COVID-19, caused by SARS-CoV-2, has caused a global health crisis. More than 190 million people have tested positive for SARS-CoV-2 worldwide, with more than 4 million deaths from COVID-19 (WHO epidemiological update: July 20, 2021).
Although initially the main concern focused on the risk of pneumonia progressing to acute respiratory distress syndrome with high mortality, there are increasing reports of cardiovascular manifestations and thrombotic complications after COVID-19. The prognosis is worse in COVID-19 patients who present with these complications, highlighting the acute need to determine the magnitude of cardiovascular complications and identify at-risk populations.
The evidence focusing on the association between COVID-19 and cardiovascular complications is based on relatively small studies, limited to the initial phase of the pandemic, and mainly includes hospitalized patients, that is, those with severe disease. Consequently, population-level studies are needed to identify the burden of acute cardiovascular events after COVID-19.
The aim of this study was to quantify the relative risk of acute myocardial infarction and ischemic stroke after COVID-19 using two different methods:
(1) The self-controlled case series (SCCS) method in a large national registry cohort of all COVID-19 patients in Sweden.
(2) A matched cohort study to identify the increased risk of acute cardiovascular events conferred by COVID-19 compared to the background population.
Background
COVID-19 is a complex disease that affects many organs. Previous studies highlight COVID-19 as a probable risk factor for acute cardiovascular complications.
We aimed to quantify the risk of acute myocardial infarction and ischemic stroke associated with COVID-19 by analyzing all COVID-19 cases in Sweden.
Methods
This self-controlled case series (SCCS) and matched cohort study were conducted in Sweden. The personal identification numbers of all COVID-19 patients in Sweden from February 1 to September 14, 2020 were identified and linked to national inpatient, outpatient, cancer, and cause-of-death registries. Controls were matched by age, sex, and county of residence in Sweden.
International Classification of Diseases codes for acute myocardial infarction or ischemic stroke were identified in the causes of hospital admission for all COVID-19 patients in the SCCS and all COVID-19 patients and matched control individuals in the matched cohort study.
The SCCS method was used to calculate the incidence rate (IRR) for the first acute myocardial infarction or ischemic stroke after COVID-19 compared to a control period.
The matched cohort study was used to determine the increased risk conferred by COVID-19 compared to the background population of an increase in acute myocardial infarction or ischemic stroke in the first 2 weeks after COVID-19.
Results
86,742 COVID-19 patients were included in the SCCS study, and 348,481 matched control individuals were also included in the matched cohort study.
When the exposure day was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 289 (95% CI 1 51-5 55) during the first week, 2 53 (1 29-4 94) during the second week and 1 60 (0 84-3 04) in weeks 3 and 4 after COVID-19.
When the exposure day was included in the risk period, the IRR was 8 44 (5 45-13 08) during the first week, 2 56 (1 31-5 01) during the second week, and 1 62 (0 85 -3 · 09) during weeks 3 and 4 after COVID-19.
The corresponding IRRs for ischemic stroke when the exposure day was excluded from the risk period were 2 97 (1 71–5 15) in the first week, 2 80 (1 60–4 88) in the second week, and 2 80 (1 60–4 88) in the second week. 10 (1·33–3·32) in weeks 3 and 4 after COVID-19; When the exposure day was included in the risk period, the IRRs were 6 18 (4 06-9 42) for the first week, 2 85 (1 64-4 97) for the second week, and 2 14 (1 97) for the second week. 36 –3 · 38) during weeks 3 and 4 after COVID-19.
In the matched cohort analysis excluding day 0, the odds ratio (OR) for acute myocardial infarction was 3.41 (1.58-7.36) and for stroke was 3.63 (1.69-7.80) in the 2 weeks post-COVID-19.
When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 661 (3 56-12 20) and for ischemic stroke was 6 74 (3 71-12 20) at 2 weeks after COVID-19.
Interpretation
Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischemic stroke.
This indicates that acute myocardial infarction and ischemic stroke represent part of the clinical picture of COVID-19 and highlights the need for COVID-19 vaccination.
Discussion
In our study, we identified COVID-19 as an independent risk factor for ischemic stroke and acute myocardial infarction. To the best of our knowledge, our study involving 86,742 COVID-19 patients is the largest study conducted on the association between COVID-19 and acute cardiovascular events.
The nationwide inclusion of all patients diagnosed with COVID-19 in Sweden adds to the robustness of the data. We used two different methodological approaches to test our hypothesis. In the SCCS method, cases act as their own controls and confounding factors, for example, comorbidities or sociodemographic factors, are controlled for in the analyses.
Additionally, because we observed a large number of events on day 0, which could reflect testing bias, we did two separate matching and SCCS cohort analyses, one excluding and one including day 0. The incubation period average for COVID-19 is 5 days, and less than 2·5% of patients develop symptoms within 2·2 days of infection; Within 12 to 5 days, 97 5% of patients have developed symptoms.
