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Table of contents
3. Pathophysiology - Mechanism of Disease in Relation with the Cardiovascular System
4. Strategies for Diagnosing SARS-CoV-2
5. Protective Measures for Health Care Personnel and Patients in Cardiology
6. Triage Systems (Reorganization and Redistribution)
7. Diagnosis of Cardiovascular Conditions in COVID-19 Patients
8. Categorization of Emergency/Urgency of Invasive Procedures
9. Management/Treatment Pathways
10. Treatment of SARS-CoV-2 infection
11. Patient Information
13. List of Figures
14. List of Tables
15. List of References
Last updated on 28 May 2020
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The SARS-CoV‑2 causing COVID-19 has reached pandemic levels since March 2020. In the absence of vaccines or curative medical treatment, COVID-19 exerts an unprecedented global impact on public health and health care delivery. Owing to the unexpected need for large capacities of intensive care unit (ICU) beds with the ability to provide respiratory support and mechanical ventilation, temporary redistribution and reorganization of resources within hospitals have become necessary with relevant consequences for all medical specialties. In addition, protective measures against SARS-CoV‑2 gain particular significance for health care personnel (HCP) in direct contact with patients suffering from COVID-19 as well as for ambulatory and hospitalized patients without infection. In view of finite health care resources, health care providers are confronted with ethical considerations on how to prioritize access to care for individual patients as well as providing care for COVID-19 while not neglecting other life-threatening emergencies. Of note, assays to detect the virus in asymptomatic and symptomatic patients have important limitations in terms of sensitivity and specificity and will be complemented by tests for antibodies to identify those that already have been infected previously.
SARS-CoV‑2 not only causes viral pneumonia but has major implications for the CV system. Patients with CV risk factors including male sex, advanced age, diabetes, hypertension and obesity as well as patients with established CV and cerebrovascular disease have been identified as particularly vulnerable populations with increased morbidity and mortality when suffering from COVID-19. Moreover, a considerable proportion of patients may develop cardiac injury in the context of COVID-19 which portends an increased risk of in-hospital mortality. Aside from arterial and venous thrombotic complications presenting as acute coronary syndromes (ACS) and venous thromboembolism (VTE), myocarditis plays an important role in patients with acute heart failure (HF). Moreover, a wide range of arrhythmias has been reported to complicate the course of COVID-19 including potential pro-arrhythmic effects of medical treatment targeted at COVID-19 and associated diseases. Owing to redistribution of health care resources, access to emergency treatment including reperfusion therapy may be affected depending on the severity of the epidemic at a local level. This is further aggravated by increasing concerns of delayed presentation of CV emergencies as patients are afraid to seek medical attention during the pandemic.
For all these reasons, the European Society of Cardiology (ESC) has assembled a group of experts and practitioners with experience in the care of COVID-19 patients to provide a guidance document relevant for all aspects of CV care during the COVID-19 pandemic. While the document is comprehensive, it is important to point the reader to what the document is unable to do and what the limitations are:
By 10 March 2020, 4296 persons world-wide had died from COVID-19 infection. By 7 May, 3.67 million had tested positive and more than 250 000 had died.1 The overall case-fatality rate is very country-specific for COVID-19 infection and depending on the phase of the epidemic, testing, registration, demography, healthcare capacity and governmental decisions.2
For most countries, it is uncertain how the registration is organized which makes the comparison of case-fatality rates between countries difficult. The excess death rate is a more reliable approach to compare the impact of the COVID-19 pandemic in different countries. An article in the New York Times demonstrated that there are large differences in the excess date rates. Germany has only an excess death rate of 4% which is surprisingly low in comparison with other countries or cities such as Italy (49%), the United Kingdom (65%) (UK), Spain (67%) or New York City (297%).3
Furthermore, COVID-19 infection has similar infection rates in both sexes; however, mortality rates are higher in men.4 Daily situation reports of the COVID-19 pandemic are disseminated by the WHO on their website.
After the start of the COVID-19 pandemic in Wuhan, China, the epicenter of the epidemic is now in Europe. Figure 1 gives an overview of the evolution of laboratory-confirmed cases of COVID-19 in Europe.
A large Chinese study analyzed 72 314 patient records which consisted of 44 672 (61.8%) confirmed cases, 16 186 (22.4%) suspected cases, and 889 (1.2%) asymptomatic cases.4 Among confirmed cases in this study, 12.8% had hypertension, 5.3% diabetes and 4.2% CVD.4 Strikingly, these numbers are lower than the prevalence of CVD risk factor in a typical Chinese population, but it is important to mention that these are not age-adjusted and 53% of cases had missing data on comorbidities.5 A study including 5700 patients from New York City, Long Island, and Westchester County (United States of America (USA)) reported a similar message that hypertension (56.6%), obesity (41.7%), diabetes (33.8%), coronary artery disease (11.1%) and congestive heart failure (6.9%) were the most common comorbidities.6 In comparison, the prevalence of hypertension, obesity and diabetes in the general population in the USA is respectively 45%, 42.4% and 10.5%.7-9 In early retrospective analysis based on data from 138 patients in Wuhan, China, approximately 50% of patients with COVID-19 infection had one or more comorbidities.10 Moreover, in patients admitted with a severe COVID-19 infection this proportion was as high as 72%.10 It remains vague whether diabetes, hypertension and CVD are causally linked or associated due to age.6 However, an important message is the fact that patients who develop severe disease are more likely to be vulnerable because of comorbid disease, including CVD.
Ethnicity seems to be linked to susceptibility and outcomes of a COVID-19 infection.11, 12 Data from the United Kingdom show that one third of patients admitted to an intensive care unit due to COVID-19 infection were from an ethnic minority background.11, 13 Reports from the USA reveal the same message that ethnic minority groups have also been disproportionately affected by COVID-19 infections.12 There are multiple potential mechanisms such socioeconomic, cultural, or lifestyle factors and genetic predisposition. Also, pathophysiological differences in susceptibility or response to infection such as increased risk of admission for acute respiratory tract,14 an increased prevalence of vitamin D deficiency,15 increased inflammatory burden, and higher prevalence of cardiovascular risk factors such as insulin resistance and obesity than in white populations.11, 16
Verity et al.17 estimated that the case fatality ratio in China (adjusted for demography) was 1.38% but estimated case-fatality depends very much on the testing strategy of non-severe cases as many cases remain unverified. Case-fatality is highest in older age groups: The case fatality ratio was 0.32 in patients aged < 60 years of age in comparison with 6.4% in patients aged > 60 years.17 In Italy case fatality ranged from 0% below age 30 years to 3.5% for age 60–69 years and 20% above age 80 years.18 Higher mortality of a COVID-19 infection in older age groups was also revealed in an American dataset.6 This underlines the fact that increasing age is an important risk factor for severe course of COVID-19 infections. Underlying CVD is also associated with higher risk for a severe COVID-19 infection. In a retrospective cohort study of 72 314 cases in China19 patients with CV comorbidities had fivefold higher mortality risk (10.5%), however, without age adjustment. Multinational cohort analyses will give more insights in the prevalence and risk of CV comorbidities in COVID-19 infection. There are several potential mechanisms explaining why the course of the disease is more severe in patients with underlying CV risk factors and CVD.20 These are described in sections 3 and 9.
Preceding coronaviruses outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) were associated with a significant burden of CV comorbidities and complications.20,21 Common cardiac complications in SARS were hypotension, myocarditis, arrhythmias, and sudden cardiac death (SCD).22,23 Diagnostic workup during SARS infection revealed electrocardiographic changes, sub-clinical left ventricular (LV) diastolic impairment and troponin elevation. MERS was associated with myocarditis and HF.22
COVID-19 infection seems to have comparable cardiac manifestations. Autopsies of patients with COVID-19 infection revealed infiltration of the myocardium by interstitial mononuclear inflammatory cells.24 COVID-19 infections are associated with increased cardiac biomarkers levels due to myocardial injury.24-26 The myocardial injury and the increased levels of biomarkers are likely associated with infection-induced myocarditis and ischaemia.27 In a study by Shi et al.26 in 416 patients of whom 57 died, cardiac injury was a common finding (19.7%). In the patients who died, 10.6% had coronary artery disease (CAD), 4.1% had HF, and 5.3% had cerebrovascular disease.26 Moreover, in multivariable adjusted models, cardiac injury was significantly and independently associated with mortality (hazard ratio [HR]: 4.26).26 Similarly, in a study by Guo et al.25, elevated troponin T levels due to cardiac injury was associated with significantly higher mortality. These patients were more likely to be men, to be older and to have more comorbidities such as hypertension, coronary heart disease.25 Severe COVID-19 infections are also potentially associated with cardiac arrhythmias at least in part due to infection-related myocarditis.10
Next to acute complications, COVID-19 infection may also be linked with an elevated long-term CV risk. It is well established that in patients with pneumonia, hypercoagulability and systemic inflammatory activity can persist for a long period.2,20 Moreover, follow-up studies of the SARS epidemic demonstrated that patients with a history of SARS-coronavirus infection often had hyperlipidaemia, CV system abnormalities or glucose metabolism disorders.20-22 However, SARS was treated with pulses of methylprednisolone which could be the explanation for the long-term perturbation of lipid metabolism rather than a consequence of the infection itself.24 Naturally, no long term effects of a COVID-19 infection are known yet but these effects of a SARS-coronavirus infection justify surveillance of recovered COVID-19 infection patients.
