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Protective role of chronic treatment with direct oral anticoagulants in elderly patients affected by interstitial pneumonia in COVID-19 era

      Highlights

      • Elderly COVID-19 patients with chronic heart disease have a worse prognosis.
      • Cardio-active treatment has a protective role in COVID-19 pneumonia.
      • Anticoagulant chronic assumption in elderly with heart disease reduce mortality.

      Keywords

      ACEIs,
      angiotensin-converting enzyme;
      ARBs,
      angiotensin II receptor blockers;
      BMI
      body mass index;
      COVID-19,
      coronavirus disease 2019;
      DAPT,
      dual antiplatelet therapy;
      DOAC,
      direct oral anticoagulants;
      SARS-CoV-2,
      severe acute respiratory syndrome coronavirus 2.
      Since December 2019, coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing global health emergency [
      • Guo T.
      • Fan Y.
      • Chen M.
      • et al.
      Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).
      ]. Elderly patients affected by chronic heart disease showed a high mortality risk in the setting of COVID-19 interstitial pneumonia [
      • Geng Y.J.
      • Wei Z.Y.
      • Qian H.Y.
      • et al.
      Pathophysiological characteristics and therapeutic approaches for pulmonary injury and cardiovascular complications of coronavirus disease 2019.
      ,
      • Wu Z.
      • McGoogan J.M.
      Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention.
      ]. This study aimed to assess if pharmacological cardio-active treatment reduce mortality risk in the setting of COVID-19 interstitial pneumonia.
      We retrospectively enrolled elderly patients affected by COVID-19 interstitial pneumonia between February 25, 2020, and April 20, 2020. All the patients were affected by chronic heart disease (CHD) and they were followed in the divisional outpatient clinic of the Cardiology Unit of the Policlinico of Modena Hospital. The follow-up ended on May 5, 2020. The only endpoint of the study was all-cause mortality. This study was approved by the local Ethical Committee (protocol number AOU 0012597).
      Continuous variables were expressed as mean ± one SD or median (range) values; and categorical data as percentages or proportions. All dichotomous variables were compared for the study outcome utilizing the χ2 test; and continuous variables using analysis of variance or Mann-Whitney U test, as appropriate. Survival probabilities were estimated with the Kaplan-Meier method and survival curves were plotted and compared between groups using the log-rank test. Multivariate Cox regression model was utilized to determine the independent risk factors for mortality. P < 0.05 was statistically significant.
      The entire population counted 70 patients, aged > 70 years (median age: 79 years; range: 70–92), with known CHD and a diagnosis of SARS-Cov-2 infection confirmed by nasopharyngeal swab. The majority of our patients were affected by bilateral (n = 58; 82.8%) interstitial pneumonia, confirmed by chest x-ray and/or chest CT images.
      During follow-up, 31 patients/70 (44.3%) died. Those who died were older, showed more cardiovascular risk factors (especially hypertension, obesity, and diabetes) and coronary or cerebro-vascular disease (Table 1).
      Table 1Baseline characteristics of the study population.
      parameterDiedSurvivedp
      n31 (44.3%)39 (55.7%)
      Age, years, median (range)85 (74–92)73 (70–85)< 0.0001
      Risk factors for cardiovascular diseases
      Male gender61.3% (n = 19)41.0% (n = 16)0.01
      Hypertension74.2% (n = 23)51.3% (n = 20)0.01
      type II Diabetes Mellitus32.2% (n = 10)20.5% (n = 8)0.03
      Hypercolesterolemia41.9% (n = 13)43.6% (n = 17)0.5
      Obesity (BMI > 30 Kg/m2)22.6% (n = 7)15.4% (n = 6)0.04
      Pre-existing chronic heart diseases
      Coronary artery disease51.6% (n = 16)46.7% (n = 18)0.06
      Cerebro-vascular disease12.9% (n = 4)10.2% (n = 4)0.09
      Aortic or Mitral valvulopathy16.1% (n = 5)15.4% (n = 6)0.1
      Chronic heart failure48.4% (n = 15)46.7% (n = 18)0.5
      Hystory of pulmonary embolism9.7% (n = 3)10.2% (n = 4)0.9
      Chronic obstructive pulmonary disease16.1% (n = 5)15.4% (n = 6)0.3
      Chronic renal failure22.6% (n = 7)20.5% (n = 8)0.1
      Chronically
      chronically taken drugs refer to therapies regularly taken by the patient for at least 6 months. ACEIs = angiotensin converting-enzyme inhibitors; ARBS = angiotensin II receptors blockers; BMI = body mass index; DAPT = dual antiplatelet therapy; DOAC = direct oral anticoagulants.
      taken drugs
      Aspirin58.1% (n = 18)61.5% (n = 24)0.3
      P2Y12 Inhibitors12.9% (n = 4)15.4% (n = 6)0.2
      DAPT6.4% (n = 2)7.7% (n = 3)0.1
      DOAC22.6% (n = 7)48.7% (n = 19)0.001
      Beta-blockers48.4% (n = 15)47.6% (n = 10)0.7
      Statins38.7% (n = 12)41.0% (n = 16)0.9
      ACEIs58.1% (n = 18)61.5% (n = 24)0.6
      ARBs29.0% (n = 9)30.8% (n = 12)0.7
      Calcium-antagonists9.7% (n = 3)10.2% (n = 4)0.9
      low asterisk chronically taken drugs refer to therapies regularly taken by the patient for at least 6 months. ACEIs = angiotensin converting-enzyme inhibitors; ARBS = angiotensin II receptors blockers; BMI = body mass index; DAPT = dual antiplatelet therapy; DOAC = direct oral anticoagulants.
      The most important and strongest data from our study refers to anticoagulant chronic intake prevalence in the survivor group (48.7%; p < 0.001) respect to other pharmacological treatments.
      A total of 26/70 patients (37.1%) were treated with direct oral anticoagulants (DOAC) which underlying indication was pulmonary embolism (n = 7; 26.9%), deep vein thrombosis (n = 6; 23%) or atrial fibrillation (n = 13; 50%). The majority of our patients received rivaroxaban (n = 11; 42.3%); followed by apixaban (n = 9; 34.6%), edoxaban (n = 4; 15.4%), and dabigatran (n = 2; 7.7%). The effect of male gender and chronic utilization of DOAC in influencing mortality were plotted in Fig. 1, panel A and B, respectively.
      Fig. 1
      Fig. 1Effect of gender (Panel A) and DOAC (Panel B) and on mortality.
      Only three parameters increased mortality risk. The strongest was age; then the male gender and the chronic DOAC intake (multivariate analysis reported in Table 2).
      Table 2Results of the multivariate analysis.
      parameterTWaldHazard ratio (95% CI)p
      Age.3330.51.39 (1.24 – 1.57)< 0.0001
      DOAC−1.6911.90.38 (0.17 – 0.58)0.01
      Male gender1.575.71.49 (1.11 - 1.63)0.02
      Our study demonstrated that elderly patients affected by interstitial pneumonia have a severe prognosis, with a mortality risk of around 40%. Considering the octogenarian mortality rate is 30% in Italy [], our patients had a 1.5 - 2-fold increased risk. The higher mortality rate of our population mainly depends on the presence of a large number of cardiovascular risk factors, a finding confirmed by epidemiological studies in many countries [
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area.
      ]. Age represents the most powerful independent and prognostic factor in the multivariate analysis. On the contrary, hypertension, obesity, and diabetes were not significant maybe because their prevalence is often age-related. Male gender, which represents a self-determining factor, not depending on age, was significantly associated with mortality risk. The latter finding is a consolidated hallmark in Italy [
      • 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.
      ].
      It is important to underline that any of the drugs chronically taken for the cardiovascular disease increased mortality risk. Following our assumption, we should not interrupt cardio-active drugs in elderly patients affected by cardiovascular disease and COVID-19.
      Most cardio-active drugs did not influence mortality risk. Among these, we underline the neutral role of the renin-angiotensin system inhibitors: angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), confirmed by several studies [

