
==== Front
World J Crit Care Med
WJCCM
World Journal of Critical Care Medicine
2220-3141
Baishideng Publishing Group Inc

jWJCCM.v13.i3.eid96882
10.5492/wjccm.v13.i3.96882
96882
Observational Study
Outcome of COVID-19 infection in patients on antihypertensives: A cross-sectional study
Varatharajan S et al. COVID-19 outcome in patients on antihypertensives
Varatharajan Sakthivadivel Department of General Medicine, All India Institute of Medical Sciences - Bibinagar, Hyderabad 508126, Telangana, India. vsakthivadivel28@gmail.com

Bohra Gopal K Department of General Medicine, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India

Bhatia Pradeep K Department of Anaesthesiology and Critical Care, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India

Khichar Satyendra Department of General Medicine, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India

Meena Mahadev Department of General Medicine, All India Institute of Medical Sciences, Bhopal 462020, Madhya Pradesh, India

Palanisamy Naveenraj Department of General Medicine, ESIC Medical College & Hospital, Chennai 600021, Tamilnadu, India

Gaur Archana Department of Physiology, All India Institute of Medical Sciences - Bibinagar, Hyderabad 508126, Telangana, India

Garg Mahendra K Department of Endocrinology & Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, Rajasthan, India

Co-first authors: Sakthivadivel Varatharajan and Gopal K Bohra.

Author contributions: Varatharajan S and Bohra GK conceived, designed, and coordinated the study, participated in the acquisition and interpretation of the data, and drafted the manuscript; Both of them played crucial role in all aspects of the study; Khichar S, Meena M, and Palanisamy N participated in the acquisition, analysis, and interpretation of the data, and drafted the initial manuscript; Gaur A, Bhatia PK, and Garg MK participated in the analysis and interpretation of the data and revised the article critically for important intellectual content; All authors have read and approved the final manuscript.

Corresponding author: Sakthivadivel Varatharajan, MD, Additional Professor, Department of General Medicine, All India Institute of Medical Sciences, Bibinagar, Hyderabad 508126, Telangana, India. vsakthivadivel28@gmail.com

9 9 2024
9 9 2024
13 3 9688217 5 2024
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13 8 2024
©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.
BACKGROUND

Patients with coronavirus disease 2019 (COVID-19) infection frequently have hypertension as a co-morbidity, which is linked to adverse outcomes. Antihypertensives may affect the outcome of COVID-19 infection.

AIM

To assess the effects of antihypertensive agents on the outcomes of COVID-19 infection.

METHODS

A total of 260 patients were included, and their demographic data and clinical profile were documented. The patients were categorized into nonhypertensive, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB), calcium channel blocker (CCB), a combination of ACEI/ARB and CCB, and beta-blocker groups. Biochemical, hematological, and inflammatory markers were measured. The severity of infection, intensive care unit (ICU) intervention, and outcome were recorded.

RESULTS

The mean age of patients was approximately 60-years-old in all groups, except the nonhypertensive group. Men were predominant in all groups. Fever was the most common presenting symptom. Acute respiratory distress syndrome was the most common complication, and was mostly found in the CCB group. Critical cases, ICU intervention, and mortality were also higher in the CCB group. Multivariable logistic regression analysis revealed that age, duration of antihypertensive therapy, erythrocyte sedimentation rate, high-sensitivity C-reactive protein, and interleukin 6 were significantly associated with mortality. The duration of antihypertensive therapy exhibited a sensitivity of 70.8% and specificity of 55.7%, with a cut-off value of 4.5 years and an area under the curve of 0.670 (0.574-0.767; 95% confidence interval) for COVID-19 outcome.

CONCLUSION

The type of antihypertensive medication has no impact on the clinical sequence or mortality of patients with COVID-19 infection. However, the duration of antihypertensive therapy is associated with poor outcomes.

