Correlation between anti-hypertensive drugs and disease progression among moderate, severe, and critically ill COVID-19 patients in the second referral hospital in Surbaya: A retrospective cohort study

Introduction

Coronavirus disease (COVID-19) had become a pandemic since almost one year ago. (Huang et al., 2020) Over 90 million cases and 1.5 million death-cases had happened during 2020 and several comorbidities associated with an increase in COVID-19 cases. Cardiovascular disease had become one of the most frequent comorbidities among COVID-19 patients which had a poor prognosis and high mortality rate. (WHO, 2021)

The mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is associated with the angiotensin-converting enzyme 2 receptor (ACE-2R) in the host cell and related with endothelial dysregulation. (Saha et al., 2021) Angiotensin-converting enzyme 2 (ACE2) plays a crucial role in renin-angiotensin-aldosterone system (RAAS) that regulate the blood pressure and main cause of hypertension. Hence, hypertension, and all complication-caused by hypertension, is associated with increased incidence and severity or risk of death in COVID-19. ( Ferrario et al., 2005; Li et al., 2020b)

One of the most common drugs for hypertension are angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARB). Some evidence had suggested the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ACEIs/ARB) in increasing the expression of ACE2 and hypothetically worsening the outcome of COVID-19 patients. (Li et al., 2020b; Ren et al., 2021; Sanders et al., 2020) Several anti-hypertensive drugs had been studied about the relation of increasing inflammatory markers like C-reactive protein in cardiovascular disease. In COVID-19, there was an evidence of hyper-inflammation process that caused acute respiratory distress syndrome (ARDS) via the cytokine storm mechanism. (Bas et al., 2005; Moore & June, 2020) Therefore, in several studies, the use of anti-hypertensive drugs had become a debate in the occurrence of worsening disease progression in COVID-19 patients. (Li et al., 2020b; Li et al., 2020d; Palvesky et al., 2020; Parveen et al., 2020; Ren et al., 2021; Sunden-Cullberg, 2020; Zuin et al., 2020) We hypothesize that the use of ACEI/ARBs might be correlated to ICU admission rate and length of stay, and may influence the inflammatory markers in COVID-19 patients.

Although several studies had associated few anti-hypertensive drugs to the severity and risk of death due to COVID-19, we aim to test for an association between the use of anti-hypertensive drugs and the disease progression from moderate, severe, and critically ill COVID-19 patients in Universitas Airlangga Hospital (UAH). We used the UAH COVID-19 database that we had built since March 15, 2020.

Methods

Study design and population

We conducted a retrospective cohort study with consecutive sampling and eligibility criteria COVID-19 adult patients from moderate to critically ill patients admitted to Universitas Airlangga Hospital (UAH) Surabaya during March 15, 2020 to August 31, 2020 through hospital medical records. Universitas Airlangga Hospital is a teaching hospital and one of the referral hospitals for COVID-19 in Surabaya, East Java. Our inclusive sample consisted of patients with a medical history of hypertension with moderate to critically ill COVID-19. Diagnosis of COVID-19 was made based on WHO guidelines and the Indonesian Ministry of Health guidelines, which were proven by oropharyngeal and nasopharyngeal swabs for SARS-CoV-2 PCR. Grouping of anti-hypertensive drugs based on three main groups ACEIs or ARBs (ACEI/ARB), calcium channel blockers (CCB) and beta blockers (BB) and we divided it into subgroups: single anti-hypertensive drugs, double anti-hypertensive drugs, and triple anti-hypertensive drugs. The outcome of this study were mortality rate, ICU admission and days of death. The potential confounding was multiple comotbidities of population. To minimize bias we eliminated patient without a history of antihypertensive and had serial clinical and laboratory examinations until patient discharged or died. The study size wsa decribed at Figure 1. Serial chest x-ray and laboratory inflammatory marker evaluation was performed, and we grouped it into three periods of time evaluation. The first time was when the patient came to the hospital; means of second time evaluation was at day six, and the third time was when the patient was either discharged or died (mean time 13 days).

Figure 1. Selection of patients.

ACEI/ARB: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; CCB: calcium channel blocker.