      Varga Z. Endothelial cell infection and endothelitis in COVID-19. The Lancet's website. https://www.thelancet.com/lancet/article/s0140-6736(20)30937-5. April17, 2020.

      ,
      • Mehera M.R.
      • Desai S.S.
      • Kuy S.
      • Henry T.D.
      • Patel A.N.
      Cardiovascular disease, drug therapy, and mortality in COVID-19.
      ].
      The most important finding of our study is the demonstrated protective role of anticoagulant drugs. Chronic DOAC intake is an independent parameter associated with a decreased mortality risk in our population. COVID-19 is mainly treated as a primary pulmonary disease, but according to the available literature, it is a more complex disease. Recent observations suggest a pivotal role of vascular damage (a sort of endothelitis, associated with thrombosis of the small pulmonary vessels) [

      Varga Z. Endothelial cell infection and endothelitis in COVID-19. The Lancet's website. https://www.thelancet.com/lancet/article/s0140-6736(20)30937-5. April17, 2020.

      ]. Therefore, mortality risk would not be conducted to the acute respiratory distress syndrome alone, but also the thrombosis in pulmonary and other district vessels [

      Varga Z. Endothelial cell infection and endothelitis in COVID-19. The Lancet's website. https://www.thelancet.com/lancet/article/s0140-6736(20)30937-5. April17, 2020.

      ,
      • Klok F.A.
      • Kruip M.J.H.A.
      • Van der Meer N.J.M.
      • et al.
      Incidence of thrombotic complications in critically ill ICU patients with COVID-19.
      ].
      According to these findings, anticoagulant treatment with a prophylactic dose of low molecular weight heparin reduced mortality in patients with COVID-19 [
      • Tang N.
      • Bai H.
      • Chen X.
      • et al.
      Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
      ]. In this scenario, the role of DOAC, the most powerful drugs that directly inhibit coagulation factors, is easy to understand. We believe that the importance of DOAC lies in the chronic intake, which is the only one capable of guaranteeing a real defense against thrombosis since the early stages of the disease, even before the onset of symptoms.
      Further studies on a larger population of patients, possibly randomized, are needed to confirm the protective role of DOAC in reducing the mortality risk in COVID-19 patients with pre-existing cardiac diseases.

      CRediT authorship contribution statement

      Rosario Rossi: Data curation, Formal analysis, Writing - original draft. Francesca Coppi: Conceptualization, Project administration, Supervision, Writing - review & editing. Marisa Talarico: Data curation, Formal analysis, Writing - original draft. Giuseppe Boriani: Conceptualization, Project administration, Supervision, Writing - review & editing.

      Declaration of Competing Interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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