Effects on Mortality and Major Bleeding of Radial Versus Femoral Artery Access for Coronary Angiography or Percutaneous Coronary Intervention: Meta-Analysis of Individual Patient Data From 7 Multicenter Randomized Clinical Trials.

BACKGROUND: In some randomized clinical trials, transradial access (TRA) compared with transfemoral access (TFA) was associated with lower mortality in patients with coronary artery disease undergoing invasive management. We analyzed the effects of TRA versus TFA across multicenter randomized clinical trials and whether these associations are modified by patient or procedural characteristics. METHODS: We performed an individual patient data meta-analysis of multicenter randomized clinical trials comparing TRA with TFA among patients undergoing coronary angiography with or without percutaneous coronary intervention. The primary outcome was all-cause mortality and the co-primary outcome was major bleeding at 30 days. The primary analysis was conducted by 1-stage mixed-effects models on the basis of the intention-to-treat cohort. The effect of access site on mortality and major bleeding was assessed further by multivariable analysis. The relationship among access site, bleeding, and mortality was investigated by natural effect model mediation analysis with multivariable adjustment. RESULTS: A total of 21 600 patients (10 775 TRA, 10 825 TFA) from 7 randomized clinical trials were included. The median age was 63.9 years, 31.9% were women, 95% presented with acute coronary syndrome, and 75.2% underwent percutaneous coronary intervention. All-cause mortality (1.6% versus 2.1%; hazard ratio, 0.77 [95% CI, 0.63-0.95]; P=0.012) and major bleeding (1.5% versus 2.7%; odds ratio, 0.55 [95% CI, 0.45-0.67]; P<0.001) were lower with TRA. Subgroup analyses for mortality showed consistent results, except for baseline hemoglobin level (Pinteraction=0.003), indicating that the benefit of TRA was substantial in patients with moderate or severe anemia, whereas it was not significant in patients with milder or no baseline anemia. After adjustment, TRA remained associated with 24% and 51% relative risk reduction of all-cause mortality and major bleeding, respectively. A mediation analysis showed that the benefit of TRA on mortality was only partially driven by major bleeding prevention and ancillary mechanisms are required to fully explain the causal association. CONCLUSIONS: TRA is associated with lower all-cause mortality and major bleeding at 30 days compared with TFA. The effect on mortality was driven by patients with anemia. The reduction in major bleeding only partially explains the mortality benefit. REGISTRATION: URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42018109664.

Periprocedural myocardial infarction in patients undergoing complex versus noncomplex percutaneous coronary intervention.

BACKGROUND: Limited data are available on the risk of periprocedural myocardial infarction (MI) in patients undergoing complex versus noncomplex percutaneous coronary intervention (PCI). METHODS: We assessed the risk of periprocedural MI according to the fourth Universal definition of myocardial infarction (UDMI) and several other criteria among patients undergoing elective PCI in a prospective, single-center registry. Complex PCI included at least one of the following: 3 coronary vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, treatment of chronic total occlusion, and use of rotational atherectomy. RESULTS: Between 2017 and 2021, we included 1010 patients with chronic coronary syndrome, of whom 226 underwent complex PCI (22.4%). The rate of periprocedural MI according to the fourth UDMI was significantly higher in complex compared to noncomplex PCI patients (26.5% vs. 14.5%, p < 0.001). Additionally, periprocedural MI was higher in the complex PCI group using SCAI (4% vs. 1.1%, p = 0.009), ARC-2 (13.7% vs. 8.0%, p = 0.013), ISCHEMIA (5.8% vs. 1.7%, p = 0.002), and EXCEL criteria (4.9% vs. 2.0%, p = 0.032). SYNTAX periprocedural MI occurred at low rates in both groups (0.9% vs. 0.6%, p = 0.657). Complex PCI was an independent predictor of the fourth UDMI periprocedural MI (odds ratio [OR] 1.54, 95% confidence interval [CI]: 1.04-2.27, p = 0.031). CONCLUSIONS: In patients with chronic coronary syndrome undergoing elective PCI, complex PCI is associated with a significantly higher risk of periprocedural MI using multiple definitions. These findings highlight the importance of considering upfront this risk in the planning of complex PCI procedures.

Platelet Inhibition with Ticagrelor 60 mg Versus 90 mg Twice Daily in Elderly Patients with Acute Coronary Syndrome: Rationale and Design of the PLINY THE ELDER Trial.

