Does Intensive Blood Pressure Lowering Prevent Dementia? A Podcast with Jeff Williamson

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

Alex: This is Alex Smith.

Eric: And Alex, I see somebody in the room with us.

Alex: We have a guest host today with us. We have Lauren Hunt who is a nurse postdoctoral fellow here at UCSF and presented the article we’re going to discuss today at journal club a couple of weeks ago. Welcome to GeriPal podcast, Lauren.

Lauren: Thanks for having me. Hi, everybody.

Eric: And we have the lead author of the article I heard online. Is that right Alex?

Alex: That’s right. We have the lead author. This is a paper about, in JAMA, Effective Intensive Versus Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. This is a hot topic. We have Jeff Williamson who’s the lead author, who is chief of geriatrics at Wake Forest, a great place. We know many people there. We were talking to Bill Applegate just yesterday. Welcome to the GeriPal podcast, Jeff.

Jeff : Thank you. Thank you for having me. I’ve been looking forward to this. Great to be here.

Eric: I’m super excited to talk about this. I’m just looking at two different news headlines on this article. One saying intensive blood pressure treatment does not reduce dementia risk. And another one saying it’s slashes dementia risk. So I’m excited to hear which of those two news articles should I believe. But before we go into the article, Jeff, we always start off with a song recommendation for Alex. Do you have a song for him?

Jeff : Yes. I, lately have been thinking about the, the song Old Blue Chair. It’s a Kenny Chesney song, so I’m not sure how familiar the audience would be with it. But it reminds me of where I want to be.

Alex: Mm, that’s nice.

Eric: Okay. Alex, let’s give it a try.

Alex: [Singing].

Eric: That was awesome. Nicely done, Alex.

Alex: Thank you.

Jeff : Very good. Wow.

Alex: That was fun to learn. Thank you very much for that. Thank you Jeff.

Jeff : I can’t wait to download that.

Eric: Any particular reason you chose that song besides wanting to sit in that blue chair?

Jeff : Yeah. I have a chair like that. I have a few chairs like that and I just love to think about … even the topic we’re going to talk about today, and that’s a really relaxing place for me. So that’s why I chose it.

Eric: Great. So we’re going to be talking about the SPRINT mine trial, so the JAMA article that came out effective intensive versus standard blood pressure control on probable dementia. But usually before we go deep into the article, I’d love to hear just how did you get interested in this as a subject? Has this been something that you’ve been … has been an academic lifelong thing that you’ve been interested in?

Jeff : Well, I’ve been very interested for many years in the need to include older adults and the outcomes in clinical trials that are important to older adults like cognition, like physical function in clinical trials, in tests of therapy. So often outcomes are disease based like stroke, or myocardial infarction, or mortality. And those are important outcomes, but SPRINT, and we have other SPRINT articles that actually incorporate what are important to us as geriatricians and more importantly to our patients. That is how am … how is this going to affect my physical and cognitive function if I do that? So that’s really one of the main reasons that we started on this journey.

Lauren: So that brings me to actually one of the issues that came up when we were reading this in Journal club, which was the issue of generalized ability. Because we were struck that actually you guys had excluded people who lived in nursing homes, and people with diabetes, and people who had a history of stroke. And so then we were wondering if those of us who work in geriatrics would have any patients left after excluding all those people.

Alex: Tough questions right up front Lauren. Wooh Alright.

Jeff : She is trying to nail me right away.

Alex: Right off the bat.

Jeff : It’s like a congressional hearing. I think this is a great question, this is a common question.

Eric: Oh, well we’re going to be asking about your Russian ties.

Alex: That’s right.

Jeff : Yeah. that’s right. There’s a lot I could say there, but I won’t. Back to the science. So thank you Lauren for that question. I think this is one of the most important questions and I think as Geriatricians we often always think of the subset of the population that we see that it’s sort of like a cardiologist that might see only people with an ejection fraction of less than 20%. But there are a lot of older people out there who are very functional.