COVID-19 is caused by a novel betacoronavirus officially named by the WHO as SARS-CoV‑2. Coronaviruses are enveloped, single-stranded ribonucleic acid (RNA) viruses with surface projections that correspond to surface spike proteins.28 The natural reservoir of SARS-CoV‑2 seems to be the chrysanthemum bat,29 but the intermediate host remains unclear. SARS-CoV‑2 is highly virulent and the transmission capacity is greater than the previous SARS virus (outbreak in 2003), with high abundance in infected people (up to a billion RNA copies/mL of sputum) and long-term stability on contaminated surfaces.30 SARS-CoV‑2 is more stable on plastic and stainless steel than on copper and cardboard, and viable virus has been detected for up to 72 hours after application to these surfaces.30 While the infectivity of SARS-CoV‑2 is greater than that of influenza or SARS-coronavirus, more data are needed for accurate assessment.31 Transmission occurs primarily by a combination of spread by droplet, and direct and indirect contact, and may possibly be airborne as well. The viral incubation period is 2–14 days, (mostly 3–7 days).32 It is contagious during the latency period. SARS-CoV‑2 can initially be detected 1–2 days prior to onset of upper respiratory tract symptoms. Mild cases were found to have an early viral clearance, with 90% of these patients repeatedly testing negative on reverse transcriptase polymerase chain reaction (RT-PCR) by day 10 post-onset. By contrast, all severe cases still tested positive at or beyond day 10 post-onset.33 Median duration of viral shedding was 20 days (interquartile range: 17–24) in survivors.34 The longest observed duration of viral shedding in survivors was 37 days.34
The host receptor through which SARS-CoV‑2 enters cells to trigger infection is ACE2 (Figure 2).35,36 ACE2 is a multifunctional protein. Its primary physiological role is the enzymatic conversion of angiotensin (Ang) II to Ang-(1–7), and Ang I to Ang-(1–9), which are CV protective peptides.37 In the context of COVID-19, however, ACE2 is also involved in SARS through its function as the coronavirus receptor.38 Binding of the SARS-CoV‑2 spike protein to ACE2 facilitates virus entry into lung alveolar epithelial cells, where it is highly expressed, through processes involving cell surface associated transmembrane protein serine 2 (TMPRSS2)39 (Figure 2). Within the host cell cytoplasm, the viral genome RNA is released and replicates leading to newly formed genomic RNA, which is processed into virion-containing vesicles that fuse with the cell membrane to release the virus. SARS-CoV‑2 is spread mainly through the respiratory tract by droplets, respiratory secretions and direct contact. The RAS/ACE2 seems to be disrupted by SARS-CoV‑2 infection, which likely plays a pathogenic role in severe lung injury and respiratory failure in COVID-19.40 In addition to the lungs, ACE2 is highly expressed in human heart, vessels and gastrointestinal tract.41,42
COVID-19 is primarily a respiratory disease, but many patients also have CVD, including hypertension, acute cardiac injury and myocarditis (Figure 3 from Guzik et al.43).21,44 This may be secondary to the lung disease, since acute lung injury itself leads to increased cardiac workload and can be problematic especially in patients with pre-existing HF. CVD may also be a primary phenomenon considering the important (patho)physiological role of the RAS/ACE2 in the CV system and the fact that ACE2 is expressed in human heart, vascular cells and pericytes.45
The prevalence of pre-existing hypertension seems to be higher in COVID-19 patients who develop severe disease versus those who do not.34,46 This seems to also be true for acute respiratory distress syndrome (ARDS) or death. These earlier studies were not age-adjusted and the impact of age still needs to be addressed. The mechanisms underlying potential relationships between hypertension and COVID-19 are thought most likely to relate confounding due to age and associated comorbidities.47 Previous speculation proposed that treatment of hypertension with RAS inhibitors may influence SARS-CoV‑2 binding to ACE2, promoting disease.48 This is based on some experimental findings that RAS inhibitors cause a compensatory increase in tissue levels of ACE2,49 and that ACE-inhibitors or ARBs may be detrimental in patients exposed to SARS-CoV-2.50 It is however important to emphasize that there is no clear evidence that using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) lead to up-regulation of ACE2 in human tissues. The available data from blood samples suggest that there is no association between circulating levels of ACE2 and use of RAAS antagonists.51 It also appears that in experimental models ARBs may have a potentially protective influence.52,53 A recent observational study of over 8910 patients from 169 hospitals in Asia, Europe, and North America, did not show a harmful association of ACEIs or ARBs with in-hospital mortality,54 while a Wuhan study demonstrated that in 1128 hospitalized patients use of ACEI/ARB was associated with lower risk of COVID-19 infection or serious complication or deaths from COVID-19 infection.47, 54-60 The recent data are all-cause mortality compared with ACEI/ARB non-users.60 This is in line with prior guidance from major CV Societies, that stated that patients on ACEIs or ARBs should not stop their treatment.51,61
Myocarditis appears in COVID-19 patients several days after initiation of fever. This indicates myocardial damage caused by viral infection. Mechanisms of SARS-CoV-2-induced myocardial injury may be related to upregulation of ACE2 in the heart and coronary vessels.44,61 Respiratory failure and hypoxia in COVID-19 may also cause damage to the myocardium and immune mechanisms of myocardial inflammation may be especially important.27,44,61 For example, cardiac injury leads to activation of the innate immune response with release of proinflammatory cytokines, as well as to the activation of adaptive auto-immune type mechanisms through molecular mimicry.
Inflammatory mechanisms and activation of immune responses underlie a large range of CVDs including atherosclerosis, HF and hypertension.62,63 This dysregulation may have different degrees in COVID-19. Firstly another receptor through which SARS-CoV‑2 may enter cells is cluster of differentiation 209 (CD209).64 CD209 is expressed in macrophages promoting virus invasion into immune cells in cardiac and vascular tissues. More importantly, in severe cases of COVID-19, systemic increases of numerous cytokines including IL-6 IL-2, IL-7, granulocyte colony-stimulating factor, C-X-C motif chemokine 10 (CXCL10), chemokine (C-C motif) ligand 2, and tumour necrosis factor-α have all been observed in subjects with COVID-19,65 which corresponds to the characteristics of a cytokine release syndrome (CRS). Altered vascular permeability can result in non-cardiogenic pulmonary oedema and promotes ARDS as well as multi-organ dysfunction. High serum IL-6 levels are a common feature in CRS. IL-6 is a clinical predictor of mortality in COVID-19.66 Thus IL-6 targeting may be permissive for use in COVID-19 to tackle the CRS. Finally, it has been shown that hypertension is associated with circulating lymphocytes in patients67 and CD8 T cell dysfunction with development of CVD.68 CD8 T cells are a pillar of antiviral immunity, thus their dysfunction can make the organism inefficiently target virally infected cells.
As evidenced by previous epidemics, including SARS and MERS, highly sensitive and specific laboratory diagnostics are essential for case identification, contact tracing, animal source finding, and efficient and rational containment measures.69 Precise case identification is essential in order to isolate vulnerable individuals. Based on current epidemiological analysis, CVD conveys risk of a more severe outcome of COVID-19;21,44 therefore, testing should be particularly widely considered in CVD patients. Moreover, in similarity to influenza, efficient testing of carers and people in contact with high risk patients may allow protection of subjects with multiple comorbidities. The decision to test should be based on clinical and epidemiological factors and linked to an assessment of the likelihood of infection, in particular when availability of tests is limited. Available testing strategies are outlined below (Table 1).
While isolation of the virus itself using electron microscopy would be the most specific diagnostics, it requires biosafety level-3 facilities which are not available in most healthcare institutions. Serum antibody and antigen detection tests would be the easiest and fastest, but have not yet been validated, and there may be cross-reactivity with other coronaviruses, especially SARS-coronavirus. Furthermore, antibodies are not measurable in the initial phase of the infection. Therefore, real-time PCR remains the most useful laboratory diagnostic test for COVID-19 worldwide.
Comparative specificity and sensitivity of these tests needs to be carefully assessed, when more data is available. It is important to note that negative results of molecular testing (RT-PCR) do not preclude SARS-CoV‑2 infection and should not be used as the sole basis for patient management decisions but must be combined with clinical observations, patient history, and epidemiological information. There are a number of factors that may lead to a negative result in an infected individual. These include poor quality of the specimen (small material), collection late or very early in the infection, poor handling/shipping as well as technical reasons inherent in the test such as virus mutation or PCR inhibition. Therefore, retesting is recommended after 48 hours in clinically suspected cases that test negative.
It is essential that adequate standard operating procedures are in use and that staff are trained for appropriate specimen collection, storage, packaging, and transport. This must be observed in order for testing to be reliable and safe for staff and patients.
The optimal testing material includes nasal swab rather than pharyngeal. In order to obtain a sufficiently deep swab, the sample must be obtained by experienced and trained staff. According to a comparative study using lung CT as comparator, the sensitivity of nasopharyngeal swab may be limited to 60–70%.72 It has also been concluded that the test does not seem to change clinical decisions and diagnostic considerations in subjects with pretest probability exceeding 60–70% (e.g. subjects with positive epidemiological and clinical criteria fulfilled). This however does not indicate that such tests should not be performed to confirm infection, but it is important that the test is repeated if there is clinical suspicion of COVID-19 infection. Lung CT has a high sensitivity for diagnosis of COVID-19 in hospitalized patients who are RT-PCR positive. In a study undertaken between 06 January and 06 February 2020 in Tongji Hospital, Wuhan, China, in a population of 1014 patients – when using RT-PCR as a reference, the sensitivity of lung CT imaging for COVID-19 was 97%.72 Importantly, 60–93% of patients had initial positive lung CT consistent with COVID-19 before the initial positive RT-PCR results.
Nucleic acid shedding is also an important tool to verify patient improvement, although 42% of patients showed improvement of follow-up lung CT scans before the RT-PCR results turning negative.72 It is important, however, that nucleic acid shedding does not always indicate presence of live virus.
Widespread testing strategies included drive-through testing in South Korea. However, testing capacity may be insufficient. Thus testing priorities have been suggested by individual health systems such as one proposed by Centers for Disease Control for the United States (US) (Table 2). Sample pooling strategy has been proposed in relation to sample collection as the most cost-efficient tool for population-wide screening, for example at airports.
Taking into account that there are only a few documents regarding type and level of protection of HCP, the ESC Guidance Document considered the WHO document,73 the American Center for Disease Control and Prevention guidelines on COVID-19,74 the European Centre for Disease Control guidelines on COVID-19;75 but also Chinese data76,77 and experiences from European countries with the largest outbreaks of COVID-19. Importantly, the ESC Guidance document aims to suggest a high level of protection for HCP in the worst transmission scenario of SARS-CoV‑2 infection. Different settings, such as countries with no cases, countries with sporadic cases, countries experiencing case clusters in time, geographic location and/or common exposure should prepare to respond to different public health scenarios, recognizing that there is no one size fits all approach to managing cases and outbreaks of COVID-19. Each country should dynamically assess its risk and rapidly change the definitions according to their local situation, depending on the phase of the epidemic, demography, healthcare capacity, and governmental/local health authorities’ decisions.
In a recent report related to 138 confirmed COVID-19 cases, 41.3% were considered acquired infection from the hospital, and more than 70% of these patients were HCP.78 Health care workers are in fact at increased risk for contracting the virus, as demonstrated by Wu and colleagues, who reported that in China 1716 of the 44 672 (3.8%) infected individuals were professionals (see later).19
Generally, protection against COVID-19 needs to be differentiated according to the level of risk based on patient presentation, type of procedures and interaction and HCP risk status. Table 3 provides general recommendations.
The precautions taken depend on COVID-19 case definition as defined in Table 4.
The level of protection of HCP depends on patient risk status, setting and procedure performed (Table 5). In addition to personal protective equipment (PPE) for HCP, all suspected/probable or confirmed SARS-CoV‑2 patients should wear a disposable surgical mask when in room with HCP or other persons.
FFP3, FFP2 and N95 are designed to achieve a very close facial fit and very efficient filtration of airborne particles. Powered air-purifying respirator (PAPR) is a type of PPE consisting of a respirator in the form of a hood, which takes ambient air contaminated with pathogens, actively filters these hazards, and delivers the clean air to the user's face and mouth (Figure 4).
All HCP should be well-versed in proper techniques for donning and removing PPE including eye protection (Figure 5 and Figure 6).77
Because there is no time to wait for nasopharyngeal swab result, the procedure should be performed in a dedicated COVID-19 catheterization laboratory if available and patients should be triaged according to Table 4. In regions with high rates of community transmission, it is reasonable to regard all patients as possible SARS-CoV‑2 positive and HCP protected accordingly (Table 5)
Most of the electrophysiology (EP) activity is being markedly reduced or suspended in areas that have been severely affected by COVID-19 outbreak. Residual EP activity should be maintained for selected categories of patients (Table 7 and Table 13).
Protection of the HCP:83
The major issue is that the viral load in the airway is probably very high and very contagious.84 This poses significant risks for HCP performing non-invasive ventilation by CPAP or invasive ventilation with orotracheal intubation. Accordingly, a high level of vigilance is necessary to prevent contracting the infection when managing patients using CPAP, when intubation is performed or the transesophageal echocardiogram (TEE) probe is inserted.
