key: cord-355805-ajlf5je4
authors: Qaseem, Amir; Yost, Jennifer; Etxeandia-Ikobaltzeta, Itziar; Miller, Matthew C.; Abraham, George M.; Obley, Adam Jacob; Forciea, Mary Ann; Jokela, Janet A.; Humphrey, Linda L.
title: 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)
date: 2020-05-13
journal: Ann Intern Med
DOI: 10.7326/m20-1998
sha: 
doc_id: 355805
cord_uid: ajlf5je4

nan

Using chloroquine or hydroxychloroquine, with or without azithromycin, to prevent coronavirus disease (COVID-19) after infection with novel coronavirus (SARS-CoV-2) or to treat COVID-19 began to receive attention following preliminary reports from in vitro (1) and human (2) studies. While multiple studies are planned or under way (3, 4) , it is imperative to continually synthesize the results from the best available evidence to inform point-of-care decisions about the use of chloroquine or hydroxychloroquine. These practice points are based on a rapid and living systematic evidence review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group and will be updated as new evidence becomes available. The practice points development and update methods are included in the appendix, available at Annals.org. This version of the practice points, based on an evidence review conducted on 17 April 2020, was approved by the American College of Physicians Board of Regents on 4 May 2020 and submitted to Annals of Internal Medicine on 6 May 2020.

The efficacy of chloroquine or hydroxychloroquine alone or in combination with azithromycin to prevent COVID-19 after infection with SARS-CoV-2 or to treat patients with COVID-19 is not established and future clinical trials are needed to answer these questions. There are known harms of these medications when used to treat other diseases (5, 6) . Current evidence about efficacy and harms for use in the context of COVID-19 is sparse, conflicting, and from low quality studies, increasing the uncertainty and lowering our confidence in the conclusions of these studies when assessing the benefits or understanding the balance when compared with harms. These interim practice points are based on best available evidence. We will maintain these practice points as a living guidance document, updated as new evidence becomes available. (9).

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the conversion to negative on day 3 (50% vs. 6%), day 4 (60% vs. 25%), day 5 (65% vs. 19%), and day 6 (70% vs. 13%) via nasopharyngeal PCR in 1 cohort study (11) . Pulmonary radiologic assessment

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on the progression or exacerbation of pulmonary lesions on CT scan in 2 RCTs (33.3% vs. 46.7% [7] and 6.5% vs. 29% [8] ) and radiologic improvement of pneumonia (80.6% vs. 54.8%) in 1 RCT (8).

Resolution of fever, respiratory symptoms, and oxygenation

The evidence is very uncertain about the effect of hydroxychloroquine alone (50%) compared with standard treatment (43.6%) in 1 RCT (9).

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 RCTs; median, 1 day vs. 1 day in 1 RCT (7), and mean, 2.2 days vs. 3.2 days in another RCT (8) .

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (mean 2.0 days vs. 3.1 days) in 1 RCT (8) .

Progression to severe disease

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 RCTs; 6.7% vs. 0% (7) and 0% vs. 12.9% (8).

All-cause mortality 1 RCT The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (0% vs. 0%) in 1 RCT (7).

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment in 2 cohort studies; 12.9% vs. 3.13% (10) and 2.8% vs. 4.6% (12) .

Continued on the following page 

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment on adverse effects in 3 RCTs; 26.7% vs. 20% (7), 6.5% vs. 0% (8), and 30% vs. 8.8% (9) . Prolonged QTc interval

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment (8.3% vs. 0%) in 1 cohort study (12) .

The evidence is very uncertain about the effect of hydroxychloroquine alone compared with standard treatment; 13.3% vs. 0% (7) and 10% vs. 0% (9).

Abnormal liver function

The evidence is very uncertain about the effect of hydroxychloroquine alone (6.7%) compared with standard treatment (6.7%) in 1 RCT (7).

The evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 RCT (8).

The evidence is very uncertain about the effect of hydroxychloroquine alone (3.2%) compared with standard treatment (0%) in 1 RCT (8).

The evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 RCT (7).

Elevated serum creatinine

The evidence is very uncertain about the effect of hydroxychloroquine alone (0%) compared with standard treatment (6.7%) in 1 RCT (7).

Hydroxychloroquine in combination with azithromycin for treatment of COVID-19 Diarrhea 1 OBS The evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin in 1 case series study (14) ; 5.0% patients experienced diarrhea.

Any adverse event series study; 8.7% of patients treated with hydroxychloroquine alone experienced adverse effects (14) .

The evidence is very uncertain about the effect of hydroxychloroquine in combination with azithromycin. In 2 case series studies, 9% (15) and 11% (13) of patients showed a prolonged QTc. The QTc interval significantly increased (435 6 24 ms at baseline to a maximal value of 463 6 32 ms) in 1 case series study (13) ; however, a prolonged QTc interval was not reported for any patients in another case series study (16) .

