Ramipril in High-Risk Patients With COVID-19

Ignacio J Amat-Santos, Sandra Santos-Martinez, Diego López-Otero, Luis Nombela-Franco, Enrique Gutiérrez-Ibanes, Raquel Del Valle, Erika Muñoz-García, Víctor A Jiménez-Diaz, Ander Regueiro, Rocío González-Ferreiro, Tomás Benito, Xoan Carlos Sanmartin-Pena, Pablo Catalá, Tania Rodríguez-Gabella, Jose Raúl Delgado-Arana, Manuel Carrasco-Moraleja, Borja Ibañez, J Alberto San Román, Ignacio J Amat-Santos, Sandra Santos-Martinez, Diego López-Otero, Luis Nombela-Franco, Enrique Gutiérrez-Ibanes, Raquel Del Valle, Erika Muñoz-García, Víctor A Jiménez-Diaz, Ander Regueiro, Rocío González-Ferreiro, Tomás Benito, Xoan Carlos Sanmartin-Pena, Pablo Catalá, Tania Rodríguez-Gabella, Jose Raúl Delgado-Arana, Manuel Carrasco-Moraleja, Borja Ibañez, J Alberto San Román

Abstract

Background: Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory-syndrome coronavirus-2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2. This interaction has been proposed as a potential risk factor in patients treated with RAAS inhibitors.

Objectives: This study analyzed whether RAAS inhibitors modify the risk for COVID-19.

Methods: The RASTAVI (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation) trial is an ongoing randomized clinical trial randomly allocating subjects to ramipril or control groups after successful transcatheter aortic valve replacement at 14 centers in Spain. A non-pre-specified interim analysis was performed to evaluate ramipril's impact on COVID-19 risk in this vulnerable population.

Results: As of April 1, 2020, 102 patients (50 in the ramipril group and 52 in the control group) were included in the trial. Mean age was 82.3 ± 6.1 years, 56.9% of the participants were male. Median time of ramipril treatment was 6 months (interquartile range: 2.9 to 11.4 months). Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving ramipril; hazard ratio: 1.150; 95% confidence interval: 0.351 to 3.768). The risk of COVID-19 was increased in older patients (p = 0.019) and those with atrial fibrillation (p = 0.066), lower hematocrit (p = 0.084), and more comorbidities according to Society of Thoracic Surgeons score (p = 0.065). Admission and oxygen supply was required in 4.9% of patients (2 in the ramipril group and 3 in the control group), and 4 of them died (2 in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p = 0.039).

Conclusions: In a high-risk population of older patients with cardiovascular disease, randomization to ramipril had no impact on the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS inhibitor treatment during the COVID-19 crisis. (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation [RASTAVI]; NCT03201185).

Keywords: COVID-19; SARS-CoV-2; renin-angiotensin; transcatheter aortic valve replacement.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Patient Flowchart Schematic flowchart of the patients included in the RASTAVI (Renin-Angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation) trial and the interim analysis showing their rate of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and the mortality. COVID-19 = coronavirus disease-2019.
Central Illustration
Central Illustration
COVID-19 Symptoms Onset From January 1, 2020 Development of symptoms from January 1, 2020, according to the administration of ramipril or standard care. COVID-19 = coronavirus disease-2019.
Figure 2
Figure 2
Impact of BMI on Mortality Body mass index (BMI) in patients with coronavirus disease (COVID-19) according to mortality. The box shows the interquartile range and the T-bars represent the highest and lowest values (the range). The horizontal line in the box is the median. SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2.
Figure 3
Figure 3
Interplay of RAAS and SARS-CoV-2 Hypothetic model of renin-angiotensin-aldosterone system (RAAS) activation and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cell entry. (A) Angiotensin-converting enzyme 2 (ACE2) converts angiotensin (Ang) I to Ang-(1-9) and Ang II to Ang-(1-7). When angiotensin-converting enzyme inhibitors (ACEIs) are present, they prevent the conversion of Ang I to Ang II. Angiotensin-receptor blockers (ARBs) act at angiotensin II type 1 receptor (AT1R). (B) When A disintegrin and metalloprotease 17 (ADAM17) binds ACE2, it results in the occurrence of soluble (s) ACE2, which can no longer mediate SARS-CoV-2 entry and which might even prevent such entry by keeping the virus in solution. (C) The SARS-CoV-2 spike links to ACE2 and is internalized after priming by the transmembrane protease serine 2 (TMPRSS2).

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Source: PubMed

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