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ACE2: From Renoprotection to a Potential
Therapy for Coronavirus Infection
Daniel Batlle MD
Earle, del Greco
Levin Professor of Medicine
Division of Nephrology and Hypertension
Northwestern University Feinberg School of Medicine
Chicago IL
DISCLOSURES
• Dr. Batlle is a co-inventor of a patent entitled ‘Active Low Molecular
Weight Variants of Angiotensin Converting Enzyme 2’ and has submitted
patent applications on ‘’Novel ACE2 proteins for coronavirus
infection” and ‘’Active low molecular weight variant of Angiotensin
Converting Enzyme 2 for the treatment of diseases and conditions of the
eye ’’
• Dr. Batlle is Founder and majority shareholder of ‘Angiotensin
Therapeutics Inc’.
• Dr. Batlle has received consultant fees from Relypsa , Tricida and Astra
Zeneca.
3
Before…
After…
Modified from Danser , Epstein and Batlle Hypertension 2020
ACE2: From Renoprotection to a Potential Therapy for Coronavirus Infection
What is ACE2 ?
• Angiotensin Converting Enzyme II is a
monocarboxypepetidase that hydrolyzesAngiotensin
II and other peptides.
• The name ofACE2 was given when it was discovered
in 2000 because of considerable homology with
Angiotensin Converting Enzyme (ACE) ( 61%
homology)
• UnlikeACE,ACE2 does not convert angiotensin I to
angiotensin II, and moreoverACE inhibitors do not
block its activity
4
Monika Rella, Richard Jackson, Tony Turner
Amino acid sequences and ACE/ACE2 cleavage sites of various peptides
Eriksson et al. Current Biology 2002
PheProHisILeTyrValArgAsp
1 2 3 4 5 6 7 8
N C
ProHisILeTyrValArgAsp
1 2 3 4 5 6 7
N C
Phe
ACE2
Ang II (1-8)
Ang-(1-7)
ACE2 catalyzes the conversion of Ang II to Ang ( 1-7)
LHFPHIYVRD
Angiotensinogen (AOG)
Angiotensin (1-10)
HFPHIYVRD
Angiotensin (1-9)
Angiotensin (1-8)
Angiotensin (2-8)
FPHIYV
Angiotensin (3-8)Angiotensin (1-5)
Angiotensin (1-7)
Renin
ACE
ACE2
ACE2
Chymase
PEP
PRCP
ACE
APA
ACE
Neprilysin
LHFPHIYVRD
FPHIYVRD
PHIYVRD
IYVRD
FPHIYVR
Native Soluble ACE2 740 aa (100-110 kDa)
Transmembrane domain
Signal peptide
Catalytic domain
Full length ACE2 805 aa (>110 kDa)
N- -C
ACE2 is a tissue enzyme widely distributed preferentially in epithelial cells .
Where is ACE2 located ?
From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
9
Serfozo et al. Hypertension 2019
POP = Prolyl endopeptidase ( also known as PEP)
ACE2 , Hypertension and SARS Cov2
Immunofluorescence staining of ACE; green; and ACE2 (red; middle) in proximal tubules.
Minghao Ye et al. JASN 2006;17:3067-3075
In polarized epithelia like kidney , lungs and intestine ACE2 is localized in the apical site
Normallung tissue
Type IIalveolarcells
Hamming J pathol. 2004 jun; 203:631-637
ACE2 and ACE immunogold labeling in glomeruli.
Minghao Ye et al. JASN 2006;17:3067-3075
Triple immunofluorescence staining of ACE (green; A), ACE2 (red; D), and the endothelial cell
marker platelet-endothelial cell adhesion molecule (PECAM-1; blue; B and E).
Minghao Ye et al. JASN 2006;17:3067-3075
Fig. 1. (ACE) (green; A) and ACE2 (red; B) in a kidney arteriole from mouse kidney. Merging both images show no
colocalization of ACE and ACE2 (C). By contrast, neighboring tubules (see arrow) stain in yellow
Soler et at AJP 2008 DOI: (10.1152/ajprenal.90488.2008)
Jan Wysocki et al. Diabetes 2006;55:2132-2139
©2006 by American Diabetes Association
Kidney ACE2 in mouse models of diabetes ( left db/db , right stz )
©2006 by American Diabetes Association
Kidney ACE in mouse models of diabetes ( left db/db , right stz )
Jan Wysocki et al. Diabetes 2006;55:2132-2139
17
ACE2, ACE AngII(protective)
ACE2, ACE AngII(deleterious)
Control Diabetic db/db
Ye et al. JASN 2006
Glomerular ACE and ACE2 in controls and diabetic mice
19Mizuri et al. AJKD 2008
Expression of ACE and ACE2 in control individuals (left) and with diabetic kidney disease ( right)
ACE2 inhibitors
• MLN- 4760 ( MILLENIUM )
• DX-600
• In vivo MLN-4760 can cause worsening of kidney disease ( Ye et al. Hypertension 2012 , Soler et al. Kidney int. 2007)
21
Nadarajah et al. Kidney Int. 2012
Podocyte specific ACE2 transgenic
22Oudit et al. Diabetes 2010
Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy (Akita mice)
Effect of ACE2 Fc in a Renin Transgenic Mice: a model of Ang II dependent
hypertension
23Liu et al. Kidney Int. 2008
ACE2 amplification using native ACE2 failed to improve early DKD caused
by STZ administration
Wysocki et al. Kidney Int. 2017
ACE2 activity after native ACE2 administration
Wysocki et al. Kidney int. 2017
Native ACE2
740 aa (100-110 kDa)
Catalytic domain
??? aa kDa
Short ACE2 Catalytic domain
Shortening of native soluble ACE2
-C
Jan Wysocki MD , PhD
Native Soluble ACE2
1-740 aa
1-605 aa
(~100-110 kD)
(~50 kD)1-522 aa
(~69 kD)
Recombinant ACE2 constructs
Truncations from the C-terminus
1-650 aa (~75 kD)
Full length ACE2
805 aa (>110 kD)
1-619 aa (~71 kD)
1-805 aa
- No Enzymatic Activity
Short ACE2 variants are filterable whereas native ACE2 is not
Mina Shirazi et al. ASN 2019
Marquez A. and Batlle D. , Kidney Int. 2019
30
Before…
After…
ACE2 Before & After COVID-19: Basic Concepts
Modified from Danser , Epstein and Batlle Hypertension 2020
Highlights
Study of the ACE2 receptor for SARS-CoV1
• ACE2 as a Functional receptor for the SARS-CoV1. Wenhui Li et al, Nature, 2003.
• SARS-CoV1 binding domain with ACE2 Receptor. Fang Li et al, Science, 2005.
