COMMENTARY

INFINITY: SBP Goal in High-Functioning Elderly Clear as White Matter Hyperintensity

An Interview With William B. White, MD

Melissa K. Walton-Shirley, MD; William B. White, MD

Disclosures

March 22, 2019

This transcript has been edited for clarity.

Melissa K. Walton-Shirley, MD: Hello. I'm Melissa Walton-Shirley and I'm here at the American College of Cardiology meeting with Dr William White from the University of Connecticut. We are going to discuss the very interesting INFINITY trial.[1,2] I'd like to congratulate you on the fact that this was a National Institutes of Health (NIH)–sponsored trial, which is a rarity these days. There was no pharma sponsoring in this trial.

Tell us a little bit about the trial design and the impetus behind it. I don't think I've ever discussed white matter issues in any trial in the history of my doing this job.

William B. White, MD: Thank you. The study was developed because we had been following older people who had developed problems with their balance, mobility, or cognitive function but did not necessarily have high blood pressure. Going through that process about 12-15 years ago, we learned a couple of things: Blood pressure was the leading risk factor for the development of white matter hyperintensity (WMH) lesions and the decline that occurs with it.

On an MRI of a patient's brain, the white matter, which is deep in the brain, gets less and less blood flow as arteries start to thicken and lumens are reduced, just like they would in any other part of the body. Once that happens, neurons start to 'knock off' over the course of time. Glial cells, which are on the outside of neurons, don't die initially and light up as white spots on the brain. But this is not functioning tissue. In looking at the cohort we had followed prospectively for 4 years, we found longitudinally that 24-hour blood pressure versus the doctor's office blood pressure was the better predictor of the risk of getting and accumulating white matter disease and it then translating into problems with function.

Study Population

Walton-Shirley: Who were the patients you enrolled in terms of age and cognitive function?

White: Patients had to be at least 75; there was no upper age limit. They had to have systolic hypertension, defined as ≥ 150 mm Hg in the clinic or ≥ 140 mm Hg over 24 hours on the monitor. We excluded people who had low scores on their mini-mental status test (< 24); low scores on their mobility performance tests (< 9); and if they had any kind of underlying neurologic problems that would impair gait, such as a prior stroke, Parkinson disease, or very severe osteoarthritis.

Walton-Shirley: These patients were in relatively good shape.

White: They had to be able to walk. They could use a cane if they wanted to. They could not be a wheelchair-bound individual. They had to have both their limbs. They had to be able to pass a mental status test. We felt that if we put people in this study who had too much morbidity when they went in, how would they last for 3 or 4 years?

Walton-Shirley: Tell me about your trial design.

White: We learned that there may be a "sweet spot" for the best levels of blood pressure. We knew that 110 mm Hg systolic was too low and 152 mm Hg was too high, but we did not know if 130 mm Hg was better than 140 or 145 mm Hg. In 2010, when I started this and wrote the grant, the standard of care was 145 mm Hg systolic for older people, so that was our standard group. We knew from our data that 130ish systolic may be better, so that was our intensive group. People were randomized to a 24-hour systolic blood pressure goal of 130 mm Hg on average or 145 mm Hg. The ambulatory monitor guided therapy over 3 years. Patients were followed at sequential visits with MRI, cognitive testing, and mobility testing.

Ambulatory Blood Pressure Monitoring

Walton-Shirley: I want to talk a little bit about the ambulatory blood pressure monitoring. I hate to confess that when I was in private practice, I bought an ambulatory blood pressure cuff but it dry-rotted. I could not get anyone to wear it. I'd like to know a little bit about what type of gadget you utilized and how often the patients were monitored for 24 hours during the course of your study.

White: We looked at a variety of units, and one of the smaller ones, which was comparable for patients to wear, was the Oscar II unit (SunTech Medical Instruments; Morrisville, North Carolina). SunTech has been in this for years and they have really good software, which I like for analysis.

Patients who are older tend to be a little bit more tolerant of things like this. I thought it may be a problem; it was not. Most patients had to wear the 24-hour blood pressure monitor for a minimum of four 24-hour days in the study, but many had to wear it much more than that. Remember, I was using it to guide the therapy. The good news is that probably only one or two times did we have a total decline with someone saying, "I'm not wearing that monitor." I did hundreds and thousands of studies over the course of the INFINITY trial because it took us about 7 years from start to finish.

Study Outcomes

Walton-Shirley: Tell me about your outcomes.

White: We had a variety of outcomes. The most interesting was what happened to the progression of white matter disease in the brain, which is basically like damaged brain tissue. The accrual or accumulation of that was significantly less in the patients who were randomized and maintained in that intensive lowering of blood pressure compared with the standard group. Relatively speaking, it was about 40% less over the course of 3 years, which is a lot from a clinical perspective.

