Temporary omission of oral anticoagulation in atrial fibrillation patients undergoing percutaneous coronary intervention: rationale and design of the WOEST-3 randomised trial.

The optimal antithrombotic management of atrial fibrillation (AF) patients who require oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) remains unclear. Current guidelines recommend dual antithrombotic therapy (DAT; OAC plus P2Y12 inhibitor - preferably clopidogrel) after a short course of triple antithrombotic therapy (TAT; DAT plus aspirin). Although DAT reduces bleeding risk compared to TAT, this is counterbalanced by an increase in ischaemic events. Aspirin provides early ischaemic benefit, but TAT is associated with an increased haemorrhagic burden; therefore, we propose a 30-day dual antiplatelet therapy (DAPT; aspirin plus P2Y12 inhibitor) strategy post-PCI, temporarily omitting OAC. The study aims to compare bleeding and ischaemic risk between a 30-day DAPT strategy following PCI and a guideline-directed therapy in AF patients requiring OAC. WOEST-3 (ClinicalTrials.gov: NCT04436978) is an investigator-initiated, international, open-label, randomised controlled trial (RCT). AF patients requiring OAC who have undergone successful PCI will be randomised within 72 hours after PCI to guideline-directed therapy (edoxaban plus P2Y12 inhibitor plus limited duration of aspirin) or a 30-day DAPT strategy (P2Y12 inhibitor plus aspirin, immediately discontinuing OAC) followed by DAT (edoxaban plus P2Y12 inhibitor). With a sample size of 2,000 patients, this trial is powered to assess both superiority for major or clinically relevant non-major bleeding and non-inferiority for a composite of all-cause death, myocardial infarction, stroke, systemic embolism or stent thrombosis. In summary, the WOEST-3 trial is the first RCT temporarily omitting OAC in AF patients, comparing a 30-day DAPT strategy with guideline-directed therapy post-PCI to reduce bleeding events without hampering efficacy.

Impact of the number of modifiable risk factors on clinical outcomes after percutaneous coronary intervention: An analysis from the e-Ultimaster registry.

Aims: A substantial proportion of the patients undergoing percutaneous coronary intervention (PCI) have none of the of standard modifiable cardiovascular risk factors (SMuRFs): hypertension, diabetes, hypercholesterolaemia and smoking. The aim of this analysis was to compare clinical outcomes after PCI according to the number of SMuRFs. Methods: Patients with an indication for a PCI were stratified based upon the number of SMuRFs: 0, 1, 2 or 3-4. The primary outcome was target lesion failure (TLF), a composite of cardiac death, target vessel-related myocardial infarction or clinically driven target lesion revascularization at 1-year. Inverse weighted propensity score (IWPS) adjustment was performed to adjust for differences in baseline characteristics. Results: The prevalence of SMuRFs was: 0 SMuRF 16.4 %; 1 SMuRF 27.8 %; 2 SMuRFs 34.7 % and 3-4 SMuRFs 21.1 %. Patients without SMuRFs were younger, more likely to be male and had less complex coronary artery disease. The incidence of TLF increased with the number of SMuRFs: 2.65 %, 2.75 %, 3.23 %, and 4.24 %, Ptrend < 0.001. The relative risk (RR) for a TLF was 60 % higher (95 % confidence interval 1.32-1.93, p < 0.01) for patients with 3-4 SMuRFs compared to patients without SMuRFs. The trend remained (Ptrend < 0.01) after IWPS with TLF rates of 2.88 %, 2.64 %, 2.88 % and 3.65 %. The RR for a TLF was 27 % higher (95 % CI 1.05-1.53, p < 0.01). Conclusion: The incidence of clinical events at 1-year increased with the number of SMuRFs. While patients without SMuRFs have a relatively favourable risk profile, more research is needed to optimize therapeutic management in the majority of patients.

Semi-Quantitative Versus Visual Analysis of Adenosine Perfusion Magnetic Resonance Imaging in Intermediate-Grade Coronary Artery Stenosis Using Fractional Flow Reserve as the Reference: A Pilot Study.

