key: cord-0731455-e4m6bm7z
authors: Brouns, Steffie H.; Brüggemann, Renée; Linkens, Aimée; Magdelijns, Fabienne J.; Joosten, Hanneke; Heijnen, Ron; ten Cate‐Hoek, Arina J.; Schols, Jos; ten Cate, Hugo; Spaetgens, Bart
title: Mortality and the use of Antithrombotic Therapies among Nursing Home Residents with COVID‐19
date: 2020-07-07
journal: J Am Geriatr Soc
DOI: 10.1111/jgs.16664
sha: 0714f3278cd3b27f7081e1a9b88eeedb6b402578
doc_id: 731455
cord_uid: e4m6bm7z

BACKGROUND/OBJECTIVES: Nursing home (NH) residents are a vulnerable population, susceptible to respiratory disease outbreaks such as coronavirus disease 2019 (COVID‐19). Poor outcome in COVID‐19 is at least partly attributed to hypercoagulability, resulting in a high incidence of thromboembolic complications. It is unknown whether commonly used antithrombotic therapies may protect the vulnerable NH population with COVID‐19 against mortality. This study aimed to investigate whether the use of oral antithrombotic therapy (OAT) was associated with a lower mortality in NH residents with COVID‐19. DESIGN: A retrospective case‐series SETTING: 14 NH facilities from the NH organization Envida, Maastricht, the Netherlands PARTICIPANTS: 101 NH residents with COVID‐19 were enrolled. MEASUREMENTS: The primary outcome was all‐cause mortality. The association between age, sex, comorbidity, OAT, and mortality was assessed using logistic regression analysis. RESULTS: Overall mortality was 47.5% in NH residents from 14 NH facilities. Age, comorbidity and medication use were comparable among NH residents who survived and who died. OAT was associated with a lower mortality in NH residents with COVID‐19 in the univariable analysis (OR 0.89 95%CI 0.41‐1.95). However, additional adjustments for sex, age and comorbidity, attenuated this difference. Mortality in males was higher compared with female residents (OR 3.96 (95%CI 1.62‐9.65)). Male residents who died were younger compared to female residents (82.2 (SD 6.3) vs. 89.1 years (SD 6.8), p<.001). CONCLUSION: NH residents in the 14 facilities we studied were severely affected by the COVID‐19 pandemic, with a mortality of 47.5%. Male NH residents with COVID‐19 had worse outcomes than females. We did not find evidence for any protection against mortality by OAT, necessitating further research into strategies to mitigate poor outcome of COVID‐19 in vulnerable NH populations. This article is protected by copyright. All rights reserved.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the disease it causes, coronavirus disease 2019 (COVID-19), currently places a tremendous burden on public life and health care worldwide. It is associated with very poor outcome in certain high-risk populations and has decimated nursing home (NH) populations in several parts of the world. NHs are known to be especially vulnerable to respiratory disease outbreaks, such as COVID-19, resulting in substantial morbidity and mortality. 1,2 Furthermore, it is likely that distinct risk factors determine the poor outcome in NH populations relative to the general population. Most notably are an increased susceptibility to infection due to immune dysfunction, and preexisting hyperinflammation attributed to the ageing process leading to a higher risk of adult respiratory distress syndrome 3, 4 , and a higher proportion of comorbidities and reduced pulmonary reserves. 5 Even though NH residents are among the most severely affected populations by the current pandemic, they are severely underrepresented in the literature on COVID-19. To date, only one study has reported on outcome in older patients (defined as 60 years and older) with COVID-19. 6 high mortality rate. 8 The origin of this profound thrombotic tendency appears to comprise a complex interplay of several hemostatic and inflammatory mechanisms. 9, 10 In the Dutch NH population, a relatively large part of the population is using some form of oral antithrombotic therapy (OAT) for (secondary) prevention of cardiovascular or venous thromboembolic events (VTE), such as anticoagulant therapy (AT) or antiplatelet therapy (APT). 11 In combination with their high event rate, the Dutch NH population constitutes an important entity to test the hypothesis whether pre-existing use of AT or APT is associated with a lower mortality in NH residents with COVID-19.

In view of these considerations, the objective of the current study was to investigate whether the use of OAT was associated with lower mortality in NH residents with COVID-19.

A retrospective case-series of 101 NH residents with COVID-19 was collected at 14 NH facilities from the NH organization Envida between March 20 th 2020 and May 1 st 2020 in Maastricht, the Netherlands. The NH facilities are both small and large scale homes, ranging from 14 (smallest) to 150 (largest) beds, adding up to a total capacity of 727 beds, which were all occupied. On most locations, medical as well as psychogeriatric wards are present. This article is protected by copyright. All rights reserved.