It is now well known that CV patients who develop a COVID-19 infection have a higher risk of poor in-hospital outcome.20 This is why it is mandatory to effectively protect them from being in contact with infected subjects whose COVID-19-related symptoms are still not evident or not specific. Wang et al reported a significant percentage of hospital-associated transmission of the virus (12.3% of all patients) in a cohort of hospitalized patients with novel coronavirus-infected pneumonia in Wuhan, China at the start of the pandemic.10 Based on this data, patients accessing the hospital for an acute cardiac disease with no signs or symptoms of viral infection should complete their diagnostic workflow in a clean area and finally access a COVID-19-free ward. All the measures to keep chronic cardiac outpatients at home as much as possible as well as to limit in-hospital stay of cardiac patients to the shortest acceptable time should be implemented. The adoption of a restrictive visitor policy is also strongly recommended.85
Elective procedures should be avoided during the current COVID-19 pandemic so as not to overload the health system or increase the risk of disease propagation. In this context, in order to minimize risk for COVID-19 transmission, the use of telemedicine is highly desirable especially for vulnerable groups, such as older patients. Additionally, telemedicine provides an opportunity for tele-consultations with different specialists and professionals, thus allowing patients to receive a comprehensive therapeutic approach without moving from home to the outpatient clinic or to the hospital. Also telerehabilitation (or home based rehabilitation with telephone contact with the rehab team) is an option for patients discharged from the hospital after an acute event. Finally telemedical follow up of HF and device patients is becoming more and more standard and may be considered. Telemedicine has been considered relevant in contributing to viral outbreak containment while preventing patient health from deteriorating because of misdiagnosed or mistreated CVDs.86
Beyond telemedicine ‘home care’ and ‘mobile clinics’ are currently proposed as a way to prevent unnecessary movement of patients towards hospitals, provided that nurses and physicians wear the appropriate PPE. This solution could prevent clinical instability of many cardiac diseases (i.e. chronic HF), assure patient adherence to long-term treatment and contribute to a ‘community-centred’ form of care that might be more advantageous than a purely ‘patient-centred’ care model, where only infected, hospitalized patients consume most of the available resources of the healthcare system.87
When CV patients temporarily access the hospital facilities for diagnostic or therapeutic reasons they should always protect themselves by systematically wearing surgical masks, practicing social distancing and appropriate washing/cleaning their hands with alcoholic solutions, which should be provided by the hospital staff.88 Patients should also be protected by HCP donning surgical masks, depending on the local community prevalence of COVID-19.
Patient triage is of paramount importance when medical services are overwhelmed by a pandemic and healthcare resources are limited. This is particularly true for the COVID-19 epidemic, whose outbreak is currently seriously challenging the healthcare systems across the world. Some peculiar aspects of this pandemic, potentially affecting triage of cardiac patients, should be outlined:
Hub centres are committed to provide acute reperfusion to all patients requiring an urgent PCI. Patients with STEMI or high-risk NSTEMI should be triaged by the emergency medical services team and timely transported to hub centres, if feasible. As a general rule we recommend that the number of catheterization laboratories available for primary PCI should not be reduced during the pandemic, to avoid an increase in door-to-balloon time, to diminish the risk of infection during transfer for both professionals and/or patients, and to unload the health care system. Regional STEMI networks should adapt to dynamic changes of the pandemic in every region according to local medical and logistic resources. As an example, in Lombardy, Italy, a system of specialized COVID-19 referral hospitals has been defined at the start of the virus epidemic, reducing by more than 60% the number of previous referral centres with 24 hour/7 day capacity to perform a primary PCI.91 Active shifts have been also assigned to interventional cardiologists, in order to satisfy the foreseen increased number of STEMI or NSTEMI patients arriving at the hospital.92
The ambulance networks also need to be reorganized in order to bring the patients straight to the COVID-19 referral hospital, skipping the spoke centres from where a secondary transportation could be difficult to arrange and time-consuming. The major objective of this rearrangement is primarily to allow for a timely treatment of the acute CVD, despite the unavoidable epidemic-related delays. It is also functional to secure patients to COVID-19-dedicated hospitals or to hospitals with isolated COVID-19 dedicated facilities when patients with acute CVDs are highly suspect for COVID-19 infection. China has been the first country to receive specific recommendations for a transport work programme directly by the country Health Authorities.93
In countries highly affected by the COVID-19 pandemic EDs have been re-organized to provide possible COVID-19 patients with dedicated access areas and isolated facilities from their first arrival to the hospital. Local protocols for rapidly triaging patients with respiratory symptoms should be issued with the aim of differentiating patients with CVDs from COVID-19 patients. In China for example patients with no geographical or family history of virus infection, fever, respiratory symptoms, fatigue or diarrhoea were considered ‘COVID-19 unlikely’ and their CVD was usually treated with standard protocols.94 A check-list should be adopted to quickly differentiate patients with possible or probable COVID-19 infection from non-infected patients (Table 3 and Table 4). Patients with mild, stable diseases should be discharged from the ED as soon as possible (Figure 8), with the suggestion to stay at home in quarantine if a COVID-19 infection is suspected or confirmed.
Conversely, patients in need of hospital admission for acute CVD with concomitant possible/probable SARS-CoV‑2 infection (Table 4) should rapidly undergo testing and be managed as SARS-CoV-2 infected until they have two negative tests within 48 hours. Patients in need of hospital admission not suspected of SARS-CoV‑2 infection can be managed according to standard of care.
ICU beds are mainly devoted to complicated COVID-19 patients in need of intensive care, who frequently present with underlying CVD and poor prognosis.19,95 Provided that in a pandemic situation the ethical value of maximizing benefits is recognized as the most relevant to drive resource allocation,96 this might invariably disadvantage patients with advanced age and more severe CVD who will not be prioritized for advanced care provision.
Acute CV patients who tested negative (and without clinical suspicion for) COVID-19 infection, should be accurately identified and admitted, if feasible, to dedicated areas ICUs or ICCUs free from COVID-19 patients (‘clean’ ICUs or ICCUs), particularly in COVID-19 referral hospitals. If a fully ‘clean’ facility is not available, because of overwhelming numbers of COVID-19 patients, it should be guaranteed that airborne isolation rooms are set up in the facility, effectively separating patients with COVID-19 infection from all the others to minimize their infective risk. Such organization should also allow for adequate protection of HCP and well-defined pathways to and from the isolated rooms, in order to contain the spread of infection.97
Intermediate care units (also identifiable as ICCUs level II or I according to the Association for Acute Cardiovascular Care position paper98) share the same problems of ICUs, being usually equipped with CPAP machines for non-invasive ventilation. The same solutions already discussed for ICUs are therefore also applicable to intermediate care units. Triaging CV patients in need of CPAP from COVID-19 patients with pneumonia is mandatory, but still isolated rooms for COVID-19 positive CV patients (with acute HF for example) different from rooms for COVID-19 negative CV patients are very much needed.
The symptom of chest pain or tightness is common in patients with active COVID-19 infection. It is usually poorly localized and may be associated with breathlessness due to the underlying pneumonia. Associated profound hypoxaemia together with tachycardia may result in chest pain and electrocardiographic changes suggestive of myocardial ischaemia. Where biomarkers are altered, Type 2 myocardial infarction (MI) may be suggested. Patients with ACS do, however, experience the more typical symptoms related to ischaemia. The presence of a COVID-19 infection can make the differential diagnosis more difficult, as shortness of breath and respiratory symptoms may be present and may precede or precipitate cardiac signs and symptoms.
Dyspnoea (shortness of breath) is one of the typical symptoms in COVID-19. Of 1099 adult inpatients and outpatients in China, 18.7% presented with dyspnoea.80 With increasing disease severity, the proportion of dyspnoea significantly increases (31–55% in hospitalized patients and up to 92% of patients admitted to ICUs).10,65
Cough is present in 59.4–81.1% of patients with COVID-19, irrespective of disease severity.34,99 Unproductive (dry) cough is more frequent, whereas sputum production is present in 23.0–33.7%.10,34,65,80
ARDS is characterized by bilateral opacifications on chest imaging (e.g. bilateral ground glass opacifications on CT) and hypoxaemia that cannot be explained by other causes.100 Among 1099 adult inpatients and outpatients in China, ARDS occurred in 3.4%,80 but in hospitalized patients, the rates are significantly higher (19.6–41.8%).10,34,99 The median time from disease onset to ARDS is 8–12.5 days.65 The risk of ARDS increases with older age (≥ 65 years old), presence of comorbidities (hypertension, diabetes), neutrophilia, lymphocytopenia, elevated laboratory markers of organ dysfunction (e.g. lactate dehydrogenase [LDH]), inflammation (C reactive protein) and D-dimer.99 Mortality of patients treated for ARDS in COVID-19 is high (e.g. 52–53%).10,34,65,66,80,99,100
An early, accurate, and rapid diagnosis of CS in patients with confirmed or suspected COVID-19 is essential.101 The exact incidence of CS in these patients is unknown. However, the median duration between onset of symptoms and admission to ICU in critically ill COVID-19 patients has been 9–10 days, suggesting a gradual respiratory deterioration in most patients.102 A simple, actionable classification scheme for CS diagnosis has recently been proposed.103
In critically ill COVID-19 patients at risk for CS (such as those with large AMI, acute decompensated HF; Society for Cardiovascular Angiography and Interventions stage A)103 and sepsis, a mixed aetiology of CS and septic shock should be considered in addition to the sole cardiogenic component. Parameters allowing for a differential diagnosis between CS and septic shock, such as the presence of vasodilatation and central venous oxygen saturation values may be assessed. In selected cases, such as in patients with unclear reasons for haemodynamic deterioration, invasive haemodynamic monitoring via a pulmonary artery catheter may provide useful information.
The diagnostic work-up of critically ill patients with confirmed or suspected COVID-19 infection requires specific considerations:
There is very limited literature available on the occurrence of arrhythmia in the context of an infection by the SARS-CoV‑2 virus. In a study of 138 hospitalized patients with COVID-19 in Wuhan, arrhythmia was reported in 16.7% of total patients and in 16 of 36 patients admitted to the ICU (44%), although the authors did not further specify its type.10 In a subsequent publication from the same institution, ventricular tachycardia (VT)/ventricular fibrillation (VF) was reported as a complication of the COVID-19 disease in 11 of 187 patients (5.9%), with a significantly higher incidence in patients with elevated troponin T.25 However, the largest observational study from China, with 1099 patients from 552 hospitals, did not report any arrhythmia.80 Hypoxaemia and a systemic hyperinflammation status may lead to new-onset atrial fibrillation (AF), although there are no published data so far. However, important consideration should be given to rhythm management (drug interactions with COVID-19 treatment) and anticoagulation.
The clinical presentation of brady- or tachyarrhythmias in the context of COVID-19 does not differ from those previously described (i.e. palpitations, dyspnoea, dizziness, chest pain, syncope, etc.). However, there are concerns that in areas where the epidemic is extended, hospitals have experienced a significant decrease in emergency consultations for cardiac. Whether the underlying reason is concern for in-hospital contagion, a result of self-isolation measures or a saturation of the EDs and ambulances needs to be explored.
Pneumonia and severe influenza infections have been associated with a markedly increased short term risk of MI and subsequent mortality, that is more common among patients at older age, nursing home resident, and patients with history of HF, coronary disease or hypertension.105-108 Moreover, for influenza epidemics it has been demonstrated that there is a consistent rise in autopsy-confirmed coronary deaths.109 Fatal AMIs have also been observed in the short term after coronavirus associated SARS.110
Notably, recent data from China suggest that myocardial injury during COVID-19 infection – as indicated by elevated troponin levels – represent one predictor of a higher risk of CV complications and an adverse clinical outcome.25,26 Moreover, an increased rate of thromboembolic events has been observed in the context of COVID-19 infection.
So far no specific ECG changes have been described in patients with SARS-CoV‑2 infection. Therefore, we have to assume that the overall minimal level of myocardial injury associated with the infection (see the following section on biomarkers) does not translate into characteristic ECG manifestations in the majority of patients, although ST-segment elevation in the setting of myocarditis have been described.61 As a consequence, the same ECG diagnostic criteria for cardiac conditions apply in patients affected by SARS-CoV‑2 infection and in the general population. Little is known about COVID-19 infection and arrhythmias. One report on 138 patients described an arrhythmia (not further specified) in 16.7% and the prevalence increased to 44.4% in the 16 patients who were admitted to the ICU.10 For considerations of arrhythmia and corrected QT interval (QTc) prolongation of COVID-19 therapies see section 10.1.