Results

Outcome associated to anti-hypertension

Based on the inflammatory markers and evaluation on the case severity using x-ray follow ups, it is crucial to discuss the effect of hypertension to the clinical outcome of patients with COVID-19. Based on the single anti-hypertension analysis, patients who received only BBs had a longer length of stay than ACEI/ARB or CCB alone (17, 13.36, and 13.73 respectively). After the evaluation, patients who received anti-hypertension BBs also had the highest rates of ICU admission (63.64). This rate is quite high in number when compared to ACEI/ARB or CCB (p 0.04). Nevertheless, although ACEI / ARB had a fairly high rate for ICU admission (28.57), the discharge rate was also quite high (71.43%) with a mortality rate of 7.14%. The highest mortality was found in the BB group (54.55%) with a discharge rate of 45.45% (p 0.032) (see Table 2 and Figure 2).

Table 2. Evaluation anti-hypertensive drugs in COVID-19 patients.

ACEI/ARB: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; CCB: calcium channel blocker; BB: beta blocker.

	Single				Double				Single	Double	Triple	p-value
	ACEI/ARB	CCB	BB	p-value	ACEI/ARB+CCB	ACEI/ARB+BB	CCB+BB	p-value
	14	22	11	47	13	7	4	24	47	24	6
Comorbidity (within group)
Geriatric (age>60 years old) (%)	42.86	45.45	36.36		30.77	42.86	25.00		42.55	33.33	50.00
DM (%)	28.57	45.45	54.55		61.54	85.71	0.00		42.55	58.33	66.67
HT (%)	50.00	40.91	36.36		53.85	85.71	50.00		42.55	62.50	66.67
Heart Disease (%)	21.43	4.55	9.09		0.00	14.29	0.00		10.64	4.17	33.33
Chronic Kidney Disease (%)	0.00	4.55	0.00		7.69	0.00	50.00		2.13	12.50	33.33
Obesity (%)	0.00	0.00	9.09		0.00	14.29	0.00		0.00	0.00	0.00
Vital Sign
Systolic Pressure (mean)	136.43	142.91	117.91	0.05	152.92	142.29	136.75	0.32	135.13	147.13	159.67	0.038
Diastolic Pressure (mean)	82.29	83.41	74.73	0.22	86.23	88.00	83.00	0.81	81.04	86.21	84.17	0.313
Pulse (mean)	98.07	101.18	101.73	0.78	95.46	113.71	101.25	0.04	100.38	101.75	114.17	0.12
Respiration Rate (mean)	25.00	24.76	29.55	0.09	23.46	25.29	24.00	0.57	25.98	24.08	27.67	0.262
Temperature (mean)	36.93	37.38	36.64	0.09	36.85	36.57	36.50	0.63	37.07	36.71	37.17	0.259
Oxygen saturation (mean)	92.21	92.27	92.45	0.99	93.00	90.00	94.75	0.53	92.30	92.42	93.33	0.92
Length of Stay	13.36	13.73	17	0.332	12.54	10	13.25	0.486	14.38	11.92	15.83	0.249
ICU admission (%)	28.57	9.09	63.64	0.04	7.69	28.57	25.00	0.43	27.66	16.67	16.67	0.539
Outcome
Discharge (% within group)	71.43	86.36	45.45	0.032	76.92	85.71	50.00	0.82	72.34	75.00	100.00	0.907
Death (% within group)	7.14	4.55	54.55		15.38	14.29	25.00		17.02	16.67	0

DM, diabetes mellitus; HT, hypertension; ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BB, beta blocker; CCB, calcium channel blocker; ICU, intensive Care Unit; SD, standard deviation