Half of my practice is people in their eighties and nineties who are driving, independent. I just saw a woman yesterday who is playing tennis. She’s just had her 90th birthday. And so, all trials have exclusion criteria. And so as a geriatrician, the goals of care are clearly very different for someone who lives in a nursing home or assisted living. But I’m talking that SPRINT was really focused on ambulatory older people who can come to see their physician. And still, I think many of us, even as geriatricians still see a subset of people and certainly primary care, family practitioners, and internists see a lot of people who are older who are ambulatory and still living a very independent life who would benefit from this therapy.

So you’re correct, this doesn’t cover all the landscape of older people and it was not meant to be. Just like if you do a cancer trial, is it generalizable the people who don’t have cancer? No. We’re talking about people who have cancer in a cancer trial. And so I think that’s a confusing thing sometimes for geriatricians

Eric: Well, maybe we could take a step back and let’s think about … what, it’s been now three years since the original SPRINT came. Three years, has it been that long already? Two years. Three years.

Jeff : Three years.

Eric: 2015. So it was a randomized controlled trial looking at two different blood pressure target goals of less than 120 versus less than 140. Nearly 10,000 people 50 years and older. And everybody had to have a blood pressure of somewhere between 130 and 180. And they all have to have some other increased risk for cardiovascular events. Like they had to have CKD, or cardiovascular disease other than a stroke, or an age greater than 75 or a Framingham risk score of greater than 10. [inaudible] a good summary of the SPRINT kind of what the population was. And like Lauren said there are some exclusions.

Jeff : There are some exclusions, correct.

Eric: Stroke, diabetes.

Jeff : Let me explain those exclusions just very quickly. We excluded people with heart failure because they have to have these medications and then people with diabetes and prevalent stroke, were already having a trial looking at lowering blood pressure. So we didn’t want to get halfway through the trial and have to deal with how are we going to incorporate the findings from those trials into our current trial.

Eric: And then also importantly, everybody right, you screened out people with orthostatic hypotension, right?

Jeff : Yes, we did. We screened out people whose systolic blood pressure fell more than 20 points I believe. But that is a different … I don’t have the paper in front of me from the original paper, but yes we did. And of course we didn’t include anyone whose blood pressure was below 135 to start with. So if your blood pressure fell below 135 or was below 135, you weren’t in the trial.

Eric: And also importantly, the, the way we measured blood pressure in this study is probably different than the way most people measure blood pressure in their clinical practices. It was automated, there was periods of silence and quietness. People weren’t here trying to run to their clinic appointment and then get their blood pressure checked right away. I’ve talked to Dr. Mark Supiano about this and arguing that, “Oh, like this just doesn’t apply to real life. Like real clinical practice. We’re not measuring blood pressure this way.” And his argument is, “We should.” Thoughts on that?

Jeff : Yes. I think one of the most prevalent risk factors that comes through our practices is hypertension, is blood pressure. And, you know, we would not draw blood on people and measure cholesterol or renal function as casually as we measure blood pressure and in such an un-standardized way. So I think you’re right and Mark is right that we need it to not accept such a poor quality blood pressure measurement. And yes, SPRINT, like all research studies has a standard measure for blood pressure and when I see patients now, I tell them, look, we’re in our clinic now. We’re, having people sit still quietly for five minutes and we’re measuring their blood pressure and taking the average of two readings instead of three. And so that’s the basis on which we perform SPRINT. And I think we need to be more careful about that.

By the way, we’re also looking at how we might improve blood pressure measurement in our non geriatric practices. And one of the things we’re thinking of is maybe measuring blood pressure at the end and having an advanced practice provider such as Lauren or others manage the blood pressure. They do a much better job anyway. But measuring blood pressure at the end. Like we do lab work

Lauren: Actually one of the fellows in the VA Quality Scholars program just gave a presentation on a project to try to improve blood pressure measurement and just how difficult that was to actually implement and practice. One of the things that we talked about in the group when we were watching it was the idea of maybe even taking blood pressure measurement out of the office setting and, and moving it into the home and having more regular checks in the home.

