John M. Mandrola, MD

Disclosures

November 16, 2015

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Editor's Note Paul K. Whelton, MD, MSc, Show Chwan professor of global public health from Tulane University School of Public Health and Tropical Medicine in New Orleans, presented the SPRINT trial at the American Heart Association (AHA) Scientific Sessions in Orlando, Florida. The trial was stopped early by the data and safety monitoring board, a decision that was announced at a press conference on September 11, 2015 without any details on the absolute numbers of events. John M. Mandrola, MD, interviewed Dr Whelton on the detailed findings.

Dr Mandrola: Hi, everyone. This is John Mandrola from theheart.org on Medscape. I'm here in Orlando at the AHA meetings, and I'm very pleased to be joined by Dr Paul Whelton, who is chairman of public health at Tulane University and an investigator in the SPRINT trial.

Welcome, Dr Whelton.

Dr Whelton: Thanks, John. It's a pleasure to be with you.

Dr Mandrola: Because we're going to talk about the SPRINT trial,[1,2] which is a blood pressure trial, give us some background information on blood pressure.

Dr Whelton: As you well know, high blood pressure is a very important risk factor for cardiovascular disease, with a continuous relationship and no evidence of threshold. We know that high blood pressure is one of the most important risk factors. In fact, everyone who's studied it would say that it's the most important worldwide for mortality, for disability-adjusted life years. Over a billion people worldwide have established hypertension.

We know that treating hypertension nonpharmacologically and with drugs, especially with drugs, will reduce the risk for cardiovascular disease. We know a lot about the drugs, the comparisons with classes.

The big unanswered question in clinical practice is how low do you take that blood pressure? That was really the basis for designing the SPRINT trial.

Big Trial in a High-Risk, Diverse Group

Dr Mandrola: This was a big trial, conducted in multiple centers with some pretty strict methodology.

Dr Whelton: Yes, it was conducted in 102 centers across the United States and the Commonwealth of Puerto Rico. We enrolled quite a large number—9361 participants. They had to be over the age of 50 years. They had to have an average systolic blood pressure (SBP) between 130 mm Hg and 180 mm Hg. They could be on medications—90% of them were on blood pressure medications—and had to have some other indication of risk. Their 10-year Framingham score would be over 20%, so we recruited a pretty high-risk group to be sure that we would answer the question.

Dr Mandrola: This was a pretty diffuse population that included multiple races and some elderly patients.

Dr Whelton: We wanted to be sure that we could answer the question in older people, so about 30% of the cohort was over the age of 75 years. We wanted to be sure that we could answer it in kidney disease patients, so almost 30% had kidney disease. We wanted to be sure that we could answer it in African American patients, again, about 30% were African Americans, so, yes, we had a diverse group of participants. We did exclude patients with diabetes, those who had stroke, and those who had polycystic kidney disease because at the time we were designing SPRINT, there were trials ongoing in all of those areas.

Dr Mandrola: The diabetes exclusion is a big one. That was probably based on the ACCORD trial?[3]

Dr Whelton: Yes, exactly.

Dr Mandrola: Which showed that aggressive blood pressure control wasn't effective, or at least probably not effective.

Dr Whelton: ACCORD failed to demonstrate the benefit, but there was a wide confidence interval. Unfortunately, it turned out to be underpowered statistically, so it really didn't answer the question.

Dr Mandrola: One other thing about the methodology of SPRINT—I noticed that there was pretty intense follow-up, monthly visits, and then every-3-month visits afterwards.

Dr Whelton: Yes. SPRINT is, in many ways, very similar to what you do in clinical practice. We used the same medications, but we were very careful about how we measured blood pressure.

Dr Mandrola: Tell us about that.

Dr Whelton: We followed the standard AHA recommendations. When an individual came in, they had to sit in a chair with their back upright. They couldn't have their blood pressure measured for 5 minutes, so they were in a quiet room for 5 minutes, unlike in a busy practice, where your tendency is to come in and measure straightaway. We took several blood pressures, and we averaged three blood pressures per visit.

We used the standard medications. We recommended using the medications that were best documented as being helpful from clinical trials, and we went to full doses. That's the difference. To get to our lower target of blood pressure (less than 120 mm Hg) required less than three medications, 2.8 on average.

The other arm that we randomly assigned to was what's currently recommended in most guidelines—less than 140 mm Hg systolic, on average. There was only a one-medication difference, on average, between those two arms.

SPRINT Results and Early Termination

Dr Mandrola: Let's talk about the results. What was the primary endpoint?

Dr Whelton: Well, the first thing is that we got good blood pressure separation. We were happy with that. We got exactly what we hoped for, 15 mm Hg at 1 year, and that pretty much stayed that way throughout the trial.

Our primary outcome was a cardiovascular disease composite, a mix of heart attack, acute coronary syndrome that didn't result in a heart attack, stroke, heart failure, or death from cardiovascular disease, the first occurrence of any one of those five. We were also very interested in all-cause mortality.

We planned to follow our participants for 4-6 years, pretty standard for this type of trial. One day, I get a call, and it says "Good news. The institute has decided to stop the blood pressure intervention, on the basis of advice from the data and safety monitoring committee." The median follow-up was actually 3.26 years, less than what we had anticipated, and by that stage, the decision was in.

We have been working hard in the last 4-6 weeks to get everything cleaned up, find all of the events that trickle in over time, and adjudicate them. Based on that experience, we could say that we found a 25% reduction in the primary outcome, cardiovascular events, and a 27% reduction in all-cause mortality.