	ACEI/ARB			CCB			BB			p-value			ACEI/ARB+CCB			ACEI/ARB+BB			CCB+BB			p-value			Single			Double			Triple			p-value
Evaluation	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3	1	2	3
Radiology evaluation
RALE score (mean)	5	3	4	5	5	5	5	5	5	0.87	0.41	0.39	4	4	5	4	5	4	3	4	4	0.83	0.85	0.95	5	4	5	4	4	4	4	4	6	0.23	0.99	0.69
Lab evaluation
WBC (103/uL; mean)	15.48	13.80	11.02	8.46	8.36	9.93	9.95	13.67	20.47	0.01	0.04	0.02	7.45	9.15	9.39	10.54	13.72	15.03	9.70	8.97	11.32	0.17	0.28	0.10	10.90	11.12	13.14	8.73	10.42	11.06	12.65	13.99	10.98	0.24	0.53	0.61
ALC (103/uL. mean)	1409.98	887.48	907.88	1194.26	957.58	927.80	1201.26	1108.56	1027.68	0.64	0.74	0.95	1208.42	1012.31	1534.75	2374.58	1316.24	794.55	829.08	1353.15	888.78	0.08	0.57	0.34	1260.15	972.04	945.24	1485.33	1157.77	1211.20	1963.14	1183.51	920.11	0.24	0.52	0.55
NLR (mean)	10.31	8.06	3.41	5.91	5.94	3.94	7.20	10.18	12.64	0.01	0.35	0.06	4.83	5.77	3.14	4.96	7.67	6.16	12.02	9.28	12.04	0.02	0.77	0.14	7.52	7.56	5.82	6.07	6.91	5.50	7.39	9.01	5.05	0.46	0.71	0.85
Plt (103/uL; mean)	249.57	249.10	301.63	255.55	348.44	375.62	260.09	368.67	220.75	0.95	0.10	0.04	296.23	374.27	381.50	288.29	340.17	398.25	384.25	297.00	294.33	0.55	0.65	0.65	254.83	326.51	312.48	308.58	349.81	370.06	300.83	382.40	470.25	0.11	0.63	0.08
CRP (mg/L; mean)	20.53	36.46	71.40	13.91	3.00	32.07	0.50	48.45	9.99	0.49	0.79	0.87	3.01	10.30	58.20	9.89		10.30	6.07			0.68			13.58	34.56	51.25	5.63	10.30	34.25	60.10	86.70	54.42	0.01	0.89	0.95
PCT (ng/ml; mean)	3.29	2.46	8.32	0.27	0.76	0.43	2.67	2.25	8.89	0.45	0.61	0.60	0.02	1.56	40.14	0.25	0.05		0.03	0.05	0.24	0.16	0.82	0.72	1.71	1.97	5.66	0.09	1.18	32.16	5.09	0.38		0.25	0.39	0.32
BUN (mg/dl; mean)	18.13	27.90	42.97	15.67	16.69	20.14	26.76	25.25	56.49	0.14	0.38	0.33	30.92	13.69	17.99	21.10	29.13	27.87	79.50	51.35	47.05	0.12	0.03	0.23	18.83	22.34	39.58	36.15	26.00	24.74	21.43	52.17	30.00	0.07	0.16	0.57
Scr (mg/dl; mean)	0.99	16.30	1.25	1.81	1.47	2.22	1.41	1.41	1.73	0.52	0.35	0.68	2.37	1.34	1.61	1.61	0.90	1.30	6.61	4.63	4.24	0.14	0.10	0.23	1.47	6.05	1.78	2.85	2.08	1.94	2.36	2.43	1.07	0.19	0.80	0.84
SGOT(u/L; mean)	48.69	47.17	49.80	22.20	36.60	40.00	326.67	86.33	54.00	0.15	0.17	0.78	26.08	51.29	21.50	50.86	76.00	38.00	33.50	567.00	132.00	0.59	0.08	0.21	95.64	57.88	47.00	34.91	149.55	47.89	31.00	27.00	33.00	0.72	0.37	0.96
SGPT(u/L; mean)	33.15	95.50	111.40	21.00	37.40	55.57	148.67	216.17	118.80	0.07	0.37	0.65	27.33	95.14	32.17	46.86	116.00	114.00	21.00	247.00	30.00	0.68	0.33	0.02	52.12	121.00	90.59	32.17	126.55	40.78	19.50	23.67	33.00	0.71	0.65	0.38
D-Dimer (mcg/ml; mean)	1.52	2.15	2.20	5.93	3.93	1.86	5.88	7.31	1.87	0.34	0.37	0.94	1.49	2.52	1.31	1.52	3.10	0.00	0.00		11.16	0.31	0.52	0.16	5.04	4.45	1.93	1.44	2.61	4.59	7.93	5.25	4.77	0.43	0.72	0.51
P/F ratio (mean)	131.72	427.33	490.00	210.43	367.25	285.50	141.03	324.36	401.75	0.33	0.21	0.67	165.66	385.00	272.00	192.60	568.75	326.50	99.08	375.00	669.00	0.72	0.37	0.30	161.63	358.68	398.25	161.02	488.57	452.60	91.08	573.00	396.50	0.56	0.03	0.87

ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BB, beta blocker; CCB, calcium channel blocker; RALE, radiographic assessment of lung edema

WBC, white blood cells; ALC, absolute lymphocyte count; NLR, neutrophil to lymphocyte ratio; Plt, platelet; CRP, C-reactive protein; PCT, procalcitonine;

BUN, blood urea nitrogen; SCr, serum creatinine; SGOT, Serum Glutamic Oxaloacetic Transaminase; SGPT, Serum Glutamic Pyruvic Transaminase; P/F ratio, PO2/FiO2 ratio

Figure 2. Comparison between group anti-hypertensive drugs.

ACEI/ARB: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; CCB: calcium channel blocker; BB: beta blocker; ICU: intensive care unit; RALE: radiographic assessment of lung edema.

Disease progression can be observed through number patients died and days of death (time from first admission to death) from comorbidity, anti-hypertensive drugs, severity of chest x-ray, and inflammatory markers. It showed that heart disease (25%) and being geriatric (19.35%) contributed to a higher mortality rate than the others’ comorbidities. Nevertheless, all comorbidities were not significantly different for the days of death. No mortality had occurred in patients with CKD. Compared to the anti-hypertensive drugs used, there was significance in single use BBs for mortality events and days of death (RR: 9.82; 95% CI: 2.3–41.89; HR: 6.64; 95% CI: 1.3–33.04) (see Table 3 and Figure 3). Comparing single, double and triple anti-hypertensive drugs groups, there were no significant differences in length of stay, ICU admission, mortality rate, and days of death. Even though patients taking ACEI/ARB in both the single and combination groups had quite a high number of inflammatory marker variables, the mortality rate was still lower when compared to other anti-HT drug combinations. This suggests that ACEI/ARB has a protective effect (see Table 2 and Table 3). Additionally, more severe chest x-ray findings and higher inflammatory markers correlated to a higher mortality rate but had no significant effect on days of death.

Table 3. Disease progression among anti-hypertensive drugs.

ACEI/ARB: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; CCB: calcium channel blocker; BB: beta blocker; CI: confidence interval.

Comorbidity	Mortality rate (%)	Days of death (mean)	HR	95%CI	RR	95% CI
Geriatric (age>60 years old)	19.35	23.52	1.91	(0.57-6.38)
DM	15.79	27.91	1.54	(0.46-5.13)
HT	17.95	25.98	1.11	(0.34-3.7)
Heart Disease	25.00	22	1.26	(0.27-5.83)
Chronic Kidney Disease	0.00	0	0
Anti-hypertensive Drugs
Single
ACEI/ARB	7.14	23	0.33	(0.41-2.71)	0.33	(0.05-2.49)
CCB	4.55	28.79	0.22	(0.03-1.83)	0.16	(0.02-1.22)
BB	54.55	21.11	6.64	(1.3-33.04)	9.82	(2.33-41.89)
Double
ACEI/ARB+CCB	15.38	20.39	0.33	(0.03-3.66)	0.85	(0.14-5.06)
ACEI/ARB+BB	14.29	14	0.56	(0.05-6.31)	0.81	(0.10-6.51)
CCB+BB	25	15.67	2.30	(0.21-25.39)	1.27	(0.17-9.72)
Overall
Single	17.02	25.19	1.03	(0.3-3.49)	1.28	(0.42-3.49)
Double	16.67	19.81	0.51	(0.14-1.83)	1.10	(0.37-3.31)
Triple	0	0	0	0
Severity of chest X-Ray
Normal	0	0	0	0
Mild	7.14	19	0.16	(0.01-2.43)
Moderate	14.29	18	0.11	(0.03-0.46)
Severe and Critcal ill	24.32	25.03	0.15	(0.02-0.95)
Inflammatory marker
Leucocyte
>6.16x103/uL	12.99	26.22	2.19	(0.39-12.32)
<6,16×103/uL	2.60	21.27
Neutrophil-lymphocyte ratio (NLR)
High (>6.5)	7.79	25.88	0.85	(0.23-3.15)
Low (<6.5)	7.79	24
Absolute Lymphocyte Count (ALC)
Low < 1.0 × 103 cells/µL	7.79	23.54	2.04	(0.57-7.3)
High > 1.0x103 cells/µL	7.79	27.31
CRP
High (>41.8 mg/L)	6.49	23.26	1.8	(0.50-6.49)
Low (<41.8 mg/L)	9.09	27.64
Procalcitonin
High (>0.07 ng/mL)	9.09	23,96	1.59	(0.47-5.35)
Low (<0.07 ng/mL)	6.49	28,07

