Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in multiple medical complications related to inflammatory and immune system responses, which often include respiratory distress or pneumonia.1 In particular, COVID-19 can increase the risk of venous thromboembolism (VTE) due to the underlying inflammatory process.2
There are no clear guidelines on the implications of SARS-CoV-2 infection for patients at increased thrombotic risk. Therefore, this commentary from a group of international experts aims to provide a summary of the risk of COVID-19 infection for patients at increased thrombotic risk and considers potential management approaches for these patients. The authors take into consideration that our understanding of COVID-19 is constantly evolving, raising significant challenges for both guideline recommendations and the selection of individual patient management strategies.
Methods
International cardiology experts with clinical and academic experience in cardiovascular (CV) risk assessment and the management of CV patients during the COVID-19 pandemic met online in January 2024. The panel consisted of a professor of cardiometabolic medicine (NS), experts in cardiac intervention (RR, PGS and JMS), cardiologists (DP, RR, JMS and LT) and an epidemiologist (DP). Members came from the UK (NS), France (PGS), Italy (RR), Turkey (LT), India (DP) and the US (JMS).
The study was structured according to the three-step online Delphi method and took place between January and July 2024. In round one, a targeted literature review using PubMed was carried out to identify the research conducted in this area. Key search words used were “COVID-19,” “thrombosis,” “thrombotic,” “myocardial infarction,” “stroke,” “ischaemic,” “deep vein thrombosis,” “pulmonary embolism,” “venous thromboembolism,” “acute coronary syndrome,” “cardiovascular disease” and “in-stent thrombosis”. Given the volume of publications available, preference was given to more recent studies of larger size, variable clinical scenarios, and from diverse regions. These articles were summarised and reviewed and screened by the panel members.
The panel then drew up a number of statements in the form of a survey for a global CV expert pool to complete, giving weight to the available evidence along with their own clinical experience and judgement. The target participants for the pool was based a few different criteria, namely those healthcare professionals (HCPs) who had opted into the Radcliffe Cardiology database with the following job titles: cardiologist non-invasive, emergency medicine, HCPs in training, heart failure specialist, interventional cardiologist, nephrologist, neurologist, nurse/nurse practitioner, pharmacist, primary care physician and pulmonologist.
In round two, this survey was distributed to the pool to gauge perceptions of COVID-19 infection as a risk factor for thrombotic events and real-world clinical approaches to these patients. The statements described a position that required an opinion and asked the participants to independently rate their level of agreement using a four-point Likert scale (strongly agree, agree, disagree, strongly disagree). The content of the survey was measured against the statements from the expert panel to gauge levels of agreement between the experts and the clinical community. Consensus was defined as >70% of participants agreeing/strongly agreeing or disagreeing/strongly disagreeing with a given statement.
Results
A total of 323 responses were received from five regions of the world and included cardiology interventionalists, non-interventionists, general practitioners and non-cardiology specialists (Supplementary Figures 1–3). The results of the survey are available in Supplementary Figures 4–17.
