Hydroxychloroquine-Chloroquine,QT-Prolongation,and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review

Abstract

Objectives:

We aimed to evaluate the high-quality literature on the frequency and nature of major adverse cardiac events (MACE) associated with either hydroxychloroquine (HCQ) or chloroquine (CQ).

Data sources:

We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onward using search strategies created in collaboration with medical science librarians.

Study selection and data extraction:

Randomized controlled trials (RCTs) published in English language from January 1996 to September 2022, involving adult patients at least 18 years of age, were selected. Outcomes of interest were death, arrhythmias, syncope, and seizures. Random-effects meta-analyses were performed with a Treatment Arm Continuity Correction for single and double zero event studies.

Data synthesis:

By study drug, there were 31 HCQ RCTs (n = 6677), 9 CQ RCTs (n = 622), and 1 combined HCQ-CQ trial (n = 105). Mortality was the most commonly reported MACE at 220 of 255 events (86.3%), with no reports of torsades de pointes or sudden cardiac death. There was no increased risk of MACE with exposure to HCQ-CQ compared with control (risk ratio [RR] = 0.90, 95% CI = 0.69-1.17, I² = 0%).

Relevance to patient care and clinical practice:

These findings have important implications with respect to patient reassurance and updated guidance for prescribing practices of these medications.

Conclusions:

Despite listing as QT-prolonging meds, HCQ-CQ did not increase the risk of MACE.

Keywords

hydroxychloroquine chloroquine QT interval torsades de pointes

Introduction

Background

The antimalarials chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) were originally indicated to prevent and cure malaria, and since the 1940s have been repurposed to treat rheumatological, immunological, and infectious diseases.^1
-3 Hydroxychloroquine is thought to have fewer safety concerns such as retinopathy, cardiomyopathy, and agranulocytosis.^4
-8 These drugs were used early in the COVID-19 pandemic as potential therapies given their antiviral properties; however, HCQ-CQ proved ineffective for improving COVID-19 mortality, viral clearance, or clinical recovery.^9
-13 Both drugs are classified by CredibleMeds as “known” causes of QT-prolongation (QTP) and torsades de pointes, but the link to clinical outcomes is based mainly on very low-quality evidence including pharmacologic mechanisms and case reports.^14
-16

QT-prolongation is a commonly used surrogate marker for the risk of torsades de pointes and other arrythmias. The Food and Drug Administration (FDA) lists major adverse cardiac events (MACE) related to QTP as torsades de pointes, sudden death, ventricular tachycardia, ventricular fibrillation and flutter, syncope, and seizures.¹⁷ The data on MACE related to HCQ-CQ prescribed for patients arise mainly from observational studies, pharmacovigilance, preclinical, and pharmacokinetic/pharmacodynamic modeling studies, which are susceptible to biases and confounding. In a 2016 review of the cardiotoxicity of antimalarials in malaria patients, the World Health Organization found no significant difference in risks of cardiotoxicity following exposure to CQ at recommended doses.¹⁸ A 2021 meta-analysis of 25 observational trials (N = 41 339) and 11 randomized trials (N = 8709) comparing HCQ with active drug, placebo, or observation comparators in COVID-19 patients found no association with mortality when pooling the randomized controlled trials (RCTs) but a 20% lower mortality risk for patients taking HCQ when pooling cohort studies.¹⁹ Similarly, a large retrospective study of 2.2 million patients with rheumatoid arthritis suggested that HCQ was associated with lower rates of MACE (hazard ratio: 0.827, 95% CI = 0.80-0.86).²⁰ These findings all include lower quality evidence.

As part of research aimed to clarify the risk of FDA-defined MACE outcomes associated with medications classified as “Known Risk” QT-prolonging medications, we undertook a scoping review of the RCT data for adult patients exposed to HCQ-CQ to estimate the relative rate of MACE—specifically death, torsades de pointes, ventricular tachyarrhythmia, nonfatal cardiac arrest, syncope, and seizures, compared with placebo, standard of care, or observation.

Methods

We conducted this scoping review with guidance from the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) extension for scoping reviews (PRISMA-ScR).²¹ The completed PRISMA-ScR checklist is included as Supplemental Appendix 1. This review was prospectively registered on Open Science Framework (https://doi.org/10.17605/OSF.IO/ZU9F2).

Study Identification

We searched Medline, Embase, International Pharmaceutical Abstracts (IPA), and Cochrane CENTRAL from early January 1996 until end-October 2020 with an update to end-September 2022 using search strategies developed with advice from research librarians. Complete search strategies are available in supplementary appendices (see Appendix 2). We also completed supplemental searches on Google Scholar using key text words for placebo-controlled trials, HCQ, CQ, safety, and adverse drug reactions.

Inclusion Criteria

Our inclusion criteria were as follows: (1) parallel-group or crossover design RCTs of any duration; (2) adult patients defined as 18 years or older; (3) at least one intervention arm where the independent effect of HCQ or CQ (either given alone or with the same active agent in both QTPmed and control arm) was measured; and (4) a comparison arm consisting of placebo, active comparator, or no treatment. We did not exclude trials that did not report any MACE (zero-zero event trials).

Study Selection

Several authors performed title and abstract screening independently and in duplicate in Covidence.²² Potentially relevant publications were assessed further during in-duplicate full-text screening. We excluded RCTs involving only pediatric patients or mixed pediatric-adult populations where the adult data could not be separated. Randomized controlled trials involving healthy volunteers, protocols, and conference abstracts were excluded. We did not include any observational studies including health system data base analyses or postmarketing studies due to biases and confounders inherent to these study designs. Studies not written in English language were also excluded. Disagreements were resolved by a third author to attain consensus.

Extraction of Study Characteristics and Outcomes

Study characteristics and outcomes were extracted independently by pairs of reviewers. We pilot-tested and used a prospectively designed standardized data-extraction form to extract details on study characteristics, dose and frequency of study drugs, participant characteristics, and MACEs. Our primary outcome was the MACE composite adapted from FDA, which included all-cause mortality, sudden cardiac death, nonfatal cardiac arrest, torsades de pointes, ventricular tachycardia, ventricular fibrillation, syncope, and seizure.¹⁷ We extracted data on whether any of our MACE or QTP were prespecified outcomes of interest, or whether patients with electrocardiogram (ECG) abnormalities or cardiac comorbidities were excluded. Risk-of-bias assessment included allocation concealment, degree of blinding, and loss to follow-up. Discrepancies and disagreements were resolved through discussion or adjudicated by a third senior author.

