key: cord-0854694-6v4jj4rj
authors: Rubini-Costa, Ricardo; Francisco, Bermudez‐Jimenez; Rivera-López, Ricardo; Sola-García, Elena; Nagib-Raya, Hadi; Moreno-Escobar, Eduardo; López-Zúñiga, Miguel Ángel; Briones-Través, Adela; Sanz-Herrera, Francisco; Sequí-Sabater, Jose Miguel; Romero-Cabrera, Juan Luis; Maíllo-Seco, Javier; Fernández-Vázquez, Felipe; Rivadeneira-Ruiz, María; López-Valero, Lucas; Gómez-Navarro, Carlos; Aparicio-Gómez, Jose Antonio; López, Miguel Álvarez; Tercedor, Luis; Molina-Jiménez, María; Macías-Ruiz, Rosa; Jiménez-Jáimez, Juan
title: Prevalence of bleeding secondary to anticoagulation and mortality in patients with atrial fibrillation admitted with SARS-CoV-2 infection
date: 2021-07-15
journal: Med Clin (Barc)
DOI: 10.1016/j.medcli.2021.06.015
sha: 25b062755d1acf076f7230cc781cd99beca997c6
doc_id: 854694
cord_uid: 6v4jj4rj

Introduction and purpose: Atrial fibrillation (AF) is common in patients admitted with severe COVID-19. However, there is limited data about the management of chronic anticoagulation therapy in these patients. We assessed the anticoagulation and incidence of major cardiovascular events in hospitalized patients with AF and COVID-19. Methods: We retrospectively investigated all consecutive patients with AF admitted with COVID-19 between March and May 2020 in 9 Spanish hospitals. We selected a control group of non-AF patients consecutively admitted with COVID-19. We compared baseline characteristics, incidence of major bleeding, thrombotic events and mortality. We used propensity score matching (PSM) to minimize potential confounding variables, as well as a multivariate analysis to predict major bleeding and death. Results: 305 patients admitted with AF and COVID-19 were included. After PSM, 151 AF patients were matched with 151 control group patients. During admission, low-molecular-weight heparin was the principal anticoagulant and the incidence of major bleeding and mortality were higher in the AF group [16(10.6%) vs 3(2%), p=0.003; 52(34.4%) vs 35(23.2%), p=0.03, respectively]. The multivariate analysis showed the presence of AF as independent predictor of in-hospital major bleeding and mortality in COVID-19 patients. In AF group, a secondary multivariate analysis identified high levels of D-dimer as independent predictor of in-hospital major bleeding. Conclusions: AF patients admitted with COVID-19 represent a population at high risk for bleeding and mortality during admission. It seems advisable to individualize anticoagulation therapy during admission, considering patient specific bleeding and thrombotic risk.

The study protocol was approved by the Local Ethics Committee of the coordinator centre.

None.

The authors declare that there is no conflict of interest Authors contribution All of the authors had access to the data and participated in the preparation of the manuscript. 

Retrospectivamente, se identificaron todos los pacientes con FA ingresados por COVID-19 entre marzo y mayo de 2020, en 9 hospitales españoles. Se seleccionó un grupo control de pacientes ingresados consecutivamente por COVID-19 sin FA. Se compararon las características basales, incidencia de hemorragias mayores, eventos trombóticos y mortalidad. Para reducir potenciales factores de confusión se realizó un emparejamiento por puntuación de propensión (EPP), así como un análisis multivariante para predecir hemorragia mayor y mortalidad.

Se incluyeron 305 pacientes con FA ingresados por COVID-19. Tras el EPP, 151 pacientes con FA fueron emparejados con 151 controles. Durante el ingreso, la heparina de bajo peso molecular fue el principal anticoagulante y la incidencia de hemorragia mayor y mortalidad fue mayor en el grupo de FA [16(10. However, there is limited data about the management of chronic anticoagulation therapy in these patients. We assessed the anticoagulation and incidence of major cardiovascular events in hospitalized patients with AF and COVID-19.

We retrospectively investigated all consecutive patients with AF admitted with COVID-19 between March and May 2020 in 9 Spanish hospitals. We selected a control group of non-AF patients consecutively admitted with COVID-19. We compared baseline characteristics, incidence of major bleeding, thrombotic events and mortality. We used propensity score matching (PSM) to minimize potential confounding variables, as well as a multivariate analysis to predict major bleeding and death. Several studies have repeatedly suggested that pre-existing cardiovascular comorbidities are associated with a worse prognosis COVID-19 [2] [3] [4] [5] . Specifically, atrial fibrillation (AF) has been reported as a common condition in patients admitted with severe forms of COVID-19 3,6,7 . It has been suggested that AF might be an independent predictor of mortality for these patients 8 Certainly, the systematic anticoagulation with heparin is the most common strategy adopted by the physicians in this clinical scenario. However, there are not data regarding the different anticoagulation therapies in these patients and the incidence of potential outcomes, especially, thrombotic and major bleedings.