Evidence Gaps for COVID-19 Clinical Considerations • The use and extent of parallel treatment interventions, in addition to hydroxychloroquine alone or in combination with azithromycin, is difficult to determine. • Known harms of chloroquine in patients without COVID-19 include (but not limited to): cardiovascular (cardiomyopathy, ECG changes), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (5). • Known harms of hydroxychloroquine in patients without COVID-19 include (but not limited to): cardiovascular (cardiomyopathy, cardiac failure, ventricular arrhythmias, torsade de pointes), endocrine (hypoglycemia), hematologic (aplastic anemia, thrombocytopenia), nervous system (seizures, psychosis, extrapyramidal disorders), ophthalmic macular degeneration) (6). • Shared and informed decision making with a patient (and/or families) should include a discussion of potential harms of chloroquine and hydroxychloroquine and lack of known benefits in patients with COVID-19. • In the evidence reviewed, hydroxychloroquine doses did not exceed 600 mg daily for 5 to 10 days. • Chloroquine and hydroxychloroquine are used to manage other major ailments, such as rheumatic diseases, with a known benefit and are in short supply in the United States. • Inappropriate and overuse of antibiotics (e.g., azithromycin) is an important contributor to the antibiotic resistance, an immediate public health threat (17) . CT = computed tomography; ECG = electrocardiography; ECMO = extracorporeal membrane oxygenation; ICU = intensive care unit; OBS = observational study; PCR = polmerase chain reaction; RCT = randomized controlled trial. Evidence search conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. * Efficacy cannot be evaluated in case-series studies (16, 18) . † Certainty: insufficient, when confidence is inadequate to assess the likelihood of benefit (benefit minus harm) of an intervention or its impact on a health outcome; low, confidence in the effect is limited as the true effect may be substantially different from the estimated effect; moderate, confidence in the effect is moderate as the true effect is likely close to the estimated effect, but there is a sizable possibility that it is substantially different; high, confident that the true effect is close to the estimated effect. Financial Support: Financial support for the development of the Practice Points comes exclusively from the ACP operating budget.

Disclosures: All financial and intellectual disclosures of interest were declared and potential conflicts were discussed and managed. A record of disclosures of interest and management of conflicts of is kept for each Scientific Medical Policy Committee meeting and conference call and can be viewed at https://www.acponline.org/about-acp/who-we-are/leadership/ boards-committees-councils/scientific-medical-policy-committee/ disclosure-of-interests-and-conflict-of-interest-managementsummary-for-scientific-medical-policy. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterest Forms.do?msNum=M20-1998.

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

A brief review of antiviral drugs evaluated in registered clinical trials for COVID-19

Accessed at www.accessdata.fda.gov/drugsatfda_ docs/label/2013/006002s043lbl

Plaquenil Hydroxychloroquine Prescribing Information

A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. Preprint. Posted online 14

Clinical outcomes of hydroxychloroquine in hospitalized patients with COVID-19: a quasi-randomized comparative study. NEJM submission

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial

The QT interval in patients with SARS-CoV-2 infection treated with hydroxychloroquine/ azithromycin

Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study

No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection

The latest hydroxychloroquine data

High Value Care Task Force of the American College of Physicians and for the Centers for Disease Control and Prevention. Appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the American College of Physicians and the Centers for Disease Control and Prevention

The hierarchy of evidence: levels and grades of recommendation

SPECIAL ARTICLE

Current Author Addresses: Dr. Qaseem: American College of Physicians, 190. N Independence Mall West

Etxeandia-Ikobaltzeta: 1, Santa Margarita Hospital Street, Ground Floor

123 Summer Street

Obley: 3030 SW Moody

Dr. Jokela: 1405 West Park, #207, Champaign, IL 61801. Dr. Humphrey: 3710 SW U.S. Veterans Hospital Road

Critical revision for important intellectual content

Administrative, technical, or logistic support: A. Qaseem

The Scientific Medical Policy Committee (SMPC), in collaboration with staff from ACP's Department of Clinical Policy, developed these Practice Points based on a rapid systematic evidence review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. The SMPC comprises 11 internal medicine physicians representing various clinical areas of expertise and 1 public (nonclinician) member and includes members with expertise in epidemiology, healthy policy, and evidence synthesis. In addition to contributing clinical, scientific, and methodological expertise, Clinical Policy staff provided administrative support and liaised among the SMPC, evidence review funding entity and evidence team, and the journal. Clinical Policy staff and the SMPC reviewed and prioritized potential topic suggestions from ACP members, SMPC members, and ACP governance. A committee subgroup, including the chair of SMPC, worked with staff to draft the key questions and lead the development of the Practice Points. Clinical Policy staff worked with the subgroup and the evidence review team to refine the key question(s) and determine appropriate evidence synthesis methods for each key question. Via conference calls and e-mail, Clinical Policy staff worked with the committee subgroup to draft the Practice Points based on the results of the rapid systematic evidence review. The full SMPC reviewed and approved the final Practice Points. Before publication, ACP's Executive Committee of the Board of Regents also reviewed and approved the Practice Points on behalf of the ACP Board of Regents. The evidence review will be continually updated by the evidence review team. ACP will update the Practice Points based on the evidence review using the same process as for Version 1 (described above).