Antihypertensive
COVID-19
Hypertension
Mortality
Outcome
==== Body
pmc Core Tip: Hypertension is a common co-morbidity among patients with coronavirus disease 2019 (COVID-19) infection. Antihypertensives have various effects on the outcome of COVID-19. In this single-center study, we evaluated the effects of antihypertensives, especially angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers, on the outcome of COVID-19 infection. Duration of antihypertensive therapy rather than the type of antihypertensive medication was significantly associated with poor outcomes.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has different presentations, and the outcome depends on various risk factors. In individuals infected with COVID-19, hypertension is a significant co-morbidity[1] and a significant predictor of unfavorable outcomes. The main objective of blood pressure management in COVID-19 patients should be systolic blood pressure. Furthermore, there is evidence that high blood pressure variability is associated with higher mortality and intensive care unit (ICU) admission rates. These findings highlight the significance of stable in-hospital blood pressure management for patients. Increasedblood pressure variability may be the cause of severe blood vessel stiffness and dysfunction of endothelial cells, which are linked to cardiovascular events[2]. In patients with COVID-19 who are critically ill, a myriad of vascular abnormalities, including extensive microthrombotic and macrothrombotic episodes, are often encountered. These vascular events may be worsened by potential microvascular complications induced by persistent hypertension, which also impact the prognosis and aftermath of the ailment[3].

Studies have reported that hypertension is associated with poor outcomes in COVID-19; however, whether this effect is due to hypertension itself or antihypertensive therapy remains unclear[4-6]. It is widely known that coronaviruses bind to receptors that contain angiotensin-converting enzyme2 (ACE-2). The renin-angiotensin-aldosterone system (RAAS) is impeded by angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs). Controversial results have been reported regarding the role of ACEIs in the outcome of COVID-19. Beta-blockers also suppress ACE receptors and may be helpful in the management of COVID-19[7]. In a similar vein, there is a continuing discussion over how calcium channel blockers (CCBs) impact COVID-19 outcomes[8,9].

This study evaluated the effects of antihypertensive agents on the outcomes of COVID-19 infection in patients with hypertension.

MATERIALS AND METHODS

This 1-year cross-sectional observational study began in June 2019 and was carried out at a tertiary care facility in Northern India. The institute's ethics committee approved the study (AIIMS/IEC/2020-21/2003). After obtaining written informed consent, patients with COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) were included in the study. Patients with additional bacterial or viral infection, inconsistent antihypertensive drug use, insufficient medical records, or not willing to participate in the study were excluded. A total of 260 patients > 18 years of age were included via the consecutive sampling method. The patients’ demographic data and clinical profile were noted. Furthermore, the duration of antihypertensive therapy and antihypertensive agents was recorded.

The patients were categorized into the following groups: ACEi/ARB, CCB, combination of ACEI/ARB and CCB, and beta-blocker groups. Complete hemogram, renal and liver function tests, high-sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), interleukin 6 (IL-6), ferritin, D-dimer, lactate dehydrogenase, and N-acetyl-cysteine-activated creatin kinase were determined for all patients. The patients were monitored for hypotension, sepsis, multiple organ dysfunction syndrome (MODS), pneumonia, acute respiratory distress syndrome (ARDS), respiratory failure, acute kidney injury (AKI), deep vein thrombosis, pulmonary thromboembolism, and stroke. The severity of the infection was assessed according to the Ministry of Health and Family Welfare guidelines and World Health Organization (WHO) criteria[10,11]. Intensive care requirement and patient outcomes were noted.

Statistical analyses

SPSS 25.0 was used to analyze the data. The median or mean ± standard deviation (SD) were used to represent quantitative variables. Conversely, percentages and numbers were utilized to represent qualitative data. The quantitative variables of both parametric and non-parametric data were analyzed using the Kruskal-Wallis test/or one-way analysis of variance. Additionally, to determine the differences between the qualitative data, the χ2 test was employed. Furthermore, multivariable logistic regression analysis was conducted to examine the factors associated with mortality. In multivariable logistic regression, variables with P < 0.25 were included. To forecast the results for COVID-19 patients, the cut-off value for the duration of antihypertensive medication was determined using the receiver operating characteristic curve. P < 0.05 was considered statistically significant.

RESULTS

A total of 260 hospitalized patients with a molecular diagnosis (RT-PCR) of COVID-19 were included in this study. Of these, 200 (76.9%) patients had prior hypertension and were on medication. In all groups, the average age of the patients was almost 60years, with the exception of the nonhypertensive group in which younger patients were present (39.53 ± 14.7 years). Men were predominant in all groups. Most patients were on ACEI/ARB, CCB, and a combination of ACEI/ARB and CCB. A few patients were on beta-blockers. Diabetes accounted for 40.4% of all co-morbidities, followed by ischemic heart disease and hypothyroidism. A significantly higher number of patients with diabetes were on ACEI/ARB (66.1%), and a significantly higher number of those with ischemic heart disease were on beta-blockers (28.6%). Fever (52.7%) was the most common presenting symptom. Cough and respiratory distress were the next common symptoms and were predominantly seen in patients on beta-blockers. There was no discernible variation in the length of stay across the groups (Table 1).

