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Time to Benefit of Statins for Primary Prevention: A Podcast with Lindsey Yourman and Sei Lee


How long does it take to see a benefit of statin therapy for primary prevention of cardiovascular events in adults aged 50 to 75 years?  That's the question we try to answer with our two guests today, Drs Lindsey Yourman and Sei Lee, the lead and senior author of a JAMA IM study that tried to answer this question.

In the podcast Drs. Yourman and Lee define what time to benefit is, why it is important in regards to decision making for older adults, and common lag time to benefits for common preventative interventions.  We then take a deep dive into the JAMA IM meta-analysis of 8 trials, which showed 2.5 years were needed to avoid 1 cardiovascular event for 100 patients aged 50 to 75 years of age treated with a statin.  

So give it a listen and tell us what you think on either our Twitter or Facebook posts about this podcast.


  


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TRANSCRIPT

Eric: Welcome to the GeriPal podcast. This Is Eric Widera.

Alex: This is Alex Smith.

Eric: And Alex, most people won't even recognize this. But just in case, we want to tell all of our listeners that we're switching podcast hosts, so we're going to Libsyn. So if you're having any difficulty getting a hold of us through your favorite podcast apps, just shoot us an email and let us know because we can try to look into why our podcast isn't refreshing there. And again, we always appreciate any reviews or likes on your favorite podcasting app, including iTunes. So if you have a moment, please do that. And with that, Alex, should we talk about who's with us today?

Alex: Yes. We have some special guests with us. We have Lindsey Yourman, who is well known to us. Graduate of UCSF, took a year off, did some research with me, has been working with Sei, and is one of the founding members of ePrognosis. Lindsey is currently an assistant professor and director of Geriatrics Quality Improvement at the University of California San Diego. Welcome to the GeriPal podcast, Lindsey.

Lindsey: I'm excited to be here.

Alex: So good to have you on. And we have returning to GeriPal podcast, Sei Lee, who's professor of medicine at UCSF in the Division of geriatrics, and has been a guest and a host frequently on the GeriPal podcast. Welcome back, Sei.

Sei: Hello.

Eric: So we're going to be talking about the concept of lag time to benefit including your most recent article published with JAMA IM. But before we do that, we always ask for a song request. Lindsey, do you have a song request for Alex?

Lindsey: Yes. Imagine by John Lennon.

Alex: And why Imagine?

Lindsey: Well, I knew we'd be doing this during election week. And I wanted to pick a song that had a relatively tranquilizing effect or-

Eric: We have to call it election month.

Lindsey: Election month. Yeah, at the time of this podcast everybody, the election is not officially over yet. So we still don't know the result. When you listen to it, hopefully it will be over.

Alex: Hopefully, we hope so.

Lindsey: It has a theme of unity and compassion that I think is really important right now.

Alex: It's great. And I've recruited Kai Smith, my son here. Give a wave Kai. Kai is in ninth grade and he plays guitar and he's appeared previously on this podcast. So he's going to do the guitar part for Imagine here. Here it goes. (singing).

Eric: That was fantastic. Not to downplay your guitar skills, Alex. But Kai, that was pretty amazing.

Lindsey: Yeah. That was beautiful on all accounts.

Kai: Oh, thank you.

Alex: All right. Kai has got to go back to class. But on the podcast version, he'll join me at the end.

Eric: Lindsey, I'm going to start off with you. We're going to be talking about lag time to benefit. Maybe even before I asked the question about how did you get interested in this subject? Can you just give us a brief definition of what lag time to benefit is?

Lindsey: Sure, lag time to benefit answers the question of when you will benefit from something. So we often in research studies look at, "How much will I benefit?" Or, "How much will it help?" But, we less often look at, "When will I benefit?" Or "when will I help?" So a definition would be, the time between when usually, a preventive intervention is started, to the time when an improved health outcome is seen.

Eric: How did you get interested in this as a subject?

Lindsey: I got interested in this because of my interest in prognostication. Which, in other words, predicting how long somebody will live or how well someone will do in their disease course. And my interest in prognostication, was really about decision making. When should we give tests and interventions, especially to seriously ill or frail older adults? And one of those things is thinking about, "Well, how long will this is this person likely to live?" But then the next question is, "When will this intervention or test that I'm thinking for this person, when will the benefits occur?" And it's really hard to know whether something that you're going to do to somebody is going to do more harm than good, unless you know that they're likely to live long enough to benefit. So how long it takes for people to benefit from tests and interventions really matters.

