No effect on PA cognition, lipid reduction: publication of HOPE-3



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The cognitive results of the HOPE-3 trial, which studies the reduction of blood pressure and cholesterol in people without known or requiring cardiovascular disease, but with moderate cardiovascular risk, have now been published.

While the overall results, which had been presented for the first time at the American Heart Association's scientific sessions in 2016, showed no effect of the treatment strategy on cognitive decline, the results of a Exploratory analysis suggests a slowing down of cognitive decline in the most at-risk group.

The results of cognition were published online yesterday in Neurology.

"At first glance, our results do not suggest any benefit from lowering blood pressure on cognitive function, but when we go into a post-hoc analysis, it seems that treatment has an advantage for people at higher risk," he said. Principal Writer Jackie Bosch, Ph.D., McMaster University, Hamilton, Canada, commented Medscape Medical News.

She points out that this is part of the SPRINT MIND study which showed a slowing of cognitive decline in the most aggressive group of lowering blood pressure.

"The SPRINT trial involved a much higher risk population, all patients being hypertensive, and the study looked at different therapeutic targets," Bosch said. "HOPE-3 involved a moderate cardiovascular risk population, but most participants had not actually increased blood pressure."

Their goal was to see if a global strategy of lowering blood pressure to a certain level of cardiovascular risk would have a beneficial effect on cognition, even if the participants were not hypertensive at first, did she said.

"The underlying theory is that, as we know that the increase in blood pressure is very closely related to stroke and AIT, we thought that in patients with vascular dysfunction, reducing stress on the vascular wall could improve brain perfusion and reduce subclinical stroke, and thus cognitive decline, but this was not the case, which was disappointing, "Bosch said.

However, they saw something in the most at-risk group of patients who had high blood pressure initially. "This suggests that the negative effects of high blood pressure in people with moderate cardiovascular risk are only apparent in people whose pressure is above the threshold of hypertension."

Noting that the cognitive study only included individuals aged 70 or older, Bosch said: "Our findings could suggest that if you were 70 years old [years old] with normal blood pressure, you probably will not experience major vascular problems such as stroke and cognitive decline due to increased blood pressure. [the] future."

Neutral lipid results: good news?

Speaking of nonsense results with global hypolipidemia, Bosch said: "Cholesterol does not have as strong a relationship with stroke as high blood pressure, so it may have been a long wait in the hope of a reduction in cognitive decline by a decrease in cholesterol have enjoyed a benefit on cognitive decline with the statin, the fact of not seeing any difference is always a positive result. "

"Observational studies and anecdotal reports have possibly had adverse effects on the memory of statins, which has led the FDA to warn about the prescription information situation," Bosch continued. "However, our results do not show any additional cognitive decline in individuals taking a statin compared to those taking placebo, so they really help to allay these fears."

Bosch pointed out that current results should in no way detract from previous observations that healthy eating and regular exercise can help prevent cognitive decline. "These benefits could result from many different mechanisms – not just through lipid reduction or blood pressure reduction – the entire life-cycle well into quarantine for later benefits is definitely a good approach," he said. she declared.

The main trial HOPE-3 was conducted in 12,105 participants (men aged 55 years and older and women aged 65 or older with at least one additional clinical cardiovascular risk factor or women aged 60 or two additional risk factors).

In a 2 × 2 factorial design, they were randomly allocated between lowering blood pressure with candesartan and hydrochlorothiazide (HCTZ), lowering cholesterol with rosuvastatin, the combination of both, or with a placebo.

The main results showed after a mean follow-up of 5.6 years: no effect of antihypertensive treatment on vascular events in general, but a 24% reduction in the number of events in those with the highest baseline blood pressure levels. high; Rosuvastatin reduced vascular events by 25% in all participants.

This publication focuses on the cognitive substudy of participants aged 70 or older at baseline (mean 74 years), 1626 people who had cognitive tests at the beginning and end of the study (median follow-up). 5.7 years).

In this population, candesartan / HCTZ reduced systolic blood pressure by 6.0 mmHg and rosuvastatin by LDL cholesterol by 24.8 mg / dL.

The results showed no difference in the main result – change of score to digital symbol substitution test (DSST). Overall, there was an average decrease of 5.4 from the DSST scores compared to departure. The mean difference in DSST scores was -0.91 (95% confidence interval) [CI], -2.25 to 0.42) for candesartan / HCTZ compared to placebo, -0.54 (-1.88 to 0.80) for rosuvastatin compared to placebo, and -1.43 (-3 , 37 to 0.50) for combination therapy versus double placebo.

No significant difference was found for two other measures of cognition – the modified 12-element Montreal cognitive assessment (mMoCA) and the trajectory test, part B (TMT-B).

In an exploratory subgroup analysis of 181 participants of the highest tertile of initial systolic blood pressure (mean of 156 mm Hg) and baseline higher LDL-C titer (mean of 164 mg / dL) treated with combination of the lipid-lowering drug compared to the double placebo, there was a significant reduction in cognitive decline as measured by the DSST (reduction of the score of 5.84 compared to 10.30 points, P for interaction = .04).

"Our results indicating an effect of combined blood pressure and lipid reduction in preventing cognitive decline in people with the highest initial blood pressure levels suggest that people with the highest cardiovascular risk could benefit." ", conclude the authors. "This is consistent with the main findings of the study, demonstrating an effect in those with the highest systolic blood pressure at baseline."

Bosch said it would expect blood pressure reduction to drive this benefit, "but the numbers are very low, so it's almost impossible to draw definitive conclusions."

In terms of study limitations, the researchers noted that taking these drugs for six years may not have been long enough to prevent cognitive decline. Longer studies are therefore needed. They also point out that participants chose to participate in the trial, which means that they may be in better health and have a lower risk of cognitive impairment than the average population.

In an accompanying editorial, Christopher Chen, MD, National University Health System, Singapore, and Craig Anderson, MD, George Institute for Global Health, Sydney, Australia, suggest that a preventative treatment may need to be triggered earlier in life to have any effect. on cognitive decline.

They note that at the age of 70 and over ", it can be argued that it is too late to reverse the pathophysiological process resulting from long exposure to cardiovascular risk factors such as as hypertension and hyperlipidemia ".

They also point to the possibility of detecting a treatment effect by using more sensitive cognitive tests or by using neuroimaging to identify patients with severe small vessel brain disease who have had a silent stroke, a risk of cognitive decline.

Editorialists call for further research into mechanisms, new therapeutic targets and biomarkers to identify individuals at high risk of cognitive decline. "Analyzing large data from different populations, different treatment approaches, longer follow-up time, and statistical adjustment approaches to account for confusion could overcome the limitations of controlled trials." randomized ", suggest the authors.

"Even delaying the onset of dementia by one year could dramatically improve public health," they conclude.

The study was funded by the Canadian Institutes of Health Research and AstraZeneca. Bosch has not disclosed any relevant financial relationship. Chen served on the scienti Fi c advisory boards and consultant for Lundbeck and Accera; received travel funds from Moleac, Eisai and Lundbeck; and has received research support from TauRx, Eisai, Nutricia and Lundbeck. Anderson served on the scienti Fi c Amgen Advisory Committee and received donations, fees and travel expenses from Takeda.

Neurology. Posted online February 27, 2019. Abstract, Editorial

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