Jeff : I love that idea. Lauren. This is a risk factor that should be owned more about the patient than the healthcare system. It’s not that complicated. So, many of my patients now, I say, “Here, I want you to get this automated blood pressure cuff and then send to our team your results after two weeks.” And that’s how we were basing our decisions often.

Eric: Great. So in the SPRINT trial, people who got the standard treatment had a mean blood pressure, like 135, took nearly two medications to control the blood pressure versus three meds almost for those in the intensive group and they almost got to goal 122 and big results was … What were the big results of the study?

Alex: But wait, before we get to the results, hold on. That is a big difference. I think we should just note that in previous blood pressure controlled trials they haven’t been quite as successful. That is a big difference between the two groups. So something worked. Right?

Eric: That one additional medicine

Alex: One additional medicine. And it probably was … What did it take to get these people down? Did they have coaches? Did they have … How aggressive where the study investigators, you and the others in helping people to achieve these goals?

Jeff : Yes, another excellent question. First of all, a lot of geriatricians, were in SPRINT. There were probably seven or eight geriatricians in SPRINT, maybe half the geriatricians in the country. Not really but both arms had non-medication lifestyle recommendations for getting blood pressure to target, number one. Number two, at the beginning for the first three months, all patients, all participants were seen monthly to make sure they were at their goal. And then quarterly after that, and there was no additional coaching or anything like that, it was simply a one visit quarterly for managing this very common and dangerous risk factor. So we didn’t have a whole five people around each participant.

It was basically done … in probably half the places it was done in we’re physician’s offices that are not even academic offices per se. So, but the key was to standardize the measurement of blood pressure and attention to detail. And then of course, when you provide medications at no charge to your patients, well that shows you how much good you can do in that situation. So all the medications, by the way, 95% of the medications used in SPRINT were generic. This was not a study that was supported at all by pharmaceutical companies, 5% of the medications were. So very important to say all that.

Alex: Yeah, those are key points there. That is an interesting, wrinkle to this story. Eric, you were going to ask about what the results were.

Eric: Well, the results. Should we talk about the results because that was the big thing, right?

Lauren: I have a question before that. I just wanted to ask a about how you assessed. You guys had a very robust assessment of cognitive status and dementia and whether you could just talk about that a little bit and it seemed like maybe there was some change from the original protocol. When I was reading it, it seemed like there was an original plan to take a sample of everybody, but then you guys ended up doing the cutoff score. But maybe I’m not reading that correctly. So, just wondering if you could talk about that.

Jeff : Yeah, another great question, Lauren. And so this question is intimately tied to the fact that SPRINT is very demographically representative. One third of the participants were over the age of 75. One third of the participants were African American, one in ten participants were Hispanic. And so, it’s a very demographically diverse study because of that there really have not been good screening batteries for cognition that had been well adjusted for age, culture and social economic backgrounds. So we built into the original protocol that at the end of the first year we would look at … and everyone had the basic screening battery and 30% of the individuals had an entire screening battery that lasted about one hour.Everybody got the 20 minute battery. But the bottom line is at the end of one year, we wanted to take a pause and see what should be our cutoffs based on the various demographic representations in the trial. And that’s why you see that change in the study. We intentionally and purposefully set that in there in at the beginning of the protocol. Does that make sense?

Lauren: Yes, definitely. Yeah, and we thought it was interesting that the cutoff score and the MoCA was actually kind of … we thought it was kind of low. But then in looking at the average score it wasn’t actually that much lower than the average score.

Jeff : That’s true. And I think again, if you look at the baseline MoCA scores, which are in the paper, you can see that this was not a cognitively pristine group of individuals. The mean score was 23. I’m not looking at the paper, I should know all this data by heart and I feel like I do, but you may have it there in front of you. But the bottom line is, and one third-

Lauren: Yeah, its 23.

Jeff : And one third of the people over 75 had a gait speed of less than 0.8. So this goes back to your original question. While this was not meant to be representative of people who are cared for and live outside of the home in a nursing center or whatever, it is fairly diverse in terms of physical and cognitive frailty for ambulatory people.

