Collectively, these effects can all result in the aggravation of existing CVDs and trigger severe events, such as acute coronary syndromes, thrombosis, myocardial ischemia or exacerbation of HF. Indeed, cardiovascular protective strategies are needed for the prevention and management of severe adverse cardiovascular events to improve the prognosis of COVID-19 patients (Table 5, Table 6 ).
Table 5 Overview of proposed pharmacological approaches to attenuate COVID-19 associated cardiovascular injury.
Pharmacological intervention Sample size and criteria Treatment protocol Key findings Conclusion Reference
• Colchicine for the improvement of cardiac biomarkers, inflammation, and clinical outcomes • Prospective, open-label randomized controlled trial (RCT)
•  N = 55 colchicine + standard care
•  N = 50 standard care
• Primary endpoints included maximum cardiac troponin level, time for C-reactive protein (CRP) to reach 3× upper limit normal, time to deterioration by at least 2 points on clinical status scale • Colchicine 1.5 mg loading dose, 0.5 mg after 60 min, and then 0.5 mg twice daily + standard care for up to 3 weeks • No difference in cardiac troponin or CRP levels
• Clinical deterioration less common with colchicine treatment odd ratio (OR) 0.11 (95% CI 0.01–0.96)
• Abdominal pain and diarrhea significantly more common with colchicine treatment • Colchicine may not have a significant effect on cardiac or inflammatory biomarkers, however it may be useful in stabilizing patients with severe COVID-19 infection and preventing clinical deterioration (Deftereos et al., 2020)
• Statin therapy and impact on inflammation and patient prognosis • Retrospective cohort study
• Primary endpoint of 28-day all-cause mortality
• Secondary endpoint included acute cardiac injury
•  N = 1219 statin use
•  N = 12, 762 no statin • In-hospital statin use
• Atorvastatin 83.2%,
• Rosuvastatin 15.6%
• Dose differences between statins were converted to a daily equivalent dose of atorvastatin ranging from 18.9–20.0 mg/day • Reduced all-cause mortality with statin use hazard ratio (HR) 0.63 (95% CI 0.48–0.84)
• Patients on ACEi/ARB therapy in addition to statin did not have increased mortality compared to statin alone
• Statin therapy not associated with acute cardiac injury
• Inflammatory markers CRP, IL-6 were lower in statin treated patients while in hospital • Reduced mortality and improved prognosis associated with in-hospital statin use may be due to the anti-inflammatory and immunomodulatory effects of statins (Zhang, Qin, Cheng, et al., 2020)
• ACEi/ARB impact on mortality in COVID-19 patients with concomitant hypertension • Retrospective, multi-centre cohort study
• Patients with comorbid hypertension hospitalized with COVID-19
• Age 18 to 74 years
• Primary endpoint of 28-day all-cause mortality
•  N = 188 ACEi/ARB therapy
•  N = 940 no ACEi/ARB • ACEi/ARB for treatment of hypertension
• individual patient dosing regimens not specified • Risk of all-cause mortality lower in ACEi/ARB treated group HR 0.42 (95% CI 0.19–0.92).
• Use of ACEi/ARB in comparison to other anti-hypertension therapies was associated with lower mortality HR 0.30 (95% CI 0.12–0.70).
• No difference in acute cardiac injury outcome between groups • Chronic ACEi/ARB therapy may not increase mortality of COVID-19 patients
• May not have much benefit in acute heart injury due to COVID-19 inflammation (Zhang, Zhu, Cai, et al., 2020)
• Statin use impact on acute myocardial injury patient outcomes • Retrospective observational cohort study
• Patients with elevated troponin
• History of CVD in 24% of patients
•  N = 3069
• Objective to characterize myocardial injury and associated outcomes • 36% of patients using statins
• Doses and regimens not specified • Statin use amongst patients with acute myocardial injury was associated with improved survival HR 0.57 (95% CI 0.47–0.69) • Statin treatment may be associated with a survival benefit in patients with CVD and elevated troponin levels
• Exact beneficial mechanism(s) associated with statins in COVID-19 remain to be studied (Lala et al., 2020)
Table 6 Summary of the ongoing trials investigating pharmacological agents targeting a cytokine storm and acute cardiac injury secondary to SARS-CoV-2 infection.
