Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial.

BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency is a very rare but serious disease, with an estimated prevalence of 1 per 500,000 persons. There are no approved therapies to treat or prevent angioedema swelling in patients with this condition. Deucrictibant is a specific, orally bioavailable, competitive antagonist of the bradykinin B2 receptor currently under investigation for hereditary angioedema. OBJECTIVE: Our aim was to assess the efficacy and safety of deucrictibant as acute and prophylactic treatment for angioedema due to acquired C1-inhibitor deficiency. METHODS: A 2-part, randomized, double-blind, placebo-controlled crossover study was conducted. In Part 1, 4 consecutive angioedema attacks were treated with 3 doses of deucrictibant (10 mg, 20 mg, and 30 mg) or placebo. In Part 2, deucricibant, 20 mg, or placebo was administered twice daily for 2 treatment periods of 8 weeks. RESULTS: Three patients were enrolled; of those 3 patients, 1 completed both study parts and 2 completed only Part 2. In Part 1, a reduction in attack severity was observed in the 3 attacks treated with deucrictibant as opposed to an increase in severity of the attack treated with placebo. In Part 2, the individual mean monthly attack rates were 2.0, 0.6, and 1.0 during the placebo period and 0.0 across all patients during treatment with deucrictibant. There were no severe adverse events and 1 self-limiting treatment-emergent adverse event (abdominal pain). CONCLUSIONS: Deucrictibant has the potential to effectively and safely treat and prevent angioedema attacks due to acquired C1-inhibitor deficiency.

The additional value of 68Ga-PSMA PET/CT SUVmax in predicting ISUP GG ≥ 2 and ISUP GG ≥ 3 prostate cancer in biopsy.

BACKGROUND: Prebiopsy magnetic resonance imaging (MRI) increases the detection rate of clinically significant prostate cancer (csPCa). Prostate-specific membrane antigen-positron emission tomography/computed tomography (PSMA PET/CT) maximum standardized uptake value (SUVmax) of the prostate may offer additional value in predicting the likelihood of csPCa in biopsy. METHODS: A single-center cohort study involving patients with biopsy-proven PCa who underwent both MRI and PSMA PET/CT between 2020 and 2021. Logistic regression models were developed for International Society of Urological Pathology (ISUP) Grade Group (GG) ≥ 2 and GG ≥ 3 using noninvasive prebiopsy parameters: age, (log-)prostate-specific antigen (PSA) density, PI-RADS 5 lesion presence, extraprostatic extension (EPE) on MRI, and SUVmax of the prostate. Models with and without SUVmax were compared using Likelihood ratio tests and area under the curve (AUC). DeLong's test was used to compare the AUCs. RESULTS: The study included 386 patients, with 262 (68%) having ISUP GG ≥ 2 and 180 (47%) having ISUP GG ≥ 3. Including SUVmax significantly improved both models' goodness of fit (p < 0.001). The GG ≥ 2 model had a higher AUC with SUVmax 89.16% (95% confidence interval [CI]: 86.06%-92.26%) than without 87.34% (95% CI: 83.93%-90.76%) (p = 0.026). Similarly, the GG ≥ 3 model had a higher AUC with SUVmax 82.51% (95% CI: 78.41%-86.6%) than without 79.33% (95% CI: 74.84%-83.83%) (p = 0.003). The SUVmax inclusion improved the GG ≥ 3 model's calibration at higher probabilities. CONCLUSION: SUVmax of the prostate on PSMA PET/CT potentially improves diagnostic accuracy in predicting the likelihood of csPCa in prostate biopsy.

