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36 RUSSIAN JOURNAL OF ANAESTHESIOLOGY AND REANIMATOLOGY, 1, 2022
Original articles
Impact of cardiovascular diseases and their therapy on mortality of ICU
patients with COVID-19
© L.V. ERMOKHINA1, 2, L.B. BERIKASHVILI1, M.YA. YADGAROV1, N.I. CHAUS2, A.A. BAEVA1,
N.S. MELNIKOVA2, S.N. PEREKHODOV2, A.N. KUZOVLEV1
1Federal Research and Clinical Center of Reanimatology and Rehabilitation, Moscow, Russia;
2Demikhov Moscow City Clinical Hospital, Moscow, Russia
ABSTRACT
There are various data on negative impact of comorbidities on treatment outcomes in patients with novel coronavirus infection
(COVID-19). However, the impact of cardiovascular diseases and especially their therapy on the course of infectious process
and unfavorable outcomes in COVID-19patients has not been sufficiently studied.
Objective. To assess the impact of concomitant cardiovascular diseases and chronic drug intake for their treatment on in-hospi-
tal mortality in ICU patients with COVID-19.
Material and methods. A single-center retrospective cohort study of ICU patients with COVID-19 was carried out between March
6, 2020 and June 3, 2020 at the Demikhov Moscow City Clinical Hospital. We analyzed the following data: age, gender, previous
comorbidities, Charlson comorbidity index, therapy of chronic cardiovascular diseases, severity of COVID-19, NEWS and SOFA
scores. Univariate analysis included assessment of relative risk (RR). Multivariate analysis was carried out using regression model.
Results. We analyzed medical records of 403 patients (231 (57.3%) men). Mean age of patients was 62.4±15.3 years. Over-
all 30-day mortality rate was 44.9% (n=181). Multivariate analysis showed that coronary artery disease (adj. OR 2.459, 95% CI
1.589—3.806, p<0.001) and hypertension (adj. OR 2.893, 95% CI 1.667—5.019, p<0.001) were independent predictors of mor-
tality in ICU patients with COVID-19.
Conclusion. Coronary artery disease and hypertension are independent predictors of poor outcomes. Long-term use of angioten-
sin-converting enzyme inhibitors, β-blockers, acetylsalicylic acid or statins for cardiovascular diseases does not significantly affect
clinical outcomes in ICU patients with COVID-19.
Keywords: COVID-19, cardiovascular diseases, hypertension, angiotensin-converting enzyme inhibitors, β-blockers, acetylsali-
cylic acid, statins.
INFORMATION ABOUT THE AUTHORS:
Ermokhina L.V. — https://orcid.org/0000-0002-0891-4937; e-mail: ermokhina_92@mail.ru
Berikashvili L.B. — https://orcid.org/0000-0001-9267-3664
Yadgarov M.Ya. — https://orcid.org/0000-0003-3792-1682
Chaus N.I. — https://orcid.org/0000-0001-5891-3417
Baeva A.A. — https://orcid.org/0000-0002-5189-8602
Melnikova N.S. — https://orcid.org/0000-0002-6671-8467
Perekhodov S.N. — https://orcid.org/0000-0002-6276-2305
Kuzovlev A.N. — https://orcid.org/0000-0002-5930-0118
Corresponding author: Ermokhina L.V. — e-mail: ermokhina_92@mail.ru
TO CITE THIS ARTICLE:
Ermokhina LV, Berikashvili LB, Yadgarov MYa, Chaus NI, Baeva AA, Melnikova NS, Perekhodov SN, Kuzovlev AN. Impact of cardiovascular
diseases and their therapy on mortality of ICU patients with COVID-19. Russian Journal of Anaesthesiology and Reanimatology = Anesteziologiya
i Reanimatologiya. 2022;1:36–43. (In Russ.). https://doi.org/10.17116/anaesthesiology202201136
Introduction
The COVID-19 pandemic has posed many problems
for modern medical science. We cannot hope for significant
progress in searching for an effective therapy of this serious in-
fectious disease without solution of these issues [1-3]. In partic-
ular, today we know that COVID-19 is especially severe in elder-
ly patients [4-6], and comorbidity is one of the most significant
predictors of an unfavorable outcome [7, 8].