NH residents with COVID-19, as confirmed by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) assay of SARS-CoV2-mRNA in nasal or pharyngeal swabs, or those with symptoms, such as fever, respiratory complaints (cough, sneezing, sore throat), but also malaise, muscle aches, headache and gastrointestinal symptoms and a disease course consistent with COVID-19 (rapid respiratory deterioration over several hours, or opposite, lingering, persistent illness with later deterioration) in absence of an alternative diagnosis were enrolled. In all facilities, according to directives from the area health organization (GGD), after 2 residents per location had been diagnosed with COVID-19 based on a positive rRT-PCR, subsequent residents with symptoms consistent with COVID-19 were no longer tested, due to limited testing capacity. These residents were considered as COVID-19 highly-suspected and included in the current analysis. Overall, COVID-19 was rRT-PCR confirmed in 66% of the residents, and 34% were considered COVID-19 highly-suspected.

Age, sex, NH facility, medical history, medication use, and the result of the SARS-CoV2-mRNA rRT-PCR were retrospectively gathered from the patient records. In addition, we retrieved additional data on type and indication for OAT, vital status and date of death.

Based on the medical history, the Charlson Comorbidity Index (CCI) was calculated to assess the comorbidity levels of the residents. AT was divided into vitamin K antagonists (VKA), direct oral anticoagulants (DOAC) and APT. The primary outcome of this study is all-cause mortality. This article is protected by copyright. All rights reserved.

Statistical analyses were performed using SPSS version 25.0. The characteristics of the residents were compared with a Chi-square test for categorical variables, and unpaired T-test or Mann Whitney U test for numerical variables which ever was appropriate. In order to estimate the effect of OAT (VKA, DOAC and APT were also tested separately) on mortality, univariable and multivariable logistic regression analyses were performed, and presented as odds ratios (OR) with 95% confidence intervals (CI). Potential confounders assessed included age, sex, CCI, other medication and rRT-PCR COVID-19 result. Multivariable analysis included all variables considered clinically relevant. A p-value <.05 was considered statistically significant.

To determine whether associations with mortality were underestimated by including individuals without rRT-PCR proven COVID, a sensitivity analysis was performed excluding these residents from the analyses on mortality and OAT.

In total, 101 NH residents, from 14 NH facilities with a total capacity of 727 beds, were included in this case series. Prevalence of COVID-19 varied from 3.3% to 28.8% in the different facilities. Overall, the NH residents had a mean age of 85 years (SD 8.1), and 32.7% was male. The mean CCI was 2.0 (SD 1.4), and mean medications used was 8.2 (SD 3.8) (Table 1) . Overall, 51.5% received OAT, of which 18% received either VKA or DOAC, and 34% received APT. Table 2 shows the characteristics of the NH residents with COVID-19 confirmed by rRT-PCR.

COVID-19 highly-suspected NH residents used on average fewer medications (mean This article is protected by copyright. All rights reserved. Accepted Article 6.5 vs. 9.0, p=.001) and were more often diagnosed with dementia (100% vs. 49.3%, p<.001) compared to NH residents with rRT-PCR confirmed COVID-19 (Supplementary Table S1 ).

Overall, 47.5% of the NH residents with COVID-19 died. Demographic characteristics were similar between survivors and non-survivors in the total population (Table 1) , while in the population with rRT-PCR confirmed COVID-19 non-survivors were more often male (Table 2) .

We found no obvious associations between age, COVID-19 rRT-PCR, CCI, hypertension, other medication and mortality. Additionally, OAT was associated with lower mortality in NH residents with COVID-19 in the univariable analysis (OR 0.89 95%CI 0.41-1.95). However, this effect attenuated in the multivariable analysis after adjustment for age, sex, CCI, and hypertension (Table 3) .

Male sex was associated with considerably higher mortality compared with female residents (OR3.96 (95%CI 1.62-9.65)). This association did not attenuate after adjustment for age, OAT, CCI and hypertension (OR 4.79 (95%CI 1.74-13.18).

Moreover, male residents with COVID-19 who died were relatively younger compared with those who recovered (82.2 (SD 6.3) vs. 85.2 years (SD 4.9)) and compared to female residents who died (89.1 (SD 6.3)) years, p<.001) (Figure 1.) .

We found similar results when we excluded the COVID-19 highly-suspected residents. (Supplementary Table S2 ).

This article is protected by copyright. All rights reserved.

This study did not demonstrate any obvious benefit from the use of OAT in vulnerable NH residents on mortality from COVID19 infection. Strikingly, almost half of the population had died within two weeks after the diagnosis of COVID19 was made.

This was particularly the case for male residents, and this risk was not attenuated after adjustment for OAT as well as other potential confounders.

A protective effect of OAT was postulated based on current literature showing a high rate of VTE, as well as ischemic stroke. 7,12 APT provides some protection against VTE, although it is not a cornerstone treatment in the prevention of VTE.

Therefore, since the majority of OAT comprised of APT, the protective effect of OAT may have been insufficient in these patients with such high mortality. The slight but nonsignificant benefit of OAT in the univariable analysis might theoretically be related to the use of oral anticoagulants, but the fraction of AT users may have been too small and the disease burden too high, to reveal any effect on mortality.

