Detection of Fraud in a Clinical Trial Using Unsupervised Statistical Monitoring

Background A central statistical assessment of the quality of data collected in clinical trials can improve the quality and efficiency of sponsor oversight of clinical investigations. Material and Methods The database of a large randomized clinical trial with known fraud was reanalyzed with a view to identifying, using only statistical monitoring techniques, the center where fraud had been confirmed. The analysis was conducted with an unsupervised statistical monitoring software using mixed-effects statistical models. The statistical analyst was unaware of the location, nature, and extent of the fraud. Results Five centers were detected as atypical, including the center with known fraud (which was ranked 2). An incremental analysis showed that the center with known fraud could have been detected after only 25% of its data had been reported. Conclusion An unsupervised approach to central monitoring, using mixed-effects statistical models, is effective at detecting centers with fraud or other data anomalies in clinical trials.

The Evolution of the Use of Extracorporeal Membrane Oxygenation in Respiratory Failure

Extracorporeal membrane oxygenation (ECMO) has been used with increasing frequency to support patients with acute respiratory failure, most commonly, and severe forms of acute respiratory distress syndrome (ARDS). The marked increase in the global use of ECMO followed the publication of a large randomized trial in 2009 and the experience garnered during the 2009 influenza A (H1N1) pandemic, and has been further supported by the release of a large, randomized clinical trial in 2018, confirming a benefit from using ECMO in patients with severe ARDS. Despite a rapid expansion of ECMO-related publications, optimal management of patients receiving ECMO, in terms of patient selection, ventilator management, anticoagulation, and transfusion strategies, is evolving. Most recently, ECMO is being utilized for an expanding variety of conditions, including for cases of severe pulmonary or cardiac failure from coronavirus disease 2019 (COVID-19). This review evaluates modern evidence for ECMO for respiratory failure and the current challenges in the field.

Which Target Temperature for Post-Anoxic Brain Injury? A Systematic Review from “Real Life” Studies

There is a persistent debate on the optimal target temperature to use during cooling procedures in cardiac arrest survivors. A large randomized clinical trial (RCT) including more than 900 patients showed that targeted temperature management (TTM) at 33 °C had similar mortality and unfavorable neurological outcome (UO) rates as TTM at 36 °C in out-of-hospital cardiac arrest patients with any initial rhythm. Since then, several observational studies have been published on the effects of changes in target temperature (i.e., from 33 to 36 °C) on patients’ outcome. We performed a systematic literature search from 1 January 2014 to 4 December 2020 and identified ten retrospective studies (very low levels of certainty; high risk of bias), including 5509 patients, that evaluated TTM at 33 °C vs. TTM at 36 °C on the occurrence of UO (n = eight studies) and mortality (n = ten studies). TTM at 33 °C was associated with a lower risk of UO when studies assessing neurological outcome with the Cerebral Performance Categories were analyzed (OR 0.80 [95% CIs 0.72–0.98]; p = 0.03). No differences in mortality were observed within the two TTM strategies. These results suggest that an inappropriate translation of TTM protocols from large well-conducted randomized trials into clinical management may result in unexpected effects on patients’ outcome. As for all newly commercialized drugs, epidemiological studies and surveillance programs with an adequate follow-up on large databases are necessary to understand how RCTs are implemented into medical practice.

Evolving Concepts in Post-PCI Antiplatelets Therapy

The standard duration dual antiplatelet therapy (DAPT) is considered as gold standard for post percutaneous coronary intervention (PCI) medical therapy, as mentioned in American College of Cardiology/American Heart Association 2016 and European Society of Cardiology 2017 guidelines. Recently it has been challenged, in terms of duration and composition of this therapy. Many newer regimens and therapeutic drugs are being tried in large randomized clinical trial studies and found to be as effective as DAPT if not superior. There is general trend to introduce better antiplatelets like P2Y12 inhibitor (prasugrel and ticagrelor) as monotherapy for longer duration and restricting use of aspirin beyond 3 months. This review article helps us in understanding the evolution of DAPT therapy, formation of guidelines, and what are the new and evolving concepts in post-PCI medical therapy.

