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MeSH Disease

Human Phenotype

Transmission

Seroprevalence

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    A Systematic Review Assessing the Under-Representation of Elderly TRANS Adults TRANS in COVID-19 Trials

    Authors: Virginie Prendki; Noam Tau; Tomer Avni; Marco Falcone; Angela Huttner; Laurent Kaiser; Mical Paul; Yaara Leibovici-Weissmann; Dafna Yahav

    doi:10.21203/rs.3.rs-39538/v1 Date: 2020-07-01 Source: ResearchSquare

    BackgroundCoronavirus disease MESHD (COVID-19) has caused a pandemic threatening millions of people worldwide. Yet studies specifically assessing the geriatric population are scarce. We aimed to examine the participation of elderly TRANS patients in therapeutic or prophylactic trials on COVID-19.MethodsIn this review, randomized controlled trials (RCTs; n=12) comparing therapeutic or prophylactic interventions registered on preprint repositories and/or published since December 2019 were analyzed. We aimed to describe the age TRANS of included patients, the presence of an upper age TRANS limit and of adjusted analyses on age TRANS, any exclusion criteria that could limit participation of elderly TRANS adults TRANS such as comorbidities, cognitive impairment HP, limitation of life expectancy; and the assessment of long-term outcomes such as the need of rehabilitation of institutionalization. Mean participant ages TRANS were reported and compared with observational studies.ResultsTwelve RCTs assessing drug therapy for COVID-19 were included. Mean age TRANS of patients included in RCTs was 56.3 years. An upper age TRANS limit was applied in three published trials (25%) and in 200/650 (31%) trials registered at clinicaltrials.gov. One trial reported a subgroup analysis in patients ≥65. Patients were excluded for liver-function abnormalities in eight trials, renal disease MESHD in six, cardiac disease MESHD or risk of torsade de pointes MESHD torsade de pointes HP in five, and four for cognitive or mental criteria, which are frequent comorbidities in the oldest patients. Only three trials allowed a family member TRANS to provide consent. Patients enrolled in RCTs were on average 20 years younger than those included in large (n≥1000) observational studies. Seven studies had as their primary outcome a clinical endpoint, but none reported cognitive, functional or quality of life outcomes or need for rehabilitation or long-term care facility placement.ConclusionsElderly patients are clearly underrepresented in RCTs, although they comprise the population hardest hit by the COVID-19 pandemic. Long-term outcomes such as the need of rehabilitation or institutionalization were not reported. Future investigations should target specifically this vulnerable population.

    Chloroquine, but not hydroxychlorquine, prolongs the QT interval HP in a primary care population

    Authors: Jonas L Isaksen; Anders Gaarsdal Holst; Adrian Pietersen; Jonas Bille Nielsen; Claus Graff; Jorgen K Kanters

    doi:10.1101/2020.06.19.20135475 Date: 2020-06-20 Source: medRxiv

    Background: Chloroquine (CQ) and Hydroxychloroquine (HCQ) have recently been suggested as treatment for the current Corona Virus Disease MESHD 2019 (COVID-19) pandemic. However, despite their long-term use and only few case reports on adverse effects, CQ and HCQ are listed as a known risk of the lethal ventricular arrhythmia HP Torsade de Pointes MESHD Torsade de Pointes HP and their cardiac safety profile is being questioned. Thus, we aimed to investigate the electrocardiographic and mortality effects of CQ and HCQ in a primary care population. Methods: We used Danish health care registers and electrocardiograms (ECGs) from primary care to define three studies. 1) A paired study of subjects with ECGs before and during use of CQ/HCQ, 2) a matched ECG study of subjects taking CQ/HCQ compared to controls, and 3) a mortality study on people taking HCQ matched to control. In both matched studies, we adjusted for connective tissue diseases MESHD, use of QT-prolonging drugs, and cardiac disease MESHD. We used the QTc interval as the marker for electrocardiographic safety. In the mortality study, cases were followed from first claimed prescription until 300 days after estimated completion of the last prescription. 95% confidence intervals follow estimates in parenthesis. Results: Use of CQ was associated with a 5.5 (0.7;10) ms increase in QTc in the paired study (n=10). In the matched study (n=28, controls=280), QTc was insignificantly increased in subjects taking CQ by 4.7 (-3.4;13) ms. With a {Delta}QTc of 1.0 (-5.6;7.5), use of HCQ was not associated with an increased QTc in the paired study (n=32). In the matched study (n=172, controls=1,720), QTc also was not different between groups (p=0.5). In the mortality study (n=3,368), use of HCQ was associated with a hazard ratio of 0.67 (0.43;1.05). Conclusions: In subjects free of COVID-19, we found a small increase in QTc associated with use of chloroquine, but not hydroxychloroquine. We found no increased mortality associated with use of hydroxychloroquine.