Eric: Alex, can I now talk about the results?

Alex: Lauren, should we let him?

Lauren: Yes.

Alex: Okay.

Eric: Okay. So, original SPRINT stopped early because of a 1.2% mortality benefit in the folks who got the intensive treatment. Also reduction combined MI, stroke, CHF, heart failure. But the new study, what did you guys find as far as, did it affect rates of cognitive impairment, dementia?

Jeff : Well, it’s interesting at the very beginning of this, you talked about the fact that two headlines were common. One says no effect and another says it’s a game changer. One of those individuals, one of those headline makers didn’t read the paper. I wonder which one it would be. So one of the reasons you’re talking to me is, is because of, there’s one of those headlines, it maybe has more impact on our field. So, we found, and you quoted the absolute risk reduction, the relative risk for redeductio we found a highly significant 20%, 19% reduction in the onset of mild cognitive impairment in the intensive group.

So, uh, these are people that went from normal to mild cognitive impairment. And, and in many ways as a geriatrician as all of you are or gerontologist, I’m so sad that we named this mild cognitive impairment because it has all of the people with mild cognitive impairment and it’s milder than dementia, but it has real impact on their daily life and increasingly technological society. So, being able to prevent or delay this is huge, especially when you have a prevalence of hypertension, upwards of 70% in the population. So, some 1% drops are not that big or one to 2% absolute. But some are when you think of how many people have the condition that we’re studying. So I want to put that in there.

So the second thing about the results is yes, we found a 19% reduction in MCI, which was significant 0.008. We actually also found a 17% reduction in dementia, but it was not significant. 0.10 was the … and the confidence intervals crossed one. So what that tells … and if you see you had more than twice the number of MCI incident cases then we had of dementia. So fortunately for us, human beings, dementia doesn’t develop a rapidly. And so the stopping of intervention early at 3.5 years and also frankly because after we stopped the intervention a fairly significant percentage of individuals didn’t come back for any additional follow-up because they weren’t getting any medication.

So those two things probably prevented our ability to have a significant result in dementia. But we are continuing to follow one additional round. And at that point we may have more clarity on whether the dementia incidents achieve significance or not. Does that help you?

Eric: Yeah. So the take home is it reduces mild cognitive impairment or reduces the risk for mild cognitive impairment and there seems to be a signal that it reduces dementia, but it’s hard to tell because the trial was cut off early. Would that be a good summary?

Jeff : That’s correct. That’s a good summary. And a clue here is that if you combine those two, one thing I’ve learned from mainly hanging out with heart researchers is their primary endpoints combine many outcomes like heart failure, stroke, MI, death. We didn’t do that and I wish we had of because if you look at the combined outcome of MCI plus dementia, you can see that it is significant if you live in the JAMA paper. So that tells you that these events, these outcomes were in the same direction and that they were fairly close in terms of percentile there just wasn’t enough of the outcome of dementia.

Eric: We can also tell you’re hanging out with the cardiologist because of the great titles like SPRINT. I remember the newspapers came out, should we sprint to a new low blood pressure target? Lets not sprint to judgment.

Jeff : That’s right. No. Yeah. That one can learn a lot when you hang out with other people and they learn a lot from us. I think the other part of this podcast is I really wanna encourage gerontologists and geriatricians get outside of our group. You know, we talked to the choir a lot. Like we say down in the south, we’re preaching to the choir. Well, you know what, some of the most impactful science I’ve done and had been welcomed is by cardiovascular docs. I remember back at ALHAT I was the only geriatrician. I was just a little baby at that point. And they said, “Wow, it’s just fascinating to have someone in our midst who understands or is interested in aging,” because they’d never heard of some of the things we’re talking about.

So I think all of us who listen to this podcast need to be getting more outside of our own group and sort of integrating ourselves into some of these other conditions in disease states. And we can do a lot, I believe, in that area.

Eric: I got one more question too. Um, has this changed how you care for older adults in your practice?