Statistical Analysis

We used the meta 6.0 package in R to conduct the meta-analysis and pool trial data. The unit of analysis was individuals exposed to study medications (HCQ-CQ or control) and data are reported as incident events (number of participants who developed MACE during the study period). Analysis included all participants, including dropouts, to minimize bias due to differences in dropout numbers between groups. To retain studies with zero events in both arms, we used Mantel-Haenzel odds ratios (MH ORs) with Treatment Arm Continuity Correction (TACC) along with 95% CIs.²³ Publication bias was assessed using funnel plots and Harbord test. As a post hoc analysis, we performed a meta-regression in R of the effect based on the cumulative CQ base dose on MACE, similar to the methodology of other systematic reviews involving CQ compounds.^24,25

Statistical heterogeneity was assessed using the I² statistic, with values of 50% or more indicating a moderate level of heterogeneity.²⁶ Statistical significance was set at 2-sided α of 0.05. In trials that had more than 2 intervention groups, for example 2 arms of HCQ or CQ that differed by dose, we preserved randomization but collapsed the multiple intervention arms into single treatment arms.

Subgroup and Sensitivity Analyses

Prespecified subgroup analyses were conducted for each individual MACE outcome, exclusion of cardiac disease or risk factors or ECG abnormalities, >50% versus < 50% female participants, mean/median age < 65 versus ≥65 years, MACE outcomes or QTP as prespecified outcomes of interest, and HCQ versus CQ alone. Our sensitivity analyses involved investigating the robustness of our effect estimates when using alternative zero-event correction approaches such as the Peto statistical model approach (excluding zero event trials), and the exclusion of all-cause mortality from the overall MACE composite.

Results

A total of 3215 records were retrieved from our literature searches. After de-duplication, 2767 records remained for evaluation. Title and abstract screening yielded 58 eligible records for full-text evaluation, which resulted in 41 randomized trials included in this scoping review and meta-analysis (N = 7404). See Figure 1 for PRISMA flowchart of the study selection process.

Figure 1.

PRISMA flow diagram of the included studies in the meta-analysis.

Study Characteristics

Characteristics of the trials are summarized in Table 1. Of 41 trials, 31 investigated HCQ only,^27
-57 9 CQ only,^58
-66 and 1 studied HCQ or CQ analyzed as a single arm.⁶⁷ The mean sample size was 197 (SD = 26.7), mean 59.2% (SD = 26.6) female, and most trials (n = 38, 92.3%) reported mean or median ages of their participants to be younger than 65 years. Location of the trials was mainly North America (n = 14, 34.1%), Europe (n = 8, 19.5%), and Asia (n = 8 trials, 19.5%). The mean duration of follow-up was 26.1 weeks (SD = 39.5). Only 2 trials reported data on cardiac comorbidities at baseline.^34,54 Thirteen trials (31.7%) listed at least one MACE as an outcome of interest in their methods and 8 trials (19.5%) examined QTP during the trial.

Table 1.

The Main Characteristics of Studies Included in the Meta-analysis.

