• „ ORIGINAL ARTICLE

Association between cardiovascular disease, cardiovascular drug therapy, and in-hospital outcomes in patients with COVID-19: data from a large single-center registry in Poland

Michał Terlecki1, Wiktoria Wojciechowska1, Marek Klocek1, Agnieszka Olszanecka1, Katarzyna Stolarz-Skrzypek1, Tomasz Grodzicki2, Maciej Małecki3, Barbara Katra3, Aleksander Garlicki4, Monika Bociąga-Jasik4, Krzysztof Sładek5, Andrzej Matyja6, Jerzy Wordliczek7, Agnieszka Słowik8, Tomasz Mach9, Katarzyna Krzanowska10, Marcin Krzanowski10, Paweł Stręk11, Piotr Chłosta12, Piotr Hydzik13, Mariusz Korkosz14, Tadeusz Popiela15, Maciej Pilecki16, Artur Gądek17, Marek Rajzer1

1Department of Cardiology, Interventional Electrocardiology and Arterial Hypertension, Jagiellonian University Medical College, Kraków, Poland

2Department of Internal Diseases and Geriatrics, Jagiellonian University Medical College, Kraków, Poland

3Department of Metabolic Diseases and Diabetology, Jagiellonian University Medical College, Kraków, Poland

4Department of Infectious and Tropical Diseases, Jagiellonian University Medical College, Kraków, Poland

5Department of Pulmonology and Allergology, Jagiellonian University Medical College, Kraków, Poland

6Department of General, Oncological, Metabolic, and Emergency Surgery, Jagiellonian University Medical College, Kraków, Poland

7Department of Interdisciplinary Intensive Care, Jagiellonian University Medical College, Kraków, Poland

8Department of Neurology, Jagiellonian University Medical College, Kraków, Poland

9Department of Gastroenterology and Hepatology, Jagiellonian University Medical College, Kraków, Poland

10Department of Nephrology and Dialysis, Jagiellonian University Medical College, Kraków, Poland

11Department of Otolaryngology, Jagiellonian University Medical College, Kraków, Poland

12Department of Urology and Oncological Urology, Jagiellonian University Medical College, Kraków, Poland

13Department of Toxicology, Jagiellonian University Medical College, Kraków, Poland

14Department of Rheumatology and Immunology, Jagiellonian University Medical College, Kraków, Poland

15Department of Diagnostic Imaging Unit, Jagiellonian University Medical College, Kraków, Poland

16Department of Psychiatry for Adults, Children, and Youth, Jagiellonian University Medical College, Kraków, Poland

17Department of Trauma and Orthopedics, Jagiellonian University Medical College, Kraków, Poland

Editorial

by Tadic et al.,

see p. 730

INTRODUCTION

Since the WHO declared coronavirus disease 19 (COVID-19) a global pandemic in March 2020, more than 144 500 000 people worldwide (2 700 000 in Poland) have been affected, with approximately 3 000 000 fatal cases (64 000 in Poland) [1]. COVID-19 is currently one of the leading causes of mortality in many countries, with the number of deaths similar to those from cardiovascular disease (CVD) or cancer [1, 2].

The relation between the severity of the COVID-19 disease course and concomitant CVD is being studied worldwide; however, no large reports from Poland have yet been published. Many studies in other countries have confirmed that patients with pre-existing CVD or cardiovascular risk factors had worse COVID-19 outcomes [3–5]. The aforementioned data come mostly from non-European countries and meta-analyses of small observational studies with heterogeneous definitions of CVD. The frequency of cardiovascular risk factors and CVD among patients hospitalized due to COVID-19 is similar to that observed in the general population, but there is a disproportionately higher frequency of CVD among non-survivors of COVID-19 [3–6]. It is uncertain whether this finding is incidental or secondary to differences in age and sex distribution, or if there is an association between CVD and higher mortality in patients with COVID-19. Another problem is the lack of uniform standards for COVID-19 diagnosis, hospitalization, and therapy between countries. Therefore, differences in therapeutic models for COVID-19 may influence final outcomes, including the association between COVID-19 mortality and CVD. The impact of cardiovascular drugs on the clinical course of COVID-19 has also not yet been determined. At the beginning of the pandemic, the biggest controversies involved angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs/ARBs), as it has been hypothesized that these drugs may increase susceptibility to infection by SARS-CoV-2 and promote viral replication, subsequently worsening the disease course and outcomes [7, 8]. However, this hypothesis has not been confirmed in consecutive studies on mortality in COVID-19 [8–11]. Currently, there are limited data on prognosis for patients with COVID-19 being treated with other cardiovascular drugs such as β-blockers, statins, or antiplatelet therapy.

