Spotlight on Givosiran as a Treatment Option for Adults with Acute Hepatic Porphyria: Design, Development, and Place in Therapy.

Small interfering ribonucleic acids [siRNAs] are short ribonucleic acid (RNA) fragments cleaved from double-stranded RNA molecules that target and bind to specific sequences on messenger RNA (mRNA), leading to their destruction. Therefore, the siRNA down-regulates the formation of selected mRNAs and their protein products. Givosiran is one such siRNA that uses this mechanism to treat acute hepatic porphyrias. Acute hepatic porphyrias are a group of rare, inherited metabolic disorders, characterized by acute potentially life-threatening attacks as well as chronic symptoms with a negative impact on quality of life. It has four types, each associated with distinct enzyme defects in the heme biosynthesis pathway in the liver. By targeting the expression of hepatic 5-aminolevulinic acid [ALA] synthase-1 [ALAS1], givosiran can down-regulate levels of toxic metabolites, leading to biochemical and clinical improvement. Givosiran selectively targets hepatocytes due to its linkage to N-acetylgalactosamine (GalNac) leading to its selective uptake via asialoglycoprotein receptors (ASGPR). We provide an up-to-date literature review regarding givosiran in the context of a clinical overview of the porphyrias, an overview of siRNAs for therapy of human disorders, the design and development of givosiran, key clinical trial results of givosiran for prevention of acute porphyric attacks, emerging concerns regarding chronic use of givosiran, and the overall management of acute hepatic porphyrias. These insights are important not only for the management of acute hepatic porphyrias but also for the emerging field of siRNAs and their role in novel therapies for various diseases.

Meta-analysis of minimalist versus standard care approach for transcatheter aortic valve replacement.

BACKGROUND: The change in practice of transcatheter aortic valve replacement (TAVR) to a minimalist approach is a debate. METHODS: Online database search for studies that compared the minimalist approach with the standard approach for TAVR were searched from inception through September 2020. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) using the fixed or random-effects model. RESULTS: A total of 9 studies with 2,880 TAVR patients (minimalist TAVR;1066 and standard TAVR; 1,814) were included. Compared to standard approach, there were no significant differences in in-hospital mortality, 30-day mortality, or hospital readmissions. However, there was a reduced risk of acute kidney injury (OR0.49;95%CI0.27-0.89), major bleeding (OR0.21;95%CI0.12-0.38) and major vascular complications (OR0.60,95%CI0.39-0.91) associated with the minimalist TAVR group. There was comparatively shorter hospital length of stay (mean difference -2.41;95%CI-2.99,-1.83) days, procedural time (mean difference -43.99;95%CI-67.25,-20.75) minutes, fluoroscopy time (mean difference -2.69;95%CI-3.44,-1.94) minutes and contrast volume (mean difference -26.98;95%CI-42.18,-11.79) ml in the minimalist TAVR group. CONCLUSIONS: This meta-analysis demonstrated potential benefits of the minimalist TAVR approach over the standard approach regarding some adverse clinical outcomes as well as procedural outcomes without significant differences in mortality or readmission rates.

Systematic review with meta-analysis: abnormalities in the international normalised ratio do not correlate with periprocedural bleeding events among patients with cirrhosis.

BACKGROUND: Cirrhotic coagulopathy is a delicate interplay comprising deficiencies of both procoagulant and anticoagulant factors. AIM: To identify the relationship between international normalised ratio [INR] with periprocedural bleeding risk among patients with cirrhosis. METHODS: Following a thorough database search of the primary literature, 29 studies were targeted for analysis, including 13 276 patients with cirrhosis undergoing indicated procedures. RESULTS: There was no significant association between periprocedural bleeding events and pre-procedural INR [pooled odds ratio 1.52; 95% CI 0.99, 2.33; P = 0.06]. Furthermore, there was no significant difference in mean INR [pooled mean difference 0.05; 95% CI -0.03, 0.13; P = 0.23] upon comparison of patients who either did or did not experience a periprocedural bleeding event. Significant heterogeneity among some studies was primarily fuelled by significant subgroup effects of both specific procedure types performed. Additionally, there were markedly inconsistent transfusion practices across studies. CONCLUSIONS: INR fails to serve as a significant correlate for periprocedural bleeding events among patients with cirrhosis. Ideally, these new findings will help serve as a springboard for future studies, as well as to minimize transfusion of blood products, which command a myriad of adverse effects among patients with cirrhosis.

Risk of Mortality Associated With Therapeutic Hypothermia Among Sudden Cardiac Arrest Survivors With Known Heart Failure.

Current guidelines do not inform about use of therapeutic hypothermia among heart failure (HF) patients who suffer from cardiac arrest. We assessed the risk of mortality associated with hypothermia among cardiac arrest survivors with HF. This analysis includes 1,416 comatose patients with cardiac arrest who achieved return of spontaneous circulation on admission and had a left ventricular ejection fraction (LVEF) assessment or HF admission within the previous year. HF was defined as either previous episode of HF or presence of left ventricular ejection fraction <50%. Hazard ratios (HR) and 95% confidence intervals (CI) for association of hypothermia and mortality among patients with and without HF were computed using Cox proportional hazard models adjusted for several risk factors. A propensity score matched analysis was also performed. There were 624 patients (44%) with pre-existing HF and 467 patients (33.0%) received hypothermia. The mortality rate was higher in HF patients treated with hypothermia compared with patients without hypothermia (75.4% vs 53.2%, p <0.0001). Hypothermia was associated with increased mortality among HF patients (HR 1.69; 95% CI 1.27, 2.24, p <0.001) and was not associated with mortality among non-HF patients (HR 1.21; 95% CI 0.93, 1.56, p = 0.15). The association of hypothermia with mortality was higher among HF patients who presented with shockable rhythm compared with nonshockable rhythm (interaction p value = 0.0495). Hypothermia is associated with increased mortality among cardiac arrest survivors with known HF.

Relation of Marital Status and QT Interval Prolongation (from the Third National Health and Nutrition Examination Survey).

Although the link between marital status and mortality is well established, the pathophysiological basis is unclear. An investigation of the association of marital status with prolonged QT interval may highlight the underlying mechanism for poor outcomes associated with being unmarried. This analysis included 6,562 participants (mean age 58.6 years, 52% women, 50.1% non-Hispanic whites) without a history of cardiovascular disease from the Third National Health and Nutrition Examination Survey. QT was automatically measured from digital 12-lead electrocardiogram in a central reading center. Marital status was defined by self-report as married and unmarried (never married, divorced/separated or widowed). A multivariable logistic regression model was used to examine cross-sectional association between marital status and prolonged QT interval (≥450 ms in men, ≥460 ms in women). Compared with married, unmarried was associated with 46% higher odds of the prolonged QT interval (odds ratio [OR] 95% confidence interval [95% CI]: 1.46[1.16-1.83]). This association was stronger among men versus women (OR[95% CI]: 1.75[1.27-2.41] vs 1.26[0.92-1.73] respectively; interaction p value = 0.03) and in younger versus older participants (OR [95% CI]: 1.72[1.21-2.42] vs 1.40[1.05-1.88], respectively; interaction p value = 0.002). When the types of unmarried were compared to married, a dose-response relation with prolonged QT was observed with the highest odds in never married followed by divorced/separated, and then widowed. In conclusion, marital status is associated with a prolonged QT interval, especially among men and younger participants. Prolonged QT interval may indicate a biologic substrate through which social isolation defined by unmarried state increases the risk of poor outcomes in the future.