COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke, according to a large Swedish study in The Lancet.
COVID-19, caused by SARS-CoV-2, has led to a global health crisis. 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 following COVID-19.
The prognosis is worse in patients with COVID-19 who have these complications, highlighting an acute need to determine the magnitude of cardiovascular complications and identify populations at risk.
A Lancet report on a Swedish study says that evidence focusing on the association between COVID-19 and cardiovascular complications is based on relatively small studies, limited to the pandemic's early phase, and includes mainly hospitalised patients—ie, those with severe disease. Consequently, there is a need for studies at the population level to identify the burden of acute cardiovascular events following COVID-19.
The aim of this Swedish study was to quantify the relative risk of acute myocardial infarction and ischaemic stroke following COVID-19 using two different methods: (1) the self-controlled case series (SCCS) method in a large, nationwide register-based cohort of all patients with COVID-19 in Sweden; and (2) a matched cohort study to identify the increased risk of acute cardiovascular events that COVID-19 confers compared with the background population.
Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study
Ioannis Katsoularis, MD Osvaldo Fonseca-Rodríguez, Paddy Farrington, Krister Lindmark, Anne-Marie Fors Connolly
Published in The Lancet 29 July 2021
In this self-controlled case series (SCCS) and matched cohort study, the identification numbers of patients with COVID-19 in Sweden from 1 February to 14 September 2020, were identified and cross-linked with national inpatient, outpatient, cancer, and cause of death registers. The controls were matched on age, sex, and county of residence in Sweden. International Classification of Diseases codes for acute myocardial infarction or ischaemic stroke were identified in causes of hospital admission for all patients with COVID-19 in the SCCS and all patients with COVID-19 and the matched control individuals in the matched cohort study. The SCCS method was used to calculate the incidence rate ratio (IRR) for first acute myocardial infarction or ischaemic stroke following COVID-19 compared with a control period. The matched cohort study was used to determine the increased risk that COVID-19 confers compared with the background population of increased acute myocardial infarction or ischaemic stroke in the first two weeks following COVID-19.
A total of 86 742 patients with COVID-19 were included in the SCCS study, and 348 481 matched control individuals were also included in the matched cohort study. When day of exposure was excluded from the risk period in the SCCS, the IRR for acute myocardial infarction was 2·89 (95% CI 1·51–5·55) for the first week, 2·53 (1·29–4·94) for the second week, and 1·60 (0·84–3·04) in weeks 3 and 4 following COVID-19.
When day of exposure was included in the risk period, IRR was 8·44 (5·45–13·08) for the first week, 2·56 (1·31–5·01) for the second week, and 1·62 (0·85–3·09) for weeks 3 and 4 following COVID-19.
The corresponding IRRs for ischaemic stroke when day of exposure 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 2·10 (1·33–3·32) in weeks 3 and 4 following COVID-19; when day of exposure 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 (1·36–3·38) for weeks 3 and 4 following 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 following COVID-19. When day 0 was included in the matched cohort study, the OR for acute myocardial infarction was 6·61 (3·56–12·20) and for ischaemic stroke was 6·74 (3·71–12·20) in the 2 weeks following COVID-19.
Our findings suggest that COVID-19 is a risk factor for acute myocardial infarction and ischaemic stroke. This indicates that acute myocardial infarction and ischaemic stroke represent a part of the clinical picture of COVID-19, and highlights the need for vaccination against COVID-19.
Their study findings were commented on in the same edition of The Lancet by Marion Mafham and Colin Baigent: What is the association of COVID-19 with heart attacks and strokes?
It has been known for several decades that there is a transient increase in the risk of myocardial infarction and stroke in association with influenza, pneumonia, acute bronchitis, and other chest infections.