BACKGROUND: Elderly status is steadily increasing among patients with acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 receptor inhibitor is the cornerstone of treatment to prevent recurrent thrombotic complications in patients with ACS. However, DAPT in older patients is challenged by a concurrent heightened risk of ischemia and bleeding. The aim of this study is to evaluate the pharmacodynamic and pharmacokinetic profile of a lower dose of ticagrelor (60 mg twice daily) among elderly patients during the early phase of ACS. STUDY DESIGN: PLINY THE ELDER (PLatelet INhibition with two different doses of potent P2y12 inhibitors in THE ELDERly population) (NCT04739384) is a prospective, randomized, open-label, crossover trial to evaluate the non-inferiority of a lower dose of ticagrelor (60 mg twice daily) compared with a standard dose (90 mg twice daily) among elderly patients with ACS undergoing percutaneous coronary intervention (PCI). A total of 50 patients, aged 75 years or more, with indication to potent P2Y12 receptor inhibitors will be randomized within 3 days from PCI for the index ACS. Patients with indication to oral anticoagulant therapy, treatment with glycoprotein IIb/IIIa inhibitors, or active bleeding will be excluded. The primary endpoint is platelet reactivity determined by P2Y12 reaction units (PRU) (VerifyNow, Accumetrics, San Diego, CA, USA) after treatment with ticagrelor 60 or 90 mg twice daily for 14 days. Secondary endpoints will include other pharmacodynamic tests of ADP-induced aggregation (light transmittance aggregometry and multiple electrode aggregometry) and determination of pharmacokinetic profile (plasma levels of ticagrelor and its metabolite AR-C124910XX) by high performance liquid chromatography-tandem mass spectrometry. CONCLUSIONS: The PLINY THE ELDER trial will determine whether a lower dose of ticagrelor confers non-inferior platelet inhibition compared with the standard dose in the early phase of ACS among elderly patients undergoing PCI, informing future clinical investigation.

Short dual antiplatelet therapy followed by P2Y12 inhibitor monotherapy vs. prolonged dual antiplatelet therapy after percutaneous coronary intervention with second-generation drug-eluting stents: a systematic review and meta-analysis of randomized clinical trials.

AIMS: After percutaneous coronary intervention (PCI) with second-generation drug-eluting stent (DES), whether short dual antiplatelet therapy (DAPT) followed by single antiplatelet therapy (SAPT) with a P2Y12 receptor inhibitor confers benefits compared with prolonged DAPT is unclear. METHODS AND RESULTS: Multiple electronic databases, including PubMed, Scopus, Web of Sciences, Ovid, and ScienceDirect, were searched to identify randomized clinical trials comparing ≤3 months of DAPT followed by P2Y12 inhibitor SAPT vs. 12 months of DAPT after PCI with second-generation DES implantation. The primary and co-primary outcomes of interest were major bleeding and stent thrombosis 1 year after randomization. Summary hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fixed-effect and random-effects models. Multiple sensitivity analyses including random-effects models 95% CI adjustment were applied. A sensitivity analysis comparing trials using P2Y12 inhibitor SAPT with those using aspirin SAPT was performed. A total of five randomized clinical trials (32 145 patients) were available. Major bleeding was significantly lower in the patients assigned to short DAPT followed by P2Y12 inhibitor SAPT compared with those assigned to 12-month DAPT (random-effects model: HR 0.63, 95% 0.45-0.86). No significant differences between groups were observed in terms of stent thrombosis (random-effects model: HR 1.19, 95% CI 0.86-1.65) and the secondary endpoints of all-cause death (random-effects model: HR 0.85, 95% CI 0.70-1.03), myocardial infarction (random-effects model: HR 1.05, 95% CI 0.89-1.23), and stroke (random-effects model: HR 1.08, 95% CI 0.68-1.74). Sensitivity analyses showed overall consistent results. By comparing trials testing ≤3 months of DAPT followed by P2Y12 inhibitor SAPT vs. 12 months of DAPT with trials testing ≤3 months of DAPT followed by aspirin SAPT vs. 12-month of DAPT, there was no treatment-by-subgroup interaction for each endpoint. By combining all these trials, regardless of the type of SAPT, short DAPT was associated with lower major bleeding (random-effects model: HR 0.63, 95% CI 0.48-0.83) and no differences in stent thrombosis, all-cause death, myocardial infarction, and stroke were observed between regimens. CONCLUSION: After second-generation DES implantation, 1-3 months of DAPT followed by P2Y12 inhibitor SAPT is associated with lower major bleeding and similar stent thrombosis, all-cause death, myocardial infarction, and stroke compared with prolonged DAPT. Whether P2Y12 inhibitor SAPT is preferable to aspirin SAPT needs further investigation.

