2 Minute Medicine Rewind August 3, 2020

Characteristics and Strength of Evidence of COVID-19 Studies Registered on ClinicalTrials.gov

1. While there has been a rise in clinical trials on COVID-19, a large proportion of these studies are expected to yield low levels of evidence.

Evidence Rating Level: 3 (Average)

The rapid and widespread transmission of coronavirus disease 2019 (COVID-19) has resulted in a wide range of clinical research to better understand its characteristics and course. It has been speculated that the inherent urgency imposed by the pandemic may have an impact on the methodologies being used by researchers, though this has not been formally assessed. This cross-sectional analysis sought to characterize these studies and methodologies through a March 19, 2020 search of ClinicalTrials.gov. Only active studies were included. A total of 1,551 studies registered between March 1, 2011 and May 19, 2020 met inclusion criteria. Of these, 76.1% were single-center, 41.3% observational studies, and 42.8% randomized clinical trials (RCTs). Treatment complications (23.1%), ventilation requirements (26.6%), and mortality (33.9%) were common primary and secondary outcomes. Of all studies, 29.1% harbored the capacity to yield the highest level of individual study evidence (OCEBM level 2). Across the 664 RCTs, clinical course was the most common primary outcome (48.6%) while 7.7% had a primary outcome of mortality. Approximately 54.8% of the RCTs were blinded, such that they could achieve OCEBM level 2 evidence. Only 11.3% were placebo-controlled and blinded. Most evaluated drugs and biologic agents: hydroxychloroquine or chloroquine (23.3%), remdesivir (1.1%), other antivirals (7.2%), tocilizumab (3.2%), and corticosteroids (3.0%). Overall, this analysis of clinical trials suggests that majority of studies are expected to yield a low level of evidence. With rising rates of COVID-19 cases and difficulty controlling its spread on a national scale, it is important that researchers do not forego methodology in favour of speed and convenience, in order to maximize the ability to generate clinically meaningful results.


Trends in Antihypertensive Medication Use Among Individuals With a History of Stroke and Hypertension, 2005 to 2016

1. In a large, national sample, approximately 37.1% of patients with stroke history had uncontrolled blood pressure.

2. Most patients on medication were taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, or calcium channel blockers.

Evidence Rating Level: 2 (Good)

Stroke is ranked as a leading cause of mortality and disability in the U.S. Hypertension among individuals with a history of stroke is both common and undertreated, serving as an area for improvement in stroke prevention. In this cross-sectional study, researchers utilized data on blood pressure and antihypertensive treatment trends among stroke survivors from the National Health and Nutrition Examination Survey (NHANES) to further characterize the relationship between the hypertension and stroke. These cross-sectional surveys of nationally-representative samples were conducted between 2005 and 2016. A total of 4,971,136 individuals with a history of hypertension and stroke were included in the analyses (M age = 67.1 years, 95% CI 66.1 to 68.1, 56.1% female). Of these individuals, 37.1% were determined to have uncontrolled blood pressure upon examination while 80.4% were prescribed and taking antihypertensive medication. Most of these patients were taking angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (59.2%, 95% CI 54.9 to 63.4) and beta-blockers (43.8%, 95% CI 40.3 to 47.3). Diuretics were used by 41.6% (95% CI 37.3 to 45.9) and calcium channel blockers were used by 31.5% (95% CI 28.2 to 34.8). When evaluating trends of antihypertensive use across time with linear regression models, diuretics became significantly less common in 2015-2016 compared to 2005-2006 (35.7% vs. 49.4%, p = 0.005). This study was the first to investigate national trends of medication use among stroke patients in the U.S. Limitations include lack of validation of stroke histories, such that stroke was self-reported by participants. Nonetheless, study findings demonstrate a significant need for improvement in secondary prevention in those with histories of stroke.


Assessment of Cognitive and Neural Recovery in Survivors of Pediatric Brain Tumors In a Pilot Clinical Trial Using Metformin

1. Metformin was found to be safe and tolerable in survivors of pediatric brain tumors.

2. Metformin was associated with retention of memory and processing speed abilities, as well as a reduction of white matter loss.

Evidence Rating Level: 1 (Excellent)

It is believed that endogenous neural precursor cells (NPCs) can promote tissue repair in the human brain due to its precursor cell populations. This is an important consideration due to limited self-repair capacities of the brain, such that agents inducing proliferation and differentiation of NPCs in vivo, validated in rodent models, could benefit humans. The hypoglycemic agent metformin has been found to increase neurogenesis in rodent models, particularly through activating the atypical protein kinase C (APKC)-CREB-binding protein (CBPT) pathway in NPCs. Metformin also improved cognitive faculties such as spatial memory. Its ability to decrease disease-related hippocampal neuron loss, metformin may also have the ability to recruit NPCs to repair brain tissue in humans. This pilot randomized, double-blind, placebo-controlled clinical trial with crossover focused on survivors of pediatric brain tumors treated with cranial radiation due to the hippocampus and white matter, high in NPCs, are most commonly damaged during cranial radiation. Specifically, safety and feasibility of metformin among this population was investigated. A total of 24 participants were randomly assigned to 12-week cycles of metformin (n = 11; M [SD] age = 7.26 [3.34] years) and placebo (n = 12; M [SD] age = 6.44 [3.63] years) in either an AB or BA sequence. A 10-week washout period occurred at crossover. Cranial radiation of participants occurred 2 to 15 years prior to the study. Blood draws, MRI, medication and procedural adherence, and cognition were measured throughout the study. A total of 12 participants were medulloblastoma survivors. This study found that, in spite of increased mild gastrointestinal events, metformin was both tolerable and safe. It also appeared that metformin reduced the negative impacts of radiation on processing speed, memory, and white matter loss consistent with the population. While this study’s sample was relatively small, it suggests that metformin may be beneficial to this population through the recruitment of NPCs to repair tissue damage and retain cognitive faculties.


