Introducing the fragility index—A case study using the Term Breech Trial

The fragility index (FI) is a sensitivity analysis of the statistically significant result of a clinical study. It is the number of hypothetical changes in the primary event of one of the two cohorts in a 1-to-1 comparative trial to render the statistically significant result non-significant (ie, to alter the P-value from ≤0.05 to >0.05). The FI can be compared with the patient drop-out rates and protocol violations, which, if much higher than the FI, may arguably suggest less robustness/stability of the trial's results. To illustrate the concept, we have chosen the Term Breech Trial (TBT) as a case study. The TBT results favor planned cesarean birth, as opposed to planned vaginal delivery, in the term singleton fetus with breech presentation. Our analysis shows that the FI of the TBT is 21, which is small in comparison to the number (hundreds) of protocol violations present. Some experts have suggested the inclusion of the FI in data analysis and subsequent discussion of clinical trial data. Routine use of such a metric may be valuable in encouraging readers to maintain a healthy degree of skepticism, especially when interpreting trial results which may directly influence clinical practice.     

Defibrillation strategies for refractory ventricular fibrillation out-of-hospital cardiac arrest: A systematic review and network meta-analysis

Background and Objective

Double sequential external defibrillation (DSED) and vector-change defibrillation (VCD) have been suggested to enhance clinical outcomes for patients with ventricular fibrillation (VF) refractory of standard defibrillation (SD). Therefore, this network meta-analysis aims to evaluate the comparative efficacy of DSED, VCD, and SD for refractory VF.

Methods

A systematic review and network meta-analysis synthesizing randomized controlled trials (RCTs) and comparative observational studies retrieved from PubMed, EMBASE, WOS, SCOPUS, and Cochrane through November 15th, 2022. R software netmeta and netrank package (R version 4.2.0) and meta-insight software were used to pool dichotomous outcomes using odds ratio (OR) presented with the corresponding confidence interval (CI). Our protocol was prospectively published in PROSPERO with ID: CRD42022378533 .

Results

We included seven studies with a total of 1632 participants. DSED was similar to SD in survival to hospital discharge (OR: 1.14 with 95% CI [0.55, 2.83]), favorable neurological outcome (modified Rankin scale ≤2 or cerebral performance category ≤2) (OR: 1.35 with 95% CI [0.46, 3.99]), and return of spontaneous circulation (ROSC) (OR: 0.81 with 95% CI [0.43; 1.5]). In addition, VCD was similar to SD in survival to hospital discharge (OR: 1.12 with 95% CI [0.27, 4.57]), favorable neurological outcome (OR: 1.01 with 95% CI [0.18, 5.75]), and ROSC (OR: 0.88 with 95% CI [0.24; 3.15]).

Conclusion

Double sequential external defibrillation and VCD were not associated with enhanced outcomes in patients with refractory VF out-of-hospital cardiac arrest, compared to SD. However, the current evidence is still inconclusive, warranting further large-scale RCTs.     

Association of gut microbiome dysbiosis with the progression of atrial fibrillation: A systematic review

Objective

Many clinical and preclinical studies have implicated an association between atrial fibrillation (AF) and its progression to imbalances in the gut microbiome composition. The gut microbiome is a diverse and complex ecosystem containing billions of microorganisms that produce biologically active metabolites influencing the host disease development.

Methods

For this review, a literature search was conducted using digital databases to systematically identify the studies reporting the association of gut microbiota with AF progression.

Results

In a total of 14 studies, 2479 patients were recruited for the final analysis. More than half (n = 8) of the studies reported alterations in alpha diversity in atrial fibrillation. As for the beta diversity, 10 studies showed significant alterations. Almost all studies that assessed gut microbiota alterations reported major taxa associated with atrial fibrillation. Most studies focused on short-chain fatty acids (SCFAs), whereas three studies evaluated TMAO levels in the blood, which is the breakdown product of dietary l -carnitine, choline, and lecithin. Moreover, an independent cohort study assessed the relationship between phenylacetylglutamine (PAGIn) and AF.

Conclusion

Intestinal dysbiosis is a modifiable risk factor that might provide newer treatment strategies for AF prevention. Well-designed research and prospective randomized interventional studies are required to target the gut dysbiotic mechanisms and determine the gut dysbiotic-AF relationship.