Cangrelor, Tirofiban, and Chewed or Standard Prasugrel Regimens in Patients With ST-Segment-Elevation Myocardial Infarction: Primary Results of the FABOLUS-FASTER Trial.

BACKGROUND: Standard administration of newer oral P2Y12 inhibitors, including prasugrel or ticagrelor, provides suboptimal early inhibition of platelet aggregation (IPA) in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention. We aimed to investigate the effects of cangrelor, tirofiban, and prasugrel, administered as chewed or integral loading dose, on IPA in patients undergoing primary percutaneous coronary intervention. METHODS: The FABOLUS-FASTER trial (Facilitation Through Aggrastat or Cangrelor Bolus and Infusion Over Prasugrel: A Multicenter Randomized Open-Label Trial in Patients with ST-Elevation Myocardial Infarction Referred for Primary Percutaneous Intervention) is an investigator-initiated, multicenter, open-label, randomized study. A total of 122 P2Y12-naive patients with ST-segment-elevation myocardial infarction were randomly allocated (1:1:1) to cangrelor (n=40), tirofiban (n=40) (both administered as bolus and 2-hour infusion followed by 60 mg of prasugrel), or 60-mg loading dose of prasugrel (n=42). The latter group underwent an immediate 1:1 subrandomization to chewed (n=21) or integral (n=21) tablets administration. The trial was powered to test 3 hypotheses (noninferiority of cangrelor compared with tirofiban using a noninferiority margin of 9%, superiority of both tirofiban and cangrelor compared with chewed prasugrel, and superiority of chewed prasugrel as compared with integral prasugrel, each with α=0.016 for the primary end point, which was 30-minute IPA at light transmittance aggregometry in response to 20 µmol/L adenosine diphosphate. RESULTS: At 30 minutes, cangrelor did not satisfy noninferiority compared with tirofiban, which yielded superior IPA over cangrelor (95.0±8.9 versus 34.1±22.5; P<0.001). Cangrelor or tirofiban were both superior to chewed prasugrel (IPA, 10.5±11.0; P<0.001 for both comparisons), which did not provide higher IPA over integral prasugrel (6.3±11.4; P=0.47), despite yielding higher prasugrel active metabolite concentration (ng/mL; 62.3±82.6 versus 17.1±43.5; P=0.016). CONCLUSIONS: Cangrelor provided inferior IPA compared with tirofiban; both treatments yielded greater IPA compared with chewed prasugrel, which led to higher active metabolite concentration but not greater IPA compared with integral prasugrel. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02978040; URL: https://www.clinicaltrialsregister.eu; EudraCT 2017-001065-24.

Single, Dual, and Triple Antithrombotic Therapy in Cancer Patients with Coronary Artery Disease: Searching for Evidence and Personalized Approaches.

Improvement in life expectancy of patients suffering from oncohematologic disorders has turned cancer from an acute into a chronic condition, making the management of comorbidities problematic, especially when it comes to both acute and chronic cardiovascular diseases. Treatment-related adverse events and drug-drug interactions often influence the therapeutic approach of patients with active malignancies and cardiovascular disease. Furthermore, tumor cells and platelets maintain a complex crosstalk that on one hand enhances tumor dissemination and on the other hand induces hemostasis abnormalities. Hence, clinicians should move carefully in the intricate land mines established by patients with active cancer under antithrombotic therapy. To date, there is no consensus on the antithrombotic treatment of patients with cardiovascular diseases and concomitant malignancies. The aim of this review is to collect the available scientific evidence, including the latest clinical trials and guidelines, in order to provide guidance on the management of antithrombotic treatment (both antiplatelet and anticoagulant therapy) in cancer patients with either pre-existent or new-onset coronary artery disease. Randomized-controlled trials on antithrombotic treatment in oncologic populations, which by far have thus far been excluded, have to be promoted to supply recommendations in the oncohematologic setting.

Validation of high bleeding risk criteria and definition as proposed by the academic research consortium for high bleeding risk.

