Early Outpatient Treatment of Symptomatic, High-risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis

Harvey A. Risch

Disclosures

Am J Epidemiol. 2020;189(11):1218-1226. 

In This Article

Adverse Events

Both proposed drug regimens have shown side effects. Remdesivir, in its phase 3 trial of 10-day versus 5-day therapeutic courses in hospitalized patients, produced a range of adverse events in more than 70% of patients in both treatment arms.[33] Adverse events requiring medication discontinuation were many fewer: 5% in the 5-day group and 10% in the 10-day group. In the Chinese trial, 12% of remdesivir patients stopped using the medication before the end of the 10-day treatment because of drug-related adverse events.[10]

For HCQ + AZ use, the argued issue concerns fatal cardiac arrhythmia: the warnings issued by the FDA, the NIH, and the cardiology societies. Indeed, both HCQ and AZ produce QT prolongation, rare instances of fatal torsades de pointes (TdP) ventricular tachycardia, and long QT-interval syndrome. A number of essays by cardiologists published in the Journal of the American Medical Association and other journals have anxiously warned about these risks but have not examined mortality from them. The sole question is whether these fatal events, or even any fatal cardiac arrhythmia events, would occur with enough frequency that general treatment of noncontraindicated high-risk outpatients with HCQ + AZ would outweigh benefit in preventing hospitalization and mortality. A number of studies have examined hospital inpatient use, but these studies have had major flaws, not least of which is that patients hospitalized with multiple medical problems and more advanced disease do not represent the mortality experience for outpatient use of these medications in patients otherwise well enough not to be hospitalized. One source of data on mortality associated with these medications is the FDA Adverse Event Reporting System (FAERS) database.[34] Examination of the database for adverse events reported from the creation of the database in 1968 through 2019 and into the beginning of 2020 shows 1,064 adverse event reports for HCQ, including 200 deaths for all of the cardiac causes that could be both specifically and broadly classified as rhythm-related. Of these, 57 events, including 10 deaths, were attributed to TdP tachycardia and long QT-interval syndrome combined. This concerns the entirety of HCQ use over more than 50 years of data—probably millions of uses and longer-term use than the 5 days recommended for COVID-19 treatment. For AZ use, the numbers of reported TdP and long QT-interval syndrome events total 37, of which 2 were deaths. FAERS data are generated by patient, physician, and pharmacist report initiation and probably underrepresent true event occurrences. However, even if the true numbers were 10-fold larger, they would still be minuscule compared with the amounts of medication usage. How much the risk of QT prolongation would be enhanced with HCQ and AZ taken together is unknown, but the Prescribers' Digital Reference says that coadministration of these medications risks "additive QT prolongation"[35]—not multiplicative. Tisdale states, "Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide" (,[36] p. 139). Nevertheless, even if the use of combined HCQ + AZ produced a 10-fold higher incidence of fatal TdP tachycardia and long QT-interval syndrome than either agent alone, and even if both events were 10-fold underreported in FAERS, thus hypothetically giving 1,200 fatal events, that would still be very small compared with the millions of uses of these medications that the FAERS database represents. Therefore, while it is established that HCQ + AZ lengthens the QTc interval (the corrected duration of the electrocardiogram Q-T wave) by 18–55 ms, on average,[37–40] in 40, 84, 90, and 98 severely ill hospitalized patients in the 4 studies, respectively, who were treated with these medications and had this lengthening, a total of 1 case of TdP tachycardia occurred, and it was not fatal—there were no deaths. Substantial fractions of these hospitalized patients were taking diuretics, which may be contraindicated for HCQ + AZ use in the first place. This arrhythmia issue is a real, physiologically measurable effect of the use of these combined medications, but fatal arrhythmia outcomes are so rare that they are of much lesser clinical significance than the hospitalization and mortality that the drugs prevent. This fact is also clear from the lack of any cardiac arrhythmia events or arrhythmia mortality noted in the 405 Zelenko patients or the 1,061 Marseilles patients or the 412 Brazil patients. Patients were not enrolled in these studies if they had known histories of QTc prolongation. History of cardiac arrhythmia or other possible contraindications for use of HCQ or AZ or DOX is a normal part of workup and clinical judgment in a physician's choice to use these medications and in how to monitor the patients (see Web Appendix).

Further evidence of the real-world unimportance of arrhythmia and other cardiovascular adverse event endpoints of HCQ + AZ use is given in the large Oxford, United Kingdom-based record-linkage study.[41] Fourteen large medical-records databases were examined for all-cause mortality and for 15 specified classes of adverse events among hundreds of thousands of patients with rheumatoid arthritis who had used these drugs. First, 323,122 users of HCQ + AZ were compared with 351,956 users of HCQ + amoxicillin. No significant difference in all-cause mortality was seen: As reported by the authors, the relative risk was 1.36 (P = 0.10), and as I calculate from the data provided by the authors in their Web supplement to the paper,[41] the relative risk was 1.18 (P = 0.37)—either way, a null association within the range of chance. However, the authors selectively presented from among the 15 analyzed endpoints the 3 most significant associations: those for cardiovascular mortality (relative risk (RR) = 2.19, P = 0.0088), chest pain/angina (RR = 1.15, P = 0.0027), and heart failure (RR = 1.22, P = 0.027). What is misrepresented in the authors' presentation of these data in this way is that these 3 outcomes were not individually specified to be of more interest than any of the other 12 specific outcomes that they examined, and they did not correct their calculated levels of statistical significance for the 15 classes of outcomes. In lay terms, it was a fishing expedition. When accounting is done by means of the standard Bonferroni correction for multiple comparisons, the respective P values are 0.12, 0.04, and 0.35. The large amount of data in this study thus shows that there is no significant relationship of HCQ + AZ use versus HCQ + amoxicillin use with any of the 15 outcomes specified or with all-cause mortality, except for a just-barely-significant association with chest pain/angina (a 15% higher risk). Even if the chest pain/angina association were a true finding, it would still be of little clinical import for a relatively infrequent outcome in the context of the mortality to be prevented by HCQ + AZ use in widespread symptomatic high-risk outpatient COVID-19 treatment.

Second, the stated concern of the FDA and NIH advisories and the cardiology society opinion restricting use of HCQ + AZ was for fatal TdP tachycardia and long QT-interval syndrome, 2 rare types of cardiac arrhythmia, as well as for cardiac arrhythmia in general. In the Oxford study, Lane et al.[41] examined cardiac arrhythmia outcomes and obtained, for their random-effects meta-analysis result, a relative risk of 1.08 (P = 0.36) for HCQ + AZ use versus HCQ + amoxicillin use. The fixed-effects meta-analysis relative risk was 1.04 (P = 0.41). This study clearly demonstrates that cardiac arrhythmia adverse events are not appreciably increased by combining HCQ with AZ. In the same study, the investigators compared HCQ use with sulfasalazine use and again found no difference in cardiac arrhythmia risk: For HCQ, there was a slightly lower relative risk of 0.89 (P = 0.13). The subjects analyzed in the Oxford study were largely older adults with multiple comorbid conditions in addition to rheumatoid arthritis.

Finally, the Oxford study allows for a direct estimate of the number of arrhythmia events attributable to HCQ + AZ use.[41] Among 306,106 people taking sulfasalazine (which is known not to produce QT prolongation), 877 with cardiac arrhythmia were identified (0.287%). In 320,589 people taking HCQ + AZ, 1,068 had arrhythmia (0.333%). The difference, 0.047% or 47 per 100,000 older multicomorbidity patients taking HCQ + AZ, is attributable to the HCQ + AZ use. These are events, not fatalities. As I noted above, fatalities according to FAERS comprise less than 20% of HCQ-related arrhythmia events. The maintenance HCQ dose in the Oxford study patients, 200 mg/day, gives as large or larger plasma drug levels as 5 days of HCQ at 400 mg/day, the recommended dose for outpatient COVID-19. These very small numbers of arrhythmias, as well as the null results in this very large empirical study, should therefore put to rest the anxieties about population excess mortality from HCQ + AZ outpatient use, either from cardiac arrhythmia or from all causes.

This discussion shows that the FDA, NIH, and cardiology society warnings about cardiac arrhythmia adverse events, while appropriate for theoretical and physiological considerations about use of these medications, are not borne out in mortality in real-world usage of them. Treatment-failure mortality will be much higher, but even that pales in comparison with the lives saved. It would therefore be incumbent upon all 3 organizations to reevaluate their positions as soon as possible. It is unclear why the FDA, NIH, and cardiology societies made their recommendations about HCQ + AZ use now, when the Oxford study[41] analyzed 323,122 users of HCQ + AZ compared with 351,956 users of HCQ + amoxicillin—that is, that the combination of HCQ + AZ has been in widespread standard-of-care use in the United States and elsewhere for decades, with use being comparable to HCQ + amoxicillin as if it just involved an alternate antibiotic choice, this use being predominantly in older adults with multiple comorbid conditions, and with no such strident warnings about the use given during that time. I note that since DOX is believed to cause even fewer cardiac arrhythmias than AZ, in patients where that is a concern,[42] the evidence from long-term-care facilities suggests that HCQ + DOX likely will work about as well.

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