I was somewhat disappointed because mobility, which was another major co-primary endpoint of this study, was not necessarily different between the two groups. In hindsight, we think it might have been the fact that they were pretty healthy and the study might not have been long enough. In our prior research, this kind of difference in WMH lesions was definitely associated with declines in mobility. The fact that we saw it in a prospective cohort and not in a randomized trial was somewhat of a surprise to me.

We also looked at cognitive parameters, and most of this was focused on memory as well as how fast a person can process something. For example, we have these little computer gadgets where somebody would see something pop up on a screen and they would have to hit a button on the computer or they would have to have both hands on the screen and do it twice—one after another or sequentially. This outcome was a bit better in the intensive group than it was in the standard group. But some of the other things that we expected to be different were not, so it was a mixed bag when it came to cognitive differences. We are still looking at those data; that was a secondary endpoint. We want to find out if there is a relationship with perhaps tertiles of white matter progression, or maybe people whose blood pressure did not decline at night versus those that did and so forth.

Walton-Shirley: You had a significant reduction in cardiovascular (CV) events. Predictable, right?

White: It's a pretty small study compared with something like SPRINT, which had thousands of people. We enrolled 340 people and randomized 199. Most everybody stayed in the study until the bitter end, but you are right. There was a highly significant reduction in nonfatal CV events such as heart attack, stroke, heart failure admissions, arrhythmias, and things of that nature in the intensive group relative to the standard group. In fact, the relative risk was pretty much cut by 75% for that particular outcome. In contrast, things that everybody at the National Institute on Aging worried about, like people falling and injuring themselves and having syncope, were not any different between the two treatment groups.

Walton-Shirley: It's interesting. Let me give some bullet points and please correct me if I'm wrong.

We proved that intensive lowering of blood pressure on ambulatory monitoring to 130 mm Hg systolic reduced CV events over 3 years and reduced white matter disease accrual by 40%, but did not impact mobility or cognition. Is that correct?

White: It did not impact mobility for sure. But we had one test whose results were so much better in the intensive group, that I would say there was a partial finding with cognition. We are still exploring that.

Blood Pressure Goals and Monitoring

Walton-Shirley: Should we repeat this trial on a 60-year-old population? And should we have a more SPRINT-like goal of 120 mm Hg on our next trial?

White: The SPRINT MIND cohort, which was done almost in parallel with our study timewise and had 65-year-old patients, has already done some of this work. They did not use ambulatory monitoring to guide the therapy; they used clinical measurements. They found no difference in mobility at the end of 3.5 years of study. They also showed some changes in cognitive parameters, but not the big one, which is reducing incident dementia. Their MRI results are pending and have not been published yet. The study was stopped early—they wanted to go 6 years but they only went 3 years—because there was a big heart failure and mortality benefit.

It would be nice to be able to do a study in 60-year-olds, but I'm not positive that, ethically, anyone is going to want to sit on systolic blood pressures of 145 mm Hg or so in any age group at risk right now, after the findings of our trial and all the data associated with SPRINT. Mortality was reduced at 3 years, and I just cannot see anybody doing this study again. Follow-up of these cohorts, even though they have been sort of contaminated by everybody getting back down to the lower blood pressure, just for a legacy effect could be evaluated in both of our groups as well as in SPRINT. I think the Alzheimer's Foundation is very interested in people who are at high risk for developing Alzheimer disease having better control of their blood pressure, and they want to look at that group moving forward.

Walton-Shirley: Your quote really struck me: "I would not rely on home blood pressure monitoring to make a clinical decision in this age group." That is pretty big because where I'm from, not a lot of people use home ambulatory monitoring.

White: I did not show this at the ACC meeting, but we have analyzed how home blood pressures did compared with clinical measurements and with the ambulatory measurements. They just simply did not show any relationship with white matter disease progression or any of the functional parameters. I have presented a little bit about this. A lot of physicians like home blood pressure monitoring to help them in practice—I did too. Sometimes a patient would come in and say, "My blood pressure is so much lower than what you're getting." I'd say, "Okay let's do an ambulatory recording to find out if it's true or not." The patient was usually right 65%-70% of the time, but they were wrong 30%-35% of the time too. Part of that was because they did not know what was happening at night because blood pressures rise in some people at night unexpectedly. We trained our patients and made sure they knew what they were doing in regard to the devices. Everybody used the same validated device made by Omron. I think they knew what they were doing, but we just did not get a reliable finding. At least in people who were in their 80s, which is what this group was, I don't think I could recommend using home blood pressures as a surrogate for the other kinds of measurements right now.

Walton-Shirley: Aside from all of the information we learned from the trial, I thought that point was also extremely striking and impactful on daily CV practice and treatment of hypertension.

I really appreciate your joining us today. I know you are busy at this meeting. It might be interesting to put an ambulatory blood pressure monitor on all of us as we go back and forth to all the things we are doing. Thank you very much for joining us today on theheart.org | Medscape Cardiology, at ACC 2019.

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