DM, diabetes mellitus; HT, hypertension; ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BB, beta blocker; CCB, calcium channel blocker; ICU, intensive Care Unit; SD, standard deviation; NLR, Neutrophil-lymphocyte ratio; ALC, Absolute Lymphocyte Count; CRP, C- Reactive Protein

Figure 3. Time survival in 30 days among antihypertensive drugs.

ACEI/ARB: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; CCB: calcium channel blocker; BB: beta blocker.

Discussion

According to the results of our study, COVID-19 confirmed cases may appear with multiple comorbidities, inducing significant inflammatory markers that affect the clinical outcomes of the patients. We analyzed the results by grouping the antihypertension agents into three groups: ACEI/ARB, CCB, and BB. Hypertension is believed to be one of the most common comorbidities. Patients involved in this research had a medical history of hypertension and was previously given the anti-hypertension agent before or during the hospital care. Most of the patients with a previous history of hypertension along with other comorbidities, such as heart failure, diabetes mellitus and received BBs. Although BB seems to be frequently used by patients with heart failure, it is also vastly used to lower the blood pressure in diabetes mellitus patients.

COVID-19 has been known to stimulate an inflammation cascade. Immune responses of critically ill patients with sepsis can be classified into three patterns: macrophage-activation syndrome (MAS), sepsis-induced immune-paralysis characterized by low expression of the human leukocyte antigen D related (HLA-DR) on CD14 monocytes, and an intermediate functional state of the immune system lacking obvious dysregulation. A preceding result states that approximately one-fourth of patients with septic condition have MAS and that most patients suffer from immune dysregulation dominated by low expression of HLA-DR on CD14 monocytes, which is triggered by monocyte hyperactivation, excessive release of interleukin-6 (IL-6), and profound lymphopenia. Addtionally, lower absolute lymphocyte count (ALC) (< 1.0x10³ cells/μL) could be a prognostic factor for COVID-19. (Giamarellos-Bourboulis et al., 2020; Wagner et al., 2020)

It has been shown that proinflammatory cytokines and chemokines including tumor necrosis factor (TNF) α, interleukin 1β (IL-1β), IL-6, granulocyte-colony stimulating factor, interferon gamma-induced protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory proteins 1-α were significantly elevated in COVID-19 patients. It is characterized by sustained and substantial reduction of the peripheral lymphocyte counts, mainly CD4-T and CD8-T cells in COVID-19 patients, and is associated with a high risk of developing secondary bacterial infection. (Li et al., 2020a)

Our study showed that high levels of inflammatory markers, such as WBC, PCT, and NLR, were correlated with higher mortality rates but showed no diffrerences for days of death. CRP levels were higher in the ACEI/ARB group, both single and double, but the mortality rate wasn’t higher than BB groups.

