ATTENTION. This website is an unrevised working draft on an unadvertised platform. If you encounter this website through internet search, please do not share the URL. I hope to have the site up and running in early April at this URL: HostResponse.Info. Draft Time Stamp: April 17, 10:00 a.m.
SUMMARY. This website describes an approach to treating and preventing pandemic-capable viral illnesses (COVID-19, SARS, MERS, ebola, avian influenza, etc.), as well as severe cases of seasonal flu. The approach was first proposed by David. S. Fedson, M.D., though other physicians and researchers have independently arrived at some of the same ideas. The approach aims to mitigate self-destructive aspects of the patient’s immune response, including inflammatory cytokine excess and endothelial leak, by using repurposed generic drugs that are inexpensively available worldwide. The approach can be combined with other treatments, such as antiviral drugs, but can be used alone if other treatments are not available. This website emphasizes the model proposed by David Fedson and his colleagues, but it also points to the contributions of other researchers. EVIDENCE: This approach has not been rigorously tested and it should be regarded as experimental. It’s efficacy is unknown. However, several lines of evidence suggest that it might work. MEDICATIONS: The basic regimen discussed here, which should be applicable to many pandemic diseases, is a two-drug combination consisting of a statin (a type of cholesterol-lowering medication) and an angiotensin receptor blocker (a type of cardiovascular medication; abbreviated ARB). These two drugs may produce synergies when given together. If safety concerns or lack of availability require the exclusion of one of the drugs, the other can be used alone, though the efficacy may be reduced. SAFETY: I discuss the safety of immunotherapy in general and both drugs, with particular emphasis on how these might bear on patents with COVID-19. No specific recommendations are made. Rather, the goal is to provide information that will help clinicians weigh risks and potential benefits for themselves should they wish to consider using either or both of these medications before rigorous trial information is available. CLINICAL TRIALS: Trials for ARBs are planned or ongoing in Minnesota, Pennsylvania, California, Kansas, and Canada. Trials are needed for stains. Ongoing ARB trials should do sub-group analyses for patients also on statins, also analyzing by type and dosage if numbers allow. New intervention trials should study both drugs simultaneously. AUDIENCE: The website is written in plain English. It is designed to be useful to a variety of readers, including: physicians and other medical professionals, researchers, public health officials and workers, heavily exposed first-responders, and family members of patients. Nonetheless, at a few points, I include some technical medical information that may not be fully understandable to all readers. OBJECTIVES: In posting this website, I have six objectives: (1) encourage studies of statins in combination with ARBs; (2) present an ethical and intellectual framework for considering the clinical use of this and other unproven medical interventions when treatment options are limited and definitive trial information is not yet available; (3) discuss evidence, and provide links, to journal articles that bear on using statins and ABRs; (4) explain arguments for and against ARBs and statins and discuss choice of particular drugs within these two classes; (5) discuss how physicians and other medical providers might, during a pandemic emergency, informally collect and distribute outcome information about unproven therapies, including considerations relevant to poor or developing countries; and (6) stimulate greater interest among researchers, clinicians, and philanthropic funders in potential therapies that lack scientific, institutional, and financial constituencies, especially non-patentable approaches that are, or rapidly could be, inexpensively available worldwide. STATUS OF WEBSITE: The website is currently under construction. I will post whatever of the above is now available and will continue to add or modify material during the coming weeks. ADDITIONAL APPROACHES: I hope to soon post an appendix to this website that will provide an entry point for exploring additional “out of the box” ideas for treating and preventing COVID-19 and other pandemic-capable illnesses. These ideas need not address the host response. However, they must meet SIPS criteria: Safe (relatively or absolutely), Inexpensive, PubMed searchable, and Scalable.
1. DISCLAIMER
This website is educational in nature. I am not providing medical advice or telling individuals what they should do. Any persons considering using the approach discussed here should consult with their physician or other qualified medical providers, and providers should independently evaluate the approach. I have endeavored to provide accurate information but cannot warrant the correctness of all facts, interpretations, and judgments presented here. Neither I nor any person connected to this website bears liability for any errors the website might contain or for any harm that might result from using or misusing the information provided.
2. CONTENTS OF WEBSITE
This website consists of a single page, divided into XXXX short sections by horizontal blue bars, each bearing a descriptive title. To build knowledge systematically, read straight through the website, top to bottom. To read selectively, simply scroll. If you are considering using the medications discussed here, please read the entire website first, including the section on Potential Benefits and Risks of Using ARBs, and the caveats near the end.
3. UPDATES
I am continuing to work on this website. During the weeks or months after posting it (posting date: April XXXX, 2020) I expect to make edits, additions, and corrections. You may wish to check back periodically. If I make major substantive changes or additions, I will list them directly beneath this paragraph, to make it easier for returning visitors to find them. I will not list minor changes here, but I will change the “last modified” date even for small edits. Last modified: No modifications since posting date.
4. COPIES
The contents of this website may be freely copied or excerpted in any form (digital, print, audio, etc.) so long as the authorship and URL of the website is given. Please include the date on which the website was sampled. If you digitally repost parts of the website or create a mirror website, please update it periodically to reflect any changes or additions, and again please note the date on which the website was sampled.
5. AUTHORSHIP
This site was created by Benjamin Abelow, M.D., previously a Lecturer in Medicine at the Yale School of Medicine. I am posting this website because I believe that the approach warrants attention and immediate clinical testing. All opinions expressed here are my own. I have no financial interest in the approach. I wish to thank Elisabeth Sperling for her invaluable help editing this website, and David Zhang for his expert instruction and assistance with the technical aspects of website creation.
6. CONTACT AND CORRECTIONS
I can be reached at Abelow347 at gmail dot com. If you notice an error or other problem, either typographical or in content, please let me know. I also welcome suggestions and other comments, as well as relevant journal articles, abstracts, video links, and other information, including reports about new research or clinical experience relevant to the themes of this website. If you are an expert in some aspect of the material covered here, and you see an error or other problem, I would be thankful if you would contact me. I plan to read all messages but may not be able to respond. I cannot give medical advice.
7. INTRODUCTION
This website provides information about an innovative and potentially life-saving approach to treating several severe acute viral illnesses, including COVID-19, SARS, MERS, Ebola, avian influenza (“bird flu”), and advanced cases of seasonal flu. Although these illnesses can present in small outbreaks, epidemics, and pandemics, for simplicity I refer to them as “pandemic illnesses.” The approach was discussed here was first proposed by David S. Fedson, M.D., Professor of Medicine (retired) at the University of Virginia, along with several of his colleagues, including Professor Steven M. Opal, M.D., of Brown University. It uses inexpensive generic medications that are already available worldwide. Others who independently came to aspects of the approach are now actively involved in involved in researching host-response medications and concepts.
The regimen that Dr. Fedson is advocating is a two-drug combination of a statin (a kind of cholesterol-lowering drug) and an ARB (a kind of blood-pressure medication). These two drugs may produce synergies when given together but either can be used alone if the clinical situation, or lack of availability, requires it. There is currently a debate about the relative risks and benefits of starting a new ARB in patients specifically for the purpose of treating COVID. Two multi-center, clinical trials organized by the University of Minnesota are now testing ARBs for COVID; these should resolve that uncertainty. I anticipate the investigators will publish interim findings on-line as soon as reliable, statistically meaningful information is obtained. If I learn when such findings are likely to be available, I will report that prominently at the website (see Section 3, Updates, above). If others hear of data from this or other trials for either ARBs or statins for pandemic illness, please contact me so I can update the website.
Statins and ARBs both have immune-modifying effects, though neither was developed or is marketed for that purpose. These drugs are not under patent protection. They are produced as inexpensive generics in several countries and are available worldwide. The cost to treat a pandemic patient with generic statins and ARBs would be just a few dollars. In most countries, these medications are available immediately and could be used even at the very start of an outbreak, epidemic, or pandemic.
In addition to a possible role in treatment, statins and ARBs also might be used prophylactically (that is, for prevention) to inhibit the development of serious illness among currently uninfected persons who are heavily exposed or at an elevated risk of death if they become infected. Such persons may include: exposed medical and public health workers, first responders, frail older persons and/or persons with serious pre-existing conditions, and at-risk family members and other close contacts of patients. It does not appear likely these drugs would prevent the patient from becoming infected by the virus but they might allow for the mitigation of the clinical illness at an early stage.
Although evidence of various types raise the possibility that statins and ARBs might be effective, neither drug has been rigorously tested, alone or together, for the purposes being discussed here. No definitive proof of efficacy exits. The drugs may or may not work as hoped. The relevant question is this: given the uncertainties, does the preponderance of currently available evidence suggest a net benefit for the patient? This is a key question that always should inform medical decision making, including in cases when only partial information is available.
If a statin or ARB, or both together, is being used for a research trial, or is being considered for off-label clinical use, which ones might be best? The evidence here is sparse and merely inferential. Nonetheless, among the statins, atorvastatin (generic Lipitor, among others) and simvastatin (generic Zocor, among other names) may deserve preference. Regarding ARBs, there are various arguments for choosing one over another. I discuss the question of choice among these drugs in Sections XXXX and YYYY.
These medications are currently used by tens of millions of persons worldwide. In the U.S., roughly half of all persons age 65-74 take statins. A much smaller but still substantial fraction take ARBs. Physicians and other clinicians are familiar with these medications and often use them together, since high cholesterol and high blood pressure frequently coexist. The medications are generally considered safe and are typically prescribed without undue concern.
