The sudden outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
virus, which causes coronavirus disease 2019 (COVID-19), occurred in China in late
2019 and was followed by rapid transmission across Europe in early 2020. National
healthcare systems experienced immense pressure and stretch in terms of the availability
of medical personnel, access to treatments and consequently, the sustainability of
outpatient clinics. The treatment of patients affected by COVID-19 has been prioritised,
and all resources have been focused on serving that growing population. As a result,
the management of familial hypercholesterolaemia (FH), in both the common heterozygous
(heFH) and the much more rare homozygous (hoFH) forms is impacted and has been handled
differently in different countries. The management of FH already varies between countries
due to factors related to population characteristics, practice, resources and policies
[1]. The aim of this document is to share practical recommendations about the management
of FH patients and optimisation of their treatment during the COVID-19 pandemic.
The pandemic of a new coronavirus is a great challenge for healthcare systems worldwide,
with 3.3 million infected individuals, and almost 235,000 deaths (as of May 1st) [2].
Observational data allows us tentatively to identify patients at the highest risk
of severe consequences resulting from COVID-19, which includes those over 75 years
of age (death rate: 14.2%), with baseline cardiovascular disease (CVD) (>13% for confirmed
cases), with diabetes (9.2%), chronic respiratory disease, hypertension and cancer
(death rate ≥7.5% for all) [3]. Therefore, in order to reduce the risk of a severe
disease course in individuals with COVID-19, it is critically important to improve
the treatment of all concomitant diseases, for both healthy people and those already
infected. Moreover, physicians need to know whether a patient’s baseline therapy regimen
should be continued concomitantly with antiviral, antiretroviral, anti-parasitic,
antirheumatic, and antibiotics (mainly macrolides) that may be administered to individuals
with symptoms of COVID-19 [4]. An equally important challenge is to provide accessible
healthcare to those patients with concomitant diseases, including ambulatory and in-patient
care, and continued access to laboratory measurements, imaging tests, and medicines.
FH patients are a group with important healthcare needs who require frequent and continued
medical attention. It is estimated that more than 30 million individuals worldwide
have FH, and this large number of patients is of special importance at the time of
a global pandemic of SARS-CoV-2 [5]. Both heFH and hoFH patients (especially the latter)
have a genetic predisposition to very high circulating concentrations of low-density
lipoprotein cholesterol (LDL-C). Recent recommendations suggest that all FH patients
should be considered to have (at least) a high CVD risk [6]. If they have any additional
risk factors, FH patients are at very high risk. The most recent recommendations suggest
that FH patients should be considered to have an extremely high risk of repeated events
if they have had an occurrence of acute coronary syndrome (ACS) [7]. Consequently,
all these patient groups should be treated in order to achieve a circulating concentration
of LDL-C below 70 mg/dL (1.8 mmol/L), and those at very high risk below 55 mg/dL (1.4 mmol/L),
according to the principle of ‘the lower, the better’. This is critically important
in order to stabilize and potentially even reduce the burden of atherosclerotic plaque,
and consequently to lower CVD events’ risk as well as mortality [8,9]. Lipid-lowering
therapy (LLT) with statins, fixed combinations of statins with ezetimibe, and/or triple
therapy with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors results
in stabilization of plaques and prevention of CVD events [8,9]. However, these drugs
have additional mechanisms of action. Statins may substantially reduce inflammation
and oxidative stress beyond that attributable to LDL-C reduction (and the reduction
of oxidized LDL-C), through pleiotropic (anti-inflammatory) effects. PCSK9 inhibitors
potentially reduce inflammation as a result of (among other effects) downregulation
of LDL receptors, reduction of proinflammatory mediators, reduced infiltration of
monocytes into the subendothelial layer and monocyte migration, and amelioration of
vascular inflammation [[10], [11], [12]]. These mechanisms are critically important
in the context of COVID-19, because available data suggests that the disease results
in a cytokine storm in susceptible patients, which would be expected to promote instability
of the atherosclerotic plaque and consequent myocardial infarction with a very poor
prognosis [13]. Therefore, because FH patients are at high, or extremely high risk
of CVD, they need to be treated optimally and it is vital for them to have access
to drugs and procedures (such as lipid apheresis in the case of severe HeFH and HoFH).
Physicians need to know how to optimally manage FH patients who become infected with
coronavirus, and to be aware of any interactions between drugs used to treat COVID-19,
and drugs used in the management of FH.
Equally important is the effective organization of healthcare systems at this difficult
time in order to continue the treatment of patients with FH and to enable the diagnosis
of new cases, and consequent initiation of suitable treatments including PCSK9 inhibitors.