AIMS: To validate the set of clinical and biochemical criteria proposed by consensus by the Academic Research Consortium (ARC) for High Bleeding Risk (HBR) for the identification of HBR patients. These criteria were categorized into major and minor, if expected to carry in isolation, respectively, ≥4% and <4% Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding risk within 1-year after percutaneous coronary intervention (PCI). High bleeding risk patients are those meeting at least 1 major or 2 minor criteria. METHODS AND RESULTS: All patients undergoing PCI at Bern University Hospital, between February 2009 and September 2018 were prospectively entered into the Bern PCI Registry (NCT02241291). Age, haemoglobin, platelet count, creatinine, and use of oral anticoagulation were prospectively collected, while the remaining HBR criteria except for planned surgery were retrospectively adjudicated. A total of 16 580 participants with complete ARC-HBR criteria were included. After assigning 1 point to each major and 0.5 point to each minor criterion, we observed for every 0.5 score increase a step-wise augmentation of BARC 3 or 5 bleeding rates at 1 year ranging from 1.90% among patients fulfilling no criterion, through 4.01%, 5.98%, 7.42%, 8.60%, 12.21%, 12.29%, and 17.64%. All major and five out of six minor criteria, conferred in isolation a risk for BARC 3 or 5 bleeding at 1 year exceeding 4% at the upper limit of the 95% confidence intervals. CONCLUSION: All major and the majority of minor ARC-HBR criteria identify in isolation patients at HBR.

Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.

BACKGROUND: We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS: ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS: From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION: In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING: Daiichi Sankyo.

Impact of diabetes mellitus on clinical outcomes in patients affected by Covid-19.

A possible association could exist between type 2 diabetes mellitus (T2DM) and Coronavirus-19 (Covid-19) infection. Indeed, patients with T2DM show high prevalence, severity of disease and mortality during Covid-19 infection. However, the rates of severe disease are significantly higher in patients with diabetes compared with non-diabetes (34.6% vs. 14.2%; p < 0.001). Similarly, T2DM patients have higher rates of need for Intensive Care Unit (ICU, 37.0% vs. 26.7%; p = 0.028). Thus, about the pneumonia of Covid-19, we might speculate that the complicated alveolar-capillary network of lungs could be targeted by T2DM micro-vascular damage. Therefore, T2DM patients frequently report respiratory symptoms and are at increased risk of several pulmonary diseases. In addition, pro-inflammatory pathways as that involving interleukin 6 (IL-6), could be a severity predictor of lung diseases. Therefore, it looks intuitive to speculate that this condition could explain the growing trend of cases, hospitalization and mortality for patients with T2DM during Covid-19 infection. To date, an ongoing experimental therapy with monoclonal antibody against the IL-6 receptor in Italy seems to have beneficial effects on severe lung disease and prognosis in patients with Covid-19 infection. Therefore, should patients with T2DM be treated with more attention to glycemic control and monoclonal antibody against the IL-6 receptor during the Covid-19 infection?

Safety and efficacy outcomes of double vs. triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention: a systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials.

AIMS: To investigate the safety and efficacy of double vs. triple antithrombotic therapy (DAT vs. TAT) in patients with atrial fibrillation (AF) and acute coronary syndrome or who underwent percutaneous coronary intervention (PCI). METHODS AND RESULTS: A systematic review and meta-analysis was performed using PubMed to search for non-vitamin K antagonist oral anticoagulant (NOAC)-based randomized clinical trials comparing DAT vs. TAT in AF patients undergoing PCI. Four trials encompassing 10 234 patients (DAT = 5496 vs. TAT = 4738) were included. The primary safety endpoint (ISTH major or clinically relevant non-major bleeding) was significantly lower with DAT compared with TAT [risk ratio (RR) 0.66, 95% confidence interval (CI) 0.56-0.78; P < 0.0001; I2 = 69%], which was consistent across all available bleeding definitions. This benefit was counterbalanced by a significant increase of stent thrombosis (RR 1.59, 95% CI 1.01-2.50; P = 0.04; I2 = 0%) and a trend towards higher risk of myocardial infarction with DAT. There were no significant differences in all-cause and cardiovascular death, stroke and major adverse cardiovascular events. The comparison of NOAC-based DAT vs. vitamin K antagonist (VKA)-TAT yielded consistent results and a significant reduction of intracranial haemorrhage (RR 0.33, 95% CI 0.17-0.65; P = 0.001; I2 = 0%). CONCLUSION: Double antithrombotic therapy, particularly if consisting of a NOAC instead of VKA and a P2Y12 inhibitor, is associated with a reduction of bleeding, including major and intracranial haemorrhages. This benefit is however counterbalanced by a higher risk of cardiac-mainly stent-related-but not cerebrovascular ischaemic occurrences.

