I should have paid more attention in medical school.
If I had, I might have remembered enough about basic pathophysiology to know why everyone was suddenly pulling their patients off of lisinopril.
For those of you who need a quick primer: When the pressure in the renal artery drops, the kidney secretes renin. Working together, renin and a second enzyme—angiotensin converting enzyme 2 (ACE2)—produce angiotensin, which gives your blood pressure a boost.
ACE2 is also the traitor that holds the door open for SARS-CoV-2. By binding ACE2, SARS-Co-V-2 gains entry to cells in the lungs and gut, leading to the syndrome we recognize as COVID-19.1
If ACE2 is a traitor, then many of us may have been complicit in its crimes. Some antihypertensives, such as lisinopril, are believed to increase production of ACE2, potentially making it easier for SARS-CoV-2 to breech the barricades.
There’s no proof of this, of course, but the theory was alluring enough that it led to a global back and forth among multiple, high-powered institutions regarding which would be the greater sin: taking patients off proven therapies or ignoring a plausible hypothesis until it was too late.2
On May 1, 2020, we had an answer. Mandeep R. Mehra, MD, PhD, medical director of the Heart and Vascular Center at Brigham and Women’s Hospital, Boston, published an analysis in The New England Journal of Medicine of 8,910 patients admitted to 169 hospitals on three continents with COVID-19 between December 2019 and March 2020.3
Mehra et al. identified multiple risk factors for COVID-19-associated mortality, including older age, cardiac disease, chronic obstructive pulmonary disease and smoking. Unlike other groups, however, the authors did not identify hypertension as a significant risk factor. Even more reassuringly, they concluded there was no evidence linking the use of ACE inhibitors or angiotensin 2 receptor blockers with an increased risk of mortality.
One month later, 174 investigators from every continent (except Antarctica) sent an open letter to The New England Journal of Medicine titled “Expression of Concern Regarding Data Integrity and Results.” In it, they noted:4
“It is difficult to reconcile the UK data … with publicly available government data. Mehra et al. report electronic patient data from 706 patients hospitalized with PCR confirmed COVID-19 in just 7 of the UK’s 1,257 NHS hospitals. A high proportion of patients hospitalized in the UK on March 15th were in London, and yet no London borough, let alone hospital, had more than 100 PCR positive confirmed cases by this date. The numbers from Turkey also appear incorrect.”
On June 18, 2020, Eric J. Rubin, MD, PhD, editor in chief of The New England Journal of Medicine published an “Expression of Concern,” noting he had “asked the authors to provide evidence that the data are reliable.”5
On June 25, 2020, the paper was retracted.6
Whoa.
As the son of physicians, The New England Journal of Medicine was sacrosanct in my house. I learned to revere the red-on-white seal long before I knew what it meant. A retraction by The New England Journal of Medicine, the standard bearer for the medical publication industry, was big news. It was like Moses retracting one of the Ten Commandments.
The retraction was only two sentences long, but its reverberations were felt throughout the scientific community. Another major paper, based on the same dataset, was simultaneously retracted by The Lancet.7 The New York Times declared, “The pandemic claims new victims: prestigious medical journals. Two major study retractions in one month have left researchers wondering if the peer review process is broken.”8 But what, precisely, is peer review, and where did it go wrong in this case?