However, no drug is without risk. Serious problems can occur, though they are not common; some of these are listed in the “Caveats” section (sec. XXX). In addition, a number of specific safety concerns are highlighted in Sections XXX and YYYY. The greatest uncertainties pertain to ARBs, which is why, pending trial or other information, I have not so far listed them in the “conservative” regimen for those who might be seeking an off-label treatment or prophylaxis before definitive trial information becomes available.
The framing of a “conservative regimen” that does not include ARBs is my own and may not reflect the opinions of Dr. Fedson or others. I am simply erring on the side of caution, though I have no way of knowing whether this is actually optimal decision. In excluding the initiation of ARBs from the conservative regimen, I do not mean to suggest that current users of ARBs should discontinue those medications. Neither do I imply that a good argument cannot be made for including ARBs in appropriate and carefully observed patients. Both sides of this question will be presented.
8. “HOST RESPONSE” — WHAT’S IN A NAME?
The name “host-response therapy” is used because the approach aims to modify the immune response of the patient, who is the “host” for the virus. Unlike vaccines, which attempt to interrupt the process of infection, or antiviral medications, which attack the virus itself, host-response therapies change how the patient’s body reacts to the virus.
Modifying the host response is important because a full-blown immune response, especially those aspects of the response referred to as inflammation, can have lethal consequences for the patient. In some viral infections, these inflammatory responses, rather than the direct toxic effects of the virus itself, appear to be the most immediate cause of death.
For example, it appears that the immune response can increase the “leakiness” of the thin layer of cells (the endothelium) that line small blood vessels. This can lead to a flooding of the lung with excess fluid, causing ARDS (acute respiratory distress syndrome). Endothelial leak in other organs may contribute to multi-organ failure. The aim of the approach described at this website is to control these and other harmful inflammatory responses, thereby helping patients survive until their natural immunity develops and eliminates virus from the body. Some of the same host responses also occur in pneumonia and sepsis.
I sometimes use the terms “pandemic illness” or “pandemic disease.” This is a convenient shorthand, but in reality these diseases do not always cause pandemics, which is the extreme end of the epidemiological spectrum. Typically, these diseases occur in more localized forms, such as epidemics or outbreaks.
9. THE CURRENT TREATMENT MODEL IS INADEQUATE
The current model for treating and preventing pandemic illness relies heavily on vaccines and antiviral drugs (“antivirals,” for short). While vaccines and antivirals have an important role, they cannot currently provide an adequate response to pandemic illnesses.
The process of developing, testing, and producing a vaccine is slow and protracted. To produce even the first dose of a new vaccine typically takes at least six months. For novel viruses (for example, the virus of COVID-19) the process usually takes much longer. Mass producing the vaccine adds additional months. This means that even when the development process is successful (which is not always the case) several waves of a pandemic may pass before widespread vaccination is possible. In a highly communicable and lethal pandemic, it is likely that most deaths will occur before a vaccine is available. Antiviral drugs cannot fill the gap because they have shown only modest benefits in many severe viral infections.
In addition, vaccines and antiviral drugs will be unavailable in many developing countries. In those countries, high costs and the lack of a pre-existing vaccination infrastructure mean that whole populations may be exposed to unchecked infection for the entire duration of a pandemic.
10. A POTENTIAL SOLUTION
Unlike vaccines and antiviral drugs, the approach described at this website could potentially be used, starting almost immediately, anywhere in the world. The approach uses inexpensive generic medications that are widely available in both developed and developing countries. If it proves effective, host-response treatments could become a crucial “third leg,” along with vaccines and antiviral drugs, in the treatment of pandemic illness.
11. THE BACK STORY
David Fedson served as the Harry T. Peters, Jr. Professor of Medicine at the University of Virginia, and subsequently held the position of Director of Medical Affairs at Aventis Pasteur MSD, a European vaccine company. It was during his time in the vaccine industry that Dr. Fedson came to recognize that the current framework for approaching pandemic illness was fundamentally incapable of protecting the populations in either developed or developing countries.
Since 2006, Dr. Fedson, along with colleagues, has been publishing peer-reviewed articles on host-response therapy in a wide variety of medical and public health journals. In addition, Dr. Fedson has been advocating directly to the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), Physicians Without Borders, and various scientific and philanthropic bodies, as well as several universities, urging them to conduct clinical trials of generic host-response treatments. To date, none of these organizations or institutions has undertaken or supported such trials.
To hear Dr. Fedson describe why he began to focus on host-response therapy, listen to the first 90 seconds of this brief audio segment from National Public Radio. The expert speaking immediately after Dr. Fedson is Dr. Jeffrey Jacobson, a statins researcher and Professor of Medicine at the University of Illinois at Chicago, who has collaborated with Dr. Fedson on a number of publications. If you wish to see a transcript of this audio, click here.
Those who wish to delve into details of this approach before continuing to read here may find this selection articles useful. Additional articles can be found at PubMed by searching Fedson DS.
- Fedson DS. Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola. Annals of Translational Medicine, 2016 Nov; 4 (21):421. [PDF]
- David S. Fedson DS, Opal SM , Rordam OM. Hiding in Plain Sight: an Approach to Treating Patients with Severe COVID-19 Infection. mBio, March/April 2020 Volume 11 Issue 2 [https://mbio.asm.org/content/11/2/e00398-20]
- Fedson DS, Jacobson JR, Rordam OM, Opal SM. Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers. mBio. 2015 Jun 23;6(3) [PDF]
- Fedson DS. Treating the host response: an alternative way to manage Ebola in Africa and the next influenza pandemic. Journal of Global Health. 2019 Jun;9(1). [PDF]
- Fedson DS. Influenza pandemic preparedness: A special challenge for India. Indian Journal of Medical Research. 2019 Sep;150(3):217-220 [Download PDF from this website]
- Opal SM and Fedson DS. The dysfunctional host response to influenza A H7N9: a potential treatment option? Critical Care. 2014, April 22, 18 (2): 135-137. [PDF]
12. FIELD TRIAL IN WEST AFRICA: A STORY OF INCOMPLETE INFORMATION
In 2014, the statin-ARB regimen was informally field tested in Sierra Leone, located in West Africa. Approximately 100 Ebola patients were treated with 40 milligrams per day atorvastatin (the generic form of Lipitor, a type of statin) and 150 milligrams per day irbesartan (the generic form of Avapro, a type of ARB). Most of these Ebola patients received the statin-ARB combination for five to ten days. Memoranda and letters shared among treating physicians suggest that the treatment reduced Ebola mortality sharply, possibly to as low as one–tenth its usual 50-70 percent level, that is, to around five percent.
This treatment experience was unconventional in nature. It was funded and organized through the generosity of a private Norwegian physician, Dr. Ole Martin Rordam, who purchased the medications and arranged for their distribution in Sierra Leone. Dr. Martin undertook this action independently, without the involvement of any organization. He did so after reading an op-ed that Fedson and Opal published in The New York Times, viewable by clicking here.
Drs. Fedson and Opal learned of this informal trial only after it was in progress. Dr. Fedson and Martin attempted to identify relevant documents, reports, and similar records associated with the treatments and their outcomes. Dr. Fedson contacted the WHO and other international organizations that had on-the-ground access in West Africa. He asked that they undertake a formal review by examining the documents and speaking with local physicians and health officials, with the objective of validating or invalidating the findings. Such validation would have been important, because, for uncertain reasons, senior health officials in Sierra Leone refused to release full numerical information about patient outcomes.
The Ebola outbreak in West Africa was ongoing (in all, over 11,000 persons died). Accordingly, Dr. Fedson also sought for the WHO to repeat the trial with systematic reporting and quality controls in place. Unfortunately, no validation was attempted, and neither the trial nor other human testing was done.
13. WHAT TO MAKE OF THE SIERRA LEONE EXPERIENCE?
What can one make of this unconventional, independently initiated philanthropic field trial in Sierra Leone? How much weight should one give it?
The trial was unusual in inception, idiosyncratic in execution, and not reported or validated in a manner that would rise to the level of unequivocal evidence of efficacy. At the same time, the reports, memoranda, and letters from treating physicians, which included some numerical outcome data as well as impressive qualitative assessments about the efficacy of the approach, constitute much more than a random collection of anecdotes.
While rigorous, carefully controlled trials are essential to medical progress, they are not the only source of information that warrants close scrutiny; and such trials are not always possible. Sometimes, chance events in nature, or the vagaries of human happenstance, provide relevant information of an unexpected type. Empirical findings are often dichotomized as either “unverified anecdotes” or “reliable data,” yet the universe of potentially valuable evidence is not captured by this binary distinction. Rather, data quality lies at some point on a continuum between the extremes of certainty and irrelevance. It is not always easy to determine precisely where on the continuum such evidence lies, or how much weight to give to that evidence, but it is an error to dismiss the intermediate categories of evidence out of hand.
14. WHY HAS THIS IDEA BEEN SLOW TO GAIN RESEARCH TRACTION?
Generic statins and ARBs are inexpensive, immediately available world-wide, and considered to be relatively safe. Physicians and other clinicians are familiar with how to use these drugs from their experience treating tens of millions of patients with high cholesterol, elevated blood pressure, heart failure, and other problems. The concept of host-response treatment with generic drugs thus seems to be perfectly positioned to generate awareness and interest. Yet it was not till just recently–after years of effort by Dr. Fedson and others to raise awareness about the approach–that the idea has gained any traction for a clinical trial. Even now, no studies are planned to test the use of statins, alone or in combination with ARBs, for COVID or any other pandemic illness. How can we understand this lack of interest?
