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 If statins are withdrawn, their beneficial effects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outpatients but whose treatment was withdrawn after hospital admission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statins were withdrawn in 23% of hospitalized patients.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.