Evidence-Based Medical Therapy for the Treatment of Critically Ill COVID-19 Patients: A Primer for Cardiologists

COVID-1 9 endemicity challenges clinicians, because the virus can cause or exacerbate patient’s preexisting cardiovascular conditions. Various pharmacological therapies might improve outcomes in COVID-19 patients. Clinicians must stay current with guidelines. In this article we summarize evidence regarding the pharmacological treatment of critically ill COVID-19 patients, with the aim of assisting clinicians in decision-making.

Diagnosis

One of the main challenges in treating critically ill SARS-CoV-2-positive patients is determining if the virus is the primary cause of their symptoms, or if it exacerbates an underlying condition. This is difficult, because patients who present with hypoxemic respiratory failure and a white lung on chest radiograph might have acute pulmonary edema, COVID-19 pneumopathy, a bacterial lung infection, or a combination of these conditions. In such cases, the presence of fever and other viral symptoms might increase the likelihood that COVID-19 is the cause of the patient’s disease. Other factors that suggest COVID-19 is the predominant condition include the timing of the severe symptoms (10-14 days after pathogen exposure), laboratory abnormalities (eg, elevated inflammatory marker levels), and chest radiograph findings (eg, consolidation and ground-glass opacities, predominantly bilateral, peripheral, and lower zone).

After determining that COVID-19 is a contributing factor to the patient’s disease, clinicians must grade disease severity, because drug therapies are tailored to the clinical presentation. Most studies define a moderate disease as one that requires hospitalization for respiratory surveillance or oxygen supplementation of ≤ 15 L/min. A severe disease is defined as one that requires high-flow oxygen or noninvasive ventilation (NIV) because of hypoxemia. Critical disease involves mechanical ventilation (MV) or extracorporeal membrane oxygenation for respiratory failure, or is associated with septic shock or multiorgan failure. Clinicians should consider alternative causes for critically ill patients who test positive for SARS-CoV-2, because some treatments might exacerbate acute or chronic conditions.

Drug Therapy

In addition to standard critical care supportive therapies, some drug therapies have been shown to improve outcomes in SARS-CoV-2-infected patients. These include anti-inflammatory drugs, antivirals, antithrombotics, and monoclonal antibodies. Indications for these drugs are summarized in Table 1 , and their dosing and side effects are provided in Table 2 . For more information on the evidence summarized herein, including detailed summaries of appropriate randomized controlled trials, readers may refer to the living systematic review of the World Health Organization¹ and the National Institutes of Health (www.covid19treatmentguidelines.nih.gov/therapies/).

Table 1.

Drug therapy for COVID according to disease severity^∗

Disease severity	Corticosteroids (dexamethasone)	JAK inhibitors (barcitinib)	IL-6 pathway inhibitors (tocilizumab/sarilumab)	Remdesivir	Anti-SARS-CoV-2 monoclonal antibodies	Anticoagulation (UFH/LMWH)
Moderate
a) Hospitalized for respiratory surveillance without O2 supplementation	X	X	X	X	X	√ Consider full-dose anticoagulation if D-dimers ≥ upper limit of normal
b) O2 supplementation ≤ 15 L/min	√	√ Consider for patients with low-flow oxygen progressing toward increased needs	√ Consider for patients with low-flow oxygen progressing toward increased needs with CRP ≥ 75 mg/L	√	X
Severe
Hypoxemia requiring high-flow oxygen or NIV	√	√	√	√	X	X VTE prophylaxis only
Critical
Respiratory failure requiring MV or ECMO, or associated with septic shock or multi-organ failure	√	√	√	X	X	X VTE prophylaxis only

Combination of corticosteroids with JAK inhibitors and IL-6 pathway inhibitors is safe.

CRP, C-reactive protein; ECMO, extracorporeal membrane oxygenation; IL, interleukin; JAK, Janus kinase; LMWH, low molecular weight heparin; MV, mechanical ventilation; NIV, noninvasive ventilation; UFH, unfractionated heparin; VTE, venous thromboembolism; √, indicated; X, not indicated.

^∗This table shows a summary of current evidence for drug treatment of moderate to critically ill patients with COVID. It should be used with consideration of new literature, of the local institution protocols, and medication availability.

Table 2.