Healthcare systems should be organized in such a way to allow the effective therapy
of patients with COVID-19 (including those with FH), but also to allow the optimal
treatment of uninfected FH patients, especially those with life-threatening CV complications,
to avoid an increase in morbidity and mortality unrelated to COVID-19. Meeting these
two objectives simultaneously is difficult because of the large number of SARS-CoV-2
cases being admitted to hospital and also changes the out-patients’ routine practices.
When implementing lockdown procedures, which limit access to healthcare, and developing
legislation relating to COVID-19, Ministries of Health (or equivalent organizations
responsible for healthcare administration) should consider allowing temporary access
to drugs, which are effective in FH but are not currently widely available. Lomitapide
may effectively prevent CVD events when lipid apheresis is unavailable [14]. Reimbursement
for PCSK9 inhibitors could be extended for those at very high and extremely high-risk
patients of CVD events, who do not meet the current criteria in given countries. Access
to these drugs for new and already treated patients could be improved by allowing
GPs to prescribe them. In this way, it would be possible to have most FH patients
on optimal LLT, resulting in fewer CVD events, and better prognosis should these patients
become infected with SARS-CoV-2. [13,15]. Finally, it is essential that educational
activities for patients at the highest risk of CVD (including those with FH) are continued.
These include joint activities of governmental organizations, scientific societies
and patient organizations, which provide regular and extensive information on drug
accessibility. It is also essential to maintain the availability of necessary procedures
for FH patients in specialized centers (e.g. drug programs, lipid apheresis).
Based on the information summarised above, experts from the International Lipid Expert
Panel (ILEP) and the European FH Patient Network (FH Europe) have taken part in online
meetings and discussions with the representatives of the European countries. These
meetings resulted in the preparation of recommendations on how to manage FH patients
during the coronavirus pandemic. Taking into account the similar way of management
they might be also extended for non-FH patients with severe hypercholesterolemia being
at high/very high CV risk. The recommendations are presented in a ‘question and answer’
(Q&A) format (Table 1
).
Table 1
Q&A recommendations for the management with patients with FH during the COVID-19 pandemic.
Table 1
1.
Are there any additional beneficial effects of LLT on SARS-Cov-2 infection?
This still needs to be confirmed with further research on SARS-CoV-2. However, in
one study with infectious bronchitis coronavirus (IBV-CoV), it was demonstrated that
cholesterol reduction disrupted lipid rafts and prevented binding of coronavirus with
the host cells. In another study with porcine deltacoronavirus (PD-CoV), the authors
observed that cholesterol present in the cell membrane and viral envelope contributed
to virus replication by acting as a key component in viral entry. Therefore, the pharmacological
reduction of cellular or viral cholesterol with effective LLT might block both virus
attachment and internalization [16,17]. There is also data suggesting that statins
might enhance angiotensin converting enzyme 2 (ACE2), which could mitigate the invasion
of SARS-CoV-2 through the ACE2 receptor, potentially having a beneficial effect in
attenuating risk of infection [18]; another data, based on in-silico study, showed
that pitavastatin, rosuvastatin, lovastatin, and fluvastatin could be efficient SARS-CoV-2
main protease inhibitors [19].
2.
Are patients with FH at increased risk of COVID-19 complications?
At every age FH patients have an increased risk of experiencing a severe course of
COVID-19. This is because of their elevated lifelong risk of CVD (which may be as
much as 100x higher at the age of 20-40 in comparison to healthy subjects, and is
at least similar to that of patients with baseline CVD) [6]. Therefore, FH patients
should strictly follow the directions of social distancing and isolation, wear masks
and gloves when outside, and should wash their hands as often as possible. Detailed
advice is available elsewhere, e.g., https://www.nhs.uk/conditions/coronavirus-covid-19/advice-for-people-at-high-risk/
3.
Can FH patients be suitably monitored and treated when ambulatory clinics visits and
scheduled hospitalizations are cancelled?
FH patients should receive all the necessary medical information via electronic resources
(e-advice) and/or e-consultations (with a physician or nurse). Drugs should be prescribed
electronically (e-prescription). In the case of ongoing therapy, LDL-C measurements
can be postponed. For newly diagnosed patients, the intensification of the therapy
should be based on CVD risk stratification and the last two available LDL-C measurements
(also necessary for further monitoring of LLT effectiveness). When tools for telemedicine
are unavailable in hospitals, phone consultations can be used to provide advice to
patients. Drugs should be prescribed for at least 3 months. This also applies when
appointments are postponed or cancelled due to staff unavailability.
4.
What about ongoing screening and identification as well as treatment of newly confirmed
patients?