Study	Geographic region	Duration of follow-up (weeks)	Patient population	Age^a Female (F) %	Treatment arms	Sample size	Comparator
Arnaout et al⁵⁸	North America	6	Breast cancer	Age: 56.8 (9.2) F(%): 100	CQ 500 mg OD	70	Placebo
Boulware et al²⁹	North America	2	Adults exposed to COVID-19	Age: HCQ: 41 (33-51); Ctrl: 40 (32-50); F(%): 51.6	HCQ 800 mg once; or 600 mg 6-8 hours; or 600 mg OD ×4d	821	Placebo
Cavalcanti et al³⁰	South America	2.1	COVID-19 patients	Age: 50.3 (14.6) F(%): 41.7	HCQ 400 mg BID	665	Standard of care (unspecified)
Gottenberg et al³⁶	Europe	48	Primary Sjögren Syndrome	Age: HCQ: 55.6 (13.9); Ctrl: 56.3 (11.9) F(%): 91.7	HCQ 400 mg OD	120	Placebo
Jokar et al³⁷	Asia	24	Knee osteoarthritis	Age: HCQ: 47.6 (8.54); Ctrl: 48.3 (11.14) F(%): 84.3	HCQ 200 mg BID	51	Placebo
Kedor et al³⁹	Europe	56	Inflammatory and erosive hand osteoarthritis	Age: HCQ: 52.4 (8.1); Ctrl: 50.2 (6.6); F(%): 98.1	HCQ 200 mg/d; 200 and 400 mg every other day; or 200 mg BID	156	Placebo
Das et al³³	Asia	12	Rheumatoid arthritis	Age: HCQ: 40.3 (9.7); Ctrl: 40.0 (10.9) F(%): 78.7	HCQ 200 mg BID	122	Placebo
Liu et al⁴³	North America	2	COVID-19 patients	Age range: 22-84 F(%): 63.5	HCQ 200 mg BID	51	Observation (unspecified)
Meinao et al⁶²	South America	52	Systemic lupus erythematosus	Mean age: 31.7 F(%): 87.5	CQ 250 mg OD	24	Placebo
Mitja et al⁴⁴	Europe	4	COVID-19 patients	Age: HCQ: 41.7 (12.6); Ctrl: 41.3 (12.4) F(%): 58.6	HCQ 400 mg OD	353	Standard of care (unspecified)
Paton et al⁴⁶	Europe	48	HIV patients	Age: HCQ: 31.7 (7.7); Ctrl: 38.3 (10.8); F(%): 7.2	HCQ 400 mg OD	83	Placebo
Reis et al⁴⁷	South America	12	COVID-19 patients	Age: 53 (18-94) F(%): 55	HCQ 400 mg OD	685	Placebo
Rojas Puentes et al⁶⁴	North America	182	Brain metastases	Age: CQ: 55.7 (13); Ctrl: 52.0 (10.6) F(%): 79	CQ 150 mg OD	78	Placebo
Schwartz et al⁴⁸	North America	4	COVID-19 patients	Age: HCQ: 46.7 (11.5); Ctrl: 46.9 (11.0); F(%): 45.0	HCQ 200 mg BID	124	Placebo
Self et al⁴⁹	North America	4	COVID-19 patients	Age: HCQ: 58 (45-96); Ctrl: 57(43-68); F(%): 44.3	400 mg of HCQ BID ×2 doses, then 200 mg BID	479	Placebo
Solomon et al⁵⁰	North America	16	Rheumatoid arthritis	Age: 56 (11.4) F(%): 95.7	HCQ 6.5 mg/kg/d	23	Placebo
Sotelo et al⁶⁵	North America	86	Glioblastoma multiforme	Age: CQ: 40.8 (11.8); Ctrl: 46.1 (12.7); F(%): 43.3	CQ 150 mg OD	30	Placebo
Tang et al⁵¹	Asia	4	COVID-19 patients	Age: HCQ: 48.0 (14.1); Ctrl: 44.1 (15.0) F(%): 45.3	HCQ 1200 mg OD ×3d, then 800 mg OD	150	Standard of care (National COVID-19 clinical practice guidelines—China)
Toledo et al⁵²	North America	13	Insulin-resistant adults without rheumatic disease	Age: HCQ: 47.9 (14.4); Ctrl: 44.6 (14.7); F(%): 73.5	HCQ 400 mg OD	34	Placebo
Ulander et al⁵³	Europe	52	Myocardial infarction patients	Age: HCQ: 59.9 (9.5); Ctrl: 58.5 (9.9); F(%): 20.8	HCQ 300 mg OD	125	Placebo
Ulrich et al⁵⁴	North America	4	COVID-19 patients	Age: HCQ: 66.5 (16.4); Ctrl: 65.8 (16.0); F(%): 40.6	HCQ 400 mg BID ×1d, then 200 mg BID ×2-5 d	128	Placebo
Van Gool et al⁵⁵	Europe	78	Alzheimer disease	Age: HCQ: 70.4 (8.3); Ctrl: 70.7 (8.5); F(%): 57.7	HCQ 400 mg or 200 mg OD	168	Placebo
Yoon et al⁵⁷	Asia	16	Primary Sjögren syndrome patients	Age: HCQ: 59.4 (9.42); Ctrl: 55 (9.72); F(%): NR	HCQ 300 mg OD	26	Placebo
Avezum et al²⁷	South America	4.3	COVID-19	Age: 45 (36-56) F(%): 53	HCQ 400 mg BID ×1 d, then 400 mg OD ×7 d	1372	Placebo
Boonpiyathad et al²⁸	Asia	12	Chronic spontaneous urticaria	Age: HCQ: 33 (12.11); Ctrl: 33.95 (11.91) F(%): 85.3%	HCQ 400 mg OD	48	Placebo
Tsakonas et al³²	North America	156	Systemic lupus erythematosus	Age: HCQ: 45 (14); Ctrl: 44 (16) F(%): 97	HCQ: 100-400 mg OD	47	Placebo
Chen et al³¹	Asia	0.9	COVID-19	Age: 44.7 (15.3) F(%): 53.2%	HCQ: 400 mg OD	62	Standard of care (oxygen, antivirals, antibacterial, immunoglobulin +/− corticosteroids)
Dubee et al³⁴	Multiple regions	4	COVID-19	Age: HCQ: 76 (60-85); Ctrl: 78 (57-87) F(%): 51.6	HCQ: 200 mg BID	250	Placebo
Gonzalez et al³⁵	North America	4.2	COVID-19	Age: 53.8 (16.9) F(%): 37.8	HCQ: 400 mg BID ×1d, then 200 mg BID ×4 days	106	Placebo
Kavanaugh et al³⁸	North America	12	Systemic lupus erythematosus	Age: NR F(%): 100	HCQ: 400 mg OD; 800 mg OD	17	Placebo
Kingsbury et al⁴⁰	Europe	52	Hand osteoarthritis	Age: HCQ: 62.8 (9.1); Ctrl: 62.5 (9.2) F(%): 81.5	HCQ: 200, 300, 400 mg OD	248	Placebo
Lee et al⁴¹	Europe	24	Hand osteoarthritis	Age: HCQ: 58.3 (7); Ctrl: 57.7 (8.2) F(%): 86	HCQ: 400 mg OD	202	Placebo
Levy et al⁴²	South America	12	Systemic lupus erythematosus	Age: HCQ: 29 (3); Ctrl: 29 (4) F(%): 100	HCQ: NR	20	Placebo
Omrani et al⁴⁵	Multiple regions	2	COVID-19	Age: HCQ: 40 (31-47); Ctrl: 41 (31-47) F(%): 1.7	HCQ: 600 mg OD	456	Placebo
Rea-Neto et al⁶⁷	South America	4	COVID-19	Age: CQ: 54.7 (12.1); Ctrl: 52.8 (12.6) F(%): 33.4	CQ: 250 mg BID ×1d, then 450 mg OD ×5d; HCQ 400 mg BID ×1d, then 400 mg OD ×5d	142	Standard of care (unspecified)
Yokogawa et al⁵⁶	Asia	16	Cutaneous lupus erythematosus	Age: HCQ: 43.1 (12.8); Ctrl: 41.6 (12.7) F(%): 74	HCQ: 200 mg OD or 400 mg OD	103	Placebo
Baltzan et al⁵⁹	North America	24	Advanced pulmonary sarcoidosis	Age^b: 42.5 (29-67) F(%): 41.7	CQ: 250 mg OD	24	Observation^b systemic corticosteroids
Borges et al⁶⁰	South America	1	Dengue fever	Age: 31.64 (11.74) F(%): 51.3	CQ: 300 mg BID	37	Placebo
De Lamballerie et al⁶¹	Africa	3.4	Acute chikungunya infection	Age: NR F(%): NR	CQ: 300 mg BID ×3d, then 300 mg OD ×2d	54	Placebo
Peymani et al⁶³	Eastern Mediterranean	12	Hepatitis C virus nonresponders	Age^b: CQ: 50 (45-52); Ctrl: 49 (25-60) F(%): 0	CQ: 150 mg OD	10	Placebo
Tricou et al⁶⁶	Asia	2	Dengue fever	Age: CQ: 22 (18-27); Ctrl: 22 (19-28) F(%): 31.6	CQ: 600 mg ×2d, then 300 mg ×1d	307	Placebo

Abbreviations: BID, twice daily; CQ, chloroquine; Ctrl, control; HCQ, hydroxychloroquine; IQR, interquartile range; NR, not reported; OD, once daily.