Eric: You say you've been doing this for a while, how did you get interested in it?

Sei: Yeah, I mean, I think the way that I think about this is just going back to most of the patients that I see, have multiple diseases and about 50 things that are recommended for them. And I look at this as a way of thinking about how do I prioritize what's most important? Because clearly, the answer can't be that they should be on 50 different medicines. The answer has to be that we should focus on the things that are most important. And one way to think about what's most important is, what's going to have the most benefit? The magnitude of benefit. But the other thing that we can use to help figure out what's going to be most helpful is, we want to focus on things, medicines, interventions that are likely to help patients sooner rather than later because, many of our patients aren't going to be around forever. And so what that means is that, I wanted to kind of have another lens to think about how best to prioritize all the different medicines and interventions that are possible with modern medicine.

Alex: Can we just go round and round robin style and each one give an example of a medication, a test or an intervention that has a lag time to benefit? And I'll go first because I came up with this idea. How about if somebody has serious illness and is nearing the end of their life and has depression, should you treat them with an SSRI that takes weeks to have an effect, or methylphenidate, which acts in a matter of days, right? So there's a lag time to benefit for those different antidepressant medications. Eric I'm going to pick on you next.

Eric: I'm going to go for finasteride. We see alpha-agonists for benign prostatic hyperplasia and symptoms, they work pretty quickly. But finasteride takes like six months to start kicking in and working because you're trying to decrease the size of the prostate. So using finasteride in hospice patients, my head explodes when I see that.

Eric: Lindsey, how about you?

Lindsey: Well, one that comes up a lot for me, especially with the focus on quality metrics these days, is screening for cancer. So screening for colon cancer screening for breast cancer. And if I have a patient that already has a stage four cancer of another type, it may not make sense to be screening for another cancer, that's not causing them problems. So for example, they show that to get a mortality benefit from screening for colon cancer, it takes at least five to seven years. Well, if my patient has a stage for cervical cancer that may limit their life expectancy to two to three years, by referring them for colon cancer screening, I'm putting them perhaps it more risk than potential to benefit. So that comes up for me.

Alex: Yeah. That's a great one and there's a paper in JAMA about how common this is, using SEER-Medicare data. And I wrote a blog post about that called Dumb Medicine. So it came down a little more strongly than it may not benefit- [laughter]

Lindsey: Because I agree, it takes care of a guy's scratchiness- [laughter]

Alex: That's right. That is the one. Sei, how about you?

Sei: I'll talk about the blood pressure treatment. I think what's pretty clear is that when you start blood pressure medicines, at least for the first couple of months, you increase the risk of low blood pressure orthostatic hypotension, and potentially also falls especially in this, but the frail population, such as like nursing home residents. And what we have done and this is unpublished work at this point, but in the abstract form we've showed that, the time that it takes for blood pressure medicines to decrease strokes are about two years. And so if you have somebody who has a life expectancy less than two years, you're exposing them to all of the risks of starting blood pressure treatment, but you are unlikely to see the benefit of decreased drugs.

Eric: Is that what we were also saying around SPRINT trial, around improvement, around two to three years? Is that where the curve started separating?

Sei: The SPRINT trial, the curve starts separating a little bit earlier. But you're starting to get into the gory details of a lot of this time. The benefit depends on which outcome are you looking at. Are you looking at just stroke or are you looking at all sorts of cardiovascular outcomes? And so, yes. I think the time to benefit, depending on some of those details, are going to be for anywhere from one year, two years, I think that's going to be the ballpark for blood pressure.

Eric: I'm going to throw out another one because, Sei has taught me about this one, tight sugar control. Takes many, many years, say around nine to 10 years to start seeing a benefit of tight sugar control versus usual as far as the microvascular events. We're not going to talk about macrovascular events, but micro, the first complications of tight sugar control, you're looking at nine or 10 years later, is that right Sei?

Sei: We have not done quantitative estimates, so I feel a little bit nervous saying anything at this point. But I do think that it depends a lot on how you define what microvascular outcomes are. If you're looking at hard clinical outcomes like dialysis-

Eric: Hard clinical?

Sei: ... then I think you're looking at least, that amount of time. If you're looking at things like albuminuria, or kind of these markers of worsening kidney function, for example, that actually may be a little bit shorter. But I would also argue that the heart clinical outcomes are probably what's most important to patients and the stuff that we should kind of keep our focus on.