Cardiovascular diseases (CVD) are an important medi-
co-social problem regardless of the pandemic [9]. Therefore,
it is not surprisingly that patients with concomitant CVD con-
stitute a significant group of patients with COVID-19. Ac-
cording to a retrospective analysis of 575 Chinese hospitals
for COVID-19 management (n=1,590), hypertension was ob-
served in 16.9% of patients, other CVDs — 53.7%, diabetes
mellitus (DM) — in 8.2% of patients [4]. In an Italian cohort
of patients with COVID-19 (n = 22 512), coronary artery dis-
ease (CAD) was found in 30% of patients, atrial fibrillation
(AF) — 24.5%, DM — 35.5% of patients [7]. Another anal-
ysis of 5,700 COVID-19 patients at 12 hospitals in New York
revealed hypertension in 56.6% of patients, CAD — 11.1%,
obesity — 41.7%, DM — 33.8% of patients [8]. Russian da-
ta are closer to the findings of North American colleagues. In-
deed, concomitant CVDs were detected in 61.4% of patients
among 1.007 ones with COVID-19 admitted to intensive care
units. Incidence of hypertension was 56.3%, CAD — 16.3%,
AF — 9.3% [10].
Russian Journal of Anaesthesiology and Reanimatology
2022, No. 1, pp. 36–43
https://doi.org/10.17116/anaesthesiology202201136
37
RUSSIAN JOURNAL OF ANAESTHESIOLOGY AND REANIMATOLOGY, 1, 2022
Original articles
Most researchers emphasize higher incidence of ad-
verse outcomes in patients with concomitant CVDs. Analysis
of 44,672 patients with COVID-19 and CVDs in the Chinese
Center for Disease Control and Prevention revealed mortality
up to 10.5%, while in general population this value was 2.3% [5].
Inciardi R.M. et al. [6] reported 2.4-fold higher risk of mortality
in patients with concomitant CVDs (p = 0.019).
Apparently, a viral infection contributes to additional dam-
age to cardiovascular system and increases the risk of mortality
in patients with pre-existing cardiovascular diseases [11]. Thus,
course of COVID-19 in patients with concomitant CVDs de-
serves a special attention.
However, correlation and interdependence of CVD
and course of COVID-19 are not limited to this. Soon after
identification of pathogen, an evidence appeared that angioten-
sin-converting enzyme 2 (ACE2) was involved into intracellular
penetration of the virus [12-14]. In this regard, it was hypothe-
sized that ACE inhibitor intake may be associated with unfavor-
able outcomes of COVID-19 [12, 13, 15].
However, research of etiology, pathogenesis and clini-
cal manifestations of COVID-19 resulted an opposite opinion
about positive effect of drugs influencing renin-angiotensin-al-
dosterone system (RAAS) [13, 14, 16-19]. Sarzani R. et al. [20]
found more severe destructive effect of coronavirus following
the binding of the virus to ACE2 and RAAS hyperactivation.
Accordingly, the drugs inhibiting RAAS will weaken this ef-
fect [9, 21, 22].
There are equally contradictory ideas about prescription
of antiplatelet agents (acetylsalicylic acid, clopidogrel, etc.) [9,
13, 23]. There is still no consensus on feasibility and effectiveness
of additional intake of antiplatelet agents. Advisability of statins
in patients with COVID-19 is also unclear. Virani S.S. et al. [24]
and Kollias A. et al. [25] suggest that these drugs can reduce se-
verity of virus-induced myocardial damage and intensity of cyto-
kine storm. Therefore, they recommend continuing statin thera-
py in patients with COVID-19. Russian colleagues support this
opinion [26].