COVID-19 is a viral pneumonia that may result in severe systemic inflammation and ARDS, and both conditions have profound effects on the heart.26,34,111 As a quantitative marker of cardiomyocyte injury, the concentrations of cardiac troponin I/T in a patient with COVID-19 should be seen as the combination of the presence/extent of pre-existing cardiac disease AND the acute injury related to COVID-19.34,66,89,111-113
Cohort studies from patients hospitalized with COVID-19 in China showed that 5–25% of patients had elevations in cardiac troponin T/I, and this finding was more common in patients admitted to the ICU and among those who died.24-26,66,111 Concentrations remained in the normal range in the majority of survivors. In non-survivors, troponin levels progressively increased in parallel with the severity of COVID-19 and the development of ARDS (Figure 10). 24,26,34,66,111
Mild elevations in cardiac troponin T/I concentrations (e.g. < 2–3 times the ULN), particularly in an older patient with pre-existing cardiac disease, do NOT require work-up or treatment for T1MI, unless strongly suggested by angina chest pain and/or ECG changes (Figure 11). Such mild elevations are in general well explained by the combination of possible pre-existing cardiac disease AND/OR the acute injury related to COVID-19.
Marked elevations in cardiac troponin T/I concentrations (e.g. > 5 times the ULN) may indicate the presence of shock as part of COVID-19, severe respiratory failure, tachycardia, systemic hypoxaemia, myocarditis, Takotsubo syndrome or T1MI triggered by COVID-19.26,34,89,111 In the absence of symptoms or ECG changes suggestive of T1MI, echocardiography should be considered in order to diagnose the underlying cause. Patients with symptoms and ECG changes suggestive of T1MI should be treated according to ESC-guidelines irrespective of COVID-19 status.24,66,113,114
BNP/NT-proBNP as quantitative biomarkers of haemodynamic myocardial stress and HF are frequently elevated among patients with severe inflammatory and/or respiratory illnesses.26,115-117 While experience in patients with COVID-19 is limited, very likely the experience from other pneumonias can be extrapolated to COVID-19.26,115-117
As quantitative markers of haemodynamic stress and HF, the concentrations of BNP/NT-proBNP in a patient with COVID-19 should be seen as the combination of the presence/extent of pre-existing cardiac disease AND/OR the acute haemodynamic stress related to COVID-19.26,115-117 At least to some extent, the release of BNP/NT-proBNP seems to be associated with the extent of right ventricular haemodynamic stress.
D-dimers are generated by cleavage of fibrin monomers by prothrombin and indicate the presence of thrombin formation or reflect an unspecific acute phase response from infection or inflammation. D Dimers also may indicate the presence of disseminated intravascular coagulation associated with shock.118 It is tempting to speculate that markers of activated coagulation or impaired fibrinolysis might contribute to acute myocardial injury, eventually also affecting coronary capillaries. Therefore, markers of haemostasis including activated partial thromboplastin time, prothrombin time, fibrin degradation products and D-Dimers should be monitored routinely. In particular, elevations of D-Dimers have been associated with poor outcome.84 Although the D-dimers have a lower specificity for the diagnosis of acute PE, 32–53% of patients still have a normal D-dimer and the vast majority has D dimers below 1000 ng/ml.10,34,80 Therefore, recommended diagnostic algorithms combing pre-test probability assessment and D dimer tests can be used in case of suspected acute PE.119 In particular, algorithms applying a pre-test probability dependent D-dimer threshold may yield a decent specificity.120-122
The potential mechanisms underlying myocardial injury in those with COVID-19 infection are not fully understood. However, in keeping with other severe inflammatory and/or respiratory illnesses, direct (‘non-coronary’) myocardial injury is most likely the cause. Myocarditis, septic shock, tachycardia, severe respiratory failure, systemic hypoxaemia, Takotsubo syndrome or T1MI triggered by COVID-19, are alternative causes. Direct myocardial involvement mediated via ACE2, cytokine storm, or hypoxia induced excessive intracellular calcium leading to cardiac myocyte apoptosis have been suggested as alternative mechanisms.2,48,123 As quantitative biomarkers of haemodynamic myocardial stress and HF, intracardiac filling pressures and end-diastolic wall stress seem to be the predominant triggers of the release of BNP/NT-proBNP.115-117
As in patients without COVID-19, cardiac troponin T/I concentrations should be measured whenever on clinical grounds T1MI is suspected.113 In patients with COVID-19, diagnostic algorithms for rapid rule out and/or rule-in of MI in patients with acute chest discomfort such as the ESC high-sensitivity cardiac troponin (hs-cTn) T/I 0/1-h algorithm can be expected to provide comparable performance characteristics as in other challenging subgroups with higher baseline concentrations such as the elderly and patients with renal dysfunction: very high safety for rule-out and high accuracy for rule-in, but reduced efficacy with a higher percentage of patients remaining in the observe zone.113,124-126 Detailed clinical assessment including chest pain characteristics, assessment of COVID-19 severity, hs-cTn T/I measurement at 3 hours, and cardiac imaging including echocardiography are the key elements for the identification of MI in this heterogeneous subgroup.113,124-126
Similarly, BNP/NT-proBNP should be measured whenever on clinical grounds HF is suspected.26,115-117 In patients who are not critically ill, rule-in cut-offs for HF maintain high positive predictive value even in patients with pneumonia.26,115-117 In contrast, currently recommended cut-offs should not be applied in critically-ill patients, as most critically-ill patients have substantial elevations in BNP/NT-proBNP, most likely due to the near-universal presence of haemodynamic stress and HF in these patients.26,115-117
It is a matter of ongoing debate whether cardiac troponin T/I should be measured as a prognostic marker in patients with COVID-19. The strong and consistent association with mortality observed in the currently available reports of patients hospitalized with COVID-19, with some evidence suggesting cardiac troponin T/I even as an independent predictor of mortality, should be seen in favour of this approach.25,26,34,111 On the other hand, at this point in time, based on three arguments we consider a more conservative approach even more appropriate.26,34,66,89,111-113 First, beyond cardiac troponin T/I other routinely available clinical and laboratory variables have also emerged as strong predictors of death in COVID-19 including older age, higher Sequential Organ Failure Assessment (SOFA) score, D dimers, IL-6 and lymphocyte count. It is unlikely that cardiac troponin T/I provides incremental value to a full model. Second, there is a recent risk of inappropriate diagnostic and therapeutic interventions triggered based in cardiac troponin T/I concentrations measured for prognostic purposes. Third, in patients with COVID-19 as well as with other pneumonias or patients with ARDS, at this point in time, no specific therapeutic intervention can be justified based on the use of cardiac troponin T/I as a prognostic marker.26,34,66,89,111-113
Therefore, routine measurements of cardiac troponin T/I and/or BNP/NT-proBNP in patients with COVID-19 given the current very limited evidence for incremental value for clinical decision-making is discouraged.
Non-urgent or elective cardiac imaging should not be performed routinely in patients with suspected or confirmed COVID-19 infection. Accordingly, non-urgent or elective exams should be postponed until the COVID-19 infection has ceased (Table 6).127,128
Echocardiography can be performed bedside to screen for CV complications and guide treatment. POCUS, FoCUS and critical care echocardiography are probably the preferred modalities to image patients with COVID-19. Limited evidence exists for the use of lung ultrasound to differentiate ARDS (single and/or confluent vertical artefacts, small white lung regions) from HF.129 The presence of dilated right ventricle and pulmonary hypertension may indicate contrast CT to rule out PE. In COVID-19 infected patients, echocardiography should focus solely on the acquisition of images needed to answer the clinical question in order to reduce patient contact with the machine and HCP.
It should not be forgotten that the risk of infection remains in the reading rooms and therefore the material used should be also frequently sanitized.
Cardiac CT should be performed when there is a potential impact on clinical management, including evaluation of symptomatic suspected CAD, acute symptomatic heart valve dysfunction, left ventricular assist device (LVAD) dysfunction, PE, urgent structural intervention.130 Cardiac CT is preferred to TEE to rule out the presence of intracardiac thrombus. In patients with acute chest pain and suspected obstructive CAD, CCTA is the preferred non-invasive imaging modality since it is accurate, fast and minimizes the exposure of patients. In patients with respiratory distress, lung CT is recommended to evaluate imaging features typical of COVID-19 and differentiate from other causes (HF, PE).94 However, it should not be used to screen for or as a first-line test to diagnose COVID-19 and should be reserved for hospitalized patients.131 A dedicated CT scanner for patients with suspected or confirmed COVID-19 is preferred. As in other imaging modalities, local standards for prevention of virus spread and protection of personnel should be followed.
Many of the diagnoses can be evaluated with other imaging modalities that limit the risk of virus spread. Nuclear cardiology tests require long acquisition times and exposure of patients and personnel.132 The use of PET-CT can be limited to patients with suspected endocarditis of prosthetic valves or intracardiac devices when other imaging modalities are inconclusive or to avoid the performance of a TEE which is associated with larger risk of spreading. Single photon emission computed tomography (SPECT) or PET may also be used for diagnosing ischaemia in patients with suspected obstructive CAD when CCTA is not appropriate or available.
The risks of contamination during a CMR scan is probably similar to a CT scan, but lower than during an echocardiographic study. Only clinically urgent CMR scans should be accepted.133
Longer time exposure in the scanner will probably increase the chances of contamination of equipment and staff. In order to minimize the examination time, shortened CMR protocols focused to address the clinical problem should be used.133 A dedicated MR scanner for patients with suspected or confirmed COVID-19 is a clear advantage. Allow time for a deep cleaning after each patient with suspected or confirmed COVID-19 infection.
The role of CMR in COVID-19 patients is currently not clear. Accepted diagnostic indications for CMR should be considered as appropriate in these patients, but should not be performed unless clinically necessary and after a reconsideration of best suited imaging technique.128
Another important attention is the use of CMR contrast in patients with COVID-19. Renal function might be decreased in patients with COVID-19 and might contradict a clinically urgent CMR scan.
One indication for an acute CMR might be suspicion of acute myocarditis, which has been reported in patients with COVID-19.134 Typical symptoms might be elevated troponins, ventricular dysfunction and/or severe arrhythmias that cannot be explained by other diagnostics and imaging methods.20
Performance of exercise testing (either conventional, Echo or nuclear) has major limitations in the COVID-19 era. During exercise the patient increases breath rate and the amount of aerosol or droplets production, even if wearing a surgical mask (that could strongly affect his/her exercise capacity). This problem is further increased since rooms of outpatient clinics are rarely large and well aerated. Performance of exercise testing is discouraged in COVID-19 suspect or positive patients and, in general, in every patient in COVID-19 epidemic or potentially epidemic areas. Alterative diagnostic methods for CAD not requiring exercise should be used as an alternative to exercise testing whenever possible. There remain conditions where exercise testing is necessary. These mainly concern patients with heart failure. Cardiopulmonary exercise testing remains the method of choice for the assessment of exercise capacity, a well-known prognostic index, and for the indication to heart transplantation in patients with heart failure. In addition, exercise testing is proposed as the method of choice for the diagnosis of heart failure with preserved ejection fraction (HFpEF) in patients with breathlessness and intermediate scores for HFpEF diagnosis. A low-level exercise may be, however, sufficient in these cases.135
In COVID-19-infected patients with clinical presentation compatible with CVD, three main entities should be considered:
The rearrangement of the healthcare service required to face the COVID-19 pandemic has posed a series of relevant issues on prioritization of cardiac invasive procedures.136 Different regions in Europe and worldwide differ substantially in terms of local healthcare resources, epidemic density of the COVID-19 outbreak, changes of the epidemic over time and therefore access to healthcare services other than COVID-19 care. These differences have a wide range of implications for national/regional healthcare services, national health care authorities and in-hospital redistribution of resources. Regions (also within the same country) may be categorized into three groups according to the degree of involvement in the epidemic, with subsequent different implications for the healthcare system as summarized in Table 7.