The purpose of this study was to analyze the impact of CVD and selected cardiovascular drugs on the course of hospitalisation and mortality of patients with COVID-19.

METHODS

We retrospectively studied the medical records of all consecutive patients who were admitted to the University Hospital in Kraków (which was converted temporarily into an infectious disease hospital dedicated to COVID-19 treatment) between March 6, 2020, and October 15, 2020. Patients were admitted from the whole Małopolska Voivodship and neighboring regions. Thus, our study cohort may be assumed to be representative of the whole macro-region. Patients were diagnosed with COVID-19 according to WHO and Polish guidelines with the use of RT-PCR [12–14]. The treatment algorithm for COVID-19 was in accordance with the recommendations of the Polish Association of Epidemiologists and Infectiologists [13, 14]. Patient data were obtained from the Hospital Information System. Cardiovascular risk factors and CVD were identified based on a medical history of prehospital diagnosis and/or treatment and defined according to current European Society of Cardiology guidelines [15]. The analyzed endpoints in our study were: in-hospital mortality from any cause, need for treatment in the intensive care unit (ICU), non-invasive oxygen therapy, mechanical ventilation, length of hospital stay, and length of ICU stay. We also analyzed the use of cardiovascular drugs grouped into drug classes (β-blockers, ACEIs/ARBs, statins, and antiplatelet therapy). The study was approved by the Jagiellonian University Ethics Committee, decision number 1072.6120.278.2020.

Statistical analysis

We used the SAS software, version 9.2 (SAS Institute, Cary, NC, USA), for database management and statistical analysis. The results were expressed as numerical values and percentages for categorical variables and mean values and standard deviation (SD) if parametric (assessed using the Kolmogorov-Smirnov test) or median and interquartile range (IQR) for continuous variables. To test the differences between survivors and non-survivors in means and proportions we applied the t-test and the chi-square statistic, respectively while in the case of nonparametric data, the Wilcoxon Signed Rank test were used. Using multivariable logistic regression, we searched for possible covariates of the likelihood of in-hospital death or the use of oxygen therapy. Then odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were calculated for covariates influencing in-hospital death. To investigate factors determining prolonged hospitalisation (after log-transformation) the linear regression was implemented. We used Kaplan-Meier method to estimate survival curves among patients with established cardiovascular diseases, and the difference between survival curves for patients treated versus untreated with cardiovascular drugs during hospitalization were assessed with the log rank tests. In all analyses a P-value of 0.05 or less was considered statistically significant.

RESULTS

Study population

From March 6, 2020 to October 15, 2020, 1729 patients were admitted to the University Hospital in Kraków due to COVID-19 and completed their hospital course (i.e. from admission to discharge or death). Our study population included 843 women (median age [IQR], 64 [51–77] years) and 886 men (median age [IQR], 62 [50–74] years). In our sample, 950 (55%) patients were over 65 years of age.

The most prevalent cardiovascular risk factor was arterial hypertension (56.1%), followed by hyperlipidemia (27.4%) and diabetes mellitus (25.7%) (Table 1). The most common CVD were coronary artery disease (16.8% of patients), heart failure (10.3%), atrial fibrillation (13.5%), and a history of stroke (8%); 2.8% of patients had a previously implanted cardiac pacemaker or implantable cardioverter defibrillator (Table 1).

The median hospitalization length was 16 days (Table 2).

Admission to the ICU was needed in 194 patients with a median length of ICU stay of 9 days. The overall in-hospital mortality was 12.9% (223 of 1729 patients), and 81% of non-survivors were older than 65 years (180 of 223 patients).

Of 1729 patients, 25.0% were treated with an ACEIs/ARBs, 40.7% with a β-blocker, 15.6% with a statin, and 19.9% with an antiplatelet drug (Table 2).

Comparison of survivors with non-survivors

Tables 1 and 2 summarize the clinical characteristics of survivors and non-survivors, including risk factors and pre-existing diseases, use of medication, and results of medical tests at the time of admission. As compared to survivors, non-survivors were older, predominantly male, and had a higher prevalence of arterial hypertension, diabetes mellitus, coronary artery disease, heart failure, atrial fibrillation, stroke, and use of cardiac pacing.