• SARS-CoV1 binding Affinity to ACE2 receptor. Fang Li et al, Antiviral Research , 2013.
Structure of SARS Coronavirus spike receptor-binding domain complexed with ACE2 receptor
A. ACE2 (green), RBD (cyan) and RBM (red).
B. Distribution of tyrosines (magneta) and Cysteines (yellow)
Fang Li et al, SCIENCE; Sep 2005.
• Receptor recognition by SARS-CoV2 to ACE2 Receptor. Fang Li et al, Journal of Virology , Jan 2020.
• SARS-CoV2 uses ACE2 receptor and TMPRSS2 for entry into target cells. Hoffmann, Biorxiv, Jan 2020.
• Cryo-EM structure of the SARS-CoV-2 spike in the prefusion conformation. Wrapp et al, Science, Mar 2020.
• Structure of the SARS-CoV-2 spike RBD bound with ACE2 receptor Lan et al, Nature, Mar 2020.
• Structural basis for the recognition of the SARS-CoV2 by ACE2 Receptor. Yan et al, Science, Mar 2020.
• Structure, Function, and Antigenicity of the SARS- CoV-2 Spike Glycoprotein . Walls et al, Cell, Apr 2020.
• SARS-CoV C-terminal domain with ACE2 receptor. Wang et al, Jama, Apr 2020.
Highlights of ACE2 as receptor for SARS-CoV2
Crystal structure of the SARS-CoV-2 bound with the ACE2
receptor
Overall structure of SARS-CoV-2 RBD bound with
ACE2.
1. ACE2 (green)
2. Receptor-binding domain (cyan)
3. Receptor-binding motif (red)
Lan et al, Nature , Mar 2020.
SARS-CoV2 bind to the human ACE2 Receptor and priming by TMPRSS2
Binding
1. ACE2 Receptor (Blue).
2. Spike Protein (Green).
3. TMPRSS2 (Red).
Activation
TMPRSS2*
Fusion
* TMPRSS2: Transmembrane protease , serine 2.
From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
(From Batlle et al. Clinical Science 2020 )
Proposed mechanism whereby soluble ACE2 attenuates viral cell entry by
competing with full length ACE2 in the plasma membrane
35
Animal models of SARS-CoV-2
• Transgenic mice
• Syrian Hamsters
• Ferrets and Cats
• Nonhuman primates
36From Koen Van Rompay Vumedi Presentation 2020
37Monteil et al. Cell 2020
ACE2 significantly decreased the level of SARS-CoV-2 infections in the
kidney organoids.
38Monteilet al. Cell 2020
ACE2 immunofluorescence staining
6-17-20
Human kidney
Kidney Organoids
Wysocki et al. Unpublished 2020
(-)
m740
h740
h618h618(longacting)
Cytoplasm
Soluble ACE2 (administered)Full length, membrane-bound ACE2 (endogenous)
Virion
binding
SARS-CoV-2
TMPRSS2 TMPRSS2
40
Soluble ACE2 as potential therapy for SARS-CoV-2 infection
From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
ADAMS17
Putative target cells for SARS-CoV2
Pneumocyte Type II
Ziegler et al, 2020, cell
42
What about the use of Ang II as a vasopressor in COVID patients ?
Courtesy of Dr Matthew Sparks
The COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group
Angiotensin II is increased in Acute Lung Injury (experimental)
43
Imai et al, Nature,2005
Effect of Ang II on ACE2 in a cell model
Deshotels et al Hypertension 2014
Ghallager et al. Am J Physiol Cell 2004
Regulation of ACE2 protein by Ang II
Downregulation of ACE2 expression by SARS-CoV infection
46
Kuba et al. Nature 2005
The renin-angiotensin-aldosterone system
Vaughan, DE JCI 1995
Vaughan DE Am J Cardiol 2001
Dzau et al. Am j cardiol 2001
Vaduganathan NEJM 2020
Wan et al J Virol 2020
Kuba Nat Med 2005
ACE
Angiotensinogen
Angiotensin-I
RENIN
Angiotensin-II
Angiotensin-I – 7
Angiotensin-1- 9
ACE2
Spike
protein
ACE2
fibrinolysis
Hypercoagulable
State
Acute lung injury
Inflammation
Platelet
activation
Courtesy of Dr Hau Kwaan
Prognosis of Acute Organ Injury
Incidence(%) 28-day mortality (%)
Overall 28-day mortality: 35.4%
↑SCr ≥100% or RRT
Gupta et al. JAMA July 2020
Targeting of ACE2 by SARS-CoV-2 results in angiotensin dysregulation, innate and adaptive
immune pathway activation, and hypercoagulation to result in organ injury and AKI associated
with COVID-19.
Daniel Batlle on behalf of the The COVID-19 and ACE2 in
Cardiovascular, Lung, and Kidney Working Group et al. JASN
doi:10.1681/ASN.2020040419
Marquez A. and Batlle D. , Kidney Int. 2019
What does ACE2 do ?
B.
Short ACE2 variant improves AKI in the ischemia reperfusion model
Mina Shirazi et al. ASN 2019
Tilman Muller and Alonso Marquez Jeannette Tang
Gvantca Gulua and Mina Shirazi
Peter Serfozo
Benedikt Marahrens
Enrique Lores
Jan Wysocki MD , PhD Minghao Ye , MD
53
Thank you!
RAS Inhibitors in
Hypertension and
Heart Failure:
TRUTHS AND MISTRUTHS
OF TREATMENT IN THE
COVID-19 ERA
J o r d y C o h e n , M D , M S C E
A s s i s t a n t P r o f e s s o r o f M e d i c i n e a n d E p i d e m i o l o g y
R e n a l - E l e c t r o l y t e a n d H y p e r t e n s i o n D i v i s i o n
P e r e l m a n S c h o o l o f M e d i c i n e , U n i v e r s i t y o f P e n n s y l v a n i a
@ j o r d y _ b c
Disclosure information
•Funding: NIH (NHLBI) K23-HL133843
•Disclosures: I have no financial relationships with commercial interests to disclose. I am co-PI and
chair of the DCC of the Randomized Elimination or Prolongation of ACE Inhibitors and ARB in
Coronavirus Disease 2019 (REPLACE COVID) trial (NCT04338009) and a contributor to
nephjc.com/news/covidace2
•Off-Label Use: My presentation includes cautionary discussion of off-label or investigational use of
ACE Inhibitors and ARBs in COVID-19
A long time
ago...
