Abstract
Introduction
Recent surgery is a well-known major transient risk factor for venous thromboembolism (VTE) due to the low risk of VTE recurrence after anticoagulation is discontinued. On the other hand, the risk of VTE recurrence among patients with COVID-19-associated VTE is unknown. This study aimed to compare the risk of VTE recurrence between patients with COVID-19- and surgery-associated VTE.
Methods
A prospective observational single-center study was performed including consecutive patients diagnosed with VTE in a tertiary hospital from January 2020 to May 2022 and followed up for at least 90 days. Baseline characteristics, clinical presentation, and outcomes were assessed. The incidence of VTE recurrence, bleeding, and death was compared between both groups.
Results
A total of 344 patients were included in the study: 111 patients with surgery-associated VTE and 233 patients with COVID-19-associated VTE. Patients with COVID-19-associated VTE were more frequently men (65.7% vs 48.6%, p = 0.003). VTE recurrence was 3% among COVID-19 patients and 5.4% among surgical patients, with no significant differences (p = 0.364). The incidence rate of recurrent VTE was 1.25 per 1000 person-months in COVID-19 patients and 2.29 person-months in surgical patients, without significant differences (p = 0.29). In the multivariate analysis, COVID-19 was associated with higher mortality (HR 2.34; 95% CI 1.19–4.58), but not with a higher risk of recurrence (HR 0.52; 95% CI 0.17–1.61). No differences were found in recurrence in the multivariate competing risk analysis (SHR 0.82; 95% CI 0.40–2.05).
Conclusions
In patients with COVID-19 and surgery-associated VTE, the risk of recurrence was low, with no differences between both groups.
Keywords: COVID-19, Deep vein thrombosis, Pulmonary embolism, Risk factor, Surgery, Venous thromboembolism
Abstract
Introducción
La cirugía reciente es un importante factor de riesgo transitorio bien conocido para tromboembolismo venoso (TEV) debido al bajo riesgo de recurrencia de TEV después de suspender la anticoagulación. Por otro lado, se desconoce el riesgo de recurrencia de TEV entre pacientes con TEV asociado a COVID-19. Este estudio tuvo como objetivo comparar el riesgo de recurrencia de TEV entre pacientes con TEV asociado a cirugía y COVID-19.
Métodos
Se realizó un estudio prospectivo observacional unicéntrico que incluyó pacientes consecutivos diagnosticados de TEV en un hospital terciario desde enero de 2020 hasta mayo de 2022 y seguidos durante al menos 90 días. Se evaluaron las características iniciales, la presentación clínica y los resultados. Se comparó la incidencia de recurrencia de TEV, hemorragia y muerte entre ambos grupos.
Resultados
Se incluyeron en el estudio un total de 344 pacientes: 111 pacientes con TEV asociada a cirugía y 233 pacientes con TEV asociada a COVID-19. Los pacientes con TEV asociada a COVID-19 fueron con mayor frecuencia hombres (65,7% vs 48,6%, p = 0,003). La recurrencia de TEV fue del 3% entre los pacientes con COVID-19 y del 5,4% entre los pacientes quirúrgicos, sin diferencias significativas (p = 0,364). La tasa de incidencia de TEV recurrente fue de 1,25 por 1000 personas-mes en pacientes con COVID-19 y de 2,29 personas-mes en pacientes quirúrgicos, sin diferencias significativas (p = 0,29). En el análisis multivariado, la COVID-19 se asoció con mayor mortalidad (HR 2,34; IC 95% 1,19-4,58), pero no con mayor riesgo de recurrencia (HR 0,52; IC 95% 0,17−1,61). No se encontraron diferencias en la recurrencia en el análisis multivariado de riesgos competitivos (SHR 0,82; IC 95% 0,40 – 2,05).
Conclusiones
En pacientes con COVID-19 y TEV asociada a cirugía, el riesgo de recurrencia fue bajo, sin diferencias entre ambos grupos.
