COVID-19 and the quality use of medicines

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In the mad scramble that has been the first couple of months of this pandemic, there has been a lot of searching for therapies that will make a difference. It’s been all the talk around the metaphorical water coolers around the country, and we’ve been introduced to a public discussion about pharmacotherapeutics to a level that rarely occurs. Not all of that discussion has been as scientific as we might like, in fact some of it has been very far from that, but in many ways, given the situation, it’s unsurprising that good prescribing and the quality use of medicines has come under pressure more than ever before. Why did this happen, how did this happen, and what can we do about it?

I’m David Liew, your host, and today on the podcast we look at some of these issues. We’re joined by Darren Roberts, a clinical pharmacologist and nephrologist at St Vincent’s in Sydney, who also serves as the chair of the Editorial Executive Committee of Australian Prescriber. He’s written an online first article out on May 8th, 2020 about the evidence, risks and fads affecting quality use of medicines during COVID-19.

Darren, welcome back to the program.

Thank you, David. Always good to be here.

It's always good to have you on. Now, let's talk a bit about this because I think it might not be obvious to the average healthcare professional on the street as to why quality use of medicines is such an issue during COVID-19. Why are we talking about this?

So, first of all, we should talk about what is the quality use of medicines. Quality use of medicines relates to only prescribe if it's useful. And if you are going to prescribe, make sure you're prescribing a drug that is available and you know the right dose. And we know that the drug that you're actually prescribing is going to have more benefits than it is going to have harms. And we just don't have this information for COVID-19 at the moment. I think there's so many factors that we're all suffering from or experiencing associated with COVID-19 that's impacted on our decision making when it comes to prescribing. Upfront is that of values and expectations of patients, colleagues and of course ourselves. We want to help people. We want to do a good job. We don't want people to suffer.

Of course, these aren't new challenges. We do this all the time. But with COVID-19, in Australia, we're watching what's happening overseas and it's carnage. People are suffering, people are dying and we don't want that to happen here. And so I think we then find ourselves thinking, I want to do something. And so what should I do? And how should I do that? And people are telling us, you need to do something, prescribe something. There's all these drugs that are being discussed. Big personalities are telling us that these drugs are game changers, these drugs should be used. But I'm not sure we have that evidence yet.

I guess there's a whole lot of anxiety in the community, certainly within the healthcare community and that reflects the anxiety in the broader community. I mean, we’re hearing an unprecedented number of mentions of the word unprecedented, and there's all this pressure on us as to try and provide solutions, I guess. And maybe this is why we're in a situation where we're suggesting things that we wouldn't necessarily suggest in peace time in the light of day outside of COVID.

No, I think you're right. And I think that it is that pressure on us. I think the other difficulty that we have is that the information that's coming to us is imbalanced. So we're getting all of this information, which through various sorts of media, whether it be even just chatting with our friends overseas, being part of social media groups, the media itself has just been promoting a lot of, what I'd say is optimism regarding possible treatments. And I just don't think that that evidence is there to support it. And so it makes it difficult for us to say no.

I mean, if we were to make the decision to prescribe a drug for COVID-19, if someone comes in and they've got a positive, and particularly if they're not that well, we need to think what drug will I prescribe? What dose will I prescribe? How long will I do that for? How will I monitor that? And in most cases, a lot of us don't know this information. The doses that we're using for drugs are different to what we'd use for other conditions we might be more familiar with. For example, hydroxychloroquine. And I just think that there's so much information that's lacking.

And so for the average healthcare practitioner, I think it's kind of easy. This is for us to respond with, this is a very specialised area. There is not enough information, I need to defer to experts on that. And at the moment in Australia, the position is don't prescribe these drugs unless it's part of a clinical trial.

Yeah, absolutely.

I mean, if we're talking to our patients who want a drug or even if a colleague says, should I prescribe this? I mean, to be able to prescribe these drugs since they're not standard care really means that they're an experimental treatment. So we need to be able to explain to that person, what is the risks and what are the benefits of taking this medicine? And at the moment, I don't think many of us can actually succinctly say that.

I really want to come back to that point, because I think that gets to the crux of a lot of the issues that surround prescribing during COVID-19. But it's really interesting this idea of optimism that you bring up. I mean, it was really kind of well encapsulated, I thought, with the discussion around ivermectin and this idea that something which is very early in the piece, all of a sudden encourages this disproportionate amount of optimism. And early in the piece from good researchers as well. I mean, it seems like we've got a really distorted environment of dissemination of research information without necessarily the academic filters that would usually surround them.