Effectiveness of the Ready to Reduce Risk (3R) Complex Intervention for the Primary Prevention of Cardiovascular Disease: A Pragmatic Randomised Controlled Trial

1. The standardized Ready to Reduce Risk (3R) program resulted in improvements to lifestyle among those taking medication for prevention of cardiovascular disease.

2. 3R did not improve medication adherence compared to the control group.

Evidence Rating Level: 2 (Good)

Nearly one-third of deaths across the globe are attributable to cardiovascular disease (CVD), 80% of which are due to premature stroke and heart disease. Primary prevention strategies are important to curb this mortality rate and reduce risk of disease. The Ready to Reduce Risk (3R) intervention was created to respond to multiple risk factors of CVD, particularly improving statin adherence. 3R also includes two group education sessions with follow-up phone support and text messages. This pragmatic, randomized controlled trial aimed to standardize a curriculum for intervention and incorporate an objective biochemical measure of statin adherence. Recruitment and initial data collection occurred between May 2016 and March 2017. Participants were required to be aged 40 to 74 years, have a current statin prescription for at least the past two years for CVD prevention, total cholesterol level ≥5.0 mmol/l, and no pre-existing CVD or inherited lipid disorders or type 1 or type 2 diabetes. A total of 212 participants were randomized, with 120 participants having available urine data and 81 attending the final education sessions and receiving text messages. MMAS-8 data were used to compensate for missing urine values, resulting in a sample size of 206 (M [SD] age = 63.9 [7.2] years, 97% White, 54% female). Baseline statin adherence was 47% for the control group (n = 33) and 62% for the intervention group (n = 40). At 12 months, no differences were discovered between control and intervention groups in medication adherence (adjusted OR 0.91). Diastolic blood pressure was significantly different between groups, such that the intervention group had lower recordings (M difference = -4.28 mmHg, 95% CI -0.98 to -1.58, p = 0.002). Waist circumference also favored the intervention group (M difference = -2.55cm, 95% CI -4.55 to -0.55, p = 0.012). This study also reported that the intervention group demonstrated greater understanding of the condition and control of their treatment. Overall, 3R seems to be a beneficial primary prevention method for populations at risk for CVD but does not improve medication adherence. Thus, further efforts are necessary to improve adherence to medication regimens.


Neonatal Outcome in 29 Pregnant Women With COVID-19: A Retrospective Study in Wuhan, China

1. Approximately 41.4% of neonates born to COVID-19-positive women in Wuhan, China presented with radiological findings of pneumonia

2. Limited sample size and comparisons limit interpretations, but intrauterine or intrapartum transmission may be possible.

Evidence Rating Level: 3 (Average)

Coronavirus disease 2019 (COVID-19) has surged over the course of several months, with more than 6,000,000 known cases and 360,000 deaths across the globe since June 1, 2020. Previous studies have revealed that pregnant women experience clinical symptoms similar to non-pregnant women. However, the outcomes of neonates born to COVID-19-infected women is not yet known. This retrospective study of 29 pregnant women (M [SD] age = 29.59 [3.56] years, 56.6% higher education, 51.7% employed) with COVID-19 (13 confirmed, 16 clinically diagnosed) across two general hospitals in Wuhan, China sought to investigate these neonatal outcomes. Data was collected between January 30 and March 10, 2020 with 30 neonates, with one set of twins. Maternal demographic and clinical information was included, along with laboratory tests and chest x-ray and/or computed tomography of neonates who were hospitalized. Hospitalization occurred with 18 cases, where neonates either had symptoms (5 cases) or their guardians agreed to quarantine (13 cases). All but 3 cases (10.34%) were born between 36- and 41-weeks’ gestation. For 12 cases, neonates were discharged following birth with telephone follow-up. A total of 12 hospitalized neonates presented with radiological features of pneumonia through chest screening, 1 presented with cough and other associated symptoms. SARS-CoV-2-specific serum immunoglobulin M and immunoglobulin G were measured in 4 neonates, with 2 being positive. In spite of the limited sample size and reduced statistical power, this study suggests that intrapartum or intrauterine transmission of COVID-19 may be possible, resulting in associated radiological findings of pneumonia in certain neonates.

Image: PD

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