It is against this background that Ioannis Katsoularis and colleagues studied a possible association of these conditions with COVID-19 during the first wave of the pandemic in Sweden, between February and September, 2020. The study linked data from the national registers for outpatient and inpatient clinics and the cause of death register for all 86,742 people (median age 48 years, 43% male, 57% female) with COVID-19 who were reported to SmiNet (Swedish Public Health Agency) and 348,481 matched controls. Two analysis methods were used to assess the association of COVID-19 with the risk of acute myocardial infarction and of ischaemic stroke.
First, the investigators used the self-controlled case series (SCCS) method to compare incidence rate ratios (IRRs) for first acute myocardial infarction and ischaemic stroke before and after patients were determined to have COVID-19. Second, they used a matched cohort study to compare the odds of an acute myocardial infarction or ischaemic stroke in the 14 days after onset of COVID-19 with control individuals who did not have a diagnosis of COVID-19 and who were similar in age, sex, and region, with additional adjustment for comorbid disease, income, education, and country of birth.
Because the actual date of infection was unknown, the researchers defined the closest available surrogate (the date of COVID-19 symptom onset, SARS-CoV-2 sample date, or the date of the relevant clinic visit or hospital admission), and denoted it as day 0.
There was a large peak of both acute myocardial infarctions and ischaemic strokes recorded on day 0.
If day 0 were excluded, the risks of acute myocardial infarction were about three times higher in the first few weeks after COVID-19, irrespective of the study method in the first week and 2·53 in the second week after day 0 in the SCCS study, and odds ratio [OR] 3·41 in the first two weeks in the matched cohort study).
If day 0 were included, the risks of acute myocardial infarction were much higher (IRR 8·44 [95% CI 5·45–13·08] in the first week and 2·56 in the second week after day 0 in the SCCS study, and OR 6·61 in the first two weeks in the matched cohort study).
Similarly, COVID-19 was associated with a three times higher risk of ischaemic stroke when day 0 was excluded (IRR 2·97 in the first week and 2·80 [1·60–4·88] in the second week after day 0 in the SCCS study, and OR 3·63 in the first two weeks in the matched cohort study). Again, the risks were much higher when day 0 was included (IRR 6·18 in the first week and 2·85 in the second week after day 0 in the SCCS study, and OR 6·74 in the first two weeks in the matched cohort study).
How should these results be interpreted, and what are their implications for the management of patients with COVID-19? The most important consideration is the potential for bias.
Why is there such a striking peak of myocardial infarction and stroke on day 0? Such a peak could occur if COVID-19 is a potent cause of myocardial infarction and stroke, events that in turn lead patients to seek medical help, but it could also occur if patients presenting with such a condition were more likely to be tested for SARS-CoV-2 than those without symptoms suggestive of such a diagnosis (ie, a test bias).
Excluding day 0 removes the potential for test bias, but might lead to an underestimate of the true risks of myocardial infarction and stroke secondary to COVID-19.
If there is indeed a moderately increased risk of myocardial infarction and stroke secondary to COVID-19, then why was there a 30–40% fall in admissions for both acute coronary syndromes and stroke during the first wave of the pandemic?
The answer is that any possible attributable excess due to COVID-19 was far smaller than the numbers of people who did not seek medical attention for symptoms of acute coronary syndrome or stroke during this period. For myocardial infarction, for example, during the period from February to mid-September, 2020, there were 381,000 confirmed cases of COVID-19 in the UK.
The estimated excess attributable risk due to COVID-19 in the present study was 0·02%, which, if it had been observed in the UK, would have caused about 76 additional myocardial infarctions, as compared with approximately 5,000 people who might not have presented to hospital with myocardial infarction during the first wave of the pandemic.
It seems reasonable to infer that the persistence of risk for several weeks after SARS-CoV-2 infection is consistent with COVID-19 causing an increased risk of thrombo-occlusive disease, as has been reported for other respiratory infections.
The absolute risks are small, but further studies are needed to evaluate the time course of increased cardiovascular risk in patients with COVID-19 and to investigate possible mechanisms. However, it is important to keep in mind that the excess risks of myocardial infarction and stroke in a person with COVID-19 are substantially smaller than those resulting from respiratory failure.
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