Preoperative computed tomography-imaging with patient-specific computer simulation in transcatheter aortic valve implantation: Design and rationale of the GUIDE-TAVI trial.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe aortic valve stenosis, but is still associated with relatively high rates of pacemaker implantation and paravalvular regurgitation. Routine preoperative computed tomography (CT) combined with patient-specific computer modelling can predict the interaction between the TAVI device and the patient's unique anatomy, allowing physicians to assess the risk for paravalvular regurgitation and conduction disorders in advance to the procedure. The aim of this trial is to assess potential improvement in the procedural outcome of TAVI by applying CT-based patient-specific computer simulations in patients with suitable anatomy for TAVI. METHODS: The GUIDE-TAVI trial is an international multicenter randomized controlled trial including patients accepted for TAVI by the Heart Team. Patients enrolled in the study will be randomized into 2 arms of each 227 patients. In patients randomized to the use of FEops HEARTGuide (FHG), patient-specific computer simulation with FHG is performed in addition to routine preoperative CT imaging and results of the FHG are available to the operator(s) prior to the scheduled intervention. In patients randomized to no use of FHG, only routine preoperative CT imaging is performed. The primary objective is to evaluate whether the use of FHG will reduce the incidence of mild to severe PVR, according to the Valve Academic Research Consortium 3. Secondary endpoints include the incidence of new conduction disorders requiring permanent pacemaker implantation, the difference between preoperative and final selected valve size, the difference between target and final implantation depth, change of preoperative decision, failure to implant valve, early safety composite endpoint and quality of life. CONCLUSIONS: The GUIDE-TAVI trial is the first multicenter randomized controlled trial to evaluate the value of 3-dimensional computer simulations in addition to standard preprocedural planning in TAVI procedures.

Postoperative Myocardial Injury and Inflammatory Biomarkers in Patients Undergoing Vascular Surgery: A Subanalysis of the Platelet Reactivity and Postoperative Myocardial Injury after Major Vascular Surgery (PROMISE) Study.

BACKGROUND: Postoperative myocardial injury (PMI) is associated with morbidity and mortality, but the aetiology remains unclear. We studied whether PMI is associated with perioperative systemic inflammation. The objective is the examination of the relationship between inflammatory biomarkers (Interleukin 6[IL-6], C-reactive protein [CRP]) and PMI, detected by elevated cardiac troponin (cTn), in patients undergoing elective open abdominal aortic surgery. METHODS: This prospective, single-center, observational cohort study included 54 patients undergoing elective open abdominal aortic surgery between March 2018 and April 2021. Patients were routinely treated with aspirin. IL-6 and CRP were measured preoperatively, directly after surgery, 24 hr and 48 hr postoperatively. The primary outcome was cTn release assessed by a fifth-generation high-sensitive cTn assay. Multivariable generalized linear regression models were used to evaluate the association between inflammatory biomarkers and cTn concentrations. RESULTS: Fifteen patients (27.8%) developed PMI. IL-6 directly and 24 hr postoperatively was associated with elevated cTn concentrations (1.28 [1.07-1.54], P = 0.009) and 1.75 [1.18-2.59], P = 0.006, respectively). Also, CRP directly and 24 hr postoperatively was associated with elevated cTn concentrations (1.25 [1.06-1.47], P = 0.009) and 1.61 [1.1-2.33], P = 0.013, respectively). No association was found between IL-6 or CRP and cTn concentrations when measured at 48 hr postsurgery. CONCLUSIONS: Biomarkers of inflammation are associated with elevated postoperative cTn concentrations in the early postoperative period in patients undergoing elective open abdominal aortic surgery.

Clinical Outcomes of Concomitant Secondary Chordal Cutting to Surgical Myectomy in HOCM.