… a hypothesis
emerged
Fang L et al, Lancet Resp Med 2020;8(4):E21
… a hypothesis
emerged
•“The most frequent comorbidities reported in… studies of
patients with COVID-19 are often treated with angiotensin-
converting enzyme (ACE) inhibitors”
•SARS-CoV and SARS-CoV-2 bind to their target cells through ACE2,
which is expressed by epithelial cells of the lung, intestine, kidney,
and blood vessels
•ACE2 is “upregulated” by ACEIs and ARBs
•“We suggest that patients with cardiac diseases, hypertension,
or diabetes, who are treated with ACE2-increasing drugs, are
at higher risk for severe COVID-19 infection and, therefore,
should be monitored for ACE2-modulating medications, such
as ACE inhibitors or ARBs”
Fang L et al, Lancet Resp Med 2020;8(4):E21
•49,556,127 US adults are taking medication
for the treatment of hypertension
•Among those, 41,329,810 (83%) are taking an
ACEI or ARB
National Health and Nutrition Examination Survey data, c/o Bress AP
The gravity of
the hypothesis
What epidemiologic
evidence drove the
hypothesis?
Hypertension
in COVID-19
Guan W et al, N Engl J Med 2020;382:1708-20
Hypertension
in COVID-19
Guan W et al, N Engl J Med 2020;382:1708-20
Hypertension
in COVID-19
Wang D et al, JAMA 2020;323(11):1061-1069
Hypertension
in COVID-19
McMichael TM et al, N Engl J Med 2020; 382:2005-11
Hierarchy of
quality of evidence
•Case series fall somewhere
between expert opinion and
ecological studies
Meta
RCTs
Cohortstudies
Case-control studies
Cross-sectional studies
E c o l o g i c a l s t u d i e s
Case reports & case series
E x p e r t o p i n i o n & e d i t o r i a l s
Ho PM et al, Circ 2008;118(16):1675–1684
Hypertension
in COVID-19
McMichael TM et al, N Engl J Med 2020; 382:2005-11
Hypertension
and aging
•>75% of individuals over age
75 have a diagnosis of
hypertension
Whelton PK et al. J Am Coll Cardiol 2018; 71(19)
SBP/DBP ≥130/80 mm Hg or
Antihypertensive Medication
SBP/DBP ≥140/90 mm Hg or
Antihypertensive Medication
Overall, crude 46% 32%
Men
(n=4717)
Women
(n=4906)
Men
(n=4717)
Women
(n=4906)
Overall, age-sex
adjusted
48% 43% 31% 32%
Age group, years
20–44 30% 19% 11% 10%
45–54 50% 44% 33% 27%
55–64 70% 63% 53% 52%
65–74 77% 75% 64% 63%
75+ 79% 85% 71% 78%
Hypertension
and aging
•>75% of individuals over age
75 have a diagnosis of
hypertension
Garg S et al, MMWR 2020 69(15);458–464
What physiologic
evidence drove the
hypothesis?
ACE2ACE
Mas
Renin
AT2RAT1R
Angiotensinogen
Ang IIAng I Ang-(1-7)
Vasoconstriction
Renal sodium and water reabsorption
Oxidative stress
Inflammation
Fibrosis
Impaired fibrinolysis
ACEI
ARB
Cohen JB et al, J Clin Hypertens 2020, in press
South AM et al, Nat Rev Nephrol 2020;16:305-307
South AM et al, Nat Rev Nephrol 2020;16:305-307
Nicholls J and Peiris M, Nat Med 2005;11:821-822
Summary of
the evidence in
March 2020
•Case series showed many patients with concomitant COVID-19
and hypertension (which could potentially be explained by age)
•In some experimental models, ACEIs and ARBs increase ACE2
expression
• This could potentially lead to increased SARS-CoV-2 virulence
• However, these findings are not consistent across studies, and have not been
corroborated in humans
•Alternatively, animal models of SARS-CoV-1 suggest that
overexpression of ACE2 protects against lung injury
• ACEIs and ARBs could improve mechanisms of host defense or
hyperinflammation
Sparks MA et al, Clin J Am Soc Nephrol 2020 7;15(5):714-716
•“We suggest that patients with cardiac diseases, hypertension, or diabetes,
who are treated with ACE2-increasing drugs, are at higher risk for severe
COVID-19 infection and, therefore, should be monitored for ACE2-modulating
medications, such as ACE inhibitors or ARBs”
Fang L et al, Lancet Resp Med 2020;8(4):E21
The media reacted…
The media reacted…
Patients
reacted…
Vaduganathan M et al, JAMA 2020; 323(24) doi:10.1001/jama.2020.9184
… and the medical societies reacted
… and the medical societies (thankfully) reacted
Society Summary of recommendations
American Heart Association, Heart Failure Society of
America, American College of Cardiology
Continue ACEis/ARBs for all patients already prescribed them
European Society of Hypertension Continue ACEis/ARBs due to lack of evidence to support differential use in COVID-19 patients
In those with severe symptoms or sepsis, antihypertensive decisions should be made on a case-by-case
basis
Hypertension Canada Continue ACEis/ARBs due to lack of evidence that patients with hypertension or those treated with
ACEis/ARBs are at higher risk of adverse outcomes from COVID-19 infection
Canadian Cardiovascular Society Continue ACEis/ARBs and Angiotensin Receptor Neprilysin Inhibitors due to a lack of clinical evidence to
support withdrawal of these agents
The Renal Association, United Kingdom Continue ACEis/ARBs due to unconvincing evidence that these medications increase risk
International Society of Hypertension Routine use of ACEis/ARBs to treat hypertension should not be influenced by concerns about COVID-19
in the absence of compelling data
American College of Physicians Continue ACEis/ARBs because there is no evidence linking them to COVID-19 disease severity, and
discontinuation of antihypertensive therapy without medical indication could in some circumstances
result in harm
British and Irish Hypertension Society All patients taking ACEi/ARBs should continue to do so during the COVID-19 pandemic; patients could
be put at risk by stopping these medications until we have more information
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
… and the research world reacted
… and the research world reacted
Clinical trials for RAS blockade and COVID-19
Continuing or discontinuing ongoing RAS blockade
Study Identifier Target N
Country
Population Interventions Primary Outcome
NCT04329195
(ACORES-2)
554
France
Hospitalized with COVID-19 Discontinue ACEI/ARB
Comparator: Continue ACEI/ARB (open-label)
Time to 2-point improvement on WHO
scale or discharged alive up to day 28
NCT04338009
(REPLACE COVID)
152
United States
(International)
Hospitalized with COVID-19 Discontinue ACEI/ARB during hospitalization
(resumed on discharge)
Comparator: Continue ACEI/ARB throughout
hospitalization (open-label)
Composite global rank score for death,