Jeff : Yes, it has. I think like almost all the geriatricians, I expected there to be harm for older people who were lowered to 120. And now I use this, like all clinical trials just in the clinical interface between me and the patient, it’s a starting point for my discussion. So now I say, “Look, let’s see if we can get you into the 120s. If you start feeling poorly, my goal always is to make you function well and feel well. But, now instead of trying to get you to 140, I want to get you down into the 120s,” because the patient usually just told me the one thing I fear most, Jeff is not dying. It’s becoming cognitively impaired. And so, yeah, I think if we say we’re evidence based practitioners and we have an ambulatory older person in front of us, then I think that this is the best evidence we have to say … this is the only thing we have that can say we can lower that most feared outcome.

And so I use that in my practice a lot. I still have some patients that I can only get from 150 down to 135 and then they feel poorly. But that’s okay. We’ve made a big gain. But I have a lot of patients and if you look there was actually a quality of life paper published in New England Journal on the SPRINT trial and the quality of life between the two groups on a very extensive battery was not any different. And so I’m surprised often at how many of my patients can actually get there, and get there quite safely.

Eric: And I just want to … you said your goal is to get them into the 120s not less than 120. Can you clarify that?

Jeff : And that’s the guidelines. Yes. So another great question if you look on the ACC/AHA guidelines, I was the AGS representative to that committee for new blood pressure guidelines. And we only said below 130. And because SPRINT is one trial for sure. By the way, this was also shown to be safe in accord but when we look at office based measures of blood pressure, they actually do run about 10 points higher than the standard well conducted measurement of blood pressure such as in trials by SPRINT. So we felt we could safely say 130, below 130 but getting to 120 in an office based practice, the way the quality of the measurement is now, I don’t think we can say that.

Alex: Hmm. That’s an important point. I want to ask … we have a question here, Jeff from Twitter. We have a few different questions. First one is from David Door who says, given the trend, you see what duration of follow-up or increase in N would you need to achieve significance if the point estimate of the primary outcome was truth. And you’ll have to get out your calculator there..

Jeff : This is a timely question because we are resubmitting this now for one additional follow-up. We believe pretty strongly that if we have one additional follow up for two years, so that would be somewhere between 7.5 and 8.5 years that we will definitively know whether dementia was also prevented or the risk for dementia was reduced. So I think we also feel likely that if we had done treatment to what we initially planned, if we had treated to five years rather than three and a half years, we probably would have this answer.

So, uh, that’s a great question. I’ll just say one more thing about that is, is there needs to be some advances in trials, especially for this age group. Cardiovascular end points and mortality are not the most important endpoint to them. So stopping at trial because we had fewer cases of heart failure is probably not the most important end point for older people. So we need to do, and we have proposed some designs that would make cognition and physical function, the primary and the others the secondary outcome.

Alex: Okay. And then we got a couple of softballs tossed to you from Mark Supiano here on Twitter who says what other interventions for older adults have been demonstrated to improve CVD outcomes and mortality and prevent cognitive impairment? If this intervention was a new treatment, how much would we be willing to pay for it?

Jeff : I need to get Mark that $35 I promised him. I didn’t know he was asking questions. But nevertheless, there are no other treatments that have been shown to be effective for the heart and the brain, and there are no other treatments period that had been shown effective for the brain. So, thank you for that question Mark. And I think that again, because this is generic again, I tell my patients, even if you have to be on three medications a month, a day, excuse me. Uh, the cost is typically less than what it would cost to have a cell phone in your pocket every month. And so to preserve your cognition, every penny is important but this is one of the most important you will spend.

Alex: Hmm. That’s great. Well, so we can’t end on an easy question like that. We got to go back to the well here, go to Lauren.

Jeff : Okay. Hit me Lauren. Hit me with your best shot.

Lauren: Well, I had one comment and then they have a question. I just wanted to follow up on what you had said earlier about integrating geriatrics into other professions and Alex and I just wrote an editorial where we talk about exactly this, about how there is really just insufficient number of geriatric and palliative care providers and we really need to be training people in other fields and primary care on these issues.

