2 Minute Medicine Rewind May 4, 2020

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

1. Adults with severe COVID-19 treated with remdesivir had numerically faster time to clinical improvement compared to controls, but the difference was not statistically significant

Evidence Rating: 1 (Excellent)

Months into declaration of COVID-19 as a pandemic, there still remains to be an antiviral therapy of proven effectiveness in treating the disease. Remdesivir has been an agent receiving great media attention, as it has shown significant anti-viral activity against coronaviruses in vitro, including SARS-CoV-2, and isolated case studies have reported a benefit in using the drug for affected patients. To formally address its clinical efficacy, researchers recruited 237 patients with laboratory confirmed pneumonia from SARS-CoV-2 in a randomized, double-blind, placebo-controlled multicenter trial, randomly assigning patients in a 2:1 ratio to either receive remdesivir (200mg on day 1 IV followed by 100mg for 9 days following) or a placebo infusion. The primary endpoint of interest was clinical improvement up to day 28, defined as time from randomization to point of a decline in two levels on a six-point ordinal scale. Patients assigned to the treatment group had a numerically faster time to clinical improvement compared to the placebo group  (median 18·0 days [IQR 12·0–28·0] vs 23·0 days [15·0–28·0]; HR 1·52 [0·95–2·43]), but results were not statistically significant. Likewise, rates of clinical improvement at days 14 and 28 were higher for the treatment group than placebo, but again, not statistically significant. Similar mortality rates were observed, and no significant differences were observed between the two groups in length of oxygen support, hospital stay, days from randomisation to discharge, or time to clearance of virus. The treatment regimen was well tolerated by the remdesivir group, with similar rates of adverse events compared to the placebo recipients. Overall, while minute differences in clinical course were observed between the two groups, no significant clinical or antiviral effects were found at the treatment dose in this study. Future investigations may choose to use larger sample sizes or initiate treatment earlier in the disease course to continue informing the collective understanding of potential antiviral therapies for COVID-19.

Association of the Risk of a Venous Thromboembolic Event in Emergency vs Elective General Surgery

1. Patients undergoing emergency general surgery in a retrospective cohort study were at nearly twice the risk of venous thromboembolism when compared to patients undergoing elective surgery.

Evidence Rating: 2 (Good)

Despite comprising a relatively small proportion of the total surgeries performed, procedures classified as emergency general surgery (EGS) account for a significant portion of postoperative complications and mortality.  To date however, no studies have established an association between risk of venous thromboembolism (VTE) and EGS, leading to a knowledge gap that may have prevented patients benefiting from more aggressive VTE chemoprophylaxis. In this retrospective cohort study, researchers examined data from 604,537 adult patients in the American College of Surgeons National Surgical Quality Improvement Program database over a 12 year period to investigate a possible link between VTE risk and EGS. Data from emergency surgeries were compared with elective surgeries of the same type, largely consisting of laparoscopic and open cholecystectomies, ventral hernia repairs (VHRs), and partial colectomies (PCs), with the primary outcome of interest being VTE occurrence at 30 days. After controlling for age, sex, BMI, surgery type, and other demographic features, it was found that VTE rates were significantly higher in the EGS patient group than the elective surgery group (1.9% vs. 0.8%; P < .001), with nearly triple the rate of DVT or thrombophlebitis (1.4% vs. 0.5%; P <.001), and double the rate of pulmonary embolism (0.6% vs. 0.3%; P <.001).  In concordance with prior literature, patients undergoing EGS were also more prone to surgical site infections, general complications, major complications, and had higher rates of 30 day readmission and 30 day mortality. This study represents the first investigation finding an independent association between EGS and VTE risk, and provides further evidence of greater morbidity and mortality associated with EGS compared with elective surgeries. As VTE are a highly preventable cause of morbidity and mortality among hospitalized patients, findings from this study support the use of more aggressive venous thromboembolism chemoprophylaxis and may be a new standard of practice with further investigation.

Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19)

1. Use of hydroxychloroquine with or without azithromycin to treat COVID-19 was frequently associated with QTc prolongation, with results being more pronounced for patients taking both hydroxychloroquine and azithromycin.

2. Likelihood of QTc prolongation was greater with concomitant usage of loop diuretics.

Evidence Rating: 2 (Good)

Although studies have found varying degrees of efficacy for hydroxychloroquine with or without azithromycin as a treatment option for COVID-19, the drug (combination) has gained significant traction worldwide and is one of the most common therapies used for affected patients. Though the drugs are generally well-tolerated amongst patients, both can cause corrected QT (QTc) prolongation, which should continue to be taken account in clinical practice despite the desperate search for effective treatment options. To better characterize the risk and degree of QTc prolongation in patients with COVID-19 associated with hydroxychloroquine and azithromycin usage, researchers performed a single-centre retrospective observational study consisting of 90 patients with laboratory confirmed COVID-19. The 90 patients included in the study received a standard regimen consisting of 400mg of hydroxychloroquine twice on the first day, followed by 400mg daily from days 2 through 5, and 53 patients additionally received azithromycin. Median baseline QTc reported was 455 milliseconds. Both groups were observed to have QT prolongation, at a median of 5.5 milliseconds and 23 milliseconds for the monotherapy and combinational therapy groups, respectively. Within a 4 week observation period, 21 of the 90 total patients (23%) had QTc prolongation of 60 milliseconds or greater, 11 of which had received azithromycin (21% of subgroup). Furthermore, the risk of QTc prolongation was also greater in patients who had received concomitant loop diuretics in addition to hydroxychloroquine, with significantly higher rates of patients having a QTc of 500 milliseconds or more (12 of 39 patients [31%] vs. 6 of 51 patients [12%]; P = .03). Though some studies may have found positive evidence for the application of hydroxychloroquine and azithromycin for the treatment of COVID-19, findings from the present study serve as a reminder for clinicians to continuing weighing the risks and benefits associated with drugs even in times of pandemic, and adopt strict QTc monitoring and vigilance for treatment cessation when necessary if they do decide to treat patients with the drug(s).

Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19

1. Amongst the five examined classes of antihypertensive medications (ACE Inhibitors, ARBs, Beta Blockers, Calcium-channel Blockers, and thiazide diuretics), none were associated with a substantial increase in likelihood of COVID-19.

Evidence Rating: 2 (Good)

Infection of host cells by SARS-CoV-2 is mediated via an interaction with membrane-bound angiotensin-converting enzyme (ACE) 2, and as such, it has been suggested that treatment with ACE inhibitors or angiotensin-receptor blockers (ARBs) may be associated with an increased risk of developing COVID-19. As such, antihypertensive medications such as calcium channel blockers, which do not interact with the renin-angiotensin-aldosterone system (RAAS), have been suggested as potential beneficial alternatives in affected patients. As hypertension affects nearly half of the American population, any potential interactions between antihypertensive medications and COVID-19 must be meaningfully sorted out, especially when considering ACE inhibitors are often prescribed as first line pharmacologic treatment for the condition. In this retrospective cohort study, data from a large health care network in New York City was used to determine whether antihypertensive medications were associated with any difference in risk of developing COVID-19. The study included 12,594 patients, 5894 (46.8%) who had confirmed COVID-19, of which 1002 patients had severe illness as indicated by ICU admission, mechanical ventilation requirements, or death. A total of 4357 (34.6%) patients from the dataset had hypertension, of which 2573 (59.1%) were COVID-19 positive. Using propensity-score matched analyses, an absolute difference of at least 10 percentage points in the likelihood of a positive test with at least 97.5% certainty was ruled out for ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, and thiazide diuretics. Likewise, there was no substantial difference in risk of developing severe disease among patients taking any of the antihypertensive medications. Overall, evidence from the study suggests that there are no direct adverse effects associated with ACE inhibitors, ARBs, or any of the other examined antihypertensive medications in the context of increasing risk of developing COVID-19.

Effect of Gonadotropin-Releasing Hormone Antagonist on Risk of Committing Child Sexual Abuse in Men With Pedophilic Disorder. A Randomized Clinical Trial..

1. Men with pedophilic disorder treated with gonadotropin-releasing hormone antagonist degarelix were at significantly lower risk of committing sexual abuse 2 weeks following initial injection, as measured by a composite risk score.

Evidence Rating: 1 (Excellent)

It is estimated that roughly half of child sexual offenders have pedophilic disorder, defined as recurrent sexual attraction to prepubescent children associated with distress or negative consequences. Prior literature have found that offenders often report long periods of struggle with sexual urges prior to first offence, suggesting a possible window for intervention before a crime is committed. Currently, treatment options are limited, with psychotherapy, testosterone-suppressing medications, and antidepressants being some of the few recommended intervention options. In this randomized clinical trial, researchers recruited 52 men with pedophilic disorder to investigate the possible efficacy of degarelix, a gonadotropin-releasing hormone antagonist to rapidly reduce the risk of committing child sexual abuse. Prior literature have found the drug to be effective in decreasing testosterone levels to castration levels within 3 days without causing a testosterone flare, which is associated with significant side effects, and as such, the drug was hypothesized as a potentially effective rapid-onset treatment option that would be relatively well tolerated. A composite risk score (range, 0-15 points) consisting of 5 domains (pedophilic disorder, sexual preoccupation, impaired self-regulation, low empathy, and self-rated risk) was derived to operationally define sexual abuse risk and used as the primary end point. The composite risk score decreased from 7.4 to 4.4 for the 25 participants assigned to receive 240mg of degarelix subcutaneously, and from 7.8 to 6.6 for the 26 participants in the placebo group, a significant mean between-group difference of –1.8 (95% CI, –3.2 to –0.5; P = .01) – a result that was still present at 10 weeks post injection. The drug was also found to be effective in the high risk group (defined as composite risk score >10), which achieved a composite score reduction of 3.3 points by week 2, compared to no change in the placebo group. The drug was well tolerated, with no major adverse events being recorded and the majority of adverse events being confined to the injection site. Although findings concerning the primary end point appear promising, it was noted that there was no significant difference in quality of life between the treatment and placebo groups at 2 and 10 weeks, indicating that quality of life in affected individuals are governed by more than the core symptoms of the disorder alone. Nevertheless, study findings are promising and suggest that degarelix, or other gonadotropin-releasing hormone antagonists may emerge as a novel treatment option for rapid risk reduction in individuals with pedophilic disorder.

Image: PD

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