OBJECTIVES: In patients who underwent surgical septal myectomy for hypertrophic obstructive cardiomyopathy (HOCM), additional mitral valve repair may offer additional benefits in terms of further reducing left ventricle outflow tract (LVOT) gradients, systolic anterior motion (SAM) and mitral regurgitation (MR). We performed a systematic review of the literature to evaluate the evidence of surgical myectomy with additional secondary chordal cutting in patients with HOCM. METHODS: A systematic literature search in MEDLINE and EMBASE was performed until April 2024. The primary outcome studied was postoperative echocardiographic LVOT-gradient. A random effects meta-analysis of means was performed for the primary outcome. The secondary outcomes studied were postoperative residual MR-grade, 30-day new permanent pacemaker implantation, and in-hospital mortality. RESULTS: From 1911 unique publications, a total of 6 articles fulfilled the inclusion criteria and comprised 471 patients with a pooled mean preoperative resting LVOT gradient of 84 mmHg (95% CI: 76-91). The postoperative pooled mean LVOT-gradient was 11 mmHg (95% CI: 10 - 12) with a low heterogeneity (I2 = 44%). The residual LVOT gradient exceeding 30 mmHg was present in 9 (1%) patients. MR-grade 3 or 4 at hospital discharge was present in 7 (1%) patients. The 30-day new permanent pacemaker implantation rate was 7% and the in-hospital mortality was 0.4%. CONCLUSION: This systematic review and meta-analysis demonstrate that combining surgical septal myectomy with secondary chordal cutting can be performed safely and effectively eliminate LVOT obstruction in HOCM patients. Further studies are needed to determine the additive effectiveness of additional secondary chordal cuttings.

Treatment of elderly patients with non-ST-elevation myocardial infarction: the nationwide POPular age registry.

OBJECTIVE: We describe the current treatment of elderly patients with non-ST-elevation myocardial infarction (NSTEMI) enrolled in a national registry. METHODS: The POPular AGE registry is a prospective, multicentre study of patients ≥ 75 years of age presenting with NSTEMI, performed in the Netherlands. Management was at the discretion of the treating physician. Cardiovascular events consisted of cardiovascular death, myocardial infarction and ischaemic stroke. Bleeding was classified according to the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: A total of 646 patients were enrolled between August 2016 and May 2018. Median age was 81 (IQR 77-84) years and 58% were male. Overall, 75% underwent coronary angiography, 40% percutaneous coronary intervention, and 11% coronary artery bypass grafting, while 49.8% received pharmacological therapy only. At discharge, dual antiplatelet therapy (aspirin and P2Y12 inhibitor) was prescribed to 56.7%, and 27.4% received oral anticoagulation plus at least one antiplatelet agent. At 1­year follow-up, cardiovascular death, myocardial infarction or stroke had occurred in 13.6% and major bleeding (BARC 3 and 5) in 3.9% of patients. The risk of both cardiovascular events and major bleeding was highest during the 1st month. However, cardiovascular risk was three times as high as bleeding risk in this elderly population, both after 1 month and after 1 year. CONCLUSIONS: In this national registry of elderly patients with NSTEMI, the majority are treated according to current European Society of Cardiology guidelines. Both the cardiovascular and bleeding risk are highest during the 1st month after NSTEMI. However, the cardiovascular risk was three times as high as the bleeding risk.

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Quality of Life in Patients With Definite Chronic Pancreatitis: A Nationwide Longitudinal Cohort Study.

INTRODUCTION: Chronic pancreatitis (CP) has a negative impact on quality of life (QoL). Because CP is a chronic condition, multiple assessments of QoL are required to obtain a thorough understanding of its impact on patients. Such studies are currently lacking. This study aims to gain insight into the course and predictors of QoL in patients with CP using prospective longitudinal data from a large cohort of patients. METHODS: Post hoc analysis of consecutive patients with definite CP registered in a prospective database between 2011 and 2019 in the Netherlands. Patient and disease characteristics, nutritional status, pain severity, medication usage, pancreatic function, and pancreatic interventions were assessed from medical records and through standard follow-up questionnaires. The physical and mental component summary scales of the Short-Form 36 were used to assess physical and mental QoL at baseline and during follow-up. The course of both physical and mental QoL and their associated factors were longitudinally assessed by using generalized linear mixed models. RESULTS: Overall, 1,165 patients with definite CP were included for this analysis. During 10-year follow-up, generalized linear mixed model analyses revealed improvements in both physical (41.6-45.2, P < 0.001) and mental (45.9-46.6, P = 0.047) QoL. Younger age, current alcohol consumption, employment, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, and pain coping mechanism were positively associated with physical QoL ( P < 0.05). For mental QoL, a positive correlation was found between employment, nonalcoholic CP, no need for dietetic consultation, no steatorrhea, lower Izbicki pain score, pain coping mechanism, and surgical treatment. No association was observed between disease duration and longitudinal QoL per patient. DISCUSSION: This nationwide study provides insight into the dynamics of physical and mental QoL in patients with CP over time. Important and potentially influenceable factors to improve QoL are nutritional status, exocrine pancreatic function, employment status, and patients' coping strategy.