Table 1 Characteristic frequency among the study population

Parameter	Total population, n = 260	Nonhypertensive, n = 60	ACEI/ARB, n = 62	Calcium channel blockers, n = 64	ACEI/ARB + CCB, n = 60	Beta-blockers, n = 14	P value	
Mean age in years (SD)	55.84 (15.8)	3 9.53 (14.7)1	61.3 (11.9)	60.3 (12.6)	59.83 (13.7)	64 (9.6)	< 0.001	
Male	192 (73.8)	35 (58.3)	53 (85.5)	44 (68.8)	48 (85.7)	12 (85.7)	0.005	
Female	68 (26.2)	25 (41.7)	9 (14.5)	20 (31.2)	12 (14.3)	2 (14.3)		
Duration of antihypertension in years (IQR)	-	-	2-7	2-6	2-8	2-11.25	0.080	
Diabetes	105 (40.4)	3 (5)	41 (66.1)2	23 (35.9)	32 (53.3)	6 (42.9)	< 0.001	
Hypothyroidism	10 (3.8)	1 (1.7)	4 (6.5)	3 (4.7)	1 (1.7)	1 (7.1)	0.523	
Ischemic heart disease	29 (11.2)	1 (1.7)	6 (9.7)	7 (10.9)	11 (18.3)	4 (28.6)4	0.011	
Smoking	7 (2.7)	3 (5)	1 (1.6)	-	3 (5)	-	0.301	
Mean duration of stay in days (SD)	8.9 (4.5)	10.28 (5.4)	8.2 (4.2)	8.5 (3.4)	8.6 (4.7)	8.57 (4.7)	0.113	
Symptoms								
Fever	137 (52.7)	18 (30)	38 (61.3)	33 (51.6)	40 (66.7)3	8 (57.1)	0.001	
Cough	126 (48.5)	20 (33.3)	33 (53.2)	29 (45.3)	35 (58.3)	9 (64.3)4	0.039	
Respiratory distress	81 (31.2)	4 (6.7)	26 (41.9)	22 (34.4)	23 (38.3)	6 (42.9)4	< 0.001	
Myalgia	7 (2.7)	4 (6.7)	-	1 (1.6)	2 (3.3)	-	0.190	
Sore throat	9 (3.5)	8 (13.3)1	1 (1.6)	-	-	-	< 0.001	
Diarrhea	3 (1.2)	-	-	1 (1.6)	1 (1.7)	1 (7.1)	0.195	
1 Significant difference between the nonhypertensive group and others.

2 Significant difference between the ACEI/ARB group and others.

3 Significant difference between the ACEI/ARB + CCB group and others.

4 Significant difference between the beta-blocker group and others.

Data are n (%) unless indicatedotherwise. ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; CCB: Calcium channel blocker; IQR: Interquartile range; SD: Standard deviation.

The most common complication was ARDS (11.5%), which was mostly found in the CCB group, followed by AKI, renal failure, pneumonia, and MODS. However, there was no significant difference among the groups. According to Ministry of Health and Family Welfare severity criteria, most severe cases (43.3%) were significantly higher in the ACEI/ARB + CCB group. By contrast, as per WHO criteria, critical cases were significantly higher in the CCB group (28.1). ICU intervention and mortality were also significantly higher in the CCB group (Table 2).