The Impact of Drosophila Awd/NME1/2 Levels on Notch and Wg Signaling Pathways.

Awd, the Drosophila homologue of NME1/2 metastasis suppressors, plays key roles in many signaling pathways. Mosaic analysis of the null awdJ2A4 allele showed that loss of awd gene function blocks Notch signaling and the expression of its target genes including the Wingless (Wg/Wnt1) morphogen. We also showed that RNA interference (RNAi)-mediated awd silencing (awdi) in larval wing disc leads to chromosomal instability (CIN) and to Jun amino-terminal kinases (JNK)-mediated cell death. Here we show that this cell death is independent of p53 activity. Based on our previous finding showing that forced survival of awdi-CIN cells leads to aneuploidy without the hyperproliferative effect, we investigated the Wg expression in awdi wing disc cells. Interestingly, the Wg protein is expressed in its correct dorso-ventral domain but shows an altered cellular distribution which impairs its signaling. Further, we show that RNAi-mediated knock down of awd in wing discs does not affect Notch signaling. Thus, our analysis of the hypomorphic phenotype arising from awd downregulation uncovers a dose-dependent effect of Awd in Notch and Wg signaling.

SGLT2 inhibition to address the unmet needs in diabetic nephropathy.

Current treatment of diabetic nephropathy is effective; however, substantial gaps in care still remain and new therapies are urgently needed to reduce the global burden of the complication. Desirable properties of an "ideal" new drug should include primary prevention of microalbuminuria, additive/synergistic anti-proteinuric effect in combination therapy with renin angiotensin system blockers, reduction of chronic kidney disease progression to lower the risk of end-stage renal disease, and cardiovascular protection. Growing evidence suggests that sodium-glucose cotransporter 2 inhibitors (SGLT2i) may fulfil many of these criteria and represent novel tools to cover the unmet needs in diabetic nephropathy care. However, the underlying mechanisms of SGLT2i renal benefits are still poorly understood and promising results from cardiovascular outcome trials with SGLT2i need confirmation in dedicated renal outcome trials.

ECG analysis in patients with acute coronary syndrome undergoing invasive management: rationale and design of the electrocardiography sub-study of the MATRIX trial.

BACKGROUND: The twelve­lead electrocardiogram (ECG) has become an essential tool for the diagnosis, risk stratification, and management of patients with acute coronary syndromes (ACS). However, several areas of residual controversies or gaps in evidence exist. Among them, P-wave abnormalities identifying atrial ischemia/infarction are largely neglected in clinical practice, and their diagnostic and prognostic implications remain elusive; the value of ECG to identify the culprit lesion has been investigated, but validated criteria indicating the presence of coronary occlusion in patients without ST-elevation are lacking; finally, which criteria among the multiple proposed, better define pathological Q-waves or success of revascularisation deserve further investigations. METHODS: The Minimizing Adverse hemorrhagic events via TRansradial access site and systemic Implementation of AngioX (MATRIX) trial was designed to test the impact of bleeding avoidance strategies on ischemic and bleeding outcomes across the whole spectrum of patients with ACS receiving invasive management. The ECG-MATRIX is a pre-specified sub-study of the MATRIX programme which aims at analyzing the clinical value of ECG metrics in 4516 ACS patients (with and without ST-segment elevation in 2212 and 2304 cases, respectively) with matched pre and post-treatment ECGs. CONCLUSIONS: This study represents a unique opportunity to further investigate the role of ECGs in the diagnosis and risk stratification of ACS patients with or without ST-segment deviation, as well as to assess whether the radial approach and bivalirudin may affect post-treatment ECG metrics and patterns in a large contemporary ACS population.

Extracellular NME proteins: a player or a bystander?