Therefore, it is very likely that patients on day 0 were indeed infected with SARS-CoV-2 before their event, and that the systemic response to the infection precipitated the event. How to manage the spike on day 0 reflects contrasting statistical perspectives (excluding day 0 due to risk of selection bias) and clinical perspectives (including day 0 in the risk period); However, the risk of acute myocardial infarction and ischemic stroke was consistently and significantly increased in patients with COVID-19 compared to the control period, regardless of whether day 0 was included in the risk period.
These effects were clinically significant, and the risk increased twofold or more. The risk of acute myocardial infarction and ischemic stroke increased significantly during the buffer period (day -28 to -4), likely due to reverse causality, i.e., nosocomial COVID-19 during hospitalization for acute myocardial infarction or Ischemic stroke. This hypothesis is supported by Lauer and her colleagues’ study in which most people developed symptoms within 12 to 5 days after SARS-CoV-2 infection.
Our buffer period includes a time when most people develop COVID-19 symptoms after SARS-CoV-2 infection. The increased number of acute myocardial infarctions and ischemic strokes during the month before day 0 probably indicates nosocomial infection. This finding highlights the need to protect patients from nosocomial COVID-19.
Furthermore, our findings are contrary to evidence showing a decrease in hospital admissions for acute myocardial infarction and stroke during the initial phase of the pandemic. This paradox could be explained by a real decrease in the overall incidence of cardiovascular events due to lifestyle changes during lockdown, or by the patient’s delay in seeking medical help due to physical distancing and fear of contagion.
In addition to COVID-19, other coronavirus infections (i.e., MERS-CoV or SARS-CoV) have been shown to increase the risk of cardiovascular disease. The nature of this observation is still unclear, but unique pathophysiological mechanisms such as viral pneumonia or ACE2 downregulation are proposed as potential mechanisms. Additionally, atrial fibrillation, a well-known risk factor for stroke, is common in patients with severe COVID-19.
The identification of COVID-19 as an independent risk factor for acute myocardial infarction and ischemic stroke in our and other studies is supported by previous studies in which infections with other viruses or bacteria transiently increase the risk of ischemic stroke and acute myocardial infarction. myocardium. However, this risk appears to be higher after COVID-19 (e.g., stroke risk was 7-6 times higher with COVID-19 compared to influenza), likely due to pathophysiological alterations unique to the disease.
The exaggerated inflammatory response (cytokine storm) and the direct effect of the virus on endothelial cells are likely to precipitate cardiovascular events through downregulation of the ACE2 receptor, platelet activation, hypercoagulability, and effects on endothelial cells. (activation, injury, dysfunction and apoptosis). The long-term effects of COVID-19 on cardiovascular risk may also be of concern, but need further analysis.
| In conclusion, our findings suggest that COVID-19 is an independent risk factor for acute myocardial infarction and ischemic stroke. Our results indicate that acute cardiovascular complications could represent an essential clinical manifestation of COVID-19 and long-term effects could be a challenge for the future. |
Research in context
Evidence before this study
Infection and inflammation are known to transiently increase the risk of stroke and acute myocardial infarction; Therefore, SARS-CoV-2 that causes COVID-19 could increase the risk of acute myocardial infarction and ischemic stroke.
PubMed was searched from database inception to March 10, 2021, for peer-reviewed studies and preprints published in English. We identified only one study that used the self-controlled case series method to estimate the incidence rate of acute myocardial infarction and ischemic stroke after COVID-19 and found an increased risk of acute myocardial infarction and ischemic stroke in the first 2 weeks after COVID -19.
Additionally, two studies were identified that used the retrospective cohort study and the retrospective case-control method to determine the risk of ischemic stroke after COVID-19.
A retrospective cohort study compared patients with COVID-19 with patients with influenza. The odds of stroke after COVID-19 were higher than the odds after influenza. A small (n = 41) retrospective case-control study found that patients with COVID-19 were associated with increased odds of acute ischemic stroke.
Current evidence focusing on the association between COVID-19 and cardiovascular complications is based on small studies and primarily includes hospitalized patients (i.e., those with severe disease), thus presenting a high risk of bias.
Added value of this study
To our knowledge, this is the largest study that used all patients diagnosed with COVID-19 to identify the risk of first acute myocardial infarction and first ischemic stroke using two separate methods, the self-controlled case series method and the matched cohort study (control individuals adjusted for major cardiovascular risk factors).
This study finds that laboratory-diagnosed COVID-19 is an independent risk factor for acute myocardial infarction and ischemic stroke, even after adjusting for the effect of important confounders.
Implications of all available evidence
Evidence indicates that acute cardiovascular complications could represent an essential clinical manifestation of COVID-19 and long-term effects could be a challenge for the future.
These findings could change clinical practice and justify a prioritization of preventive and diagnostic strategies, which may affect treatment and therefore reduce the burden of morbidity and mortality in this group of patients.