    The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis

    Authors: Imad Tleyjeh; Zakariya Kashour; Oweida AlDosary; Muhammad Riaz; Haytham Tlayjeh; Musa A Garbati; Rana Tleyjeh; Mouaz H Al-Mallah; Rizwan M Sohail; Dana Gerberi; Aref A Bin Abdulhak; John R Giudicessi; Michael John Ackerman; Tarek Kashour

    doi:10.1101/2020.06.16.20132878 Date: 2020-06-18 Source: medRxiv

    Abstract Importance The antimalarial agents chloroquine (CQ) and hydroxychloroquine (HCQ) have been proposed as a potential treatment for COVID-19 due their effect on several cellular processes that impact viral replication. Although more than 100 ongoing trials are testing their efficacy, CQ and HCQ are being used widely in clinical practice, exposing COVID-19 patients to potentially significant cardiac adverse effects. Objective To systematically review the literature and estimate the risk of cardiac toxicity in patients receiving CQ or HCQ for COVID-19. Data Sources A systematic search was conducted on May 27, 2020 of Ovid EBM Reviews, Ovid Embase (1974+), Ovid Medline (1946+ including epub ahead of print, in-process & other non-indexed citations), Scopus (1970+) and Web of Science (1975+) and preprint servers (Medrvix and ResearchSquare) and manual search of references lists. Study Selection Studies that included COVID-19 patients treated with CQ or HCQ, with or without azithromycin, were included as follows: (1) COVID-19 patient population, (2) the study included more than 10 patients receiving either one of the medications, (3) reported electrocardiographic changes and/or cardiac arrhythmias MESHD arrhythmias HP. Data Extraction and Synthesis Study characteristics and endpoints incidence were extracted. Due to the very low incidence of torsades de pointes MESHD torsades de pointes HP (TdP) and other endpoints (rare events), the arcsine transformation was used to obtain a pooled estimate of the different incidences using a random-effects meta-analysis. Meta-regression analyses were used to assess whether the incidence of different endpoints significantly varied by multiple study-level variables specified a priori. Main Outcomes and Measures Pooled Incidence of: (1) change in QTc value from baseline [≥] 60 ms, (2) QTc [≥] 500 ms, (3) the composite of endpoint 1 and 2, (4) TdP arrhythmia or ventricular HP ventricular tachycardia MESHD tachycardia HP (VT) or cardiac arrest HP, (5) discontinuation of treatment due to drug-induced QT prolongation or arrhythmias HP. Results A total of 19 studies with a total of 5652 patients were included. All included studies were of high methodological quality in terms of exposure ascertainment or outcome assessment. Among 2719 patients treated with CQ or HCQ, only two episodes of TdP were reported; the pooled incidence of TdP arrhythmia HP or VT or cardiac arrest HP was 3 per 1000, 95% CI (0-21), I2=96%, 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias HP was 5%, 95% CI (1-11), I2=98%. The pooled incidence of change in QTc from baseline of [≥] 60 ms was 7%, 95% CI (3-14), I2=94% (12 studies of 2008 patients). The pooled incidence of QTc [≥] 500 ms was 6%, 95% CI (2-12), I2=95% (16 studies of 2317 patients). Among 11 studies of 3127 patients, the pooled incidence of change in QTc from baseline of [≥] 60 ms or QTc [≥] 500 ms was 9%, 95% CI (3-17), I2=97%. Mean/median age TRANS, coronary artery disease MESHD, hypertension MESHD hypertension HP, diabetes, concomitant QT prolonging medications, ICU care, and severity of illness in the study populations explained between-studies heterogeneity. Conclusions and Relevance Treatment of COVID-19 patients with CQ or HCQ is associated with a significant risk of drug-induced QT prolongation, which is a harbinger for drug-induced TdP/VT or cardiac arrest HP. CQ/HCQ use resulted in a relatively higher incidence of TdP as compared to drugs withdrawn from the market for this particular adverse effect. Therefore, these agents should be used only in the context of randomized clinical trials, in patients at low risk for drug-induced QT prolongation, with adequate safety monitoring.