Pharmacological intervention Sample size and criteria Treatment protocol Reference
• TACTIC-E Trial
• Immunomodulatory agents • Multi-arm randomized trial
• Pre-intensive care unit (ICU) COVID-19 patients
• Immunomodulatory drug EDP1815 vs. dapagliflozin + ambrisentan vs. standard care
• Primary outcome includes need for cardiovascular organ support • EDP1815 as 2 capsules twice daily (1.6 × 1011 cells) for up to 7 days
• Dapagliflozin 10 mg + ambrisentan 5 mg once daily (NCT04393246, 2020)
• High dose IV Vitamin C to ameliorate cytokine storm and associated organ dysfunction • Prospective placebo controlled randomized controlled trial (RCT)
•  N = 308
• High dose i.v. vitamin C (HIVC) vs. placebo
• Primary outcome of ventilator-free days • 12 g/50 ml vitamin C infusion 12 ml/h twice daily for 7 days vs. 50 ml sterile water for injection infused at 12 ml/h (Liu, Zhu, Zhang, Li, & Peng, 2020)
• TOC-COVID Trial • Prospective placebo controlled RCT
• N = 100 tocilizumab + standard treatment
•  N = 100 placebo + standard treatment
• Primary outcome of ventilation-free days • Tocilizumab 8 mg/kg single i.v. dose (Rilinger et al., 2020)
• TACTIC-R Trial
• Immunomodulatory agents • Randomized parallel 3-arm open label trial
•  N = 125 Baricitinib
•  N = 125 Ravulizumab
• N = 125 standard of care
• Primary outcome includes need for cardiovascular organ support • Baricitinib 4 mg orally once daily on days 1–14
• Ravulizumab single i.v. weight-based dose regimen (Kulkarni et al., 2020)
• CytoResc Trial
• Cytokine storm in hyperinflammation and shock • Prospective, open-label, pilot study
• ‘CytoSorb’ polystyrene-based hemoadsorber to adsorb circulating cytokines
•  N = 40–50 ‘CytoSorb’
• N = 40–50 standard care
• Primary outcome is time to resolution of vasoplegic shock • ‘CytoSorb’ therapy administered via a shaldon catheter for 3–7 days (Stockmann et al., 2020)
• MelCOVID Trial • Double blind placebo controlled RCT
• ICU COVID-19 patients
• N = 12 melatonin + standard of care
•  N = 6 placebo control + standard care
• Secondary outcome includes CRP, IL-6 levels • Melatonin 5 mg/kg/day i.v. divided every 6 h for 7 days
• Placebo dose of 5 mg/kg/day i.v. divided every 6 h for 7 days (Rodriguez-Rubio et al., 2020)
• Siltuximab for patients diagnosed with severe respiratory complications due to COVID-19
• Anti-IL-6 mitigation of cytokine storm • Observational retrospective cohort study
• Cohort A: continuous positive airway pressure followed by siltuximab
• Cohort B: intubation followed by siltuximab
• Control group receiving continuous positive airway pressure or intubation only
•  N = 220
• Primary outcome of mortality over 30 days • Detailed siltuximab dosing regimen not specified.
