In December 2021, the U.S. Food and Drug Administration (FDA) issued emergency use
authorizations (EUAs) for two oral antiviral at-home treatments for coronavirus disease
2019 (COVID-19), nirmatrelvir/ritonavir (Paxlovid [Pfizer]), and molnupiravir (Merck).[1 ] While their mechanisms of action somewhat differ, these agents are considered “game-changers”
by some observers, since they do not require administration by intravenous infusion
as monoclonal antibodies do. Initial efficacy studies suggest that nirmatrelvir/ritonavir
may be more effective than molnupiravir,[1 ] but it also has more drug interactions of potential concern, especially related
to anticoagulant therapy.[1 ] Molnupiravir does not have any reported interaction with anticoagulant agents.[2 ] Additionally, remdesivir (Veklury [Gilead]) and bebtelovimab (Lilly) are parenteral
agents recently granted an EUA for use in the outpatient setting as treatment of mild-to-moderate
COVID-19 in adults with positive results of direct SARS-CoV-2 viral testing, who are
at high risk for progression to severe COVID-19, including hospitalization or death.[3 ] Neither of these agents have any known interaction with anticoagulants.[2 ]
Nirmatrelvir/ritonavir is comprised of nirmatrelvir, a SARS-CoV-2 main protease inhibitor,
co-packaged with ritonavir, a protease inhibitor.[4 ] While ritonavir has no activity against SARS-CoV-2, its inhibition of CYP3A-mediated
metabolism of nirmatrelvir increases nirmatrelvir plasma concentrations to levels
anticipated to inhibit SARS-CoV-2 replication. Outpatient nirmatrelvir/ritonavir use
is authorized for treatment of mild to moderate COVID-19 disease in adults and pediatric
patients older than 12 and weighting more than 40 kg who are at high risk for severe
progression of COVID-19.
Regarding pharmacokinetics, nirmatrelvir is primarily eliminated by the kidneys, with
minimal liver metabolism.[4 ] However, ritonavir is known to be an inhibitor of cytochrome P450 (CYP) isoenzymes,
particularly a strong CYP3A4 and weak 2D6 inhibitor, and an inhibitor of P-glycoprotein
(P-gp).[5 ]
[6 ] Additionally, ritonavir is an inducer of CYP 1A2, 2B6, 2C19, and 2C9.[5 ] On that premise, the risk of drug interactions with nirmatrelvir/ritonavir and many
commonly used medications, including statins and antiarrhythmic drugs, may preclude
its use or need careful adjustment of dosing. Additionally, the FDA label flags two
anticoagulants for nirmatrelvir/ritonavir users, rivaroxaban and warfarin, while other
direct oral anticoagulants (DOACs) are not mentioned. Inhibition of CYP3A4 and P-gp
leads to increased plasma levels and pharmacodynamic effects of rivaroxaban, thus
potentially increasing bleeding risk (area under the curve [AUC] change 153%, maximum
concentration (C
max ) change 53%).[7 ]
Antiplatelet or anticoagulant therapy is not currently recommended for outpatients
with COVID-19, the largest population of individuals infected.[3 ]
[8 ]
[9 ] The ACTIV-4B Outpatient Thrombosis Prevention Trial,[10 ] aimed at evaluating antithrombotic therapy in outpatients with COVID-19, was a randomized,
adaptive, double-blind, placebo-controlled trial that randomly assigned outpatients
with COVID-19 in a 1:1:1:1 ratio to receive aspirin (81 mg orally once daily), prophylactic-dose
apixaban (2.5 mg orally twice daily), therapeutic-dose apixaban (5 mg orally twice
daily), or matching placebo for 45 days. Treatment with aspirin or apixaban compared
with placebo did not reduce the rate of composite clinical outcomes, with risk of
adjudicated primary composite outcome with placebo being 0.0% (95% CI, 0.0–2.8%),
with aspirin 0.0% (95% CI, 0.0–2.6%), 0.7% in the prophylactic apixaban group (95%
CI, 0.1–4.1%) and 1.4% in therapeutic apixaban group (95% CI, 0.4% −5.0%), respectively.
In addition, a phase 2b placebo controlled randomized study of rivaroxaban 10 mg daily
in patients with COVID-19 not currently hospitalized or under immediate consideration
for hospitalization was terminated, after almost 500 of the target 600 participants
were enrolled because a prespecified interim analysis of the first 200 participants
in the intent-to-treat population demonstrated it would be futile to attempt to show
a beneficial effect of rivaroxaban in this patient population. Disease progression
rate with rivaroxaban was 20.7 versus 19.8% in placebo groups, with non-significant
risk difference of –1.0 (95% confidence interval, −6.4 to 8.4%; p = 0.78).[11 ] Thus, at this time, routine anticoagulation is not recommended for patients with
COVID-19 who do not need hospitalization.
Despite these findings, patients at high risk of thrombosis are usually prescribed
long-term anticoagulation therapy. Moreover, COVID-19 patients who require anticoagulants
for atrial fibrillation or flutter, recent surgery or immobility, heart valve replacement,
ischemic stroke or other thrombotic event should be treated with oral anticoagulant
(OAC) therapy. This may be a problem if they develop mild to moderate COVID-19 and
are considered high risk for severe COVID-19 disease as they would then be candidates
for nirmatrelvir/ritonavir.
