COVID: ACE-I/ARBs in China not change disease severity

Hypertension has been associated with adverse clinical outcomes in those with Covid-19 infection. The concern was raised that ACE inhibitors and ARBs may be associated with increased ACE2 levels (SARS-CoV-2 receptors), which could put the patients at higher risk of adverse Covid outcomes. A study with more granular data from China was released that suggested there was no Covid outcome difference on these medications vs other antihypertensives (see covid ACE ARBs ok jamacardiol2020 in dropbox, or doi:10.1001/jamacardio.2020.1624)

Details:

-- retrospective single-center case series of 1178 hospitalized patients with Covid-19 in Wuhan China, from January 15 to March 15

-- overall median age 56, 46% male

-- 362 (31%) had hypertension: median age 66, 52% were men, cerebrovascular disease 19%/coronary heart disease 17%/diabetes 35%/digestive disorders 22%/neurologic disease 11%/chronic kidney disease 10%

    -- labs: CBC, d-dimer, aminotransferases, serum creatinine, procalcitonin, interleukin-6, CRP were all similar in hypertensives who were on ACE inhibitors/ARBs vs non-ACE-I/ARBs, though alkaline phosphatase levels were a bit higher in those not on ACE-I/ARBs

    --meds: 36 patients (10%) were taking ACE-I/ARBs alone; 46% on calcium channel blockers, 18% on no drugs

    --but, ACE-I/ARBs overall, including in combination with other meds: ACE-I by 35 patients (10%) and ARBs 83 (23%), so total 115 (32%)

-- severe illness was defined as: oxygen saturation <93%, respiratory frequency of 30/minute, partial pressure of arterial oxygen/Fi0₂ <300, lung infiltrates >50% within 24 to 48 hours, septic shock, respiratory failure, and or multiple organ dysfunction or failure

-- overall in-hospital mortality was 11% (130 patients); in-hospital mortality in patients with hypertension was 21%

Results:

-- those with hypertension overall: severe manifestations of Covid-19 (including higher rates of ARDS and mortality) happened in 21% vs 7% nonhypertensives, p <0.001

-- outcomes in hypertensive patients, by med:

    --ARDS: 29 patients on ACE-I/ARB (25%) vs 65 other meds (26%)

    --severe Covid-19:  57 patients on ACE-I/ARB (50%) vs 116 other meds (47%)

    --nonsurvivor: 21 patients on ACE-I/ARB (18%) vs 56 other meds (23%)

    --hospital stays: 19 days for both groups

-- difference between those with severe vs nonsevere illness by ACE-I/ARB taken:

    -- ACE-I: no difference (9% vs 10%), p=0.80

    -- ARB: no difference (20% vs 24%), p=0.40

    -- either ACE-I or ARB: no difference (27% vs 33%), p=0.34

-- controlling for comorbidities, including coronary heart disease, cerebrovascular disease, diabetes, neurologic disease, chronic renal disease: still no difference in the frequency of severe illness or death

Commentary:

-- the relationship between ACE-I and ARBs with ACE2 levels has been found in some but not all studies. In addition, there is some evidence that the SARS-CoV-2 virus can enter cells through other receptors, specifically on T cells (see http://gmodestmedblogs.blogspot.com/2020/04/covid-new-nih-guidelines-t-cells-having.html)

-- also, the relationship between ACE2 levels and lung disease is not clear: there is certainly a concern that increased levels will increase binding of SARS-CoV-2, perhaps leading to increased inoculum and perhaps worse outcomes; but there is also some suggestion that decreased ACE2 levels are associated with pulmonary edema and reduced lung function (which can be reversed by supplying recombinant ACE2, at least in mice: see https://www.nature.com/articles/nature03712 , as well as losartan, see https://www.nature.com/articles/nm1267 )

-- in this study, those with hypertension were older and had more chronic diseases, and had more severe manifestations of Covid-19 including higher rates of acute respiratory distress syndrome and greater in-hospital mortality

   --and, not surprisingly, there was greater prevalence of coronary disease in those on ACE-I or ARBs, though overall they had similar comorbidities, laboratory profiles, inflammatory markers, renal and liver function tests, and cardiac biomarkers

 

Issues that limit the generalizability of the study:

-- there is always a concern on binary cutpoints for disease: everyone with diabetes is not the same (healthy but A1c=6.5 is pretty different from one with a combination of A1c=13%, obesity, and complications that escaped their mathematical modeling (eg, they controlled for the individual comorbidities, which also does not take into account those with diabetes plus renal diseease plus...)

    -- the same issue applies for chronic kidney disease, 11% vs 9% were on ACE inhibitors; there may well have been a predisposition to use more ACE-I in those with more severe diabetes and nephropathy.  and thereby not really comparing equivalent disease severity in the different groups

--also, 65 people (18%) were not on any meds. might be useful to separate them out from the analysis, since a major concern is how patients do on ACE-I/ARB vs other meds

--and, or course, this was not a controlled trial where patients were randomly assigned to ACE, ARB, or other med and had their outcomes outcome. As noted above, there might be signficant unquantified differences between the groups where the clinician consciously chose one antihypertensive over another (notably, in the Chinese study the most common antihypertensive overall was calcium channel blockers: in 46% on single therapy and 69% overall; this suggests that those on ACE-I/ARBs may have been deliberately put on these meds, presumably for a clinical indication)

--by the way, ibuprofen also increased ACE2 levels in a small and not great study: seehttp://gmodestmedblogs.blogspot.com/2020/03/covid-ace2-ibuprofen-and-grasping-for.html)

so, this study does reinforce that:

--it does not appear that patients on ACE/ARBs do worse if they get Covid-19 (though it still could be that those on ACE-I/ARBs may be more predisposed to infection: hard to know when we are not tracking this).

--it is always concerning when studies have shown that these meds may well raise the ACE2 levels; and at the time these studies made it into the sunlight, they appropriately raised real concern since ACE2 was considered the only known receptor for SARS-CoV-2 (and, i for one, did not initiate ACE-I/ARB in new patients in the Covid-19 era, and had a few on low doses stop them)

--the guidelines internationally from the various cardiology associations did appropriately (i think) reinforce that stopping ACE-I/ARBs was dangerous and that we should not change practice based on the ACE2 data (which, as mentioned above, was not consistent anyway). the guideline writers appropriately did not want to have worse outcomes by patients' panicking/stopping necessary meds, prior to clear confirmation of the association

so, bottom line: even as a flawed study methodologically, it does support our not changing ACE/ARBs in those on them or requiring them

geoff

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