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Continuing versus Suspending Angiotensin-Converting Enzyme Inhibitors and Angiotensin Continuing versus Suspending Angiotensin-Converting Enzyme Inhibitors and Angiotensin

Continuing versus Suspending Angiotensin-Converting Enzyme Inhibitors and Angiotensin - PowerPoint Presentation

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Continuing versus Suspending Angiotensin-Converting Enzyme Inhibitors and Angiotensin - PPT Presentation

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

acei days covid arb days acei arb covid patients clinical suspending brazil continuing trial alive hospital 2020 angiotensin 100

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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

Slide2

Declaration 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).

Slide3

Background

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.

Slide4

Trial 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

Slide5

Trial 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)

Slide6

Primary 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.

Slide7

Statistical 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

Slide8

BRACE 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

Slide9

Study

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)

Slide10

Baseline 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%)

Slide11

Baseline 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

Slide12

Baseline 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.

Slide13

Primary 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)

Slide14

Clinical 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)

Slide15

All-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

Slide16

Conclusion

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.

Slide17

Clinical 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.

Slide18

Acknowledgement

Thank you to the IDOR and BCRI teams, investigators, study coordinators, and study participants who made BRACE CORONA possible.