The Nm23/NME gene family has been under intensive study since Nm23H1/NME1 was identified as the first metastasis suppressor. Inverse correlation between the expression levels of NME1/2 and prognosis has indeed been demonstrated in different tumor cohorts. Interestingly, the presence of NME proteins in the extracellular environment in normal and tumoral conditions has also been noted. In many reported cases, however, these extracellular NME proteins exhibit anti-differentiation or oncogenic functions, contradicting their canonical anti-metastatic action. This emerging field thus warrants further investigation. In this review, we summarize the current understanding of extracellular NME proteins. A role in promoting stem cell pluripotency and inducing development of central nervous system as well as a neuroprotective function of extracellular NME have been suggested. Moreover, a tumor-promoting function of extracellular NME also emerged at least in some tumor cohorts. In this complex scenario, the secretory mechanism through which NME proteins exit cells is far from being understood. Recently, some evidence obtained in the Drosophila and cancer cell line models points to the involvement of Dynamin in controlling the balance between intra- and extracellular levels of NME. Further analyses on extracellular NME will lead to a better understanding of its physiological function and in turn will allow understanding of how its deregulation contributes to carcinogenesis.

Use of the Dual-Antiplatelet Therapy Score to Guide Treatment Duration After Percutaneous Coronary Intervention.

BACKGROUND: The dual-antiplatelet therapy (DAPT) score was developed to identify patients more likely to derive harm (score <2) or benefit (score ≥2) from prolonged DAPT after percutaneous coronary intervention (PCI). OBJECTIVE: To evaluate the safety and efficacy of DAPT duration according to DAPT score. DESIGN: Retrospective assessment of DAPT score-guided treatment duration in a randomized clinical trial. (ClinicalTrials.gov: NCT00611286). SETTING: PCI patients. PATIENTS: 1970 patients undergoing PCI. INTERVENTION: DAPT (aspirin and clopidogrel) for 24 versus 6 months. MEASUREMENTS: Primary efficacy outcomes were death, myocardial infarction, or cerebrovascular accident. The primary safety outcome was type 3 or 5 bleeding according to the Bleeding Academic Research Consortium definition. Outcomes were assessed between 6 and 24 months. RESULTS: 884 patients (44.9%) had a DAPT score of at least 2, and 1086 (55.1%) had a score less than 2. The reduction in the primary efficacy outcome with 24- versus 6-month DAPT was greater in patients with high scores (risk difference [RD] for score ≥2, -2.05 percentage points [95% CI, -5.04 to 0.95 percentage points]; RD for score <2, 2.91 percentage points [CI, -0.43 to 6.25 percentage points]; P = 0.030). However, the difference by score for the primary efficacy outcome varied by stent type; prolonged DAPT with high scores was effective only in patients receiving paclitaxel-eluting stents (RD, -7.55 percentage points [CI, -12.85 to -2.25 percentage points]). The increase in the primary safety outcome with 24- versus 6-month DAPT was greater in patients with low scores (RD for score ≥2, 0.20 percentage point [CI, -1.20 to 1.60 percentage points]; RD for score <2, 2.58 percentage points [CI, 0.71 to 4.46 percentage points]; P = 0.046). LIMITATION: Retrospective calculation of the DAPT score. CONCLUSION: Prolonged DAPT resulted in harm in patients with low DAPT scores undergoing PCI but reduced risk for ischemic events in patients with high scores receiving paclitaxel-eluting stents. Whether prolonged DAPT benefits patients with high scores treated with contemporary drug-eluting stents requires further study. PRIMARY FUNDING SOURCE: None.

Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis.

AIMS: Gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) is emerging as a new potentially important cause of increased cardiovascular risk. The purpose of this meta-analysis was to systematically estimate and quantify the association between TMAO plasma levels, mortality, and major adverse cardio and cerebrovascular events (MACCE). METHODS AND RESULTS: MEDLINE, ISI Web of Science, and SCOPUS databases were searched for ad hoc studies published up to April 2017. Associations between TMAO plasma levels, all-cause mortality (primary outcome) and MACCE (secondary outcome) were systematically addressed. A total of 17 clinical studies were included in the analytic synthesis, enrolling 26 167 subjects. The mean follow-up in our study population was 4.3 ± 1.5 years. High TMAO plasma levels were associated with increased incidence of all-cause mortality [14 studies for 16 cohorts enrolling 15 662 subjects, hazard ratio (HR): 1.91; 95% confidence interval (CI): 1.40-2.61, P < 0.0001, I2 = 94%] and MACCE (5 studies for 6 cohorts enrolling 13 944 subjects, HR: 1.67, 95% CI: 1.33-2.11, P < 0.00001, I2 = 46%,). Dose-response meta-analysis revealed that the relative risk (RR) for all-cause mortality increased by 7.6% per each 10 µmol/L increment of TMAO [summary RR: 1.07, 95% CI (1.04-1.11), P < 0.0001; based on seven studies]. Association of TMAO and mortality persisted in all examined subgroups and across all subject populations. CONCLUSIONS: This is the first systematic review and meta-analysis demonstrating the positive dose-dependent association between TMAO plasma levels and increased cardiovascular risk and mortality.