Table 2 Complication, severity, and outcome frequency among the study population

Parameter	Total population, n = 260	Nonhypertensive, n = 60	ACEI/ARB, n = 62	Calcium channel blockers, n = 64	ACEI/ARB + CCB, n = 60	Beta-blockers, n = 14	P value	
Pneumonia	8 (3.1)	-	3 (4.8)	4 (6.2)	1 (1.7)	-	0.235	
ARDS	30 (11.5)	-	9 (14.5)	11 (17.2)1	8 (13.3)	2 (14.3)	0.031	
MODS	4 (1.5)	-	1 (1.6)	2 (3.1)	1 (1.7)	-	0.694	
AKI	13 (5)	1 (1.7)	1 (1.6)	6 (9.4)	3 (5)	2 (14.3)	0.091	
Renal failure	12 (4.6)	-	1 (1.6)	5 (7.8)	5 (8.3)	1 (7.1)	0.101	
MoHFW severity								
Asymptomatic	44 (16.9)	16 (26.7)	6 (9.7)	12 (18.8)	8 (13.3)	2 (14.3)	0.003	
Mild	104 (40)	33 (55)	23 (37.1)	23 (35.9)	17 (28.3)	8 (57.1)		
Moderate	33 (12.7)	5 (8.3)	11 (17.7)	6 (9.4)	9 (15)	2 (14.3)		
Severe	79 (30.4)	6 (10)	22 (35.5)	23 (35.9)	26 (43.3)2	2 (14.3)		
WHO grade								
Asymptomatic	44 (16.9)	16 (26.7)	6 (9.7)	12 (18.8)	8 (13.3)	2 (14.3)	0.006	
Mild	104 (40)	33 (55)	23 (37.1)	23 (35.9)	17 (28.3)	8 (57.1)		
Moderate	33 (12.7)	5 (8.3)	11 (17.7)	6 (9.4)	9 (15)	2 (14.3)		
Severe	41 (15.8)	5 (8.3)	12 (19.4)	9 (14.1)	15 (25)	-		
Critical	38 (14.6)	1 (1.7)	10 (16.1)	14 (21.9)1	11 (18.3)	2 (14.3)		
ICU intervention	46 (17.7)	1 (1.7)	13 (21)	18 (28.1)1	12 (20)	2 (14.3)	0.003	
Death	24 (9.2)	-	4 (6.5)	12 (18.8)1	7 (11.7)	1 (7.1)	0.007	
1 Significant difference between the CCB group and others.

2 Significant difference between the ACEI/ARB + CCB group and others.

Data are n (%). ACEI: Angiotensin-converting enzyme inhibitor; AKI: Acute kidney injury; ARB: Angiotensin receptor blocker; ARDS: Acute respiratory distress syndrome; CCB: Calcium channel blocker; ICU: Intensive care unit; MODS: Multiple organ dysfunction syndrome; MoHFW: Ministry of Health and Family Welfare; WHO: World Health Organization.

The total neutrophil-to-lymphocyte ratio (NLR) was significantly greater in the beta-blocker group, whereas ESR and serum hs-CRP were significantly higher in the ACEI/ARB + CCB group. Plasma glucose at admission was significantly greater in the ACEI/ARB group, and patients with hypertension had significantly more urea levels than those without hypertension. Furthermore, the model ACEI/ARB group had significantly lower IL-6 values, whereas the CCB group had significantly greater serum ferritin values. However, there were no significant differences in hemoglobin, total leucocyte count, platelet count, serum creatinine, D-dimer, lactate dehydrogenase, creatine kinase, or prolactin levels among the groups (Table 3).

Table 3 Laboratory parameters at admission

Parameter	Total population, n = 260	Nonhypertensive, n = 60	ACEI/ARB, n = 62	Calcium channel blockers, n = 64	ACEI/ARB + CCB, n = 60	Beta-blockers, n = 14	P value	
Hemoglobin in gm/dL	12.95 (2.0)	13.47 (5.4)	12.94 (1.9)	12.45 (2.1)	12.9 (1.7)	13.36 (2.6)	0.077	
Total leukocyte count as /cu mm	7683.8 (3991.9)	6993.83 (3576.08)	7755.32 (3712.07)	8126.41 (4186.3)	7739.33 (4604.2)	8062.86 (3205.9)	0.606	
Neutrophil/lymphocyte ratio (IQR)	1-6	1-3	2-6.25	1.25-6	2-9.5	1-15.255	< 0.001	
Platelets as /cu mm	237765.38 (90546.23)	235183.33 (78058.10)	249467.74 (98418.26)	233046.88 (96977.24)	239116.67 (88116.08)	212785.71 (89160.33)	0.677	
ESR in mm/h (IQR)	9-38	7-28.5	8-38.5	10.5-39.5	12.5-48.54	10.5-40.2	0.007	
Serumhs-CRP in mg/dL (IQR)	3-67	1.25-15	8.5-88.2	6-85.2	3-89.54	13-85.7	< 0.001	
Plasma glucose at admission in mg/dL	135.82 (65.1)	104.9 (48.5)	162 (63.9)2	126.28 (59.0)	148.9 (60.3)	139.43 (53.8)	< 0.001	
Blood urea in mg/dL (IQR)	21-38	19-291	21-37.25	23.25-43	21-43.5	18.5-43.2	0.002	
Serum creatinine in mg/dL	1.19 (0.78)	1.1 (0.54)	1.2 (1.05)	1.2 (0.64)	1.2 (0.4)	1.4 (1.6)	0.164	
Serum interleukin 6 in pg/mL (IQR)	20-188.2	68.5-200	13.2-118.52	17.2-219.2	16.7-159.5	10.7-155.7	0.004	
Serum ferritin in ng/mL (IQR)	67.25-449.5	31.25-242.5	116-459	76.5-660.253	46.5-541	46.5-520.5	0.017	
D-Dimer in μg/mL (IQR)	0-2	0-1	0-3	0-2	0-2	0-1.2	0.43	
Serum lactate dehydrogenase in IU/L (IQR)	179-321	180.2-256.7	170-330.2	186.7-318.5	175-359.7	187.2-347.7	0.751	
Serum creatine kinase in IU/L (IQR)	45.25-107.7	49-109.5	45-98.2	39.75-118	48-108	49.75-109.7	0.964	
Serum procalcitonin in ng/mL	0.16 (0.44)	0.12 (0.32)	0.26 (0.72)	0.13 (0.4)	0.13 (0.3)	0.21 (0.4)	0.695	
1 Significant difference between the nonhypertensive group and others.