Dr Mandrola: There's been some talk and controversy[4] about the early termination. In other words, if you terminate a trial early, you may bias the results one way or the other. For instance, six free throws may not indicate a 60% success rate if you're looking at a longer trial.

Can you comment about the decision to terminate?

Dr Whelton: I didn't decide to terminate. I was an investigator. We always have to balance the collective good. We're doing a trial to inform the practice community and the patients and the general population, so that's the collective good.

At the same time, it's really important to protect the welfare of the participants. That's why we set up data and safety monitoring boards who are unblinded to the results and can monitor them carefully. They have a set of statistical monitoring guidelines. It turned out that they had exceeded those guidelines on two consecutive occasions. That's when they went back to the institute and said, "We have to inform the participants and their healthcare providers about what's going on."

Unlike a regular trial that goes to full length where you have 6 months to clean everything up and get ready, in a situation where you're stopped early, then you have to scamper. You must inform the participants and their healthcare providers. If you do no more than that, you just have a series of rumors, so I think you have to make the general public and all providers aware.

Then, we worked really hard in 4-6 weeks to get everything ready to make a presentation here with concurrent publication of our main results. That's as much as you can humanly do. You don't want to wait. You always want to share as quickly as you can, and at the same time, you want to have as complete and clean a data set as you can.

Dr Mandrola: The relative risk reductions were definitely significant. How does that translate into absolute risk reductions, in terms of the numbers needed to treat for the benefits?

Dr Whelton: It's a high-risk group, as I mentioned—the number needed to treat to prevent one primary outcome was 61. The number needed to treat to prevent death was 90. Comparing that with other trials, those are fairly low numbers, very acceptable.

The devil is in the detail, of course. You do the trial, and you hope you do it well and answer the question in the trial cohort. Then, the question becomes: How generously can you interpret that and generalize it? You can't do trials in everybody, so if you're very conservative, you would say: I'm only going to generalize this to people who look just like those who were in the trial. If you are a little more—what should I say—broadminded, you might say: Well, I'm not going to get other trials. I'm not going to get a trial in diabetics any time soon, and that's a high-risk group, and maybe I'll generalize to them. It is a conundrum for all of us, and that's where good practice comes in, and getting the data, trying to understand how that relates to the patient, and having a discussion with the patient.

Adverse Events and How Generalizable

Dr Mandrola: Before we close, I want to ask you about the adverse events. The adverse events, I read, were not different between the groups, but there were some specifics that were, maybe, important.

Dr Whelton: Right. We're always trying to see what might be beneficial, what might be adverse, and how to balance those out. We were monitoring very carefully for some things, and we did see some signals, but overall we didn't see much.

Actually, orthostatic hypotension was more common in the standard group, but when you look for hospitalizations related to things like hypotension and syncope, that was more common in the intensively treated group, but it did not result in more hospitalizations for injurious falls. There were signals from the blood chemistries with hyponatremia, hypokalemia, and hyperkalemia; all were more common, which is not terribly surprising.

There were some renal disease signals. Now, our primary renal outcome was in the cohort with chronic kidney disease. We didn't see any difference there, either for glomerular filtration change, dialysis, transplant, or albuminuria. But in the group that didn't have kidney disease, we saw slightly more reduction in estimated glomerular filtration rate in the intensive treatment group.

We also saw some more hospital reports—admission and discharge reports—of acute kidney injury, acute renal failure. Exactly what that means in the long term is uncertain. Is it just a physiologic reflection of lower pressure that would go away over time or go away if a few blood pressures come up again, or is it something more serious? We don't know, and we will need to look at that in greater detail.

Dr Mandrola: Finally, this trial is still ongoing, isn't it? There's a substudy of SPRINT looking at cognitive function.

Dr Whelton: We did get stopped in midstream, if you will, so the cardiovascular results are in. Now, there may be a few events that will trickle in later, but they're not going to affect our findings there.

We have some other outcomes that we're very interested in. We were interested in the effect of intensive blood pressure lowering on cognitive function, dementia, brain size on MRIs, and so on. Those final observations were to be made at closeout, and we've had to accelerate those closeout visits. They're ongoing right now. Those data will be available in 2016.

We also want to get final estimates of kidney function; those are still ongoing. We haven't made any decisions, but I imagine there will be a possibility of following this cohort over a longer period of time, which if it's feasible would be highly important.

Dr Mandrola: Finally, this is the last question. How do you think this informs the whole guideline debate about a blood pressure goal? I know that we have to be careful about how we interpret this, but what is your sense from doing this for a long time?

Dr Whelton: Well, I'm privileged to be chair of the AHA/American College of Cardiology 2016 blood pressure guidelines committee, and we will be meeting tomorrow night to start understanding how SPRINT informs the guidelines. I'll be asking my vice chair to run that meeting, as I'm involved in SPRINT, but it definitely will affect the guidelines. Just how much, we need to wait and see.

You do the research. You put it out there, and then a lot of smart people start digging into it. There's going to be diversity of opinions, which is healthy. The guidelines, then, are going to try to help clinicians make informed decisions based on the best available evidence.

Dr Mandrola: Thank you, Dr. Whelton, for being here.

Dr Whelton: My pleasure.

Dr Mandrola: That's it from the AHA meeting. This is John Mandrola from theheart.org on Medscape.

Disclosure: Paul K. Whelton, MD, MSc, has disclosed no relevant financial relationships.

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