Hostility predicts mortality but not recurrent acute coronary syndrome

Background: Hostility is associated with greater risk for cardiac disease, cardiac events and dysrhythmias. Investigators have reported equivocal findings regarding the association of hostility with acute coronary syndrome (ACS) recurrence and mortality. Given mixed results on the relationship between hostility and cardiovascular outcomes, further research is critical. Aims: The aim of our study was to determine whether hostility was a predictor of ACS recurrence and mortality. Methods: We performed a secondary analysis of data ( N = 2321) from a large randomized clinical trial of an intervention designed to reduce pre-hospital delay among patients who were experiencing ACS. Hostility was measured at baseline with the Multiple Adjective Affect Checklist (MAACL) and patients were followed for 24 months for evaluation of ACS recurrence and all-cause mortality. We used Cox proportional hazards modeling to determine whether hostility was predictive of time to ACS recurrence or all-cause mortality. Results: The majority of patients were married (73%), Caucasian (97%), men (68%), and had a mean age of 67 ± 11 years. Fifty-seven percent of participants scored as hostile based on the established MAACL cut point (mean score = 7.56 ± 3.8). Hostility was an independent predictor of all-cause mortality ( p = < 0.039), but was not a predictor of ACS recurrence ( p = 0.792). Conclusion: Hostility is common in patients with ACS and its relationship to clinical outcomes is important to the design of future interventions to improve long-term ACS mortality.

Preoperative, Intraoperative and Postoperative Corticosteroid Use as an Adjunctive Treatment for Rhegmatogenous Retinal Detachment

The treatment for rhegmatogenous retinal detachment (RRD) is surgery, including pars plana vitrectomy (PPV) and scleral buckling (SB). Despite surgical advances, degeneration of the photoreceptors and post-operative complications, such as proliferative vitreoretinopathy (PVR), often occurs as the result of inflammation, preventing complete visual recovery or causing RRD recurrence. There is increasing evidence that in the presence of RRD, the activation of inflammatory processes occurs and the surgery itself induces an inflammatory response. This comprehensive review focuses on the use of different formulations of corticosteroids (CCS), as an adjunctive treatment to surgery, either PPV or SB, for RRD repair. The purpose was to review the efficacy and safety of CCS in improving functional and anatomical outcomes and in preventing postoperative complications. This review is organized according to the timing of CCS administration: preoperative, intraoperative, and postoperative. The evidence reviewed supported the role of the pre-operative use of CCS in the treatment of combined RRD and choroidal detachment (CD), reducing CD height. No solid consensus exists on intraoperative and postoperative use of CCS to treat and prevent postoperative complications. However, a large randomized clinical trial including more than 200 eyes suggested that oral prednisone after surgery decreases the rate of postoperative grade B PVR.

P5733IABP use in patients with STEMI complicated by cardiogenic shock: time for rehabilitation?

Background Evidence from a large randomized clinical trial has led international guidelines to downgrade to Class III the recommendation level for the routine use of intra-aortic balloon pump (IABP) in patients with STEMI complicated by cardiogenic shock (CS). Despite this, its use in clinical practice remains high. Purpose The aim of our study was to evaluate whether IABP use could provide a prognostic benefit in a large real-world population of STEMI patients undergoing primary PCI (pPCI). Methods Our registry included 2958 consecutive patients undergoing primary pPCI for STEMI in our department from 2005 to 2017. The presence of a persistent (>30 min) systolic blood pressure <90 mmHg and signs of pulmonary congestion or impaired end organ perfusion needing catecholamine infusion qualified for CS. Among patients with CS we compared mortality between those with and those without IABP in the whole population and in the pre-specified subgroup with anterior STEMI. Univariate (cross-tables and Kaplan-Meier curves with log-rank test) and multivariate mortality analysis (Cox regressions) were performed. Results CS occurred in 246 patients (8.3%); among these patients, 145 (60%) had anterior AMI. Mortality at 30 days was 3.7 in inferior vs 7.1% in anterior STEMI (p<0.001). In these two groups of patients, IABP was used in 32% and 66.7% of cases, respectively. In the whole CS group, IABP use was associated with a lower 30-day mortality (39% vs 53%, p=0.020 – see figure panel A); this figure was confirmed at multivariable analysis (HR 0.49, 95% CI 0.27–0.87, p=0.016) after adjusting for age, CK peak, triple-vessel disease, eGFR and all-TIMI bleeding during hospital stay. IABP use in CS patients was not associated with major complications or an increased rate of Hb drop (>3 mg/dL) during hospital stay. In the subgroup of patients with anterior STEMI, there was a marked survival benefit at univariate analysis (30-day mortality 41% vs 61%, p=0.013 – see figure panel B), confirmed at multivariable analysis (HR 0.40, 95% CI 0.19–0.88, p=0.023) after adjusting for the same variables of the previous model. In the subgroup of patients with inferior STEMI, IABP use was not significantly associated with a lower 30-day mortality (32% vs 41%, p=0.380). Figure 1 Conclusion In the present large real-world cohort of unselected patients with STEMI, the use of IABP in case of CS was found to improve survival. This finding suggests that IABP could still play a role in patient with STEMI complicated by CS, especially when additional risk features are present, such as anterior MI. We suggest that additional careful prospective studies are needed before abandoning or markedly limiting the use of IABP in this clinical setting.