It is difficult to overestimate this problem considering an im-
portance of analysis of COVID-19 course in patients with con-
comitant CVDs and contradictory data on the effect of cardio-
vascular therapy in these patients.
The purpose of the study was to assess the impact
of concomitant cardiovascular diseases and chronic drug in-
take for their treatment on in-hospital mortality in ICU patients
with COVID-19.
Material and methods
Study design and patients
A single-center retrospective cohort study was performed.
We analyzed medical records of patients admitted to inten-
sive care unit of the Demikhov Moscow City Clinical Hospital
for the period from March 6, 2020 to June 3, 2020.
Inclusion criteria: age ≥ 18 years, ICU patients with diagno-
ses of "COVID-19, virus identified" (U07.1), “COVID-19 sus-
pected, no virus identified” (U07.2). Exclusion criteria: trans-
ferring to any other hospital for further treatment, clinical death
at admission to ICU, admission to ICU for the period of resolv-
ing the issue of transferring to a specialized department without
specific treatment of COVID-19.
The ethical committee of the Federal Research and Clinical
Center of Reanimatology approved this study (No. 2/21/1 dat-
ed 04.16.2021).
Data collection
We have systematized and analyzed the following data: age,
gender, concomitant diseases with assessment of Charlson comor-
bidity index, therapy of chronic CVDs (angiotensin-converting
enzyme inhibitors, angiotensin II receptor blockers, β-blockers,
statins, antiplatelet agents), development of major adverse cardio-
vascular events (non-fatal cardiac arrest, myocardial infarction,
myocardial revascularization, heart failure and heart rhythm dis-
turbances de novo) and major adverse cardiac or cerebrovascu-
lar events (MACE + ischemic stroke) [11]. We also assessed se-
verity of COVID-19 infection [1], NEWS [27] and SOFA scores
at admission to ICU [1], length of ICU-stay and hospital-stay.
The primary endpoint was in-hospital mortality (within
30 days after admission to the hospital for any reason). The sec-
ondary endpoints were length of ICU-stay and hospital-stay,
MACE + MACCE.
Statistical analysis
All data were collected from paper and electronic versions
of the Everest case history into an electronic database using Excel
tables (Microsoft Corp., USA). We applied maximum standard-
ization of all values for a qualitative analysis. All statistical proce-
dures were performed using SPSS® version 25 and MedCalc®
version 19.5.6. Differences were significant at p-value < 0.05.
Distribution normality was tested using the Shapiro-Wilk
test. Quantitative variables were presented as mean and stan-
dard deviation, in case of abnormal distribution — median (Me)
and interquartile range [IQR]. Categorical variables were de-
scribed using absolute values and percentages. We analyzed
between-group differences (dead patients / survivors) us-
ing the Mann-Whitney U-test for continuous variables (with
U and Z values). Categorical variables in between-group analysis
were compared using the Fisher's exact test. To analyze the rela-
tionship between baseline cardiovascular therapy and incidence
of poor outcomes in ICU patients with COVID-19, we used
univariate and multivariate analysis. Risk of adverse outcomes
in univariate analysis was assessed using the OR (odds ratio)
and its 95% confidence interval (CI) for each predictor. In mul-
tivariate analysis, we used a regression model with adjusted haz-
ard ratio (HR) and its 95% CI.
Results
According to inclusion/exclusion criteria, we enrolled
403 out of 4,645 patients admitted with COVID-19 (Figure).
Mean age of patients was 62.4 ± 15.3 years (range 21 — 97). There
were 231 (57.3%) men. Moderate severity of COVID-19 was ob-
served in 149 (37.0%) patients, severe infection — in 254 (63.0%)
patients. Overall mortality in intensive care unit was 44.91%
(n=181).
Characteristics of survivors and dead patients with
COVID-19 are summarized in Table 1.