The indications provided in this document refer mainly to the scenario of heavy involvement and, in part, to the scenario of moderate involvement. Importantly, healthcare services should continue to be provided according to standard-of-care as described by current clinical practice guidelines, as long as the degree of regional involvement in the epidemic allows it. The rationale to importantly reduce the number of elective hospitalizations is three-fold:
This strategy comes at the expense of time-to-treatment delays for urgent CV interventions and extension of waiting times for patients in need of elective coronary, heart valve or other CV interventions.
In this context, a strategy is needed to identify patients who are in a condition allowing to postpone procedures and those who are not. An obvious concern is to maintain the standard-of-care and timely access of patients with ACS including AMI to reperfusion therapy. In patients with chronic coronary syndromes (CCS), principles of prioritization can be based on risk stratification, taking into account prognostic implications of symptoms and the presence of known critical disease of the left main stem or of the proximal left anterior descending (LAD) coronary artery at prior coronary angiogram or at CCTA.137 Similarly, patients with decompensated, symptomatic, severe aortic stenosis (AS) scheduled for transcatheter aortic valve replacement should be prioritized.138 Table 8 summarizes a categorization of invasive cardiac procedures according to urgency that may be implemented at areas affected by the COVID-19 outbreak.
The management of patients with NSTE-ACS should be guided by risk stratification.113 Testing for SARS-CoV‑2 should be performed as soon as possible following first medical contact, irrespective of treatment strategy, in order to allow HCP to implement adequate protective measures and management pathways (section 5). Patients should be categorized into 4 risk groups (i.e. very high risk, high risk, intermediate risk, and low risk) and managed accordingly (Figure 12).
Patients with Troponin rise and no acute clinical signs of instability (ECG changes, recurrence of pain) might be managed with a primarily conservative approach. Non-invasive imaging using CCTA may speed-up risk stratification, avoid an invasive approach139 allowing early discharge.
For patients at high risk, medical strategy aims at stabilization whilst planning an early (< 24 hours) invasive strategy. The time of the invasive strategy may however be longer than 24 hours according to the timing of testing results. If feasible, a dedicated area to manage these patients while waiting for the test result should be arranged in the emergency department. In the case of positive SARS-CoV‑2 test, patients should be transferred for invasive management to a COVID-19 hospital equipped to manage COVID-19-positive patients.
Patients at intermediate risk should be carefully evaluated taking into consideration alternative diagnoses to T1MI, such as Type II MI, myocarditis, or myocardial injury due to respiratory distress or multiorgan failure or Takotsubo. In the event any of the differential diagnoses seem plausible, a non invasive strategy should be considered and CCTA should be favored, if equipment and expertise are available.
When there is a positive SARS-CoV‑2 test, patients should be transferred for invasive management to a COVID-19 hospital equipped to manage COVID-19-positive patients. At times of high demand on the infrastructure and reduced availability of catheterization laboratories or operators, non-invasive conservative management might be considered with early discharge from the hospital and planned clinical follow-up.
The COVID-19 pandemic should not compromise timely reperfusion of STEMI patients. In line with current guidelines, reperfusion therapy remains indicated in patients with symptoms of ischaemia of < 12 hours duration and persistent ST-segment elevation in at least two contiguous ECG leads.114 Concurrently, the safety of HCP should be ensured.136 To that purpose, and in the absence of previous SARS-Co-V2 testing, all STEMI patients should be managed as if they are COVID-19 positive. We provide general guidance to address the healthcare system organization and delineate possible pathways for specific STEMI settings. The proposed actions are not evidence-based, may need to be adapted to meet local hospital and health authority regulations and may be subject to change in view of the evolving COVID-19 pandemic. While general measures for healthcare systems on redistribution of hub and spoke hospital networks for CV emergency and reorganization of ED and hospital paths are described in sections 7 and 8, respectively, the main principles of STEMI management in the COVID-19 pandemic are the following:
Specific pathways for management of STEMI patients are illustrated in Figure 13. It is suggested to perform left ventriculography during catheterization of any ACS patients to reduce the need for echocardiography and shorten hospital stay.
The treatment of the non-culprit lesions should be managed according to patients’ clinical stability as well as angiographic features of those lesions. In the presence of persistent symptomatic evidence of ischaemia, subocclusive stenoses, and/or angiographically unstable non-culprit lesions, PCI during the same hospitalization should be considered. Treatment of other lesions should be delayed, planning a new hospitalization after the peak of the outbreak.
CS and OHCA are time-dependent diseases needing relevant resources and optimal trained systems and dedicated networks for optimal outcome. In general, treatment of CS and OHCA should follow current guidelines and current evidence.101,114,137,140,141 However, considering that in an overwhelmed critical care system stressed by the pandemic COVID-19 infection it will not be possible for all the patients to receive ICU treatment due to limited resources. This leads to difficult situations based also on the four widely recognized principles of medical ethics (beneficence, non-maleficence, respect for autonomy and equity) which are also crucial under conditions of resource scarcity. If resources available are insufficient to enable all patients to receive the ideally required treatment, then multiple groups have considered and recommend fundamental principles to be applied in accordance with the following rules of precedence:
Triage strategies, based on current evidence and a previously established critical care triage protocol developed by working groups for use during a worldwide influenza pandemic,142 are summarised in Table 11 and Table 12. Specific recommendations are provided for patients with and without concomitant infection in Figure 14. Two scenarios will be considered:
The infection should be suspected according to recently defined epidemiological and clinical criteria.143
HCP managing patients with CCS in geographical areas heavily affected by the COVID-19 pandemic should consider the following main points:
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been identified as a potential risk factor for serious clinical presentation of SARS-CoV‑2 infection.144 Potential impact of chronic aspirin therapy has been questioned. However, at the low dose administered in CCS, aspirin has very limited anti inflammatory effect. Therefore, CCS patients should not withdraw aspirin for secondary prevention.
Statin therapy has been variably associated with favourable outcomes in patients admitted with influenza or pneumonia.145,146 On the other side, patients with COVID-19 have been sometimes reported to develop severe rhabdomyolysis or increased liver enzymes.147 In these latter cases, it may be prudent to temporarily withhold statin therapy.
For CCS patients treated with antihypertensive drugs please refer to section 9.7.
Non-invasive testing in patients with CCS is tailored upon different clinical presentations.148 In regions with high rate of SARS-CoV‑2 infection, evaluation of asymptomatic CCS patients with non invasive testing should be postponed in order not to expose these patients to an unnecessary risk of infection or overload the health care systems.
For symptomatic patients with suspected CAD and a pre-test probability of 5–15%, functional imaging for detection of myocardial ischaemia or CCTA are normally recommended as initial tests to diagnose CAD. In regions with critical situation and medical system overloaded by the COVID-19 pandemic, CAD screening even in symptomatic patients should probably be postponed in the majority of patients. Yet, if necessary, depending upon local availability and expertise, CTA should be preferred (section 7.4).
However, the increased workload of CT departments should be acknowledged; they have been heavily disrupted by the high request of pulmonary CT for patients with COVID-19. In addition, feasibility/accuracy of CCTA might be hampered in patients with COVID-19 for the common occurrence of tachycardia and at times severe renal dysfunction. In case CCTA is not suitable (e.g. inability of heart rate control, etc.) or available, non-invasive testing should be postponed. Alternative imaging modalities should be discouraged during the acute pandemic phase unless severe ischaemia is suspected, to minimize the access of the patients to healthcare system (SPECT/PET) or to prevent a close contact between patients and personnel (stress echocardiography).
For known CCS patients, clinical follow-up should be done mostly via tele-health (a dedicated telephone line should be made available to patients). Physicians could therefore address most of the patients’ concerns related to continuation or changes in medical therapy. Possible onset/recurrence of unstable symptoms should be estimated within the clinical history of the patient in order to weigh the need for hospitalization and diagnostic testing.
Symptomatic patients with very high clinical likelihood of obstructive CAD are generally referred to ICA without prior non-invasive diagnostic testing.148 However, even in these patients, medical treatment should be attempted first in order to reserve ICA with possible ad-hoc revascularization only in case of clinical instability, especially in regions were healthcare systems are heavily overloaded by patients with COVID-19.149 Revascularization (either by PCI or coronary artery bypass graft [CABG]), can be postponed in most CCS patients. However, in hospitals whose ICUs are dedicated to or overloaded with high numbers of patients with COVID-19, the impact on CABG deferral might be even more pronounced. Priority is given to keep ICU beds available for COVID-19 patients requiring critical care. Therefore, healthcare systems might identify COVID-19-free hospitals serving as hubs for selected CCS patients in whom invasive and surgical procedures cannot be postponed. In these latter patients, SARS-CoV‑2 infection should be ruled out by nasopharyngeal swab/tracheobronchial aspiration and/or CT scan before hospital admission. Alternatively, in selected patients, hybrid revascularization CABG/PCI or even full-PCI can be considered by the heart team based on patient’s clinical conditions and local situation (see Table 13).
Patients with CV comorbidities are at increased risk of the more severe presentation and complications of COVID-19. In a meta-analysis of 6 studies (n = 1527), hypertension and cardio/cerebrovascular diseases were present in 17.1%, and 16.4%, of hospitalized COVID-19 patients, respectively, and conferred ~2-fold and ~3-fold higher risk, respectively, for the more severe COVID-19.150
In 21 patients admitted to an ICU for severe COVID-19, 7 (33.3%) patients developed dilated cardiomyopathy, characterized by globally decreased LV systolic function, clinical signs of CS, elevated creatine kinase (CK), or troponin I levels, or hypoxaemia, without a past history of systolic dysfunction.89 An analysis of mortality causes in COVID-19 patients (150 hospitalized/68 dead) revealed that myocardial damage/HF and combined respiratory failure/myocardial damage/HF were responsible for 7% and 33% of fatal cases, respectively.66
There are several, not mutually exclusive, mechanisms of acute HF in COVID-19 such as:
Incidence, underlying mechanisms and risk factors of SARS-CoV‑2-associated myocarditis are currently unclear. Recently, a high viral load has been reported in 4 patients who subsequently developed fulminant myocarditis.33 One published case involved a 38-year-old male presenting with chest pain, hypotension, bilateral pneumonia with pleural effusions and ST segment elevation, but with normal CT coronary angiogram.104 Echocardiography demonstrated dilatation and a marked decrease in LV ejection fraction (LVEF), and a 2 mm thick pericardial effusion. Troponin I and BNP levels were notably high. The patient successfully recovered after receiving high-dose parenteral glucocorticoid anti inflammatory therapy and immunoglobulin, along with other therapeutic measures.
During the COVID-19 outbreak, patients with chronic HF should be advised to closely follow protective measures aimed at preventing disease transmission (e.g. self-isolation, social distancing, frequent hand washing, use of hand sanitizers and wearing a face mask in public spaces). Ambulatory stable HF patients (with no cardiac emergencies) should refrain from hospital visits.
Routine clinical methods, ECG (arrhythmias, myocardial ischaemia, myocarditis) and chest X-ray (cardiomegaly, COVID-19 pneumonia) can provide a diagnostic clue. Due to the relatively low sensitivity of chest X-ray to detect COVID-19 pneumonia, patients with a high degree of clinical suspicion (tachypnoea, hypoxaemia), but with ambiguous chest X-ray findings, should be referred to chest CT.152 Laboratory findings, such as increased erythrocyte sedimentation rate, fibrinogen and C-reactive protein, and lymphocytopenia, may suggest COVID-19 pneumonia. TTE is very important, not only to evaluate pre-existing LV dysfunction in HF, but also to assess patients suspected of having SARS CoV 2-associated myocarditis.153 During all medical procedures, an attention should be given to prevent viral transmission to HCP.
