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Objective To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19.
Design Self-controlled case series and matched cohort study.
Setting National registries in Sweden.
Participants 1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants.
Main outcomes measures Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event).
Results Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding.
Conclusions The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.
Covid-19 has led to a health crisis, with millions of deaths globally. Symptoms range from mild to critical, with the most common severe manifestation being pneumonia with acute respiratory distress syndrome.1 Recently, reports of cardiovascular complications have been increasing,2 and we previously identified covid-19 as a risk factor for myocardial infarction and stroke.3
Previous studies on the risk of venous thromboembolism after covid-19 have shown conflicting results. Although a meta-analysis reported an incidence of venous thromboembolism of around 13%,4 the study included mainly patients with severe covid-19 during the first wave of the pandemic. Another report, including studies with a control group design, did not show an increased rate of venous thromboembolism.5 With such conflicting data, large nationwide studies are needed to better determine the risks of venous thromboembolism after covid-19. Furthermore, thromboprophylaxis raises concerns about bleeding complications. From information obtained on all people who tested positive for SARS-CoV-2 in Sweden, regardless of disease severity, we determined the risk of deep vein thrombosis and pulmonary embolism as well as bleeding after covid-19 using self-controlled case series and matched cohort study methods.
The personal identification numbers of people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 were sent from the communicable disease surveillance system, SmiNet (Public Health Agency of Sweden), to Statistics Sweden. We set the covid-19 date as the earliest from the date of disease onset, sample date, diagnosis date, or date of report to SmiNet (see supplementary table 1). Only first infections were included. Statistics Sweden identified four people who tested negative (controls) for each participant who tested positive for SARS-CoV-2, matched on age, sex, and county of residence. The index date for control participants was the corresponding date for participants who tested positive for SARS-CoV-2. The personal identification numbers for people who tested positive or negative for SARS-CoV-2 were cross linked with the Inpatient Registry (covid-19 cases: 1987-2021, controls: 1997-2021), Outpatient Registry (1997-2021), Cause of Death Registry (2020-21), Intensive Care Registry (2020-21), the Prescribed Pharmaceutical Registry from the Swedish National Board of Health and Welfare, and the Swedish Intensive Care Registry. We calculated the weighted Charlson comorbidity index for each participant.67
The sample size needed to identify a clinically relevant acute effect (incidence rate ratio or risk ratio of 2) with 90% power within a risk period of 30 days was 181 events in the self-controlled case series study and 112 events in the matched cohort study. The sample size needed to identify a clinically significant effect (incidence rate ratio or risk ratio of 1.5) with 90% power in the overall 180 day risk period was 258 events in the self-controlled case series study and 354 events in the matched cohort study. Sample size calculations were performed a priori.
No data were missing in our analysis.
Deep vein thrombosis, pulmonary embolism, and bleeding classification
Outcomes were defined using ICD-9 and ICD-10 (international classification of diseases, ninth and 10th revisions, respectively) diagnosis codes for deep vein thrombosis, pulmonary embolism, and bleeding (see supplementary table 2) as reason for contact in the outpatient or inpatient registries. Depending on the analysis, we chose the first or a recurrent event. A first event was defined as a participant with no previous event between 1 January 1987 and the start of the study period for patients with covid-19, and 1 January 1997 and the start of the study period for control participants. A recurrent event was defined as a participant with a previous event during the period 1987 to day 0 (covid 19) or 1997 to day 0 (index date) for participants with covid-19 and control participants, respectively. In the analysis, we only included the first of the recurrent events occurring within 1-30 days after the covid-19 or index date.
We calculated the mean age and standard deviation for the main cohort and for participants with a first or recurrent deep vein thrombosis, pulmonary embolism, or bleeding event. For each analysis we specify the proportion of participants who were female or male. In addition, we show the proportion of participants who had the event among the whole cohort of participants with covid-19 or control participants as the absolute risk over the follow-up period of 30 days.
Créditos: Comité científico Covid