Palabras clave: COVID-19, Trombosis venosa profunda, Embolia pulmonar, Factor de riesgo, Cirugía, Tromboembolismo venoso
Introduction
Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease is mainly characterized by respiratory symptoms; however, multiple extrapulmonary manifestations have also been described, including SARS-CoV-2-associated coagulopathy.1, 2, 3 COVID-19 has been associated with cytokine release, hyperinflammation, platelet dysfunction, endothelial dysfunction, in-situ thrombosis, and micro-thrombosis,4 leading to a high risk of thrombotic events mainly venous thromboembolism (deep vein thrombosis [DVT] or pulmonary embolism [PE]), but also arterial thrombosis. This risk is higher in patients admitted to Intensive Care Units (ICU).5, 6, 7 During the first wave of the pandemic, several single-center studies reported very high incidences of VTE among hospitalized COVID-19 patients. Different meta-analyses confirmed that COVID-19 patients had a high risk of VTE, ranging from 12 to 26%, although all reported heterogeneity of the studies and a high risk of bias.5, 8, 9, 10 The incidence of PE among COVID-19 patients has decreased through the course of the pandemic, and this is attributed to the effect of vaccination and new strains of the virus.11, 12 However, the risk of recurrence in patients with COVID-19-associated VTE is unknown, and there are only small prospective studies.13
On the other hand, VTE episodes may be classified as provoked or unprovoked according to the presence of risk factors, which may be categorized as a major transient risk factor (e.g., recent surgery, immobilization, others), minor transient risk factor (e.g., contraceptives), or persistent risk factor (e.g., active cancer).14 The importance of this classification lies in determining the duration of anticoagulant treatment in most patients.15
Due to the temporary course of COVID-19, it might be considered a transient risk factor for VTE. This study aimed to compare the risk of VTE recurrence among patients with COVID-19- and surgery-associated VTE.
Material and methods
A single-center prospective observational study was carried out including consecutive patients diagnosed with VTE (PE, DVT of the extremities, or both) in the VTE unit of a tertiary hospital from January 2020 to May 2022. All patients provided informed consent to participate in the study, which was performed following the local ethics committee requirements.
Patients were included if they had a VTE episode associated with COVID-19 or recent surgery, were older than 18 years, provided their informed consent, and agreed to follow-up. The exclusion criteria were inability to carry out a follow-up, association of both COVID-19 and surgery, or refusal of the patient to participate in the study. Diagnosis of PE was performed with pulmonary angio-CT or ventilation-perfusion scintigraphy, while the diagnosis of DVT was performed using compression ultrasound of the extremities. COVID-19-associated VTE was defined as a VTE event preceded by COVID-19 infection (confirmed by polymerase chain reaction [PCR]) in the prior 30 days. This time frame was arbitrarily chosen by the investigators since the definition of COVID-associated VTE has not been standardized. Surgery-associated VTE was defined as a VTE event preceded by surgery in the three months prior to diagnosis, following previous guideline recommendations.15 All patients were followed up in the VTE clinic for at least 90 days or until death if it occurred earlier. VTE recurrence was defined as a new symptomatic episode of PE or DVT, diagnosed using the imaging tests previously described. Baseline characteristics, clinical presentation, and outcomes were assessed. The incidence of VTE recurrence, bleeding, and death during follow-up was evaluated.
Qualitative variables were presented through the frequency distribution. Quantitative variables were presented as mean and standard deviation if they had a normal distribution or median and the 25th (P25) and 75th (P75) percentiles or Interquartile range (IQR) in case of a non-normal distribution. The analysis of qualitative variables was carried out using the Chi-square test and the Mann-Whitney test. Events (recurrence, bleeding, and death) were graphically represented by the Kaplan-Meier method with the log-rank test and were compared with Breslow and Tarone–Ware tests. Multivariate analysis using Cox regression was also performed. Competing risk analysis was performed using univariate and multivariate Fine and Gray regression. Statistical analysis was performed using SPSS Version 25 (IBM Corp.). To conduct competing risks regression analysis R Core Team (2021) was used.
