In new Practice Points, the American College of Physicians (ACP) says that evidence does not support the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with novel coronavirus (SARS-CoV-2), or for treatment of patients with COVID-19.
The ACP Practice Points also state that physicians, in light of known harms and very uncertain evidence of benefit, may choose to treat the hospitalized COVID-19 positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial using shared and informed decision-making with patients and their families.
“Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or In Combination with Azithromycin for the Prophylaxis or Treatment of COVID-19?
Living Practice Points from the American College of Physicians (Version 1)” was published today in Annals of Internal Medicine.
The ACP Practice Points provide rapid clinical advice based on a concise summary of the best available evidence on the benefits and harms of the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin for the prophylaxis or treatment of COVID-19.
The Practice Points are based on a rapid systematic review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group.
ACP Practice Points are developed by ACP’s Scientific Medical Policy Committee and provide advice to improve the health of individuals and populations and promote high value care based on the best available evidence derived from assessment of scientific work (e.g. clinical guidelines, systematic reviews, individual studies).
ACP Practice Points aim to address the value of screening and diagnostic tests and therapeutic interventions for various diseases, and consider known determinants of health, including but not limited to genetic variability, environment, and lifestyle.
“With the rapid emergence of COVID-19, physicians and clinicians have found themselves managing the frontlines of the pandemic with a paucity of evidence available to inform treatment decisions,” said Jacqueline W. Fincher, MD, MACP, president, ACP.
“ACP rapidly developed its Practice Points as concise, synthesized summaries of the current state of evidence in order to address urgent questions related to the transmission, diagnosis, and treatment of COVID-19.
As such, these Practice Points give frontline physicians guidance to provide patients with the care based on the best available evidence.”
Chloroquine and hydroxychloroquine are used to manage other major ailments with a known benefit and are in short supply in the United States.
These medications also have known harms in non-COVID patients such as cardiovascular effects; diarrhea; abnormal liver function; rash; headache; ocular issues; and anemia.
Using chloroquine or hydroxychloroquine, with or without azithromycin, to prevent or treat COVID-19 infection began to receive attention following preliminary reports from in vitro and human studies.
While several studies are planned or underway, the Practice Points provide details about the lack of and/or insufficient current research about the benefits and harms for prevention and treatment of COVID-19.
At this time, the authors of the Practice Points have identified that chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with novel coronavirus (SARS-CoV-2), or for treatment of patients with COVID-19 should not be used.
The Practice Points also state that the drugs may only be used to treat hospitalized COVID-19 positive patients in the context of a clinical trial following shared and informed decision-making between clinicians and patients (and their families) that includes a discussion of known harms of chloroquine and hydroxychloroquine and very uncertain evidence of benefit for COVID-19 patients.
The ACP Practice Points will be maintained as a “living” document and ACP’s Scientific Medical Policy Committee will monitor emerging evidence to determine its impact on the main findings and conclusions, and issue updates as needed.
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.
From a sample of 7914 patients with COVID-19 admitted in New York metropolitan hospitals during March 15 through 28, a total of 2362 records were randomly selected, and 1438 were abstracted and included in the analyses (Figure 1). The date of final follow-up was April 24, 2020. Of these patients, 735 (51.1%) received hydroxychloroquine + azithromycin, 271 (18.8%) received hydroxychloroquine alone, 211 (14.7%) received azithromycin alone, and 221 (15.4%) received neither drug.
Hydroxychloroquine was initiated at a median of 1 day (Q1-Q3, 1-2) following admission and azithromycin was given at a median of 0 days (Q1-Q3, 0-1). Additional information about dosing and administration appears in eTable 1 in Supplement 2.
Nineteen patients initiated either medication prior to admission, including 12 who began medication use on the day prior, and another 3 began medication use 2 days prior to admission. Patients receiving neither drug also received few other abstracted medications; the most common were aspirin (38/192 [19.8%]) and lisinopril (13/193 [6.7%]) (eTable 2 in Supplement 2)).
Patients receiving either drug were more likely (relative to neither drug) to be male (Table 1). Black or Hispanic patients were as likely to receive hydroxychloroquine and/or azithromycin.
Median patient age was similar in the 4 groups (hydroxychloroquine + azithromycin, 61.4 years; hydroxychloroquine alone, 65.5 years; azithromycin alone, 62.5 years; and neither drug, 64.0 years [P = .35]). Six of 25 (24.0%) children received either hydroxychloroquine or azithromycin.
Patients receiving hydroxychloroquine + azithromycin and hydroxychloroquine alone were more likely to be obese and have diabetes than those in the groups receiving azithromycin alone and neither drug. Patients receiving hydroxychloroquine alone had the highest levels of chronic lung disease (25.1%) and cardiovascular conditions (36.5%).