2 Significant difference between the ACEI/ARB group and others.

3 Significant difference between the CCB group and others.

4 Significant difference between the ACEI/ARB + CCB group and others.

5 Significant difference between the beta-blocker group and others.

Data are mean ± standard deviation unless indicated otherwise. ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; CCB: Calcium channel blocker; ESR: Erythrocyte sedimentation rate; hs-CRP: High-sensitivity C-reactive protein; IQR: Interquartile range.

In multivariate logistic regression, age and duration of antihypertensive therapy were significantly associated with mortality, with adjusted odds ratios (aORs) of 1.21 (1.06-1.39) and 0.69 (0.51-0.94), respectively. Apart from these, inflammatory parameters such as ESR, hs-CRP, and serum IL-6 were associated with mortality, with aORs of 0.92 (0.87-0.97), 0.97 (0.95-0.99), and 0.97 (0.96-0.99), respectively (Table 4).

Table 4 Predictors of mortality in coronavirus disease 2019 patients by multivariable logistic regression

Risk factor	Adjusted odds ratio (95%CI)	P value	
Age	1.21 (1.06-1.39)	0.005a	
Sex	-	0.742	
Diabetes	-	0.057	
Ischemic heart disease	-	0.686	
Duration of antihypertensive therapy	0.69 (0.51-0.94)	0.008a	
ACEI/ARB	-	0.997	
Calcium channel blockers	-	0.996	
ACEI/ARB + calcium channel blockers	-	0.997	
Beta-blockers	-	0.998	
Hemoglobin	-	0.465	
Neutrophil/lymphocyte ratio	-	0.071	
ESR	0.92 (0.87-0.97)	0.005a	
hs-CRP	0.97 (0.95-0.99)	0.014a	
Blood urea		0.095	
Serum ferritin	-	0.081	
Serum interleukin 6	0.97 (0.96-0.99)	0.009a	
a P< 0.05.

ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; CI: Confidence interval; ESR: Erythrocyte sedimentation rate; hs-CRP: High-sensitivity C-reactive protein.

The duration of antihypertensive therapy had a sensitivity of 70.8% and specificity of 55.7%, with a cut-off value of 4.5 years and an area under the curve of 0.670 (0. 574-0.767) (Table 5, Figure 1).

Figure 1 Receiver operating characteristic curve of the duration of antihypertension therapy as a predictor of coronavirus disease 2019 outcome. ROC: Receiver operating characteristic.

Table 5 Performance criteria of the duration of antihypertensive therapy in discriminating the outcome of coronavirus disease 2019

Parameter	AUC (95%CI)	Sensitivity	Specificity	Cut of value of years	P value	
Duration of antihypertensive therapy	0.670 (0.574-0.767)	70.8	55.7	4.5	0.007	
AUC: Area under the curve; CI: Confidence interval.

DISCUSSION

The COVID-19 pandemic has produced devastating effects globally. The presence of co-morbidities in patients with COVID-19 infection adversely affects the outcome. In people infected with COVID-19, hypertension is a frequent co-morbidity. In this study, the outcomes of COVID-19 infection in patients treated with different classes of antihypertensive drugs were analyzed. This study comprised 260 patients infected with COVID-19. While 60 patients were nonhypertensive, 200 (76.9%) patients were on an antihypertensive regimen, of whom62 were in the ACEI/ARB group, 64 were in the CCB group, 60 were on a combination of ACEI/ARB and CCB, and 14 were on beta-blockers. The length of antihypertensive medication did not significantly differ across the groups. The study found that serum IL-6, hs-CRP, ESR, age, and duration of antihypertensive medication were substantial indicators of fatality.