The frequency of cardiovascular drug use did not differ between survivors and non-survivors, with the exception of ACEIs/ARBs, which were less commonly used by the latter group.

The median hospitalization length was shorter, and the need for ICU admission more common, in non-survivors than in survivors (Table 2). Compared to survivors, patients who died during hospitalization had significantly lower blood pressure and oxygen saturation values, higher heart and respiratory rates, and higher levels of immune-inflammatory and cardiac biomarkers on admission (P ≤0.003).

Predictors of in-hospital death

Based on the multivariable logistic regression model, independent predictors of higher risk of in-hospital death from any cause were: age over 65 years, male sex, pre-existing diabetes mellitus, and a history of heart failure, whereas treatment with ACEIs/ARBs, β-blockers, statins, or antiplatelet therapy corresponded with a lower risk of death (Figure 1).

Figure 1. Multivariable logistic regression analysis

Based on Kaplan–Meier method the survival probability in patients with CVD was substantially higher among those treated with ACEIs/ARBs, β-blockers, or statins (Figure 2).

How to cite: Terlecki M, Wojciechowska W, Klocek M, et al. Association between cardiovascular disease, cardiovascular drug therapy, and in-hospital outcomes in patients with COVID-19: data from a large single-center registry in Poland. Kardiol Pol. 2021; 79(7–8): 773–780, doi: 10.33963/KP.15990.