I believe there are several reasons.
First, generic medications of not covered by patents, so pharmaceutical companies do not stand to profit from them. I say this not to condemn pharmaceutical companies, which do important work and, like all businesses, needs to remain vigilant about the bottom line. But the generic nature of the medications means there is not a natural financial constituency for testing and promoting the approach.
Second, the scientific and public health communities have long worked within a research and treatment paradigm that aims to directly or indirectly attack and eliminate the virus. Many of the scientists most concerned with pandemic illness are virologists, specialists whose training, research, and career trajectory are focused on anti-viral treatment. The idea of attempting to moderate some aspects of the immune response, and then letting other aspects of the immune response handle the killing and elimination of virus, falls outside their special focus, and does not have its own scientific constituency. In some cases, financial conflicts of interest exist and may produce an conscious or unconscious bias toward remunerative, patentable ideas.
Third, non-profit funders generally rely on the expertise of the scientific mainstream to guide their grant-giving process. Because this mainstream is focused on vaccines and antivirals, philanthropic activities have tended to move in the same directions. As a result, large philanthropic organizations such as the Bill and Melinda Gates Foundation have not been inclined to fund research on this approach even on a small scale. In some cases, philanthropic trusts are partly funded by pharmaceutical companies, further complicating the picture.
Fourth, governmental and intergovernmental organizations also rely on the scientific mainstream to advise them on policies, options, and research agendas. These organizations have also developed an institutional focus on vaccines and antivirals, so aggressively exploring other approaches might not come naturally to them. The potentially “disruptive” nature of generic host-response therapies may, in some cases, even engender opposition.
15. STATINS: IN DETAIL
Statins have never been adequately tested in pandemic illness, so it is not known whether they might be effective. The experience in Sierra Leone is suggestive and encouraging, but it is difficult to have full confidence based on that unconventional and incompletely reported field trial. Another source of information is to draw inferences from studies of statins for conditions that share host-response features with pandemic illness. As a practical matter, this means: sepsis, pneumonia, and seasonal influenza.
Because the statin literature (journal articles) on sepsis is the most extensive, I will focus on that literature in some detail. I then touch more superficially on pneumonia and influenza. I focus on two types of studies: large, retrospective cohort studies and randomized controlled trials (RTC’s). I will not comprehensively review this literature, even for sepsis, but I will raise some important issues. In general, cohort studies for sepsis have produced positive results for statins, but RCTs are often said to have failed. But the reality is not so straightforward for the RCTs, as I hope to make clear.
SEPSIS: COHORT STUDIES
https://www.ncbi.nlm.nih.gov/pubmed/22918991 https://www.ncbi.nlm.nih.gov/pubmed/28962887 https://journal.chestnet.org/article/S0012-3692(18)30805-5/fulltext https://pubmed.ncbi.nlm.nih.gov/29626965/ https://pubmed.ncbi.nlm.nih.gov/29349709/ https://www.ncbi.nlm.nih.gov/pubmed/31246609 https://www.ncbi.nlm.nih.gov/pubmed/23232151 https://www.ncbi.nlm.nih.gov/pubmed/24489672 https://pubmed.ncbi.nlm.nih.gov/26033076 https://pubmed.ncbi.nlm.nih.gov/24725598 https://pubmed.ncbi.nlm.nih.gov/21819615 Improved survival in sepsis survivors for new statins: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831426/
SEPSIS: RANDOMIZED CONTROLLED TRIALS (RCTs)
We have just seen strong evidence from retrospective cohort trials that suggests statins are beneficial in sepsis. Though some of those trials have used sophisticated statistical techniques, especially propensity-matched controls, they cannot completely rule out certain types of confounding. Thus, RCTs become important. At first glance, the literature on these studies for statins is not encouraging. For instance–and for reasons of time and space these will be our focus–a number of meta-analyses have concluded that statins provide not benefit. Many clinicians have disregarded statins for sepsis for this reason. However, the story is less clear cut than first appears, as we shall see.
We will begin by focusing first on the two most recent meta-analyses that I know of. The studies are by Chen et al (2018) and Pertzov et al (2019]). It is important to understand what these studies show and what they don’t. Here is the Chen abstract <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081129/ and here is the full paper by Pertzov <https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(18)30729-8/fulltext>.
The more recent study, by Pertzov, contains all the the RCTs included in the Chen study, as well as some others. Also, it analyzed more primary and secondary endpoints. I therefore will comment only on the Pertzov paper, since the Chen paper would provide little additional information. The Pertzov paper includes 14 RCTs and a total of 2628 patients. Here are seven main points (and a handful of sub-points) about this paper. I’ll include [in brackets] reference numbers from within the Pertzov paper, in case you want to follow along.
1) To begin, the majority of patients in the trial were on mechanical ventilation (MV) at enrollment. Four studies [55, 56, 59, 63], comprising 1720 patients (65 percent of the total 2628 patients), made up bulk of the Pertzov meta-analysis. These studies had MV as an inclusion criterion.
2) These four studies had additional inclusion criteria, in addition to MV. Of the 1720 patients, 1284 (75 percent) required evidence of pulmonary edema. 284 (17 percent) required greater than two days on MV, as well as suspected ventilator-associated pneumonia. The remaining 152 p=(9 percent) required greater than 48 hours in the ICU at time of enrollment. (All percentages rounded to nearest whole number, thus accounting for greater than 100 percent in toto.)
3) Of the remaining 10 RCTs in the meta-analysis, which comprised 908 patients (35 percent of total n of 2628), 4 studies [54, 61, 62, 65], comprising 460 patients (45 percent of 908), had as inclusion criteria either septic shock or critical illness with severe sepsis.
4) Combining the above points, 2180 patients (81 percent of the total meta-analysis) required, at a minimum, severe sepsis with either septic shock or critical illness as inclusion criteria, with the majority of patients (79 percent of the 2180) requiring mechanical ventilation plus either (a.) pulmonary edema, (b.) greater than two days on ventilator plus ventilator-associated pneumonia, or (c.) greater than 48 hours in the ICU at the time of enrollment. That is, 81 percent of the meta-analysis consisted of an attempt to save the lives of the most seriously ill and advanced sepsis patients.
5) Let us consider the remaining patients, those whose disease is less advanced and not so imminently life threatening. Excluding the eight studies mentioned above, six RCTs remained in the meta-analysis [52, 53, 57, 58, 60, 64]. What can we say about this group? I’ll take the six studies one at a time:
- Study [64] was not for sepsis but for community acquired pneumonia (CAP); it is unclear why it was included in this meta-analysis. Further, this study was designed to enroll 350 patients, 175 each in the statin and control arms, to achieve the desired statistical power; yet it was terminated due to lack of enrollment, with just 34 patients analyzed. It is unsurprising that this study did not produce statistically significant results.
- Study [52], not PubMed-accessible, is available at <https://www.sciencedirect.com/journal/egyptian-journal-of-anaesthesia/vol/30/issue/3>. This double-blinded RCT of 108 patients showed statistically significant benefit from statins (rousavastatin), including lower blood lactate, lower dose and duration of norepinephrine, lower incidence and duration of mechanical ventilation, and (the primary endpoint) increased number of days with acceptable blood pressure and tissue perfusion, with no increase in liver enzymes.
- Study [57], not PubMed-accesible, is available at <http://www.actamedicamediterranea.com/archive/2016/special-issue-4/the-effect-of-simvastatinon-the-outcome-of-patients-with-sepsis-a-clinical-trial-study/pdf>. This double-blinded RCT of 60 patients showed better day-7 APACHE scores (8.5 vs. 12.2, p = 0.02) and markedly better 30-day survival (43 vs. 27 percent) on statin (simvastatin), though not quite reaching statistical significance (p = 0.11). The authors conclude that “statin therapy is recommended in sepsis patients.”
- Study [53], also a double-blinded RCT of 150 patients, compared statin users who discontinued the statin at the hospital with those who continued on a statin (by switching to 20 mg atorvastatin). There were no differences between the two groups in the rate of change in sepsis, in cytokine levels, or mortality. [BEN: 32 percent baseline value of severe sepsis — go through other studies and see how this compares to evaluate whether this (?) high percentage might account for the negative finding – and see if you can determine within this study which patients (severe/simple sepsis) did not benefit from the treatment.] <https://www.ncbi.nlm.nih.gov/pubmed/20959555>
- Study [58] was not for sepsis but for bacterial infections. The study was terminated early for lack of enrollment, and most outcome measures were not analyzed, but a total of 83 patients were randomized. The only statistical measure reported in the abstract (I did not have free access the full article) was a decrease in cytokine levels (TNF-alpha, IL-6) on the third day in the statin (simvastatin) but not control group.
- Study [60], Phase II double-blind RCT, randomized 100 patients with sepsis to either placebo or statin (40 mg atorvastatin) and compared progression to severe sepsis. Four percent of the statin group compared to 24 percent in the control group progressed to severe sepsis (p = 0.007), a reduction of 83 percent.
6) Summarizing the meta-analysis by Pertzov et al, the most recent and complete analysis of RCTs for statins in sepsis: Eighty-one percent of the patients studied were on mechanical ventilation or had septic shock or severe sepsis with critical illness before being randomized. These patients did not benefit from statins. The remaining patients, those with less advanced sepsis, largely benefitted. After eliminating a misplaced and statistically impaired study of community acquired pneumonia, five studies remained. One of these showed no benefit. The remaining four showed a variety of benefits, including lower mortality, less mechanical ventilation, less pressor medication, and lower cytokine levels. The most impressive of the four studies showed a reduction in progression from sepsis to severe sepsis of 83 percent (24 vs. 4 percent).