As indicated by respiratory (chest imaging, respiratory rate, O2 saturation) and hepatic (AST, alanine aminotransferase) measurements during the first 24 hours, patients in the treatment groups, particularly hydroxychloroquine + azithromycin, presented as having more clinically severe disease than the neither drug group.
Ninety-five percent of the hydroxychloroquine + azithromycin group had abnormal chest imaging findings (top 3: air space opacity [63.0%], lung infiltrate [23.8%], and bronchopneumonia/pneumonia [20.7%]).
No differences were observed in the timing of COVID-19 diagnosis; only 13.9% (193/1384) of patients were diagnosed before admission (median, 2 days before).
Bivariate analyses of patient characteristics and 3 outcomes of interest (mortality, cardiac arrest, and abnormal ECG findings) found that age of 65 years or older; history of cancer, kidney disease, cardiovascular conditions, and diabetes; abnormal chest imaging findings; O2 saturation below 90%; low blood pressure; elevated creatinine levels; and elevated AST were significantly associated across outcomes (eTables 3, 4, and 5 in Supplement 2).
Hospital outcomes by treatment are presented in Table 2, noting 45 (3.1%) patients were still hospitalized at the time of final analysis. Patients receiving hydroxychloroquine + azithromycin (30.7%) and hydroxychloroquine alone (19.2%) had higher levels of ICU admission than those receiving azithromycin alone (10.9%) and neither drug (12.2%), although 56.1% of patients in all groups entered intensive care within 1 day of admission.
Similarly, more patients receiving hydroxychloroquine + azithromycin (27.1%) and hydroxychloroquine alone (18.8%) than those taking azithromycin -alone (6.2%) and neither drug (8.1%) received mechanical ventilation.
Among patients undergoing mechanical ventilation and receiving hydroxychloroquine + azithromycin, hydroxychloroquine alone, or azithromycin alone, 49.6% were ventilated before or concurrent with starting these treatments.Primary Outcome
Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). In unadjusted analyses, significant differences in in-hospital death were observed across the hydroxychloroquine + azithromycin (n = 189, 25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone (n = 54, 19.9% [95% CI, 15.2%-24.7%]), azithromycin alone (n = 21, 10.0% [95% CI, 5.9%-14.0%]), and neither-drug (n = 28, 12.7% [95% CI, 8.3%-17.1%]) groups (P < .001). Similar patterns were observed for death per patient-day overall and post drug initiation (Table 2).
In the primary analysis, following adjustment for demographics, specific hospital, preexisting conditions, and illness severity, no significant differences in mortality were found between patients receiving hydroxychloroquine + azithromycin (adjusted HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (adjusted HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (adjusted HR, 0.56 [95% CI, 0.26-1.21]), compared with neither drug (Table 3) (complete case analysis variable completeness was 86%).
From this model, estimated direct-adjusted mortality at 21 days was 22.5% (95% CI, 19.7%-25.1%) with hydroxychloroquine + azithromycin, 18.9% (95% CI, 14.3%-23.2%) with hydroxychloroquine alone, 10.9% (95% CI, 5.8%-15.6%) with azithromycin alone, and 17.8% (95% CI, 11.1%-23.9%) with neither drug (Figure 2).
No significant mortality difference was found between hydroxychloroquine alone and azithromycin alone (adjusted HR, 1.92 [95% CI, 0.99-3.74]). Results were similar in the 3 alternative Cox models (eTable 6 in Supplement 2).Secondary Outcomes
Across all groups, the most commonly reported adverse event was abnormal ECG findings, particularly arrhythmia (Table 4). Abnormal ECG findings were more common among patients receiving hydroxychloroquine + azithromycin and hydroxychloroquine alone, both overall and among those with a record of ECG screening.
However, in logistic regression models of abnormal ECG findings, there were no significant differences between the groups receiving neither drug and each of the hydroxychloroquine + azithromycin and hydroxychloroquine alone groups.
A greater proportion of patients receiving hydroxychloroquine + azithromycin experienced cardiac arrest (15.5%) and abnormal ECG findings (27.1%), as did those in the hydroxychloroquine alone group (13.7% and 27.3, respectively), compared with azithromycin alone (6.2% and 16.1%, respectively) and neither drug (6.8% and 14.0%, respectively).
In adjusted models with those receiving neither drug as comparison, cardiac arrest was more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]; E-value = 1.31), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) and azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), and also in patients taking hydroxychloroquine alone vs azithromycin alone (adjusted OR, 2.97 [95% CI, 1.56-5.64]; E-value = 1.81).
In models for each outcome that stratified on receipt of mechanical ventilation, all associations were not significant, with the exception of cardiac arrest between patients receiving hydroxychloroquine alone vs azithromycin alone among patients who did not receive mechanical ventilation (adjusted OR, 3.01 [95% CI, 1.07-8.51]; E-value = 1.22) (eTable 7 in Supplement 2).
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