• Treatment procedure was based on clinicians judgement
• Study completed May 8, 2020. Results pending (NCT04322188, 2020)
• COV-AID Trial
• Use of anti-interleukin agents for cytokine storm • Phase 3 prospective RCT
• Patients with signs of cytokine storm
• N = 38 Anakinra alone (anti-IL-1 receptor)
•  N = 76 Siltuximab alone (anti-IL-6)
•  N = 38 Anakinra + siltuximab
• N = 76 Tocilizumab alone (anti-IL-6 receptor)
• N = 38 Anakinra + tocilizumab
• N = 76 standard care alone
• Primary outcome as time to clinical improvement • Anakinra 100 mg s.c. daily for 28 days
• Siltuximab single i.v. infusion 11 mg/kg
• Tocilizumab single i.v. infusion 8 mg/kg max 800 mg (Maes et al., 2020)
• Sarilumab for hospitalized COVID-19 infections
• Cytokine storm syndrome • Phase 2/3 RCT
• Phase 2: Sarilumab in hospitalized patients regardless of disease severity vs. placebo
• Primary outcome of % change in CRP in patients with serum IL-6 > upper limit normal
• Phase 3 Cohort 1: Sarilumab in hospitalized critical infection receiving mechanical ventilation vs. placebo
• Cohort 2: Sarilumab in hospitalized infection receiving mechanical ventilation vs. placebo
•  N = 1912
• Primary outcome of at least 1 point improvement on 7 point clinical scale • Phase 2: Low dose sarilumab i.v.
• Phase 2: Mid-dose sarilumab i.v.
• Phase 3 Cohort 1: Low dose sarilumab i.v.
• Phase 3 Cohort 1: Mid-dose sarilumab i.v.
• Phase 3 Cohort 2: High dose sarilumab i.v.
• Placebo given to match sarilumab administration (NCT04315298, 2020)
• CORIMUNO-SARI Trial
• Sarilumab to mitigate enhanced IL-6 signalling • RCT
• Moderate, severe, or critical COVID-19 pneumonia
• Sarilumab vs. standard of care
•  N = 239 • Sarilumab 400 mg single i.v. infusion over 1 h on day 1 (NCT04324073, 2020)
• Barcitinib for hospitalized COVID-19 patients • Non-randomized clinical trial
• Any adult patient hospitalized with moderate/severe COVID-19
• Barcitinib + standard care vs. standard care alone
• Primary outcome of clinical status after 15 days • Barcitinib 2 mg orally daily for 10 days (NCT04321993, 2020)
• RUXCOVID Trial • Phase 3 placebo-controlled RCT
• Patients age ≥ 12 with cytokine storm
• Ruxolitinib + standard care vs. placebo + standard care
•  N = 402 randomized in 2:1 ratio
• treatment: placebo • Ruxolitinib 5 mg orally twice daily for 14 days
• May extend treatment to 28 days (NCT04362137, 2020)
• Losartan (ARB) in patients hospitalized for COVID-19 • Phase 2 RCT
• Losartan vs. placebo + standard care
•  N = 200
• Secondary outcome includes cardiovascular organ failure/dysfunction • Losartan 50 mg orally once daily (NCT04312009, 2020)
• Losartan (ARB) in patients not requiring hospitalization for COVID-19 • Phase 2 RCT
• Losartan vs. placebo + standard care
•  N = 500
• Primary outcome of patients admitted to hospital within 15 days of randomization • Losartan 25 mg orally once daily (NCT04311177, 2020)
• Eicosapentaenoic acid (EPA) free fatty acid for hospitalized COVID-19 patients • Phase 3 interventional trial
• Treatment with EPA gastro-resistant capsules vs. standard care
• 28-day treatment period
• Primary outcome of time to treatment failure i.e. need for additional therapy, intubation, transfer to ICU, or death
• Secondary outcome includes reduction of IL-6 levels • Eicosapentaenoic acid free fatty acid (EPA-FFA) 1 g gastro-resistant capsules twice daily (2 g total) (NCT04335032, 2020)
• COLCORONA Trial
• Colchicine and inflammatory cytokine storm • Phase 3 multi-centre placebo-controlled randomized controlled trial (RCT)
• Age 40 years or older
• Patients must have at least one high-risk factor i.e. uncontrolled hypertension, HF, coronary artery disease (CAD), diabetes, obesity, etc.
• Colchicine vs. placebo
• 30-day treatment
•  N = 6000
• Primary composite endpoint of need for hospitalization or death • Colchicine 0.5 mg orally twice daily for 3 days, then 0.5 mg once daily for 27 days
• Placebo will match colchicine administration (NCT04322682, 2020)