Hypertension, as stated by the American Heart Association, is defined as the rise of systolic blood pressure to the point of 140 mmHg and above, and/or diastolic blood pressure to 90mmHg and above. (PERHI, 2019) Hypertension is the leading cause of mortality globally. Approximately one-third of adults were estimated to have hypertension worldwide in 2010. Since the emerge of SARS-CoV-2 infection, hypertension has been frequently observed as a major comorbidity in patients with COVID-19. (Casucci et al., 2020; Yang et al., 2020) SARS-CoV2 virus penetrates into the cell through the ACE2 receptor. ACE2 was recognized as an enzyme having a role in the renin-angiotensin system (RAS) regulation. The transport of ACE2 to SARS-Cov-2 virus escalates the activity of the protein containing disintegrin domain and metalloproteinase domain-containing protein 17 (ADAM17). ADAM17 induces the release of ACE-2 ectodomain and produces soluble ACE-2 in the blood circulation. The low expression of ACE2 in the cell surface might lower the possibility for the infection to occur. The strong inhibition of ACE2 by SARS-CoV2 leading to increased vascular permeability and pulmonary edema (Yang et al., 2020). Early investigations in SARS-CoV suggest that ACE2 may have both a pathogenic role in facilitating virus infection and a protective effect in limiting lung injury during SARS-CoV-2 infection. As we know, ACE2 is recognized as a critical enzyme that regulates blood pressure, fluid and electrolyte balance, and vascular resistance by renin-angiontensi-aldosterone system. Drugs that can upregulate the expression of ACE2, such as ARBs and ACE inhibitors, have been commonly used in patients with hypertension and other cardiovascular diseases to regulate blood pressure and reduce the mortality and morbidity events (Gul et al., 2021; Shibata et al., 2020; Yang et al., 2020).

The mechanism of hypertension in worsening the clinical outcome has not been yet explained. Several studies declared that ACEI-induced angiodema was associated with increasing CRP and BB was associated with lower CRP level. Nevertheless, Yang et al declared that patients with hypertension came with highly detected inflammatory markers such as CRP (p=0.024), Procalcitonin (p=0.017) and IL6 (p=0.017). Angiotensin II is a renin-angiotensin effector peptide, responsible in pro-inflammatory cytokines induction, e.g IL-6, IL-1 β, TNF-α, IFN-ϒ, IL-17 and IL-23. Therefore, ACE inhibitors and ARBs that are capable of reducing the production of inflammatory cytokines are potential candidate drugs for treatment of patients with COVID-19 and preexisting hypertension. (Bas et al., 2005; Palmas et al., 2007; Yang et al., 2020 )

Based on the known SARS-Cov-2 pathogenesis, there seems to be a strong correlation among hypertension, anti-hypertensive agents, and SARS-Cov-2 infection. The SARS-CoV-2 receptor binds to the angiotensin-converting enzyme 2 (ACE-2) found on the respiratory cells with the help of S protein, which helps in entry and the replication process. After the multiplication process, when the virus reaches the lungs, it causes inflammation in the alveoli or lung sacs leading to pneumonia. Several patients would suffer from severe sepsis, shock, and even ARDS. (Kumar et al., 2020)

This research shows that the final clinical outcome from each of the group; ACEI/ARB, CCB, and BB might vary despite the similar initial condition. It also has been observed that the patients’ discharge and mortality numbers among these three groups show significant different results. Data shows that the discharge numbers of ACEI/ARB group are high (71.43%) while the ICU admission rate reached a third of the BB group. Comorbidities also play a role in severity and higher mortality rate among groups but isn’t different in days of death.

This result was similiar with the Ren et al study, which showed that the use of antihypertensive drugs weren’t correlated with the severity and risk of COVID-19. (Ren et al., 2021) Compared to previous local and regional studies, we didn’t find any study that compared antihypertensive drugs with disease progression in COVID-19.

The use of ACEI/ARB is still a matter of discussion due to the ACE-2 numerous receptor theories. ARBs/ACE inhibitors treatment has been reported to increase the expression of ACE2, which is also the cellular receptor for SARS-CoV-2 infection. It was suggested a protective role of ACE2 upregulation and ARBs/ACE inhibitors treatment in COVID-19 and raised concerns that ARBs/ACE inhibitors treatment could promote SARS- CoV-2 infection by increasing the expression of ACE2. (Yang et al., 2020)

Despite many hypotheses, evidence from a series of cohort studies published recently suggests that previous or current treatment with ACEIs or ARBs does not increase the risk and the complication of COVID-19 infection. ACEI and ARB act by inhibiting the renin-angiotensin-aldosterone system (RAAS). Angiotensinogen is converted to angiotensin I (AngI) by renin, then converted to angiotensin II (AngII) by angiotensin converting enzyme (ACE). Furthermore, angiotensin is converted to angiotensin (1–7) by angiotensin converting enzyme-2 (ACE-2). Angiotensin II activates angiotensin 2 type 1 receptor (AT1R) which stimulates vasoconstriction, pulmonary edema, oxidative effects, inflammation, and fibrosis. Meanwhile, angiotensin 1–7 have anti-inflammatory, anti-apoptotic, and anti-fibrosis effects. Both ACEI and ARB inhibit the ACE, hence the amount of ACE will be detected abundantly in the circulation. ACE in the systemic circulation is thought to have protective effects on the lungs, particularly in preventing the ARDS. At the same time, a decrease in ACE activity will increase Ang II levels, causing the activation of the AT1 receptor that produces ARDS. (Gul et al., 2021; Saha et al., 2020; Yang et al., 2020)