mechanical ventilation, and multiorgan
dysfunction
NCT04351581
(RASCOVID-19)
215
Denmark
Hospitalized with COVID-19 Continue ACEI/ARB at the same dose
throughout hospitalization
Comparator: Discontinue ACEI/ARB during
admission for up to 30 days (open-label)
Days alive and out of hospital by day 14
NCT04364893
(BRACE-CORONA)
500
Brazil
Hospitalized with COVID-19 Continue ACEI/ARB for 30 days
Comparator: Stop ACEI/ARB for 30 days
(open-label)
Median days alive and out of the hospital
from enrolment to day 30
NCT04353596
(ACEI-COVID)
208
Austria and
Germany
Outpatient or hospitalized with COVID-19 Discontinue ACEI/ARB
Comparator: Continue ACEI/ARB (open-label)
SOFA score and death at 30 days
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
De novo RAS blockade
Study Identifier Target N
Country
Population Interventions Primary Outcome
NCT04340557 200
United States
Hospitalized with COVID-19 requiring
supplemental oxygen
Losartan 12.5 mg twice daily for up to 10
days
Comparator: No losartan (open-label)
Mechanical ventilation up to day 45
NCT04351724
(ACOVACT substudy B)
500
Austria
Outpatient or hospitalized with COVID-19 Candesartan titrated to BP <120/80 mm Hg
Comparator: Non-ACEI/ARB
antihypertensive (open-label)
Time to sustained improvement >48
hours on the WHO scaleup to day 29
NCT04311177 580
United States
Outpatient with COVID-19 Losartan 25 mg daily
Comparator: Placebo (blinded)
Hospitalization within 15 days
NCT04328012
(COVIDMED group 3)
4000
United States
Hospitalized with confirmed COVID-19 Losartan 25 mg daily for 5-14 days
Comparator: Placebo (blinded)
NIAID COVID-19 ordinal severity scale at
day 60
NCT04335786
(PRAETORIAN-COVID)
651
Netherlands
Hospitalized with confirmed COVID-19 Valsartan 160 mg twice daily up to 14 days
Comparator: Placebo (blinded)
ICU admission, mechanical ventilation or
death within 14 days
Clinical trials for RAS blockade and COVID-19
Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
In the meantime,
what have we learned
since March 2020?
Several more case
series
Meta
RCTs
Cohortstudies
Case-control studies
Cross-sectional studies
E c o l o g i c a l s t u d i e s
Case reports & case series
E x p e r t o p i n i o n & e d i t o r i a l s
Observational data of hypertension in COVID-19
Grasselli G et al, JAMA Intern Med 2020; doi:10.1001/jamainternmed.2020.3539
Observational
data of RAS
blockade in
COVID-19
Zhang P et al, Circ Res 2020;126:1671–1681
Observational
data of RAS
blockade in
COVID-19
Death
Death
? ACEI/ARB
Hospitalization for
COVID-19
No ACEi/ARB
ACEI/ARBNo ACEi/ARB
Cohen JB et al, Circ Res 2020 5;126(12):e140-e141
Observational
data of RAS
blockade in
COVID-19
Observational
data of RAS
blockade in
COVID-19
Cohen JB et al, under review
Paper Design Question
Mehta N et al, JAMA
Cardiol doi:10.1001/
jamacardio.2020.1855
Prospective cohort
18,472 patients tested for COVID-19
2,285 (12%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity
Mancia G et al, N Engl J
Med 2020; 382:2431-
2440
Case-control study
6,272 cases and 30,759 controls
8,071 (22%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity and severe COVID-19
Reynolds et al, N Engl J
Med 2020; 382:2441-
2448
Retrospective cohort
12,594 patients tested for COVID-19
4,564 (36%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19 test
positivity and severe COVID-19
de Abajo PFJ et al,
Lancet 2020; 395:1705-
1714
Case-control study
1,139 cases and 11,390 controls
2,432 (19%) on ACEI/ARB
ACEI/ARB use and risk of COVID-19
hospitalization
Observational
data of RAS
blockade in
COVID-19
Cohen JB et al, under review
Paper Findings
Approach to
confounding
Selection/
Collider Bias
Mehta N et al, JAMA
Cardiol doi:10.1001/
jamacardio.2020.1855
OR 0.97; 95% CI 0.81, 1.15 for test
positivity
P-score weighting Conditioned on
being tested
Mancia G et al, N Engl J
Med 2020; 382:2431-
2440
ACEI: OR 0.96; 95% CI 0.87, 1.07
ARB: OR 0.95, 95% CI 0.86, 1.05 for
test positivity
Matching
Adjustment
Conditioned cases
on a positive test
Reynolds et al, N Engl J
Med 2020; 382:2441-
2448
Median % difference likelihood
ACEI: 0.1, 95% CI -4.3, 4.5
ARB: 1.6, 95% CI 2.6, 5.8 for test
positivity
P-score matching Conditioned on
being tested and on
having a positive
test
de Abajo PFJ et al,
Lancet 2020;
395:1705-1714
OR 0.94; 95% CI 0.77, 1.15 for COVID-
19 hospitalization
Matching
Adjustment
Conditioned cases
on hospitalization
for COVID-19
Observational
data of RAS
blockade in
COVID-19
Flacco ME et al, Heart 2020 0:1–6. doi:10.1136/heartjnl-2020-317336
Mackey K et al, Ann Intern Med 2020;173:195-203. doi:10.7326/M20-1515
Early RAS
blockade RCT
data
Duarte M, et al. medRxiv 2020.08.04.20167205; doi: 10.1101/2020.08.04.20167205
Telmisartan for treatment of Covid-
19 patients: an open randomized
clinical trial. Preliminary report.
•Telmisartan 80 mg bid during
14 days plus standard care vs.
standard care alone for 14
days
•78 patients were included in
the interim analysis
•Telmisartan treated patients
had lower time to discharge
(median time to discharge
control group=15 days;
telmisartan group=9 days)
Interpret with caution
Lung and kidney
ACE2
expression with
ACEI/ARB
therapy
Wysocki J et al, JASN 2020; 31, DOI: 10.1681/ASN.2020050667
Kidney
Lung
Summary
•Pandemics bring out some of the best the best and worst in medical publications and journalism
•Early case series pointed towards a high prevalence of hypertension, diabetes, and CVD in patients hospitalized with
COVID-19, which led to speculation about RAS blockade as a potential culprit
• None of these studies were adjusted for age
•We’ve learned new information about hypertension, RAS blockade, and COVID-19
• Observational evidence suggests no association of ACEI/ARB use and risk and severity of COVID-19, but these studies have
limitations
• RCTs are ongoing; not all RCTs are created equally. Consider the design and reporting when interpreting results
• ACEI/ARBs do not seem to increase ACE2 expression in the kidneys and lungs in mice
•Premature or unnecessary discontinuation of ACEIs/ARBs could elevate BP and cause decompensation of chronic
health conditions. De novo initiation of ACEIs/ARBs for use in treating COVID-19 is not recommended at this time.