Age reported as median (IQR) or mean (SD) unless otherwise indicated.

Mean (range).

Indications for the HCQ-CQ varied, the 3 most common being 15 trials for COVID-19 (n = 5844)^{27,29
-31,34,35,43
-45,47
-49,51,54,67}; 8 trials (n = 405) for patients with immune-mediated conditions, including systematic lupus erythematosus,^{32,38,42,56,62} primary Sjogren syndrome,^36,57 and chronic spontaneous urticaria²⁸; and 6 trials (n = 802) for patients with rheumatic conditions (rheumatoid arthritis, hand osteoarthritis, and knee osteoarthritis).^{33,37,39-41,50} Of the 41 RCTs, 34 (75.6%) used placebo as the comparator,^{27
-29,32
-42,45-50,52-58,60
-66} 5 used active standard of care medications as comparator,^{30,31,44,51,67} and 2 used nothing.^43,59

With respect to the selected domains of risk of bias in the included trials, 18 of 41 (43.9%) detailed appropriate allocation concealment procedures, but 22 of 41 (53.7%) failed to provide any details on allocation concealment. Most trials, 34 of 41 (82.9%), were at least double-blinded, and most (31/41, 75.6%) reported ≤15% loss to follow-up.⁶⁸

Prevalence of MACE Outcomes

A total of 255 MACEs were reported in 14 trials,^{27,30,34
-36,39,40,49,53
-55,64,65,67} with the remainder reporting no events. Of the reported MACE, most (220/255, 86.3%) were deaths. Thirteen trials named a specific MACE as an outcome of interest in their methods,^{27,29,30,34,47
-49,51,53,54,64,65,67} of which 8 of 13 (61.5%) reported MACE outcomes during the trial.^{27,30,49,53,54,64,65,67} In contrast, only 5 trials of the 28 (17.9%) that did not prespecify MACE reported MACE incidents.^{35,36,39,40,55}

Meta-analyses of Incident MACE

Hydroxychloroquine-chloroquine was not associated with an increased risk of MACE (N = 7404, risk ratio [RR]: 0.90, 95% CI = 0.69-1.17), I² = 0%. In addition, none of the individual MACE outcomes indicated a statistically significant finding (see Table 2 and Figure 2).

Table 2.

Pooled Rates of MACE for Hydroxychloroquine/Chloroquine Versus Control.

Outcome	Group; no. of events, n/N		Effect estimate(95% CI)
Outcome	HCQ-CQ(N = 3777)	Control(N = 3627)	Effect estimate(95% CI)
Any MACE	125	130	RR: 0.90 (0.69-1.17)
Mortality	107	113	RR: 0.89 (0.69-1.15)
Sudden cardiac death	0	0	NA
Nonfatal cardiac arrest	10	4	RR: 1.23 (0.71-2.12)
Torsades de pointes	0	0	NA
Ventricular tachyarrhythmia	7	6	RR: 1.01 (0.58-1.74)
Seizure	3	4	RR: 0.94 (0.53-1.67)
Syncope	0	4	RR: 0.88 (0.48-1.61)

Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; MACE, major adverse cardiac events; NA, not applicable; RR, risk ratio.

Figure 2.

Forest plot of hydroxychloroquine/chloroquine vs control for any MACE.

Mortality

Hydroxychloroquine-chloroquine was not associated with an increased risk of mortality (N=7404, RR: 0.89, 95% CI 0.69- 1.15), I2 =0%.

In prespecified subgroup analyses by treatment drug (HCQ or CQ vs control), HCQ was not associated with an increased risk of mortality (N = 6677, RR: 0.99, 95% CI = 0.73-1.36) while CQ was associated with a protective effect of mortality (N = 622, RR: 0.64, 95% CI = 0.48-0.85). The remainder of the subgroup analyses, including age, sex, prespecified outcomes, cardiac exclusion criteria, and active therapy, did not reveal statistically significant findings.

Cardiac Arrhythmias

There were no reports of torsades de pointes in our included trials. There were also no reports of sudden cardiac deaths in our included trials. One trial reported 10 nonfatal cardiac arrests in the HCQ arm, with 4 in the placebo arm.⁴⁹ The pooled effect estimate was RR: 1.23, 95% CI = 0.71-2.12.

Two trials reported ventricular tachyarrhythmia, one reporting 5 ventricular tachyarrhythmias in the HCQ arm and 6 in placebo⁴⁹ and another reporting 2 ventricular arrhythmias in the HCQ arm and none in the placebo arm.⁴⁰ There were no reports of ventricular tachyarrhythmias in the CQ trials. The pooled effect estimate for ventricular tachyarrhythmia was RR: 1.01, 95% CI = 0.58-1.74.

Seizures and Syncope

Two trials reported seizures, with a total of 3 events in HCQ-CQ compared with 4 in placebo.^49,65 The pooled effect estimate for seizure was RR: 0.94, 95% CI = 0.53-1.67. Syncopal events were also reported in 2 trials, with no events in HCQ-CQ compared with 4 events in placebo arm.^39,64 The pooled effect estimate for syncope was RR: 0.88, 95% CI = 0.48-1.61.

Subgroup and Sensitivity Analyses

A summary of subgroup and analyses are available in Tables 3 and 4 and Figure 3. Chloroquine was associated with a protective effect of MACE (N = 622, RR: 0.64, 95% CI = 0.46-0.89), with the remainder of the subgroup analyses not statistically significant by age, sex, exclusion of patients with cardiac risk, active comparator, or whether QTP or a MACE was a specified outcome of interest. Using the Peto statistical method to exclude zero-zero event trials (14 RCTs, N = 3528) produced similar effect estimates than in our primary analyses (Peto odds ratio: 0.84, 95% CI = 0.48-1.44). As well, effect estimates for overall MACE remained robust when removing all-cause mortality from the analyses (RR: 0.79, 95% CI = 0.48-1.31). In the post hoc meta-regression, there was no association between cumulative base dose and MACE (P = 0.535).

Table 3.

Subgroup Analyses for MACE.

