key: cord-0912886-eat1gz14 authors: Fedson, David S. title: Statin withdrawal and treating COVID‐19 patients date: 2021-10-27 journal: Pharmacol Res Perspect DOI: 10.1002/prp2.861 sha: 9d1fcd9a5c0652adbdcb2e19a4416db9b9f93468 doc_id: 912886 cord_uid: eat1gz14 Most but not all observational studies of statin treatment of COVID‐19 patients suggest that treatment improves outcomes. However, almost all of these studies fail to consider that withdrawing statins after hospital admission may have detrimental effects, a finding which cardiovascular investigators have known for 15–20 years. Continuing or starting statin treatment after hospital admission consistently improves cardiovascular outcomes. Similarly, inpatient statin treatment of COVID‐19 improves survival. For this reason, observational studies of the effectiveness of outpatient‐documented statin treatment of COVID‐19 patients must consider the negative consequences of statin withdrawal after hospital admission. The COVID-19 pandemic has caused worldwide social, economic, and political disruption. Its pathogenesis is largely due to extensive disruption of innate and adaptive immunity, altered interferon responses, and coagulation abnormalities that lead to microvascular immunothrombosis. Many of these changes are caused by endothelial dysfunction. 1 Antiviral treatments for COVID-19 have been only marginally effective. Antibody treatments (convalescent plasma and monoclonal antibody preparations) for the severe disease have also been disappointing. Some investigators have suggested repurposing drugs that are already licensed for use against other diseases. 2 Some of these drugs target the host response to infection, not the virus itself. One of these drugs is dexamethasone, which improves survival in COVID-19 patients who require oxygen treatment but not in those who do not require oxygen. 3 Repurposing cardiovascular drugs has attracted interest because many of these drugs (including statins) affect inflammation and endothelial dysfunction. 4 Experts recommend continuing statin treatment in COVID-19 patients who are already being treated. 5 This recommendation is based largely on numerous observational studies that suggest continuing treatment is safe. Nonetheless, most of these studies are based on outpatient-documented treatment. Because investigators seldom (if ever) consider the effects of statin withdrawal after hospital admission, their estimates of statin effectiveness are likely to be imprecise. It is unclear whether they recognize that statin withdrawal could be a problem. The study is based on a PubMed search conducted on July 24, 2021 using the search terms "statin withdrawal" (510 references) and "COVID-19, statins" (255 references). It is not a meta-analysis or systematic review. Instead, each article that reported data on statin treatment of COVID-19 patients was carefully read to determine whether the text, tables, figures, and citations contained evidence that the authors were aware of the clinical consequences of statin withdrawal. Citations for these COVID-19 articles and for statin withdrawal are available as supplementary material. The difference between the conflicting findings of outpatientdocumented statin treatment and uniform findings that inpatient treatment reduces COVID-19 severity and mortality is critically important. Documentation of statin treatment based only on outpatient information does not take into account the effects of statin withdrawal after hospital admission. Moreover, if inpatients are treated with statins, treatment might be withdrawn if they are transferred to ICUs, although intravenously administered statins are licensed if not widely available. 7 Whenever statins are withdrawn, their beneficial effects on the host response can be rapidly lost. 8 For example, cardiovascular investigators who studied patients hospitalized with acute myocardial infarction 15-20 years ago found that those who had been treated with statins as outpatients and whose statins were continued after hospital admission had lower mortality rates than those who had never received statins. 9 The same benefit was seen in those who were started on statin treatment after hospital admission. However, those who had been treated with statins as outpatients but whose treatment was withdrawn after hospital (Table 1) . 10, 11 Remarkably, all of the 42 individual studies based on outpatientdocumented statin treatment failed to mention the possible effects of statin withdrawal after hospital admission. For example, in one study, outpatient statin treatment was associated with decreased mortality, but only 77% of outpatient-treated patients continued statin treatment after hospital admission. 12 The investigators concluded that statin treatment was protective, but this was likely an underestimate because Cardiologists have known for 15-20 years that combination treatment with a statin and an ACE inhibitor (ACEI) or an angiotensin receptor blocker (ARB) is more effective than treatment with any of these agents alone. 4, 15 In COVID-19 patients, a propensity scorematched case-control study has recently shown that combination treatment with a statin and an ACEI or an ARB was more effective than single-agent treatment; combination treatment was associated with a 3-fold reduction in the odds of 28-day hospital mortality (OR = 0.33, 95% C.I. 0.17-0.69, p = .002). 6 There is a solid scientific and clinical rationale for repurposing statins and other widely available, inexpensive generic drugs to treat the host response to COVID-19 and other pandemic diseases. 2, 4 Unfortunately, a study published in late 2020 indicated that only 7% of the prospective clinical trials of COVID-19 treatments listed on ClinicalTrials.gov were focused on these drugs. 16 Most of them were single-center studies and only a few were evaluating statins, ACE inhibitors, or ARBs. To the best of my knowledge, no randomized controlled trial of combination treatment has been planned or is underway. In the absence of clinical trials, physicians may have to rely on the findings of observational studies alone. 17 Any study that seeks to determine the effectiveness of statin treatment for COVID-19 patients (either by itself or in combination with other drugs) must consider the potentially negative consequences of statin withdrawal after hospital admission. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The author declares no conflicts of interest. David S. Fedson https://orcid.org/0000-0001-9963-1934 COVID-19 is, in the end, an endothelial disease A pharmacological framework for integrating treating the host, drug repurposing and the damage response framework in COVID-19 Beyond dexamethasone, emerging immuno-thrombotic therapies for COVID-19 Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola Managing hyperlipidaemia in patients with COVID-19 and during its pandemic: an expert panel position statement from HEART UK Hospital mortality in COVID-19 patients in Belgium treated with statins, ACE inhibitors and ARBs Parenteral systems for statin delivery: a review Statin withdrawal: clinical implications and molecular mechanisms Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality Prior treatment with statins is associated with improved outcomes of patients with COVID-19: data from the SEMI-COVID-19 Registry Statins are associated with improved 28-day mortality in patients hospitalized with SARS-CoV-2 infection Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19 Early clinical and sociodemographic experience with patients hospitalized with COVID-19 at a large American healthcare system The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents Combining potent statin therapy with other drugs to optimize simultaneous cardiovascular and metabolic benefits while minimizing adverse events Characteristics of clinical trials evaluating cardiovascular therapies for Coronavirus Disease 2019 registered on ClinicalTrials.gov: a cross-sectional analysis Randomized, controlled trials, observational studies, and the hierarchy of research designs Additional Supporting Information may be found online in the Supporting Information section. How to cite this article: Fedson DS. Statin withdrawal and treating COVID-19 patients