COVID-19: AHA Guidance on Hypertension, Latest on Angiotensin Link

April 01, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

The American Heart Association (AHA) has issued new guidance for patients with hypertension during the COVID-19 outbreak. At the same time, several new review articles have been published further exploring the possible relationship between the renin-angiotensin system (RAS) and the virus.

The AHA guidance, titled "What people with high blood pressure need to know about COVID-19," notes that individuals with raised blood pressure may face an increased risk for severe complications if they are infected with the virus. Data from the outbreak in Wuhan, China, shows a 10.5% death rate among people with COVID-19 who also have cardiovascular disease, 7.3% for those with diabetes, 6.3% for those with respiratory disease, 6% for those with high blood pressure, and 5.6% for those with cancer.

The advisory reiterates previous recommendations that patients should not stop taking prescribed angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for hypertension, heart failure, or heart disease. 

"These medications don't increase your risk of contracting COVID-19. They are vital to maintaining your blood pressure levels to reduce your risk of heart attack, stroke, and worsening heart disease," it states.

Under the heading "Caution is key," the guidance warns that some common habits or medicines and supplements can raise blood pressure, including nonsteroidal anti-inflammatory drugs and decongestants. "People with heart concerns should limit or avoid them, especially if their blood pressure is uncontrolled," it states.

It also advises that people taking medication for mental health, corticosteroids, oral birth control, immunosuppressants, and some cancer medications should monitor blood pressure to make sure it's under control.

The guidance advises that people should limit both alcohol and caffeine because too much can raise blood pressure. "Caffeine should be capped at three cups per day in general, and most people with high blood pressure should avoid it," the guidance states. Some herbal supplements, such as licorice, can also raise blood pressure, it adds.

Latest on Angiotensin Drugs

Meanwhile, several more commentators have reviewed evidence on the relationship between the RAS and COVID-19 infection. These include commentaries published in the New England Journal of Medicine, Lancet Respiratory Medicine, and Mayo Clinic Proceedings. 

The controversy over use of ACE inhibitors and ARBs arose after it was discovered that the COVID-19 virus binds to the ACE-2 receptor to gain entry into cells. This, together with reports, mainly from animal studies, that ACE inhibitors and ARBs may increase expression of ACE-2, has raised concerns that use of these drugs may increase susceptibility to the virus. But other research shows that by reducing angiotensin 2 levels, these drugs may protect against lung injury in patients with COVID-19.

The latest commentaries give more detail on the potential benefits of ACE inhibitors and ARBs, and all reach the same conclusion, that patients should stay on their medication, which is in agreement with the major cardiology and hypertension societies.

The review in the Mayo Clinic Proceedings, published online on March 30, notes a report issued by the Italian Ministry of Health on March 20 showed the most common comorbidities in a cohort of 481 patients who died with COVID-19 were hypertension (74%), diabetes (34%), ischemic cardiopathy (30%), and atrial fibrillation (22%).

Noting that the average age of patients who died with COVID-19 was 78 years, the report authors, led by Fabian Sanchis-Gomar, MD, University of Valencia, Spain, and Stanford University School of Medicine, California, state: "Since hypertension prevalence increases in parallel with aging, this pattern may represent the expected prevalence for the given age group."

The Italian data also show that prior to hospitalization, 36% of patients who died with COVID-19 were taking ACE inhibitors and 16% were taking ARBs.

Regarding these figures, Sanchis-Gomar and colleagues comment: "One cannot definitively conclude risk-benefits of these therapies due to confounding variables of age, hypertension, as well as the impact of yet unidentified comorbidities on outcome with the COVID-19 pandemic."

But the latest information released March 31 by the US Centers for Disease Control and Prevention suggests diabetes is the most common comorbidity in COVID-19 cases. Data on 7162 cases of COVID-19 for whom data on underlying health conditions were reported shows 37.6% of these patients had one or more underlying health conditions or risk factors, the most common being diabetes, chronic lung disease, and cardiovascular disease.

Of 457 patients admitted to ICU with completed information on comorbidities, 32% had diabetes, 29% had cardiovascular disease, and 21% had chronic lung disease, the CDC data notes.  

The authors of all three commentaries expand on mechanisms supporting a positive role for ACE inhibitors or ARBs in COVID-19 infection,  

In a letter to Lancet Respiratory Medicine published on March 26, responding to one of the first reports suggesting potential for harm with these drugs, a group led by Christopher Tignanelli, MD, University of Minnesota, Minneapolis, write: "It is equally plausible that patients with hypertension have an overactive RAS, which has been postulated to mediate acute lung injury during COVID-19 infection." 

They report that angiotensin 2 is believed to cause pulmonary inflammation, fibrosis, and edema; ACE-2 activation results in low amounts of angiotensin 2 and impaired ACE-2 activity results in excessive amounts of angiotensin 2.

In concordance with this hypothesis, new data from China show serum angiotensin 2 was significantly higher in a group of 12 COVID-19 infected patients versus those without COVID-19, and was linearly associated with viral load and lung damage.

Referencing studies showing protective effects against severe acute respiratory syndrome (SARS) -induced lung injury with the ARB losartan in mice, and with recombinant ACE-2 in patients with SARS, Tignanelli and colleagues say this supports the initiation of clinical trials assessing recombinant human ACE-2 infusions and losartan in patients with COVID-19.

"Although controversy exists about the role of RAS inhibition in COVID-19, no evidence is available to support the routine discontinuation of ACE inhibitors or ARBs. Preclinical evidence suggests that RAS blockade might attenuate progression of COVID-19. We argue that clinical equipoise exists and, before the medical community makes recommendations for patients to withhold potentially life-saving drugs, there is a critical and urgent need for multicenter trials to test this hypothesis in patients with COVID-19," they conclude.

The authors of the Mayo Clinic Proceedings report add: "While hypertension is one of the most common comorbidities associated with a poor prognosis of COVID-19, hypertension has also been found to be associated with decreased levels of ACE-2 expression."

They also suggest that COVID-19 binding to ACE-2 may attenuate residual ACE-2 activity increasing angiotensin 2 levels and cite studies suggesting that the binding of ARBs to the angiotensin 2 type 1 receptor (AT1R) may stabilize the AT1R-ACE2 complex and prevent the COVID-ACE-2 interaction.

They conclude: "We speculate that RAS dysregulation may play a central role in COVID-19 associated lung injury." But they add that "whether RAS modulation may have a beneficial effect in selected patients with severe COVID-19 at risk for acute lung injury/acute respiratory distress syndrome is entirely unknown at the present time."

Finally, in the review published online in the New England Journal of Medicine on March 30, a group led by Muthiah Vaduganathan, MD, Brigham and Women's Hospital, Boston, Massachusetts, note that clinical trials are underway to test the safety and efficacy of RAS modulators, including recombinant human ACE-2 and the ARB losartan in patients with COVID-19.

They conclude that "Abrupt withdrawal of RAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes...Until further data are available, we think that RAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with COVID-19."

Lancet Resp Med 2020. Published online March 26, 2020. Full text

N Engl J Med 2020. Published online March 30, 2020. Full text

Mayo Clin Proc. Published online March 30, 2020. Full text

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