Subgroup	No. of RCTs	Group; no. of events, n/N		Effect estimate(95% CI)
Subgroup	No. of RCTs	HCQ-CQ	Control	Effect estimate(95% CI)
Overall	41	125/3777	130/3627	RR: 0.90 (0.69-1.17)
HCQ vs control	31	80/3398	74/3279	RR: 1.06 (0.59-1.41)
CQ vs control	9	29/326	46/296	RR: 0.64 (0.46-0.89)
Female > 50%	26	47/2716	58/2651	RR: 1.04 (0.65-1.65)
Female ≤50%	13	78/1023	72/934	RR: 1.07 (0.75-1.55)
Age ≥65 years	3	21/275	20/271	RR: 1.00 (0.55-1.82)
Age <65 years	35	104/3431	110/3305	RR: 0.88 (0.65-1.19)
QTP specified outcome	8	61/1681	52/1667	RR: 1.14 (0.81-1.60)
QTP not specified outcome	33	64/2096	78/1960	RR: 0.82 (0.59-1.14)
MACE specified outcome	13	115/2329	120/2241	RR: 0.88 (0.65-1.20)
MACE not specified outcome	28	10/1448	10/1386	RR: 1.01 (0.55-1.87)

Rea-Neto et al⁶⁷ not included in subgroup by drug (HCQ-CQ combined). Yoon et al⁵⁷ and De Lamballerie et al⁶¹ not included in subgroup on % female (missing data). Liu et al,⁴³ De Lamballerie et al,⁶¹ and Kavanaugh et al³⁸ not included in subgroup on age (missing data).

Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; QTP, QT-prolongation; MACE, major adverse cardiac events; RR, risk ratio.

Table 4.

Sensitivity Analyses for the Outcome of Overall MACE.

Statistical method	Statistical model	No. of RCTs	Group; no. of events, n/N		Effect estimate(95% CI)
Statistical method	Statistical model	No. of RCTs	HCQ-CQ	Control	Effect estimate(95% CI)
(Default) TACC – 0.5	Random (MH)	41	125/3777	130/3627	RR: 0.90 (0.69-1.17)
Peto (excluding zero-zero trials)	Random OR	14	125/1830	130/1698	OR: 0.84 (0.48-1.44)
Removing all-cause mortality from MACE	Random (MH)	41	8/3777	16/3627	RR: 0.79 (0.48-1.31)

Abbreviations: CQ, chloroquine; HCQ, hydroxychloroquine; MACE, major adverse cardiac events; MH, Mantel-Haenszel; OR, odds ratio; RCTs, randomized controlled trials; RR, risk ratio; TACC, Treatment Arm Continuity Correction.

Figure 3.

Number of individuals with ≥1 MACE, by study drug.

Publication Bias

Statistical evaluation of publication bias using Harbord test on overall MACE does not suggest funnel plot asymmetry (publication bias) (P = 0.0622). Funnel plots are presented in Supplemental Appendix 3.

Discussion

We believe this to be the first scoping review with meta-analysis of HCQ-CQ trials to evaluate the cardiac safety of these medications. Despite being the subject of prescribing alerts related to cardiac events, we did not find that treatment with HCQ-CQ was associated with an increased risk of mortality, ventricular tachyarrhythmias, seizures, or syncope compared with control. There were no reports of torsades de pointes or sudden cardiac death. We observed that treatment with CQ itself was associated with a 36% reduction in risk of overall MACE (RR: 0.64, 95% CI = 0.46-0.89). This finding was mostly driven by deaths. This was unexpected since CQ is generally considered to have a less favorable safety profile than HCQ. For example, of the 2 CQ trials that reported MACE, both were in cancer patient populations where CQ was used as an adjunct to proven cancer therapy (radiotherapy and chemotherapy).^64,65 Chloroquine’s efficacy for treating cancer remains an ongoing area of research, with both preclinical and human trials ongoing investigating its use to increase the efficacy of other anticancer agents.⁶⁹

Medications including HCQ and CQ considered as “known risk” medications on the CredibleMed’s QTdrugs list are evaluated using ADECA (Adverse Drug Event Causality Analysis) to stratify them by their ability to cause QT prolongation and/or torsades de pointes.¹⁶ The process uses the classic Bradford Hill criteria to assess available laboratory, adverse event databases, and “clinical evidence” for drug safety. Known risk medications are considered to have “substantial evidence” for associations with both QTP and torsades de pointes, but the evidence can be small case series or individual case reports.¹⁶ By modern GRADE level of evidence standards, many “known risk” medications have been so classified based on very low-quality evidence.⁷⁰ This may be a reasonable precaution for drugs which are new to market, or which are not standard of care for diseases or conditions which themselves are known dangers to patient health. The surrogate properties of QTP are suspect for many drugs and subsequent higher quality evidence has not been incorporated into the criteria. For example, the vast majority of patients with QTP do not develop cardiac events, and torsades de pointes may occur without QTP or even with QT shortening.^71
-73 The World Health Organization itself has commented that QTP and its relationship with torsades de pointes is not straightforward.¹⁸

There are strengths and limitations to this review. Strengths include a focus on randomized controlled trials, forming the highest level of evidence in terms of minimizing bias including balancing differences in concomitant therapies and other potential confounders between arms. This review also excluded trials with healthy volunteers, allowing for the representation of diverse patient demographics and clinical populations. For example, various daily doses (HCQ ranged from 300 to 1200 mg, CQ ranged from 150 to 600 mg) and a variety of conditions were studied, including rheumatologic, infectious, immunologic, and oncologic conditions. In addition, we followed the recommended methods to include all available data in our meta-analyses, including zero-zero event trials.^23,74,75 Even when zero-zero event trials were removed from the meta-analyses, the effect estimates did not significantly change, suggesting these findings are robust despite the diversity in therapeutic doses and durations.

