Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial.

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Optimal door-to-balloon time for primary percutaneous coronary intervention for ST-elevation myocardial infarction.

BACKGROUND: Door-to-balloon time (DTBT) for ST-elevation myocardial infarction (STEMI) is a performance metric by which primary percutaneous coronary intervention (PPCI) services are assessed. METHODS: Consecutive patients presenting with STEMI undergoing PPCI between January 2007 to December 2019 from the Singapore Myocardial Infarction Registry were included. Patients were stratified based on DTBT (≤60 min, 61-90 min, 91-180 min) and Killip status (I-III vs. IV). Outcomes assessed included all-cause mortality and major adverse cardiovascular events (MACE) at 30-days and 1-year. RESULTS: In total, 13,823 patients were included, with 82.59% achieving DTBT ≤90 min and 49.77% achieving DTBT ≤60 min. For Killip I-III (n = 11,591,83.85%), the median DTBT was 60[46-78]min. The 30-day all-cause mortality for DTBT of ≤60 min, 61-90 min and 91-180 min was 1.08%, 2.17% and 4.33% respectively (p < 0.001). On multivariate analysis, however, there was no significant difference for 30-day and 1-year outcomes across all DTBT (p > 0.05). For Killip IV, the median DTBT was 68[51-91]min. The 30-day all-cause mortality for DTBT of ≤60 min, 61-90 min and 91-180 min was 11.74%, 20.48% and 35.06% respectively (p < 0.001). On multivariate analysis for 30-day and 1-year outcomes, DTBT 91-180 min was an independent predictor of worse outcomes (p < 0.05), but there was no significant difference between DTBT of ≤60 min and 61-90 min (p > 0.05). CONCLUSION: In Killip I-III patients, DTBT had no significant impact on outcomes upon adjustment for confounders. Conversely, for Killip IV patients, a DTBT of >90 min was associated with significantly higher adverse outcomes, with no differences between a DTBT of ≤60 min vs. 61-90 min. Outcomes in STEMI involve a complex interplay of factors and recommendations of a lowered DTBT of ≤60 min will require further evaluation.

Combining Machine Learning with a Rule-Based Algorithm to Detect and Identify Related Entities of Documented Adverse Drug Reactions on Hospital Discharge Summaries.

INTRODUCTION: Discharge summaries contain valuable information about adverse drug reactions, but their unstructured nature makes them challenging to analyse and use as a signal source for pharmacovigilance. Machine learning has shown promise in identifying discharge summaries that contain related drug-adverse event pairs but has fared relatively poorer in entity extraction. METHODS: A hybrid model is developed combining rule-based and machine learning algorithms using discharge summaries with the aim of maximising capture of related drug-adverse event pairs. The rule first identifies segments containing adverse event entities within a 100-character distance from a drug term; machine learning subsequently estimates the relatedness of the drug and adverse event entities contained. The approach is validated on four independent datasets that are temporally and geographically separated from model development data. The impact of restricted drug-adverse event pair detection on recall is evaluated by using two of the four validation datasets that do not impose rule-based restrictions to annotations. RESULTS: The hybrid model achieves a recall of 0.80 (fivefold cross validation), 0.80 (temporal) and 0.76 (geographical) on validation using datasets containing only pre-identified target text segments that fulfil the rule-based algorithm criteria. When tested on datasets that additionally contained drug-adverse event pairs not restricted by the rule-based criteria, recall of the model declines to 0.68 and 0.62 on temporally and geographically separated datasets, respectively. CONCLUSIONS: The proposed hybrid model demonstrates reasonable generalisability on external validation. Rule-based restriction of the detection space results in an approximately 12-14% reduction in recall but improves identification of the related drug and adverse event terms.

Making a Traditional Spine Surgery Clinic Telemedicine-Ready in the "New Normal" of Coronavirus Disease 2019.

STUDY DESIGN: An original article describing a comprehensive methodology for making a traditional spine surgery clinic telemedicineready in terms of logistical considerations and workflow. PURPOSE: The aim of this study is to promote the use of telemedicine via videoconferencing to reduce human exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and reduce the risk of coronavirus disease 2019 (COVID-19) transmission at outpatient clinics. OVERVIEW OF LITERATURE: The COVID-19 pandemic is the biggest healthcare crisis in the 21st century. Until a vaccine is developed or herd immunity against SARS-CoV-2 is achieved, social distancing to avoid crowding is an important strategy to reduce disease transmission and resurgence. Telemedicine has already been applied in the field of orthopedics with encouraging results. METHODS: We reviewed the evidence behind telemedicine and described our clinical protocol, patient selection criteria, and workflow for telemedicine. We discussed a simple methodology to convert pre-existing traditional clinic resources into telemedicine tools, along with future challenges. RESULTS: Our methodology was successfully and easily applied in our clinical practice, with a streamlined workflow allowing our spine surgery service to implement telemedicine as a consultation modality in line with the national recommendations of social distancing. CONCLUSIONS: Telemedicine was well incorporated into our outpatient practice using the above workflow. We believe that the use of telemedicine via videoconferencing can become part of the new normal and a safe strategy for healthcare systems as both a medical and an economic countermeasure against COVID-19.