Thank you!
• jco@pennmedicine.upenn.edu
• @jordy_bc

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ACE2 , Hypertension and SARS Cov2

  • 1. ACE2: From Renoprotection to a Potential Therapy for Coronavirus Infection Daniel Batlle MD Earle, del Greco Levin Professor of Medicine Division of Nephrology and Hypertension Northwestern University Feinberg School of Medicine Chicago IL
  • 2. DISCLOSURES • Dr. Batlle is a co-inventor of a patent entitled ‘Active Low Molecular Weight Variants of Angiotensin Converting Enzyme 2’ and has submitted patent applications on ‘’Novel ACE2 proteins for coronavirus infection” and ‘’Active low molecular weight variant of Angiotensin Converting Enzyme 2 for the treatment of diseases and conditions of the eye ’’ • Dr. Batlle is Founder and majority shareholder of ‘Angiotensin Therapeutics Inc’. • Dr. Batlle has received consultant fees from Relypsa , Tricida and Astra Zeneca.
  • 3. 3 Before… After… Modified from Danser , Epstein and Batlle Hypertension 2020 ACE2: From Renoprotection to a Potential Therapy for Coronavirus Infection
  • 4. What is ACE2 ? • Angiotensin Converting Enzyme II is a monocarboxypepetidase that hydrolyzesAngiotensin II and other peptides. • The name ofACE2 was given when it was discovered in 2000 because of considerable homology with Angiotensin Converting Enzyme (ACE) ( 61% homology) • UnlikeACE,ACE2 does not convert angiotensin I to angiotensin II, and moreoverACE inhibitors do not block its activity 4 Monika Rella, Richard Jackson, Tony Turner
  • 5. Amino acid sequences and ACE/ACE2 cleavage sites of various peptides Eriksson et al. Current Biology 2002
  • 6. PheProHisILeTyrValArgAsp 1 2 3 4 5 6 7 8 N C ProHisILeTyrValArgAsp 1 2 3 4 5 6 7 N C Phe ACE2 Ang II (1-8) Ang-(1-7) ACE2 catalyzes the conversion of Ang II to Ang ( 1-7)
  • 7. LHFPHIYVRD Angiotensinogen (AOG) Angiotensin (1-10) HFPHIYVRD Angiotensin (1-9) Angiotensin (1-8) Angiotensin (2-8) FPHIYV Angiotensin (3-8)Angiotensin (1-5) Angiotensin (1-7) Renin ACE ACE2 ACE2 Chymase PEP PRCP ACE APA ACE Neprilysin LHFPHIYVRD FPHIYVRD PHIYVRD IYVRD FPHIYVR
  • 8. Native Soluble ACE2 740 aa (100-110 kDa) Transmembrane domain Signal peptide Catalytic domain Full length ACE2 805 aa (>110 kDa) N- -C ACE2 is a tissue enzyme widely distributed preferentially in epithelial cells . Where is ACE2 located ? From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
  • 9. 9 Serfozo et al. Hypertension 2019 POP = Prolyl endopeptidase ( also known as PEP)
  • 11. Immunofluorescence staining of ACE; green; and ACE2 (red; middle) in proximal tubules. Minghao Ye et al. JASN 2006;17:3067-3075 In polarized epithelia like kidney , lungs and intestine ACE2 is localized in the apical site Normallung tissue Type IIalveolarcells Hamming J pathol. 2004 jun; 203:631-637
  • 12. ACE2 and ACE immunogold labeling in glomeruli. Minghao Ye et al. JASN 2006;17:3067-3075
  • 13. Triple immunofluorescence staining of ACE (green; A), ACE2 (red; D), and the endothelial cell marker platelet-endothelial cell adhesion molecule (PECAM-1; blue; B and E). Minghao Ye et al. JASN 2006;17:3067-3075
  • 14. Fig. 1. (ACE) (green; A) and ACE2 (red; B) in a kidney arteriole from mouse kidney. Merging both images show no colocalization of ACE and ACE2 (C). By contrast, neighboring tubules (see arrow) stain in yellow Soler et at AJP 2008 DOI: (10.1152/ajprenal.90488.2008)
  • 15. Jan Wysocki et al. Diabetes 2006;55:2132-2139 ©2006 by American Diabetes Association Kidney ACE2 in mouse models of diabetes ( left db/db , right stz )
  • 16. ©2006 by American Diabetes Association Kidney ACE in mouse models of diabetes ( left db/db , right stz ) Jan Wysocki et al. Diabetes 2006;55:2132-2139
  • 17. 17 ACE2, ACE AngII(protective) ACE2, ACE AngII(deleterious)
  • 18. Control Diabetic db/db Ye et al. JASN 2006 Glomerular ACE and ACE2 in controls and diabetic mice
  • 19. 19Mizuri et al. AJKD 2008 Expression of ACE and ACE2 in control individuals (left) and with diabetic kidney disease ( right)
  • 20. ACE2 inhibitors • MLN- 4760 ( MILLENIUM ) • DX-600 • In vivo MLN-4760 can cause worsening of kidney disease ( Ye et al. Hypertension 2012 , Soler et al. Kidney int. 2007)
  • 21. 21 Nadarajah et al. Kidney Int. 2012 Podocyte specific ACE2 transgenic
  • 22. 22Oudit et al. Diabetes 2010 Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy (Akita mice)
  • 23. Effect of ACE2 Fc in a Renin Transgenic Mice: a model of Ang II dependent hypertension 23Liu et al. Kidney Int. 2008
  • 24. ACE2 amplification using native ACE2 failed to improve early DKD caused by STZ administration Wysocki et al. Kidney Int. 2017
  • 25. ACE2 activity after native ACE2 administration Wysocki et al. Kidney int. 2017
  • 26. Native ACE2 740 aa (100-110 kDa) Catalytic domain ??? aa kDa Short ACE2 Catalytic domain Shortening of native soluble ACE2 -C Jan Wysocki MD , PhD
  • 27. Native Soluble ACE2 1-740 aa 1-605 aa (~100-110 kD) (~50 kD)1-522 aa (~69 kD) Recombinant ACE2 constructs Truncations from the C-terminus 1-650 aa (~75 kD) Full length ACE2 805 aa (>110 kD) 1-619 aa (~71 kD) 1-805 aa - No Enzymatic Activity
  • 28. Short ACE2 variants are filterable whereas native ACE2 is not Mina Shirazi et al. ASN 2019
  • 29. Marquez A. and Batlle D. , Kidney Int. 2019
  • 30. 30 Before… After… ACE2 Before & After COVID-19: Basic Concepts Modified from Danser , Epstein and Batlle Hypertension 2020
  • 31. Highlights Study of the ACE2 receptor for SARS-CoV1 • ACE2 as a Functional receptor for the SARS-CoV1. Wenhui Li et al, Nature, 2003. • SARS-CoV1 binding domain with ACE2 Receptor. Fang Li et al, Science, 2005. • SARS-CoV1 binding Affinity to ACE2 receptor. Fang Li et al, Antiviral Research , 2013. Structure of SARS Coronavirus spike receptor-binding domain complexed with ACE2 receptor A. ACE2 (green), RBD (cyan) and RBM (red). B. Distribution of tyrosines (magneta) and Cysteines (yellow) Fang Li et al, SCIENCE; Sep 2005.