Drosophila 4EHP is essential for the larval-pupal transition and required in the prothoracic gland for ecdysone biosynthesis.

Maternal expression of the translational regulator 4EHP (eIF4E-Homologous Protein) has an established role in generating protein gradients essential for specifying the Drosophila embryonic pattern. We generated a null mutation of 4EHP, which revealed for the first time that it is essential for viability and for completion of development. In fact, 4EHP null larvae, and larvae ubiquitously expressing RNAi targeting 4EHP, are developmentally delayed, fail to grow and eventually die. In addition, we found that expressing RNAi that targets 4EHP specifically in the prothoracic gland disrupted ecdysone biosynthesis, causing a block of the transition from the larval to pupal stages. This phenotype can be rescued by dietary administration of ecdysone. Consistent with this, 4EHP is highly expressed in the prothoracic gland and it is required for wild type expression levels of steroidogenic enzymes. Taken together, these results uncover a novel essential function for 4EHP in regulating ecdysone biosynthesis.

A Critical Appraisal of Aspirin in Secondary Prevention: Is Less More?

Aspirin represents the sine qua non for antiplatelet pharmacotherapy in patients with cardiovascular diseases because of its well-established role in secondary prevention and its widespread availability and affordability. Historical studies, conducted in an era that bears little resemblance to contemporary clinical practice, demonstrated large reductions in thrombotic risk when aspirin was compared with placebo, thus forming the evidence base promulgated in practice guidelines and recommendations. P2Y12 inhibitors have mostly been studied in addition to aspirin; dual-antiplatelet therapy proved superiority compared with aspirin monotherapy for the prevention of ischemic events, despite increased bleeding risks. An alternative approach currently under investigation includes evaluation of single-antiplatelet therapy with P2Y12 inhibitors alone versus dual-antiplatelet therapy after acute coronary syndromes or coronary stent implantation. As the availability of more effective antiplatelet agents increases, it is time to revisit the existing and long-standing paradigm supporting aspirin use for secondary prevention of atherothrombotic events. Ongoing trials will provide new evidence whether the less-is-more strategy is justified.

Diabetes does not impact the diagnostic performance of contrast-based fractional flow reserve: insights from the CONTRAST study.

BACKGROUND: Adenosine-free coronary pressure wire metrics have been proposed to test the functional significance of coronary artery lesions, but it is unexplored whether their diagnostic performance might be altered in patients with diabetes. METHODS: We performed a post-hoc analysis of the CONTRAST study, which prospectively enrolled an international cohort of patients undergoing routine fractional flow reserve (FFR) assessment for standard indications. Paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, contrast-based FFR, and FFR) were made. A central core laboratory analyzed blinded pressure tracings in a standardized fashion. RESULTS: Of 763 subjects enrolled at 12 international centers, 219 (29%) had diabetes. The two groups were well-balanced for age, clinical presentation (stable or unstable), coronary vessel studied, volume and type of intracoronary contrast, and volume of intracoronary adenosine. A binary threshold of cFFR ≤ 0.83 produced an accuracy superior to both Pd/Pa and iFR when compared with FFR ≤ 0.80 in the absence of significant interaction with diabetes status; indeed, accuracy in subgroups of patients with or without diabetes was similar for cFFR (86.7 vs 85.4% respectively; p = 0.76), iFR (84.2 vs 80.0%, p = 0.29) and Pd/Pa (81.3 vs 78.9%, p = 0.55). There was no significant heterogeneity between patients with or without diabetes in terms of sensitivity and specificity of all metrics. The area under the receiver operating characteristic (ROC) curve was largest for cFFR compared with Pd/Pa and iFR which were equivalent (cFFR 0.961 and 0.928; Pd/Pa 0.916 and 0.870; iFR 0.911 and 0.861 in diabetic and non-diabetic patients respectively). CONCLUSIONS: cFFR provides superior diagnostic performance compared with Pd/Pa or iFR for predicting FFR irrespective of diabetes (clinicaltrials.gov identifier NCT02184117).