Funding Acknowledgement Type of funding source: None

Early neurological deterioration prediction in patients with hemorrhagic hemispheric stroke on the ground of quantitative evaluation of secondary interventricular hemorrhage severity

The early neurological deterioration criteria in patients with hemorrhagic hemispheric stroke (HHS) were elaborated on the ground of quantitative evaluation of secondary interventricular hemorrhage (IVH) severity. The prospective study with 339 patient’s involvement with the participation of patients with an average age (64.8±0.6) years old with spontaneous (hypertensive) supratentorial intracerebral hemorrhage. The diagnosis was made by brain computed tomography with quantitative evaluation of secondary intraventricular hemorrhage severity by using Graeb, Leroux and Intraventricular Hemorrhage (IVH). Early neurological deterioration (END) was taken as a combined clinical end-point. END was detected as one of the following criteria onset: reduction of the summary score according to Full Outline of UnResponsiveness coma scale &gt; 2; increasing of the summary score on National Institute of Health Stroke Scale &gt; 4; lethal outcome. Statistic processing of the results was made with the use of Mann-Whitney criteria and ROC-analysis. Combined clinical end-point was registered in 29.2 % cases. It was detected that patients with END are characterized with higher values of summary score according to Graeb (7 [4–8] vs 0 [0–4], p&lt;0.0001), Leroux (9 [5–12] vs 0 [0–5], p&lt;0.0001) and IVH scales (17 [13–20] vs 0 [0–12], p&lt;0.0001). While the mentioned scales do not differ in diagnostic informativeness when individual END detection prognosis in patients with HHS (AUC is 0.80-0.81). Summary score according to Graeb &gt; 5 (Se = 68.7%, Sp = 82.9%), Leroux &gt; 4 (Se = 76.8%, Sp = 74.6%) and IVH &gt; 13 (Se =72.7%, Sp = 80.8%) scales are predictors of END in patients with HHS. It was detected that in case of FOUR score &lt; 13, volume of intracerebral hemorrhage &gt; 40 ml and midline shift &gt; 5 mm, positive predictive value of these criteria exceeds 90%, while in general cohort – does not reach 65%. The threshold values of summary score in Graeb, Leroux and IVH scales are the informative criteria of END prognosis in patients with HHS. Keywords: hemorrhagic stroke, intraventricular hemorrhage, early neurological deterioration, prognosis.

Однонуклеотидний поліморфізм Val66Met (rs6265) гена мозкового нейротрофічного фактора в передбаченні кінцевих точок після інфаркту міокарда з елевацією сегмента ST

Мета роботи – дослідити асоціації між однонуклеотидним поліморфізмом (ОНП) Val66Met гена мозкового нейротрофічного фактора (brain-derived neurotropic factor, BDNF), іншими біомаркерами прогнозу та комбінованою клінічною серцевою точкою, що виникла протягом 6-місячного періоду спостереження в пацієнтів, які перенесли інфаркт міокарда з елевацією сегмента ST (ST-segment elevation myocardial infarction, STEMI).Матеріали і методи. У дослідження залучено 256 пацієнтів після успішного відновлення кровотоку на рівні TIMI III з приводу STEMI. Однонуклеотидний поліморфізм Val66Met гена BDNF визначали за допомогою ланцюгової реакції в реальному часі. Спостереження за хворими здійснювали протягом 6 міс.Результати та обговорення. Комбінована клінічна кінцева точка (великі серцево-судинні події та госпіталізація із серцево-судинних причин) виникла у 61 (23,8 %) пацієнта, у 195 (76,2 %) – ні. Частота ОНП Val66Met гена BDNF була такою: Val66Val – 74,2 % (n=190), Val66Met+Met66Met – 25,8 % (n=66). Не корегований мультиваріантний лінійний регресійний аналіз показав, що піковий рівень тропоніну І, вміст N-кінцевого фрагмента попередника мозкового натрійуретичного пептиду (NT-protein natriuretic peptide, NT-proBNP), шкали SYNTAX та TIMI, а також Val66Met+Met66Met генотип ОНП Val66Met гена BDNF були незалежними предикторами виникнення комбінованої клінічної кінцевої точки. Після корекції за шкалами SYNTAX та TIMI генотип Val66Met+Met66Met (відношення шансів 1,5476; 95 % довірчий інтервал 1,1277–4,1426; р=0,0246) та біомаркер NT-proBNP (відношення шансів 1,7546; 95 % довірчий інтервал 1,0219–3,1002; р=0,046) залишилися незалежними предикторами комбінованої клінічної кінцевої точки. Криві Каплана – Мейєра продемонстрували, що пацієнти – носії генотипу Val66Val мали нижчу акумуляцію комбінованої кінцевої точки порівняно з носіями генотипу Val66Met+Met66Met (Cox-критерій, р=0,019; log-rang критерій, р=0,03).Висновки. Однонуклеотидний поліморфізм Val66Met гена BDNF є незалежним предиктором комбінованої клінічної точки через 6 міс спостереження за пацієнтами, які перенесли STEMI.