In most countries, active searching and diagnosis of new FH patients has been put
on hold. However, based on the above recommendations, when a new phenotypic and/or
genetic diagnosis is made (e.g. during hospitalization) patients should be immediately
directed to a specialized lipid center and should receive an e-consultation in order
to start effective therapy (with e-prescription) as quickly as possible. For further
details see above.
5.
Are statins safe in FH patients with coronavirus infection?
Lipid-lowering drugs are generally safe in patients with coronavirus infections and
should be continued. When COVID-19 is treated with antiretroviral drugs (lopinavir/ritonavir)
it is recommended that prescribers discontinue atorvastatin, simvastatin, and lovastatin.
It is possible to continue therapy with rosuvastatin, with preference for starting
a low dose (5-10 mg) and titrating up (with careful monitoring of muscle symptoms
and creatine kinase levels). It is also reasonable to lower the dose of rosuvastatin
and prescribe it in fixed combination with ezetimibe, or to continue therapy with
pravastatin or fluvastatin (with or without ezetimibe, as necessary) [10,20]. Caution
is necessary when treating patients with some macrolides (erythromycin, clarithromycin,
and telithromycin) [9]. However, there is no data on severe or serious interactions
of rosuvastatin and fluvastatin with azithromycin (inconsistent data refers to the
potential interactions with atorvastatin; moderate to severe interactions were observed
for simvastatin, lovastatin and pitavastatin) [21]. In case of muscle symptoms occurrence
patients should be managed based on available recommendations for statin intolerance
[22]. There are no contraindications to use statins with chloroquine and hydroxychloroquine
[9]. There is also no data on any interactions of statins with remdesivir [23]. In
case of therapy with tocilizumab, rosuvastatin is recommended, as simvastatin and
atorvastatin concentrations may be reduced when used concomitantly with this drug
[24].
6.
What about therapy with ezetimibe and PCSK9 inhibitors?
In patients not meeting the therapeutic target for LDL-C with high intensity statin
therapy, as well as in those with statin intolerance, therapy with ezetimibe and PCSK9
inhibitors is recommended [9,25,26]. In addition to significantly reducing the risk
of CVD events and mortality, PCSK9 inhibitors may exert some additional anti-inflammatory
effects. There is no data on any interactions of ezetimibe and PCSK9 inhibitors with
any drugs that might be used during coronavirus infections [9,10,25].
7.
What about patients requiring lipid apheresis when the treatment is not accessible?
All patients requiring regular (every 1-2 weeks) lipid apheresis, including very high
risk HoFH patients, should be enabled to access this procedure. Where this is not
possible, treatment might be postponed safely by as much as 2 months while using intensive
LLT, and strict monitoring of symptoms. When clinical symptoms arise, patients should
be admitted to hospitals as urgent cases. In the absence of apharesis appropriate
health organizations shall consider alternative therapies. There is therefore a need
to lobby governments to ensure FH patients are able to access effective therapies
within reimbursement programs (lomitapide/PCSK9 inhibitors).
8.
What can patients do in order to monitor their disease?
With the help of the national scientific societies and patients’ organizations, it
is important to continuously advise and educate FH patients on self-monitoring and
the self-reporting of symptoms. Education and advise on continuting lifestyle changes,
exercise and dietary treatment should be provided, as they can be severely compromised
by stay-at-home directives. It may be critically important to enable e-consultations
with physicians to prevent undesirable events.
1
Financial disclosure
MB - speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm,
KRKA, MSD, Polpharma, Sanofi-Aventis, Servier and Valeant; consultant to Abbott Vascular,
Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Polfarmex,
Resverlogix, Sanofi-Aventis; Grants from Sanofi and Valeant; PEP owns four shares
in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events
sponsored by AKCEA, Amgen, AMRYT, Link Medical, Napp, Sanofi; ZF has received reimbursements
for lectures, advice and research / institutional grant support from Sanofi-Aventis,
as well as reimbursements by Amgen, Astra Zeneca, Bayer, Boehringer-Ingelheim, Krka,
Novo Nordisk, Pfizer, Sanofi-Aventis, and Servier; MV has received research support
and consulting fees from Amgen, Pfizer, Sanofi, and MSD; and nonfinancial support
from Amgen and Sanofi; ZR has received honoraria from Sanofi-Aventis; MK has received
honoraria (for lectures and consultancy) from Abbott and Menarini, and research funding
from Amryt Pharma, Amgen, and Sanofi, and has participated in clinical trials with
Amgen, Medicines Company, Regenerone, and Sanofi within the last 2 years. All other
authors have noting to disclose.
Declaration of Competing Interest
No professional writer was involved in the preparation of this review.
Funding
No external founding.