This article focuses on:
- Registry features and data acquisition
- Study design
- Data collection
- Statistical analysis
- Antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for the treatment of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis has been widely used.
- These drugs have been shown to have antiviral properties as well as immunomodulatory effects.
- The combination of hydroxychloroquine with a second-generation macrolide, such as azithromycin (or clarithromycin), has also been advocated, despite limited evidence for its effectiveness.
- Previous studies have shown that treatment with chloroquine, hydroxychloroquine, or either drug combined with a macrolide can have the cardiovascular adverse effect of prolongation of the QT interval, which predisposes to ventricular arrhythmias.
- To evaluate the use of chloroquine or hydroxychloroquine alone or in combination with a macrolide for treatment of COVID-19 using a large multinational registry to assess their real-world application. Principally, we sought to analyse the association between these treatment regimens and in-hospital death.
- To evaluate the occurrence of de-novo clinically significant ventricular arrhythmias.
Registry features and data acquisition
- A multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19 was done.
- The registry comprised 671 hospitals located in six continents.
- The Surgical Outcomes Collaborative consists of de-identified data obtained by automated data extraction from inpatient and outpatient electronic health records, supply chain databases, and financial records.
- A manual data entry process was used for quality assurance and validation to ensure that key missing values are kept to a minimum.
- Real-world data are collected through automated data transfers that capture 100% of the data from each healthcare entity at regular, predetermined intervals, thus reducing the impact of selection bias and missing values, and ensuring that the data are current, reliable, and relevant.
- Verifiable source documentation for the elements include electronic inpatient and outpatient medical records and, in accordance with the FDA guidance on relevance of real-world data, data acquisition is performed through use of a standardised Health Level Seven-compliant data dictionary, with data collected on a prospective ongoing basis.
- The validation procedure for the registry refers to the standard operating procedures in place for each of the four ISO 9001:2015 and ISO 27001:2013 certified features of the registry: data acquisition, data warehousing, data analytics, and data reporting.
- The standardised Health Level Seven-compliant data dictionary used by the Collaborative serves as the focal point for all data acquisition and warehousing.
- Once this data dictionary is harmonised with electronic health record data, data acquisition is completed using automated interfaces to expedite data transfer and improve data integrity.
- Collection of a 100% sample from each healthcare entity is validated against financial records and external databases to minimise selection bias.
- To reduce the risk of inadvertent protected health information disclosures, all such information is stripped before storage in the cloud-based data warehouse.
- The Collaborative is intended to minimise the effects of information bias and selection bias by capturing all-comer data and consecutive patient enrolment by capturing 100% of the data within electronic systems, ensuring that the results remain generalisable to the larger population.
- With the onset of the COVID-19 crisis, this registry was used to collect data from hospitals in the USA and internationally, to achieve representation from diverse populations across six continents.
- Data have been collected from a variety of urban and rural hospitals, academic or community hospitals, and for-profit and nonprofit hospitals.
- All patients hospitalised between Dec 20, 2019, and April 14, 2020, at hospitals participating in the registry and with PCR-confirmed COVID-19 infection, for whom a clinical outcome of either hospital discharge or death during hospitalisation was recorded.
- Patients who did not have a record of testing in the database, or who had a negative test, were not included in the study.
- Only one positive test was necessary for the patient to be included in the analysis.
- Patients who received either hydroxychloroquine or a chloroquine analogue-based treatment (with or without a second-generation macrolide) were included in the treatment group.
- Patients who received treatment with these regimens starting more than 48 h after COVID-19 diagnosis were excluded.
- Data from patients for whom treatment was initiated while they were on mechanical ventilation or if they were receiving therapy with the antiviral remdesivir were excluded.
- Thus, four distinct treatment groups wre defined in which all patients started therapy within 48 h of an established COVID-19 diagnosis: chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide.
- All other included patients served as the control population.
- Patient demographics, including age, body-mass index (BMI), sex, race or ethnicity, and continent of origin were obtained.
- Underlying comorbidities present in either the inpatient or outpatient electronic health record were collected, which included cardiovascular disease, current or previous history of smoking, history of hypertension, diabetes, hyperlipidaemia, or chronic obstructive pulmonary disease (COPD), and presence of an immunosuppressed condition.
- Data on use of medications at baseline, including cardiac medications or use of antiviral therapy other than the drug regimens being evaluated were obtained.
- The initiation of hydroxychloroquine or chloroquine during hospital admission was recorded, including the time of initiation.
- The use of second generation macrolides, specifically azithromycin and clarithromycin, was similarly recorded.
- A quick sepsisrelated organ failure assessment was calculated for the start of therapy and oxygen saturation) on room air was recorded, as measures of disease severity.
- The primary outcome of interest was the association between use of a treatment regimen containing chloroquine or hydroxychloroquine (with or without a secondgeneration macrolide) when initiated early after COVID-19 diagnosis with the endpoint of in-hospital mortality.
- The secondary outcome of interest was the association between these treatment regimens and the occurrence of clinically significant ventricular arrhythmias during hospitalisation.
- The rates of progression to mechanical ventilation use and the total and intensive care unit lengths of stay (in days) for patients in each group was also analysed.
- For the primary analysis of in-hospital mortality, confounding factors, including demographic variables, comorbidities, disease severity at presentation, and other medication use were controlled.
- Comparison of continuous data between groups was done using the unpaired t-test and categorical data were compared using Fisher’s exact test.
- A p value of less than 0·05 was considered significant.
- Cox proportional hazards regression analysis was done to evaluate the effect of age, sex, race or ethnicity, comorbidities, medications and severity of illness scores on the risk of clinically significant ventricular arrhythmia and mortality.
- Age and BMI were treated as continuous variables and all other data were treated as categorical variables in the model.
- From the model, hazard ratios (HRs) with 95% CIs were estimated for included variables to determine their effect on the risk of in-hospital mortality (primary endpoint) or subsequent mechanical ventilation or death (composite endpoint).
- Proportionality between the predictors and the hazard was validated through an evaluation of Schoenfeld residuals, which found p>0·05 and thus confirmed proportionality.
- To minimise the effect of confounding factors, a propensity score matching analysis was done individually for each of the four treatment groups compared with a control group that received no form of that therapy.
- For each treatment group, a separate matched control was identified using exact and propensity-score matched criteria with a calliper of 0·001.
- The propensity score was based on the following variables: age, BMI, gender, race or ethnicity, comorbidities, use of ACE inhibitors, use of statins, use of angiotensin receptor blockers, treatment with other antivirals, qSOFA score of less than 1, and SPO2 of less than 94% on room air.
- The patients were well matched, with standardised mean difference estimates of less than 10% for all matched parameters.
- Additional analyses were done to examine the robustness of the estimates initially obtained.
- Individual analyses by continent of origin and sex-adjusted analyses using Cox proportional hazards models were performed.
- A tipping-point analysis was also done.
- All statistical analyses were done with R version 3.6.3 and SPSS version 26
- 96032 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.
- All included patients completed their hospital course 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 patients from North America, 16 574 from Europe, 7555 from Asia, 4402 from Africa, 3577 from South America, and 609 from Australia.
- The mean age was 53·8 years, 44 426 were women, mean BMI was 27·6 kg/m², 64220 were white, 9054 were black, 5978 were Hispanic, and 13 519 were of Asian origin.
- In terms of comorbidities, 30 198 had hyperlipidaemia, 25 810 had hypertension, 13 260 had diabetes, 3177 had COPD, 2868 had an underlying immunosuppressed condition, 16 553 were former smokers, and 9488 were current smokers.
- In terms of preexisting cardiovascular disease, 12 137 had coronary artery disease, 2368 had a history of congestive heart failure, and 3381 had a history of arrhythmia.
- The mean length of stay in hospital was 9·1 days , with an overall in-hospital mortality of 10 698 of 96 032.
- The use of other antivirals was recorded in 38 927 patients as treatment for COVID-19.
- The most common antivirals were lopinavir with ritonavir, ribavirin and oseltamivir.
- Combination therapy with more than one of these antiviral regimens was used for 6782 patients.
- 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.
- The mean daily dose and duration of the various drug regimens were as follows: chloroquine alone, 765 mg and 6·6 days; hydroxychloroquine alone, 596 mg and 4·2 days ; chloroquine with a macrolide, 790 mgand 6·8 days ; and hydroxychloroquine with a macrolide, 597 mg and 4·3 days.
- Nonsurvivors 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.
- No significant between-group differences were found among baseline characteristics or comorbidities.
- Ventricular arrhythmias were more common in the treatment groups compared with the control population.
- Mortality was higher in the treatment groups compared with the control population.
- 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 and use of statins was associated with reduced in-hospital mortality risk.
- Compared with the control group, hydroxychloroquine alone, hydroxychloroquine with a macrolide, chloroquine alone and chloroquine with a macrolide were independently associated with an increased risk of in-hospital mortality.
- 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 , hydroxychloroquine with a macrolide, chloroquine alone and chloroquine with a macrolide were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.
- 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.
- 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 nonsignificance 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.
- 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 which suggested that the combination of hydroxychloroquine with the macrolide azithromycin was successful in clearing viral replication.
- 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.
- 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.
- 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.
- Chloroquine and hydroxychloroquine are associated with concerns of cardiovascular toxicity, particularly because of their known relationship with electrical instability, characterised by QT interval prolongation.
- This mechanism relates to blockade of the hERG potassium channel, which lengthens ventricular repolarisation and the duration of ventricular action potentials.
- Under specific conditions, early after depolarisations can trigger ventricular arrhythmias.
- 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.
- Pathological studies have pointed to derangements in the vascular endothelium and a diffuse endotheliitis noted across multiple organs in COVID-19.
- 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.
- The use of chloroquine or hydroxychloroquine in combination with a macrolide is designed to use their antimicrobial properties in a synergistic manner.
- Macrolides, such as azithromycin and clarithromycin, are antibiotics with immunomodulatory and anti-inflammatory effects.
- However, these drugs prolong the QT interval and increase the risk of sudden cardiac death.
- In a preliminary analysis, Borba and colleagues25 reported a doubleblind, 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.
- The hazard of de-novo ventricular arrhythmias increased when the drugs were used in combination with a macrolide.
- Higher BMI emerged as a risk marker for worse in-hospital survival.
- Obesity is a known risk factor for cardiac arrhythmias and sud – den cardiac death.
- 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 the 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 the previous findings in a smaller cohort of 8910 patients, 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.
- 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.
- QT intervals were not measured nor the arrhythmia pattern (such as torsade de pointes).
- The association of increased risk of in-hospital death with use of the drug regimens is linked directly to their cardiovascular risk was not established nor a drug dose-response analysis of the observed risks was conducted.
This multinational, observational, realworld 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.