SARS-CoV‑2 utilizes the ACE2 receptors for cell entry and some data indicate that ACEIs and ARBs may upregulate ACE2,154 thus hypothetically increasing the susceptibility to the infection. Recently, a case series of 12 patients with COVID-19-associated ARDS, demonstrated that plasma Ang II levels were markedly elevated and linearly associated with viral load and lung injury.33 This has led to a suggestion that ARB treatment could have a beneficial effect in curbing the Ang II-mediated lung injury. Clearly, further research in required to resolve the controversies regarding the role of ACEI/ARB in COVID-19.
There is currently no clinical evidence of an association between ACEI/ARB treatment and the susceptibility to infection, or the clinical course. Withdrawal of medical treatment in HF patients may increase the risk of worsening HF.155 Available data do not support discontinuation of ACEI/ARB and it could be recommended that HF patients continue guideline-directed medical therapy, including beta blockers, ACEI, ARB, or sacubitril/valsartan, and mineralocorticoid receptor antagonists, irrespective of COVID-19.156
COVID-19 patients may become hypotensive due to dehydration and haemodynamic deterioration, hence adjustment of medication doses should be considered.
The more widespread use of telemedicine should be encouraged to minimize the risk of SARS-CoV‑2 transmission, in both HF patients, and HCP. Whenever possible, this technology should be utilized to provide medical advice and follow-up of stable HF patients, and to reserve direct patient provider contact for the emergency situations. It is advisable that HCP make a telephone contact with the ambulatory chronic HF patient to verify the need for the hospital visit, but also to provide psychological support. If feasible (and necessary), home delivery and mailing of standard HF drugs to the patients is a viable option.
Due to the nature of the device, LVAD patients have an increase susceptibility to the infection, and every measure should be used to prevent viral transmission. Cautious monitoring and management of anticoagulation therapy is advised, because both COVID-19 and antiviral medications can affect anticoagulant dosing. If technically feasible, assessment of LVAD function by telemonitoring is preferable. General recommendations for all LVAD patients should be also applied, regardless of COVID-19.
The susceptibility to the infection and the clinical course of COVID-19 in heart transplant recipients is not known. Recently, two cases (one mild, another more severe) of COVID-19 have been described in heart transplant recipients in China.159 Importantly, the presenting symptoms were similar to those of immunocompetent individuals, including fever, elevated inflammatory markers (e.g. C-reactive protein), lymphocytopenia and chest CT demonstrating bilateral ground-glass opacities. The treatment of the patient with more severe infection included temporary discontinuation of baseline immunosuppressant medications and institution of high-dose glucocorticoids, immunoglobulins and fluroquinolone antibiotics, along with other treatment measures. Of note, both patients recovered and remained rejection-free.
Yet another report of 87 heart transplant recipients from China, indicated that high-degree adherence to preventive measures (see above), resulted in a low rate of possible infection and transition to manifest illness (e.g. 4 patients were reported to have airway tract infection and 3 of them had a negative SARS-CoV‑2 test result, whilst 1 patient was not tested).160 Importantly, all patients fully recovered after treatment.
Although VHD has not been explicitly linked to increased morbidity and mortality in early COVID-19 case series, up to 40% of the patients admitted to the ICU had pre-existing congestive HF.89 VHD mainly affects the elderly and the symptoms of disease progression (mainly dyspnoea) may mimic those of lung infection or infiltration. In addition, VHD may aggravate the course of COVID-19 infection and complicate haemodynamic management of the systemic inflammatory response (cytokine storm),161 ARDS, and any superimposed bacterial septicaemia (observed in up to one third of ICU patients).65
Elective surgical and transcatheter interventions for VHD consume significant health care resources and many (or all, according to circumstances) may be inappropriate during the pandemic given the immense pressure on acute and intensive care facilities. However, patients with severe VHD must remain under close telephone surveillance and be encouraged to report progressive symptoms. Concentration of resources on the treatment of pandemic victims guides decisions with the overall aim of avoiding shortage of ICU beds and ventilators. Prioritization of valve interventions should therefore balance the immediate and short-term prognosis of individual patients against available resources and the risk to patients and HCP of acquiring in-hospital infection. In this respect, use of less invasive procedures (particularly transcatheter aortic valve implantation [TAVI] via transfemoral approach performed under conscious sedation and/or local anaesthesia), may present an opportunity to minimize ICU and hospital stay. The need for clinical decision making by Heart Teams remains of paramount importance and use of telemedicine (or other means of virtual communication) is essential if face-to-face meetings are difficult (or impossible) during the acute phase of the pandemic.
The prognosis of patients with severe aortic stenosis (AS) depends on several factors, including age, symptomatic status, peak aortic jet velocity/mean transvalvular gradient,162,163 LVEF, pulmonary hypertension,164 and elevated biomarkers (natriuretic peptides or troponin).165-167 Mortality of patients with severe symptomatic AS who are treated conservatively is high, reaching 50% at 1 year and 70–80% at 2 years.168 Deferring surgical aortic valve replacement (SAVR) or TAVI by several months may therefore affect prognosis.
In the context of the COVID-19 pandemic, the Heart Team should undertake systematic individual risk assessment based on objective criteria that determine disease progression. Priority should be given to patients with syncope or HF (New York Heart Association [NYHA] Class III/IV), high or very high transvalvular gradients and those with reduced LV function Table 8, whereas a watchful waiting strategy is more appropriate in those with minimal or no symptoms. TAVI (or balloon aortic valvuloplasty) may be considered in haemodynamically unstable patients (COVID-19 positive/negative). However, the potential benefits of valve intervention in a critically ill COVID-19 positive patient (no cases reported to date) should be carefully weighed against the likelihood of futility given the > 60% mortality of COVID-19 positive patients admitted to ICU.169
All cases should be discussed by the Heart Team and indications for TAVI extended to intermediate170,171 and selected low-risk patients.172,173 Increased use of transfemoral TAVI (when feasible) may allow optimal utilization of resources by avoiding general anaesthesia and intubation, shortening (or preventing) ICU stay and accelerating hospital discharge and recovery.174
The management of MR differs according to its aetiology and presentation. Chronic primary MR (flail leaflet and Barlow disease) is usually stable and well tolerated. In contrast, SMR is a more variable entity and whilst many patients remain stable under guideline directed medical and device treatment (including sacubitril/valsartan and cardiac resynchronization therapy when indicated),175 others may develop unstable HF syndromes that are refractory to medical treatment, particularly in the context of acute infection.176
In the context of the COVID-19 pandemic, priority should be given to the treatment of patients with acute primary MR complicating AMI or IE, and those with severe primary or SMR who remain symptomatic despite guideline-directed medical and device treatment and seem likely to require hospital admission. All other patients should be managed conservatively.175-178
Transcatheter mitral edge-to-edge repair may be considered in anatomically suitable high-risk or inoperable patients with acute MR (excluding those with IE) or highly selected patients with decompensated primary MR or SMR refractory to guideline-directed medical and device treatment. Despite a low risk of complications requiring ICU admission,179 the procedure requires general anaesthesia (in distinction to transfemoral TAVI) and prolonged echocardiographic guidance, thereby exposing interventionists and anaesthetists to the risk of COVID-19 transmission. Use of temporary circulatory support (intra-aortic balloon pump or Impella) should be restricted to patients with a good prospect for recovery in the context of available ICU resources.
Initial reports from China noted that hypertension was one of the most common co-morbidities (20–30% of cases) associated with the need for ventilatory support due to severe respiratory complications of COVID-19 infection.10,65,80,99,180 These analyses did not adjust for age, which is important because hypertension is very common in older people (~50% in people aged over 60 years are hypertensive) and hypertension prevalence increases sharply in the very old. Older age is also the most important risk factor for severe complications and death due to COVID-19, thus, a high frequency of hypertension would be expected in older patients with severe infection because of their older age. Indeed, a higher frequency of hypertension would be expected in older COVID-19-infected patients, than has been reported.
It now seems likely that the reported association between hypertension and risk of severe complications or death from COVID-19 infection is confounded by the lack of adjustment for age and other unmeasured confounders.47 There is currently no evidence to suggest that hypertension per se is an independent risk factor for severe complications or death from COVID-19 infection.
RAS blockade with ACEIs or ARBs are the foundation of antihypertensive therapy in the current ESC-ESH Guidelines for the management of arterial hypertension (2018).181 The recommended treatment of hypertension for most patients is combinations of an ACEI or ARB with a calcium channel blocker (CCB) or thiazide/thiazide like diuretic.181
Concern has been expressed that treatment with ACEIs or ARBs might increase the risk of infection, or developing the severe consequences of infection with COVID-19.21,46,182 This concern originates from a hypothesis that links the observations that COVID-19 invades cells by binding to the enzyme ACE2 which is ubiquitous and expressed on the surface of alveolar cells in the lung.39,41,183 In some animal studies, but not all, ACEIs or ARBs have been shown to increase ACE2 levels mainly in cardiac tissue.49,184,185
Importantly, there have been no studies showing that RAS-blocking drugs increase ACE2 levels in human tissues and no studies in animals or humans showing that RAS-blocking drugs increase ACE2 levels in the lung, or that the level of ACE2 expression in the lung is rate limiting for COVID-19 infection.
Moreover, there have been no studies in humans demonstrating an independent link between RAS blocker use and the development of severe complications of COVID-19 infection, after adjustment for age and other comorbidities. Recently a series of observational cohort studies have been published which consistently show that treatment with RAS blockers does not increase the risk of COVID-19 infection, or increase the risk of severe complications or death from COVID-19 infection.54-60 In one study, there was even a substantial reduction in risk of severe complications or death from COVID-19 infection in patients with diabetes mellitus.56 These recent findings are very important and provide reassurance to patients and their doctors that prior speculation about the safety of RAS blockers in the context of COVID-19 infection has not been proven.
Indeed, studies in animal models of infection with influenza or coronaviruses have suggested that ACE2 is important in protecting the lung against severe injury and that RAS-blocking drugs are also protective against severe lung injury due to these viruses.186-188 Human studies of RAS-blockade or recombinant ACE2 to prevent respiratory decompensation in COVID-19 infected patients have been suggested, planned or are ongoing.189,190
In summary, there is currently no evidence to suggest that ACEIs or ARBs increase the risk associated with COVID-19 infection and there is no reason why these drugs should be discontinued due to concern about COVID-19 infection. Treatment of hypertension when indicated, should continue to follow the existing ESC-ESH guideline recommendations.191
Most patients with hypertension require only infrequent visits to the clinic to manage their hypertension. Many patients with treated hypertension will be in self isolation to reduce the risk of COVID-19 infection and unable to attend for their usual routine clinical review. When possible, patients should monitor their own BP as frequently as they usually would, using a validated home BP monitor.181
Videoconference or telephone consultation with patients when required may facilitate urgent physician follow up until normal clinic attendance resumes.
Most patients who are hospitalized, will have more severe infection and be hospitalized for respiratory support. They are likely to be older with comorbidities such as hypertension, diabetes and chronic kidney disease. Patients with severe disease may also develop multi-organ complications in severe disease.
Hypertensive patients may also have LV hypertrophy or heart disease and be at increased risk of developing arrhythmias, particularly when hypoxic.192 Plasma potassium levels should be monitored because arrhythmias may be exacerbated by the frequent occurrence of low plasma potassium levels or hypokalaemia that was first noted in SARS coronavirus infection193 and early reports suggests is also prominent in hospitalized COVID-19-infected patients.194 This is thought to be due to increased urinary loss of potassium, which may be exacerbated by diuretic therapy.
If patients are acutely unwell and become hypotensive or develop acute kidney injury due to their severe disease, antihypertensive therapy may need to be withdrawn. Conversely, parenteral antihypertensive drugs are rarely but sometimes needed for hypertensive patients who are ventilated and have sustained and significant increases in BP after withdrawal of their usual treatment (i.e. grade 2 hypertension, BP > 160/100 mmHg) but the objective in these acute situations is to maintain BP below these levels and not aim for optimal BP control.
