May 1, 2020 — Drugs taken by millions of Americans to curb high blood pressure do not appear to increase the risk of either getting COVID-19 or having a more severe infection, according to the results of three large new studies.
ACE inhibitors, including drugs like lisinopril, enalapril, and ramipril, are the most widely used high blood pressure drugs in the U.S. Whether or not to leave patients on ACE inhibitors or another popular class of high blood pressure medications called ARBs, or angiotensin-receptor blockers, in the midst of the COVID-19 pandemic has been hotly debated.
Those medications may increase the ACE2 enzyme, which sits on the surface of many different kinds of cells throughout the body.
ACE2 is also the doorway the new coronavirus uses to invade our cells. Doctors had feared that drugs that make more of these doorways could make COVID-19 infections more likely or more dangerous for patients.
“Patients were calling, they were writing and asking if these medications increase their risk and should they stop,” said George Thomas, MD, a nephrologist at the Cleveland Clinic in Ohio.
Thomas said he told his patients to continue to take the drugs, since evidence of possible harm came from animal studies and was mostly theoretical. Several medical societies also came out with statements urging people to continue to take the drugs.
“Now we have evidence to support that, so that’s good,” says Thomas, who was not involved in the studies.
A Survival Benefit?
The new studies, which are published in The New England Journal of Medicine, reviewed the medical records of thousands of COVID-19 patients in the U.S. and around the world to learn more about their other medical conditions and the drugs they use to manage them.
The first study was a review of the medical records from nearly 9,000 patients who have been entered into an international registry of COVID-19 cases. The patients were admitted to 169 hospitals on three continents between Dec. 20, 2019, and March 29, 2020.
Researchers were particularly interested in patients’ other health conditions and the medications they were taking to manage those, including blood thinners, different kinds of blood pressure drugs, cholesterol-lowering medications, and medications to control blood sugar.
“The question we were asking is, ‘Are any of these harmful?’ We didn’t expect any to be beneficial. Because that’s where the debate was going,” says study author Mandeep Mehra, MD, medical director of the Brigham and Women’s Heart and Vascular Center in Boston.
As expected, many of these hospitalized patients with serious COVID-19 infections had risk factors like high cholesterol, high blood pressure, and diabetes. Many were current or former smokers. Being older than 65 and having heart disease are linked to higher odds of dying of the disease.
But the study also found a surprise: Patients who were taking ACE inhibitors appeared to have a survival benefit. Around 3% of the patients who died in the hospital (16 out of 515 total patients who died) were taking an ACE inhibitor, compared with 9% of those who survived their infections (754 of 8,395 total patients who survived.) The odds of dying were about two-thirds lower in patients taking ACE inhibitors than those who were not. Taking a statin medication to control cholesterol was also linked to improved survival, as was female sex. All those differences were statistically significant. Taking an angiotensin receptor blocker, or ARB, appeared to have no significant impact on a patient’s odds of dying.
The study is observational, which means it can’t prove that the medications, alone, were responsible for the benefit. There could be other similarities between patients taking ACE Inhibitors or statins that could explain the differences.
But Mehra believes his findings point to a biological effect that may be important in COVID-19 infections. ACE inhibitors may increase ACE2 enzymes — the doorways the virus uses to attack our cells. Once the virus infects a cell, it actually gets rid of these enzymes, which may be part of the way it causes so much damage. But the nzymes also have another important function — to help make products that protect our blood vessels and calm inflammation.
Taking ACE inhibitors and statins, Mehra believes, may protect cells from this damage.
So far, evidence to support this theory is limited, but studies are underway that hope to answer the question of whether these kinds of drugs could protect COVID-19 patients.
No Evidence of Harm
The other two studies also found no evidence that either ACE inhibitors or ARBs increase the risk of infection.
One study, from the Lombardy region of Italy, compared more than 6,000 patients infected with COVID-19 to nearly 31,000 similar adults who didn’t have the infection. COVID-19 patients were more likely to take high blood pressure drugs and were likely to be in poorer health overall than patients who didn’t get the infection, but when a variety of factors were weighed, there was no indication that being on the medications made a person more likely to be infected with COVID-19 or become severely ill.
Another study, which reviewed the medical records of 12,594 patients who were tested for COVID-19 in New York, looked at their health history as well as their medication use. The study found no difference in infections in patients taking ACE inhibitors or ARBs. It also found that patients with severe infections were not more likely to be on any particular medication. The study did find that patients taking different blood pressure drugs called beta-blockers had a slightly lower risk of testing positive for COVID-19.
In an accompanying comment on the article, five New England Journal of Medicine editors said the studies’ conclusions are good news for patients and doctors.
“Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with Covid-19,” the comment said.
George Thomas, MD, nephrologist, Cleveland Clinic, Ohio.
Mandeep Mehra, MD, medical director, Brigham and Women’s Heart and Vascular Center, Boston.
The New England Journal of Medicine: “Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19,” “Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19,” “Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19,” “Inhibitors of the Renin-Angiotensin-Aldosterone System and Covid-19.”
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