Concluding remarks: A meta-analysis can tell a great deal, but it can also conceal a great deal. Choices have to be made for reasons of space and the demands placed on both researcher and reader. For our purposes, this meta-analysis was both helpful and harmful. The analysis was helpful in that it forces us to be realistic: if statins were a miracle drug, we’d likely know it, and even the sickest patients probably would have benefited in discernible ways. It also is helpful in that even among the sickest, mechanically ventilated patients, the statistical analysis revealed no evidence of harm. The analysis was harmful in that, the meta-analysis, while analyzing the entire set of patients, and also that subset of patients with severe sepsis, did not statistically analyze those six (five, once corrected) studies of less severely ill patients. Even if they had, the varied nature of the outcomes studied, as well as variety in the benefits observed, might not have been captured in a single, outcome-focused analysis. Nonetheless, by looking at the individual studies, we see a pattern of benefit in four out of the five studies in the less severely ill sepsis patients, with some of the benefits being truly impressive.
Let me point to one last element of the meta-analysis that may be helpful. Pertzov notes that in the subgroup analysis of nine trials for patients with severe sepsis, “the effect of atorvastatin was larger and close to statistical significance” (p. 284). The relative risk was 0.79 (CI-95: 0.58-1.08)–a 21 percent reduction compared to non-statin users. When this analysis was subjected to a sensitivity analysis, which limited it to the four trials that had low risk of bias for “allocation concealment,” benefit persisted, though the effect was smaller: RR was 0.84 (CI-95: 0.6-1.18)–a reduction of 16 percent. This finding, thought only trending toward significance, is relevant to our discussion about which statin might be preferred.
PNEUMONIA
https://www.ncbi.nlm.nih.gov/pubmed/29532779
https://www.ncbi.nlm.nih.gov/pubmed/24489672
https://www.ncbi.nlm.nih.gov/pubmed/29953536
https://www.ncbi.nlm.nih.gov/pubmed/27169476
https://www.ncbi.nlm.nih.gov/pubmed/22835463
https://www.ncbi.nlm.nih.gov/pubmed/26517133
Mortensen EM, Nakashima B, Cornell J, et al. Population-based study of statins,
angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on
pneumonia-related outcomes. Clinical infectious diseases : an official publication of the
Infectious Diseases Society of America 2012; 55(11): 1466-73.
INFLUENZA
https://www.ncbi.nlm.nih.gov/pubmed/22170954
https://www.ncbi.nlm.nih.gov/pubmed/31463620
https://www.ncbi.nlm.nih.gov/pubmed/27686457
https://www.ncbi.nlm.nih.gov/pubmed/26034777
https://www.ncbi.nlm.nih.gov/pubmed/32040667
https://www.ncbi.nlm.nih.gov/pubmed/19956645
https://www.ncbi.nlm.nih.gov/pubmed/31125254
https://www.ncbi.nlm.nih.gov/pubmed/21541017
WHICH STATIN MIGHT BE BEST?
If one is going to use a statin, which ones might be best? Again the evidence is less clear cut than would be desirable, but taking all we have seen into account, including the results of cohort studies, RCTs, and the experience in Sierra Leone (however much or little weighs that), my impression is that the weight of evidence falls on atorvastatin 40 mg per day, with an alternative being a mid-range dosage of simvastatin being either as good or a close second. Though one RCT discussed above [52] showed a range of benefits from rousavastatin, the failure of the cohort study of Lee and colleagues to show any benefit from this statin, while confusing and hard to reconcile, seems to make a choice for rousavastatin more conflicted and less desirable.
If in fact differences in efficacy among the statins does exist, what could account them? One possibility pertains to solubility: some statins are preferentially soluble in water where as others are more soluble in lipids. This differential could bear on how they are distributed in the body and, potentially, on their efficacy in modulating inflammatory reactions. Atorvastatin and simvastatin are both considered lipid soluble, whereas rosuvastatin is considered water soluble. Another possibility pertains to an intrinsic antibacterial activity, and it has been asserted that simvastatin and atorvastain have this activity, whereas rousavastin does not (Lee XXXXX)
I have not surveyed the journal literature thoroughly, but am aware of one clinical study that points to a particular benefit for lipid-soluble statins. That study found benefit from atorvastatin and simvastatin (lipid soluble) but not rosuvastatin (water soluble). In addition, I have read that these two lipid-soluble statins have greater intrinsic bactericidal activity than rosuvastain, which could potentially be of benefit for bacterial superinfections in viral diseases. The most successful of the RCTs [62] tested atorvastatin, 40 mg per day, the same drug and dosage used in Sierra Lenone. These studies lend weight to the impression that initial trials, and any current off-label clinical use, should be with atorvastatin and, more generally, lipid-soluble statins, though I say this tentatively; a careful literature search might lead to different conclusions. [Give Links–Lee, SQS, 2012 Birmingham study]
Statins also vary in the extent to which they are removed from the blood by the liver (“first-pass removal”) after being absorbed from an oral dose. Questions also remain about the optimal dosage levels. For example, one study found that “low-intensity” rather than “high-intensity” dosing might have preferential benefits. However, it is hard to know what to make of this study, given that 40 mg per day atorvastatin was considered high intensity in that study. [Give link–maybe I sent this one to David]
If the general statin-ARB approach proves effective, these and other chemical differences among statins might eventually become the focus of trials that compare the efficacy of different generics and dosages.
16. ARBS: IN DETAIL
ARB is an acronym for “Angiotensin Receptor Blocker,” a kind of medication most commonly used to lower blood pressure (“anti-hypertensive”) or treat heart failure. This name applies because the drug blocks the binding of the a hormone in the angiotensin family, in particular angiotensin II, its receptor, which is located on the surface of cells. It follows that the more technical name for ARBs is “Angiotensin II Receptor Blockers.” ARBSs are also sometimes called “Angiotensin Type 1 Receptor Blockers” (or “AT1R blockers”), because they bind to the angiotensin type-1 subclass of receptors. There is also a type-2 receptor (AT2R), but ARBs bind to these only very weakly, and I will not discuss them. And if you read the research literature, you may see mention of type-a and type-b variants of the type-1 receptor (AT1a and AT1b) but these are not present in humans, only in mice.
I’ll begin by introducing and explaining some terms, to help orient those who don’t have a medical background, though a few of the terms may be useful to those
- Angiotensin. From the word root angi, meaning “vessel,” in this case a blood vessel, and “tense,” meaning stretched, taught, or distended. Angiotensin is a chemical messenger that most typically acts to raise blood pressure. The rise in pressure can make some blood vessels feel more tense. (Actually, the name angiotensin refers to a group of related chemical messengers, some of which are described below.)
- Angiotensinogen. Note the ending, gen, which means to make or create. This is the same root as in gene, genital, generate, and the biblical book of Geneiss. Angiotensinogen is a large molecule that gets split into pieces. One of the remaining pieces is a molecule known as angiotensin. So, angiotensinogen generates, makes, or creates angiotensin. More specifically, angiotensinogen generates the molecule known as angiotensin I . Angiotensin I consists of ten amino acids linked together in a short chain.
- Angiotensin II. This molecule gets produced when an enzyme known as Angiotensin Converting Enzyme (ACE, pronounced like the playing card) acts on angiotensin I. Specifically, ACE converts angiotensin I into angiotensin II by removing two amino acid.
- Angiotensin Converting Enzyme 2 (ACE2). Just as ACE acts on angiotensin I, ACE2 acts on angiotensin II. It removes one amino acid and converts it to a molecule called angiotensin-1-7, which is sometimes written angiotensin-(1-7), pronounced “angiotensin one seven.” The “7” refers to the number of amino acids. Both ACE and ACE2 also act on other molecules as well, but those are not important for our purposes.
- Angiotensin II receptor (“AT receptor” or “ATR”). Sometimes called simply the angiotensin receptor. (There is little discussion about a receptor for angiotensin I, so the II is often dropped.) This receptor resides in the membrane that surrounds cells. When angiotensin II binds with the receptor, a signal gets sent to the inside of the cell. There are two types of AT’s in humans, known as AT1R (AT receptor type I) and AT2R (AT receptor type II). The binding of angiotensin II to AT1R causes blood pressure to rise and tends to produce inflammation, including making blood vessels more leaky. I won’t be talking about AT2R at all.
- Angiotensin II receptor blocker (ARB) . Often called simply angiotensin receptor blockers. This is a class of drugs that binds to the AT1R without causing it to send signals into the cell. Their main function is to keep angiotensin II from binding and sending signals into the cell. The drugs in the ARB class all have -sartan at the end of their names (irbesartan, losartan, telmisartan, etc.).
- Mas receptor. Angiotensin-1-7 binds to this receptor, producing somewhat opposite effects to those produced when angiotensin II binds to AT1R.
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Development Research. 2020 Mar 4 [PDF]
>FEDSON ATM ARTICLE.
- THIS SHOULD GO IN SAFETY SECTION. Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine. 2020 Mar 3. [PDF] [This paper is problematic, in that they refer to a losartan study as being beneficial, but then don’t discuss generic ARBs as being one of the “small molecules” that can target the ACE2. However, they do discuss the proprietary drug being developed by their company. One comes away with the impression that they are touting their own patentable drug without explicitly mentions the currently available generic that might have the same effect.]