There are limitations to our approach. Randomized trials tend to recruit healthier patients, which would tend to lower the frequency of events in both groups. Our review identified 255 major cardiac events, which is a reasonable number, but an elderly rheumatic population with co-existing cardiovascular disease would be expected to have a higher event rate. In addition, the trade-off of restricting our included studies to randomized trials in order to avoid the biases and confounding of observational studies means a loss of power to detect rare adverse events.⁷⁶ We calculated our study to have 80% power to rule out an actual 1% MACE outcome rate in the underlying population.⁷⁷ While a frequent criticism of RCTs is their lack of focus on harm, the usual reporting of serious adverse events would include all of our MACE outcomes. As a scoping review, another limitation is the lack of certainty of evidence (GRADE) evaluation.⁷⁰

Relevance to Patient Care and Clinical Practice

The American College of Rheumatology recommends HCQ between 200 and 400 mg daily, and the Centers for Disease Control and Prevention (CDC) advises up to 500 mg weekly for CQ in the context of malaria.^78,79 As only a handful of included trials used above these recommended doses,^{29,38,45,51,60,66} and none of these trials reported any MACE, the findings of this review are reassuring for patients prescribed HCQ and CQ at usual doses. Evaluating the proarrhythmic effect of HCQ-CQ is necessary for assessments of cardiac safety, and this review found that these serious events were not more common in HCQ-CQ arms than comparator arms in the high-quality literature. Clinical decision-making and prescribing guidelines for HCQ and CQ should similarly consider factors such as the event rate, severity of outcome, and quality of evidence. Clinically, there remains a major clinical need for a valid clinical prediction rule for QT-prolonging medications such as HCQ-CQ and MACEs, as existing support is limited to surrogate outcomes.⁸⁰ This research supports the ongoing effort to emphasize high-quality evidence and patient-important outcomes such as MACEs, over surrogates like QTP.

Conclusions

We found no high-quality evidence that HCQ-CQ increases the risk of MACE. Further research should seek to develop a clinical prediction rule for known risk QT-prolonging medications such as HCQ-CQ and MACE so that decision support can be improved.

Supplemental Material

sj-docx-1-aop-10.1177_10600280231204969 – Supplemental material for Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review

Supplemental material, sj-docx-1-aop-10.1177_10600280231204969 for Hydroxychloroquine-Chloroquine, QT-Prolongation, and Major Adverse Cardiac Events: A Meta-analysis and Scoping Review by Michael Cristian Garcia, Kai La Tsang, Simran Lohit, Jiawen Deng, Tyler Schneider, Jessyca Matos Silva, Lawrence Mbuagbaw and Anne Holbrook in Annals of Pharmacotherapy

Footnotes

Acknowledgements

The authors have no acknowledgements to make.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This review was supported by a grant to Dr Holbrook from the Academic Health Sciences Innovation Fund of the Ontario Ministry of Health and Long-Term Care.

ORCID iDs

Michael Cristian Garcia

Jessyca Matos Silva

Anne Holbrook

Supplemental Material

Supplemental material for this article is available online.

References

Zhou

Wang

Yang

Chen

Zou

Zhang

Chloroquine against malaria, cancers and viral diseases. Drug Discov Today. 2020;25:2012-2022. doi:10.1016/j.drudis.2020.09.010

Ben-Zvi

Kivity

Langevitz

Shoenfeld

Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012;42(2):145-153. doi:10.1007/s12016-010-8243-x

Schrezenmeier

Dörner

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166. doi:10.1038/s41584-020-0372-x

Pareek

Sharma

Mehta

RT.

Hydroxychloroquine and QT prolongation: reassuring data in approved indications. Rheumatol Adv Pract. 2020;4(2):rkaa044. doi:10.1093/rap/rkaa044

Sharma

Wasko

Tang

, et al. Hydroxychloroquine use is associated with decreased incident cardiovascular events in rheumatoid arthritis patients. J Am Heart Assoc. 2016;4:e002867. doi:10.1161/JAHA.115.002867

Page

O’Bryant

Cheng

, et al. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134:e32-e69. doi:10.1161/CIR.0000000000000426

Rynes

Bernstein

HN.

Ophthalmologic safety profile of antimalarial drugs. Lupus. 1993;2(suppl 1):S17-S19.

Mohammad

Clowse

MEB

Eudy

Criscione-Schreiber

LG.

Examination of hydroxychloroquine use and hemolytic anemia in G6PDH-deficient patients. Arthritis Care Res (Hoboken). 2018;70(3):481-485. doi:10.1002/acr.23296

Browning

. Pharmacology of chloroquine and hydroxychloroquine. In: Hydroxychloroquine and Chloroquine Retinopathy. Springer; 2014:35-63. doi:10.1007/978-1-4939-0597-3_2

10.

Sahraei

Shabani

Shokouhi

Saffaei

Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020;55:105945. doi:10.1016/j.ijantimicag.2020.105945

11.

Yazdany

Kim

AHJ

. Use of hydroxychloroquine and chloroquine during the COVID-19 pandemic: what every clinician should know. Ann Intern Med. 2020;172:754-755. doi:10.7326/M20-1334

12.

Singh

Ryan

Kredo

Chaplin

Fletcher

Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19. Emergencias. 2022;34:305-307. doi:10.1002/14651858.CD013587.pub2

13.

Schwartz

Boulware

Lee

TC.

Hydroxychloroquine for COVID19: the curtains close on a comedy of errors. Lancet Reg Health Am. 2022;11:100268. doi:10.1016/j.lana.2022.100268

14.

Woosley

Romero

Assessing cardiovascular drug safety for clinical decision-making. Nat Rev Cardiol. 2013;10(6):330-337. doi:10.1038/nrcardio.2013.57

15.

Postema

Neville

de Jong

Romero

Wilde

Woosley

RL.

Safe drug use in long QT syndrome and Brugada syndrome: comparison of website statistics. Europace. 2013;15(7):1042-1049. doi:10.1093/europace/eut018

16.

Woosley

Romero

Heise

, et al. Adverse drug event causality analysis (ADECA): a process for evaluating evidence and assigning drugs to risk categories for sudden death. Drug Saf. 2017;40(6):465-474. doi:10.1007/s40264-017-0519-0

17.

Food and Drug Administration. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. US Department of Health and Human Services; 2005.

18.

World Health Organization Evidence Review Group. The Cardiotoxicity of Antimalarials. World Health Organization; 2016.

19.

Di Castelnuovo

Costanzo

Cassone

Cauda

De Gaetano

Iacoviello

. Hydroxychloroquine and mortality in COVID-19 patients: a systematic review and a meta-analysis of observational studies and randomized controlled trials. Pathog Glob Health. 2021;115(7-8):456-466. doi:10.1080/20477724.2021.1936818

20.