Although COVID-19 is associated with hypercoagulability and a strikingly high incidence of thromboembolic complications in other, predominantly ICU, populations 7 , mortality may not be greatly reduced by expanding the prescription of OAT in the NH population to protect this vulnerable population against excess mortality when a COVID-19 outbreak in a NH becomes apparent. However, retrospective analyses in hospital settings suggest a possible benefit of the use of low molecular weight heparin/heparin on COVID-19-related mortality. 13, 14 Given the fact that most patients in this study on OAT used an antiplatelet agent, the addition of LMWH thromboprophylaxis may therefore be of benefit, and should be investigated in the NH setting. An important consideration is that we also did not find evidence for a negative impact of OAT on mortality, suggesting the relative safety of OAT in the context of COVID-19. This article is protected by copyright. All rights reserved.

COVID-19 is a very heterogenic disease, and may therefore run a different course in NH residents compared to other populations. This is substantiated by the alarming proportion of residents that died after COVID-19 diagnosis. These residents might die because of respiratory failure due to the viral pneumonia itself, while patients with a larger pulmonary reserve, and have less competing risk to die as a direct result of the pulmonary disease, allowing for a higher event rate of fatal VTE.

To the best of our knowledge, this is the first study to report a mortality of 47.5% in NH residents with COVID-19, residented in 14 NH facilities. Male residents had a particularly high mortality, which is consistent with previous studies. 15, 16 In our current study, we found no confounding effect by hypertension or CCI. Higher previous smoking rates, higher BMI and more subclinical atherosclerosis are possible candidates that may explain this association, but these factors could not be recorded in the current study. As our study population consisted solely of older nursing home residents, a higher mortality rate was to be expected, although the excessively high mortality emphasizes the vulnerability of this population. Moreover, disease presentation is often atypical, which may result in underestimation of disease severity and delayed diagnosis of COVID-19 17 , while subsequent implementation of infection prevention is compromised. 2 Our study offers important insights into the tremendous impact of COVID-19 on NH residents, a vulnerable population in which information on outcomes is currently limited. Nevertheless, our study has several limitations that warrant careful consideration, such as its retrospective design and observational nature.

Furthermore, we investigated mortality in 14 NH facilities in the southern region of the Netherlands. Even though, we were not able to estimate conclusive prevalence figures due to limited testing capacity, this region appeared to be one of the country's This article is protected by copyright. All rights reserved.

Accepted Article most severely affected. Therefore, our findings may not be generalizable to all NHs.

Next, as mentioned before, older patients and in particular NH residents who are frail and have multiple chronic conditions, often have an atypical disease presentation and therefore NH residents with COVID-19 could have been missed.

However, the opposite is also true, despite having typical symptoms, we might have included residents without COVID-19 but with, for example, influenza albeit flu season was largely over.

Further, residual confounding is likely as we had no access to clinical variables such as pack-years smoked, body weight index and systolic blood pressure.

Additionally, not all residents had a rRT-PCR confirmed diagnosis of COVID-19 and although the sensitivity analysis revealed no differences, this may have resulted in underestimation of the effect that OAT may have on mortality due to possible misclassification. Also, none of the residents had been assessed for occurrence of VTE. We therefore cannot exclude that OAT prevented VTE and we may have missed effects on mortality due to limited statistical power.

In conclusion, our case-series demonstrates that NH residents are severely affected by the COVID-19 pandemic, with a mortality of 47.5%. In particular, male NH residents with COVID-19 appear to have a poor outcome. We did not find evidence for any protection against mortality by OAT. Therefore, additional studies evaluating compressive stockings and LMWH are urgently needed in NH residents, as an approach to reduce mortality by COVID-19 in this vulnerable population. This article is protected by copyright. All rights reserved. rRT-PCR = real-time reverse-transcriptase polymerase chain reaction; CCI = Charlson comorbidity index; OAT = oral antithrombotic therapy; OR = odds ratio; CI = confidence interval; OR adj. = adjusted odds ratio. * adjusted for age, sex, COVID-19 rRT-PCR result, CCI, hypertension, medication use, and OAT.

Epidemiology of Covid-19 in a Long-Term Care Facility

Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility

Inflammaging: a new immunemetabolic viewpoint for age-related diseases

Mechanisms and consequences of oxidative stress in lung disease: therapeutic implications for an aging populace

The aging lung

This article is protected by copyright. All rights reserved

Risk Factors for Mortality in 244 Older Adults With COVID-19 in Wuhan, China: A Retrospective Study

Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Diagnosis, prevention, and treatment of thromboembolic complications in COVID-19: Report of the national institute for public health of the Netherlands

Coagulation abnormalities and thrombosis in patients with COVID-19

Prevalence of Preventive Cardiovascular Medication Use In Nursing Home Residents. Room for Deprescribing? The SHELTER Study

Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical characteristics of coronavirus disease 2019 in China

Typically Atypical: COVID-19 Presenting as a Fall in an Older Adult

Hoek, ten Cate, Spaetgens.All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication.

This article is protected by copyright. All rights reserved.Accepted Article