Results
The database included 1178 patients with VTE during the study period. A total of 344 patients were included in the study: 111 patients with surgery-associated VTE and 233 patients with COVID-19-associated VTE. Eleven patients were excluded due to the presence of both risk factors.
Baseline characteristics are shown in Table 1 . Patients with COVID-19-associated VTE were more frequently men (65.7% vs 48.6%, p = 0.003) and more often hospitalized at diagnosis (54.5% vs 40%, p = 0.012). Heart failure (12.6% vs 4.7%, p = 0.008), active cancer (29.7% vs 135%, p = 0.001), and smoking (13.5% vs 3.9%, p = 0.001) were more frequent in patients with surgery-associated VTE, with no differences in the rest of cardiovascular risk factors among both groups.
Table 1.
Baseline characteristics, risk factors, and clinical presentations.
| Surgery (N = 111) |
COVID-19 (N = 233) | p-value | |
|---|---|---|---|
| Male | 54 (48.6%) | 153 (65.7%) | 0.003 |
| Age, years (Median (IQR)) | 66 (51–75) | 66 (55–76) | 0.424 |
| Recent major bleeding | 14 (12.6%) | 5 (2.1%) | <0.001 |
| Ischemic heart disease | 7 (7.4%) | 24 (9.4%) | 0.567 |
| Stroke | 6 (5.4%) | 19 (8.2%) | 0.359 |
| Peripheral artery disease | 4 (3.6%) | 4 (1.7%) | 0.278 |
| Smoking | 15 (13.5%) | 9 (3.9%) | 0.001 |
| Diabetes | 21 (18.9%) | 34 (14.6%) | 0.306 |
| Hypertension | 53 (47.7%) | 102 (43.8%) | 0.489 |
| Heart failure | 14 (12.6%) | 11 (4.7%) | 0.008 |
| Atrial fibrillation | 9 (8.1%) | 9 (3.9%) | 0.098 |
| Dyslipidemia | 33 (29.7%) | 70 (30%) | 0.953 |
| Obesity | 42 (39.6%) | 69 (30.7%) | 0.107 |
| Cancer | 33 (29.7%) | 35 (15%) | 0.001 |
| History of VTE | 9 (8.1%) | 11 (4.7%) | 0.209 |
| Familiar history of VTE | 6 (5.5%) | 4 (1.7%) | 0.081 |
| Patients hospitalized at diagnosis | 44 (40%) | 127 (54.5%) | 0.012 |
| Patients on anticoagulants | 4 (3.6%) | 14 (6%) | 0.345 |
| Hereditary thrombophilia | 5 (4.5%) | 14 (6%) | 0.568 |
| Clinical presentation | |||
| PE | 74 (66.7%) | 179 (76.8%) | 0.046 |
| DVT | 52 (46.8%) | 78 (33.5%) | 0.017 |
| PE/DVT | 22 (19.8%) | 39 (16.7%) | 0.484 |
| Asymptomatic | 5 (4.5%) | 15 (6.4%) | 0.474 |
| Dyspnea | 57 (51.8%) | 162 (69.8%) | 0.001 |
| Syncope | 12 (10.9%) | 7 (3%) | 0.003 |
| Chest pain | 21 (19.1%) | 45 (19.4%) | 0.947 |
| Fever | 7 (6.4%) | 42 (18.1%) | 0.004 |
| Central location (only PE) | 7 (9.5%) | 10 (5.6%) | 0.277 |
| RV hypokinesia (only PE) | 21 (33.3%) | 44 (31.6%) | 0.810 |
| Elevated troponin (only PE) | 16 (29.1%) | 42 (31.1%) | 0.784 |
| Elevated Nt-proBNP (only PE) |
22 (40%) | 62 (51.2%) | 0.166 |
| D-dimer, ng/mL (Median (IQR)) |
1947 (1081–3638) |
2979 (1575–8127) |
<0.001 |
| Kidney failure | 19 (17.1%) | 33 (14.2%) | 0.475 |
IQR, interquartile range; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; RV, right ventricle.