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.).

Antibiotic prophylaxis for acute cholecystectomy: PEANUTS II multicentre randomized non-inferiority clinical trial.

BACKGROUND: Guidelines recommending antibiotic prophylaxis at emergency cholecystectomy for cholecystitis were based on low-quality evidence. The aim of this trial was to demonstrate that omitting antibiotics is not inferior to their prophylactic use. METHODS: This multicentre, randomized, open-label, non-inferiority clinical trial randomly assigned adults with mild-to-moderate acute calculous cholecystitis (immediate cholecystectomy indicated) to 2 g cefazolin administered before incision or no antibiotic prophylaxis. The primary endpoint was a composite of all postoperative infectious complications in the first 30 days after surgery. Secondary endpoints included all individual components of the primary endpoint, other morbidity, and duration of hospital stay. RESULTS: Sixteen of 226 patients (7.1 per cent) in the single-dose prophylaxis group and 29 of 231 (12.6 per cent) in the no-prophylaxis group developed postoperative infectious complications (absolute difference 5.5 (95 per cent c.i. -0.4 to 11.3) per cent). With a non-inferiority margin of 10 per cent, non-inferiority of no prophylaxis was not proven. The number of surgical-site infections was significantly higher in the no-prophylaxis group (5.3 versus 12.1 per cent; P = 0.010). No differences were observed in the number of other complications, or duration of hospital stay. CONCLUSION: Omitting antibiotic prophylaxis is not recommended.

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y12 inhibitors in ST-segment elevation myocardial infarction: A subanalysis of the POPular Genetics trial.

BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. METHODS: GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. RESULTS: In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. CONCLUSION: In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.

The efficacy of botulinum toxin a injections in pelvic floor muscles in chronic pelvic pain patients: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Chronic pelvic pain (CPP) is a common multifactorial condition affecting 6 to 27% of women aged 18-50 years worldwide. This study was conducted to review and meta-analyse the current literature on the reduction of chronic pelvic pain after botulinum toxin A (BTA) injection. METHOD: In July 2021 we performed a systematic search in PubMed and EMBASE to assess the benefits of BTA injection in pelvic floor muscles in women with chronic pelvic pain. Primary outcome was reduction in visual analogue scale (VAS) after treatment. Secondary outcomes evaluated were: reduction of dyspareunia, pelvic floor resting pressure and quality of life. Identified reports were assessed on quality of reporting and risk of bias. Standardized mean difference (SMD) was used to combine and analyse outcomes of the included studies. RESULTS: Eight studies with 289 participants were considered eligible to be included in this systematic review and meta-analysis. After recalculating SMD into VAS scores (0-100), long-term follow-up (24-26 weeks) showed a significant 15-point improvement in VAS scores (95% CI: 8.8-21.5) for non-menstrual pelvic pain and a 13-point improvement (95% CI: 2.1-24.0) for dyspareunia. BTA injection had a significant effect on pelvic floor resting pressure and quality of life. CONCLUSION: There is limited scientific evidence on the effectiveness of BTA injections in pelvic floor muscles in women with chronic pelvic pain. The available studies show that BTA injections significantly reduce pain levels and improve quality of life at 6 months follow-up. PROSPERO ID: CRD42018105204.

Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG): A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 mg or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomly assigned patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), odds ratio, 1.29 [95% CI, 0.73-2.30]; P=0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (odds ratio, 1.22 [95% CI, 0.72-2.05]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02352402.

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial.

BACKGROUND: Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS: Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION: In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk. FUNDING: ZonMw.

Complications After Surgical Treatment of Geriatric Ankle Fractures.

