Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE – Coalition COVID-19 Brazil VIII)

Oliveira, Gustavo B. F.; Neves, Precil Diego M. M.; Oliveira, Haliton A.; Catarino, Daniela Ghidetti Mangas; Alves, Lucas B. O.; Cavalcanti, Alexandre B.; Rosa, Regis G.; Veiga, Viviane C.; Azevedo, Luciano C.P.; Berwanger, Otávio; Lopes, Renato D.; Avezum, Álvaro

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Arquivos Brasileiros de Cardiologia

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Original Article • Arq. Bras. Cardiol. 120 (3) • Mar 2023 • https://doi.org/10.36660/abc.20220431 copy

Rivaroxaban in Outpatients with Mild or Moderate COVID-19: Rationale and Design of the Study CARE (CARE – Coalition COVID-19 Brazil VIII)

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background

Previous studies have demonstrated a high risk of arterial and venous thromboembolic events as a consequence of direct viral damage to endothelial cells by SARS-CoV-2 and a procoagulant milieu due to increased biomarkers, such as D-dimer, fibrinogen, and factor VIII. Although randomized controlled trials of antithrombotic therapies have been conducted in hospitalized patients, few have evaluated the role of thromboprophylaxis in an outpatient setting.

Objective

To assess whether antithrombotic prophylaxis with rivaroxaban reduces the risk of venous or arterial thrombotic events, invasive ventilatory support, and death in COVID-19 outpatients.

Methods

The COVID Antithrombotic Rivaroxaban Evaluation (CARE) study, a multicenter, randomized, open-label, controlled trial of rivaroxaban 10 mg once daily for 14 days or local standard treatment alone to prevent adverse outcomes, is registered in clinicaltrials.gov (NCT04757857). The inclusion criteria are adults with confirmed or suspected SARS-CoV-2 infection and mild or moderate symptoms without indication for hospitalization, within 7 days of symptom onset, and 1 risk factor for COVID-19 complication (> 65 years, hypertension, diabetes mellitus, asthma, chronic obstructive pulmonary disease or other chronic lung diseases, smoking, immunosuppression, or obesity). The primary composite endpoint, which includes venous thromboembolism, invasive mechanical ventilation, major acute cardiovascular events, and mortality within 30 days of randomization, will be assessed according to the intention-to-treat principle. All patients will provide informed consent. A significance level of 5% will be used for all statistical tests.

Results

Major thrombotic and bleeding outcomes, hospitalizations, and deaths will be centrally adjudicated by an independent clinical events committee blinded to the assigned treatment groups.

Conclusion

The CARE study will provide relevant and contemporary information about the potential role of thromboprophylaxis in outpatients with COVID-19.

COVID-19; Thrombosis; Treatment Outcome; Rivaroxaban; Outpatient Clinics, Hospital

COVID-19 status

Definition

Confirmed

Patients with a laboratory confirmed COVID-19 diagnosis by RT-PCR, preferably collected between the fourth and seventh days after symptom onset by nasopharyngeal/oropharyngeal swab, regardless of signs and symptoms.
Validated rapid immunochromatographic assay for viral antigen detection in sample collected from the upper respiratory tract, preferably between the second and seventh days after sign/symptom onset.
Immunological (rapid test or classic serology to detect IgM/IgG antibodies), in a sample collected on at least the seventh day after symptom onset, analyzed by a validated test.

Suspected

Patients who meet at least one of the following criteria *:

Patients with acute respiratory disease (fever AND at least 1 sign/symptom of respiratory disease, eg, cough or dyspnea), AND a history of travel or residence in a location that has reported the community transmission of COVID-19 during the 14 days prior to symptom onset.
Patient with acute respiratory disease AND contact with a confirmed or probable case of COVID-19 (acute respiratory disease without laboratory confirmation) in the 14 days prior to symptom onset.

General Criteria
Adult outpatients (aged > 18 years) who seek medical care and have a suspected or confirmed diagnosis of COVID-19, are within 7 days of symptom onset, present with mild to moderate symptoms, have no clear indication for hospitalization, and at least two of the following risk factors for complications:

Inclusion Criteria

Age ≥ 65 years Hypertension Diabetes mellitus Asthma COPD or other chronic lung diseases Smoking Immunosuppression Obesity (BMI > 30) History of non-active cancer Bed restriction or reduced mobility (≥ 50% of waking time without walking)) Previous history of venous thromboembolic events Use of oral hormonal contraceptives

Exclusion Criteria

Patients aged <18 years Hospitalization indicated at initial treatment Positive test for influenza at the first visit Any known liver disease associated with coagulopathy; INR > 1.5 Women who are pregnant, lactating, may become pregnant, or are not using an adequate contraception method Patients with a high risk of bleeding, a history of bronchiectasis or pulmonary cavitation, significant bleeding in the last 3 months, an active gastroduodenal ulcer, a history of recent bleeding (within 3 months), or a high risk of bleeding Stroke in the last month, a history of hemorrhagic or lacunar stroke, any intracranial bleeding or neoplasia, brain metastasis, arteriovenous malformation, or brain aneurysm Severe heart failure with left ventricular ejection fraction < 30% (identified by echocardiogram or another previously validated method) or symptoms of New York Heart Association heart failure class III or IV Estimated glomerular filtration rate < 30 mL/min according to the CKD-EPI equation Clinical indication for dual antiplatelet therapy or anticoagulation therapy (venous thromboembolic events, atrial fibrillation/flutter, or mechanical valve prosthesis) Marked thrombocytopenia (platelets < 50,000/mm3) Non-cardiovascular disease associated with a poor prognosis, eg, active cancer (excluding non-melanoma skin cancer), defined as cancer not in remission or that requires active chemotherapy or adjuvant therapies, such as immunotherapy or radiation therapy, or that increases the risk of an adverse reaction to the interventions A history of hypersensitivity or known contraindication to rivaroxaban Systemic treatment with strong inhibitors of CYP3A4 and P-glycoprotein (systemic azole antimycotics, such as ketoconazole, or HIV protein inhibitors, such as ritonavir) or strong inducers of CYP3A4, ie, rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine Current treatment in test phase Concomitant participation in another COVID-19 study involving experimental drugs Use of chloroquine or hydroxychloroquine associated with azithromycin Active cancer Other contraindications to rivaroxaban

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E-mail: revista@cardiol.br

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[1] Mailing Address: Álvaro Avezum • International Research Center – Hospital Alemão Oswaldo Cruz – Rua Treze de Maio, 1815. Postal Code 01323-020, Bela Vista, São Paulo, SP – Brazil E-mail: aavezum@haoc.com.br