Possibly. I mean, it depends on who's saying what and how it's being portrayed. I mean, I think the media generally is picking up on taking a very optimistic perspective on these. I think as researchers and as clinicians, we would like to give some sort of hope and optimism to patients in the community that there are options coming, but we still need to exercise restraint in any sort of recommendation or interpretation that this may now be an acceptable standard of care that we should trial.

In particular, I mean, I think this has been encapsulated quite well with hydroxychloroquine. This feels a little bit old news now because it was two months ago, or maybe three months ago, but there was so much optimism. And now the signals we're getting a more of danger from that drug. And ivermectin, we still don't know.

Okay. So that gets to a really good point. And I I know there's been a lot of talk about hydroxychloroquine, but I suspect a lot of the issues are reflected in other medications. I mean, let's first talk a little bit about anecdotes and the way that they seem to get distributed throughout the community. Because that seems to be one of the things that happened with hydroxychloroquine quite quickly, but it seems to have happened over a whole variety of different medications as well. So I mean, how are we meant to deal with that as healthcare practitioners?

So anecdotes in general or hydroxychloroquine?

Anecdotes regarding pharmacotherapeutics in COVID-19, which seem to be all over the place.

Look, at the risk of being controversial, I actually think anecdotes are great. I think all of this discussion of anecdotes in terms of this is a small study, which looked at this, and this is an in vitro study that looked at this, and this is a retrospective study that looked at this, these things are all good because what they're giving is small pieces of information that are helping to build up an overall picture. They can show some potential role for a drug and in particular, it can remove any sort of further consideration of a drug. In particular, some of these studies are quite useful for identifying risks that we may not be aware of.

I mean, I think this has been done very well increasingly only in the last sort of couple of weeks with the hydroxychloroquine. There's been all these new studies that are coming out that's showing that people who take that drug are more likely to die. They're more likely to have severe cardiac-related disease. And of course, this is a major concern. Now but these studies are extremely biased because they're observational, there's going to be various sorts of confounding, which is going to impact on some of the decisions and how we interpret it. But it's at least telling us that these drugs aren't safe. We need to be careful and we need to monitor patients properly.

So I think all of these anecdotes are useful. The problem is, is how do we take that information as average prescribers and decide how do I now use this to influence my decisions? And I think ultimately that that's a simple one... Don't. Unless the experts come forward with guidelines to say this is what we currently do, then we don't use these drugs. These are still experimental. We're still trying to understand them. I read an interesting thing on Twitter the other day where they said in the era of COVID, we've had more editorials on the topic than we have actually had good science. And it was sort of mentioned as a joke, but I don't think that this is a problem. I think this is where experts are sitting down and synthesising information available to tell the average reader who hasn't got time to do all of that this is where we currently are.

I guess the flip side of that though, is that anecdotes have gone into the broader community. I mean, and the obvious example here, back to hydroxychloroquine, is the man in Arizona who died from aquarium chloroquine toxicity. Basically a victim of an anecdote. So I guess, when thinking about how we have these frontline discussions with our patients who have heard about anecdotes through the lay media, how do we try and kind of form that discussion to make sure that we are representing well as experts?

I think that's a really good point. And that case in the US of poisoning I think is a really interesting example. If we just talk about the drug, but we don't talk about the dose and we don't talk about the risks then people will make decisions that can be fatal. And this is where I think the discussions about the limitations and the complexity with this decision making, it shouldn't just be within circles of experts of healthcare practitioners, we need to take this out to the media. And exactly like you said, the media has taken it to the public, but it's unbalanced. And this is where we need to respond to that by highlighting what the risks are and the importance of doing research. We're not doing research just because it's a hobby, this is what we consider good scientific method.

So I hear you there. And basically that if we leave a vacuum of information there, then rubbish will fill it. And I think that seems to have been a little bit of what's going on. We can't afford to not say anything. How do we know what to say ourselves then? Because the thing I'd really like to address here is evidence in this time seems a little bit different to how evidence would normally look in an era where we didn't have a rapidly evolving problem. How are we meant to deal with it? I think a lot of people hadn't heard about preprint literature until a month and a half to two months ago.