Although solid evidence is unavailable to date, a number of case reports suggest that the incidence of PE in patients with COVID-19 infection may be high.195-197 Taking this into account, together with COVID-19-associated systemic inflammation, coagulation activation, hypoxaemia and immobilization, anticoagulation at standard prophylactic doses should be considered for all patients admitted to the hospital with COVID-19 infection.
Patients with COVID-19 infection often present with respiratory symptoms and may also report chest pain and haemoptysis.80 These symptoms largely overlap with the presentation of acute PE which may cause underdiagnosis of this relevant complication.198 Unexpected respiratory worsening, new/unexplained tachycardia, a fall in BP not attributable to tachyarrhythmia, hypovolaemia or sepsis, (new-onset) ECG changes suggestive of PE, and signs of deep vein thrombosis of the extremities should trigger a suspicion of PE. It is recommended to only order diagnostic tests for PE when it is clinically suspected, although it is recommended to keep a low threshold of suspicion. The specificity of D-dimer tests may be lower in patients with COVID-19 compared to other clinical settings. Even so, it is still advised to follow diagnostic algorithms starting with pre-test probability and D-dimer testing, especially when pre-test probability dependent D-dimer thresholds are being used.120-122 This may help to rationalize the deployment of resources and personnel for transporting a patient to the radiology department with all the associated isolation precautions. In the clinical scenario of a patient with COVID-19, who has just undergone CT of the lungs but the findings cannot explain the severity of respiratory failure, CT pulmonary angiography may [or should] be considered before leaving the radiology department.
When acute PE is confirmed, treatment should be guided by risk stratification in accordance with the current ESC guidelines.119 Patients in shock should receive immediate reperfusion therapy. Haemodynamically stable patients may be treated with either unfractionated heparin (UFH), low molecular weight heparin (LMWH) or a NOAC, depending on the possibility of oral treatment, renal function and other circumstances. When choosing the appropriate drug and regimen (parenteral versus oral) for initial, in-hospital anticoagulation, the possibility of rapid cardiorespiratory deterioration due to COVID-19 should be taken into account. Of note, some of the investigational drugs for COVID-19 may have relevant interactions with NOACs. In particular, this may be the case for lopinavir/ritonavir via Cytochrome P450 3A4 (CYP3A4) and/or P-glycoprotein (P-gp) inhibition. In such cases, the bleeding risk may be elevated and NOACs should be avoided. Because close monitoring is necessary which may contribute to spreading of the infection, vitamin K antagonists (VKAs) should only be considered in special circumstances such as the presence of mechanical prosthetic valves or the antiphospholipid syndrome.119
Very few data are available on antiarrhythmic management specifically in COVID-19 patients. Therefore, this text reflects a consensus based on limited evidence. This text will be updated if more information becomes available.
The general principles of management of patients with cardiac arrhythmias and cardiac implantable devices during the COVID-19 pandemic are based on:
Several national societies and health services including the Heart Rhythm Society, National Health Service (UK) and the Cardiac Society of Australia and New Zealand have issued similar local recommendations to achieve these goals and guide the management of patients with cardiac arrhythmias and cardiac implantable devices during the COVID-19 pandemic.199-201 Below, we review considerations for implantable cardiac device monitoring and follow-up, elective and urgent EP procedures and treatment options of cardiac arrhythmias during the COVID-19 pandemic.
The categorization of EP procedures in the context of COVID-19 is depicted in Table 14. In summary, all elective ablation and cardiac device implantation procedures should be postponed, and antiarrhythmic medications should be reviewed and intensified if necessary, to allow control of symptomatic arrhythmia recurrences during the COVID-19 pandemic period.
Urgent EP procedures in patients without suspected or confirmed COVID-19 infection should be performed in a designated non-infected catheterization laboratory area, while limiting direct contact with personnel, and with the appropriate use of PPE (Section 5) during the procedure. In patients with suspected or confirmed COVID-19 infection, the procedure should be performed in a designated catheterization laboratory area, while limiting direct contact with personnel, and with the appropriate use of PPE (Section 5) during the procedure. If intubation is required, this should be performed outside the EP laboratory to avoid contamination.
The hospital stay and all ancillary procedures (ECG, echocardiography) should be reduced to minimum and be performed after clinical reassessment of their necessity.
The incidence and type of cardiac arrhythmias as a direct consequence of COVID-19 infection is currently unknown. In a single centre retrospective study including 138 patients hospitalized with COVID-19 pulmonary infection in Wuhan, China, cardiac arrhythmias occurred in 23 patients (16.7%) and acute cardiac injury in 10 (7.2%) patients (defined as troponin rise, or new ECG and echocardiographic abnormalities). Cardiac arrhythmias were considered a major complication and occurred more frequently in patients who were transferred to the ICU as opposed to the patients treated on the general ward (16 [44%] of 36 patients vs. 7 [6.9%] of 102 patients, p < 0.001, respectively).10 However, the type and duration of arrhythmias was not specified in this report.
In general, the acute treatment of arrhythmias should not be significantly different from their management in non-COVID-19 patients and should be in line with the current ESC, European Heart Rhythm Association and related guidelines.202-208
22.214.171.124.1. Supraventricular Tachycardia
There are no specific reports on the incidence of non-AF/atrial flutter type of paroxysmal supraventricular tachycardia (PSVT) during COVID-19 infection. In theory, exacerbation of known PSVT or new-onset PSVT may occur in patients with COVID-19 infection. Special considerations during the COVID-19 pandemic are the transient unavailability of catheter ablation procedures for definitive treatment, the risk of nosocomial infection during repeated ED visits, and the possibility of therapy interactions with AADs (see Section 10).
126.96.36.199.2. Atrial Fibrillation and Flutter
There are no specific reports on the occurrence of AF during COVID-19 infection. It is likely that AF may be triggered by COVID-19 infection (fever, hypoxia, adrenergic tone), either new onset or recurrent. In patients with severe pneumonia, ARDS and sepsis, the incidence of AF during hospitalization is known to be high. Reportedly 23–33% of critically ill patients with sepsis or ARDS had AF recurrence and 10% developed new-onset AF.202,209-211 New-onset AF in sepsis and ARDS has been associated with higher short- and long-term mortality, very high long-term recurrence rate and increased risk of HF and stroke.202,209-211 In a recent report from Italy, among 355 COVID-19 patients who died (mean age 79.5 years, 30% women), retrospective chart review identified a history of AF in 24.5%.18 This finding supports the estimates that especially older patients admitted to the hospital (and ICU) with COVID-19 associated pneumonia, ARDS and sepsis frequently develop new-onset or recurrent AF, which may further complicate management. Specific precipitating factors in this setting are hypokalaemia and hypomagnesaemia (induced by nausea, anorexia, diarrhoea and medications), metabolic acidosis, the use of inotropic agents (especially dobutamine and dopamine), ventilator dyssynchrony, volume overload, increased sympathetic tone, inflammation, hypoxia, ischaemia, bacterial superinfection and myocardial injury.202
As in all patients with AF, treatment goals have to consider ventricular rate control, rhythm control and thromboembolic prophylaxis. Specifically in the context of COVID-19 infection, the following considerations should be made (Figure 16):
188.8.131.52.3. Ventricular Arrhythmias
Although there are no reports on the incidence of ventricular arrhythmias in the general population of patients with COVID-19 infection, a recent single centre retrospective study from Wuhan analyzed the occurrence and significance of malignant ventricular arrythmias in 187 hospitalized patients with confirmed COVID-19 infection. Among the 187 patients (mean age 58 ±14.7 years, 49% male), 43 (23%) patients died during hospitalization. Overall, 66 (35.3%) patients had underlying CVD including hypertension (32.6%), coronary heart disease (11.2%), and cardiomyopathy (4.3%), and 52 (27.8%) patients exhibited myocardial injury as indicated by elevated Troponin T levels. During hospitalization, malignant ventricular arrhythmias (defined as sustained VT or VF) occurred in 11 (5.9%) patients. VT/VF occurred more frequently in patients with elevated troponin levels (17.3% vs. 1.5%, p < 0.001).25 These findings suggest that new-onset malignant ventricular arrhythmia is a marker of acute myocardial injury and may warrant more aggressive immunosuppressive and antiviral treatment. In patients with a history of CVD and ventricular arrhythmias, exacerbation of the known VT/VF may occur due to COVID-19 infection as trigger. Although reports are not available for COVID-19, a correlation between increased appropriate ICD therapies and influenza epidemic has been shown.212
Special considerations during the COVID-19 pandemic are depicted in Figure 17 and summarized below:
There are no specific reports on the occurrence of COVID-19 infection in patients with channelopathies. However, COVID-19 infection may occur in patients with known congenital LQTS, Brugada syndrome (BS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome, with a risk of pro-arrhythmia. The specific interactions of these channelopathies and COVID-19 has been reviewed in a recent review.213
In theory, exacerbation of known conduction system or sinus node disease or new-onset high degree AV block or sinus node dysfunction may occur in patients with COVID-19 infection, especially in case of myocardial involvement. Other mechanisms of AV block in COVID-19 are vagally mediated due to neuroinvasion, or hypoxia. A case of transient AV block in a critical COVID patient was recently published.215 One experimental study from 1999 has shown that coronavirus-infected rabbits have ECG abnormalities including 2nd degree AV block secondary to myocarditis and HF.212 In critically ill patients in the ICU, transient bradycardia and asystole may occur due to patient turning for prone respiration, intubation, or trachea suction and is probably due to transient increased vagal tone.202 Hypoxaemia should be ruled out.
A heart rate/temperature discordance was observed in patients with COVID-19:10,102 The heart rate at admission was about 80 beats per minute (bpm), slower than expected in these patients with fever. This has also been observed in other infectious disease such as typhoid fever.
Special considerations for permanent PM implantation in patients with COVID-19 are the poor prognosis of patients requiring mechanical ventilation, increased risk of bacterial superinfection and device infection in the critically ill patients, risk of nosocomial infection during device implantation in COVID-19 negative patients (see above) and transient bradyarrhythmic side effects of antiviral therapy.
Treatment strategies against SARS-CoV‑2 potentially use a combination of several drugs exerting synergistic effects. Despite the lack of definitive evidence on their efficacy, drugs with suspected viricide effect that are being used ‘off-label’ include chloroquine/hydroxychloroquine, protease inhibitors (like lopinavir-ritonavir or, in a minority of cases, darunavir-cobicistat), remdesivir and azithromycin.217-220 In specific cases, interferon and, for the ARDS glucocorticoids and/or tocilizumab, may also be administered.221
Chloroquine has been widely used as an antimalarial drug and in the treatment of rheumatological diseases like systemic lupus erythematosus and rheumatoid arthritis, and has been found to inhibit SARS-CoV‑2 growth in vitro.218-220 Hydroxychloroquine is an analogue of chloroquine with less gastric intolerance and less concerns for drug interactions. In vitro, hydroxychloroquine was found to be more potent than chloroquine in inhibiting SARS-CoV‑2.220 A recent small clinical study reported that SARS-CoV‑2 positivity in nasopharyngeal secretions is significantly decreased at day 6 after inclusion (i.e. day 10 after symptom onset) in hydroxychloroquine-treated COVID-19 patients (n = 26) versus patients who received supportive care only (n = 16). However, several major limitations (small sample size; non-homogeneous groups with differences in viral loads, number of days since onset of symptoms and quality of follow-up; and rather late administration of the drug, close to the expected time of viral clearance), raise doubts about the significance of the findings.218 The current evidence therefore does not imply yet a translation of (hydroxy)chloroquine in vitro activity to clinically relevant outcomes. Results of ongoing clinical trials of chloroquine/hydroxychloroquine efficacy in the treatment of SARS-CoV‑2 should be awaited before definite recommendations are provided for or against the use of these drugs. One major concern with these drugs is the very rare risk of QTc prolongation and TdP/sudden death. A recent metanalysis on arrhythmogenic cardiotoxicity of the quinolines and structurally related antimalarial drugs suggested that this risk is minimal (no events of SCD or documented VF of TdP in 35 448 individuals, 1207 of whom were taking chloroquine).222 However, during COVID-19 infection, the QT-related risk may be amplified by concomitant use of other QTc-prolonging drugs and/or electrolyte imbalances (hypokalaemia, hypomagnesaemia and/or hypocalcaemia). A second concern with chloroquine/hydroxychloroquine is the potential occurrence of conduction disturbances, although these are rare and appear to be linked mostly to long-term treatment (Table 15).
