Blockers Impact on Adverse Outcomes in Hospitalized Patients with Severe Acute Respiratory Distress Syndrome Coronavirus 2 SARSCoV2 THE BRACE CORONA TRIAL Renato D Lopes MD PhD on behalf of the BRACE CORONA Investigators ID: 907945
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Slide1
Continuing versus Suspending Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor
Blockers
:
Impact on Adverse Outcomes in Hospitalized Patients with Severe Acute Respiratory Distress Syndrome Coronavirus 2 (SARS-CoV-2)
THE BRACE CORONA TRIAL
Renato D. Lopes, MD, PhDon behalf of the BRACE CORONA Investigators
Slide2Declaration of InterestResearch grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer,
Sanofi-Aventis.Funding for educational activities or lectures from Pfizer.Funding for consulting or other services from Bayer,
Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Portola.
Details at: https://dcri.org/about-us/conflict-of-interest/The BRACE CORONA trial was sponsored by the D'Or Institute for Research and Education (IDOR) and the Brazilian Clinical Research Institute (BCRI).
Slide3Background
Membrane-bound angiotensin-converting enzyme 2 (ACE2) is the
functional receptor for SARS-CoV-2, the virus responsible for the coronavirus disease 2019 (COVID-19).ACE2 expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs).
There is conflicting observational evidence about the potential impact of ACEIs/ARBs on patients with COVID-19.Select preclinical investigations have raised concerns about their safety in patients with COVID-19. Preliminary data hypothesize that renin-angiotensin-aldosterone system (RAAS) inhibitors could benefit patients with COVID-19 by decreasing acute lung damage and preventing angiotensin-II-mediated pulmonary inflammation.Given the frequent use of these agents worldwide, randomized clinical trial evidence is urgently needed to guide the management of patients with COVID-19.Gheblawi M et al. Circulation Res 2020;126:1456-74.Soler MJ et al. Curr
Hypertens Rep 2008; 10:410. Patel AB
et al. JAMA 2020;323:1769-1770.
Slide4Trial Design
Lopes RD et al. Am Heart J 2020;226:1-10
Multicenter, phase IV,
randomized clinical trial
RANDOMIZE
N: 659 patients
PRIMARY OUTCOMEDays alive and out
of hospital
at 30 days
Temporarily suspend
ACEI/ARB treatment for 30 days
Continue to use
ACEI/ARB treatment
INCLUSION
Patients aged ≥ 18 years
Hospitalized with a confirmed diagnosis
of COVID-19
Chronic use of ACEI or ARB
EXCLUSION
Hospitalization due to decompensated heart failure in the last 12 months
Use of more than 3 anti-hypertensive drugs
Use of sacubitril/valsartan
Hemodynamic instability in the first 24 hours until the moment of confirmed diagnosis of COVID-19
Slide5Trial Organization
EXECUTIVE COMMITTEE
Renato D. Lopes
(Study Chair)André Feldman (Brazil)Andréa Silvestre de Sousa (Brazil)Ariane Vieira Scarlatelli Macedo (Brazil)C. Michael Gibson (USA)
Christopher B. Granger (USA)Denilson Campos de Albuquerque (Brazil)
Guilherme D`Andréa Saba Arruda (Brazil) John H. Alexander (USA)
Lilian Mazza Barbosa (Brazil)Mayara Fraga Santos (Brazil)
Natalia Zerbinatti Salvador (Brazil)
Olga Ferreira de Souza (Brazil)
Pedro Gabriel Melo de Barros e Silva (Brazil)
Renata Moll Bernardes (Brazil)
DATA SAFETY MONITORING BOARD
Alexandre Biasi Cavalcanti (Chair)
Luciano Drager
Lucas Petri Damiani
CLINICAL EVENTS CLASSIFICATION (CEC) COMMITTEE
Brazilian Clinical Research Institute (BCRI)
ACADEMIC COORDINATING CENTERS
D'Or Institute for Research and Education (IDOR)
Brazilian Clinical Research Institute (BCRI)
Slide6Primary Outcome
Number of days alive and
out of hospital through 30 days
This endpoint represents the follow-up time (30 days or the day of death) minus the hospitalization days.
Lopes RD et al. Am Heart J 2020;226:1-10Fanaroff AC et al. Circ-cardiovasc Qual 2018;11:e004755.
Slide7Statistical Analysis
The primary analysis followed the intention-to-treat principle.
Continuous variables were described as mean ± standard deviation or medians (25th, 75th percentiles) according to the distribution. As the primary outcome was measured as days alive and out of hospital
at 30 days, the analyses were based on the mean and standard deviation as well as median (25th, 75th) of this outcome. The comparison between the groups were made using a generalized additive model for location scale and shape with zero inflated beta-binomial distribution.