Lindsey: I think in all of these interventions that we're talking about, one of the remarkable things to consider is we're talking about times to benefit that are at least weeks, and then sometimes years, but the time to harm is often right away from side effects. So thinking about the trade offs, is really important.

Alex: Llike in diabetes? What is the example?

Lindsey: I think with diabetes, the big one with tight glycemic control that we all experiences is, if we tried to do that, we can bottom someone out and they can have a hypoglycemic event that could cause a fall and a major injury or just the burden on their quality of life of checking their blood sugar all day. Versus they may not benefit from reduced eye disease for many years to come. So there, they may have some harm before they have benefit.

Eric: I got a question. I see a lot of folks on statins. Where do statins fall into this?

Lindsey: Well, we often prescribed statins in patients that aren't having any symptoms from cardiovascular disease, so we're starting with well patients and-

Eric: So that's not primary prevention?

Lindsey: Primary prevention. And the idea is that we're going to prevent some cardiovascular event in the future. But we all know that many of our patients do report some musculoskeletal side effects from statin, so talk about myalgias. And there's some debate about how much statins really cause myalgias, but we all know from clinical experience that for some patients, it's very real, for them at least, that they do experience myalgias, as well as just the burden of additional medication. So with statins, which we prescribe so frequently, I found myself wondering how long will it take for my patients to benefit from prescribing this statin. But when does the payoff come? Yeah.

Alex: And when we're talking about statins, and the payoffs, there are many different payoffs, which payoffs in particular, did you focus on in this paper?

Lindsey: Yeah, so in this paper, the really interesting thing is the data lifted us to really focus on a hodgepodge of cardiovascular events as the payoff. And what I mean by that is, when we were looking at how long does it take for an older adult to benefit from a statin, we looked at stroke, we looked at all cause mortality, we looked at cardiovascular specific mortality. And in the time period of the studies, usually they range from four to seven years, there actually wasn't a clear cut, statistically significant benefit for those outcomes on their own. For all cause mortality, for stroke, only a few of the studies showed benefit, and for cardiovascular, specific mortality.

Lindsey: So what that meant is, for us to think about how long does it take to benefit from a statin, we had to look at all those outcomes combined, called composite cardiovascular outcomes. And so that's how we did it. And if each of the studies combines all the potential cardiovascular outcomes, they could find a statistically significant benefit within the duration of the study. So hopefully, that answers the question of what outcomes we looked at. Those were things like a combination of anywhere from angina to recess rotation after a cardiac arrest, to death from coronary artery disease. So we looked at a combination.

Alex: So there's a whole bunch of cardiovascular badness.

Lindsey: Yeah.

Alex: Sei, do you want to comment on that?

Sei: Yeah, I would say that, whenever you do a meta analysis or combining a bunch of different trials, there's always messiness, because one trial had people, 60 and older, another trial had people, 50 and older, one trial looked at defined their outcome of major adverse cardiovascular events as cardiovascular mortality and revascularization. Another study may also include stroke and heart failure readmissions. So all the studies were a little bit different, but kind of looking at all of them, all of them had heart attacks, and MI. All of them had cardiovascular mortality, and most had things like heart failure readmissions.

Sei: So I think these are all things that people would recognize are kind of serious, heart related badness. But I think, to Lindsey's point, it would've been nice if we could have actually focused on something that everybody recognizes is a clinical outcome that patients would really care about. And for me, number one in terms of cardiovascular outcomes, would be strokes. I think everybody recognizes that strokes are incredibly bad and can have profound functional limitations. But we looked at stroke and we didn't find enough studies that actually had enough data so that we could do that. And so we ended up looking on something that included stroke, but also included lots of other cardiovascular badness, as you said, Alex.

Alex: And so when you put these studies together, and then you follow them out over time, you're looking to see, we've talked about the benefits. And we've talked about how you combine these different benefits together. The other side of the equation, we alluded to before. And that is, what are the harms of statins? So setting this up for our listeners, what are the potential harms of statins? Because I think most people feel like, "Statins, so what if there isn't a big benefit? They're not really that harmful." How do you view this benefit?

Eric: Wasn't there a push to make them out like over the counter medications a little while ago?

Alex: Yeah. There was even this push to make them over the counter. There was this idea of the polypill, that if we had one pill that had a little beta blocker, a little statin, a little aspirin in it, we gave it to everybody. Look, we could have a huge public improvement in the public health with very little harm. So what are the what are the harm systems?