Venous Thromboembolism
Numerous studies have shown that infection is associated with thrombotic events, which was recognised by the majority of survey respondents (83%; Supplementary Figure 4).3 Confirmed SARS-CoV-2 infection has been shown to be associated with early elevations in risk of thrombotic events, including MI and ischaemic stroke, and substantially stronger and prolonged elevations in risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) both in hospital and in community settings (Figure 1).4
In a meta-analysis of studies evaluating patients with recent infection (29 million patients, 2 million with SARS-CoV-2), the incidence of VTE was increased by 2.3% and PE by 1.2%.5 Another study found that the risk of VTE following a respiratory or other infection was 2.4-fold higher than for no infection.4
An assessment of the risk of VTE in non-hospitalised patients with COVID-19 (n=398,530) found that the sharpest increase in VTE risk was observed during the first 30 days after COVID-19 diagnosis, consistent with the global survey (83% agreed that the risk of VTE is highest during the acute infection stage; Supplementary Figures 5 and 6).6
In a large nationwide study that used self-controlled case series and matched cohort study methods, there was an increased risk of a first DVT up to 3 months after COVID-19 and an increased risk of PE up to 6 months, while the risk of PE in the acute phase was especially high.7 After hospital discharge, both VTE and arterial thromboembolism (ATE) have been found to occur frequently after hospitalisation for COVID-19.8 Additionally, thrombotic risk has been shown to be greater in more severe cases of COVID-19 that require hospitalisation or intensive care unit (ICU) care, despite a high usage rate of thromboprophylaxis.9,10 Analysis of a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Massachusetts General Hospital and Brigham and Women’s Hospital integrated health network found the rate of major VTE or ATE in ICU was up to 35%, whereas for those hospitalised but not in ICU, it was 2.6%.10
The panel also noted the available evidence comparing the risk of thrombotic complications in influenza with that in COVID-19 hospitalised patients: the 30-day cumulative incidence of any thrombotic complication in influenza was 11% compared with 25% in COVID-19; in both groups, rates were higher in patients admitted to the ICU.11
A large UK registry examined the association of COVID-19 with major arterial and venous thrombotic diseases in 48 million adults and 1.4 million COVID-19 cases (Figure 2). It found there were an estimated 10,500 excess ATE and VTE events and the relative incidence was higher, and remained elevated for longer, after hospitalisation than non-hospitalisation for COVID-19.12
A European network cohort study of nearly 1 million COVID-19 patients in five countries showed that the 90-day incidence of VTE was 0.2–0.8% in COVID-19 patients, and up to 4.5% for those hospitalised with the disease (Figure 3).13
Stroke, MI and Other Systemic Arterial Emboli
Following a respiratory or other infection, the risk of arterial thrombosis, such as MI and ischaemic stroke, can increase for a short period of time (Figure 1).14,15 The risk of MI peaks at the onset of infection, declines after the first 1–2 weeks and is proportional to the severity of the illness.16 With mild respiratory infection, the risk of MI returns to baseline within months. This was consistent with the results of the global survey (Supplementary Figure 7). A total of 81.31% of participants strongly agreed or agreed that the increased risk of MI in patients with acute infections is more pronounced in patients with chest infections (viral and bacterial) and is proportional to time from infection and severity of illness.
A meta-analysis of 24 million patients showed that the risk of ischaemic stroke in patients who had recovered from COVID-19 increased twofold, and there was a higher risk of stroke among patients who had been hospitalised and/or had pre-existing CV risk factors, a risk recognised by a consensus in the survey (75.47% of participants strongly agreed or agreed) (Supplementary Figure 8).17
Acute Coronary Syndrome
The association between COVID-19 and acute coronary syndrome (ACS) and myocardial injury was confirmed in a cohort observational study of 2,736 patients with COVID-19.18
A retrospective cohort study followed individuals who had a positive COVID-19 test alongside a test-negative control group of individuals with no symptoms of COVID-19 for a median of 300 days.19 Compared with the control group, individuals with COVID-19 had increased risk and excess burden of new-incident CV and cerebrovascular complications.
Procedural Considerations
The thrombogenic predisposition of COVID-19 also affects interventional cardiology activity, and an increase in the incidence of stent thrombosis was observed during the COVID-19 pandemic.20,21 This increased risk of thrombotic complications in percutaneous coronary intervention (PCI) with stent implantation in patients infected with COVID-19 was agreed by 74% of participants in the survey (Supplementary Figure 9).
Hospital Readmissions
A nationwide readmission database analysis in the US found that during the first COVID-19 outbreak, 30-day readmission rates after ST-elevation MI (STEMI) were similar between patients with and without COVID-19, and cardiac causes were the most common reasons for readmission.22 In contrast, a UK study found that patients presenting with STEMI and concurrent COVID-19 had high rates of cardiac arrest, increased thrombus burden, bigger infarcts and worse outcomes.23 Comparing STEMI patients treated by primary PCI across all waves of the pandemic, the outcomes for COVID-19-positive patients improved until, by wave 3, there were no differences in outcome between COVID-19-positive and -negative patients.23 This suggests that CV outcomes after STEMI may have improved over time as a result of the less virulent SARS-CoV-2 variants, increased number of vaccinated individuals, increased number of patients who have recovered from COVID-19, adjustments in anticoagulation regimens and improved treatment of COVID-19 overall.