ANGIOTENSIN RECEPTOR BLOCKERS Regarding ARBs, one particular ARB (telmisartan) has a characteristic that might make it especially effective. In addition to the class effect, telmisartan binds and activates a receptor known as the PPAR-gamma receptor. Activation of this receptor appears to have beneficial immune-modulating effects that are independent of the ARB class effect. Again, a study might reveal whether this theoretical difference has practical benefit for patients. [Give Citation – Mark McCarty’s article]
16. PUTTING IT ALL TOGETHER
There is no single piece of definitive evidence in support of the host-response therapies discussed here. Nonetheless, the concatenation of findings from laboratory science, randomized clinical trials, retrospective cohort studies, and the field raises the distinct possibility that the inexpensive, widely available medications discussed here might be effective and of substantial benefit in saving life and in alleviating and preventing suffering. I emphasize the word “might,” but the point stands.
In the absence of additional information, and making allowances for patient-specific variables (body size, drug sensitivities, known abnormalities in the rate of drug metabolism, etc.), it seems reasonable to consider atorvastatin and irbesartan, perhaps at the dosages used in Sierra Leone, as a starting point for formal research and for any off-label treatment that might be considered. The duration of treatment should probably be at least ten days and continue till the patient is well. The question of whether treatment should terminated if the patient’s condition deteriorates is discussed in the Safety section (section XXXX), along with several other important safety concerns, including one that is specific to COVID-19 and SARS.
17. WHAT ABOUT OTHER STATINS AND ARBS? Might statins and ARBs other than atorvastatin and irbesartan be effective? How about different dosages? The probable answer is yes, because the immune-modulating effects of these drugs seem to be largely a “class” effect inherent in the statin and ARB categories, not the particular drug. Nonetheless, within these categories, there may also be relevant differences among chemical subclasses and specific drugs. XXXXXXX Certain statins and ARBs have characteristics that could potentially make them more or less effective. For example, some statins are preferentially soluble in water where as others are more soluble in lipids. This could bear on how they are distributed in the body and, potentially, on their efficacy in modulating inflammatory reactions. As illustrations, atorvastatin (Lipitor) and simvastatin (Zocor) are considered lipid soluble, whereas rosuvastatin (Crestor) is considered water soluble. XXXXX I have not surveyed the journal literature thoroughly, but am aware of one clinical study that points to a particular benefit for lipid-soluble statins. That study found benefit from atorvastatin and simvastatin (lipid soluble) but not rosuvastatin (water soluble). In addition, I have read that these two lipid-soluble statins have greater intrinsic bactericidal activity than rosuvastain, which could potentially be of benefit for bacterial superinfections in viral diseases. Another study tested only atorvastatin and showed efficacy at the same dosage (40 mg per day) that was used in Sierra Lenone. These studies weight to the impression that initial trials should be with atorvastatin and, more generally, lipid-soluble statins, though I say this tentatively; a careful literature search might lead to different conclusions. [Give Links–Lee, SQS, 2012 Birmingham study] XXXXXX Statins also vary in the extent to which they are removed from the blood by the liver (“first-pass removal”) after being absorbed from an oral dose. Questions also remain about the optimal dosage levels. For example, one study found that “low-intensity” rather than “high-intensity” dosing might have preferential benefits. However, it is hard to make of this study, given that 40 mg per day atorvastatin was considered high intensity in that study. [Give link–maybe I sent this one to David] XXXXXXXX If the general statin-ARB approach proves effective, these and other chemical differences among statins might eventually become the focus of trials that compare the efficacy of different generics and dosages.
18. WHAT KIND OF TESTING IS NEEDED?
Studies are needed to test the efficacy and safety of the approach for three groups:
- Infected persons who have mild illness but are at risk of progressing to severe clinical illness,
- Infected persons who already are sick enough to be admitted to the hospital, and
- Uninfected persons who are at high risk of contracting the infection, including front-line medical and public health workers, and family members of patients.
For each of these three groups, both clinical and epidemiological studies should be done. Both are important but I believe the clinical ones are of most immediate relevance and also can be conducted most quickly, so I will discuss them first.
Two multi-center trials — one for outpatients (not hospitalized) and one for hospitalized patients — are ready to begin at the University of Minnesota. However, the FDA has not yet given the go-ahead. It is unclear what is delaying their decision to allow these important trials to begin. I know of no trials for statins, or for testing both drugs together, which Dr. Fedson believes may be important to achieve useful synergies, as may have been the case in Sierra Leone.
Clinical Studies: Each of the three groups listed above should be evaluated separately. It is conceivable that efficacy in one group would not translate into efficacy in the others; and failure of efficacy in one would not translate into failure in the others. Achieving these varied types of testing has been Dr. Fedson’s primary objective in all his scholarly writing and advocacy work since he began publishing on this subject in the early 2000s. Depending on the disease being targeted and its baseline case-fatality rate (the statistical likelihood that a sick patient will die), and the magnitude of the clinical benefit being sought, even small studies might be sufficient.
There is no need to start “ground up” with either in vitro (cell culture, etc.) or animal “models.” The medications have already demonstrated acceptable safety in a wide variety of human populations. Residual safety questions (see “Safety Concerns,” below) could not be resolved in non-humans. Further, the informal field trial in Sierra Leone, almost regardless how much weight one ascribes to the information that emerged from it, points directly to the suitability for clinical testing; and the context of that field trial points to the urgency of the need.
Finally, studies in non-humans frequently do not correlate well with the result of studies in humans. Even studies in non-human primates (NHP’s) do not reliably translate into human beings; in fact, it is well known that trials of the same medication in different species of NHP’s can produce entirely different results. In the face of the already extant human evidence, negative animal studies would mean nothing and positive studies would do no more than point to the need for human studies. Animals studies may have utility for new and unfamiliar drugs; but in this case they would be an expensive waste of time, one that could delay an effective pandemic treatment at the cost of many lives.
Epidemiological Studies: A large fractions of the older population in the United States (and perhaps in some other developed countries as well), are taking a statin. A meaningful fraction of these statin uses are also taking an ARB. This means that as a pandemic illness spreads through the population (COVID -19 may provide a perfect opportunity) many persons who are already taking the statin-ARB combination will become sick. Some of these will enter the hospital, a fraction of these will end up in the ICU, and, unfortunately, some will die.
The question is: how frequent will these different disease stages be for (a) statin-ARB users, (b) users of just statins, (c) users of just ARBs, (d) persons who use neither statins nor ARBs? By comparing the rates for different degrees of illness, and for the rate of death, among these three groups, valuable information about the efficacy of statins, ARBs, and their combination can be obtained.
In addition, depending on the size of the data set, and the ease of accessing this information, it may be possible to determine whether specific categories of statins (e.g., lipid- vs. water-soluble), dosages (high- vs. low-intensity, perhaps adjusted for body mass), and even specific drugs (e.g., atorvastatin vs. simvastatin, both lipid-soluble). Some statins (e.g., atorvastatin, simvastatin) seem to have anti-bacterial effects as well and these could be considered as relevant variables. Similar analysis could be done on ARBs, including an attempt determine in the PPAR-gama activity that is specific to telmisartan (see Section 14) has clinical benefit relative to other ARBs.
A variety of epidemiological studies are possible. I am not a professional epidemiologist but my impression–offered merely to stimulate thought–is that these studies would all be worth considering:
- Retrospective cohort study with propensity-matched controls;
- Case-control study;
- Coss-sectional study examining plasma cytokine levels and other physiological variables; if it is possible to non-invasively but specifically assess endothelial barrier function, and perhaps lung epithelial barrier function, those might be especially worthwhile;
- Prospective cohort study tracking new hospital admissions and evaluating their relative rates of progression to severe illness or death, perhaps with serial measures of cytokines, endothelial function, or other relevant physiological variables, There might even be a way to simultaneously analyze two or more of these studies to achieve methodological synergies.
One limitation to these epidemiological studies is that they all would be observational, looking at patients who had been prescribed statins and ARBs for the usual cardiovascular indications (high cholesterol and blood pressure). Therefore, they would not study patients with baseline normal blood pressure who had received an ARB. This is one important reason why these studies could not replace the clinical ones, which would likely involve persons who had not previously been on these medications, and thus would include (or be limited to) patients who had normal blood pressure.
(For both the clinical and epidemiological studies, a decision would need to be made about how to handle patients who, at their untreated baseline, had hypertension but were already on a different (non-ARB) blood pressure medication. The question would be: would they be excluded from the study or simply switched to the ARB?)
The financial cost of some of these studies might be significant, but a single commitment from a large funder, which might be small compared to that institution’s total expenditures on COVID or other diseases, could provide all that is needed for a comprehensive set of clinical and epidemiological studies. Such an organization might also provide a coordinating function, to ensure that the studies together provide maximal information. If studies were to prove the statin-ARB regimen effective, it could transform the treatment of pandemic disease throughout the world.
19. SAFETY
Both statins and ARBs have been used to treat millions of patients in many countries, including unstable patients with multiple serious health conditions. They are typically thought of as safe medications. In addition, even in patients who have never previously used a statin, some have been started on a statin for the first time while they were medically unstable in the intensive care unit, without causing harm. ARBs have been used by many who have subsequently been hospitalized, also without adverse consequences and sometimes with benefit. Relative to other drugs that are proposed or tested for serious health conditions, statins and ARBs have a remarkably well documented safety record.
Nonetheless, some significant safety concerns exist, and these should be fully considered, especially if these drugs are being contemplated for off-label use to treat patients, or for prophylaxis of heavily exposed persons, before definitive trial information becomes available. I will start with a very broad and general concern about the entire category of immune-modulating therapies and then focus on some more specific concerns that pertain to statins and ARBSs.