Lindsey: Well, I think there's one study that was done by Jean Kutner and her friends at University of Colorado, Denver that really made an impression on me. They had patients that were near the end of life, hospice, eligible patients, I believe, and they had half of the patients discontinue statins and half of the patients continue their statins. And the patients that discontinued statins, actually reported a better quality of life. So they didn't necessarily prove why that was, what the side effect or mechanism was but there is always some trade off or some downside of taking a pill. So medication burden would just be one potential harm, but then the other is myalgias.

Lindsey: And it sounds like a little thing, "Oh, just a little muscle ache." but if there's one thing that seems to plague my patients the most in clinical practice, it's musculoskeletal pain and disease. And so for me, that is a huge deal in thinking about risks and benefits of statins.

Sei: Yeah, I think the thing that I would say is that, this is one of those things where I feel like, as doctors or as clinicians, we're taught to focus on rare but serious things. And so for statin side effects, rare and serious would be things like hepatotoxicity. We worry about liver enzymes getting too high. We worry about rhabdomyolysis, which is literally your muscles kind of dissolving and that can cause kidney damage and that's really serious. The reason why I think doctors feel like statins are so safe, is that those serious side effects are pretty rare, kind of on the one in 10,000 level. But what is super common is what Lindsey talked about, about muscle aches, when we do lab tests, we don't actually find anything's wrong, but patients said, "I am having so much pain in my muscles. I'm having trouble getting out of bed." This actually is an important quality of life issue. And if you look at how frequently myalgias happen, some studies suggest that it says as frequent as kind of one in four.

Alex: One in four? Wow!

Sei: Other studies say that it's actually much less than that, kind of less than 10%. There's this huge range of exactly how often this happens, but if we look at how frequently some patients are not renewing their standard prescription, one in four is probably on the high side of the actual estimate, but it doesn't seem that crazy. Again, from the doctor's perspective of what are kind of life threatening side effects, the rates that statins cause those are pretty low. But in terms of a patient centered approach of, is this going to make me feel better or make me feel worse? I think myalgia is something that we need to take seriously. And that actually occurs relatively frequently, so I think that's an important outcome that we need to be focused on.

Eric: Early on, there was a lot of focus on statins and whether or not it impacts cognition. I was worried that it may worsen cognition, it seems like things changed potentially, statins over the long term helping. Where are we with statins in cognition? Do you guys know?

Lindsey: My impression is that it's inconclusive at this time. And especially just because we really don't have a lot of data with statins for adults after the age of 75 years old. And hopefully, we'll have more conclusion about its effect on cognition from this relatively recent trial called, the STAREE trial that should end next year, in the next two years. But I am not aware of a definite conclusion on statins and cognition, but they may have more.

Sei: I'll just, it's clear as mud right now.

Alex: It's clear as mad. Right? Well, the other thing then to think about is-

Eric: Just want to be clear, we're talking about primary prevention through all of this, right?

Lindsey: Right.

Eric: We're not talking about people with a history of cardiovascular disease, or stroke, these are people with no history?

Alex: Yeah.

Eric: All right.

Alex: And but before we move on to what you found, I just want to add to that list of potential harms. Are there any drug-drug interactions with statins?

Lindsey: There are and it depends on which statin and you use too. Some more than others, but for sure, there are drug-drug interactions there. Yeah.

Alex: And there's risk of polypharmacy?

Lindsey: Polypharmacy.

Alex: One more pill?

Lindsey: Exactly. One more pill. And then even potential drug disease interactions, I was looking at this. It's a delayed one, but there is a small but real statistically significant benefit of increased risk of diabetes, over the long term with statin.

Alex: So small but real increased risk of diabetes over the long term, and many patients are on statins for the long term for primary prevention.

Lindsey: That's right.

Alex: And we should also say, cost, right?

Lindsey: Yeah.

Alex: Some are generic now, but some prescribers prescribe non generic medications that may cost quite a bit. And even the generic versions may be an additional burden for some older adults.

Lindsey: Totally. Exactly and I think that a lot of this is also kind of up to the patient. The answer isn't necessarily that "Oh, statins have immediate bad harms and benefits far off into the future, and therefore, we should discourage that." But the patients deserve to have this information, right?

Alex: Mm-hmm (affirmative).

Lindsey: They can assess the burden and harm, but we can help provide them with more information about benefit so they can decide whether the trade off is worth it.