While the package insert for nirmatrelvir/ritonavir mentions an increased bleeding
risk with rivaroxaban and warns against concomitant use, it is may be reasonable to
adjust the dose of apixaban, which like rivaroxaban is a substrate of both CYP3A4
and P-gp. Apixaban, edoxaban, and dabigatran have dose reduction strategies in their
prescribing information for certain high bleeding risk populations that can be adopted
for use with nirmatrelvir/ritonavir. For apixaban, it may be considered to reduce
the dose to 2.5 mg twice daily, and in patients already taking apixaban at a dose
of 2.5 mg daily, concurrent use of nirmatrelvir/ritonavir should be avoided.[12 ] For edoxaban, one might consider reducing the dose to 30 mg once daily.[13 ] Similarly, consideration of dose reduction of dabigatran to 110 mg twice daily instead
of the standard dose of 150 mg twice daily[14 ] may allow for dabigatran use with nirmatrelvir/ritonavir. However, unlike rivaroxaban,
there are no data available evaluating or demonstrating the same level of protection
from thrombotic events, or less bleeding, if reduced dose strategies are used in combination
with nirmatrelvir/ritonavir. There are no reported drug interactions with the use
of low molecular weight heparin (LMWH) (e.g., enoxaparin), unfractionated heparin
(UFH), fondaparinux, or the antiplatelet agent aspirin, with nirmatrelvir/ritonavir,
and these agents can be considered better alternatives if nirmatrelvir/ritonavir is
used.
Warfarin, which is metabolized by CYP450 isozymes including CYP2C9, 2C19, 2C8, 2C18,
1A2, and 3A4, also interacts with nirmatrelvir/ritonavir.[4 ] The S-enantiomer, which is the more potent isomer, is metabolized by CYP2C9, while
the R-enantiomer is metabolized by CYP1A2 and 3A4.[15 ] Induction of CYP1A2 and CYP2C9 leads to decreased levels of R-warfarin while minimal
pharmacokinetic effect is noted on S-warfarin when co-administered with ritonavir.
Decreased R-warfarin levels may lead to reduced anticoagulation, therefore it is recommended
that international normalized ratio (INR) is closely monitored when warfarin is administered
with ritonavir.
When selecting an agent for thromboprophylaxis in COVID-19 outpatients who are already
on an anticoagulant or are at high risk for arterial or venous thromboembolism (VTE),
it is essential to conduct a thorough review of potential drug interactions which
may diminish efficacy or increase risk of bleeding. Many of the drug interactions
are manageable and should not preclude patients from taking nirmatrelvir/ritonavir.
Nirmatrelvir/ritonavir is only for outpatient use prior to hospitalization for COVID-19
and the current data and recommendations are against initiating anticoagulants in
these patients regardless of other treatments.[16 ] Moreover, the only anticoagulant warning in the nirmatrelvir/ritonavir label is
for use with rivaroxaban (increased bleeding). Finally, other heparin compounds (UFH
or LMWH) do not interact with nirmatrelvir/ritonavir.
An ongoing large, randomized trial of approximately 4,000 patients, PREVENT-HD, is
comparing rivaroxaban 10 mg once daily with placebo in outpatients with COVID-19 (NCT04508023).
The trial may provide evidence as to whether there may be a benefit for anticoagulation
in outpatients. Patients who need to be on oral anticoagulation for reasons other
than COVID-19 present a challenge when starting nirmatrelvir/ritonavir. If possible,
the OAC should be temporarily discontinued for 5 days while the patient is taking
nirmatrelvir/ritonavir and for two additional days following discontinuation, to allow
washout of ritonavir.[17 ] If patients are not able to temporarily discontinue OAC (e.g., mechanical heart
valves, recent VTE, etc.), the following recommendations should be considered. If
the patient is unable to be off anticoagulation for a week, a bridging strategy using
LMWH may be considered the most feasible strategy while the patient is taking nirmatrelvir/ritonavir.
Otherwise, in patients who are on warfarin, the dose of warfarin should be reduced
and the patient should undergo more frequent INR testing to prevent over anticoagulation.
Patients currently taking rivaroxaban should either stop the drug temporarily or be
bridged with LMWH before initiating nirmatrelvir/ritonavir. If a patient is on another
DOAC (e.g., apixaban, dabigatran, edoxaban), consider using lower doses of these drugs;
however, there is no data available on safety or efficacy of lower doses of alternative
DOACs in combination with nirmatrelvir/ritonavir. If there is concern about temporarily
stopping OAC, bridging with LMWH, or using lower doses of OAC, patients can be placed
on other oral antivirals (molnupiravir), intravenous antivirals (remdesivir), or a
monoclonal antibody (bebtelovimab)[3 ] instead of using nirmatrelvir/ritonavir ([Fig. 1 ]) and continued on their current OAC at therapeutic doses.
Fig. 1 Proposed algorithm for the management of oral anticoagulation therapy in COVID-19
outpatients prescribed nirmatrelvir/ritonavir. COVID-19, coronavirus disease 2019; DOAC, direct oral anticoagulant; INR, international
normalized ratio; LMWH, low molecular weight heparin; OAC, oral anticoagulant.