The most common comorbidities were hypertension (74.2%,
n = 299), cerebrovascular insufficiency (57.6%, n = 232), cor-
onary artery disease (41.4%, n = 167), chronic kidney disease
(40.2%, n = 162), obesity (37.2%, n = 150) and diabetes mel-
litus type 2 (25.8%, n = 104). Incidence of various comorbidi-
ties in the entire sample, as well as in survivors and dead patients
is presented in Table 2 (univariate analysis).
According to gender- and age-adjusted multivariate anal-
ysis, independent cardiovascular predictors of mortality were
coronary artery disease (adj. OR = 2.459, 95% CI 1.589-3.806,
p <0.001) and hypertension (adj. OR = 2.893, 95 % CI 1.667 —
5.019, p <0.001).
38 RUSSIAN JOURNAL OF ANAESTHESIOLOGY AND REANIMATOLOGY, 1, 2022
Original articles
Univariate analysis of patients with/without therapy (ACE
inhibitors, β-blockers, antiplatelet agents, statins) for chronic
cardiovascular diseases is presented in Table 3. Intake of these
drugs had no effect on the risk of mortality. Similarly, multivar-
iate analysis found no significant relationships.
Multivariate analysis of the effect of CVDs and appropriate
therapy on the length of hospital-stay or ICU-stay in patients
with COVID-19 revealed no significant relationships.
Univariate analysis revealed no significant between-group
differences in the incidence of composite outcome (MACE +
MACCE) in patients without therapy and those taking drugs
for concomitant CVDs (Table 4).
Discussion
Hypertension (adj. OR = 2.893, 95% CI 1.667-5.019,
p <0.001) and coronary artery disease (adj.OR = 2.459, 95%
CI 1.589-3.806, p <0.001) significantly worsen the progno-
sis in ICU patients with COVID-19. These data do not contra-
dict the results of other studies. Indeed, Noor F.M. and Islam
M.M. [28] performed a meta-analysis of 58 studies (122,191 pa-
tients) and found a significant correlation between mortality
in patients with COVID-19 and pre-existing hypertension (RR =
2.08, 95% CI 1.79 — 2.43, p <0.001) and other CVDs (RR 2.51,
95% CI 1.20 — 5.26, p <0.05).
Zhou F. et al. [29] performed a retrospective study (n = 191)
and found previous coronary artery disease as a significant pre-
dictor of poor outcomes in patients with COVID-19 (OR = 2.14,
95% CI 0.26-17.79, p = 0.48). Higher mortality rates in our study
may be explained by analysis of the most severe patients requir-
ing intensive care.
We found no significant effect of baseline cardiovascular
therapy on mortality in ICU patients with COVID-19. Thus,
we cannot confirm the positive effect of ACE inhibitors, statins
or antiplatelet agents previously discovered by some research-
ers [13, 14, 16-19]. At the same time, these drugs had no nega-
tive effect on the outcomes of COVID-19. Currently, the Amer
-
ican College of Cardiology, the European Society of Cardiology
and the Russian Society of Cardiology recommend continu-
ing therapy with RAAS blockers previously prescribed for cer-
Overall number of patients admitted to the Demikhov
Moscow City Clinical Hospital (n=4645)
Overall number of patients admitted to intensive care
unit (12.3%, 571/4645)
ICU patients enrolled in the study (70.6%,403/571)
Discharged from intensive care unit (55.1%, 222/403) Dead in intensive care unit (44.9%, 181/403)
Clinical death at admission to intensive
care unit (7,7%, 13/168)
Transferring to other hospitals for any
reason (52.4%, 88/168)
COVID-19 was no confirmed after
examination (39.3%, 66/168)
Te mporary follow-up in intensive care unit without specific
therapy of SARS-CoV-2 (0.6%, 1/168)
Excluded from the study
(29.4%, 168/571)
Exclusion criteria.