I think you're exactly right. And for those who still aren't aware of what preprint literature is, this is where someone will do research and then put it into a PDF and upload it onto a server so that people can then see it and review it. The expectation is that that will then be submitted to a journal for consideration. But what's important is that this has not yet been peer reviewed. So there may be errors in the methods. There may be errors in the analysis. We're humans. We're not all perfect. We can make errors. And this is part of the reason why peer review is so essential. And the media are picking up these reports and propagating them. And so there is such risk that early data may actually have errors.

But of course the positives are that it shortens the time that new information, new hypotheses and new data are actually being seen by the medical profession and also the community. At the moment, the experts in Australia say none of these medicines have been proven to be effective and therefore all we should be doing is doing clinical trials to confirm that they are useful and effective. And as part of a clinical trial have appropriate monitoring for safety and efficacy. I think that should become our default response when people ask us to prescribe these medicines.

Absolutely. I mean, that's what the living guidelines, the national COVID-19 living guidelines really strongly emphasise. Tell me a bit about this clinical trials space and I guess the questions that are being asked. Because it seems to me that in a lot of places, if there are more editorials than research, then there's certainly, in some places, it seems like there's just as many clinical trials as patients.

Well, that's... Exactly. So, this is the sort of fascinating thing that's happening in part, it takes time to develop a clinical trial. And this is necessary. You need to make sure that if you do a clinical trial, that you actually have the resources to be able to do it properly. You can monitor for unexpected adverse events, which is what we're seeing, for example, from hydroxychloroquine. And you need to be able to interpret the data so that it's actually useful. Otherwise you're wasting everyone's time. Patient's, your own, money. It would be unethical to do so. So clinical trials are important.

I mean, I think just confirming the fact that none of us feels strongly about any of the existing treatment options. There are hundreds and hundreds of randomised controlled trials that have currently been registered and at advanced stage of being planned, if not already commenced, to look at the various treatments proposed for COVID-19. So this space has become massive in terms of people doing clinical trials. So I think we're going to be seeing more research coming out, which will inform our decision making.

It's so important just to emphasise why these trials are necessary. And I mean, I think you've spoken about a lot of the reasons why, but not everything that's plausible necessarily actually ends up leading to clinical benefit. And I think that's an idea which is probably not necessarily always reflected in lay media coverage, but also it's the kind of thing when we're desperate or when things are moving quickly, it's easy for us to try and build that optimism on an idea of plausibility.

I think this is exactly correct. We might see, for example, in an in vitro study, so using cells which are in a test tube, that hydroxychloroquine at a certain concentration will reduce shedding of cells and therefore seem to decrease progression of disease. But if that concentration is not a safe concentration in humans, the plausibility of that effect which is proposed by that study then becomes irrelevant to us.

The other issue relates to what is the timing? So if someone's critically ill with established ARDS, it might be too late to reduce viral replication at that point. The main thing we need to do is take down that inflammatory response and improve our supportive care. So instead, maybe those medicines are better for earlier than later. Already, as you can see we're starting to come up with different hypotheses and different sorts of explanations as to why certain medicines may be useful earlier or later, maybe not even useful at all. And so it's very difficult, I think, to directly translate from one bit of information to the next. They don't relate. You need to go through a series of proper clinical studies to be able to go from plausibility based on in vitro to routine clinical use, and many things need to be considered during that time.

And I mean, this process of trials isn't just of the rigour or of the stages of drug development. This isn't just a theoretical kind of bureaucratic barrier. I mean, we know that so many successful phase II studies don't necessarily lead to successful phase III studies and so many successful phase I studies don't necessarily lead to successful phase II studies. And so much useful preclinical data doesn't actually translate in the clinic. So this is something which is real and probably not, is often hidden from the public discussion. And now is getting exposed in an era of, dare I say, unprecedented interest in this space.

Definitely. But there's also been other examples beyond what you've mentioned there of where a phase III study has shown amazing benefits, but then when it's rolled out into routine clinical practice, there's a high risk of adverse events and even deaths. So spironolactone for heart failure is an excellent example of that because all of a sudden prescribing of a drug is outside of the very controlled and considered inclusion criteria of a phase III study. And then when it goes into phase IV, there's less monitoring, giving it to patients who weren't part of the original group and are more predisposed to adverse events and people are dying.

Well, I guess that gets to the reasons why we shouldn't ignore it because I know there've been proponents in the global discussion that we should just try things, what have we got to lose? But I don't think we can say enough that there is plenty to be lost in this situation, isn't there?

