Mortality and Changes in Deep Vein Thrombosis Prevalence Associated with the SARS-CoV-2 P.1 variant
Background and purpose
Thrombosis is one of the significant challenges associated with cardiovascular disease and the leading cause of death globally. This study aims to determine the monthly and overall mortality rates by sex and age group in hospitalized patients with coronavirus disease 2019 (COVID-19) and the prevalence of deep vein thrombosis (DVT) in these patients. We also investigated whether the P.1 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects DVT.
Method
We determined the overall prevalence of COVID-19 per gender, age, and monthly mortality using hospital data at the São José do Rio Preto School of Medicine, state of São Paulo, Brazil. Data of COVID-19 patients with DVT as determined by echo-Doppler ultrasound (EDU) were analyzed considering two time periods (before and after the onset of the predominance of the SARS-CoV-2 P. Patients with COVID-19 but without DVT comprised the control group. The first period is from March 2020 to February 2021, and the second period is March to June 2021.
Results
Between March 2020 and June 2021, 6,199 patients were hospitalized with COVID-19 at our institution. Of these, 2,805 (45.25%) were women and 3,376 (54.47%) were men. Two hundred and fifty-four were diagnosed with DVT based on lower extremity EDU. The mean mortality rate was significantly related to gender (38.36% for men and 27.16% for women; p=0.01). The incidence of DVT in patients with COVID-19 increased significantly from 1.6% during the first study period to 7.7% during the second study period (p=0.0001), when the P.1 variant was the dominant strain. The mortality rate was significantly higher in patients with COVID-19 and DVT (58.1%) compared to the control group (33.6%; p=0.0001).
Conclusion
Based on our findings, the incidence and prevalence of DVT increased with P.1 predominance. viral variants. Early diagnosis and prophylactic reassessment are the two most important factors that must be addressed in this patient population.
introduction
Thrombosis is one of the significant challenges facing cardiovascular disease and the leading cause of death globally. The primary goal of antithrombotic therapy is to disrupt the coagulation cascade, but there is an inherent risk of bleeding and possible failure of prophylaxis because antithrombotic therapy does not involve an inflammatory process. [1]. Activation of the coagulation system by inflammation is a host defense mechanism to avoid the spread of aggressors through the bloodstream and occurs through interactions between innate immune cells and platelets through immunothrombosis. [2,3].
An autopsy study by Wichmann et al. detected deep vein thrombosis (DVT) in seven of 12 patients (58%) with coronavirus disease 2019 (COVID-19) of whom there was suspicion of venous thromboembolism before death; Pulmonary embolism was the direct cause of death in four patients [4]. Macrovascular and microvascular complications are associated with an increased risk of in-hospital death. Therefore, early diagnosis of coagulation disorders in COVID-19 patients is very important for appropriate prophylaxis or antithrombotic therapy to improve clinical outcomes. [5]. Another study detected thrombotic complications in 31% of COVID-19 patients in intensive care despite systematic thromboprophylaxis [6,7]. In another study, 30% of COVID-19 patients developed DVT. without symptoms [8]. However, routine systematic assessment of these patients is not always performed. Therefore, the prevalence and incidence of thrombotic events may be underestimated in this patient population.
We conducted this study to determine monthly and overall mortality rates by sex, age, and monthly prevalence of DVT in a university hospital in Brazil. The study also investigated whether the occurrence of DVT had an impact on the mortality rate of COVID-19 patients hospitalized at the institution. We also examined whether the P.1 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects the prevalence of DVT.
Materials & Methods
Study design and setting
We conducted an observational study of patients who had been treated or undergoing treatment for COVID-19 with DVT in a general hospital (Hospital de Base – São José do Rio Preto) between March 2020 and June 2021. A group of 105 consecutive patients negative for DVT served as as a control group.
Inclusion and exclusion criteria
Patients were included in this study if they were diagnosed with COVID-19 in a public hospital and underwent bilateral venous echo-Doppler ultrasound (EDU) of the lower limbs to assess for DVT. Patients were excluded if they were treated in an outpatient setting.
Ethical considerations
This study received approval from the Institutional Review Board of the São Jose do Rio Preto School of Medicine, São José do Rio Preto, São Paulo, Brazil (Approval No. 4,720,521).