Clinical manifestations and diagnosis are summarized in Table 1. COVID-19 patients presented more frequently as PE (76.8% vs 66.7%, p = 0.046) while patients in the surgery group had more DVT (46.8% vs 33.5%, p = 0.017). There were no significant differences in PE location or right ventricular hypokinesia. There were also no differences in the levels of troponin or NT-proBNP at diagnosis. Median D-dimer levels were higher in COVID-19 patients (2979 ng/mL vs 1947 ng/mL, p < 0.001).
Treatment and clinical outcomes are presented in Table 2 . There were no differences in the need for fibrinolysis or the anticoagulant treatment used. The median duration of anticoagulation was 105 days (IQR 94–260) in surgery patients and 128 days (IQR 89.5–262) in COVID-19 patients, without significant differences (p = 0.881). The median duration of follow-up was 154 days (IQR 97–349) in the surgery group and 344 days (IQR 128–572) in the COVID-19 group, with significant differences (p < 0.001).
Table 2.
Treatment and clinical outcomes.
| Surgery (N = 111) |
COVID-19 (N = 233) | p-value | |
|---|---|---|---|
| Treatment | |||
| Thrombolytic therapy | 6 (5.4%) | 9 (3.9%) | 0.575 |
| Acute phase anticoagulant • LMWH • UFH |
101 (91%) 14 (12.6%) |
200 (85.8%) 49 (21%) |
0.177 0.059 |
| Long term anticoagulant • DOAC • LMWH • VK < A Treatment duration (days, median (IQR)) |
72 (64.9%) 41 (36.9%) 12 (10.8%) 105 (94–260) |
144 (61.8%) 74 (31.8%) 20 (8.6%) 128 (89.5–262) |
0.583 0.341 0.506 0.881 |
| Clinical outcomes (2 year follow-up) | |||
| Death | 11 (9.9%) | 47 (20.2%) | 0.017 |
| Bleeding | 22 (19.8%) | 53 (22.7%) | 0.539 |
| Major bleeding | 10 (9%) | 24 (10.3%) | 0.708 |
| VTE recurrence Recurrence as PE Recurrence after stopping anticoagulation |
6 (5.4%) 3 (2.7%) 5 (4.5%) |
7 (3%) 5 (2.1%) 7 (3%) |
0.364 0.428 0.534 |
| Thrombocytopenia | 1 (0.9%) | 5 (2.2%) | 0.668 |
| Bone fractures | 1 (0.9%) | 3 (1.3%) | 1 |
| Arterial ischemia | 5 (4.7%) | 6 (2.7%) | 0.343 |
| Follow-up (days, median (IQR)). |
154 (97–349) | 344 (128–572) | <0.001 |
LMWH, low molecular weight heparin; UFH, unfractionated heparin; DOAC, direct oral anticoagulants; VKA, vitamin K antagonists; VTE, venous thromboembolism; IQR, interquartile range.
Regarding clinical outcomes at a 2-year follow-up, VTE recurrence was 3% among COVID-19 patients and 5.4% among surgical patients, with no significant differences (p = 0.364). Mortality was higher among COVID-19 patients (20.2% vs 9.9%, p = 0.017). There were no differences in the incidence of all-cause bleeding or major bleeding.
Since there were differences in follow-up, incidence rate ratios were calculated and compared for recurrence. The incidence rate for VTE recurrence was 1.25 per 1000 person-months in COVID-19 patients and 2.29 in surgical patients, without significant differences (p = 0.29). In the Kaplan Meier analysis at 2-year follow-up, differences were found for mortality (p-value = 0.018) as expressed in Fig. 1 . No differences were observed in terms of recurrence (p = 0.270), or major bleeding (p = 0.707) between both groups (Figure 2, Figure 3 ).
Figure 1.