There was a discernible age difference between the hypertension and nonhypertensive groups. One significant risk factor for the emergence of hypertension is age[12]. In our study, men were more significantly affected than women. The onset of hypertension is significantly influenced by sex. In women, sex hormones and chromosomal differences serve as protective factors against hypertension. In addition, behavioral factors in men, such as high body mass index and smoking habits, make them prone to hypertension despite high physical activity[13]. Diabetes was the common co-morbidity in the current study. The prevalence of diabetes was considerably higher in patients on ACEI/ARB. ACEI and ARB are the drugs of choice for hypertension in patients with diabetes mellitus to prevent microalbuminuria and nephropathy[14]. There was a significantly higher number of patients with ischemic heart disease in the beta-blocker group, as the initial class of medications for treatment of ischemic heart disease is beta-blockers[15]. Hypothyroidism was the next common co-morbidity observed in this study; however, the difference among groups was insignificant. In a meta-analysis performed by Damara et al[16], hypothyroidism was significantly associated with poor outcomes. Smoking increases the risk of COVID-19 infection by upregulating ACE-2 levels and adversely affects outcomes such as hospitalization and mortality[17]. A few studies have reported the protective effect of smoking against COVID-19 infection[18,19]. Unfortunately, smoking was also insignificant among the study groups, which could be attributed to the small number of smokers in our study. Fever was the usual symptom, followed by cough and breathlessness, which were significantly higher in patients on beta-blockers. One likely reason is that beta 2 receptor blockage-induced bronchospasm could lead to cough and breathlessness[15]. ACEIs are more prone to produce cough and bronchospasm due to the accentuation of the bradykinin pathway. In our study, these symptoms were second most common in the ACEI/ARB group, as most of our patients were predominantly on ARB, which causes fewer respiratory side effects.

In our research, pneumonia, MODS, ARDS, AKI, and renal failure were common complications in the patients studied. Surprisingly, significant differences were not observed among the groups in these complications. However, patients treated with CCBs showed a higher incidence of ARDS, critical cases as per WHO criteria, ICU interventions, and mortality rates than the other groups. These findings contradict the results of Solaimanzadeh et al[8], who reported that CCBs are associated with a reduced possibility of requiring mechanical ventilation and intubation. Additionally, they found that medications such as nifedipine and amlodipine are linked to lower mortality rates among elderly patients with COVID-19, which could be explained by the increased blood flow to the pulmonary vasculature. However, these studies did not consider the severity of hypertension and its impact on the outcomes, which could have resulted in a potential bias as higher blood pressure levels can lead to a heightened inflammatory state.

Total leukocyte count is a marker of inflammation as well as a risk factor for hypertension[20]. In our study, there was no noteworthy variance among the groups in this parameter, which suggests that antihypertensives may exert anti-inflammatory effects, as described by Hussain et al[21] and Karaman et al[22]. In this study, NLR was significantly higher in the beta-blocker group. In several clinical diseases, such as diabetes, hypertension, and metabolic syndrome, NLR is a reliable biomarker of low-grade inflammation. Increased NLR exhibits a significant independent relationship with the severity of hypertension. In the beta-blocker group, nebivolol exerts a better anti-inflammatory effect than metoprolol[21], which could explain the increased NLR in the beta-blocker group as most of the patients were on metoprolol in this study. Karaman et al[22] observed that amlodipine alleviates vascular inflammation by decreasing the NLR, which is contradictory to our findings. ACEI and ARB also exert anti-inflammatory effects by suppressing the RAAS system[23]. Nonetheless, in our study, NLR was minimally elevated in the ACEI and ARB groups. Despite these established mechanisms, our study unexpectedly found that NLR was only minimally elevated in patients treated with ACEI and ARB. This finding suggests a potential discrepancy between the expected anti-inflammatory effects of these medications and their observed impacts on inflammatory markers in our specific patient population.