Eric: And what did you guys find? What are we looking at as far as the time to see a benefit from the statins, in your study?

Eric: We'll have a link to it. Also, on our show notes on our GeriPal website.

Lindsey: Right. So basically, we looked at the studies, and we looked at the event curves for people taking a statin and the event curves for people not taking a statin. And we look from time zero, to what time in the future do we see a difference in cardiovascular events between those taking a statin and those not taking a statin. I.e. when the curves separate, if you're looking at a graph. And it took about two and a half years before we saw a difference in cardiovascular outcomes between those taking a statin and those not taking a statin. And I should say, two and a half years for every 100 patients treated with a statin, before we saw a difference in outcomes.

Alex: So you'd have to treat 100 patients for two and a half years to see a difference between those taking the statin versus...

Lindsey: Versus not taking a statin. For TC, even for one person to have a benefit.

Alex: You'd have to treat 100 people for two and a half years where they statin in order to see a difference from another 100 people who were not treated with a statin?

Lindsey: Correct.

Sei: So you have to treat 100 people to avoid one major adverse cardiovascular event at two and a half years. So-

Eric: And remind me what these major cardiovascular events are.

Lindsey: It was anywhere from angina to myocardial infarction, to a revascularization procedure, to stroke, to resuscitated cardiac arrest. So a huge range.

Eric: Yeah. And death?

Lindsey: And death from coronary artery disease. Yes.

Eric: So some bad, some very, very bad. But a big range of from bad to very bad to extremely, extremely bad.

Lindsey: Yes, well put.

Eric: We don't have a lot of studies and folks that are older than 75, right? So when you think about this two and a half years, what patient population should I be thinking about that this applies to? A, primary prevention, people without history of cardiovascular disease, how else should I think about generalizing this?

Lindsey: I think, if you look at the studies that we looked at, it was people with a little bit of elevated cardiovascular risk. So, people with what we'd consider stage one hypertension, average of blood pressure's a little bit greater than 140. People that have slightly elevated cholesterol averaging in the 150s or and some people that were smokers, or that had diabetes. But were otherwise healthy in that they'd never had a stroke never had a heart attack. So we're looking at a slightly elevated risk patients, whether or not we should treat with a statin. And for those patients, yeah.

Alex: So these don't sound like patients you'd see in geriatrics clinic. They sound younger, and they sound healthier and we're talking primary prevention. And many patients we see in geriatrics clinic, I would say, you are both in geriatrics clinic and I'm not, so for words, if they're on a statin, it's more likely to be a secondary prevention. Thoughts about that?

Sei: Yeah. I'll just jump in and say that I definitely felt like doing the study. My clinician hat and my researcher hat was kind of pulling in opposite directions. With my clinician hat, I wanted to focus on people who are 80 and 85. So we tried to do that and then we looked at the studies, and there were no studies on patients that old. And as a researcher, to be able to do this study, I needed randomized trials that had already been published. And so we kept looking at, "Okay, how do we include enough studies to be able to do our study?" And we had to inch up our age restriction to include younger and younger people so that we had enough randomized trials that had already been done.

Sei: And so we ultimately used the criteria of, your mean age in the study had to be greater than 55, which is a lot younger than we wanted to go to. But ultimately, if we kept it at, for example, greater than 70, we would have had zero trials. And so we just kept making it younger so that we could include more people. So to get to your question about how representative is this? I feel like this study result, puts clinicians in the same awkward position that so many data does, we're like, "We are fairly certain about this with this younger age group." And we're kind of asked to see how well it can be extrapolated to the older, sicker patient population that we usually take care of.

Alex: And I'm interested in thoughts about, it's hard to extrapolate but, if you did, what would you expect the findings would be, if you were able to conduct a review studies that were an older folks? Would you expect that oh, they may benefit more because they have greater risk, because they're older? Or would you expect they may benefit less?

Sei: I don't know.

Lindsey: Such a good question. And I would say that I would expect that the trade off may be the same or worse other. In other words, that the older and more frail that a patient is, the more likely they are going to have side effects from a statin. That said, because they're also probably at higher risk for these cardiovascular events, I wouldn't be that surprised if their time to benefit from the cardiovascular badness was a little bit shorter than in two and a half years. So I-

Alex: Yeah, so it is hard to say?

Lindsey: Yeah, it is hard to say.