Prednisone and azathioprine in patients with inflammatory cardiomyopathy: systematic review and meta-analysis.

AbstractAimsChronic non‐viral myocarditis, also called inflammatory cardiomyopathy, can be treated with immune suppression on tops of optimal medical therapy (OMT) for heart failure, using a combination of prednisolone and azathioprine (IPA). However, there has been inconsistency in the effects of immunosuppression treatment. This meta‐analysis is the first to evaluate all available data of the effect of this treatment on left ventricular ejection fraction (LVEF) and the combined clinical endpoint of cardiovascular mortality and/or heart transplantation‐free survival.Methods and resultsAll trials with using IPA vs. OMT in this syndrome were searched using OVID Medline and ClinicalTrials.gov, following the PRISMA guidelines. Missing data were retrieved after contacting the corresponding authors. All data was reviewed and analysed using and standard meta‐analysis methods. A random effect model was used to pool the effect sizes. A total of four trials (three randomised controlled trials and one propensity‐matched retrospective registry) including 369 patients were identified. IPA on top of OMT did not improve LVEF [mean difference 9.9% (95% confidence interval −1.8, 21.7)] with significant heterogeneity. When we limited our pooled estimate to the published studies only, significant LVEF improvement by IPA was observed [14% (1.4, 26.6)]. No cardiovascular mortality benefit was observed with the intervention [risk ratio 0.34 (0.08, 1.51)].ConclusionsAt the moment, there is insufficient evidence supporting functional and prognostic benefits of IPA added to OMT in virus negative inflammatory positive cardiomyopathy. Further adequate‐powered well‐designed prospective RCTs should be warranted to explore the potential effects of adding immunosuppressive therapy to OMT.

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss‐of‐function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate‐induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single‐nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on‐clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Subclinical emotional distress predicts 6-month clinical outcomes after ST-segment elevation myocardial infarction.

Aim: To investigate associations between subclinical distress and 6-month clinical outcomes after ST-segment elevation myocardial infarction(STEMI). Materials & methods: The case-control study involved 144 STEMI patients (72 STEMI having subclinical emotional disturbances were included to the case group and 72 STEMI individuals matched with age, sex and cardiovascular risk factors were enrolled to the control group). The primary end point was the combination of 6-month events including CV death, recurrent angina, newly diagnosed heart failure and re-hospitalization. Results: The emotional distress predicted out-hospital combined end point (odds ratio [OR] =2.48; 95% CI:1.12-5.33; p = 0.034). Other independent predictors of out-hospital end point were Type 2 diabetes mellitus (OR=1.10; 95% CI: 1.02-1.23; p = 0.048), thrombolysis in myocardial infarction score<6 units (OR=0.86; 95% CI:0.67-0.92; p = 0.001) and the number of culprit vessels (OR=1.19; 95% CI:1.02-1.34; p = 0.002). Conclusion: Premorbid emotional distress independently predicted 6 month combined clinical end point in STEMI patients.