Mortality at 2 years (730 days). Kaplan–Meier method. Blue: COVID-19. Red: Surgery. P-value (log-rank test) 0.018.
Figure 2.
Recurrences at 2 years (730 days). Kaplan–Meier method. Blue: COVID-19. Red: Surgery. P-value (log-rank test) 0.270.
Figure 3.
Major bleeding at 2 years (730 days). Kaplan–Meier method. Blue: COVID-19. Red: Surgery. P-value (log-rank test) 0.707.
Multivariate Cox regression analysis for mortality, recurrence, and major bleeding at 2-year follow-up showed that COVID-19-associated VTE presented a higher risk of mortality (HR 2.34; 95% CI 1.19–4.58), but not a higher risk of recurrence (HR 0.52; 95% CI 0.17–1.61), or major bleeding (1.10; 95% CI 0.59–2.40) compared to surgery-associated VTE. The analysis was adjusted by age, sex, cancer, smoking, personal history of VTE, and family history of VTE.
Regarding the risk of recurrence, we performed a competing risk analysis with mortality. We found no differences in recurrence either in the univariate (SHR 0.95; 95% CI 0.42–2.13) or in the multivariate analysis (SHR 0.82; 95% CI 0.40–2.05). Multivariate analysis was adjusted by age, cancer, diabetes, smoking, and pulmonary embolism.
Discussion
Surgery is a well-known major risk factor for VTE since it is associated with a low risk of VTE recurrence.15 In this study, we found that the risk of VTE recurrence among patients with surgery and COVID-19-associated VTE was low (3% and 5.4%, respectively), with no significant differences between both groups. The baseline characteristics of both groups showed some differences: COVID-19 patients were more frequently male and admitted to the hospital, while surgical patients had more concomitant risk factors for VTE such as cancer or smoking. These differences are consistent with those described in the literature for COVID-19 vs non-COVID-19 patients.6 The proportion of PE and elevated D-dimer levels in COVID-19 patients were higher too; findings have been related to developing endothelial dysfunction and pulmonary thrombosis in severe COVID-19 patients.16, 17, 18 Besides, mortality was higher in COVID-19 patients compared to surgical patients. These differences only appear early in the course of the disease and are probably related to the infection itself. However, previous studies have described higher mortality in patients with COVID-19-associated VTE when compared with the rest of the COVID-19 patients.19, 20
Only a few studies have evaluated the risk of VTE recurrence in patients with COVID-19-associated VTE. A recent study found no VTE recurrences among 48 patients over 13 months of follow-up 13. Our study group published the experience with 100 patients with COVID-19-associated VTE followed for at least 90 days, and no VTE recurrences were found.21 A study including 77 patients with PE followed >90 days found a low incidence of VTE recurrence (1.7%).22 In the present study, the incidence of VTE recurrence among patients with COVID-19- and surgery-associated VTE was low, finding no differences between both groups (3% vs 5.4%, p = 0.364). These findings were consistent in the multivariate survival analysis at a 2-year follow-up. Moreover, no differences were found in the risk of bleeding, although previous studies have reported a high risk of bleeding in patients with COVID-19 who receive anticoagulants.23, 24 It is worth noting that most episodes of VTE recurrence occurred after stopping anticoagulation. To the best of our knowledge, this study is the largest to evaluate the risk of VTE recurrence in patients with COVID-19. More studies are required to confirm this low rate of recurrence and determine whether COVID-19 might be considered a major transient risk factor.
The present study has some limitations. First, since it is a single-center study, our results might not be extrapolated to other settings. Second, there were some differences in baseline characteristics and follow-up between both groups. Third, the severity of COVID-19 infection or the type of surgery was not included in the analysis.
Conclusions
In patients with COVID-19- and surgery-associated VTE, the risk of recurrence was low, with no differences between both groups. Further studies are required to confirm this low rate of recurrence and determine whether COVID-19 might be considered a major transient risk factor for VTE.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interest
The authors declare that they have no competing interests.
References
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