GENERAL CONCERNS ABOUT IMMUNOMODULATORS
Before considering statins and ARBs in greater detail, I want to raise a broad question. The objective of host-response therapies is to down-regulate (reduce) those aspects of immune function that might become overactive and harm the host. But even if this can be done, is enough known to do so without disabling beneficial aspects of immune function?
For instance, some have proposed that there are two main periods or phases of immune response during an acute pandemic respiratory illness. During the first phase, an aggressive response with the native immune system may be necessary. It is suggested this is essential to both suppress the virus early and to initiate the adaptive (largely B- and T- cell) immune response. In the second phase, the innate immune response becomes disregulated, resulting in cytokine storm and endothelial leakage, and injurious to the self. If this two-phase or similar model of immune response is correct, is it possible to control the later, harmful effects without impairing the earlier beneficial ones?
This is an active area of discussion and debate and a full exploration is unnecessary here. Rather, I will simply introduce the concern by linking a brief presentation relevant to the subject that formed part of a multi-speaker Grand Rounds put on by a number of Harvard-affiliated hospitals on March 26, 2020. Take a look at the brief segment featuring Jason Griffith, M.D. Ph.D., which starts at 00:34:00 and runs for about 7 minutes; after completing that segment, jump to 106:00 for 5 minutes of related cautionary comments by three other speakers:
https://externalmediasite.partners.org/Mediasite/Play/3a21e1105b104a1892a61004d33369461d
The cautions can be summarized as follows. First, in the view of the speakers, the risk-benefit tradeoffs of immunomomodulating therapies are sufficiently uncertain that use of these drugs should be limited to clinical trials. Second, that not enough is known to determine in advance whether a given patient needs a stronger or less strong pro-inflammatory response. Third, that most previous use of immunomodulatory drugs (e.g., statins for sepsis, discussed in the next section) has occurred in settings when the underlying infection was being adequately treated, for example with antibiotics, so that even if the early helpful immune response were to be inadvertently suppressed, the underlying infection would not be unchecked.
In listing these cautions, I do not intend to either credence or dispute them, but simply to make readers of this website aware of them so they can take them into account when formulating their own views.
SPECIFIC CONCERNS: STATINS
The main safety concern discussed in the MGH piece is drug-induced liver injury (DILI). Mild liver enzyme abnormalities are fairly common with these medications, but serious abnormalities are rare and in most instances are reversible with discontinuation of the drug. To get a better sense of the issue, consider reading the brief pages from Liver Tox, the NIH’s on-line reference on DILI, on (1) statins in general https://www.ncbi.nlm.nih.gov/books/NBK548236/ and (2) atorvastatin in particular https://www.ncbi.nlm.nih.gov/books/NBK548236/. Links to the Liver Tox pages on the other statins are found on both of these pages. XXXX The question of DILI may be especially relevant to Covid, since some Covid patients have liver damage, with the extent or prevalence increasing with severity of Covid. The cause of this liver damage is not well understood and could be due to direct damage by the virus but may possibly reflect the fact that these patients have already been exposed to drugs that themselves cause DILI. Two articles that discuss liver injury in Covid are https://onlinelibrary.wiley.com/doi/full/10.1111/liv.14435 and https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30057-1/fulltext. XXXXX Whether statins would be expected to help or exacerbate this prior liver injury is unclear, and there are journal publication that seem to point in both directions. But it is worth being aware that inflammatory stress can potentially increase the chance of statin-associated liver toxicity, as suggested by this article https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948878/. XXXXX The bottom line here may be that if statins are used in Covid, awareness of possible liver abnormalities should be high, and testing of liver enzymes should be be frequent and assiduous, especially in seriously ill patients.
Long-Term Outcomes of Short-Term Statin Use in Healthy Adults: A Retrospective Cohort Study. Mansi IA1,2,3, English J4, Zhang S5, Mortensen EM6,7,5, Halm EA7,5. {}
Nonetheless, risks exist, and these must be considered.
Beyond the usual occasional or rare problems associated with these drugs (see Caveats section, below), I am aware of two concerns that deserves special mention. Both pertains to ARBs. Both require some explanation.
1. Concern About Giving Anti-Hypertensive Medications to Seriously Ill Patients at Risk of Hypotension or Unstable Blood Pressure
ARBs are used as anti-hypertensive medications; they are used to lower the blood pressure of persons whose usual (untreated) baseline blood pressure is elevated. Thus, most of the safety data for ARBs pertains to patients for whom the reduction of blood pressure is an important objective, and the post-treatment blood pressure is typically in the normal range. And what little safety data might exist about their use in normotensive (normal blood pressure patients), such as that collected during FDA Phase 1 trials, tends to be done on entirely healthy individuals.
However, for the use being discussed here, the ARB would be given to sick persons regardless what their starting (normal baseline) blood pressure was. Although the baseline pressure of some of these persons might be elevated (untreated hypertension is common), and for some the ARB might replace an existing anti-hypertensive medication, the starting pressure of many or most patients might be normal. Therefore, giving an ARB would tend to push the blood pressure down toward or into the hypotensive (low) range.
Healthy persons can compensate for this tendency. They homeostatically auto-adjust blood pressure to a significant degree, keeping it in the normal range. However, for severely ill patients, the capacity to maintain an acceptable blood pressure in the face of an ARB could be impaired. In addition, some of the most seriously ill patients might be hypotensive, or have unstable blood pressure, to start with as a result of their disease. In these patients, it is possible that an ARB might precipice a further, and potentially deadly, drop in blood pressure. This concern was mentioned in the second-to-last paragraph of the article by Gurwitz that is linked to in the Going Deeper section (section XXXX) of this website.
What is challenging about this issue is this: a major reason for the fall in blood pressure is the excess of cytokines and the associated leak of fluid out of blood vessels (diminished endothelial barrier function). The resulting loss of fluid volume from the vascular system, and perhaps the loss of vascular tone produced by the high level of cytokines, may be the underlying cause of the hypotension. And these underlying causes are precisely what the ARB is intended to reverse.
Thus, in seriously ill patients, the ARBs may bring about two opposing physiological tendencies. On the one hand, they may tend to lower blood pressure, through their well-known anti-hypertensive action. On the other hand, they may help reverse the vascular leak and high cytokine levels. It is unknown which of these effects would predominate, or the rates at which each of the two tendencies would be expressed.
As the article by Gurwitz notes (see Section XXX, above), there are structural similarities (though also significant differences) between the virus causing SARS (SARS-CoV) and that causing COVID (SARS-CoV-2). Whether or not this virus ultimately expresses, like the SARS virus, a tendency to produce hypotension is (to my knowledge) currently unknown. But hypotension can arise independently, due to more generic cause, including high cytokine levels, and it may occur in other patients with severe critical illness irrespective of the particular causes. Thus, it is a relevant concern in all cases.
Maybe discuss starting at a lower dose?
2. Concern that ARBs might facilitate infection or worsen illness in COVID-19
Maybe include comment here about that excellent paragraph in Gurwitz — about how in HIV, the virus benefits from down regulation of receptor. Also note that though it is possible the cellular machinery, for some unknown reason, would physiologically require down regulation of ACE2 in response to binding of the SARS spike, it is, at least, arguably more likely that the spike specifically evolved to promote down regulation. Certainly, if the spike promoted up-regulation, we likely would view it as a feed-forward control mechanism to facilitate cell entry. Yet the lesson of HIV may be that any time there is a directional change in the expression of the receptor, we should consider it as soft evidence for a viral infection strategy. Thus, at least arguably, we should view up regulation of ACE2 by ARBs as something to be desired, simply because it runs counter to what the virus may have evolved to do.
Can angiotensin receptor-blocking drugs perhaps be
harmful in the COVID-19 pandemic?
Murray Eslera,! and Danielle Eslerb, Journal of Hypertension, Volume 38 Number 1 Month 2020
http://www.nephjc.com/news/covidace2
Angiotensin-converting enzyme 2 in acute respiratory distress
syndrome. Y. Imai*, K. Kuba and J. M. PenningerCell. Mol. Life Sci. 64 (2007)
Figure 2. Schematic diagram of the role of the RASin acute lung failure and proposed interaction between SARS infections and theRAS.
In acute lung injury, such as acid aspiration, pneumonia, or sepsis, the generation of angiotensin II(ANG II) is enhanced, most likely due to
the downregulation of ACE2 expression. ANG II induces acute lung failure through stimulation of the angiotensin II type 1 receptor
(AT1R). ACE2 and the angiotensin II type 2 receptor (AT2R) negatively regulate this pathway and protect against acute lung failure. On
the other hand, SARS-CoV infections depend on the binding of the SARS-Spike protein to ACE2 (and L-SIGN) and downregulate
expression of the protective molecule ACE2, hence promoting severe lung injury and acute lung failure.
2. Concern that in COVID-19 and SARS, Using ARBs May Augment Uptake of Virus By Cells, Promoting Infection and Accelerating Disease Progression
First, there is a concern that giving an ARB to a patient in the ICU, or to any very sick patient whose healthy baseline is normal blood pressure, might possibly cause abnormally low blood pressure, which could be dangerous or even lethal in a very tenuous patient. A health person with normal blood pressure who then takes a blood pressure medication can “auto-adjust” and keep blood pressure in the safe or normal range. However, a patient who is, for example, in the ICU, might have unstable blood pressure or even hypotension to start with, and giving an ARB to one of those might be very risky, because they cannot auto-adjust, even if they have the immune benefits that are hoped for. It is hard to know which effect of the ARB might predominate — the effect on blood pressure (bad) or the desired effect on the immune system (good). I don’t think anyone knows the answer for sure, but it certainly raises the question of whether one should start giving an ARB to a very seriously ill patient who might have, or be at risk of developing, unstable blood pressure or severe hypotension.