ICU — intensive care unit
Table 1. Characteristics of patients with COVID‑19 and concomitant therapy
Variable Survivors, n=222 Dead patients, n=181 p-value
Demographic characteristics and comorbidity:
Gender (men/women) 127/95 104/77 1.000
Age, years 57.0 [IQR: 48.0—66.0] 68.0 [IQR: 60.0—79.0] <0.001*
BMI, kg/m228.0 [IQR: 24.9—32.9] 29.1 [IQR: 24.4—34.0] 0.827
Charlson Comorbidity Index 2 [IQR: 1—5] range 0 — 11 6 [IQR: 4—8] range 0 — 14 <0.001*
Clinical severity at admission:
SOFA score 1.0 [IQR: 1.0—2.0] 3.0 [IQR: 2.0—4.0] <0.001*
NEWS score 7.0 [IQR: 5.0—8.0] 8.0 [IQR: 7.0—10.5] <0.001*
Course of COVID-19 at admission (moderate/severe) 209/13 45/136 <0.001*
Length of stay, days:
Hospital-stay 16.0 [IQR: 12.0—21.0] 9.0 [IQR: 5.5—14.5] <0.001*
ICU-stay 4.0 [IQR: 3.0—7.0] 5.0 [IQR: 3.0—9.0] 0.023*
Note. p-value — level of statistical significance; * — significant differences. BMI — body mass index.
39
RUSSIAN JOURNAL OF ANAESTHESIOLOGY AND REANIMATOLOGY, 1, 2022
Original articles
tain indications (hypertension, coronary artery disease, heart
failure) to reduce cardiovascular risk (myocardial infarction,
stroke) [9, 11]. Moreover, further intake of acetylsalicylic acid,
clopidogrel or ticagrelor is advisable because the risk of discon-
tinuation of antiplatelet therapy may be associated with signifi-
cant risk of cardiovascular events [9].
Considering own findings, we cannot support these rec-
ommendations. However, they are clearly not enough to call
for a change in attitude towards drug therapy of concomitant
CVDs in ICU patients with COVID-19. The authors found
no effect of statins on COVID-19-associated mortality and can-
not confirm the guidelines on prescription of these drugs in pa-
tients with COVID-19.
Study limitations
Our study has certain limitations. First, retrospective analy-
sis imposes certain limitations on validity of conclusions and rec-
ommendations.
Secondly, our cohort of patients was recruited within the first
wave of the pandemic. On the one hand, this fact allowed tradi-
tional CVD treatment regardless potential (but at that time un-
known) effect on the course of the underlying infectious disease.
On the other hand, attending physicians resolved various issues
at own discretion due to unavailable clinical guidelines. This as-
pect explains several treatment regimens for the same condition
in one hospital.
Conclusion
According to sex- and age-adjusted multivariate analysis,
coronary artery disease and hypertension are independent pre-
dictors of mortality in ICU patients with COVID-19.
There were no significant between-group differences in mor-
tality among ICU patients with COVID-19 taking angioten-
sin-converting enzyme inhibitors, β-blockers, acetylsalicylic acid
or statins for chronic cardiovascular diseases and those without
similar therapy. Cardiovascular diseases in COVID-19 patients
Table 4. Incidence of MACE and MACCE depending on drug intake for cardiovascular diseases in patients with COVID‑19
Drugs MACE MACCE
RR 95% CI p-value RR 95% CI p-value
Angiotensin-converting enzyme inhibitors 1.267 0.643—2.497 0.498 1.379 0.776—2.449 0.283
Beta blockers 0.986 0.460—2.114 0.283 0.80 4 0.381—1.699 0.563
Angiotensin-converting enzyme inhibitors + beta blockers 1.220 0.662—2.249 0.526 1.410 0.850—2.341 0.19 0
Statins 0.789 0.451—1.380 0.493 1.143 0.735—1.779 0.654
Note: RR [95% CI] — relative risk [95% confidence interval], p-value — level of statistical significance.