Lopes RD et al. Am Heart J 2020;226:1-10
Slide8BRACE CORONA Trial Timelines
Lopes RD et al. Am Heart J 2020;226:1-10
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
2020
First patient randomized
April 09
Last patient randomized
June 26
Last patient last visit
July 26
Database lock
August
17
ESC presentation
September 1
Protocol development
March 21
Slide9Study
Diagram
1352 patients with suspected/confirmed COVID-19 enrolled
in the COVID-19 registry were assessed for eligibility
740 underwent randomization
334
were assigned to the
suspending
ACEI/ARB
group
325
were assigned to the
continuing
ACEI/ARB
group
659
325
completed 30 days alive
9
patients died
100% complete 30-day follow-up
316
completed 30 days alive
9
patients died
100% complete 30-day follow-up
81
were excluded
04 COVID-19 not confirmed
03 duplication/randomization error
01 absence of informed consent
73 from a single site with a serious GCP violation
612
excluded (not on ACEI/ ARB
or COVID-19 not confirmed)
Slide10Baseline Characteristics
Suspending ACEI/ARB
(n=334)
Continuing ACEI/ARB
(n=325)
Total(n = 659)
Age
, mean ± SD, y
55.1 ± 12.4
56.4 ± 13.3
55.7 ± 12.9
Women
, n (%)
136(40.7%)
130 (40.0%)
266 (40.4%)
BMI
, mean ± SD, kg/m
2
31.1 ± 6.0
30.9 ± 6.0
31.0 ± 6.0
MEDICAL HISTORY
Hypertension
, n (%)
334 (100.0%)
325 (100%)
659 (100%)
Heart failure
, n (%)
2 (0.6%)
7 (2.2%)
9 (1.4%)
Diabetes
, n (%)
111 (33.2%)
99 (30.5%)
210 (31.9%)
Asthma
, n (%)
15 (4.5%)
11 (3.4%)
26 (3.9%)
Kidney disease
, n (%)
5 (1.5%)
4 (1.2%)
9 (1.4%)
Obesity,
n (%)
183 (55.3%)
158 (49.1%)
341 (52.2%)
Coronary artery disease,
n (%)
16 (4.8%)
14 (4.3%)
30 (4.6%)
Slide11Baseline Characteristics
Suspending ACEI/ARB
(n=334)
Continuing ACEI/ARB(n=325)
Total(n = 659)
DRUG THERAPY ON ADMISSION
Antihypertensive
drugs
ACEI
, n (%)
70 (21.0%)
40 (12.3%)
110 (16.7%)
ARB
, n (%)
264 (79.0%)
285 (87.7%)
549 (83.3%)
Beta blockers
, n (%)
44 (13.2%)
52 (16.0%)
96 (14.6%)
Diuretics
, n (%)
105 (31.4%)
100 (30.8%)
205 (31.1%)
Calcium-channel blockers
, n (%)
59 (17.7%)
61 (18.8%)
120 (18.2%)
Duration of ACEI/ARB prior to randomization
, median (IQR)
, years
5.0 (2.0; 8.0)
5.0 (3.0; 8.0)
5.0 (3.0; 8.0)
CLINICAL CHARACTERISTICS ON ADMISSION
Dyspnea
, n (%)
181 (54.2%)
173 (53.2%)
354 (53.7%)
Fever,
n
(%)
216 (66.3%)
233 (72.8%)
449 (69.5%)
Cough,
n (%)
246 (73.7%)
217 (66.8%)
463 (70.3%)
SaO
2 < 94% RA*
, n (%)88 (26.9%)
85 (27.4%)
173 (27.2%)Symptom onset to admission, median (IQR), days6.5 (4.0; 9.0) 6.0 (4.0; 9.0)6.0 (4.0; 9.0) *RA = Room air
Slide12Baseline Characteristics
Suspending ACEI/ARB
(n=334)
Continuing ACEI/ARB(n=325)
Total(n=659)
DEGREE OF
CHEST
CT
INVOLVEMENT ON
HOSPITAL
ADMISSION
≤ 25%, n (%)
164 (51.7%)
153 (49.7%)
317 (50.7%)
>25% - <50%, n (%)
112 (35.3%)
125 (40.6%)
237 (37.9%)
≥
50%,
n
(%)
41 (12.9%)
30(9.7%)
71 (11.4%)
CLINICAL SEVERITY ON FIRST 24
HR*
Mild
, n (%)
193 (57.8%)
183 (56.3%)
376 (57.1%)
Moderate
, n (%)
141 (42.2%)
142 (43.7%)
283 (42.9%)
Severe
, n (%)
0 (0.0%)
0 (0.0%)
0 (0.0%)
*
Clinical
severity
on
first
24 hours:
Mild
: blood oxygen saturation ≥ 94% and/
or lung infiltrates <50%; Moderate: blood oxygen
saturation < 94%, or lung
infiltrates ≥ 50% and/or partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300; Severe: invasive mechanical ventilation or hemodynamic instability, and/or multiple organ dysfunction or failure.
Slide13Primary Outcome: Days Alive and
Out of
Hospital
at 30 Days
Suspending
ACEI/ARB
mean days ± SD:
21.9 ± 8.0
Continuing
ACEI/ARB
mean days ± SD:
22.9 ± 7.1
Mean ratio
(95%CI):
0.95 (0.90–1.01); p=0.09
Mean difference
(95%CI):
-1.1 days (-2.33–0.17)
Slide14Clinical Status at 30 Days
Suspending
ACEI/ARB
median (25th, 75th):
25 days (20, 27)
Continuing
ACEI/ARB
median (25th, 75th):
25 days (21, 27)
Difference between
median
(95%CI)
:
0 days (-1, +1)
Slide15All-Cause Mortality at 30 Days
Suspending
ACEI/ARB:
2.7%Continuing ACEI/ARB: 2.8%HR (95%CI): 0.97 (0.38 – 2.52); p=0.95
Slide16Conclusion
In patients hospitalized with COVID-19, suspending ACEI/ARB therapy for 30 days did not impact the number of days alive and out of
hospital.
Slide17Clinical Implication
The
BRACE CORONA provides randomized trial evidence showing that suspending ACEI/ARB therapy for 30 days did not impact the number of days alive and out of hospital.
Because these data indicate that there is no clinical benefit from routinely suspending these medications in hospitalized patients with mild to moderate COVID-19, they should be generally continued for those with an indication. Our findings constitute contemporary and high-quality randomized evidence to guide the care of patients with COVID-19.
Slide18Acknowledgement
Thank you to the IDOR and BCRI teams, investigators, study coordinators, and study participants who made BRACE CORONA possible.