Published Guidelines and Recommendations
Trials have failed to convincingly establish the benefit of therapeutic anticoagulation or even routine prophylactic anticoagulation. Thrombotic risk has varied between trials and also been shown to be quite different during the various waves of COVID-19.24,25 In 2021 The European Society of Cardiology Task Force for the management of COVID-19, recognised that:
- CV comorbidities are common in patients with COVID-19;
- presence of CV disease is associated with severe COVID-19 and higher mortality; and
- CV risk factors are linked with severe COVID-19 and higher mortality.26
The Task Force recommended that: “Alertness for CV events, such as ACS, stroke, and venous thromboembolic events, in the short term after pneumonia, and a careful risk management approach in individuals with pre-existing CVD is needed.” However, it stopped short of making any therapeutic recommendations. A detailed review was carried out by the International Society on Thrombosis and Haemostasis in 2023 and provided somewhat complex recommendations that reflected the incomplete evidence available.27
In the US, the National Institutes of Health’s COVID-19 treatment guidelines recognise that critically ill adults with COVID-19 have been observed to have a prothrombotic state and higher rates of VTE. The published recommendations note the insufficient evidence to make clear pharmacological recommendations and highlight the need to balance thrombotic risk with bleeding risk.28
Discussion
The evidence from both published studies and global clinician experience supports the concept that thrombosis risk increases with severity of COVID-19 and is highest in the acute phase following infection. The panel and global community recognised that the clinical course and outcome of thrombotic events, such as ACS and acute MI, are negatively influenced by comorbidity and concomitant disease, such as COVID-19, although the CV impact from COVID-19 has lessened as the disease has become more endemic and less virulent worldwide.
A key difference between infection-associated thrombosis and thrombosis in other circumstances is a stronger inflammation-mediated component caused by the presence of the pathogen and its thrombo-inflammatory effects.2,29 Consequently, COVID-19 is not limited to a respiratory infection, given that its entry into endothelial cells triggers a cascade of events that leads to systemic inflammation and subsequent CV events. The panel appreciates that the mechanisms underlying the immune and coagulation systems that interact and reciprocally regulate one another in the pathophysiology of thrombosis remain incompletely understood. Furthermore, the issue of thromboprophylaxis has persisted since the beginning of the pandemic and, as noted above, guidelines for thromboprophylaxis remain unclear.29 Taken together, these observations highlight the need for increased knowledge of vascular processes and a deeper understanding of the molecular and cellular mechanisms that culminate in VTE, ATE and CV events in order to identify appropriate therapeutic approaches for these at-risk patients.2
Interpretations and Future Directions
The panel acknowledge that infections have been shown to be a trigger for thrombotic events, and the thrombotic risk for cardiac events (ACS, stent thrombosis, etc.) is highest in the first 1–2 weeks after infection and then rapidly decreases. This is supported by self-controlled series that offer the most reliable evidence because they eliminate the majority of residual confounding factors.14–17 The risk of VTE or PE is generally proportional to the degree of inflammation and this risk appears to last longer, which has led to trials of anticoagulants and other therapies.
Given the clinical data that highlight that infectious and viral agents, including SARS-CoV-2, are associated with an increased risk of micro- and macro-thrombotic complications, the panel and global community consider that it may be appropriate to include SARS-CoV-2 infection in CV risk algorithms and CV disease risk scores, particularly during the acute period in patients requiring hospitalisation. The thrombotic risks associated with COVID-19 affect the management of these patients, highlighting that patients with ACS who are co-infected with SARS-CoV-2 need tailored and probably more aggressive antiplatelet and antithrombotic approaches to care.