The incidence of geriatric ankle fractures is rising and the potential for complications is high in this population. Little is known about factors associated with increased postoperative complications after surgical fixation of ankle fractures in older-age patients. The purpose of this retrospective cohort study was to assess the epidemiology and risk factors for complications after surgically treated ankle fractures in geriatric patients. All patients who were 65 years or older and had a surgically treated ankle fracture were included. Pilon fractures, patients who were initially treated conservatively or who had less than 1 month of follow-up were excluded. Postoperative complications, demographic-, fracture- and surgical data of 282 patients were recorded from two level 2 trauma centers between 2012 and 2017. A total of 87 (30.9%) patients developed a complication, of which wound related complications were most frequently reported. Superficial and deep wound infections were observed in 27 (9.6%) and 18 (6.4%) patients, respectively. Multivariate regression analysis demonstrated increased age to be an independent predictive variable for the occurrence of postoperative complications (odds ratio 1.04; 95% confidence interval 1.00-1.09), while cast immobilization for more than 2 weeks was a protective factor for the development of wound related complications (odds ratio 0.34; 95% confidence interval 0.17-0.66). In conclusion, the incidence of postoperative complications among geriatric patients after surgical treatment of ankle fractures is high and patients should be informed accordingly.

A randomized, double-blind, placebo-controlled trial investigating the effect of ticagrelor on saphenous vein graft patency in patients undergoing coronary artery bypass grafting surgery-Rationale and design of the POPular CABG trial.

RATIONALE: An estimated 15% of saphenous vein grafts (SVGs) occlude in the first year after coronary artery bypass grafting (CABG) despite aspirin therapy. Graft occlusion can result in symptoms, myocardial infarction, and death. SVG occlusion is primarily caused by atherothrombosis, in which platelet activation plays a pivotal role. Evidence regarding the effect of stronger platelet inhibition on SVG patency after CABG is limited. The main objective of the POPular CABG trial is to determine whether dual antiplatelet therapy with aspirin plus ticagrelor improves SVG patency when compared to aspirin alone. STUDY: The POPular CABG is a randomized, double-blind, placebo-controlled, multicenter trial investigating the effect of adding ticagrelor to standard aspirin therapy on the rate of SVG occlusion. A total of 500 patients undergoing CABG with ≥ 1 SVG are randomized to ticagrelor or placebo. The primary end point is SVG occlusion rate, assessed with coronary computed tomography angiography at 1 year. Secondary end points are stenoses and occlusions in both SVGs and arterial grafts and SVG failure at 1 year, defined as a composite of SVG occlusion on coronary computed tomography angiography or coronary angiography, SVG revascularization, myocardial infarction in the territory supplied by an SVG, or sudden death. Safety end points are bleeding events at 30 days and 1 year. CONCLUSION: The POPular CABG trial investigates whether adding ticagrelor to standard aspirin after CABG reduces the rate of SVG occlusion at 1 year.

Long-term results of carotid stenting and risk factors in patients with severe carotid artery stenosis undergoing subsequent cardiac surgery.

AIMS: To identify risk factors for composite outcome of mortality, stroke or myocardial infarction in patients with severe carotid stenosis undergoing staged carotid artery stenting (CAS) with subsequent cardiac surgery. METHODS AND RESULTS: In this prospective observational study, we enrolled 643 consecutive patients with both symptomatic (i.e., with history of stroke) and asymptomatic severe carotid artery disease, who required cardiac surgery. Generally, cardiac surgery was planned 30 days after the CAS procedure. The composite outcome consisted of death, stroke and myocardial infarction. The composite outcome rate was 26.3% at 5 years and 47% at 8 years after CAS. Age ≥ 80 years (hazard ratio [HR] = 1.89; 95%CI, 1.18-3.03; P = 0.008), history of stroke (HR = 1.66, 1.16-2.37; P = 0.006), chronic obstructive pulmonary disease (HR = 1.86; 1.07-3.24; P = 0.03) and kidney disease (HR = 1.83, 1.11-3.04; P = 0.02) were independent risk factors for the composite outcome during long-term follow-up. CONCLUSIONS: In this study with staged CAS followed by cardiac surgery, we confirm previously reported event-free survival rates and identify several risk factors for the composite outcome. Future studies are needed to confirm the importance of the identified risk factors and to assess their predictive ability.