Background: To evaluate the diagnostic accuracy of semi-quantitative adenosine perfusion magnetic resonance imaging (MRI) to determine fractional flow reserve (FFR) ≤ 0.80 intermediate-grade coronary stenoses as compared to visual analysis. Methods: Forty-six patients (mean age 61 ± 9 years; 33 males) with 49 intermediate-grade stenoses (59 ± 7.6%; range, 42-70% minimal diameter reduction) underwent adenosine perfusion MRI and FFR measurement within four months in this retrospective study. MRI was visually assessed by two experienced readers twice with one-year interval, the second time with the knowledge of the diseased artery. The stress subendocardial myocardial enhancement maximal upslope was evaluated distal to the coronary stenosis (=RISK) and divided by the same value in remote myocardium supplied by normal arteries (=REMOTE) to obtain the relative myocardial perfusion index (RMPI). Results: The average FFR value was 0.84 ± 0.09 and 15/49(31%) intermediate-grade stenoses were FFR ≤ 0.80. The kappa-values for interobserver agreement assessing inducible perfusion defects on visual readings was 0.20 on the first reading and increased to 0.62 with the knowledge of the stenosis location. Consensus readings had a diagnostic accuracy of 82%(40/49) in identifying FFR ≤ 0.80 stenoses on both blinded and unblinded readings with regards to the knowledge of the stenosis location. Meanwhile, stress subendocardial RMPI had higher accuracy (43/49[88%]) than visual readings to predict FFR ≤ 0.80 stenoses, using a cutoff value of 0.84. Conclusion: By assessing perfusion changes in remote myocardium, semi-quantitative MRI analysis using stress subendocardial RMPI can provide an equal or more accurate alternative to visual analysis in identifying FFR ≤ 0.80 intermediate-grade stenoses. Larger cohorts of patients are required to validate this approach.

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI.

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).

Value of Relative Myocardial Perfusion at MRI for Fractional Flow Reserve-Defined Ischemia: A Pilot Study.

OBJECTIVE. Correcting the perfusion in areas distal to coronary stenosis (risk) according to that of normal (remote) areas defines the relative myocardial perfusion index, which is similar to the fractional flow reserve (FFR) concept. The aim of this study was to assess the value of relative myocardial perfusion by MRI in predicting lesion-specific inducible ischemia as defined by FFR. MATERIALS AND METHODS. Forty-six patients (33 men and 13 women; mean [± SD] age, 61 ± 9 years) who underwent adenosine perfusion MRI and FFR measurement distal to 49 coronary artery stenoses during coronary angiography were retrospectively evaluated. Subendocardial time-enhancement maximal upslopes, normalized by the respective left ventricle cavity upslopes, were obtained in risk and remote subendocardium during adenosine and rest MRI perfusion and were correlated to the FFR values. RESULTS. The mean FFR value was 0.84 ± 0.09 (range, 0.60-0.98) and was less than or equal to 0.80 in 31% of stenoses (n = 15). The relative subendocardial perfusion index (risk-to-remote upslopes) during hyperemia showed better correlations with the FFR value (r = 0.59) than the uncorrected risk perfusion parameters (i.e., both the upslope during hyperemia and the perfusion reserve index [stress-to-rest upslopes]; r = 0.27 and 0.29, respectively). A cutoff value of 0.84 of the relative subendocardial perfusion index had an ROC AUC of 0.88 to predict stenosis at an FFR of less than or equal to 0.80. CONCLUSION. Using adenosine perfusion MRI, the relative myocardial perfusion index enabled the best prediction of FFR-defined lesion-specific myocardial ischemia. This index could be used to noninvasively determine the need for revascularization of known coronary stenoses.

Correlation of FFR-derived from CT and stress perfusion CMR with invasive FFR in intermediate-grade coronary artery stenosis.

Only one-third of intermediate-grade coronary artery stenosis (i.e. 40-70% diameter narrowing) causes myocardial ischemia, requiring most often additional invasive work-up with invasive fractional flow reserve (FFR). To evaluate the correlations between FFR estimates derived from computed tomography (FFRCT) and adenosine perfusion cardiac magnetic resonance (CMR) with invasive FFR in intermediate-grade stenosis. Thirty-seven patients (mean age 61 ± 9 years; 25 men) who underwent adenosine perfusion CMR, quantitative coronary angiography and FFR in the work-up for intermediate-grade stenoses (n = 39) diagnosed at coronary CT angiography were retrospectively evaluated. Blinded FFRCT analysis was computed on each intermediate-grade lesion and correlated to the FFR values. On adenosine CMR, subendocardial time-enhancement maximal upslopes, normalized by respective left ventricle cavity upslopes, were obtained distal to a coronary stenosis (RISK area) and in remote myocardium (REMOTE area). The perfusion was subsequently assessed without (uncorrected RISK) and after correction for remote perfusion (relative myocardial perfusion index = REMOTE/RISK ratio), and then correlated to the FFR values. Differences in correlations were tested with z statistics and considered statistically significant different at a p < 0.05 level. The average FFR value was 0.85 ± 0.10 (0.60-0.98 range), 28% (n = 11) was ≤ 0.80. FFR value correlated poorly with uncorrected RISK upslopes (r = 0.151; p = 0.36), but equally strongly with FFRCT (r = 0.675; p < 0.001) and the relative myocardial perfusion index (r = - 0.63) (p < 0.001; z = 6.72) for assessment of lesion-specific ischemia. Both FFRCT and adenosine perfusion CMR strongly correlate with invasive FFR measurements for intermediate-grade stenosis. These preliminary findings pave the way for further studies evaluating non-invasively intermediate coronary stenosis in clinical practice.