The panel also noted that the RECOVERY trial failed to show that more aggressive antiplatelet approaches are effective in patients hospitalised with COVID-19.30 In RECOVERY, the reduction in thromboembolic complications in patients allocated to standard of care plus 150 mg aspirin once per day until discharge was offset by an increased risk of major bleeding.30
The panel and global community are in agreement that incident thrombotic complications should be monitored beyond the first 30 days after a COVID-19 diagnosis, and the care pathways for those surviving the acute episode of COVID-19 with raised CV risk could incorporate risk management of thrombotic events tailored to the individual patient.
The panel considered the available data on therapeutic management of at-risk patients with COVID-19. They agreed that antithrombotic medications might be helpful in all stages of the disease. In particular, strategies to prevent thrombotic events after COVID-19 are particularly important after severe COVID-19 leading to hospitalisation. They noted the low level of evidence from an observational study from the early first wave of the pandemic that showed that patients who received prophylactic anticoagulation had a decreased risk of 30-day mortality and no increased risk of serious bleeding events compared with those who received no anticoagulation.31
The panel shared the findings of studies that show that no anticoagulation of patients hospitalised with COVID-19 was associated with high risk among hospitalised COVID-19 patients, while therapeutic anticoagulation was associated with lower mortality than prophylactic doses, although the result was not statistically significant.32
The panel and global community support close monitoring of individuals at raised CV risk during acute infective episodes (including COVID-19) as appropriate during the month, and possibly during the year, following acute COVID-19. However, in the absence of an evidence-based indication for prophylactic oral anticoagulation, the panel is unable to recommend any prophylactic or therapeutic strategies to minimise the risk of thromboembolic events in at-risk individuals. Finally, the panel recognises that existing evidence does not yet fully identify the underlying mechanisms involved in the pathogenesis of thrombotic complications linked to COVID-19. The panel and global community concurred that more research and high-quality evidence in this area is needed to inform management strategies in patients with acute infection, including COVID-19, and identify optimal antithrombotic regimen for prevention and management of thromboembolic events in these patients.
Limitations
The findings of meta-analyses evaluating the risk of VTE and ATE following COVID-19 can show variations in incidence due to factors such as differences in healthcare systems, public health policies, and coding practices.13 The panel acknowledged that comparing risks across geographical regions remains challenging.
In the post-pandemic phase, interpretation of data is also subject to a number of challenges, including vaccination programs, new coronavirus variants and previous COVID-19 infection. These limitations were also recognised by the global community who responded to the survey. Data are additionally dependent on local considerations such as oxygen supply, medication, vaccination and device supply. Steps such as slowing down the transmission rate, mass vaccination, and following safety guidelines can be effective solutions to the new challenges and may lead to improvements in the evidence base for local therapeutic policies.33 Most significantly, the absence of randomised clinical trials in the prophylaxis and management of COVID-19-associated thrombotic events will continue to hinder any recommendations from national and international guidelines organisations. Nonetheless, the consistently higher rates of thrombotic events in the higher-risk hospitalised COVID-19 populations suggest that more intensive antithrombotic therapy is likely to remain a cornerstone of therapy for select patients meeting these high-risk criteria.
Conclusion
In the COVID-19 era, thrombotic complications such as MI, ischaemic stroke and VTE events have become prominent parts of the clinical picture for the large subset of COVID-19 patients with elevated CV risk. This calls for consideration of an innovative and individualised approach to the treatment and management of these thrombotic risks, including a review of CV care pathways and risk algorithms. However, there remain inadequate clinical trial data to provide the clarity and consistency to inform consensus decision-making on recommendations for specific therapeutic strategies. For now, the expert consensus panel and the global clinical community agree that some high-risk individuals may benefit from more intensive anticoagulant strategies (and patients hospitalised for COVID-19 in particular), although further study of this increased thrombotic risk related to infection is needed.