Table 2. Mortality rate depending on comorbidity index in patients with COVID‑19
Comorbidity Dead/patients with
pre-existing comorbidity, n (%)
Dead/patients without
pre-existing comorbidity, n (%) RR: [95% CI] p-value
Hypertension 159/299 (53.2) 22/104 (21.2) 2.514 [1.709—3.698] <0.001*
Previous myocardial infarction 79/134 (58.9) 102/269 (37.9) 1.555 [1.263—1.915] <0.001*
Atrial fibrillation 49/77 (63.6) 132/326 (40.5) 1.572 [1.269—1.9 47] <0.001*
Coronary artery disease 103/167 (61.7) 78/236 (33.1) 1.866 [1.501—2.319] <0.001*
Chronic heart failure 90/143 (62.9) 91/260 (35.0) 1.798 [1.461—2.214] <0.001*
Chronic obstructive pulmonary disease 42/66 (63.6) 139/337 (41.2) 1.543 [1.235—1.927] 0.001*
Cerebrovascular insufficiency 143/232 (61.6) 38/171 (22.2) 2.774 [2.058—3.737] <0.001*
Peripheral artery disease 175/334 (52.4) 6/69 (8.7) 6.025 [2.786—13.032] <0.001*
Diabetes mellitus type 2 56/104 (53.8) 125/299 (41.8) 1.288 [1.031—1.609] 0.039*
Chronic kidney disease 103/162 (63.6) 78/241 (32.4) 1.964 [1.582—2.439] <0.001*
Liver failure 13/20 (65.0) 168/383 (43.9) 1.482 [1.054—2.084] 0.070
Gastric and duodenal ulcer 18/32 (56.3) 163/371 (43.9) 1.280 [0.924—1.775] 0.198
Hemiplegia 15/22 (68.2) 166/381 (43.6) 1.565 [1.151—2.128] 0.028*
Cancer 22/39 (56.4) 159/364 (43.7) 1.291 [0.957—1.742] 0.209
Obesity 61/150 (40.7) 120/253 (47.4) 0.857 [0.679—1.082] 0.214
Note. RR: [95% CI] — relative risk [95% confidence interval], p-value — level of statistical significance; * — significant differences (univariate analysis).
Table 3. Mortality rate depending on drug intake for cardiovascular diseases in patients with COVID‑19
Drugs Dead/patients taking
the drug, n (%)
Dead/patients not taking
the drug, n (%) RR: [95% CI] p-value
Angiotensin-converting enzyme inhibitors 55/124 (44.4) 126/279 (45.2) 0.982 [0.776—1.243] 0.914
Beta blockers 55/124 (44.4) 126/279 (45.2) 0.982 [0.776—1.243] 0.914
Statins 43/114 (37.7) 138/289 (47.8) 0.790 [0.606—1.030] 0.076
Antiplatelet agents (except for acetylsalicylic acid) 7/19 (36.8) 174/384 (45.3) 0.813 [0.447—1.480] 0.638
Acetylsalicylic acid 25/64 (39) 156/339 (46) 0.849 [0.612—1.177] 0.339
Note. RR [95% CI] — relative risk [95% confidence interval], p-value — level of statistical significance.
40 RUSSIAN JOURNAL OF ANAESTHESIOLOGY AND REANIMATOLOGY, 1, 2022
Original articles
and appropriate therapy do not increase the length of hospi-
tal-stay and ICU-stay.
Author contribution:
Concept and design of the study — A.N. Kuzovlev.
Collection and analysis of data — Ermokhina L.V., Yad-
garov M.Ya., Baeva A.A., Perekhodov S.N., Chaus N.I., Mel-
nikova N.S.
Statistical analysis — Berikashvili L.B., Yadgarov M.Ya.
Writing the text — Ermokhina L.V., Berikashvili L.B., Yad-
garov M.Ya.
Editing — A. N. Kuzovlev
The authors declare no conflicts of interest.
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Received 10.08.2021
Accepted 08.11.2021