ESR and hs-CRP were significantly elevated in patients treated with a combination of ACE/ARB and CCB. Although ACEI/ARB is known for its anti-inflammatory effect when used as a monotherapy, this effect is modest in combination therapy. Palmas et al[24] reported a similar finding and found that beta-blockers were associated with lower CRP levels when followed by ACE/ARB as a monotherapy. Angiotensin triggers oxidative stress, activates nuclear factor kappa B and induces inflammatory cytokines and markers, such as IL-6 and hs-CRP[25]. In addition, the administration of ACE inhibitors lowers serum IL-6 levels, thereby decreasing the incidence of myocardial infarction and acute coronary syndromes[26]. Our study findings are in accordance with previous studies; serum IL-6 was significantly lower in patients receiving ACEI/ARB. Ferritin is an acute-phase reactant synthesized by the liver. Calcium ions are the key transporters of iron and play a significant role in iron metabolism and erythroid precursor differentiation. CCB therapy can cause anemia and low iron levels[27]. Serum ferritin was significantly higher in patients on CCBs in this study, which contradicts the observations of Mainous et al[28], who found that serum ferritin was low in patients on CCBs.

When multivariable logistic regression analysis was performed, age, duration of antihypertensive therapy, ESR, hs-CRP, and IL-6 emerged as the significant predictors of mortality. The antihypertensive agents ACEI/ARB, CCB, a combination of ACEI/ARB and CCB and beta-blockers were insignificantly associated with mortality.

Age is a crucial predictor of COVID-19 mortality as advanced age affects both innate and adaptive immunity, rendering individuals more susceptible to infection and its associated complications. Furthermore, aging influences the body’s response to medications and vaccines, which could potentially lead to suboptimal outcomes[29]. In our study, age was a key predictor of mortality, with an aOR of 1.21 (1.06-1.39). SARS-COV-2 attaches itself to ACE-2 receptors expressed in the renal, gut, lungs, and blood vessels. ACEI/ARB increases ACE-2 receptors, which facilitates the progression of COVID-19 infection; however, the free circulating ACE-2 inactivates SARS-COV-2 by inhibiting its binding to the receptors. RAAS inhibition by ACEI/ARB reduces inflammation and cytokine storm, leading to a favorable outcome. Moreover, diminished ACE2 activity has been tied to cardiopulmonary ailments. ACE2 provides protection against catastrophic COVID-19 infection repercussions by reducing the damaging impact of angiotensin II on the circulatory system[30]. Studies have reported variable outcomes, with some reporting favorable, some reporting poor, and others reporting neutral outcomes for ACEI/ARB[31-33]. The discrepancies in these findings highlight the need for further research to elucidate the precise role of ACEI/ARB in COVID-19 management and identify patient subgroups likely to derive optimum benefit from their use.

Beta-blockers reduce SARS-COV-2 entry into cells via the downregulation of ACE-2 and cluster of differentiation 147. Furthermore, these drugs reduce inflammation by lowering the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and IL-6 levels. Hence, beta-blockers are useful in reducing thrombotic complications and pulmonary edema. Furthermore, they exert beneficial effects on septic shock and ARDS by improving oxygenation[7]. Similar to our study, Kocayigit et al[3] reported that beta-blockers have no effect on the outcome of COVID-19 infection. By contrast, Yan et al[9] found that beta-blockers are beneficial against COVID-19 infection.

CCBs, particularly dihydropyridines, are advantageous for individuals with COVID-19 infection as they reduce pulmonary vascular resistance and enhance oxygen supply both during rest and during mobility. In our study, CCBs did not affect the outcome in multivariable logistic regression. Nonetheless, in categorical analysis, patients on CCBs exhibited higher rates of ARDS, critical cases, ICU interventions, and mortality. Categorical analysis is useful in assessing the presence or absence of an association. They are not indicative of strength of association: cause and effect. Hence, these effects on categorical analysis suggest the spurious association of the effects of CCBs on these parameters as these effects were adjusted by other variables in multivariable logistic regression. Unlike our study, Solaimanzadeh et al[8] and Yan et al[9] found that CCBs are associated with decreased severity of infection and mortality due to COVID-19. In another study, Zhang et al[34] noted that amlodipine besylate reduces post-viral entry events and enhances the outcomes of COVID-19. In a research including 444 patients at a community hospital in Massachusetts, individuals who had used dihydropyridine CCBs and had a history of hypertension showed a much higher risk of intubation or death compared to those who did not take the medication. Drugs belonging to this group appear to cause ventilation–perfusion mismatch by disrupting hypoxic pulmonary vasoconstriction[35].