Unifocal Right-Sided Ablation Treatment for Neurally Mediated Syncope and Functional Sinus Node Dysfunction Under Computed Tomographic Guidance.

Background Biatrial, extensive, and complex ablation strategies have been published for the treatment of neurally mediated syncope, sinus node dysfunction, and functional atrioventricular block. We have developed a less extensive and more specific approach compared with previously published cardioneuroablation strategies, called cardio-neuromodulation. It is based on tailored vagolysis of the sinoatrial node through partial ablation of the anterior right-ganglionated plexus, preferentially through a right-sided approach. Methods Patients with syncope were enrolled between December 2016 and December 2017. They were assigned to group A if they had a positive head-up tilt test and to group B if they presented with a pause ≥3 seconds. The area to target during cardio-neuromodulation was designed offline on a computed tomographic scan. Slow heart rates and pauses were compared during 24-hour rhythm registration at baseline, at 1-month follow-up, and 6-month follow-up. Syncope burden was assessed before the procedure and at 3- and 6-month follow-up. Results Twenty patients underwent cardio-neuromodulation through a right-sided approach (12 in group A, 8 in group B). The first application of radiofrequency energy led to a P-P interval shortening >120 ms in all 20 patients. After a mean±SD ablation time of 7±4 minutes and mean ablated surface area of 11±6 mm2, the P-P interval shortened by 219±160 ms ( P<0.001). The number of beats <50/min during 24-hour rhythm registration was reduced by a median of 100% at 6-month follow-up ( P<0.001). Syncope burden was reduced by 95% at 6-month follow-up ( P<0.001). Conclusions These data indicate that cardio-neuromodulation, through a right-sided and computed tomographic-guided procedure, is safe, fast, and highly reproducible in preventing inappropriate functional sinus bradycardia and syncope recurrence.

Efficacy and Safety of the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Concomitant Aspirin Therapy: A Meta-Analysis of Randomized Trials.

BACKGROUND: Current guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) as the first-choice therapy in patients with nonvalvular atrial fibrillation because these drugs have several benefits over the vitamin K antagonists (VKAs). It is unknown whether these benefits remain when NOACs have to be combined with aspirin therapy. To assess the efficacy and safety of NOACs compared with VKAs in patients with atrial fibrillation and concomitant aspirin therapy, we conducted a systematic review and study-based meta-analysis of published randomized controlled trials. METHODS: A systematic electronic literature search was done in MEDLINE, EMBASE, and Cochrane CENTRAL Register of Controlled Trials for studies including published data of patients ≥18 years of age with nonvalvular atrial fibrillation, randomized to either VKAs or NOACs, or receiving aspirin therapy at any time during the study that report all-cause stroke or systemic embolism, vascular death, myocardial infarction, major bleeding, or intracranial hemorrhage as an outcome. Hazard ratios (HRs) with 95% confidence intervals (CIs) for each outcome were extracted from the individual studies and pooled with random-effects meta-analysis. RESULTS: This study-based meta-analysis was restricted to the subgroups of patients on aspirin therapy (n=21 722) from 4 randomized controlled trials comparing VKAs and NOACs (n=71 681) in nonvalvular atrial fibrillation. In this meta-analysis including patients on mainly low-dose aspirin, NOACs were found to be more effective (outcome of stroke or systemic embolism: HR, 0.78; 95% CI, 0.67-0.91; vascular death: HR, 0.85; 95% CI, 0.76-0.93) and as safe as VKAs with respect to major bleeding (HR, 0.83; 95% CI, 0.69-1.01). NOACs were safer with respect to the reduction of intracranial hemorrhage (HR, 0.38; 95% CI, 0.26-0.56). CONCLUSIONS: This study-based meta-analysis shows that it may be both safer and more effective to use NOACs compared with VKAs to treat patients with nonvalvular atrial fibrillation and concomitant aspirin therapy.

