One of my patients groused, “Why don’t you ever have anything good to say about chloroquine?”
Well, that’s because there is not much good to say. There was an observational study (A type of study in which individuals are observed or certain outcomes are measured. No attempt is made to affect the outcome (for example, no treatment is given) )was done in Michigan at the Henry ford Hospitals which did show a beneficial effect.
But the study’s author concludes: “Currently, the drug should be used only in hospitalized patients with appropriate monitoring, and as part of study protocols, in accordance with all relevant federal regulations,” Dr. Zervos said.
Countering that is another observational study from JAMA which showed no benefit and an increased risk of cardiac arrest.
May 11, 2020
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State
Eli S. Rosenberg, PhD1; Elizabeth M. Dufort, MD2; Tomoko Udo, PhD1; et alLarissa A. Wilberschied, MS2; Jessica Kumar, DO2; James Tesoriero, PhD2; Patti Weinberg, PA3; James Kirkwood, MPH2; Alison Muse, MPH2; Jack DeHovitz, MD3,4; Debra S. Blog, MD2; Brad Hutton, MPH2; David R. Holtgrave, PhD1; Howard A. Zucker, MD2
Author Affiliations Article Information
JAMA. 2020;323(24):2493-2502. doi:10.1001/jama.2020.8630
Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.
Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.
Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.
Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.
Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).
Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.
Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
What we rely most on are controlled studies. Two are mentioned in the following summary available only to members and fellows of The American College of Physicians.
Latest COVID-19 research on dexamethasone, hydroxychloroquine, a vaccine, tocilizumab
Peer-reviewed details on the recent trial of dexamethasone were released, and two new trials found no benefit to early treatment with hydroxychloroquine. Positive data from a phase 1 vaccine trial were also published, as was another study of tocilizumab.
More details on the positive trial of dexamethasone in patients requiring ventilation were published by the New England Journal of Medicine on July 17. The findings, which were initially released in a press release (covered in the June 17 ACP Hospitalist Weekly), included 6,425 British patients hospitalized with COVID-19, 2,104 randomized to oral or IV dexamethasone, 6 mg/d for up to 10 days, and the rest to usual care. Dexamethasone was associated with reduced risk for death among the 1,007 trial patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio [RR], 0.64 [95% CI, 0.51 to 0.81]) and the 3,883 receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; RR, 0.82 [95% CI, 0.72 to 0.94]) but not among the 1,535 receiving no respiratory support at randomization (17.8% vs. 14.0%; RR, 1.19 [95% CI, 0.91 to 1.55]). These preliminary results provide evidence that treatment with the studied dose of dexamethasone reduces mortality in COVID-19 patients who require respiratory support, the authors said. “We found no benefit (and the possibility of harm) among patients who did not require oxygen,” they noted, also cautioning that higher doses of steroids might be harmful.
“The RECOVERY trial and the recently published randomized, controlled trial of remdesivir provide clear guidance on therapeutic strategies for Covid-19 along with insights into the pathogenesis of the disease,” according to an accompanying editorial by H. Clifford Lane, MD, MACP, and Anthony S. Fauci, MD, MACP. Remdesivir is most effective in hospitalized patients with moderate disease, while dexamethasone works best in more advanced disease, they noted.
Hydroxychloroquine failed to improve outcomes in early or mild COVID-19, according to two recent studies. One trial, published by Clinical Infectious Diseases on July 16, randomized 293 outpatients with recently confirmed SARS-CoV-2 infection and less than five days of symptoms to either hydroxychloroquine or no antiviral treatment. No significant differences were found in the mean reduction of viral load at day 3 or at day 7, risk of hospitalization, or time to complete resolution of symptoms. “Our findings provide the scientific community and policymakers with essential insights on the inefficacy of [hydroxychloroquine] as a therapeutic candidate for SARS-CoV-2, at least in similar settings and conditions to ours,” the authors wrote.
The other trial, published by Annals of Internal Medicine on July 16, included 423 outpatients with laboratory-confirmed or probable COVID-19 randomized to either hydroxychloroquine or placebo. There were no significant differences in changes in symptom severity over 14 days, or in rates of hospitalization or mortality, both of which were rare. An accompanying editorial highlighted failures on the part of the producers, publishers, and consumers of scientific research during the “saga” of hydroxychloroquine. “The scientific community needs to do a good bit of stock-taking and soul-searching about its performance in meeting the challenges of the pandemic and how it will meet these challenges in future pandemics that are certain to emerge,” the editorialist wrote.
A successful phase 1 trial of a SARS-CoV-2 vaccine was reported in the New England Journal of Medicine on July 14. It gave 45 healthy adults, 18 to 55 years of age, two vaccinations, 28 days apart, with mRNA-1273 at doses of 25 μg, 100 μg, or 250 μg. After the second vaccination, immune response was detected in all evaluated participants. Adverse events that occurred in more than half included fatigue, chills, headache, myalgia, and pain at the injection site, and events were more severe with the highest dose, but the authors said that no trial-limiting safety concerns were identified. They noted that a phase 2 trial of 50-μg and 100-μg doses is ongoing, and a phase 3 efficacy trial, expected to evaluate a 100-μg dose, is anticipated to begin this summer. “The safety and immunogenicity data in this preliminary report are promising, and they support continued development of this vaccine. However, we must bear in mind the complexity of vaccine development and the work still to be done before Covid-19 vaccines are widely available,” an accompanying editorial said.
Tocilizumab was associated with improved survival among mechanically ventilated patients, according to an observational study published by Clinical Infectious Diseases on July 11. Compared to 76 patients who did not receive the drug, the 78 who did had significant improvements in risk of death (hazard ratio, 0.55; 95% CI, 0.33 to 0.90) and status on the ordinal outcome scale (odds ratio per 1-level increase, 0.58; 95% CI, 0.36 to 0.94). Superinfections were more common in patients receiving tocilizumab, but they were not associated with any increase in 28-day mortality. “These data are encouraging and can help to inform clinical practice while results from randomized controlled trials of [interleukin]-6 inhibitors are awaited,” the study authors said.
The current state of COVID-19 research in the U.S. was highlighted by a research letter in JAMA Network Open on July 13. It found 674 current registered randomized trials, only 71.1% of which had valid control groups, and 23.5% of which were testing chloroquines. “Although these overlapping trials may afford opportunities for replication and validation, the high degree of multiplicity also enhances the likelihood of finding a positive result through chance alone, potentially resulting in widespread use of an ineffective and possibly hazardous intervention,” said the authors, who also noted the problem of competition for trial participants.