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Analysis: Can Your Medications Worsen a Coronavirus Infection?

by Amichai Perlman, PharmD PhD

Pharma Domain Expert, K Health



Introduction and Summary


Over the last few weeks, there have been suggestions that certain commonly-used medications can make coronavirus worse. Specifically, France’s health minister warned that taking anti-inflammatory drugs like ibuprofen (the active ingredient in Advil) could worsen coronavirus infection. Similarly, researchers suggested that two types of medications commonly used to treat high blood pressure—ACE inhibitors and ARBs—might increase the risk for severe and fatal coronavirus infections.


There is not much evidence to support these statements, and I would not suggest stopping these medications if you regularly take them. In particular, you should not stop taking blood pressure lowering medications without speaking to your doctor, as doing so could cause more harm than good. When it comes to NSAIDs, these medications have other real risks (like kidney failure or gastrointestinal bleeding), so if you are worried about these risks, another good choice for pain and fever is acetaminophen, the active ingredient in Tylenol. However, you should further educate yourself by reading more about this topic.



In recent weeks I have been wondering whether reading the news has ever been more challenging. We live in an age of increasing transparency and democratization of data and information, but it sometimes seems harder than ever to figure out what is going on. My pharma-sensitive radar picked up a few interesting headlines in the last few days:




These headlines have significant implications for the health of millions, but what are they based on? Most of us have now grown accustomed to the concept of "fake news". We've learned to recognize obvious telltale signs of this genre, and to double-check viral and suspicious posts and messages. However, a very wide "grey-zone", where fact and fiction cohabitate, remains.


So, what is the truth behind these headlines, can anti-inflammatory drugs, like ibuprofen, worsen coronavirus infection? Do blood pressure medications increase the risk for severe coronavirus?



NSAIDs



Ibuprofen and infection


"The country’s health minister, Olivier Véran, who is a qualified doctor and neurologist, tweeted on Saturday: “The taking of anti-inflammatories [ibuprofen, cortisone … ] could be a factor in aggravating the infection. In case of fever, take paracetamol… Jean-Louis Montastruc, the head of pharmacology at Toulouse hospital, told RTL radio: “Anti-inflammatory drugs increase the risk of complications when there is a fever or infection.”" (the Guardian)


The rationale provided by the press for this new warning is the following proposition: inflammation is part of the immune response, and therefore it would follow that anti-inflammatory drugs, known as NSAIDs, may reduce the immune response.


This proposition is somewhat reasonable, and indeed some medical experts interviewed at the BMJ support it; however, it is far from persuasive. While the inflammatory response is a component of the immune response, it is also often the primary cause of organ damage during acute and chronic illnesses. Furthermore, the history of medicine has taught us that it is extremely difficult to successfully anticipate the influence of medical interventions based on our reasoning; and often alternative theories can be proposed. In fact, the emerging therapies for severe coronavirus complications include other anti-inflammatory medications, and it has been proposed that NSAIDs themselves may have antiviral properties and may be effective in reducing the severity of coronavirus. Theories are therefore insufficient for arriving at valid conclusions, and objective and carefully collected data are necessary.



Is there any data backing the French health minister's proposition?


Following some inquiries, it seems the proposition is related to the French medication authority’s warning last year, which highlighted a suspected link between non-steroidal-anti-inflammatory agents and the development of severe infections. This warning was based on reports received in their adverse event reporting system in the past 20 years. These reports described 337 patients with perceived complications of infections which were attributed to the use of these medications.



What does this data mean?


Adverse event reporting systems are an important tool for rapidly identifying unanticipated medication side effects with new medications. The studies conducted on medication prior to authorization are limited in terms of the number of people studied, the characteristics of the people included, and the duration studied. Therefore unanticipated side effects sometimes only manifest during the initial years following authorization. During this time, receipt of reports implicating a medication as related to an adverse effect, can alert authorities to investigate the matter, and consider the need for regulatory measures.


However, this tool also has severe limitations. Adverse event reporting systems only have information on the cases reported. It is not known how many cases went unreported, how many people used the medication without any adverse event, and most importantly – how common the event is in similar people not using the medication. One can therefore not establish whether the adverse event is indeed related to use of the medication, or rather to some other characteristic of people using the medication. Most notably, these medications are naturally used by people suffering from infectious illness. Due to these limitations, many more carefully conducted studies are performed over time to establish medication safety and efficacy.


Ibuprofen has been widely used for over 50 years and has been studied in thousands of trials. These studies have provided much higher quality assessments of ibuprofen's safety. Ibuprofen, and other non-steroidal-anti-inflammatory drugs, have been convincingly linked to several adverse effects, such as kidney failure, gastrointestinal bleeding, and cardiovascular events, warranting caution when using these medications in people with increased risk for these outcomes. However, research has not established a clear link to infectious complications.