Alex: That's why I like Sei's response as well. I mean, I like your response, so that's what I was thinking. And then I was thinking who knows, maybe they've made it past the age where most people have their primary heart attacks, and they are at less risk if they survive to be you know, 85. So interesting.

Sei: Yeah I think Exactly. As Lindsey said, that is my hunch as well. If you ask me to put my nickel down now, my overall sense is that as patients get older and more frail, my guess would be that the harms increased faster than the benefits, but I think both of them are going to go up. As you get older, and I think more frail, the chance that your muscle weakness actually leads to a fall and a hip fracture, I think, it's going to increase faster than the fact that yes, as you get older, your risk of heart attacks and heart failure and stroke also goes up. And so the benefits that the statins have, are going to go up. But my sense is that the harms are going to go up faster.

Eric: Oh, it's interesting, because there was a publication last year, I think there year before in Lancet on statins. It was a meta analysis, and actually show that the benefits of statins, they were arguing the benefits were still there, but it did look like there was a significant trend towards smaller risk reductions as people got older. With the folks who are greater than 75, they're just not a lot of individuals in that group, but there was this downward trend in benefits as you got older from statins.

Lindsey: That's a good point. And I think in that meta analysis, they included people with a little higher rate of cardiovascular events than we included in our study. So it was kind of bordering on secondary prevention a little bit. That's a really good point. And that would argue that the time of benefit as patients get older, maybe a lot longer than two and a half years that study for sure.

Eric: Yeah, that's what I think. You mentioned the STAREE study coming out Australia, I believe. I think that's going to be important one because, it's in individuals greater than 70 years old. So hopefully that should give us more an indication-

Alex: Did you say greater than seven years old?

Eric: Seventy.

Alex: 70 years old, ok. I just want to clarify that for our listeners. That'll be a big study. We want to get a sense of what are the implications of this? I would say, the implications are for practicing internist, family practice docs who are taking care of folks who are in this target age range, 50s, 60s, who have some risk, and this is primary prevention, should they start a statin? Do they show the patient the lag time to benefit? Do they consider this and then make a decision about recommending it or not? Are their policy recommendations? What are the implications for you, of this finding for clinical practice and policy?

Lindsey: Yeah, I think that for me, for my younger, healthier, older patients, this study actually makes me more inclined to recommend that they take a statin to prevent a cardiovascular event. Assuming that they are motivated and of the mindset of they want to do every pill test intervention to increase their ultimate health. But on the flip side, for me, if I have a more frail or a patient that has some more life limiting illness, where they have a life expectancy of less than two to three years, I'm a lot less inclined to recommend that they take a statin because I would think, they may not live long enough to benefit but they will certainly be exposed to potential immediate harms. So different implications for my healthier younger old versus my less healthy, younger old.

Eric: Sei are you thinking about the same thing?

Sei: Absolutely. I really love the way that Lindsey talked about this. Ultimately, it gives us information to more to provide more individualized recommendations for older adults. Because some older adults are walking nine holes of golf every other day, playing tennis and those are patients that we should really be thinking of fairly similarly, in my mind to middle aged adults. Whereas we have other older adults who are much frailer, they're on lots of medicines, they're getting around, at best, they're on walkers. And those are patients that I feel like the risks are substantially higher. And I think this study really points to the fact that you really have a substantial time before they're likely to benefit. And it gives me more data to say, "You know what, this stuff just doesn't make sense for you?"

Eric: Then I guess, one question is, when we think about secondary prevention, I can imagine a study like this would become so much more complicated, because you'd have to think, is it for an MI, how soon after an MI, is it for a stroke? Like any idea of how we should think about this for secondary prevention? Or is it just going back to say, "I don't know."?

Lindsey: Well, I believe there is at least one study that suggested that the time to benefit for stains, after you've already had a heart attack or stroke is about six months. Six months till you see a difference between those that are taking statins versus not. I'm sure that, that study didn't include a lot of people over the age of 75. So we still need to wait and see, but I guess, with secondary prevention in the clinical practice, I'm still highly inclined to be recommending statins to my patients who for whom preventing another event is high on their priority list.

Alex: Yeah, I wanted to come at this issue of the implications from two different directions. And the first is from a public health perspective, is this a big benefit in a short period of time? Or is this a small benefit in a long period of time? Is there a way you can put this in context, comparing it to beta blockers for prevention of MI or aspirin or exercise? Or...