Second, ARBs, by some cellular mechanism or other, have the effect of amplifying (= “raising the level or number”) of a certain enzyme called ACE2. This enzyme is attached to the cell membrane of various cells in the body (in the lung, kidney, intestine, and endothelial lining of blood vessels). It has been pointed out that (by some unfortunate coincidence) that SARS-CoV-2 (the virus that causes COVID-19) as well as the original SARS virus (SARS-CoV-1) both bind to that ACE2 enzyme. And it appears that this binding actually helps bring the virus into the cell. There is thus a theoretical risk that ARBs might actually be risky and dangerous for COVID-19 and SARS patients, possibly making COVID-19 worse. This view is now being actively debated among the experts. There is no clear evidence that it is a problem, but I think that the concern should be taken seriously. If I had known about this when I wrote the op-ed, I would have mentioned it. Not everyone is convince that this problem is a real and practical issue, but I think some caution is warranted.
Implications. What are the implications of this line of discussion for treatment and prophylaxis, including in COVID-19? At the time I am writing, COVID-19, though probably less dangerous than most of the threats discussed at this website, is the most immediate concern, and some patients are becoming seriously ill. I therefore will frame my answer with respect to COVID-19. But the points made here would apply, in different was, to other viral threats as well. XXXX First, patients with mild COVID-19 illness, and those uninfected persons who are heavily exposed to the virus, might benefit greatly, having lower rates of progression to serious illness, while experiencing only trivial risks from the statin-ARB regimen. The question of what to do if one of these patients progressed to a dangerous stage in the illness, and began to experience overt hypotension or some instability in blood pressure, is difficult. Should the ARB be stopped or continued? That is a question for which no answer can be given here; researchers doing the trail would need to consider it carefully in designing their protocol. XXX Second, patients who are already severely ill with COVID-19, such as those in the ICU, especially those whose blood pressure is already low or unstable, would be at risk of having an adverse outcome. At the same time, these patients are already at elevated risk of dying, and the statin-ARB regimen might be found to save lives by reversing the underlying problems. The implication is that when reliable treatments do not exist, the statin-ARB regimen could be initiated, understanding both the risks and potential benefits, and with especially close monitoring of blood pressure and other tests that bear on the adequacy of blood pressure (for example, coronary blood flow and kidney function). Researchers would be especially careful to terminate the trial if clear evidence of net harm became evident. Finally, if this trial failed, it should not be taken to indicate that tests on less severely ill patients would not work. To use a phrase Dr. Fedson has in some of his publications, failure at this advanced stage of illness might be the result of “too little, too late.” XXX Third, patients at an intermediate level of COVID-19 severity, such as those sick enough to be hospitalized but not so ill as to be hypotensive or have unstable blood pressure, would lie between the first two groups. In this situation it seems easy to argue that the statin-ARB regimen should be studied, in the hopes that by mitigating or reversing the most important underlying problems, patients will be saved from progressing to a potentially lethal stage. It goes without saying that monitoring of blood pressure and related functions would need to be assiduous. At the same time, some of these patients might ultimately require ICU admission anyway, so care would need to be taken not to terminate the trail prematurely, without statistical evidence indicating a net bad outcome.
20. DEVELOPING COUNTRIES
Much of the above pertains to both developed and developing countries, but I’d like to say a few words specifically about the latter. Some of what follows will overlap with points already made, but the emphasis will be different. Here I will focus on a hypothetical situation (which, in fact, has played out in reality many times, most recently for Ebola) in which a highly lethal outbreak, epidemic, or pandemic is ravaging a community, region, or country.
Here we are considering a situation in which the rate of death or permanent harm is so high that an assessment of potential risks and benefits weighs toward using an unproven therapy even outside the context of extremely rigorous clinical trials. In this situation, clinicians, public health officials, and front-line public health workers could consider implementing host-response regimens without waiting for the WHO or other international bodies or organizations to take action. In his peer-reviewed publications, Dr. Fedson has repeatedly stressed that the generic-drug host-response paradigm can function “bottom up,” through the action of local health care and public health networks, at either the local, regional, or national levels. The approach does not require “top down” administration by large international organizations.
To say this is not to renounce scientific study, but rather to expand one’s view of what kind of scientific study would be acceptable. I would suggest that a field trial could compare treated vs. untreated patients of similar disease severity. If all patients in a community are treated, the outcomes can be compared with those in other communities where treatment is not yet available. If no such comparisons are possible, outcomes for treated patients can be compared with “historical controls,” that is, with the case-fatality rates observed during a previous disease outbreak or an earlier stage of the same outbreak, when the medications were not being offered.
In a situation where infection, or the onset of clinical illness, leads to a high case-fatality rate (for example, Ebola or a highly pathogenic strain of avian influenza) an effective host-response therapy should produce a sharp and unmistakable reduction in rates of death. For a large reduction, efficacy will be apparent even in the face of some biases and uncertainties that might otherwise undermine the validity of a small study. If no such reduction is evident, it suggests that a clinically meaningful effect has not occurred. Thus, these informal comparisons, whatever their limitations, may be able to provide actionable information that would guide future action in the same and other communities.
As Dr. Fedson has repeatedly noted in his work, the concept of generic-drug host-response therapy could massively empower developing, and even poor, countries. It could allow them to act independently, with agency and choice, at the national and community levels. To assert this is not to discount the potentially valuable help that the WHO or other international organizations might provide, or to argue against vaccination or research on new antiviral medications. Rather, it is to emphasize that developing nations, and communities within them, may have considerable potential for self-help. External assistance, if available, could then be layered upon the solid foundation of internally generated mutual aid.
21. IS IT ETHICAL AND RATIONAL TO USE UNPROVEN THERAPIES?
This section does not directly address host-response therapies. Like the section on statistical significance, it can considered a digression. If you wish to move quickly through the main presentation, feel free to skip to the next section and return here later.
Is it ethical and rational to use unproven therapies? Are such therapies compatible with scientific medicine? How do these therapies fit into a unified framework of medical decision-making? If “First, do no harm” is a foundational dictum of medical practice, how can one justify risking harm when the efficacy is not known? These are the sorts of questions I hope to answer here.
In the U.S., which is the nation I am most familiar with, physicians and certain other health professionals can legally prescribe FDA-approved medications for any medical purpose, regardless whether those purposes were formally vetted and accepted (“approved”) by the FDA. This ability to prescribe “off label” allows physicians considerable autonomy in trying to help their patients, especially when no fully adequate proven treatments are available. I assume that comparable off-label use is legal in other countries, though I am not familiar with the relevant laws.
The freedom to prescribe off label persists even when other treatments for the same illness have been approved (deemed both safe and effective) by the FDA. The reason is that “safe” and “effective” are regulatory categories, and they do not always translate into what is best for any particular patient, who is unique with respect to aspects of physiology, pathophysiology, psychology, personal values, and life circumstance. In addition, even within the context of FDA terminology, “effective” and “safe” are relative terms: an approved drug may be only slightly more effective than placebo, or slightly better than another marginally effective drug, and also may carry significant risks.
It follows from this that physicians can prescribe any drug or drugs, including the statin-ARB combination, as well as other off-label therapies, including those of uncertain efficacy and even safety, to patients with a pandemic illnesses. The question is: Should they? Underlying this question is another one: Under what circumstances would such prescribing be both reasonable and ethical?
While preparing this website, I mentioned to three seasoned physicians that I was writing about the off-label clinical use of unproven medications. Two wrote back with the cautionary admonition: “First, do no harm.” The third offered no advice but spoke personally. He would, he said, never advocate publicly for the off-label use of a drug that had not been proven effective. But his comment did not reflect an ethical or intellectual objection, but rather a desire to avoid ruining his credibility among peers. This becomes clear when he volunteered that he had once done just this kind of prescribing for a family member, and there was no implication that he viewed this decision as a mistake.
This third physician also stated that in a severe pandemic emergency doctors would begin to prescribe off label out of desperation, regardless of their stated notions on the subject, in the hopes of finding something effective to offer their dying patients. To emphasize the point, he told me that during the 1918 flu pandemic, doctors, imagining that the infectious agent was bacterial, used to bring their microscopes and petri dishes home, working at night in their kitchens to cook up vaccines on their stove tops. The effort was futile, and the technology is now different, he averred, but the motivations that drove the process would, in equivalent circumstances, express themselves anew.
The classic admonition “First, do no harm” is used in two different ways. In one, it is offered as a reminder that the patient’s health and safety must always be the paramount concern: that it is ethical to risk causing harm only after careful consideration and for the benefit of the patient. We can refer to this as the cautionary sense of “First, do no harm.” Here it functions as a reminder to act with prudence, because it is too easy for a clinician, driven by a desire to help or to feel useful to give therapies that are unduly dangerous and not truly necessary.
