Results
96 032 hospitalised patients from 671 hospitals were diagnosed with COVID-19 between Dec 20, 2019, and April 14, 2020 and met the inclusion criteria for this study (figure 1). All included patients completed their hospital course (discharged or died) by April 21, 2020. Patients who were hospitalised during the study period without a completed course were unable to be analysed. The study cohort included 63 315 (65·9%) patients from North America, 16 574 (17·3%) from Europe, 7555 (7·9%) from Asia, 4402 (4·6%) from Africa, 3577 (3·7%) from South America, and 609 (0·6%) from Australia (details of the number of hospitals per continent are presented in the appendix, p 3). The mean age was 53·8 years (SD 17·6), 44 426 (46·3%) were women, mean BMI was 27·6 kg/m2 (SD 5·5; 29 510 [30·7%] were obese with BMI ≥30 kg/m2), 64 220 (66·9%) were white, 9054 (9·4%) were black, 5978 (6·2%) were Hispanic, and 13 519 (14·1%) were of Asian origin (appendix p 4). In terms of comorbidities, 30 198 (31·4%) had hyperlipidaemia, 25 810 (26·9%) had hypertension, 13 260 (13·8%) had diabetes, 3177 (3·3%) had COPD, 2868 (3·0%) had an underlying immunosuppressed condition, 16 553 (17·2%) were former smokers, and 9488 (9·9%) were current smokers. In terms of pre-existing cardiovascular disease, 12 137 (12·6%) had coronary artery disease, 2368 (2·5%) had a history of congestive heart failure, and 3381 (3·5%) had a history of arrhythmia. The mean length of stay in hospital was 9·1 days (SD 6·4), with an overall in-hospital mortality of 10 698 (11·1%) of 96 032. The use of other antivirals was recorded in 38 927 (40·5%) patients as treatment for COVID-19. The most common antivirals were lopinavir with ritonavir (12 304 [31·6%]), ribavirin (7904 [20·3%]), and oseltamivir (5101 [13·1%]). Combination therapy with more than one of these antiviral regimens was used for 6782 (17·4%) patients.
Figure 1 Study profile
The treatment groups included 1868 patients who were given chloroquine alone, 3016 given hydroxychloroquine alone, 3783 given chloroquine with a macrolide and 6221 given hydroxychloroquine and a macrolide. The median time from hospitalisation to diagnosis of COVID-19 was 2 days (IQR 1–4). The mean daily dose and duration of the various drug regimens were as follows: chloroquine alone, 765 mg (SD 308) and 6·6 days (2·4); hydroxychloroquine alone, 596 mg (126) and 4·2 days (1·9); chloroquine with a macrolide, 790 mg (320) and 6·8 days (2·5); and hydroxychloroquine with a macrolide, 597 mg (128) and 4·3 days (2·0). Additional details of the study cohort are provided in the appendix (pp 4–5).
Demographic variables and comorbidities were compared among survivors and non-survivors (table 1). Non-survivors were older, more likely to be obese, more likely to be men, more likely to be black or Hispanic, and to have diabetes, hyperlipidaemia, coronary artery disease, congestive heart failure, and a history of arrhythmias. Non-survivors were also more likely to have COPD and to have reported current smoking.
Independent predictors of in-hospital mortality are shown in figure 2. Age, BMI, black race or Hispanic ethnicity (versus white race), coronary artery disease, congestive heart failure, history of arrhythmia, diabetes, hypertension, hyperlipidaemia, COPD, being a current smoker, and immunosuppressed condition were associated with a higher risk of in-hospital death. Female sex, ethnicity of Asian origin, use of ACE inhibitors (but not angiotensin receptor blockers), and use of statins was associated with reduced in-hospital mortality risk. Compared with the control group (9·3%), hydroxychloroquine alone (18·0%; HR 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine alone (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were independently associated with an increased risk of in-hospital mortality. The multivariable Cox regression analyses by continent are shown in the appendix (pp 6–11), as well as data from the sex-adjusted multivariable logistic regression analyses (pp 12–13) and a separate Cox regression analysis for the combined endpoint of mechanical ventilation or mortality (p 14).
