Identification of a novel LDLR p.Glu179Met variant in Thai families with familial hypercholesterolemia and response to treatment with PCSK9 inhibitor

Abstract Familial hypercholesterolemia (FH) is a genetic disease characterized by elevated LDL-C levels. In this study, two FH probands and 9 family members from two families from northeastern Thailand were tested for LDLR, APOB, and PCSK9 variants by whole-exome sequencing, PCR-HRM, and Sanger sequencing. In silico analysis of LDLR was performed to analyse its structure‒function relationship. A novel variant of LDLR (c.535_536delinsAT, p.Glu179Met) was detected in proband 1 and proband 2 in homozygous and heterozygous forms, respectively. A total of 6 of 9 family members were heterozygous for LDLR p.Glu179Met variant. Compared with proband 2, proband 1 had higher baseline TC and LDL-C levels and a poorer response to lipid-lowering therapy combined with a PCSK9 inhibitor. Multiple sequence alignment showed that LDLR p.Glu179Met was located in a fully conserved region. Homology modelling demonstrated that LDLR p.Glu179Met variant lost one H-bond and a negative charge. In conclusion, a novel LDLR p.Glu179Met variant was identified for the first time in Thai FH patients. This was also the first report of homozygous FH patient in Thailand. Our findings may expand the knowledge of FH-causing variants in Thai population, which is beneficial for cascade screening, genetic counselling, and FH management to prevent coronary artery disease

A prognostic model for predicting the disappearance of left atrial thrombi among candidates for percutaneous transvenous mitral commissurotomy

AbstractObjectivesWe sought to develop a prognostic model to predict the disappearance of left atrial thrombi (LAT) among candidates for percutaneous transvenous mitral commissurotomy (PTMC).BackgroundComplete LAT resolution can be achieved with oral anticoagulation, allowing a number of patients to safely undergo PTMC.MethodsWe randomly allocated 108 PTMC candidates with LAT into two subsets—one to derive the model and the other to validate it. The existence of LAT and its size were measured by transesophageal echocardiography. Patients were given oral anticoagulation and followed up for 6 to 34 months. There was a 62% disappearance rate of LAT.ResultsWe developed the following model: P= 1/(1 + exponential[−8.1 + 1.8 NYHA+ 0.7 area]), where NYHA = New York Heart Association functional class (from I to IV), and area = LAT area (in cm2). The model was well calibrated (goodness-of-fit test, p = 0.82) and well discriminated (area under the receiver-operating characteristics [ROC] curve = 0.92). Performance in the validating sample was equally good (area under the ROC curve = 0.94; goodness-of-fit test, p = 0.16). When a cut-off point of p > 0.7 was used to designate the LAT disappearance in the validating set, the model had a sensitivity, specificity and positive and negative predictive values of 93.3%, 79.2%, 84.9% and 90.5%, respectively.ConclusionsCombined clinical (NYHA functional class) and echocardiographic (LAT area) variables are predictive of the 34-month outcome of oral anticoagulation for LAT resolution among PTMC candidates. This simple and highly predictive model might be potentially useful for clinical assessment and proper management

Risk profiles and pattern of antithrombotic use in patients with non-valvular atrial fibrillation in Thailand: a multicenter study

Abstract Background Anticoagulation therapy is a standard treatment for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) that have risk factors for stroke. However, anticoagulant increases the risk of bleeding, especially in Asians. We aimed to investigate the risk profiles and pattern of antithrombotic use in patients with NVAF in Thailand, and to study the reasons for not using warfarin in this patient population. Methods A nationwide multicenter registry of patients with NVAF was created that included data from 24 hospitals located across Thailand. Demographic data, atrial fibrillation-related data, comorbid conditions, use of antithrombotic drugs, and reasons for not using warfarin were collected. Data were recorded in a case record form and then transferred into a web-based system. Results A total of 3218 patients were included. Average age was 67.3 ± 11.3 years, and 58.2% were male. Average CHADS2, CHA2DS2-VASc, and HAS-BLED score was 1.8 ± 1.3, 3.0 ± 1.7, and 1.5 ± 1.0, respectively. Antiplatelet was used in 26.5% of patients, whereas anticoagulant was used in 75.3%. The main reasons for not using warfarin in those with CHA2DS2-VASc ≥2 included already taking antiplatelet (26.6%), patient preference (23.1%), and using non-vitamin K antagonist oral anticoagulants (NOACs) (22.7%). Anticoagulant was used in 32.3% of CHA2DS2-VASc 0, 56.8% of CHA2DS2-VASc 1, and 81.6% of CHA2DS2-VASc ≥2. The use of NOACs increased from 1.9% in 2014 to 25.6% in 2017. Conclusions Anticoagulation therapy was prescribed in 75.3% of patients with NVAF. Among those receiving anticoagulant, 90.9% used warfarin and 9.1% used NOACs. The use of NOACs increased over time

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk