By CHITRA CHHABRA KOHLI MD, AJAY KOHLI MD, and VINAY KOHLI MD, MBA
With a doubling time of cases estimated between 3 days within the U.S. and about 6 days globally (at the time of this writing) COVID-19 is demonstrating its terrifying virulence as it spreads across the world.
What’s perhaps equally terrifying, if not more, is the absence of a known cure or treatment plan for COVID-19. While there has been a lot of attention focused on Hydroxychloroquine and Azithromycin, there has been debate on the scientific validity of these treatment options, either as therapy or as prophylaxis. The impact of a solution certainly has far reaching potential, the scope of the challenge is overwhelmingly large. The editor-in-chief of Science recently wrote that the efforts to find a cure are not just ”fixing a plane while it’s flying — it’s fixing a plane that’s flying while its blueprints are still being drawn.”
There is a promising therapy that may help us weather the COVID-19 storm and, perhaps, flatten the curve. It’s based around science that defines immunology and has already been used in many different diseases, going as far back as the 1918 flu pandemic. This potential treatment is convalescent plasma therapy — using antibodies from patients who have recovered from COVID-19 and then transfusing them into patients who are currently mounting an immune response against the rapidly rising viral loads of COVID-19.
The paper from the New England Journal of Medicine that reports azithromycin might cause cardiovascular death is not new to electrophysiologists tasked with deciding antibiotic choices in patients with Long QT syndrome or in those who take other antiarrhythmic drugs. Heck, even the useful Arizona CERT QTDrugs.org website could have told us that.
What was far scarier to me, though, was how the authors of this week’s paper reached their estimates of the magnitude of azithromycin’s cardiovascular risk.
Welcome to the underworld of Big Data Medicine.
Careful review of the Methods section of this paper reveals that “persons enrolled in the Tennessee Medicaid program” were the subjects, and that the data collected were “Computerized Medicaid data, which were linked to death certificates and to a state-wide hospital discharge database” and “Medicaid pharmacy files.” Anyone with azithromycin prescribed from 1992-2006 who had “not had a diagnosis of drug abuse or resided in a nursing home in the preceding year and had not been hospitalized in the prior 30 days.” Also, they had to be “Medicaid enrollees for at least 365 days and have regular use of medical care.”
Hey, no selection bias introduced with those criteria, right? But the authors didn’t stop there.
It was during my residency that the first indication of heart toxicity of antibiotics affected me personally. The threat was related to the use of the first of the non-drowsy antihistamines – Seldane – in combination with macrolide antibiotics, such as Erythromycin causing a potentially fatal heart arrhythmia. I remember the expressions fear from other residents, as we had used this combination of medications often. Were we killing people when we treated their bronchitis? We had no idea, but we were consoled by the fact that the people who had gotten our arrhythmia-provoking combo were largely anonymous to us (ER patients).
Fast forward to 2012 and the study (published in the holy writings of the New England Journal of Medicine) that Zithromax is associated with more dead people than no Zithromax. Here’s the headline-provoking conclusion:
During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. (Emphasis Mine).