The predictive value of vascular endothelial growth factor-A gene polymorphism for clinical outcomes among acute ST-segment elevation myocardial infarction patients: A single center prospective study

Background: Vascular endothelial growth factor (VEGF) is an angiopoetic factor; its variability in circulating levels is mediated by expression of specific VEGF-A gene variants. The aim of this study was to investigate the predictive role of VEGF-A gene polymorphism in clinical outcomes of STelevation myocardial infarction (STEMI) patients.&#x0D; Methods: For the study, 135 patients with acute STEMI and 30 healthy volunteers were enrolled. The G634C polymorphism in VEGF-A gene was performed by real-time polymerase chain reaction at baseline. The 6-month combined clinical endpoint was then determined. Design: The study was an open prospective single-center cohort study.&#x0D; Results: The entire patient population was distributed into two groups based on the G634G-genotype (n = 70) and combination of G634C and C634C-genotypes (n = 65). Unadjusted multivariate regressive logistic analysis showed peak troponin I levels at admission, Killip class of heart failure &gt; 2, GC/CC polymorphisms in VEGF-A gene, and dynamic increase of NT-pro brain natriuretic peptide (BNP) and VEGF-A levels for 6 months, which were independent predictors for the combined clinical endpoint. After adjustment for dynamic changes of NT-proBNP and VEGF-A levels, we found that GC/CC polymorphisms in the VEGF-A gene was an independent predictor of clinical outcome. Kaplan-Meier curves demonstrated that STEMI patients with GG VEGF-A genotype had a lower frequency of clinical combined endpoint accumulation when compared to those who had GC/CC VEGF-A genotypes (Log-rank p = 0.02).&#x0D; Conclusion: The G634C polymorphism in the VEGF-A gene was found to be an independent predictor for 6-month clinical combined endpoint in STEMI patients.

Clinical outcome following late reperfusion with percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction.

Up to 40% of patients with ST-segment elevation myocardial infarction (STEMI) present later than 12 hours after symptom onset. However, data on clinical outcomes in STEMI patients treated with primary percutaneous coronary intervention 12 or more hours after symptom onset are non-existent. We evaluated the association between primary percutaneous coronary intervention performed later than 12 hours after symptom onset and clinical outcomes in a large all-comer contemporary STEMI cohort. All STEMI patients treated with primary percutaneous coronary intervention in eastern Denmark from November 2009 to November 2016 were included and stratified by timing of the percutaneous coronary intervention. The combined clinical endpoint of all-cause mortality and hospitalisation for heart failure was identified from nationwide Danish registries. We included 6674 patients: 6108 (92%) were treated less than 12 hours and 566 (8%) were treated 12 or more hours after symptom onset. During a median follow-up period of 3.8 (interquartile range 2.3-5.6) years, 30-day, one-year and long-term cumulative rates of the combined endpoint were 11%, 17% and 25% in patients treated 12 or fewer hours and 21%, 29% and 37% in patients treated more than 12 hours (P<0.001 for all) after symptom onset. Late presentation was independently associated with an increased risk of an adverse clinical outcome (hazard ratio 1.42, 95% confidence interval 1.22-1.66; P<0.001). Increasing duration from symptom onset to primary percutaneous coronary intervention was associated with an increased risk of an adverse clinical outcome in patients with STEMI, especially when the delay exceeded 12 hours.

Bare metal or drug-eluting stent versus drug-coated balloon in non-ST-elevation myocardial infarction: the randomised PEPCAD NSTEMI trial.

Drug-coated balloons (DCB) may avoid stent-associated long-term complications. This trial compared the clinical outcomes of patients with non-ST-elevation myocardial infarction (NSTEMI) treated with either DCB or stents. A total of 210 patients with NSTEMI were enrolled in a randomised, controlled, non-inferiority multicentre trial comparing a paclitaxel iopromide-coated DCB with primary stent treatment. The main inclusion criterion was an identifiable culprit lesion without angiographic evidence of large thrombus. The primary endpoint was target lesion failure (TLF; combined clinical endpoint consisting of cardiac or unknown death, reinfarction, and target lesion revascularisation) after nine months. Secondary endpoints included total major adverse cardiovascular events (MACE) and individual clinical endpoints. Mean age was 67±12 years, 67% were male, 62% had multivessel disease, and 31% were diabetics. One hundred and four patients were randomised to DCB, 106 to stent treatment. In the stent group, 56% of patients were treated with BMS, 44% with current-generation DES. In the DCB group, 85% of patients were treated with DCB only whereas 15% underwent additional stent implantation. During a follow-up of 9.2±0.7 months, DCB treatment was non-inferior to stent treatment with a TLF rate of 3.8% versus 6.6% (intention-to-treat, p=0.53). There was no significant difference between BMS and current-generation DES. The total MACE rate was 6.7% for DCB versus 14.2% for stent treatment (p=0.11), and 5.9% versus 14.4% in the per protocol analysis (p=0.056), respectively. In patients with NSTEMI, treatment of coronary de novo lesions with DCB was non-inferior to stenting with BMS or DES. These data warrant further investigation of DCB in this setting, in larger trials with DES as comparator (ClinicalTrials.gov Identifier: NCT01489449).