The primary aim of this study was to assess the incidence haemorrhagic and thrombotic events, mortality and the anticoagulation regimen in a multicentric cohort of patients with AF admitted with COVID-19. In addition, we pretend to identify clinical or analytical independent predictors of major bleeding and mortality during admission.

A case-control multicentric study was performed in 9 tertiary referral hospitals from Spain. All patients with previous or newly diagnosed AF admitted with confirmed SARS-CoV-2 infection between March 1 st and May 31 st , 2020, were retrospectively identified. Confirmed SARS-CoV-2 infection was defined as a positive nasopharyngeal polymerase chain reaction and/or positive serological test. Patients without a previous diagnosis of AF were considered as newly diagnosed AF and all were confirmed by ECG at admission. We included a control group of COVID-19 patients admitted during the same period without AF. The control group was obtained from the admitted COVID-19 patient database of the coordinator centre, which was provided by the Medical Records Department, and the patients were consecutively included by admission date until reaching the same number of AF group, 305 patients. Patients were followed up a mean of 7±1.6 months after hospitalization, by revision of medical digital records or by telephone contact when necessary. The Local Ethics Committee of the coordinator centre approved the study protocol.

Baseline characteristics, hospitalization data and outcomes during admission and follow-up were analysed. Local electronic medical records served as source data, which were extracted by each centre researcher and centralized to the study coordinator in an anonymized database. The primary outcome of this study was the incidence of in-hospital major bleeding. Key secondary outcomes were in-hospital mortality and incidence of recorded during follow-up were outpatient mortality, major haemorrhage and thromboembolic events (VTE and stroke).

Numerical variables are expressed as mean and standard deviation or, for non-normally distributed variables, as median [interquartile range].

Categorical variables are expressed as absolute and relative frequencies and were contrasted with the Pearson's chi-square test or Fisher's exact test in cases where applicability conditions were not met. For the quantitative variables, the Student's t-test was used for independent samples and the Mann-Whitney test was used for those variables with a non-normal distribution.

A p value of <0.05 was considered statistically significant. Propensity score matching (PSM) was utilized to control for potential confounding variables. In order to analyse the primary outcome and predictors of it, we performed both multivariate logistic regressions for in-hospital major bleeding: first, in all the COVID-19 patients; and second, only in the AF cohort. In addition, we conducted a multivariate analysis for the key secondary outcome in-hospital mortality in COVID-19 patients. All the multivariate logistic regressions were performed before the PSM. Baseline differences (p<0.10) were introduced in the regression model. Kaplan-Meier survival analysis was performed for mortality during follow-up in the discharged patients and compared with the Log-Rank test. Individuals who experienced the event were censored at their event time. All analyses were conducted using SPSS Statistics (IBM SPSS 24.0, Armonk, NY, USA).

The primary outcome in-hospital major bleeding occurred in 37 (6%) patients: 30 (9.8%) and 7 (2.3%) in the AF and control groups, respectively as well as male sex, older age, chronic kidney disease (CKD), D-dimer and absence of anticoagulation during admission (Table 4 ). However, the presence of major bleeding during admission as well as the anticoagulant therapy with LMWH were not independently associated with the increased mortality in AF patients.

Finally, there were no differences between both groups in the other key secondary outcomes of stroke and VTE events during admission. Nevertheless, there was a trend towards a lower incidence in AF group (Figure 1 ).

Respectively, 189 (62%) and 256 (83.9%) patients with and without AF were discharged after the COVID-19 admission. In the AF group, DOAC therapy was the most frequent anticoagulant prescribed at discharge (45.7%), followed by AVK (14.5%) and LMWH (9.6%); up to 30.2% were not prescribed any anticoagulant. In the control group, most of the patients were not anticoagulated after discharge (97.3%).

During a mean follow-up period of 7±1.6 months, incidence of outpatient major bleeding was similar in the AF group compared with control group (4.8% vs 2.7%, p=0.256), as well as stroke (1.6% vs 1%, p=0.65) and VTE events (0% vs 0.8%, p=0.51). Interestingly, a significantly higher outpatient mortality rate was still present among patients with AF ( Figure 2B) . A secondary multivariate analysis was performed in the AF cohort for 6-month mortality, showing the male sex, age, dependency for basic activities of daily living and CKD as independent predictors of higher mortality in AF patients (Table A.6) .