A second use of “First, do no harm” has a more absolute and less helpful quality. It suggests that it is unethical to take any action that puts the patient at any risk. This absolutist understanding of “First, do no harm” can itself be harmful to patients. Though one may properly hope that, with the progress of science, the situation will change, the current and foreseeable reality is that most, if not all, medical interventions carry some risks and thus always bear the specter of harm. Certain non-medical healing arts may not have similar problems, or the risks may be low enough to disregard — and this is one of their advantages even when questions about their efficacy persist. But for scientifically based “conventional” medicine, to be guided by an absolute proscription against causing harm can amount to therapeutic nihilism
Thus, the essential feature of medical decision making is not a proscription against the possibility of harm, but rather a rational attempt to weight risks and potential benefits. This weighing should firmly embrace the cautionary sense of “First, do no harm,” as a vehicle for to help insure that the risk/benefit assessment is done with care, diligence, and circumspection, but it does not dethrone the risk-benefit analysis from the center of the decision-making process.
We can even say that the cautionary meaning of “First, do no harm” can provide a partial counterweight to some of the well-known systematic biases (for example, publication bias favoring positive finding) that can artificially raise estimates of both efficacy and safety and thus systematically distort risk-benefit analyses. Yet ultimately, it is the balance of risks and benefits that provides the overall structure of decision-making.
In general, when benefits exceed risks, an intervention is warranted; when risks exceeds benefits, the intervention should be shunned. The assessment of both risk and benefit is fluid, changing when new information becomes available. We can thus speak of the risk-benefit assessment as rooted in “the preponderance of currently available evidence.”
To be even more precise, we also should recognize that assessments of risk and potential benefit are (1) estimates, (2) based on a summing together of potential risks and benefits (that is, the “net” effect), and (3) statistical in nature, that is, based on how likely an “average” person is to experience a particular harm or benefit (or the average for a particular subgroup of persons, if such information is available or can be reasonably guessed); and (4) modified by the unique circumstances, both physiological and psychological, of the individual patient.
Now we have something like this: “Medical decisions should be made based on the balance between estimated net statistical likelihood of benefit and estimated net statistical risk or harm, based on the preponderance of currently available information, and titrated as best as possible to the individual patient.” It is not necessary to keep this unwieldy formulation in mind; a general reference to “risk and benefit” is sufficient; but I want to acknowledge the nature of what the simplified phrase “risk and benefit” actually entails.
Risk and benefit must include not only the bare biological facts of the patient’s body, but the patient’s psychology as well; for example, if a given treatment will produce protracted fear and anxiety, this must be taken into account as part of the balance. And of course the ultimate decision about a medical intervention must reside with patients, or those family or friends delegated or construed to be acting on their behalf; the patients’ autonomy over their own lives and bodies supersedes the clinician’s assessment of the propriety of medical treatment. (In saying that, I am setting aside certain complexities, for example, the situation of children and that of patients thought to be mentally deranged, though even in these cases the proper conclusions may be less clear than imagined.)
Notice that if the risk-benefit balance is unfavorable, then the patient is at disproportionate risk of being harmed if treatment is given. Less obvious–and hinted at in the example of surgery–is that, if the balance is favorable, and treatment is not offered, the patient also is at disproportionate risk of harm. And these points apply regardless of whether any efficacy has definitively been established. They apply even in situations where efficacy is very unlikely–so long as the safety of the intervention is sufficiently high to make the “gamble” on efficacy worthwhile; and so long as better, mutually exclusive options do not exist.
As an extreme example, if a particular medication has just one chance in a million of helping a patient, yet the risk of harm is one in two million, a favorable benefit-risk balance exists. There would be a net statistical benefit to treating with this medication, and one could well consider treatment as ethically appropriate, or perhaps even required, assuming the patient agreed. Conversely, to not offer the therapy is to subject the patient to net statistical harm and could well be considered unethical.
Again, this point applies to both proven and unproven therapies. It is thus an error in medical thinking to imagine that it is inherently irrational or unethical to offer treatment with an “unproven” therapy. Such may be the case — or the complete opposite may be — depending on preponderance of currently available evidence about risk and benefit.
Finally, in determining the net risk, we must take into account not only the direct risks of the intervention itself, but also the risks of not intervening, and this requires that one consider both the natural course of the illness and the availability or lack of availability, and adequacy, of other therapies. Fore example, if a patient has a relatively good prognosis without treatment, or if another very effective therapies exist, the intrinsic risk of an unproven treatment takes on great weight. In contrast, if an untreated disease will rapidly produce death, and no other adequate treatment exists, the same level of risk in an unproven treatment is given much less weight. And there is a great deal of ground between these two extremes.
22. SHARING OF OUTCOME INFORMATION DURING A PANDEMIC EMERGENCY
I am currently writing this section. Please check back soon.
Rough material. My comments here reflect and build on those already mentioned in the section on Developing Countries. Although they continue to apply in those countries, some of these comments apply most directly to developed countries.
Second – Informed Clinical Decisions. I hope to raise awareness of the statin-ARB proposal among physicians, nurses, and other clinicians, as well as health officials, at-risk first responders, patients, and the general public. Knowledge of this approach will translate into additional options to consider for either treatment or prevention. I want to reinforce the idea that in the right circumstances, the relative safety of the drugs means that, even though efficacy is unproven, the intervention may have a favorable risk-benefit balance. What the particular balance is will vary based on the unique circumstances of the individual or group, on what new information becomes available, as well as on other factors.
And from other materials — to be integrated — Third – Sharing of Information. I hope to communicate the idea that, should a dangerous outbreak, epidemic, or pandemic occur before definitive trials are done, it is quite possible for clinicians, acting either individually or in small groups with their peers in the community, to informally assess the efficacy of the medications.
Individual physicians and their patients would jointly decide whether to use the medications off label. These physicians could then track the outcomes of treated vs. untreated patients of roughly comparable disease severity. Findings from a number of clinicians in the community could be pooled to provide a broader perspective. Evidence of efficacy (or lack thereof) would then inform subsequent decisions by all clinicians in that community. If all patients within a community were being treated with the approach, the comparison could be made against the outcomes of untreated patients known from other communities or the nation as a whole.
The conclusions reached from such informal, pooled comparisons are imperfect and subject to certain biases. But the question is: Relative to what? If definitive formal testing has not been done, and patients are experiencing serious illness, it is wrong to think that effective individual and community action is not possible, or must be renounced. In a crisis, individual and community action will be absolutely essential.
At a minimum, the informal comparisons described here (technically, they would constitute a retrospective case-series with a comparison group) would be better than nothing. In all likelihood they would be much better. Further, they would be easy to organize; would preserve the integrity of the clinician-patient relationship; and they would retain the autonomy of patients and clinicians to jointly decide how to proceed. Thus, the ethical basis of normal, individualized patient care would persist. The process would have all the benefits of thoughtful off-label prescribing by individual physicians, with the added benefit of generating actionable data that would allow clinicians to self-correct their prescribing based on more than their own individual clinical impressions.
Are there regulatory strictures that would prevent the sharing of information among clinicians? In the U.S., if formal attempts were made to disseminate community findings widely, for example in journal publications, government regulations might require institutional review boards (IRBs) to participate. These boards are intended to protect patients and insure that ethical standards are being met. But if the pooled information were used informally within the community, my understanding is that local clinicians would be free to learn from their collective experiences without the complicating factor of mandatory IRBs. Their sharing of information might be as informal as meeting for lunch, notes in hand, and discussing what they found by examining their patient records.
I do not know what the rules are in other countries, but clinicians should keep these considerations in mind when deciding how widely, or in what form, to disseminate pooled information that is gleaned during a dangerous outbreak, epidemic, or pandemic. One would hope that in extreme circumstances, government authorities would consider the context when deciding how assiduously to enforce IRB regulations. Ideally, such regulations, or their enforcement, would be modified or simply suspended because, in a crisis, the free sharing of newly acquired efficacy and safety information could save many lives.
It should be noted that I am not here speaking of experimental trials in which patients are randomized or otherwise allocated to particular treatments, or to placebo, based on chance. Rather, I am presuming that the clinician and patient are together deciding on the best course of action for the patient. Only afterward is information about the outcome compiled, while preserving the patient’s privacy, and compared to that of patients who did not receive this treatment (or with the historical norm for untreated patients). I disagree.
23. CAVEATS — PLEASE READ CAREFULLY
- The approach described at this website has not been tested in clinical trials. It is currently unknown whether the approach would be effective for either treatment or prevention.
- The medications discussed on this website are generally considered safe. However, like most medications, they are not entirely free of risks. On rare occasions they can result in serious harm or even death. The drug atorvastin, along with other cholesterol-lowering drugs of the statin category, can uncommonly cause liver toxicity or rhabdomyolysis, a serious breakdown of muscle tissue, and in some people it can impair memory. These problems are usually reversible by stopping the medication. Irbesartan, along with other blood pressure medications, can cause light-headedness, and may cause fainting if a person stands up quickly. Other problems are also possible, some of them serious, though they are not common. Many websites comprehensively discuss drug side effects; search on line for phrases including “drug safety,” “medication side effects,” or (for example) “statin adverse reactions.”
- ARBs are usually prescribed to lower blood pressure in a person whose with high blood pressure (hypertension) and most of the safety data about ARBs pertains to its use in these patients. However, in t In a person with severe coronary artery disease, lowering blood pressure sharply could potentially exacerbate symptoms of inadequate blood flow to the heart, possibly bringing on angina or, in the extreme case, a myocardial infarction (heart attack).
- The material presented at this website is intended for educational purposes. Nothing here is meant as medical advice. Nothing is intended to tell individual patients what they should do. Neither I nor Dr. Fedson and his colleagues bears responsibility for any possible harm that might result from using the approach discussed here.