Look, there are a lot of people who are saying that. I was reading some media coverage about how apparently one of the European countries had decided not to use hydroxychloroquine because some of their studies people had dizziness, and vision changes. A lot of the responses were, "Yeah, but you're not dead, so maybe you shouldn't be complaining." Which is kind of fascinating because I think the interpretation of that in some ways is that many people in the lay think that this is a condition which everyone's going to die from. And there's almost the interpretation of that was you may have a vision problem, but at least you're alive and you would have been dead without that medicine. And these two arguments just don't compute.

And so I think we need to stop being overly optimistic and almost feeling like it's a desperate situation where doing something is better than doing nothing because I don't think that's true. At the moment, I'm just seeing more flags of risk than I am of possible benefits. And I just think we need to put the brakes on.

And I mean, I know this is a kind of thing which we just need to assess on a situation by situation basis and to try and understand the individual characteristics of each proposed therapy. I mean, without doing that, it's the kind of thing that the risk is that this just gets generalised across and then everything that gets proposed makes its way into the clinic, without all the safeguards and without all the rigour that would usually protect our patients.

Yeah. An example of this was a recent RCT that was done in Brazil. They looked at the effect of chloroquine. And the country's government had already stepped in and said, "We see that chloroquine is an acceptable treatment for COVID-19." And so because of that, they couldn't do a placebo controlled study. So instead they decided to test two doses. And at the higher dose, the mortality was about 40%. And at the lower dose was still fairly high. And it was difficult to ascertain which of these was drug effects and which wasn't. And the authors said, "This is difficult. We should have done a placebo controlled trial." But because the country had stepped forward and said, this is an acceptable treatment, it made it very difficult.

And some people have made the same argument about what's been seen in the US. The FDA's decision to have hydroxychloroquine available and to say that it was appropriate to prescribe this for individuals that weren't eligible for being in a clinical study was almost interpreted as this is an appropriate treatment for COVID-19. And since then, because of all of the toxicity, the FDA has now stepped back from that and said, "Look, really just only use it in clinical trials because there are major safety concerns." So I don't think we should rush in and rapidly say that these are drugs which are useful.

I guess the other issue is the discussion around ACE inhibitors in amongst COVID. That you can take a synthesis almost of plausibility and then well-established effective use in existing conditions. And it can bring this storm where people aren't exactly sure what they should be doing, whether they should be stopping ACE inhibitors, prescribing ACE inhibitors, but nevertheless there's a lot of anxiety which might actually stop quality use of the original medicine.

Look, I think the whole ACE discussion around COVID was fascinating. First of all, it really was put forward as a theory and a lot of the discussions of the physiology and the pathophysiology as to how these drugs may impact on COVID was, to say the least, complicated and in some places conflicting. So it was actually very difficult to interpret some of this information. And ultimately it was based on poor-quality data. And it took six weeks after that first, maybe two months, after the first reports of this could be a problem until new studies came out. And there were about four studies, which were excellent in terms of the numbers and the design, which really helped to clarify that there is no risk of continuing on these medicines. We know that taking your ACEs and then your ARBs would be protective. And there is data to show that early discontinuation of those will cause decompensation your conditions and increase adverse outcomes, including death. And so it really is a major issue. And that's where balance is always required with any of these discussions.

So thinking about all that and knowing that we have thousands of listeners who are trying every day to negotiate the situation in their own minds and with their patients, what kind of advice would you give broadly about quality use of medicines?

So I think at the moment we need to rely on trusted resources. There are experts who are dedicating a lot of time to this, and I think we need to look to their leadership. The TGA has put out a number of statements which relate to COVID-19 and some of the claims that came out in terms of risks of non-steroidals, risks of ACEs and ARBs, to provide some guidance to members of the public, in particular prescribers. So ultimately I think we just need to look to the experts for their advice. And until the experts start to tell us that we now have a guideline that says, "This is the medicine to prescribe. And under these circumstances, under this dose, and this is the monitoring." Until that happens, then at the moment we do nothing except encourage patients to be part of clinical studies, if that's something that they would like to do.

It's a tough balance to walk in these times. But I think we're better by taking on that kind of advice. Darren, thanks very much for joining us today.

Thanks very much, David.

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The views of the guests and the host on this podcast are their own and may not represent NPS MedicineWise or Australian Prescriber. I'm David Liew and, once again, it's been a pleasure joining you on the Australian Prescriber podcast.