Figure 2 Independent predictors of in-hospital mortality
Independent predictors of ventricular arrythmia are shown in figure 3. Coronary artery disease, congestive heart failure, history of cardiac arrhythmia, and COPD were independently associated with an increased risk of de-novo ventricular arrhythmias during hospitalisation. Compared with the control group (0·3%), hydroxychloroquine alone (6·1%; HR 2·369, 95% CI 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine alone (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.
Figure 3 Independent predictors of ventricular arrhythmias during hospitalisation
Analyses using propensity score matching by treatment group are shown in the appendix (pp 15–18). The results indicated that the associations between the drug regimens and mortality, need for mechanical ventilation, length of stay, and the occurrence of de-novo ventricular arrhythmias were consistent with the primary analysis.
A tipping point analysis was done to assess the effects of an unmeasured confounder on the findings of significance with hydroxychloroquine or chloroquine (appendix pp 19–20). For chloroquine, hydroxychloroquine, and chloroquine with a macrolide, a hypothetical unobserved binary confounder with a prevalence of 50% in the exposed population would need to have an HR of 1·5 to tip this analysis to non-significance at the 5% level. For a comparison with the observed confounders in this study, if congestive heart failure (which has an HR of 1·756) were left out of the model, it would need to have a prevalence of approximately 30% in the population to lead to confounding in the analysis. Similarly, for hydroxychloroquine with a macrolide, a hypothetical unobserved binary confounder with a prevalence of 37% in the exposed population would need to have an HR of 2·0 to tip this analysis to non-significance at the 5% level. Again, congestive heart failure (which has an HR of 1·756) would need to have a prevalence of approximately 50% in the population to lead to confounding in the analysis, had it not been adjusted for in the Cox proportional hazards model.
Discussion
In this large multinational real-world analysis, we did not observe any benefit of hydroxychloroquine or chloroquine (when used alone or in combination with a macrolide) on in-hospital outcomes, when initiated early after diagnosis of COVID-19. Each of the drug regimens of chloroquine or hydroxychloroquine alone or in combination with a macrolide was associated with an increased hazard for clinically significant occurrence of ventricular arrhythmias and increased risk of in-hospital death with COVID-19.
The use of hydroxychloroquine or chloroquine in COVID-19 is based on widespread publicity of small, uncontrolled studies, which suggested that the combination of hydroxychloroquine with the macrolide azithromycin was successful in clearing viral replication.7 On March 28, 2020, the FDA issued an emergency use authorisation for these drugs in patients if clinical trial access was unavailable.12 Other countries, such as China, have issued guidelines allowing for the use of chloroquine in COVID-19.13 Several countries have been stockpiling the drugs, and shortages of them for approved indications, such as for autoimmune disease and rheumatoid arthritis, have been encountered.10 A retrospective observational review of 368 men with COVID-19 treated at the US Veterans Affairs hospitals raised concerns that the use of hydroxychloroquine was associated with a greater hazard of death; however, the baseline characteristics among the groups analysed were dissimilar and the possibility of bias cannot be ruled out.14 Another observational study in 181 patients from France reported that the use of hydroxychloroquine at a dose of 600 mg per day was not associated with a measurable clinical benefit in patients with COVID-19 pneumonia.15 Our large-scale, international, real-world analysis supports the absence of a clinical benefit of chloroquine and hydroxychloroquine and points to potential harm in hospitalised patients with COVID-19.
