COMMENTARY

Any HOPE(-3) for Staving off Age-Related Cognitive Decline?

John M. Mandrola, MD; Jackie Bosch, PhD

Disclosures

November 21, 2016

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This is John Mandrola from theheart.org on Medscape. I am here at the American Heart Association Meeting in New Orleans. I am very happy to have Associate Professor Dr Jackie Bosch from McMaster University, who presented the HOPE-3 cognition study[1] today in the late-breaking session. Welcome, Jackie.

Jackie Bosch, PhD: It is a pleasure to be here, John.

Dr Mandrola: HOPE-3 is an amazing trial; this is a cognition arm of the trial. Tell us what you were thinking when designing this trial.

Dr Bosch: The primary prevention aspect of HOPE-3 is the interesting part. We wanted to effect change before major change was actually seen. Vascular events share a lot of the same risk factors with cognitive decline. If we can reduce vascular events, we should be able to see a decline or a prevention of cognitive decline in that group as well. It seemed like a great opportunity to study a variety of questions simultaneously.

HOPE-3 Cognition Substudy

Dr Mandrola: This cognition study was a different group from the original HOPE-3 trial.[1]

Dr Bosch: Our original 12,000 patients were randomized to receive either blood pressure–lowering therapy or placebo and rosuvastatin or placebo. That was our main group. They were at intermediate cardiovascular (CV) risk. They had no vascular disease and no clinical disease. In that group we asked those who were 70 years of age or older if they would complete questionnaires on cognition function at baseline and study end. We chose the 70-year-olds because we know that is the age of greatest risk for cognitive impairment, and we thought that this group would have the events.

Dr Mandrola: Tell us about some of the rationale behind the study. You thought that cognition would maybe improve, but there was also the possibility that it would worsen.

Dr Bosch: There was. In the blood pressure–lowering arm, we thought there would be less decline in those who were taking the blood pressure–lowering medication. Going back to the hypothesis that, in midlife, hypertension is associated with later-life cognitive impairment, we thought that might bear out in our study. For the rosuvastatin comparison, there is a black box warning that the US Food and Drug Administration (FDA) and other regulators have put on statins regarding episodic memory loss. We wanted to see whether that actually occurred in this population.

Dr Mandrola: How did you go about testing the hypothesis?

Dr Bosch: About 1600 of the participants aged 70 years or older agreed to participate and completed both questionnaires.[2] We used the digit symbol substitution test. This is a test of processing speed. You see a little symbol up at the top and you have to insert the right number as fast as you can. You do as many as you can for 2 minutes. It is stressful, actually; it requires you to be constantly switching, and processing speed is highly susceptible to vascular cognitive impairment. We chose the most sensitive measure.

We did not choose only that measure. We included other measures of cognition and function, because we recognized that measuring cognition is tough. We wanted to see whether, in a constellation of instruments, we actually made a difference.

Dr Mandrola: What did you find?

Dr Bosch: When we look at the results of those who were on blood pressure–lowering therapy compared with placebo, there was no difference in the mean change in cognitive decline. Overall, the study population declined by about 5 points on this test, but there was no difference in the blood pressure–lowering group. Similarly, there was no difference in effect in those on rosuvastatin versus placebo or the combination therapy versus placebo.

Dr Mandrola: The trial showed lower low-density lipoprotein cholesterol (LDL-C) levels and lower blood pressure, but these improvements had no effect on decline in cognitive function?

Dr Bosch: Exactly. They had lower blood pressure, lower LDL-C, and lower cognitive function, but no differences between the groups.

Subgroup Signal

Dr Mandrola: What do you conclude from this? You have a sad face; is that because it was a negative trial?

Dr Bosch: It is sad; we wanted to prevent cognitive decline. We went back and said that maybe there is a signal somewhere in some of our subgroups. Looking at the blood pressure–lowering subgroup, we saw that the vascular events were actually prevented in those with highest baseline systolic blood pressure. We looked at the treatment effect by baseline systolic blood pressure, and of interest, those with the lowest systolic blood pressure actually seemed to do worse than the patients on active treatment. Those with the higher systolic blood pressure did a little better. This was a visual trend that was not statistically significant, but it was interesting.

We went back and looked at the same subgroup based on LDL-C levels. There was no difference between the lowest and middle groups of baseline LDL-C level, but we saw a visual trend for a difference in the highest LDL-C group. It made us wonder whether the combination treatment might have had an effect on the people who had the highest systolic blood pressure and the highest LDL-C levels at baseline. There seemed to be something there. There was a statistically significant difference. The group on active therapy declined by 4 points, and the group on placebo by 11 points. It was a statistically significant difference, although a post hoc analysis.

Dr Mandrola: That makes sense because it goes with the hypothesis. Tell us, as a researcher, about looking into that subgroup data when overall results are negative—what do you feel about that?

Dr Bosch: That is a risky road. At best, it is hypothesis-generating, and it means that we probably do need studies that look at a variety of components. We need to identify people who are at risk. We see a signal that risk might have a difference. The other thing we found was that those who were on treatment longest seemed to do a little bit better. Maybe we have to start the treatment earlier, give it longer; and in people at elevated risk, we need to look long enough to understand a real change in cognition.

Dr Mandrola: A couple of months ago I interviewed Dr Ference, who thought that his Mendelian randomization[3] was consistent with HOPE-3 in that longer exposures to lower LDL-C and lower blood pressure levels had cumulative benefits over time. Do you agree with that?

Dr Bosch: Yes, we could see better indications of the true effect.

Dr Mandrola: This is another randomized controlled trial that shows that LDL-C lowering does not worsen cognition.

Dr Bosch: Absolutely. We have the data. It is mounting. We have the Heart Protection Study[4] and other studies that show that there is no adverse effect of statins. Given the effect on vascular events that we demonstrated, we need to make sure that patients understand that the information being provided by the regulators may not be accurate.

Dr Mandrola: Thank you for watching. This is John Mandrola from theheart.org at the American Heart Association sessions in New Orleans.

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