Drug dosage and side effects for treatment of COVID

Drug	Dosage	Common side effects/precautions
Dexamethasone	I.V./oral: 6 mg daily for up to 10 days or until discharge if sooner	Hyperglycemia, infections (including bacterial, fungal, and Strongyloides infections), psychiatric effects, myopathy, avascular necrosis, fluid retention, increased intraocular pressure/glaucoma
Barcitinib∗	Oral: 4 mg daily for up to 14 days or until discharge if sooner	• Myelosuppression, transaminases elevation, infections (mostly respiratory and urinary tract infections), DVT, GI perforation (rare) • Use it not recommended for eGFR < 15 mL/min/1.73 m2, absolute lymphocyte count < 200 cells per mm3 or ANC < 500 cells per mm3
Tocilizumab	• I.V.: single dose of 8 mg/kg (maximum dose 800 mg) • Second dose can be considered if there is no clinical improvement ≥ 8 hours after the first dose	• Neutropenia, thrombocytopenia, infections, hypersensitivity reactions, transaminases elevation, GI perforation • Use is not recommended for patients with uncontrolled serious infection other than COVID, ANC < 1000 cells per mm3, platelet counts < 50 × 109/L, ALT > 10 times ULN, elevated risk of GI perforation
Remdesivir	• I.V.: 200 mg on day 1 followed by 100 mg/d for 5 days total or until discharge if sooner • Extension for up to 10 days is possible if there is no clinical improvement	• Nausea, vomiting, transaminases elevation, anemia, AKI, fever, hyperglycemia, bradycardia, hypersensitivity reactions • Use is not recommended for eGFR < 30 mL/min/1.73m2, ALT > 10 times ULN
Anticoagulants
(A) UFH (B) LMWH (enoxaparin)∗	A) I.V.: initial bolus depending on bleeding risk followed by a continuous infusion adjusted after local nomogram (on the basis of the aPTT and weight) B) Subcutaneous: 1 mg/kg twice daily or 1.5 mg/kg/d • Continue for 14 days or until transfer to ICU or discharge if sooner	• Bleeding, heparin-induced thrombocytopenia, increased transaminases, hypersensitivity reaction, vasospasm • Use with caution for patients with severe thrombocytopenia (< 50 × 109/L) or anemia (< 80 g/L), active bleeding, or history of heparin-induced thrombocytopenia, need for dual antiplatelet therapy

AKI, acute kidney injury; ALT, alanine aminotransferase; ANC, absolute neutrophil count; aPTT, activated partial thromboplastin clotting time; DVT, deep venous thrombosis; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; I.V., intravenous; LMWH, low molecular weight heparin; UFH, unfractionated heparin; ULN, upper limit of normal.

^∗Dose should be reduced with renal insufficiency.

Anti-inflammatory therapies

Dexamethasone and other corticosteroids

Corticosteroids reduce the inflammatory response that can lead to multiorgan injury in COVID-19 patients. Dexamethasone was the first drug shown to reduce 28-day mortality by 3.3% to 8.7% and the need for MV by 3.0% in patients with moderate to critical disease, according to results from multiple randomized clinical trials (RCTs) including the Randomised Evaluation of COVID-19 Therapy (RECOVERY) and World Health Organization Solidarity trials with moderate-quality evidence.2, 3 It is now considered the cornerstone of treatment. Patients hospitalized for COVID-19 who require oxygen supplementation should receive 6 mg of dexamethasone daily for 10 days, or less if they are discharged. Side effects can include hyperglycemia and increased susceptibility to bacterial infections. No evidence supports using dexamethasone in nonhospitalized patients or in patients who do not require oxygen supplementation.

Interleukin-6 pathway inhibitors

Interleukin (IL)-6 is a proinflammatory cytokine that has been associated with more severe forms of COVID-19. Results from RCTs (RECOVERY, REMAP-CAP [Randomized Embedded Multifactorial Adaptive Platform for Community-Acquired Pneumonia]) suggest that tocilizumab, an IL-6 receptor antagonist, reduces mortality by 16 per 1000 treated patients and the need for MV by 23 per 1000 treated patients in patients with moderate to critical disease with high-quality evidence.1, 3, 4 A 6-month follow-up of critically ill patients who received an IL-6 receptor antagonist showed that it was the treatment with the greatest probability of improving survival at 180 days, with an estimated absolute mortality difference of 7.9% (REMAP-CAP Revisited).⁴

Tocilizumab should be given to patients who require high-flow oxygen or more, and considered for patients who require low-flow oxygen who progress toward increased needs because of COVID-19 with elevated inflammatory markers (C-reactive protein ≥ 75 mg/L). Patients who receive IL-6 receptor antagonists should also receive dexamethasone and might be candidates for a Janus kinase (JAK) inhibitor. A single intravenous dose of 8 mg/kg is recommended, without sufficient evidence for the routine use of a second dose. Caution should be taken in immunocompromised patients or patients with another uncontrolled infection. Possible side effects include neutropenia, thrombocytopenia, elevated transaminases, and gastrointestinal perforation.

JAK inhibitors

JAK inhibitors are thought to have immunomodulatory and antiviral effects, because they block the entry of the virus into respiratory system cells. Barcitinib reduces short-term mortality by 20 per 1000 treated patients compared with usual care in several RCTs (RECOVERY, COV-BARRIER [A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients with COVID-19 Infection]) among patients with COVID-19 who required oxygen supplementation with high-quality evidence.1, 3 Evidence suggests an 11 per 1000 decrease in MV need compared with usual care with moderate-quality evidence.¹

Barcitinib should be considered for hospitalized COVID-19 patients with increasing oxygen requirements via nasal canula, or those who require high-flow oxygen, NIV, MV, or extracorporeal membrane oxygenation. Treatment is recommended for 14 days or until discharge. Adverse effects might include myelosuppression, elevated transaminase levels, and infections. Combining a JAK inhibitor with dexamethasone and an anti-IL-6 agent has been shown to decrease mortality and could be considered in patients who are otherwise at lower risk of adverse events from these combinations of immunomodulatory therapies.