Clinical characteristics, diagnosis, and risk stratification of pulmonary hypertension in severe tricuspid regurgitation and implications for transcatheter tricuspid valve repair.

Patients with pulmonary hypertension (PHT) are often excluded from surgical therapies for tricuspid regurgitation (TR). Transcatheter tricuspid valve repair (TTVR) with the MitraClip™ technique is a novel treatment option for these patients. We aimed to assess the role of PHT in severe TR and its implications for TTVR. A total of 243 patients underwent TTVR at two centres. One hundred twenty-one patients were grouped as iPHT+ [invasive systolic pulmonary artery pressures (PAPs) ≥50 mmHg]. Patients were similarly stratified according to echocardiographic PAPs (ePHT). The occurrence of the combined clinical endpoint (death, heart failure hospitalization, and reintervention) was investigated during a follow-up of 330 (interquartile range 175-402) days. iPHT+ patients were at higher preoperative risk (P < 0.01), had more severe symptoms (P = 0.01), higher N-terminal pro-B-type natriuretic peptide levels (P < 0.01), more impaired right ventricular (RV) function (P < 0.01), and afterload corrected RV function (P < 0.01). Procedural TTVR success was similar in iPHT+ and iPHT- patients (84 vs. 84%, P = 0.99). The echocardiographic diagnostic accuracy to detect iPHT was only 55%. During follow-up, 35% of patients reached the combined clinical endpoint. The discordant diagnosis of iPHT+/ePHT- carried the highest risk for the combined clinical endpoint [HR 3.76 (CI 2.25-6.37), P < 0.01], while iPHT+/ePHT+ patients had a similar survival-free time from the combined endpoint compared to iPHT- patients (P = 0.48). In patients with isolated tricuspid procedure (n = 131) a discordant iPHT+/ePHT- diagnosis and an impaired afterload corrected RV function (P < 0.01 for both) were independent predictors for the occurrence of the combined endpoint. The discordant echocardiographic and invasive diagnosis of PHT in severe TR predicts outcomes after TTVR.

Bioresorbable scaffold implantation in STEMI patients: 5\xa0years imaging subanalysis of PRAGUE-19 study

BackgroundBioresorbable scaffold (BRS) Absorb™ clinical use has been stopped due to higher rate of device thrombosis. Scaffold struts persist longer than 2 years in the vessel wall. Second generation devices are being developed. This study evaluates long-term invasive imaging in STEMI patients.MethodsPRAGUE-19 study is an academic study enrolling consecutive STEMI patients with intention to implant Absorb™ BRS. A total of 83 STEMI patients between December 2012 and March 2014 fulfilled entry criteria. Coronary angiography and optical coherence tomography at 5 year follow-up was performed in 25 patients.ResultsPrimary combined clinical endpoint (death, myocardial infarction or target vessel revascularization) occurred in 12.6% during the five-year follow-up with overall mortality 6.3%. Definite scaffold thrombosis occurred in 2 patients in the early phase after BRS implantation. Quantitative coronary angiography after 5 years demonstrated low late lumen loss of 0.11 ± 0.35 mm with binary restenosis rate of 0%. Optical coherence tomography demonstrated complete resorption of scaffold struts and mean lumen diameter of 3.25 ± 0.30 and 3.22 ± 0.49 (P = 0.73) at baseline and after 5 years, respectively. Three patients developed small coronary artery aneurysm in the treated segment.ConclusionInvasive imaging results 5 years after BRS implantation in STEMI showed complete resorption of scaffold struts and stable lumen vessel diameter.Trial registration ISRCTN43696201 (retrospectivelly registred, June 7th, 2019). https://www.isrctn.com/ISRCTN43696201.

Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients

Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8μg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.