On the other hand, a study by Trump et al comparing the proportion of critical cases to all other severities of COVID-19 in the different patient groups with hypertension and cardiovascular diseases that receive anti-hypertensive agents, show that ACEI treatment proves to have a more profound decline in critical cases compared to other antihypertensive agent. Also, the results successfully showed the overall increased expression of both ACE2 (P = 0.0025) and TMPRSS2 (P = 0.0002) upon SARS-CoV-2 infection. However, anti-hypertensive treatment did not alter ACE2 expression, in neither patient positive for SARS-CoV-2 nor patients negative for SARS-CoV-2. Therefore, entry factor expression did not predispose ACEI or ARB-treated patients to SARS-CoV-2 infection. This finding is in accordance with observational studies, which did not reveal any effect of ACEI or ARB treatment on SARS-CoV-2 infection risk in individuals with hypertension or other cardiovascular diseases. (Trump et al., 2020)

In accordance with the guidelines of the European Society of Cardiology, there is no change in anti-hypertensive recommendations for COVID-19 patients. CCBs, both non-dihydropyridine and dihydropyridine can still be considered. Verapamil, a non-dihydropyridine CCB, is able to control heart rate in supraventricular tachycardia (SVT), prevent the migraine attack, and to manage the high blood pressure in patients with atrial fibrillation. This drug can be the drug of choice in hypertension management in COVID-19 patients. Preliminary data from animal studies suggest that verapamil has no effect on ACE2 expression, cardiac involvement, and SARS-Cov-2 related myocarditis. Amlodipine, a CCB dihydropyridine, shows some benefits in COVID-19 patients by inhibiting SARS COV-2 infection in vitro through the role of intracellular Ca2+, inhibiting viral replication at the post entry stage, showing inhibitory effects against SARS-Cov2 replication, and enhancing the anti-viral effect of chloroquine. (ESC, 2020)

The use of BBs also showed promising benefits in patients with COVID-19. Beta-adrenergic blockers block the entry of SARS-COV-2 via the ACE2 receptor as well as CD147. BBs on the juxtaglomerular cells in the kidney reduce the activity of both arms of the RAAS pathway, thereby it may decrease the ACE2 level. As ACE2 is the receptor for SARS-CoV-2 cellular entry, beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry. Therefore, beta-adrenergic blocker treatment in COVID-19 will decrease the SARS-CoV-2 cellular entry by downregulation of both ACE2 and CD147. Beta-adrenergic blockers have been shown to decrease a variety of proinflammatory cytokines expression including IL-1β, IL-6, TNFα, IFNγ. The use of beta-adrenergic blockers in COVID-19 patients may reduce the expression of the proinflammatory cytokines and the inflammation associated with it. (Vasanthakumar, 2020)

Our study showed that patients who were treated with single BB had higher ICU admission, mortality rate, and shorten days of death when compared with the others who were treated with only anti-hypertensive drugs. Nevertheless, when compared to double and triple antihypertensive drugs, as a single group, there was no significant difference.

There are some limitations of our study. First, we only used retrospective data from medical records. Second, the ratio of the population involved in the study using anti hypertension BB is quite small so it might not reflect the general population. Third, there may be an effect of multiple comorbidities in the study population which has the potential to be confounder which may effect the study results.

Conclusion

COVID-19, caused by SARS-COV-2 infection, is a disease that can activate the immune system and promotes immune system dysregulation. Hypertension is one of the comorbidities that causes increased severity of COVID-19. The effect of ACEI or ARBs on ACE-2 receptor regulation, which is thought to aggravate the condition of COVID-19 patients has not yet been proven. This is consistent with findings in other anti-hypertensive groups.

Data availability