Analysis
The overall prevalence of COVID-19 by sex, age, and monthly mortality based on hospital data from COVID-19 patients with EDU-defined DVT was analyzed before and after the onset of the predominance of the SARS-CoV-2 P.1 variant to evaluate whether the viral variant affected prevalence of DVT. The first period is from March 2020 to February 2021 (when the Zeta variant is dominant), and the second period is from March to June 2021 (when the Gamma variant dominates). (Source: SIVEP-Gripe/SVS/MS/FUNFARME-So José do Rio Preto-SP-Brazil).
Mortality rates of patients with DVT were compared with deaths in the control group during the Gamma variant period. We used descriptive and comparative statistics using Fisher’s exact test with 5% alpha error to analyze the data.
Results
Between March 2020 and June 2021, 6,199 patients were hospitalized with COVID-19 at a university hospital affiliated with the São José do Rio Preto School of Medicine, state of São Paulo, Brazil. Of these, 2,805 (45.25%) were women and 3,376 (54.47%) were men. Two hundred and fifty four were diagnosed with DVT by lower extremity EDU. A significant difference was found between the sexes regarding the mean mortality rate (38.36% for men and 27.16% for women; p=0.01, Fisher’s exact test). Number 1 and Pictures 2 describe the mortality rates between men and women per age group, respectively. Number 3 displays the overall monthly mortality over the analyzed period.
Table 1 and Pictures 4 shows monthly variations in the number of patients with COVID-19, those with DVT, and prevalence of DVT. From June 2020 to February 2021, 3,548 patients were hospitalized for COVID-19, with 57 cases of DVT (1.6%). From March to June 2021, 2,545 patients were hospitalized for COVID-19, with 197 cases of DVT (7.7%), a significant increase over the previous period (p=0.0001, Fisher’s exact test). March 2021 marks the change in viral dominance to SARS-CoV-2 P.1. variance, accounting for more than 83% of cases in March, 97% in April, and 98% in May. The mortality rate was significantly higher among patients with DVT (58.1%) compared to the group of 105 patients without DVT (33.6%; p=0.0001, Fisher’s exact test).
Discussion
This study reports on the evolution of DVT associated with COVID-19 and identified an increased prevalence of DVT with a predominance of the P.1 variant and increased mortality in these patients. Two peaks were found: July to September 2020 and March to June 2021. Moreover, the mortality rate for men is higher than for women.
More than 1,300 patients with COVID-19 were evaluated with clinical suspicion of DVT, 254 of whom had positive EDU findings. Approximately 150-200 patients with COVID-19 are admitted daily in the intensive care unit of our institution, indicating that the prevalence is underestimated. Evaluation is based on the level of D-dimer and the clinical assessment of these patients. Positive results for DVT are initially 25-30%, which increases to 45-50%, indicating that many patients are undiagnosed.
The identification of biochemical markers of thrombosis and evaluation of D-dimer levels presented worrying data, as the difference in mortality in patients with and without DVT was significant. One study reported that mortality was >50% higher in patients with 3,000 ng/ml D-dimer levels and DVT and less than 30% in patients without thrombosis. [9]. Therefore, the indication for EDU should not be based solely on the findings of D-dimer in these patients. Mortality rates were higher among those with DVT than among those without DVT. Therefore, DVT is a factor associated with death in patients with COVID-19 [10].
Prophylaxis has failed at an unacceptable rate in the intensive care unit. COVID-19 patients receive routine prophylaxis with enoxaparin and, more recently, rivaroxaban. This failure rate indicates a change in physiopathology, which indicates the need for better prophylactic options. Immunothrombosis, a broader aspect of the physiopathology of thrombosis in COVID-19, involves inflammatory, immune, and coagulation cascades. Therefore, new alternatives are needed for prophylaxis with respect to DVT, which is associated with a twofold increase in mortality in COVID-19 patients. Better prophylaxis for DVT and early diagnosis and treatment of thrombosis are two of the main challenges today for vascular surgeons.
Our study has serious limitations. We did not assess for other COVID-19-associated comorbidities including associated cardiomyopathy, obesity, and diabetes. Including these comorbidities would make our findings more robust.
Conclusion
We conducted this study to determine the mortality rate by sex and age group in patients hospitalized with COVID-19 and the prevalence of DVT, a frequent complication in COVID-19 patients. Based on our findings, the incidence and prevalence of DVT increased with the predominance of the P.1 virus variant. Early diagnosis and prophylactic reassessment are important factors in treating patients with COVID-19 and DVT.
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