Thoracoscopic ablation for the treatment of atrial fibrillation: a systematic outcome analysis of a multicentre cohort.

AIMS: To perform a systematic outcome analysis in order to provide cardiologists and general pactitioners with more adequate information to guide their decision making regarding rhythm control. Totally thoracoscopic maze (TTmaze) for the treatment of atrial fibrillation (AF) is recommended as a Class 2a indication mainly based on single centre studies including small patient cohorts and inconsistent lesion sets. METHODS AND RESULTS: We studied consecutive patients undergoing TTmaze in three European referral centres (2012-15). Primary outcome was freedom from atrial tachyarrhythmia (ATA). Secondary outcomes were 30-day complications, the composite endpoint of ischaemic stroke, haemorrhagic stroke or transient ischaemic attack (TIA), all-cause mortality, and predictors of ATA recurrence. Four hundred and seventy-five patients were included, with a mean age of 61 ± 9 years and 69.5% male. The mean CHA2DS2-VASc score was 1.7 ± 1.3. The overall freedom from ATA was 68.8% after a mean follow-up period of 20 ± 9 months. Freedom from ATA was 72.7% for paroxysmal AF, 68.9% for persistent AF, and 54.2% for longstanding persistent AF. Multivariate analysis revealed female gender [hazard ratio (HR): 1.87, P = 0.005], in-hospital AF (HR: 1.95, P = 0.040), longer duration of preoperative AF (HR: 1.06, P = 0.003) and mitral regurgitation (HR: 1.84, P = 0.025) as independent predictors of ATA recurrence. Overall 30-day freedom from any complication was 92.4%. Freedom from cerebrovascular events after mean follow-up of 30 ± 16 months was 98.7% and overall survival was 98.3%. The observed rate of ischaemic stroke, haemorrhagic stroke, or TIA was low (0.5 per 100 patient-years). CONCLUSION: Totally thoracoscopic maze is a safe and effective rhythm control therapy.

Thoracoscopic vs. catheter ablation for atrial fibrillation: long-term follow-up of the FAST randomized trial.

AIMS: Our objectives were to compare effectiveness and long-term prognosis after epicardial thoracoscopic atrial fibrillation (AF) ablation vs. endocardial catheter ablation, in patients with prior failed catheter ablation or high risk of failure. METHODS AND RESULTS: Patients were randomized to thoracoscopic or catheter ablation, consisting of pulmonary vein isolation with optional additional lines (2007-2010). Patients were reassessed in 2016/2017, and those without documented AF recurrence underwent 7-day ambulatory electrocardiography. The primary rhythm outcome was recurrence of any atrial arrhythmia lasting >30 s. The primary clinical endpoint was a composite of death, myocardial infarction, or cerebrovascular event, analysed with adjusted Cox proportional hazard ratios (HRs). One hundred and 24 patients were randomized with 34% persistent AF and mean age 56 years. Arrhythmia recurrence was common at mean follow-up of 7.0 years, but substantially lower with thoracoscopic ablation: 34/61 (56%) compared with 55/63 (87%) with catheter ablation [adjusted HR 0.40, 95% confidence interval (CI) 0.25-0.64; P < 0.001]. Additional ablation procedures were performed in 8 patients (13%) compared with 31 (49%), respectively (P < 0.001). Eleven patients (19%) were on anti-arrhythmic drugs at end of follow-up with thoracoscopy vs. 24 (39%) with catheter ablation (P = 0.012). There was no difference in the composite clinical outcome: 9 patients (15%) in the thoracoscopy arm vs. 10 patients (16%) with catheter ablation (HR 1.11, 95% CI 0.40-3.10; P = 0.84). Pacemaker implantation was required in 6 patients (10%) undergoing thoracoscopy and 3 (5%) in the catheter group (P = 0.27). CONCLUSION: Thoracoscopic AF ablation demonstrated more consistent maintenance of sinus rhythm than catheter ablation, with similar long-term clinical event rates.