Patients with previous or newly diagnosed AF, admitted with SARS-CoV-2 infection, present an increased risk of major bleeding, as well as an extremely high rate of mortality during admission and at follow up after discharge, with a low rate of thromboembolic events, which was similar to the control group.

These worst outcomes seem to be independent of previous clinical status, cardiovascular risk factors or prior cardiovascular and bleeding events.

Although in our study we describe a high incidence of major bleeding in patients with AF, we did not identify a statistical association between any anticoagulant and major bleeding events. However, we recognize that a relevant proportion of these patients received therapeutical doses of LMWH, with a residual use of DOACs. In fact, we did not observe major bleeding episodes in patients treated during admission with DOACs, although significant differences could not be demonstrated due to the retrospective and not randomized design of our study.

Regarding mortality, here we suggest that AF involves an independent poor prognosis in COVID-19 patients in the same way to other recent studies 8, 11 . However, due to the previously mentioned limitations, we cannot confirm if the high proportion of major bleeding observed in AF patients with COVID-19 is related to their high mortality rate.

Several studies have been reported AF as a frequent condition in patients admitted with severe forms of COVID-19 3,6-8 and it has lately been associated with an increased risk of unfavourable outcomes in COVID-19 patients 11 . A remarkable finding of our research was that the absence of anticoagulation during admission was independently associated with a higher mortality in patients with COVID-19, but not with thrombotic events. Although a proper anticoagulation and a lower mortality in COVID-19 patients has been established before [12] [13] [14] , our data suggest that some of these deaths might be attributable to an advanced COVID-19 disease or extreme fragility that prevent physicians from anticoagulating them. been previously named as bridging therapy and is associated with higher risk of bleeding with no significant difference in mortality or thrombotic events, especially in the setting of perioperative invasive procedures [15] [16] [17] [18] .

In line with this information, here we describe a high incidence of major bleeding in AF patients receiving full LMWH dosing during admission, before and after controlling for confounders with PSM, with low levels of thrombotic events. In contrast, control group patients without AF showed lower incidence of major bleeding before and after PSM, with a higher proportion of patients receiving a prophylactic LMWH dose.

Another important finding of our study was the independent association of AF with in-hospital major bleeding in COVID-19 patients, something that has not been previously described. This novel finding should be taken into account and it suggests that precise management of anticoagulation might reduce the risk of bleeding. Additionally, we observed that high levels of D-dimer were strongly associated with high risk of major bleeding in AF patients.

Interestingly, a common clinical approach in COVID-19 patients with elevated D-dimer levels is to intensify the anticoagulant doses of heparin, something that might aggravate haemorrhagic complications, especially in AF patients.

DOACs have repeatedly been found to be safer and more effective than VKA antagonists in the treatment of nonvalvular AF, especially in older patients 19, 20 . Taking these data into account, and the low and similar rate of thromboembolic events amongst our study groups, a change in the anticoagulation strategy in the COVID-19 patients with AF might be considered, giving a more important role to DOACs. Moreover, most of the drugs with potential interaction with DOACs have been proven to be ineffective against COVID-19, so are used less and less.

Al-Samkari, et al. 21 analysed the rate of bleeding and thrombotic complications in a large multicentre cohort of critically ill and noncritically ill COVID-19 patients, showing a major bleeding rate of 2.3%. Here, we describe a higher incidence of major bleeding events among patients with AF. Although the control group patients of the present study were very similar to the patients of their study, certainly, patients with AF in our study were older, had more comorbidities and the majority of them were treated with LMWH at therapeutic dose, than those of Al-Samkari study. All these facts are likely related with this higher bleeding rate. Anyway, these potential confounding variables were controlled with PSM; hence, the anticoagulation regimen seems to be playing an important role.

In summary, patients with prior or newly diagnosed AF admitted with COVID-19 represent a population at high risk for major bleeding and mortality during the hospitalization. It seems critical to individualize anticoagulation therapy during admission, considering patient specific risks for bleeding and VTE.

The non-randomized nature of the study limits the conclusions about the influence of the anticoagulation therapy and outcomes. This bias is partially controlled with propensity score matching study that have achieved very similar study groups. Larger and randomized studies are required to better clarify this issue. Data on the severity of the SARS-CoV-2 infection were not fully collected.

The high mortality rate is in many cases more due to the COVID-19 infection rather than cardiovascular events. However, this is similar for both PSM groups and differences related to the AF condition are still present. 

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