Antiviral therapies

Remdesivir

Remdesivir is a nucleotide analogue antiviral drug that inhibits viral replication by binding to viral RNA. In vitro and in vivo studies have shown its effectiveness against COVID-19. RCTs including the SOLIDARITY trial suggest that remdesivir might reduce mortality by 13 per 1000 treated patients and MV by 14 per 1000 treated patients in severe COVID-19 cases, with low to moderate certainty of evidence.1, 2 This treatment can be considered for patients hospitalized with high-flow oxygen or NIV. No evidence supports the use of remdesivir for critical COVID-19 cases. Treatment should be started as soon as possible and given daily for 5 days or until discharge. Treatment can be prolonged for up to 10 days in cases with slow improvement. Common side effects include nausea, vomiting, and elevated transaminase levels and use is not recommended for patients with severe kidney or liver impairment.

Anti-SARS-CoV-2 monoclonal antibodies

Anti-SARS-CoV-2 monoclonal antibodies target circulating virus variants. Although some data showed mortality benefit for certain COVID-19 seronegative patients using casirivimab-imdevimab and sotrovimab, most of these studies were conducted before the emergence of newer COVID-19 variants. Efficacy against new variants has significantly decreased, and guidelines no longer recommend their use.

Antithrombotic therapy

Anticoagulants

COVID-19 is associated with a proinflammatory state and hypercoagulability. Venous thromboembolism (VTE) incidence in hospitalized COVID-19 patients was higher at the beginning of the pandemic, but tends to be lower with newer variants.

Patients with chronic anticoagulation for other conditions should continue anticoagulation while they have COVID-19 unless there is a major bleeding event or other contraindication.

Favourable results from RCTs (ATTACC [Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19]/ACTIV-4A [Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE]/REMAP-CAP, RAPID [Therapeutic Anticoagulation vs Standard Care as a Rapid Response to the COVID-19 Pandemic], HEP-COVID [Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19]) support therapeutic anticoagulation for certain COVID-19 patients to improve outcomes including organ-free support days, transfer to the intensive care unit (ICU) and VTE incidence, with moderate-quality evidence (https://www.covid19treatmentguidelines.nih.gov/therapies/). For noncritical hospitalized patients with moderate COVID-19 and with a D-dimer level greater than the upper limit of normal, full-dose anticoagulation should be considered. Individual bleeding risk and contraindications to anticoagulation should be assessed before initiating treatment. Anticoagulation should be continued for 14 days or until hospital discharge or transfer to the ICU. Low molecular-weight heparin or unfractionated heparin are the preferred therapies when full-dose anticoagulation is required because of their shorter half-lives, easy reversibility, and fewer drug interactions. Data are lacking to support the use of oral anticoagulants, and their use was associated with an increased risk of bleeding in 1 study.⁵

Hospitalized patients who do not meet these criteria, including those in the ICU, should receive VTE prophylaxis. No data support the use of an intermediate dose of heparin.

Antiplatelets

RCT studies of antiplatelets, including aspirin and P2Y12 inhibitors, for the treatment of COVID-19 (RECOVERY, ACTIV-4A/ACTIV-4B [Accelerating COVID-19 Therapeutic Interventions and Vaccines 4], COVID-PACT [Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial]) previously failed to show a significant clinical benefit.³ Therefore, antiplatelets are not part of current recommendations unless patients have another indication.

However, recent data from an RCT on long-term outcomes of interventions for critically ill COVID-19 patients at 180 days (REMAP-CAP Revisited) showed that antiplatelets (aspirin or P2Y12 inhibitors) reduced mortality and increased organ support-free days. It was the second most likely treatment to improve survival, with an estimated difference in 180-day mortality of 3.5%.⁴ Future guideline updates might reflect these findings, but antiplatelets can be considered as an adjunct therapy in critically ill patients without contraindications who match the REMAP-CAP trial inclusion criteria.

Antibiotics

The use of empiric broad-spectrum antibiotics for patients hospitalized with COVID-19 has not been specifically studied. However, observational data do not suggest a greater risk of bacterial coinfection, and international guidelines advise limiting antibiotics to patients with proven bacterial pneumonia or those highly suspected to have bacterial infection, such as those experiencing deterioration of respiratory failure, septic shock, or a new lung consolidation on chest radiograph after initial presentation. The same principle applies to patients coinfected with other treatable viruses, such as influenza.

Other considered treatments

Convalescent plasma, ivermectin, hydroxychloroquine, intravenous immunoglobulins, lopinavir-ritonavir, colchicine, anti-IL-1 agents, interferon-β, and azithromycin have all been studied in RCTs but have not shown a clear clinical benefit for the treatment of hospitalized patients with COVID-19 and should not be used.

Conclusion

SARS-CoV-2 might contribute to clinical deterioration or exacerbate preexisting cardiovascular conditions. Various pharmacological therapies have shown efficacy in improving outcomes for patients with COVID-19. As understanding of the virus and its effects evolves, medical professionals must stay updated on the latest evidence-based treatment recommendations to optimize patient outcomes.