Cordova Sanchez

Khokhar

Olonoff

Carhart

. Hydroxychloroquine and cardiovascular events in patients with rheumatoid arthritis. Cardiovasc Drugs Ther. 2022. doi:10.1007/s10557-022-07387-z

21.

Tricco

Lillie

Zarin

, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169:467-473. doi:10.7326/M18-0850

22.

Covidence systematic review software. Veritas Health Innovation. Date unknown. Accessed September 29, 2023. www.covidence.org

23.

Sweeting

Sutton

Lambert

PC.

What to add to nothing? use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351-1375. doi:10.1002/sim.1761

24.

Schlossberg

Samuel

. Chloroquine phosphate (aralen), hydroxychloroquine. In: Antibiotics Manual. John Wiley & Sons; 2017:80-82. doi:10.1002/9781119220787.ch37

25.

Deng

Zhou

Heybati

, et al. Efficacy of chloroquine and hydroxychloroquine for the treatment of hospitalized COVID-19 patients: a meta-analysis. Future Virol. 2022;17:95-118. doi:10.2217/fvl-2021-0119

26.

Higgins

JPT

Thomas

Chandler

, et al. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Collaboration; 2019.

27.

Avezum

Oliveira

GBF

Oliveira

, et al. Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE—Coalition V): a double-blind, multicentre, randomised, controlled trial. Lancet Reg Health Am. 2022;11:100243. doi:10.1016/j.lana.2022.100243

28.

Boonpiyathad

Sangasapaviliya

Hydroxychloroquine in the treatment of anti-histamine refractory chronic spontaneous urticaria, randomized single-blinded placebo-controlled trial and an open label comparison study. Eur Ann Allergy Clin Immunol. 2017;49(5):220-224. doi:10.23822/EurAnnACI.1764-1489.11

29.

Boulware

Pullen

Bangdiwala

, et al. A Randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. N Engl J Med. 2020;383:517-525. doi:10.1056/NEJMoa2016638

30.

Cavalcanti

Berwanger

Zampieri

FG.

Hydroxychloroquine with or without azithromycin in covid-19. N Engl J Med. 2021;384:191. doi:10.1056/NEJMc2031780

31.

Chen

Zhang

, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020. doi:10.1101/2020.03.22.20040758

32.

Tsakonas

Joseph

Esdaile

, et al. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7(2):80-85. doi:10.1191/096120398678919778

33.

Das

Pareek

Mathur

, et al. Efficacy and safety of hydroxychloroquine sulphate in rheumatoid arthritis: a randomized, double-blind, placebo controlled clinical trial—an Indian experience. Curr Med Res Opin. 2007;23(9):2227-2234. doi:10.1185/030079907X219634

34.

Dubée

Roy

Vielle

, et al. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial. Clin Microbiol Infect. 2021;27(8):1124-1130. doi:10.1016/j.cmi.2021.03.005

35.

Gonzalez

Gonzalez Gamez

Mendoza Enciso

, et al. Efficacy and safety of ivermectin and hydroxychloroquine in patients with severe COVID-19: a randomized controlled trial. Infect Dis Rep. 2022;14:160-168. doi:10.3390/idr14020020

36.

Gottenberg

Ravaud

Puechal

, et al. Effects of hydroxychloroquine on symptomatic improvement in primary Sjogren syndrome: the JOQUER randomized clinical trial. JAMA. 2014;312:249-258. doi:10.1001/jama.2014.7682

37.

Jokar

Mirfeizi

Keyvanpajouh

The effect of hydroxychloroquine on symptoms of knee osteoarthritis: a double-blind randomized controlled clinical trial. Iran J Med Sci. 2013;38(3):221-226.

38.

Kavanaugh

Adams-Huet

Jain

Denke

McFarlin

Hydroxychloroquine effects on lipoprotein profiles (the HELP trial): a double-blind, randomized, placebo-controlled, pilot study in patients with systemic lupus erythematosus. J Clin Rheumatol. 1997;3(1):3-8.

39.

Kedor

Detert

Rau

, et al. Hydroxychloroquine in patients with inflammatory and erosive osteoarthritis of the hands: results of the OA-TREAT study—a randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial. RMD Open. 2021;7(2):e001660. doi:10.1136/rmdopen-2021-001660

40.

Kingsbury

Tharmanathan

Keding

, et al. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Ann Intern Med. 2018;168:385-395. doi:10.7326/M17-1430

41.

Lee

Ruijgrok

Boxma-de Klerk

, et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2018;70(9):1320-1325. doi:10.1002/acr.23471

42.

Levy

Vilela

Cataldo

, et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus. 2001;10(6):401-404. doi:10.1191/096120301678646137

43.

Liu

Ezekowitz

Columbo

, et al. Testing the feasibility of operationalizing a prospective, randomized trial with remote cardiac safety EKG monitoring during a pandemic. J Interv Card Electrophysiol. 2022;63(2):345-356. doi:10.1007/s10840-021-00989-x

44.

Mitja

Corbacho-Monne

Ubals

, et al. Hydroxychloroquine for early treatment of adults with mild coronavirus disease 2019: a randomized, controlled trial. Clin Infect Dis. 2021;73:e4073-e4081. doi:10.1093/cid/ciaa1009

45.

Omrani

Pathan

Thomas

, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe covid-19. EClinicalMedicine. 2020;29:100645. doi:10.1016/j.eclinm.2020.100645

46.

Paton

Goodall

Dunn

, et al. Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. JAMA. 2012;308:353-361. doi:10.1001/jama.2012.6936

47.

Reis

Moreira Silva

Medeiros Silva

, et al. Effect of early treatment with hydroxychloroquine or lopinavir and ritonavir on risk of hospitalization among patients with COVID-19: the TOGETHER randomized clinical trial. JAMA Netw Open. 2021;4:e216468. doi:10.1001/jamanetworkopen.2021.6468

48.

Schwartz

Boesen

Cerchiaro

, et al. Assessing the efficacy and safety of hydroxychloroquine as outpatient treatment of COVID-19: a randomized controlled trial. CMAJ Open. 2021;9(2):E693-E702. doi:10.9778/cmajo.20210069

49.

Self

Semler

Leither

, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324:2165-2176. doi:10.1001/jama.2020.22240

50.