Jeff : I’m totally agree. I’ll just give you, Lauren, one example that … I’m sorry I love to talk to, but we’re hiring now someone who’s board certified in emergency medicine and is finishing a palliative medicine fellowship with us. And that person is already changing how the emergency room cares for dying people. So I completely agree with what you just said.

Lauren: All right. And so the question is, so there was a figure in the addendum and it showed how you guys had really great results in lowering the blood pressure in the treatment group. And they got to an average of 120 and other group is in the 130s to the 140s for the first four years. And then the trials ended early and then of course everybody now it’s clear that this treatment is really effective reduces cognitive impairment, and reduces all these cardiovascular poor outcomes. And so everybody in the control group their blood pressure got lower, right? After the trial ended.

Jeff : The control group, actually, the standard treatment group stayed at 135 to 136 through the treatment and through the extended follow-up off of research therapy.

Lauren: Right. What happened to the treatment group?

Jeff : So the treatment group, the intensive group rose steadily until they leveled off at 129. A systolic blood pressure of 129 which is still below the current guidelines of 130 but it does show you that once you stopped providing medications at no charge and making this a focus of the visit, well all of a sudden the blood pressure starts to rise.

Lauren: So what do you think is … what do you think are … how we can change this? How do we make it so that … we have this great intervention and we can keep it going into the real world.

Jeff : Well two things. One, again, I would say at least the intensive group is below. Is at guidelines. So that’s good. I can’t say that they’re undertreated because they’re at 129 when we did the last follow up visit on average. So, but I do think this is one of the great opportunities of electronic health system. Mainly they’d been a billing tool now. But here and I suspect where you are, we can now begin to see what are the blood pressures of specific patients and of the panel of specific providers to say, “Look, we don’t expect all your patients to be below 130, but on average we’ve shown that you can get most of your patients, on average we can get your average to below 130.”

So I think we need to start using electronic health record keeping as a way to help providers not provide another banner but to help them maybe on a quarterly basis just say, “Hey, where are my blood pressures in my panel?” So there’s some things like that that need to be done. We need to have some innovation in our system that helps us understand what’s important and this is a really important risk factor.

Eric: I want to thank you tremendously for joining us today and really for, for doing this research too. Because like you said, I think for a lot of Geriatricians, initially when we saw this, we think, “Oh my God, this can’t be true. Like there’s something not right about this.” And when you actually read the article, it’s a great article. The original SPRINT, this, the frailty article. So I just want to say a big thank you.

Alex: Yeah, thank you so much, Jeff.

Jeff : Thank you all. I will say too, even as a geriatrician, when I saw this result, I would think, “Gosh, I spend most of my days taking people off of medicine.” And I still do that But I’m more and more even adjusting my thing to say I want people to be on the correct and the most important medicines. There are a lot of medicines that older people don’t need, but I think hypertension therapy is one of those medications where we need to be very careful before we start just backing off of everyone, especially fairly healthy older people.

Alex: Terrific.

Eric: Well, maybe Alex, do you want to end with a little bit of a song?

Alex: A little bit more of the song?

Jeff : Thank you.

Alex: From the chair I’ve caught a few fish and some rays. I’ve watched boats sail in and out of cinnamon bay. I let go of the lover that took a piece of my heart. I prayed many times for forgiveness and a brand new start. I’ve read a lot of books. I’ve wrote a few songs. looked at my life where its going, where its gone. I’ve seen the world through a bus windshield but nothing compares to the way that I feel. To the way that I see it. To the way that I see it when I sit in that old blue chair.

Jeff : Wonderful.

Eric: That was wonderful Alex.

Alex: Thank you Jeff.

Eric: Jeff, again, big thank you for joining us.

Alex: Huge thank you.

Eric: All of our listeners. Thank you for joining us this week. I forgot what my [inaudible] is.

Alex: If you’re listening to us on iTunes or some other medium. Please make sure to like us.

Eric: What Alex said.

Alex: We’ll see you again next week.

Eric: We’ll see you again.

Alex: Goodbye.

Eric: Goodbye everybody.