The effect of acenocoumarol on the antiplatelet effect of clopidogrel.

Patients exhibiting high on-clopidogrel platelet reactivity (HPR) are at an increased risk of atherothrombotic events following percutaneous coronary interventions (PCI). The use of concomitant medication which is metabolised by the hepatic cytochrome P450 system, such as phenprocoumon, is associated with HPR. We assessed the level of platelet reactivity on clopidogrel in patients who received concomitant treatment with acenocoumarol (another coumarin derivative). Patients scheduled for PCI were included in a prospective, single centre, observational registry. Patients who were adequately pre-treated with clopidogrel were eligible for this analysis, which included 1,582 patients, of whom 104 patients (6.6%) received concomitant acenocoumarol treatment. Platelet reactivity, as measured with the VerifyNow P2Y12 assay and expressed in P2Y12 Reaction Units (PRU), was significantly higher in patients on concomitant acenocoumarol treatment (mean PRU 229 ± 88 vs 187 ± 95; p < 0.001). In patients with concomitant acenocoumarol use, the proportion of patients with HPR was higher, defined as PRU > 208 (57.7% vs 41.1%; p=0.001) and PRU ≥ 236 (49.0% vs 31.4%; p< 0.001). In multivariable analysis, concomitant acenocoumarol use was independently associated with a higher PRU and the occurrence of HPR defined as PRU ≥ 236 (OR 2.00, [1.07-3.79]), but not with HPR defined as PRU > 208 (OR 1.37, [0.74-2.54]). PRU also was significantly increased after 1:1 propensity matching (+28.2; p < 0.001). As this was an observational study, confounding by indication cannot be excluded, although multivariable analyses and propensity matching were performed. The impact of the findings from this hypothesis-generating study on clinical outcome requires further investigation.

Symptomatic arrhythmogenic right ventricular dysplasia/cardiomyopathy. A two-centre retrospective study of 15 symptomatic ARVD/C cases and focus on the diagnostic value of MRI in symptomatic ARVD/C patients.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is associated with sudden death in the young and heart failure in the elderly. The purpose is to review 15 symptomatic ARVD/C cases and also to describe the use of MRI as a diagnostic tool. METHODS AND RESULTS: This retrospective analysis includes 15 patients who presented with symptomatic ARVD/C. Diagnosis was made upon the criteria proposed by the European Society of Cardiology. In all patients there was at least 1 or more abnormal MRI sign. The most frequent abnormalities were focal right ventricular dyskinesia (64%), MRI fatty infiltration (57%) and right ventricular aneurysm or right ventricular outflow tract microaneurysms (57%). Presenting symptoms were palpitations (60%), atypical chest pain (46%), syncope (40%), and aborted sudden death (26%). T-inversion in V2-V3 was seen in 60% of the patients. Thirteen patients (86%) received an ICD implantation. The mean follow-up per patient was 89 months, which resulted in a total follow-up of 111 patient years. Forty-six percent of the patients with an ICD had one or more appropriate shocks during follow-up. To this date no mortality was reported. CONCLUSION: This retrospective study demonstrates that symptomatic ARVD/C patients typically present with symptoms of syncope, palpitations in association with ventricular tachycardia and in a quarter of the cases with aborted sudden cardiac death. The electrocardiogram mostly shows T inversion in the anterior leads. All patients were treated with medication and ICD-implantation or VT-ablation. The malignant nature of the disease in symptomatic ARVD/C patients is stressed by the fact that the presenting symptom is aborted sudden death in a quarter of the cases and the fact that nearly half of the patients with an ICD had at least one appropriate shock during follow-up. There was an abnormal MRI in 100% of the investigated patients. In 20% (3 patients), the MRI criterion (right ventricular dilatation/bulging/aneurysm) was necessary to meet the ESC criteria. Therefore it has become an important tool in our diagnostic work-up when ARVD/C is suspected. We also suggest a change in the diagnostic criteria of ARVD/C. Whereas fatty infiltration seen on RV biopsy is a major criterion, MRI fatty infiltration is not regarded as a diagnostic criterion by the task force to this day.