The duration of hypertension therapy tends to vary based on individual patient factors, including the disease severity, the presence of co-morbid conditions, and the response to treatment. In our study, the duration of antihypertensive therapy was significantly associated with poor outcomes, with an aOR of 0.69 (0.51-0.94). The cut-off value was 4.5 years, with a sensitivity of 70.8% and specificity of 55.7% in predicting the outcome. Patients with chronic hypertension often exhibit target organ damage, which exacerbates their risk of contracting COVID-19 and experiencing poor outcomes. Arterial stiffness and endothelial dysfunction are significantly increased in patients with chronic hypertension, factors that play a crucial part in the etiology of cardiovascular problems afterCOVID-19 infection[36]. Similarly, the outcome of COVID-19 infection is negatively impacted by high blood pressure variability although the exact mechanism is yet to be established. In addition, hypertension stimulates the innate and adaptive immune systems, thereby increasing inflammation and resulting in the release of cytokines. Patients with hypertension who have COVID-19 show severe immune cell inflammation, which is linked to the progression of infection. Immune dysregulation is a significant factor that contributes to COVID-19 infection and hypertension. In patients with COVID-19 who have hypertension, the extent and fatality of the disease are closely correlated with T-cell lymphopenia[37]. In our study, most patients with hypertension were approximately 60 years of age. Older individuals with hypertension have an added risk of infection and advancement to critical illness. The poor outcomes in our study could possibly have been influenced by circulatory alterations, immune dysregulation, and inflammation caused by chronic hypertension, which were aggravated by aging. In their study that involved 2,864 patients with hypertension and COVID-19 infection, Chen et al[38] observed a progressive increase in disease duration, symptom severity, and complications of COVID-19 infection, which were correlated with the duration and staging of hypertension. In a retrospective anonymous study by Ran et al[39] that involved 803 patients with hypertension, inadequate blood pressure control in patients with COVID-19 and chronic hypertension was independently associated with unfavorable outcomes. Higher rates of heart failure were observed in those not treated with ARBs, which indicates the potentially protective role of these drugs in this context.

Our study has provided valuable insights into the outcomes of COVID-19 infection in patients undergoing various antihypertensive therapies. Significant differences were not observed in the incidence of pneumonia, MODS, AKI and renal failure among the groups. Although patients on CCBs exhibited higher rates of ARDS, critical cases, ICU interventions and mortality, these events were lacking in multivariable logistic regression. These findings highlight the complexity of managing patients with hypertension and COVID-19, underscoring the need for personalized treatment approaches. The role of antihypertensive agents, especially in the context of co-morbid conditions such as diabetes and ischemic heart disease, remains critical. Further research is necessary to widen our understanding of the interactions between different antihypertensive therapies and COVID-19 outcomes to optimize clinical management and improve patient prognosis.

Limitations

This study had some limitations. There was a limit to the external validity of the results, because this study was limited to 200 patients with hypertension in a single center. In this investigation, patients were on ACEI/ARB, CCB, beta-blockers, and a combination of CCB/ACEI/ARB only. Other groups of antihypertensive agents and their combined effects were not examined in this study.

CONCLUSION

Patients with COVID-19 infection frequently have hypertension as a co-morbidity. The presence of hypertension aggravates the risk of complications and poor outcomes. The type of antihypertensive medication used did not influence the clinical sequence or outcome of COVID-19 infection. However, as the duration of antihypertensive therapy was significantly associated with mortality, these medications should be continued for managing hypertension to prevent complications and mortality. To explore the functions of these drugs and their impact on the progression of COVID-19, larger studies must be conducted.

Data sharing statement

Technical appendix, statistical code, and dataset available from the corresponding author at vsakthivadivel28@gmail.com.

Institutional review board statement: This study was reviewed and approved by All India Institute of Medical Sciences- Jodhpur Institutional Review Board (AIIMS/IEC/2020-21/2003).

Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.

Conflict-of-interest statement: The authors have no conflicts of interest to declare.

STROBE statement: The authors have read the STROBE Statement—checklist of items—and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Corresponding Author's Membership in Professional Societies: The Association of Physicians of India, L15145; RSSDI-INDIA, 9132; Indian Medical Association, TN/24443/54/198/203745/2015-16/CL.

Specialty type: Infectious diseases

Country of origin: India

Peer-review report’s classification

Scientific Quality: Grade B

Novelty: Grade B

Creativity or Innovation: Grade B

Scientific Significance: Grade B

P-Reviewer: Yu T S-Editor:Liu JH L-Editor:Filipodia P-Editor: Zheng XM
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