1. 1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020; 20(5): 533–534, doi: 10.1016/S1473-3099(20)30120-1, indexed in Pubmed: 32087114.
2. 2. Woolf SH, Chapman DA, Lee JH. COVID-19 as the leading cause of death in the United States. JAMA. 2021; 325(2): 123–124, doi: 10.1001/jama.2020.24865, indexed in Pubmed: 33331845.
3. 3. Richardson S, Hirsch JS, Narasimhan M, et al. the Northwell COVID-19 Research Consortium. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020; 323(20): 2052–2059, doi: 10.1001/jama.2020.6775, indexed in Pubmed: 32320003.
4. 4. Inciardi RM, Adamo M, Lupi L, et al. Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy. Eur Heart J. 2020; 41(19): 1821–1829, doi: 10.1093/eurheartj/ehaa388, indexed in Pubmed: 32383763.
5. 5. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020; 395(10229): 1054–1062, doi: 10.1016/S0140-6736(20)30566-3, indexed in Pubmed: 32171076.
6. 6. Grasselli G, Zangrillo A, Zanella A, et al. COVID-19 Lombardy ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020; 323(16): 1574–1581, doi: 10.1001/jama.2020.5394, indexed in Pubmed: 32250385.
7. 7. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020; 8(4): e21, doi: 10.1016/S2213-2600(20)30116-8, indexed in Pubmed: 32171062.
8. 8. Kreutz R, Algharably EAH, Azizi M, et al. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19. Cardiovasc Res. 2020; 116(10): 1688–1699, doi: 10.1093/cvr/cvaa097, indexed in Pubmed: 32293003.
9. 9. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in covid-19. N Engl J Med. 2020; 382(25): e102, doi: 10.1056/NEJMoa2007621, indexed in Pubmed: 32356626.
10. 10. Zhong Y, Zhao L, Wu G, et al. Impact of renin-angiotensin system inhibitors use on mortality in severe COVID-19 patients with hypertension: a retrospective observational study. J Int Med Res. 2020; 48(12): 300060520979151, doi: 10.1177/0300060520979151, indexed in Pubmed: 33322988.
11. 11. Mancia G, Rea F, Ludergnani M, et al. Renin-angiotensin-aldosterone system blockers and the risk of covid-19. N Engl J Med. 2020; 382(25): 2431–2440, doi: 10.1056/NEJMoa2006923, indexed in Pubmed: 32356627.
12. 12. World Health Organization. Laboratory testing for coronavirus disease (COVID-19) in suspected human cases. Interim guidance 19 March 2020. https://apps.who.int/iris/bitstream/handle/10665/331501/WHO-COVID-19-laboratory-2020.5-eng.pdf?sequence=1&isAllowed=y (February 16, 2021).
13. 13. Flisiak R, Horban A, Jaroszewicz J, et al. Management of SARS-CoV-2 infection: recommendations of the Polish Association of Epidemiologists and Infectiologists as of March 31, 2020. Pol Arch Intern Med. 2020; 130(4): 352–357, doi: 10.20452/pamw.15270, indexed in Pubmed: 32231173.
14. 14. Flisiak R, Horban A, Jaroszewicz J, et al. Management of SARS-CoV-2 infection: recommendations of the Polish Association of Epidemiologists and Infectiologists. Annex no. 1 as of June 8, 2020. Pol Arch Intern Med. 2020; 130(6): 557–558, doi: 10.20452/pamw.15424, indexed in Pubmed: 32529822.
15. 15. European Society of Cardiology. Guidelines and Scientific Documents. www.escardio.org (February 16, 2021).
16. 16. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020; 94: 91–95, doi: 10.1016/j.ijid.2020.03.017, indexed in Pubmed: 32173574.
17. 17. Hessami A, Shamshirian A, Heydari K, et al. Cardiovascular diseases burden in COVID-19: systematic review and meta-analysis. Am J Energ Med. 2020: S0735-6757(20)30908-6, doi: 10.1016/j.ajem.2020.10.022, indexed in Pubmed: 33268238.
18. 18. Mueller AL, McNamara MS, Sinclair DA. Why does COVID-19 disproportionately affect older people? Aging (Albany NY). 2020; 12(10): 9959–9981, doi: 10.18632/aging.103344, indexed in Pubmed: 32470948.
19. 19. Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020; 41(19): 1810–1817, doi: 10.1093/eurheartj/ehaa373, indexed in Pubmed: 32388565.
20. 20. Lippi G, Wong J, Henry BM. Hypertension in patients with coronavirus disease 2019 (COVID-19): a pooled analysis. Pol Arch Intern Med. 2020; 130(4): 304–309, doi: 10.20452/pamw.15272, indexed in Pubmed: 32231171.
21. 21. Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease, part 1: the epidemiology and risk factors. Circ Res. 2017; 121(6): 677–694, doi: 10.1161/CIRCRESAHA.117.308903, indexed in Pubmed: 28860318.
22. 22. Barron E, Bakhai C, Kar P, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020; 8(10): 813–822, doi: 10.1016/S2213-8587(20)30272-2, indexed in Pubmed: 32798472.
23. 23. Ponikowski P, Voors AA, Anker SD, et al. ESC Scientific Document Group. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; 37(27): 2129–2200, doi: 10.1093/eurheartj/ehw128, indexed in Pubmed: 27206819.
24. 24. Holman N, Knighton P, Kar P, et al. Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study. Lancet Diabetes Endocrinol. 2020; 8(10): 823–833, doi: 10.1016/S2213-8587(20)30271-0, indexed in Pubmed: 32798471.
25. 25. Tan K, Harazim M, Tang B, et al. The association between premorbid beta blocker exposure and mortality in sepsis-a systematic review. Crit Care. 2019; 23(1): 298, doi: 10.1186/s13054-019-2562-y, indexed in Pubmed: 31484576.
26. 26. Al-Qadi MO, Kashyap R. Effect of chronic beta blockers use on sepsis-related acute respiratory distress syndrome. Am J Respir Crit Care Med. 2015; 191: A1602.
27. 27. Vasanthakumar N. Beta-adrenergic blockers as a potential treatment for COVID-19 patients. Bioessays. 2020; 42(11): e2000094, doi: 10.1002/bies.202000094, indexed in Pubmed: 32815593.
28. 28. Chow JH, Khanna AK, Kethireddy S, et al. Aspirin use is associated with decreased mechanical ventilation, intensive care unit admission, and in-hospital mortality in hospitalized patients with coronavirus disease 2019. Anesth Analg. 2021; 132(4): 930–941, doi: 10.1213/ANE.0000000000005292, indexed in Pubmed: 33093359.
29. 29. Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395(10234): 1417–1418, doi: 10.1016/S0140-6736(20)30937-5, indexed in Pubmed: 32325026.
30. 30. Godino C, Scotti A, Maugeri N, et al. Antithrombotic therapy in patients with COVID-19? Rationale and evidence. Int J Cardiol. 2021; 324: 261–266, doi: 10.1016/j.ijcard.2020.09.064, indexed in Pubmed: 33002521.