Chloroquine and hydroxychloroquine are associated with concerns of cardiovascular toxicity, particularly because of their known relationship with electrical instability, characterised by QT interval prolongation (the time taken for ventricular depolarisation and repolarisation). This mechanism relates to blockade of the hERG potassium channel,16 which lengthens ventricular repolarisation and the duration of ventricular action potentials. Under specific conditions, early after-depolarisations can trigger ventricular arrhythmias.9 Such propensity for arrhythmia provocation is more often seen in individuals with structural cardiovascular disease, and cardiac injury has been reported to occur with high frequency during COVID-19 illness.17, 18 Furthermore, individuals with cardiovascular disease represent a vulnerable population that experience worse outcomes with COVID-19.19, 20 Pathological studies have pointed to derangements in the vascular endothelium and a diffuse endotheliitis noted across multiple organs in COVID-19.21 Whether patients with underlying cardiovascular disease and those that experience de-novo cardiovascular injury have a greater predilection to ventricular arrhythmias with chloroquine or its analogues remains uncertain but plausible. COVID-19 is exemplified by initial viral replication followed by enhanced systemic inflammation.22 The use of chloroquine or hydroxychloroquine in combination with a macrolide is designed to use their antimicrobial properties in a synergistic manner.23 Macrolides, such as azithromycin and clarithromycin, are antibiotics with immunomodulatory and anti-inflammatory effects.24 However, these drugs prolong the QT interval and increase the risk of sudden cardiac death.8, 9 In a preliminary analysis, Borba and colleagues25 reported a double-blind, randomised trial with 81 adult patients who were hospitalised with severe COVID-19 at a tertiary care facility in Brazil. This study suggested that a higher dose of chloroquine represented a safety hazard, especially when taken concurrently with azithromycin and oseltamivir. In another cohort study of 90 patients with COVID-19 pneumonia, Mercuro and colleagues26 found that the concomitant use of a macrolide was associated with a greater change in the corrected QT interval. Our study did not examine the QT interval but instead directly analysed the risk of clinically significant ventricular arrythmias. We showed an independent association of the use of either hydroxychloroquine or chloroquine with the occurrence of de-novo ventricular arrhythmias. We also note that the hazard of de-novo ventricular arrhythmias increased when the drugs were used in combination with a macrolide.
In our analysis, which was dominated by patients from North America, we noted that higher BMI emerged as a risk marker for worse in-hospital survival. Obesity is a known risk factor for cardiac arrhythmias and sudden cardiac death.27, 28 The most commonly reported arrhythmias are atrial fibrillation and ventricular tachycardia. Although age, race, and BMI were predictive of an increased risk for death with COVID-19 in our analysis, they were not found to be associated with an increased risk of ventricular arrhythmias on our multivariable regression analysis. The only variables found to be independently predictive of ventricular arrhythmias were the four treatment regimens, along with underlying cardiovascular disease and COPD. Thus, the presence of cardiovascular comorbidity in the study population could partially explain the observed risk of increased cardiovascular toxicity with the use of chloroquine or hydroxychloroquine, especially when used in combination with macrolides. In this investigation, consistent with our previous findings in a smaller cohort of 8910 patients,20 we found that women and patients being treated with ACE inhibitors (but not angiotensin receptor blockers) or statins had lower mortality with COVID-19. These findings imply that drugs that stabilise cardiovascular function and improve endothelial cell dysfunction might improve prognosis, independent of the use of cardiotoxic drug combinations.21
Our study has several limitations. The association of decreased survival with hydroxychloroquine or chloroquine treatment regimens should be interpreted cautiously. Due to the observational study design, we cannot exclude the possibility of unmeasured confounding factors, although we have reassuringly noted consistency between the primary analysis and the propensity score matched analyses. Nevertheless, a cause-and-effect relationship between drug therapy and survival should not be inferred. These data do not apply to the use of any treatment regimen used in the ambulatory, out-of-hospital setting. Randomised clinical trials will be required before any conclusion can be reached regarding benefit or harm of these agents in COVID-19 patients. We also note that although we evaluated the relationship of the drug treatment regimens with the occurrence of ventricular arrhythmias, we did not measure QT intervals, nor did we stratify the arrhythmia pattern (such as torsade de pointes). We also did not establish if the association of increased risk of in-hospital death with use of the drug regimens is linked directly to their cardiovascular risk, nor did we conduct a drug dose-response analysis of the observed risks. Even if these limitations suggest a conservative interpretation of the findings, we believe that the absence of any observed benefit could still represent a reasonable explanation.
In summary, this multinational, observational, real-world study of patients with COVID-19 requiring hospitalisation found that the use of a regimen containing hydroxychloroquine or chloroquine (with or without a macrolide) was associated with no evidence of benefit, but instead was associated with an increase in the risk of ventricular arrhythmias and a greater hazard for in-hospital death with COVID-19. These findings suggest that these drug regimens should not be used outside of clinical trials and urgent confirmation from randomised clinical trials is needed.