Percutaneous pulmonary valve implantation as an alternative to repeat open-heart surgery for patients with pulmonary outflow obstruction: a reality in Singapore.

Right ventricle to pulmonary artery (RV-PA) conduits have been used for the surgical repair of congenital heart defects. These conduits frequently become stenosed or develop insufficiency with time, necessitating reoperations. Percutanous pulmonary valve implantation (PPVI) can delay the need for repeated surgeries in patients with congenital heart defects and degenerated RV-PA conduits. We presented our first experience with PPVI and described in detail the procedural methods and the considerations that are needed for this intervention to be successful. Immediate and short-term clinical outcomes of our patients were reported. Good haemodynamic results were obtained, both angiographically and on echocardiography. PPVI provides an excellent alternative to repeat open-heart surgery for patients with congenital heart defects and degenerated RV-PA conduits. This represents a paradigm shift in the management of congenital heart disease, which is traditionally managed by open-heart surgery.

Clinics in diagnostic imaging (186). Atrial septal defect with pulmonary arterial hypertension.

We report a case of a 61-year-old woman with a large atrial septal defect (ASD) that was detected incidentally on chest radiography and computed tomography when she presented with sepsis. Echocardiography confirmed a large secundum ASD with left-to-right shunt flow, right heart dilatation and severe pulmonary hypertension. The patient had a poor clinical outcome despite intensive care and eventually passed away. Haemodynamically significant ASDs have a known association with increased morbidity and mortality, and their early detection and closure cannot be understated. This article aimed to highlight the imaging features of ASD, with special emphasis on the routine chest radiograph. The pathophysiology and clinical manifestations of ASD are also briefly discussed.

Mid-term study of transcatheter aortic valve implantation in an Asian population with severe aortic stenosis: two-year Valve Academic Research Consortium-2 outcomes.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is an effective treatment for high-risk or inoperative patients with severe aortic stenosis. Given the unique characteristics of Asian populations, questions regarding mid-term outcomes in Asians undergoing TAVI have yet to be addressed. We evaluated the two-year clinical outcomes of TAVI in an Asian population using Valve Academic Research Consortium-2 definitions. METHODS: This prospective study recruited 59 patients from a major academic medical centre in Singapore. The main outcomes were two-year survival rates, peri-procedural complications, symptom improvement, valvular function and assessment of learning curve. RESULTS: Mean age was 76.8 years (61.0% male), mean body surface area 1.6 m2 and mean logistic EuroSCORE 18.7%. Survival was 93.2%, 86.0% and 79.1% at 30 days, one year and two years, respectively. At 30 days post TAVI, the rate of stroke was 1.7%, life-threatening bleeding 5.1%, acute kidney injury 25.0%, major vascular complication 5.1%, and new permanent pacemaker implantation 6.8%. 29.3% of TAVI patients were rehospitalised (47.1% cardiovascular-related) within one year. These composite outcomes were measured: device success (93.2%); early safety (79.7%); clinical efficacy (66.1%); and time-related valve safety (84.7%). Univariate analysis found these predictors of two-year all-cause mortality: logistic EuroSCORE (hazard ratio [HR] 1.07; p < 0.001); baseline estimated glomerular filtration rate (HR 0.97; p = 0.048); and acute kidney injury (HR 5.33; p = 0.022). Multivariate analysis identified non-transfemoral TAVI as a predictor of cardiovascular-related two-year mortality (HR 14.64; p = 0.008). CONCLUSION: Despite the unique clinical differences in Asian populations, this registry demonstrated favourable mid-term clinical and safety outcomes in Asians undergoing TAVI.

Oral sildenafil therapy improves health-related quality of life and functional status in pulmonary arterial hypertension.

Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase-5 inhibitor, has shown promising results as a novel oral monotherapy in the treatment of pulmonary arterial hypertension (PAH). We conducted a cross-sectional survey of 19 consecutive PAH patients, aged 16-75 years, with WHO functional class II or worse over 3 months of oral sildenafil. Improvement in exercise capacity was achieved in 15/19 (79%) patients. 6-minute walk test distance increased from 299+/-118 m to 360+/-127 m, p=0.016, and WHO functional class decreased significantly. Both PASP and CI showed a non-significant trend toward improvement. Patients also reported significant improvement in physical (p=0.002) and social (p<0.001) functioning, and general health (p=0.01) of Rand SF-36 questionnaire. There was improvement in domains of role limitation due to physical health (p=0.16), emotion (p=0.14), and energy level (p=0.4). Our study suggests that oral sildenafil monotherapy is effective in improving exercise capacity and health-related quality of life amongst PAH patients.