    QT Interval Prolongation and Torsade De Pointes MESHD Torsade De Pointes HP in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin

    Authors: Ehud Chorin; Lalit Wadhwani; Silvia Magnani; Matthew Dai; Eric Shulman; Charles Nadeau-Routhier; Robert Knots; Roi Bar-Cohen; Edward Kogan; Chirag Barbhaiya; Anthony Aizer; Douglas Holmes; Scott Bernstein; Michael Spinelli; David S Park; Stefano Carugo; Larry A Chinitz; Lior Jankelosn

    doi:10.1101/2020.04.27.20074583 Date: 2020-05-01 Source: medRxiv

    Background: The emergence of the COVID-19 pandemic has resulted in over two million affected and over 150 thousand deaths MESHD to date. There is no known effective therapy for the disease MESHD. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes MESHD torsade de pointes HP (TdP). Methods: This is a multicenter retrospective study of 251 patients with COVID-19 treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia HP and mortality. Results: QTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 15.9% of patients. One patient developed TdP requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting QTc prolongation of > 60 ms was normal. Conclusion: The combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia HP in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.

    Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring

    Authors: Archana Ramireddy; Harpriya S. Chugh; Kyndaron Reinier; Joseph Ebinger; Eunice Park; Michael Thompson; Eugenio Cingolani; Susan Cheng; Eduardo Marban; Christine Albert; Sumeet S. Chugh

    doi:10.1101/2020.04.22.20075671 Date: 2020-04-25 Source: medRxiv

    Background: Despite a paucity of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected COVID-19. Both drugs may increase risk of lethal arrhythmias HP associated with QT interval prolongation. Methods: We performed a case series of COVID-19 positive/suspected patients admitted between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine or a combination. We evaluated baseline and post-medication QT interval (QTc, Bazett) using 12-lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc [≥]500 ms (if QRS <120 ms) or QTc [≥]550 (if QRS [≥]120 ms) and b) increased QTc of [≥]60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Results: Of 490 COVID-19 positive/suspected patients, 314 (64%) received either/both drugs, and 98 (73 COVID-19 positive, 25 suspected) met study criteria ( age TRANS 62{+/-}17 yrs, 61% male TRANS). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448{+/-}29 ms and increased to 459{+/-}36ms (p=0.005) with medications. Significant prolongation was observed only in men (18{+/-}43 ms vs -0.2{+/-}28 ms in women, p=0.02). 12% of patients reached critical QTc prolongation. In a multivariable logistic regression, age TRANS, sex, Tisdale score, Elixhauser score, and baseline QTc were not associated with critical QTc prolongation (p>0.14). Changes in QTc were highest with the combination compared to either drug, with many-fold greater prolongation with the combination vs. azithromycin alone (17{+/-}39 vs. 0.5{+/-}40 ms, p=0.07). No patients manifested torsades de pointes MESHD torsades de pointes HP. Conclusions: Overall, 12% of patients manifested critical QTc interval prolongation, and traditional risk indices failed to flag these patients. With the drug combination, QTc prolongation was several-fold higher compared to azithromycin alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients with these drugs should be carefully assessed prior to use.

    Risk of drug-induced Long QT Syndrome MESHD associated with the use of repurposed COVID-19 drugs: a systematic review

    Authors: Veronique Michaud; Pamela Dow; Sweilem B Al Rihani; Malavika Deodhar; Meghan Arwood; Brian Cicali; Jacques Turgeon

    doi:10.1101/2020.04.21.20066761 Date: 2020-04-24 Source: medRxiv

    Objective: To determine the relative risk of drug-induced Long QT Syndrome MESHD (LQTS) associated with SARS-CoV-2 (COVID-19) proposed repurposed drugs compared to well-known torsadogenic compounds. Setting: Computer calculations and simulations were performed using primary pharmacokinetic and pharmacodynamic data for each proposed drug. Seven different LQTS indices were calculated and compared. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Interventions: A thorough literature search was performed to gather information on the pharmacological properties of six drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, and remdesivir) repurposed to treat COVID-19. Researchers emphasized the affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval), and cause torsade de pointes MESHD torsade de pointes HP (TdP). The risk of drug-induced LQTS for these drugs was quantified by comparing six indices that assess such risk. Primary and secondary outcome measures: Level of risk estimated for the six COVID-19 drugs being proposed compared to 23 torsadogenic drugs. Number of proarrhythmic adverse events identified for these drugs in the FAERS. Results: Estimators of LQTS risk levels indicated a very high or high risk for all COVID-19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and 23 torsadogenic compounds. Conclusion: The risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients prescribed these drugs.

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MeSH Disease
Human Phenotype
Transmission
Seroprevalence


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