Solomon

Garg

, et al. Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial. Arthritis Care Res (Hoboken). 2014;66(8):1246-1251. doi:10.1002/acr.22285

51.

Tang

Cao

Han

, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. doi:10.1136/bmj.m1849

52.

Toledo

FGS

Miller

Helbling

Zhang

DeLany

. The effects of hydroxychloroquine on insulin sensitivity, insulin clearance and inflammation in insulin-resistant adults: a randomized trial. Diabetes Obes Metab. 2021;23(6):1252-1261. doi:10.1111/dom.14333

53.

Ulander

Tolppanen

Hartman

, et al. Hydroxychloroquine reduces interleukin-6 levels after myocardial infarction: the randomized, double-blind, placebo-controlled OXI pilot trial. Int J Cardiol. 2021;337:21-27. doi:10.1016/j.ijcard.2021.04.062

54.

Ulrich

Troxel

Carmody

, et al. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open Forum Infect Dis. 2020;7:ofaa446. doi:10.1093/ofid/ofaa446

55.

Van Gool

Weinstein

Scheltens

Walstra

GJ.

Effect of hydroxychloroquine on progression of dementia in early Alzheimer’s disease: an 18-month randomised, double-blind, placebo-controlled study. Lancet. 2001;358:455-460. doi:10.1016/s0140-6736(01)05623-9

56.

Yokogawa

Eto

Tanikawa

, et al. Effects of hydroxychloroquine in patients with cutaneous lupus erythematosus: a multicenter, double-blind, randomized, parallel-group trial. Arthritis Rheumatol. 2017;69(4):791-799. doi:10.1002/art.40018

57.

Yoon

Lee

, et al. Effect of hydroxychloroquine treatment on dry eyes in subjects with primary Sjogren’s syndrome: a double-blind randomized control study. J Korean Med Sci. 2016;31:1127-1135. doi:10.3346/jkms.2016.31.7.1127

58.

Arnaout

Robertson

Pond

, et al. A randomized, double-blind, window of opportunity trial evaluating the effects of chloroquine in breast cancer patients. Breast Cancer Res Treat. 2019;178(2):327-335. doi:10.1007/s10549-019-05381-y

59.

Baltzan

Mehta

Kirkham

Cosio

MG.

Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med. 1999;160(1):192-197. doi:10.1164/ajrccm.160.1.9809024

60.

Borges

Castro

Fonseca

BA.

Chloroquine use improves dengue-related symptoms. Mem Inst Oswaldo Cruz. 2013;108(5):596-599. doi:10.1590/s0074-02762013000500010

61.

De Lamballerie

Boisson

Reynier

, et al. On chikungunya acute infection and chloroquine treatment. Vector Borne Zoonotic Dis. 2008;8(6):837-839. doi:10.1089/vbz.2008.0049

62.

Meinão

Sato

Andrade

Ferraz

Atra

Controlled trial with chloroquine diphosphate in systemic lupus erythematosus. Lupus. 1996;5(3):237-241. doi:10.1177/096120339600500313

63.

Peymani

Yeganeh

Sabour

, et al. New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial). Can J Physiol Pharmacol. 2016;94(6):613-619. doi:10.1139/cjpp-2015-0507

64.

Rojas-Puentes

Gonzalez-Pinedo

Crismatt

, et al. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat Oncol. 2013;8:209. doi:10.1186/1748-717X-8-209

65.

Sotelo

Briceno

Lopez-Gonzalez

MA.

Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144:337-343. doi:10.7326/0003-4819-144-5-200603070-00008

66.

Tricou

Minh

Van

, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. Plos Negl Trop Dis. 2010;4:e785. doi:10.1371/journal.pntd.0000785

67.

Rea-Neto

Bernardelli

Camara

BMD

Reese

Queiroga

MVO

Oliveira

MC.

An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients. Sci Rep. 2021;11:9023. doi:10.1038/s41598-021-88509-9

68.

Lundh

Gotzsche

PC.

Recommendations by Cochrane Review Groups for assessment of the risk of bias in studies. BMC Med Res Methodol. 2008;8:22. doi:10.1186/1471-2288-8-22

69.

Verbaanderd

Maes

Schaaf

, et al. Repurposing Drugs in Oncology (ReDO)—chloroquine and hydroxychloroquine as anti-cancer agents. Ecancermedicalscience. 2017;11:781. doi:10.3332/ecancer.2017.781

70.

Hultcrantz

Rind

Akl

, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017;87:4-13. doi:10.1016/j.jclinepi.2017.05.006

71.

Hondeghem

LM.

QTc prolongation as a surrogate for drug-induced arrhythmias: fact or fallacy. Acta Cardiologica. 2011;66:685-689. doi:10.1080/ac.66.6.2136950

72.

Hondeghem

LM.

Drug-induced QT prolongation and torsades de pointes: an all-exclusive relationship or time for an amicable separation?

Drug Saf. 2018;41(1):11-17. doi:10.1007/s40264-017-0584-4

73.

Shah

Hondeghem

LM.

Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm. 2005;2(7):758-772. doi:10.1016/j.hrthm.2005.03.023

74.

Friedrich

Adhikari

Beyene

Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data. BMC Med Res Methodol. 2007;7:5. doi:10.1186/1471-2288-7-5

75.

Bradburn

Deeks

Berlin

Russell Localio

Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;15:53-77. doi:10.1002/sim.2528

76.

Tsang

Colley

Lynd

LD.

Inadequate statistical power to detect clinically significant differences in adverse event rates in randomized controlled trials. J Clin Epidemiol. 2009;62(6):609-616. doi:10.1016/j.jclinepi.2008.08.005

77.

Kane

Sample Size Calculator. ClinCalc; 2021.

78.

American College of Rheumatology. Hydroxychloroquine (plaquenil). Date unknown. Accessed September 29, 2023. https://rheumatology.org/patients/hydroxychloroquine-plaquenil

79.

Medscape. Chloroquine. Date unknown. Accessed September 29, 2023. https://reference.medscape.com/drug/chloroquine-phosphate-chloroquine-342687

80.

Tisdale

Jaynes

Kingery

, et al. Development and validation of a risk score to predict QT interval prolongation in hospitalized patients. Circ Cardiovasc Qual Outcomes. 2013;6(4):479-487. doi:10.1161/CIRCOUTCOMES.113.000152

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.12 MB