Lindsey: That's great. Well, I think we need more research about time to benefit in general such that that framework is readily on the tip of our fingers. I did one comparison though, with a bisphosphonate. It takes about a year of treating 100 people before someone benefits. So statin is a little bit less pages or takes longer to benefit from a bisphosphonate. But I'd love to compare it to exercise, number needed to treat, and I don't have those numbers off the top of my head. What about-

Alex: Because it's much easier for a doctor to write a prescription for the statin, than it is to really coach, give somebody the tools and help their social situation, so they have time to exercise, give them the means to do that. And yet that may be, I would guess, benefits earlier...bigger benefits.

Lindsey: Yeah.

Alex: Sei any thoughts from that public health perspective?

Sei: Absolutely. And I think the thing for exercise, it almost seems like, "Name and outcome that exercise seems to help. Whether it is cognitive decline..." So it gets way beyond cardiovascular outcomes, exercise is good for many, many things. It's good for depressive symptoms. So it's good for so many different things, that I think it's pretty clear that the magnitude of benefit for exercise is clearly the most single most important thing that you can do. In terms of the public health effects, one thing that I'll call out is, we've made the switch from our study really focused on the timed benefit, like when is there certain benefits going to happen? Your question really talked about the magnitude of benefit of how much will the benefit happen. And I think statins compares quite favorably to most other cardiovascular interventions like blood pressure treatment.

Sei: But I think once you go from, for example, secondary prevention, to primary prevention, the numbers get substantially smaller. And so it always struck me hard when talking to an individual patient saying that, "This is going to decrease your risk by 10%." For an individual, it may not sound very much, but from our perspective, it may be very important.

Alex: Yeah, that's where I want to go with this next, this is my last question. If you said to a patient, "Hey, your cholesterol is high, we're going to statin, what do you think they're thinking about that?" Are they thinking, "Oh, I'm going to prevent, a heart attack tomorrow because I'm taking that statin today, this is my dice."? Or, "This is going to prevent every heart attack from me."? And if you showed them, your primary care patient, that it would take treating 100 people for two and a half years with this medication to prevent one heart attack, how do you think patients would respond?

Lindsey: I worry about that. I feel for the individual patient, I actually want them to have that information, so they can make a decision. Because I don't think most patients think that it would take that long and don't realize that 99 out of 100 times they won't be the one to benefit. But I would worry to hear our leader of population health at UCSD, hear me educating patients to go against this potential intervention that benefits at the population level?

Eric: Well, I can also imagine it's hard because we don't know what the number needed to treat at 10 years, or 20 years is. We know what it looks like for two and a half, but it's likely the benefit will continue to accrue in potentially a much higher number if you treat a decade or two decades later.

Sei: Yeah. I feel like as I've gotten older, and more ornery, more curmudgeonly, maybe-

Eric: It's the statins you're taking.

Sei: That's probably it. I've become much more paternalistic, I think and I try to make a determination for a patient. Do I feel like they want this information? Do I feel like this person is going to be able to process and use this information? And I think there is a large swath of my patients where I wouldn't be talking about time to benefit. I would make a global assessment of what is this person's risk and I would say, "You know what, I'm not going to recommend this for you because I don't think this is going to help you." And I think it's actually a minority of patients, where this information is helpful. And part of our role as clinicians, I think, is to filter this huge amount of data that we now have, and to try to put into our decision making the patient's values as we understand them, and recommend what makes sense.

Sei: And I think this is up for debate on whether this is the right way to do it. But I think it's trying to actually present this level of detail about time to benefit, one in 100, two and a half years. I think it's really hard for a lot of people to fully incorporate that into their decision making.

Eric: Yeah, I'm trying to imagine how to do that. Do you see [crosstalk 00:45:34] there between the end of our show and that. Well, Lindsey and Sei, thank you for joining us. But before we end, Alex, can you help us imagine?

Alex: (singing).

Lindsey: That was awesome.

Eric: Okay. Well, Sei and Lindsey, big thank you for joining us for this.

Sei: Thank you for having us.

Lindsey: Thank you so much.

Eric: And a big thank you to our listeners for continuing to support our show. Just as a reminder, we will be switching podcasting hosts to Libsyn. So if you have any issues of continuing to listen to our podcast, please contact us, so we can look into that. And if you have a moment, please share us on your favorite podcasting app, write a review or like us. And thank you Archstone Foundation for your continued support.

Alex: Thanks everybody.

Eric: Goodnight.

Lindsey: Thank you everyone.

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