Discussion
The difference between the conflicting findings of outpatient-documented statin treatment and the 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. If statins are withdrawn, their beneficial effects on the host response are rapidly reduced.6 For example, cardiovascular investigators who studied patients hospitalized with acute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.7 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 However, those who had been treated with statins as outpatients but whose treatment was withdrawn after hospital admission had greater mortality than what was seen in never-treated patients.
Studies by cardiovascular investigators suggest that the effectiveness of statin treatment on the severity and mortality of COVID-19 can be accurately determined only by evaluating in-hospital treatment. This has been confirmed in two studies that compared continuing versus not continuing statin treatment after hospital admission (Table1).8,9
Remarkably, all of the 32 studies based on outpatient-documented statin treatment failed to consider 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.10 The investigators concluded that statin treatment was protective, but this was likely an underestimate because statins were withdrawn in 23% of hospitalized patients. In another study of 247 statin-treated patients, 46% of treatments were initiated after hospital admission and yet 29% of all statin treatments were later discontinued because of elevated liver function or creatine kinase tests.11
This is not to say that outpatient statin treatment is unimportant. In studies reporting that outpatient-documented statins were effective, many patients probably had their treatment continued after hospital admission. Outpatient statins could also reduce the likelihood of developing symptomatic COVID-1912 and might even prevent the development of “long COVID”. Clinical findings clearly indicate that statin treatment should be continued in COVID-19 patients with cardiovascular diseases after hospital admission.5 No study has yet shown that statins should be used to treat all hospitalized COVID-19 patients.
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.4,13 In COVID-19 patients, a propensity score-matched 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 and 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 = 0.002).14
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, only 7% of the prospective clinical trials of COVID-19 treatments listed on ClinicalTrials.gov are focused on these drugs.15 Most of them are single center studies and only a few are evaluating statins, ACE inhibitors, or ARBs. To my knowledge, no randomized controlled trial of combination treatment has been planned or is underway.
In the absence of clinical trials of these treatments, physicians will have to rely on the findings of observational studies alone. For this reason, any study that seeks to determine the effectiveness of statin treatment (either by itself or in combination with other drugs) for COVID-19 patients must consider the consequences of statin withdrawal after hospital admission.