Observational research on this topic includes conflicting results, based on small studies with severe methodological limitations. However, several randomized controlled trials have reported on the rates of infections and the outcomes of critically ill patients with infection, when given ibuprofen and other NSAIDS, showing no effect.


In practice, standard medical guidelines encourage the provision of pain relief with NSAIDs in many infectious conditions, including HIV, tuberculosis, strep throat, etc. The European Medicines Authority, the European Association for Clinical Pharmacology & Therapeutics, and the United States National Institute of Allergy and Infectious Diseases have issued statements that there is no data to support the claims that NSAIDs increase the risk or worsen coronavirus infection, and available information does not support interruptions or changes in treatment. The public health services of Ireland and Britain have issued similar statements, and continue to endorse ibuprofen as an option for easing coronavirus symptoms.



Blood Pressure Medication


While the increased severity of coronavirus with ibuprofen was attributed to a general mechanism, which could be evaluated in the context of our general knowledge and experience with the medication, the rationale for blood-pressure medication worsening coronavirus infection is more specific.



Blood pressure medication and coronavirus


Researchers from the university-hospitals of Basel and Thessaloniki recently wrote a letter published in one of the leading medical journals, the Lancet. In this letter, they proposed that two types of medications commonly used to reduce blood pressure in people with hypertension and diabetes, might increase the risk for severe and fatal coronavirus infections. These types of medications are commonly called ACE-inhibitors and ARBs, and include popular brand-names such as Zestril (lisinopril), Lotensin (benzapril), Cozaar (losartan), Diovan (valsartan), and many others.


This idea was proposed, following the observation that people with underlying medical conditions, including hypertension and diabetes, appear to suffer more severe and fatal coronavirus infections. These medical conditions are often treated with ACE-inhibitors and ARBs, and the researchers hypothesized that these medications could be the cause of their more severe medical outcomes.


The researchers' proposition is based on our evolving understanding of the mechanism by which the current coronavirus (known as COVID-19) enters the cells in our body. The virus binds to an enzyme known as ACE2. ACE-inhibitors and ARBs lead to an increase in the number of ACE2 enzymes, thereby potentially increasing the ability of the virus to bind and enter cells.


While this proposition seems compelling, we should be mindful of our earlier lesson: the history of medicine has taught us that it is extremely difficult to successfully anticipate the influence of medical interventions. Biological systems are generally extremely complex, with a multitude of factors interacting to bring forth the observed results. These often include feedback mechanisms, whereby a change in one factor leads the body to respond by changing its behavior often leading to paradoxical effects.


In fact, several other researchers have proposed that ACE-inhibitors and ARBs may actually be protective against COVID-19, based on the exact same information. A wide range of biological theories have been proposed on this topic in a series of responses written to the British Medical Journal.


This state is characteristic of our understanding of many areas of biology and medicine, and it provides room for lots more research and hope for medical advancement. However it is crucial to recognize the limitations of our understanding, so we do not reach over-confident decisions, which can actually be detrimental.


ACE-I and ARBs have been conclusively proven to reduce the risk of heart failure, heart attack, stroke, and renal failure, among patients who have increased risk for these conditions. Discontinuing these medications has real risks. The European society of cardiology wisely responded rapidly to the headlines suggesting a possible link between these medications and COVID-19, with the following statement:


"This speculation about the safety of ACE-i or ARB treatment in relation to COVID-19 does not have a sound scientific basis or evidence to support it. Indeed, there is evidence from studies in animals suggesting that these medications might be rather protective against serious lung complications in patients with COVID-19 infection, but to date there is no data in humans. The Council on Hypertension of the European Society of Cardiology wish to highlight the lack of any evidence supporting harmful effect of ACE-I and ARB in the context of the pandemic COVID-19 outbreak. The Council on Hypertension strongly recommend that physicians and patients should continue treatment with their usual anti-hypertensive therapy because there is no clinical or scientific evidence to suggest that treatment with ACEi or ARBs should be discontinued because of the COVID-19 infection."



Summary


The evidence to support recent warnings about medications worsening COVID-19 infection is very weak, and should not lead to stopping these medications if you take them for chronic conditions. It can be particularly dangerous to stop taking blood pressure lowering medications without speaking to your doctor, as doing so could cause more harm than good. When it comes to NSAIDs, there is no evidence they worsen coronavirus, but if you are worried about these or other risks, another good choice for pain and fever is acetaminophen, the active ingredient in Tylenol.


Photo by Hal Gatewood

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