No Effect on Cognition of BP, Lipid Reduction: HOPE-3 Published

February 28, 2019

The cognition results from the HOPE-3 trial, investigating lowering blood pressure and cholesterol in individuals without known cardiovascular disease or need for treatment but at moderate cardiovascular risk, have now been published.

While the overall results, which were first presented at the American Heart Association Scientific Sessions in 2016, showed no effect of either treatment strategy on cognitive decline, results of an exploratory analysis suggest some slowing of cognitive decline in the highest risk group.

The cognition results were published online yesterday in Neurology.

"On first look, our results do not suggest a benefit of lowering blood pressure on cognitive function. However, when we dig deeper in post hoc analysis, there does appear to be some benefit of treatment in those at higher risk," lead author Jackie Bosch, PhD, McMaster University, Hamilton, Canada, commented to Medscape Medical News.  

She points out that this fits in with the SPRINT MIND study that showed there was a slowing of cognitive decline in the more aggressive blood-pressure lowering group.

"The SPRINT trial involved a much higher risk population, with all patients having hypertension, and the trial investigated different treatment targets," Bosch noted. "HOPE-3 involved a population at moderate cardiovascular risk, but most participants did not actually have raised blood pressure."

Their aim was to see if an across-the-board strategy of lowering blood pressure at a certain cardiovascular risk level would have a benefit on cognition — even if the participants were not hypertensive at baseline, she said.

"The theory behind this is that, as we know raised blood pressure is very closely tied to stroke and TIA, we thought that in patients with vascular dysfunction the reduced stress on the vessel wall could improve perfusion in the brain and reduce subclinical strokes, and therefore cognitive decline. But we didn’t find that to be the case, which was disappointing," Bosch said.

They did however, see something in the highest risk group of patients who did have raised blood pressure at baseline. "This suggests the negative effects of blood pressure in individuals at moderate cardiovascular risk are only evident in those with pressures over the hypertension threshold."

Noting that the cognition study only included individuals aged 70 or over, Bosch said: "Our results could suggest that if you have got to 70 [years old] with a normal blood pressure, you probably won't get major vascular issues such as stroke and cognitive decline secondary to increased blood pressure in [the] future."

Neutral Lipid Results – Good News?

On the null results with lipid lowering overall, Bosch said: "Cholesterol does not have such a strong relationship with stroke as blood pressure has, so perhaps it was a long shot hoping for a reduction in cognitive decline by lowering cholesterol. But while we would have liked to see a benefit on cognitive decline with the statin, the fact that we saw no difference is still a positive result."

"There have been concerns about possible detrimental effects on memory with statins from observational studies and anecdotal reports, leading to the FDA issuing a warning about this on the prescribing information," Bosch continued. "However, our results do not show any additional cognitive decline in individuals taking a statin over those on placebo, so they really help to allay those fears."

Bosch stressed that the current results should not detract in any way from previous observations that a healthy a diet and regular exercise can help to stave off cognitive decline. "These benefits could be mediated through many different mechanisms — not just via lipid or blood pressure reduction. The whole package of living well in midlife for benefits in later life is definitely a sound approach," she said.  

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

They were randomly assigned in a 2 × 2 factorial design to blood pressure lowering with candesartan plus hydrochlorothiazide (HCTZ), cholesterol lowering with rosuvastatin, the combination of both, or to placebo.

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

The current publication focuses on the cognition sub-study conducted in those participants age 70 years or older at baseline (mean 74 years), with 1626 individuals completing cognitive tests at the start and end of the study (median follow up 5.7 years).

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

Results showed no difference in the primary outcome — change in Digit Symbol Substitution Test (DSST) score. Overall, there was a mean decline in DSST scores of 5.4 from baseline. The mean difference in change in DSST scores was −0.91 (95% confidence interval [CI], −2.25 to 0.42) for candesartan/HCTZ compared with placebo, −0.54 (−1.88 to 0.80) for rosuvastatin compared with placebo, and −1.43 (−3.37 to 0.50) for combination therapy vs double placebo.

No significant differences were found for two other measures of cognition — the modified 12-item Montreal Cognitive Assessment (mMoCA), and the Trail Making Test Part B (TMT-B).

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

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

Bosch said she would expect blood pressure lowering to be the driving force behind this benefit, "but the numbers are very small, so it is almost impossible to draw definite conclusions."

In terms of study limitations, the researchers note that 6 years of taking these medications may not be long enough to prevent cognitive decline, so longer studies are needed. They also point out that participants chose to enroll in the trial, meaning they may have been healthier and at 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, The George Institute for Global Health, Sydney, Australia, suggest that preventive treatment may need to be started earlier in life to have any effect on cognitive decline.

They note that at the age of 70 and above, "it can be argued that it is by then too late to reverse pathophysiologic process arising from a long exposure to cardiovascular risk factors such as hypertension and hyperlipidemia."

They also raise the possibility that a treatment effect may have been more likely to be detected by the use of more sensitive cognitive tests, or if neuroimaging had been used to identify those with substantial cerebral small vessel disease and prior silent stroke, who are at high risk of cognitive decline.

The editorialists call for further research into the mechanisms, novel treatment targets, and biomarkers to identify individuals at high-risk of cognitive decline. "Big data analytics of diverse populations, differing treatment approaches, longer duration of follow-up, and statistical approaches to adjust for confounding might overcome the inherent limitations of randomized controlled trials," the authors suggest.

"Even delaying the onset of dementia by a year could accomplish immense public health improvement," they conclude.

The study was funded by the Canadian Institutes of Health Research and AstraZeneca. Bosch has disclosed no relevant financial relationships. Chen has served on the scienti fi c advisory boards and has been a consultant for Lundbeck and Accera; has received travel funding from Moleac, Eisai, and Lundbeck; and has received research support from TauRx, Eisai, Nutricia, and Lundbeck. Anderson has served on the scienti fi c advisory board of Amgen, and has received gifts, honoraria, and travel funding from Takeda.

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

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