  • 32. • Receptor recognition by SARS-CoV2 to ACE2 Receptor. Fang Li et al, Journal of Virology , Jan 2020. • SARS-CoV2 uses ACE2 receptor and TMPRSS2 for entry into target cells. Hoffmann, Biorxiv, Jan 2020. • Cryo-EM structure of the SARS-CoV-2 spike in the prefusion conformation. Wrapp et al, Science, Mar 2020. • Structure of the SARS-CoV-2 spike RBD bound with ACE2 receptor Lan et al, Nature, Mar 2020. • Structural basis for the recognition of the SARS-CoV2 by ACE2 Receptor. Yan et al, Science, Mar 2020. • Structure, Function, and Antigenicity of the SARS- CoV-2 Spike Glycoprotein . Walls et al, Cell, Apr 2020. • SARS-CoV C-terminal domain with ACE2 receptor. Wang et al, Jama, Apr 2020. Highlights of ACE2 as receptor for SARS-CoV2 Crystal structure of the SARS-CoV-2 bound with the ACE2 receptor Overall structure of SARS-CoV-2 RBD bound with ACE2. 1. ACE2 (green) 2. Receptor-binding domain (cyan) 3. Receptor-binding motif (red) Lan et al, Nature , Mar 2020.
  • 33. SARS-CoV2 bind to the human ACE2 Receptor and priming by TMPRSS2 Binding 1. ACE2 Receptor (Blue). 2. Spike Protein (Green). 3. TMPRSS2 (Red). Activation TMPRSS2* Fusion * TMPRSS2: Transmembrane protease , serine 2. From Davidson ,Wysocki and Batlle Hypertension 2020 , in press.
  • 34. (From Batlle et al. Clinical Science 2020 ) Proposed mechanism whereby soluble ACE2 attenuates viral cell entry by competing with full length ACE2 in the plasma membrane
  • 35. 35 Animal models of SARS-CoV-2 • Transgenic mice • Syrian Hamsters • Ferrets and Cats • Nonhuman primates
  • 36. 36From Koen Van Rompay Vumedi Presentation 2020
  • 37. 37Monteil et al. Cell 2020
  • 38. ACE2 significantly decreased the level of SARS-CoV-2 infections in the kidney organoids. 38Monteilet al. Cell 2020
  • 39. ACE2 immunofluorescence staining 6-17-20 Human kidney Kidney Organoids Wysocki et al. Unpublished 2020 (-) m740 h740 h618h618(longacting)
  • 40. Cytoplasm Soluble ACE2 (administered)Full length, membrane-bound ACE2 (endogenous) Virion binding SARS-CoV-2 TMPRSS2 TMPRSS2 40 Soluble ACE2 as potential therapy for SARS-CoV-2 infection From Davidson ,Wysocki and Batlle Hypertension 2020 , in press. ADAMS17
  • 41. Putative target cells for SARS-CoV2 Pneumocyte Type II Ziegler et al, 2020, cell
  • 42. 42 What about the use of Ang II as a vasopressor in COVID patients ? Courtesy of Dr Matthew Sparks The COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group
  • 43. Angiotensin II is increased in Acute Lung Injury (experimental) 43 Imai et al, Nature,2005
  • 44. Effect of Ang II on ACE2 in a cell model Deshotels et al Hypertension 2014
  • 45. Ghallager et al. Am J Physiol Cell 2004 Regulation of ACE2 protein by Ang II
  • 46. Downregulation of ACE2 expression by SARS-CoV infection 46 Kuba et al. Nature 2005
  • 47. The renin-angiotensin-aldosterone system Vaughan, DE JCI 1995 Vaughan DE Am J Cardiol 2001 Dzau et al. Am j cardiol 2001 Vaduganathan NEJM 2020 Wan et al J Virol 2020 Kuba Nat Med 2005 ACE Angiotensinogen Angiotensin-I RENIN Angiotensin-II Angiotensin-I – 7 Angiotensin-1- 9 ACE2 Spike protein ACE2 fibrinolysis Hypercoagulable State Acute lung injury Inflammation Platelet activation Courtesy of Dr Hau Kwaan
  • 48. Prognosis of Acute Organ Injury Incidence(%) 28-day mortality (%) Overall 28-day mortality: 35.4% ↑SCr ≥100% or RRT Gupta et al. JAMA July 2020
  • 49. Targeting of ACE2 by SARS-CoV-2 results in angiotensin dysregulation, innate and adaptive immune pathway activation, and hypercoagulation to result in organ injury and AKI associated with COVID-19. Daniel Batlle on behalf of the The COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group et al. JASN doi:10.1681/ASN.2020040419
  • 50. Marquez A. and Batlle D. , Kidney Int. 2019 What does ACE2 do ?
