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Managing anticoagulation in the COVID-19 era between lockdown and reopening phases

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. The recent spreadout of the COVID-19 pandemic requires a re-organization of Anticoagulation Clinics to prevent person-to-person viral diffusion and continue to offer the highest possible quality of assistance to patients. In this paper, based on the Italian Federation of Anticoagulation Clinics statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points: (1) re-thinking the AC organization, (2) managing patients on anticoagulants when they become infected by the virus, (3) managing anticoagulation surveillance in non-infected patients during the lockdown period, and (4) organizing the activities during the reopening phases.


Introduction
Patients on anticoagulant treatment are constantly increasing, with a prevalence of nearly 2% of the total population [1].
Anticoagulation Clinics (ACs) routinely manage thousands of patients taking anticoagulants, either vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs), or parenteral drugs. ACs are pivotal in anticoagulation management, providing site visits for patients, remote monitoring, and integration with local health facilities [2].The recent spreadout of the COVID-19 pandemic requires a re-organization also of ACs, to prevent person-to-person diffusion. As most of the patients taking oral anticoagulants show at least one comorbid condition, it is becoming more evident that the ACs should continue to offer the highest possible quality of assistance, while assuring all safety standards against viral transmission.
In this paper, based on the Italian Federation of Anticoagulation Clinics (FCSA) statements, we offer some advice aimed at improving patient care during COVID-19 pandemic, with particular regard to the lockdown and reopening periods. We give practical guidance regarding the following points (Table 1)

Re-thinking the AC organization
During pandemic periods and social distancing, all nonurgent health activities, such as periodical control visits in patients with chronic diseases or elective surgery, have been interrupted. Due to the necessity to maintain periodic controls in all anticoagulated patients, we suggests the following: 7. Information material should be made available, aiming to address ordinary difficulties in the routine management of the treatment (e.g., minor bleedings and drugdrug interactions).

Asymptomatic or paucisymptomatic patients
Many COVID-19 patients may be treated and discharged to home. For these patients, continuing the usual treatment dose should be recommended, conditional that the patient is able to maintain adequate hydration and does not need to use of interfering drugs (see below). VKAs' treatment should be continued in patients with mechanical heart valves when a careful INR control is achievable.

Symptomatic patients with moderate-to-severe disease
If the clinical conditions deteriorate, several potentially important issues may cohesist. First, the concomitant use of interfering drugs may be necessary For instance, lopinavir/ritonavir may have the potential for CYP2C9/ CYP3A4 induction, as well as for P-gp inhibition [4,5]. Second, a severe coagulopathy has been widely described [6,7]. Prolonged prothrombin time is frequently reported, making difficult the monitoring of anticoagulation with PT-INR. Third, adequate oral food intake may be impossible in these patients with unpredictable effects on the absorption of drugs. We suggest withholding oral anticoagulation with either DOACs or VKAs and start antithrombotic treatment at therapeutic dose with lowmolecular-weight heparin (LMWH) in these patients. In patients with severely reduced renal function (estimated glomerular filtration rate 15-30 mL/min), we recommend measuring anti-Xa activity to maintain the therapeutic range (aXa = 0.5-1.2 UI/mL). In case of CrCL < 15 mL/ min, we recommend switching to unfractioned heparin (UFH) with a target aPTT ratio of 1.5-2.0 or aXa activity 0.3-0.7 UI/mL [8].

Manage anticoagulation surveillance in non-infected patients during the lockdown period
In this phase, the vast majority of patients are afraid of getting infected and may have difficulties in reaching the AC. Moreover, the AC should provide a support to patient with counseling through phone calls and e-mail and to physicians directly involved in the management of COVID-19 patients for optimal antithrombotic strategy.

Patients on VKAs
All therapeutic prescriptions should be re-considered to reduce as much as possible the number of INR controls. All patients with stable anticoagulation should receive written prescriptions for longer intervals, possibly 6-8 weeks [9,10]. When longer intervals between laboratory controls are requested, patients should have easy access to telephone call with the doctors of AC, if new clinical problems occur.

Patients on DOACs
Routine control visits for patients on DOACs should be delayed, providing telephone contact to evaluate the patient's clinical conditions and to identify selected patients who need a more careful surveillance.

Organizing the activities during the reopening phases
Currently, the evolution of the COVID-19 pandemic is still unknown. Italy, like many other European countries and the US, are experiencing the reopening phases of real-world activities, but recurrences of COVID-19 infections are expected. In this phase, we recommend that all ACs actively follow up anticoagulated patients through laboratory and clinical controls.

General measures
ACs should evaluate protocols and strategies to implement telemedicine services to reduce physical contacts in the case of COVID-19 recurrences. Clinical and laboratory control should be performed in all patients and the anamnesis updated, paying particular attention to recent co-morbidities and new therapies. All centers are invited to actively participate in drafting hospital protocols, collaborating with all the staff involved in the management of COVID-19 patients.

Patients on VKAs
PT INR should be checked as soon as possible. In these periods, the switch from VKAs should promptly be considered, in the absence of contraindication, in all patients.

Scientific research
All AC should participate in scientific studies that are now approved by National Ethical Committee and ongoing in our country on this new devastating disease. FCSA is always involved in scientific research and is now promoting the national START-COVID-19 registry within the frame of the wider START2-REGISTER study (ClinicalTrials.gov Identifier NCT02219984). All ACs, which are involved in the treatment of COVID-19 patients or are connected with COVID-19-dedicated hospital units, are invited to take active part in the START-COVID-19 registry (online information available).

Compliance with ethical standards
Conflicts of interest The authors declare that they have no conflict of interest.

Statement of human and animal rights
This article does not contain any studies with human participants or animals performed by any of the authors.
Informed consent Informed consent was not required.
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