The protease inhibitor lopinavir-ritonavir has shown to be effective against SARS-coronavirus and MERS-coronavirus in vitro and in animal models.223-226 A recent randomized controlled open-label trial suggested that in hospitalized patients with severe COVID-19, lopinavir-ritonavir combined therapy does not provide additional benefit to standard of care.227 The main criticism of this study is the delayed time from illness onset to treatment assignment (median 13 days). Importantly, no pro-arrhythmic major adverse events were described in either arm and there was only one QTc prolongation in the lopinavir ritonavir arm (no details on the degree or the existence of other concomitant QTc prolonging factors).227 However, important drug-drug interactions have been described (mainly because these potent CYP3A4 inhibitors interfere with (hydroxy)chloroquine metabolism) that should be taken into consideration. In some combinations, dose adjustments or changes may be needed (Table 15). When lopinavir-ritonavir is not available and/or the patient is intolerant, darunavir-cobicistat is used as an alternative.
In vitro and animal studies suggest that remdesivir (GS-5734) is effective against zoonotic and epidemic SARS-coronavirus and MERS-coronavirus.228-230 Several randomized controlled studies are underway in the current SARS-CoV‑2 epidemic. In vitro studies suggest a better efficacy of remdesivir compared to lopinavir-ritonavir.230 An advantage of remdesivir is that no significant drug interactions have been described. However, there are no reports on its effect on QTc duration. Unfortunately, currently it is not widely available worldwide (only in clinical trials or for compassionate use from Gilead Sciences, Inc.).
The anecdotal evidence supporting the use of azithromycin (being a weak CYP3A4 inhibitor) comes from the above-mentioned open-label small non-randomized study of hydroxychloroquine treated COVID-19 patients (n = 26) versus patients who received supportive care only (n = 16). In 6 patients, the addition of azithromycin to hydroxychloroquine showed significant SARS-CoV‑2 positivity reduction in nasopharyngeal secretions compared to hydroxychloroquine alone.218 Azithromycin has in isolated cases been associated with QTc prolongation and TdP mainly in individuals with additional risk factors.231,232 Two studies have evaluated the association of chloroquine and azithromycin for the prevention and treatment for malaria in Africa with 114 and 1445 individuals, respectively in the arm treated with the combination.233,234 The association of chloroquine and azithromycin showed an acceptable safety profile.
For a detailed overview of all known direct or indirect (through drug-drug interactions) arrhythmological effects of experimental pharmacological therapies in COVID-19 patients, see Table 15.
QTc prolongation by some drugs can theoretically lead to polymorphic VT (TdP). This is however a very rare complication, and the consideration has to be balanced versus the anticipated benefit of therapy for the COVID-19 patient. Figure 19 provides a practical flow chart for the management of patients to prevent TdP, for guidance on the timing and repetition of ECG recording, and on QTc measurements that would alter therapy. Other guidance flowcharts have been published.213, 262 Briefly, the following steps are required to reduce the risk of drug induced TdP:
Bradycardia prolongs QT and facilitates TdP. While some COVID-19 drugs have a weak bradycardic effect, the concomitant use of beta-blockers, CCBs, ivabradine and digoxin should also be evaluated. If digoxin is considered mandatory for the patient, plasma level monitoring should be considered (with ensuing dose reduction if needed).
For patients with wide QRS complex (≥ 120 ms) due to bundle branch block or ventricular pacing, QTc adjustment is needed. Formulae are available, but a simpler approach may be to use a QTc cut off of 550 ms instead of 500 ms. Others propose a rule of thumb to calculate QT minus (QRS width 100 ms).
A standard 12-lead ECG may not always be easy to obtain, given the enormous burden of increasing numbers of COVID-19 patients on healthcare providers. Enhanced use of modern handheld ECG devices should be considered in order to reduce traditional ECG recording as much as possible to preserve resources and limit virus spread. In a recent study, the QTc in lead‐I and lead‐II derived from a standard 12-lead ECG was compared with a rhythm strip from a handheld ECG device in 99 healthy volunteers and 20 hospitalized patients in sinus rhythm treated with dofetilide or sotalol.264 QT on the handheld device had an excellent agreement with standard 12‐lead ECG both in the normal range and in patients with QT prolongation.264 This handheld ECG device (KardiaMobile 6L Alivecor) had a high specificity for detecting a QTc > 450 ms and should thus be considered as an effective outpatient tool for monitoring patients with prolonged QTc. Recently, KardiaMobile6L received expedited approval from the FDA for QT monitoring and can thus be used in COVID-19 patients treated with QT prolonging drugs such as chloroquine or hydroxychloroquine.
Many cardiac patients or patients with other CV history will have an indication for anticoagulation. Table 16 lists the possible interactions of COVID-19 therapies with VKAs, NOACs, LMWHs and UFH. The table includes information that was derived from several drug interaction sites, which have been referenced. Drug SmPCs often do not contain information for older drugs and/or drugs with a narrow spectrum of indications (like chloroquine). Antimalarial drugs have a P-glycoprotein inhibiting effect, which may affect NOAC plasma levels. COVID-19 patients on oral anticoagulation may be switched over to parenteral anticoagulation with LMWH and UFH when admitted to an ICU with a severe clinical presentation.
We would like to rephrase here also the conventional dose reduction criteria for NOACs, for those patients in whom oral treatment for stroke prevention in AF patients, can be continued. For more details, including the assessment of renal (and liver) function and other considerations in patients taking a NOAC, please see the 2018 EHRA Practical Guide on the use of NOACs in patients with AF.265 Of note, none of the NOACs is recommended in patients with a creatinine clearance (CrCl) <15 ml/min according to the EU label.
For patients with impaired swallowing, NOACs can be administered in the following ways:
There are many pending questions about the COVID-19 pandemic.274 What is the full spectrum of disease severity? How is the transmissibility? What is the role of asymptomatic/pre-symptomatic infected persons? How long is the virus present? What are the risk factors for severe illness? Knowledge is being accumulated very fast and our task is to deliver key information for patients with CVD.
There are several clinical features associated worse short-term outcome of SARS-CoV‑2 manifestations.54 These include asthma, age > 65-year-old, COPD, chronic HF, cardiac arrythmias, coronary artery disease. Female sex, statin therapy or ACE inhibitors appear to be independent protective factors. The effect of social background and ethnicity on survival needs some clarification. A cause-and-effect relationship between drug therapy and survival should not be inferred given the lack of ongoing randomized trials. Patients should be informed and take appropriate precautions with emphasis on measures for social distancing when the potential risk is high and medical resources are scarce.
The following information is important for individuals with CVD:
Additionally, individuals should be encouraged to follow the instruction of the Department of Health and local authorities in the resident countries as these may differ.
Maintain a healthy lifestyle (e.g. eat healthy, quit smoking, restrict alcohol intake, get adequate sleep and keep physically active).276 Isolation and physical restrictions may lead to inactivity and increased risk of VTE, in combination with co-morbidities. Physical activity should be strongly encouraged either in a home setting or outdoor areas with social space and will also improve well-being. Maintaining social network should be encouraged remotely.
Figure 1 Cumulative laboratory-confirmed cases of COVID-19 in Europe (World Health Organization)
Figure 2 Critical role of ACE2 in the regulation of viral invasion in ACE2 expressing cells (Created using BioRender Academic).
Figure 3 Cardiovascular involvement in COVID-19 – key manifestations and hypothetical mechanisms.
Figure 4 Different types of masks to be used according to type of procedures and levels of risk.
Figure 5 Guidance on donning personal protective equipment (PPE) to manage COVID-19 patients (modified from the "Handbook of COVID-19 Prevention and Treatment").77
Figure 6 Guidance on removing personal protective equipment (PPE) to manage COVID-19 patients (modified from the "Handbook of COVID-19 Prevention and Treatment").77
Figure 7 How do I protect myself?
Figure 8 Algorithm for triaging patients admitted to the ER for a suspected acute CV disease
Figure 9 Considerations in patients with suspected (or at risk for) cardiogenic shock and possible COVID-19 infection
Figure 10 Temporal changes in high-sensitivity cardiac troponin I concentrations from illness onset in patients hospitalized with COVID-19. Differences between survivors and non-survivors were significant for all time points shown. ULN denotes upper limit of normal (adapted from Zhou et al.34)
Figure 11 High-sensitivity cardiac troponin (hs-cTn) T/I concentrations should be interpreted as quantitative variables.
Figure 12 Recommendations for management of patients with NSTE-ACS in the context of COVID-19 outbreak
Figure 13 Management of patients with STEMI during COVID-19 pandemic
Figure 14 Management of patients with cardiogenic shock (CS)/out-of-hospital cardiac arrest (OHCA) during COVID-19 pandemic
Figure 15 Hypertension management in the COVID-19 context
Figure 16 Atrial tachyarrhythmias
Figure 17 Ventricular tachyarrhythmias
Figure 18 Channelopathies
Figure 19 QTc management
Figure 20 Patient information during the COVID-19 pandemic Part 1
Figure 21 Patient information during the COVID-19 pandemic Part 2
Table 1 Types of diagnostic approaches in COVID-1954, 65; *-still in experimental phase, now available for research; POC – point of care
Table 2 Testing priorities for COVID-19 pandemic according to Center for Disease Control, US
Table 3 General recommendations for Health Care Personnel, with adaption differentiated according to local community level of risk and containment strategies
Table 4 Patient risk status73
Table 5 SARS-CoV‑2 related personal protection management73, 81
Table 6 Non-invasive cardiovascular stress testing and imaging tests with the potential for deferral in the light of the COVID pandemic (Reproduced from Gluckman127)
Table 7 Impact on the healthcare system and regional involvement in the epidemic
Table 8 Strategical categorization of invasive cardiac procedures during the COVID-19 outbreak
Table 9 Recommendations for fibrinolytic therapy (Extracted from 114)
Table 10 Doses of fibrinolytic agents and antithrombotic co-therapies (Extracted from 114)
Table 11 Detailed inclusion and exclusion criteria for triage in intensive care unit upon admission (modified from Christian et al)142
Table 12 Criteria for little or no likelihood of benefit with ICU treatment (occurrence of at least 1 criterion)
Table 13 Management of chronic coronary syndromes during COVID-19 pandemic
Table 14 Categorization of electrophysiological procedures in the context of COVID-19
Table 15 Arrhythmological considerations of novel experimental pharmacological therapies in COVID-19 infection
Table 16 Interactions of anticoagulant drugs with COVID-19 therapies
Table 17 Concomitant conditions that may be associated with more severe course of SARS-CoV‑2 infection. Many of these features are confounded by age
Table 18 Potential interactions of drugs used to cure COVID-19
The European Society for Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic. https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance. (Last update: 28 May 2020).
The document is not a guideline. The recommendations are the result of observations and personal experience from health care providers at the forefront of the COVID-19 pandemic. © The European Society of Cardiology 2020. All rights reserved.
Our mission: To reduce the burden of cardiovascular disease.
© 2020 European Society of Cardiology. All rights reserved.