  • 51. B. Short ACE2 variant improves AKI in the ischemia reperfusion model Mina Shirazi et al. ASN 2019
  • 52. Tilman Muller and Alonso Marquez Jeannette Tang Gvantca Gulua and Mina Shirazi Peter Serfozo Benedikt Marahrens Enrique Lores Jan Wysocki MD , PhD Minghao Ye , MD
  • 54. RAS Inhibitors in Hypertension and Heart Failure: TRUTHS AND MISTRUTHS OF TREATMENT IN THE COVID-19 ERA J o r d y C o h e n , M D , M S C E A s s i s t a n t P r o f e s s o r o f M e d i c i n e a n d E p i d e m i o l o g y R e n a l - E l e c t r o l y t e a n d H y p e r t e n s i o n D i v i s i o n P e r e l m a n S c h o o l o f M e d i c i n e , U n i v e r s i t y o f P e n n s y l v a n i a @ j o r d y _ b c
  • 55. Disclosure information •Funding: NIH (NHLBI) K23-HL133843 •Disclosures: I have no financial relationships with commercial interests to disclose. I am co-PI and chair of the DCC of the Randomized Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACE COVID) trial (NCT04338009) and a contributor to nephjc.com/news/covidace2 •Off-Label Use: My presentation includes cautionary discussion of off-label or investigational use of ACE Inhibitors and ARBs in COVID-19
  • 57. … a hypothesis emerged Fang L et al, Lancet Resp Med 2020;8(4):E21
  • 58. … a hypothesis emerged •“The most frequent comorbidities reported in… studies of patients with COVID-19 are often treated with angiotensin- converting enzyme (ACE) inhibitors” •SARS-CoV and SARS-CoV-2 bind to their target cells through ACE2, which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels •ACE2 is “upregulated” by ACEIs and ARBs •“We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs” Fang L et al, Lancet Resp Med 2020;8(4):E21
  • 59. •49,556,127 US adults are taking medication for the treatment of hypertension •Among those, 41,329,810 (83%) are taking an ACEI or ARB National Health and Nutrition Examination Survey data, c/o Bress AP The gravity of the hypothesis
  • 61. Hypertension in COVID-19 Guan W et al, N Engl J Med 2020;382:1708-20
  • 62. Hypertension in COVID-19 Guan W et al, N Engl J Med 2020;382:1708-20
  • 63. Hypertension in COVID-19 Wang D et al, JAMA 2020;323(11):1061-1069
  • 64. Hypertension in COVID-19 McMichael TM et al, N Engl J Med 2020; 382:2005-11
  • 65. Hierarchy of quality of evidence •Case series fall somewhere between expert opinion and ecological studies Meta RCTs Cohortstudies Case-control studies Cross-sectional studies E c o l o g i c a l s t u d i e s Case reports & case series E x p e r t o p i n i o n & e d i t o r i a l s Ho PM et al, Circ 2008;118(16):1675–1684
  • 66. Hypertension in COVID-19 McMichael TM et al, N Engl J Med 2020; 382:2005-11
  • 67. Hypertension and aging •>75% of individuals over age 75 have a diagnosis of hypertension Whelton PK et al. J Am Coll Cardiol 2018; 71(19) SBP/DBP ≥130/80 mm Hg or Antihypertensive Medication SBP/DBP ≥140/90 mm Hg or Antihypertensive Medication Overall, crude 46% 32% Men (n=4717) Women (n=4906) Men (n=4717) Women (n=4906) Overall, age-sex adjusted 48% 43% 31% 32% Age group, years 20–44 30% 19% 11% 10% 45–54 50% 44% 33% 27% 55–64 70% 63% 53% 52% 65–74 77% 75% 64% 63% 75+ 79% 85% 71% 78%
  • 68. Hypertension and aging •>75% of individuals over age 75 have a diagnosis of hypertension Garg S et al, MMWR 2020 69(15);458–464
  • 70. ACE2ACE Mas Renin AT2RAT1R Angiotensinogen Ang IIAng I Ang-(1-7) Vasoconstriction Renal sodium and water reabsorption Oxidative stress Inflammation Fibrosis Impaired fibrinolysis ACEI ARB Cohen JB et al, J Clin Hypertens 2020, in press
  • 71. South AM et al, Nat Rev Nephrol 2020;16:305-307
  • 72. South AM et al, Nat Rev Nephrol 2020;16:305-307
  • 73. Nicholls J and Peiris M, Nat Med 2005;11:821-822
  • 74. Summary of the evidence in March 2020 •Case series showed many patients with concomitant COVID-19 and hypertension (which could potentially be explained by age) •In some experimental models, ACEIs and ARBs increase ACE2 expression • This could potentially lead to increased SARS-CoV-2 virulence • However, these findings are not consistent across studies, and have not been corroborated in humans •Alternatively, animal models of SARS-CoV-1 suggest that overexpression of ACE2 protects against lung injury • ACEIs and ARBs could improve mechanisms of host defense or hyperinflammation Sparks MA et al, Clin J Am Soc Nephrol 2020 7;15(5):714-716
  • 75. •“We suggest that patients with cardiac diseases, hypertension, or diabetes, who are treated with ACE2-increasing drugs, are at higher risk for severe COVID-19 infection and, therefore, should be monitored for ACE2-modulating medications, such as ACE inhibitors or ARBs” Fang L et al, Lancet Resp Med 2020;8(4):E21
  • 78. Patients reacted… Vaduganathan M et al, JAMA 2020; 323(24) doi:10.1001/jama.2020.9184
  • 79. … and the medical societies reacted
  • 80. … and the medical societies (thankfully) reacted Society Summary of recommendations American Heart Association, Heart Failure Society of America, American College of Cardiology Continue ACEis/ARBs for all patients already prescribed them European Society of Hypertension Continue ACEis/ARBs due to lack of evidence to support differential use in COVID-19 patients In those with severe symptoms or sepsis, antihypertensive decisions should be made on a case-by-case basis Hypertension Canada Continue ACEis/ARBs due to lack of evidence that patients with hypertension or those treated with ACEis/ARBs are at higher risk of adverse outcomes from COVID-19 infection Canadian Cardiovascular Society Continue ACEis/ARBs and Angiotensin Receptor Neprilysin Inhibitors due to a lack of clinical evidence to support withdrawal of these agents The Renal Association, United Kingdom Continue ACEis/ARBs due to unconvincing evidence that these medications increase risk International Society of Hypertension Routine use of ACEis/ARBs to treat hypertension should not be influenced by concerns about COVID-19 in the absence of compelling data American College of Physicians Continue ACEis/ARBs because there is no evidence linking them to COVID-19 disease severity, and discontinuation of antihypertensive therapy without medical indication could in some circumstances result in harm British and Irish Hypertension Society All patients taking ACEi/ARBs should continue to do so during the COVID-19 pandemic; patients could be put at risk by stopping these medications until we have more information Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
  • 81. … and the research world reacted
  • 82. … and the research world reacted
  • 83. Clinical trials for RAS blockade and COVID-19 Continuing or discontinuing ongoing RAS blockade Study Identifier Target N Country Population Interventions Primary Outcome NCT04329195 (ACORES-2) 554 France Hospitalized with COVID-19 Discontinue ACEI/ARB Comparator: Continue ACEI/ARB (open-label) Time to 2-point improvement on WHO scale or discharged alive up to day 28 NCT04338009 (REPLACE COVID) 152 United States (International) Hospitalized with COVID-19 Discontinue ACEI/ARB during hospitalization (resumed on discharge) Comparator: Continue ACEI/ARB throughout hospitalization (open-label) Composite global rank score for death, mechanical ventilation, and multiorgan dysfunction NCT04351581 (RASCOVID-19) 215 Denmark Hospitalized with COVID-19 Continue ACEI/ARB at the same dose throughout hospitalization Comparator: Discontinue ACEI/ARB during admission for up to 30 days (open-label) Days alive and out of hospital by day 14 NCT04364893 (BRACE-CORONA) 500 Brazil Hospitalized with COVID-19 Continue ACEI/ARB for 30 days Comparator: Stop ACEI/ARB for 30 days (open-label) Median days alive and out of the hospital from enrolment to day 30 NCT04353596 (ACEI-COVID) 208 Austria and Germany Outpatient or hospitalized with COVID-19 Discontinue ACEI/ARB Comparator: Continue ACEI/ARB (open-label) SOFA score and death at 30 days Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
  • 84. De novo RAS blockade Study Identifier Target N Country Population Interventions Primary Outcome NCT04340557 200 United States Hospitalized with COVID-19 requiring supplemental oxygen Losartan 12.5 mg twice daily for up to 10 days Comparator: No losartan (open-label) Mechanical ventilation up to day 45 NCT04351724 (ACOVACT substudy B) 500 Austria Outpatient or hospitalized with COVID-19 Candesartan titrated to BP <120/80 mm Hg Comparator: Non-ACEI/ARB antihypertensive (open-label) Time to sustained improvement >48 hours on the WHO scaleup to day 29 NCT04311177 580 United States Outpatient with COVID-19 Losartan 25 mg daily Comparator: Placebo (blinded) Hospitalization within 15 days NCT04328012 (COVIDMED group 3) 4000 United States Hospitalized with confirmed COVID-19 Losartan 25 mg daily for 5-14 days Comparator: Placebo (blinded) NIAID COVID-19 ordinal severity scale at day 60 NCT04335786 (PRAETORIAN-COVID) 651 Netherlands Hospitalized with confirmed COVID-19 Valsartan 160 mg twice daily up to 14 days Comparator: Placebo (blinded) ICU admission, mechanical ventilation or death within 14 days Clinical trials for RAS blockade and COVID-19 Sparks MA and Hiremath S et al, nephjc.com/news/covidace2
  • 85. In the meantime, what have we learned since March 2020?
  • 86. Several more case series Meta RCTs Cohortstudies Case-control studies Cross-sectional studies E c o l o g i c a l s t u d i e s Case reports & case series E x p e r t o p i n i o n & e d i t o r i a l s
  • 87. Observational data of hypertension in COVID-19 Grasselli G et al, JAMA Intern Med 2020; doi:10.1001/jamainternmed.2020.3539
  • 88. Observational data of RAS blockade in COVID-19 Zhang P et al, Circ Res 2020;126:1671–1681
  • 89. Observational data of RAS blockade in COVID-19 Death Death ? ACEI/ARB Hospitalization for COVID-19 No ACEi/ARB ACEI/ARBNo ACEi/ARB Cohen JB et al, Circ Res 2020 5;126(12):e140-e141
  • 91. Observational data of RAS blockade in COVID-19 Cohen JB et al, under review Paper Design Question Mehta N et al, JAMA Cardiol doi:10.1001/ jamacardio.2020.1855 Prospective cohort 18,472 patients tested for COVID-19 2,285 (12%) on ACEI/ARB ACEI/ARB use and risk of COVID-19 test positivity Mancia G et al, N Engl J Med 2020; 382:2431- 2440 Case-control study 6,272 cases and 30,759 controls 8,071 (22%) on ACEI/ARB ACEI/ARB use and risk of COVID-19 test positivity and severe COVID-19 Reynolds et al, N Engl J Med 2020; 382:2441- 2448 Retrospective cohort 12,594 patients tested for COVID-19 4,564 (36%) on ACEI/ARB ACEI/ARB use and risk of COVID-19 test positivity and severe COVID-19 de Abajo PFJ et al, Lancet 2020; 395:1705- 1714 Case-control study 1,139 cases and 11,390 controls 2,432 (19%) on ACEI/ARB ACEI/ARB use and risk of COVID-19 hospitalization
  • 92. Observational data of RAS blockade in COVID-19 Cohen JB et al, under review Paper Findings Approach to confounding Selection/ Collider Bias Mehta N et al, JAMA Cardiol doi:10.1001/ jamacardio.2020.1855 OR 0.97; 95% CI 0.81, 1.15 for test positivity P-score weighting Conditioned on being tested Mancia G et al, N Engl J Med 2020; 382:2431- 2440 ACEI: OR 0.96; 95% CI 0.87, 1.07 ARB: OR 0.95, 95% CI 0.86, 1.05 for test positivity Matching Adjustment Conditioned cases on a positive test Reynolds et al, N Engl J Med 2020; 382:2441- 2448 Median % difference likelihood ACEI: 0.1, 95% CI -4.3, 4.5 ARB: 1.6, 95% CI 2.6, 5.8 for test positivity P-score matching Conditioned on being tested and on having a positive test de Abajo PFJ et al, Lancet 2020; 395:1705-1714 OR 0.94; 95% CI 0.77, 1.15 for COVID- 19 hospitalization Matching Adjustment Conditioned cases on hospitalization for COVID-19
  • 93. Observational data of RAS blockade in COVID-19 Flacco ME et al, Heart 2020 0:1–6. doi:10.1136/heartjnl-2020-317336 Mackey K et al, Ann Intern Med 2020;173:195-203. doi:10.7326/M20-1515
  • 94. Early RAS blockade RCT data Duarte M, et al. medRxiv 2020.08.04.20167205; doi: 10.1101/2020.08.04.20167205 Telmisartan for treatment of Covid- 19 patients: an open randomized clinical trial. Preliminary report. •Telmisartan 80 mg bid during 14 days plus standard care vs. standard care alone for 14 days •78 patients were included in the interim analysis •Telmisartan treated patients had lower time to discharge (median time to discharge control group=15 days; telmisartan group=9 days) Interpret with caution
  • 95. Lung and kidney ACE2 expression with ACEI/ARB therapy Wysocki J et al, JASN 2020; 31, DOI: 10.1681/ASN.2020050667 Kidney Lung
  • 96. Summary •Pandemics bring out some of the best the best and worst in medical publications and journalism •Early case series pointed towards a high prevalence of hypertension, diabetes, and CVD in patients hospitalized with COVID-19, which led to speculation about RAS blockade as a potential culprit • None of these studies were adjusted for age •We’ve learned new information about hypertension, RAS blockade, and COVID-19 • Observational evidence suggests no association of ACEI/ARB use and risk and severity of COVID-19, but these studies have limitations • RCTs are ongoing; not all RCTs are created equally. Consider the design and reporting when interpreting results • ACEI/ARBs do not seem to increase ACE2 expression in the kidneys and lungs in mice •Premature or unnecessary discontinuation of ACEIs/ARBs could elevate BP and cause decompensation of chronic health conditions. De novo initiation of ACEIs/ARBs for use in treating COVID-19 is not recommended at this time.