08 Mar 2019

For people over 70 who are at intermediate risk of cardiovascular disease, taking blood-pressure- and/or cholesterol-lowering drugs does not slow cognitive decline over six years. That is the bottom line from the Heart Outcomes Prevention Evaluation-3 trial, published February 27 in Neurology. Led by Jackie Bosch of McMaster University in Ontario, Canada, HOPE-3 sought to determine whether the drugs might stave off both cardiovascular disease and cognitive decline in older people who did not yet have high enough blood pressure or cholesterol to warrant taking the medications.

HOPE-3 found no cognitive benefits of blood pressure and/or cholesterol-lowering drugs in people over 70.

Treatment did slow decline among participants with the highest cholesterol and blood pressure.

Counters claims that statins cause cognitive decline.

“The headline result—that these interventions did not significantly alter cognitive decline—may reflect that cardiovascular risk modification needs to start in midlife to confer maximum benefits on late-life cognition,” commented Jonathan Schott of University College London.

The findings come on the heels of positive results from the SPRINT-MIND study, which posted a 19 percent drop in mild cognitive impairment in people on an intensive regimen of antihypertensive meds (Jan 2019 news; Aug 2018 conference news).

What gives? Bosch said the results do not conflict, given that participants in SPRINT-MIND were younger, had higher baseline blood pressure, and underwent more aggressive treatment than participants in the HOPE-3 study. In SPRINT-MIND, blood pressure fell by almost 20 mm Hg, whereas in HOPE-3, participants saw an average drop of just under 6 mm Hg. Whether the more aggressive lowering can be achieved in a community setting remains to be seen. A follow-up to SPRINT is underway.

HOPE-3. Researchers tested whether blood pressure and/or cholesterol lowering would head off cognitive decline in people over 70 at intermediate cardiovascular risk. [Courtesy of Bosch et al., Neurology, 2019.]

HOPE-3 enrolled more than 12,000 volunteers, including men 55 and older, and women 65 and older, whose marginally high blood pressure and cholesterol did not warrant treatment. The participants also had at least one additional vascular risk factor, besides age, meaning they were at intermediate risk for cardiovascular disease. They were randomized to daily placebo or 16 mg candesartan with 12.5 mg hydrochlorothiazide to lower blood pressure, and/or 10mg of rosuvastatin to lower cholesterol, for 5.7 years. The researchers had previously reported that the blood pressure lowering had no effect on vascular events such as heart attack and stroke overall, but among people with baseline blood pressure in the top tertile, the treatment reduced such events by 24 percent (Lonn et al., 2016). Cholesterol-lowering treatment dropped vascular events by 25 percent across all participants (Yusuf et al., 2016).

Midlife vascular risk factors correlate with cognitive slippage late in life, but whether lowering blood pressure or cholesterol in late life has benefit is unclear (Aug 2014 news; Aug 2017 news; Aug 2018 conference news). Some studies indicate stiffer vessels may require more force to feed the brain in late life (AlzRisk; Jun 2018 news).

At baseline, 2,361 HOPE-3 participants had an average blood pressures of 140/79 mm Hg, and 45 percent had hypertension, defined as a systolic blood pressure above 140 mm Hg. Their mean low density lipoprotein (LDL) was 126.8 mg/dL. Nearly a quarter of participants dropped out of the trial, and 219 died, leaving 1,626 people who completed the study. Completers were more educated. Fewer were Latin American. Candesartan/hydrochlorothiazide lowered blood pressure by an average of 6 mm Hg, while rosuvastatin docked LDL by an average of 24.8 mg/dL.

Neither treatment budged the primary outcome measure of cognitive decline, as judged by the change in Digital Symbol Substitution Test (DSST) scores from baseline to the final visit 5.7 years later. Participants slipped by an average of 5.4 points, and differences were not significant between treatment groups. Secondary measures, including other cognitive tests, activities of daily living, and dementia diagnosis, also turned up no benefit. Bosch said the results do dispel findings from observational studies that linked statin use to cognitive decline, she said (Macedo et al., 2014).

The only positive cognitive signal came from a post-hoc subgroup analysis, which included 181 participants whose baseline systolic blood pressure and cholesterol were in the top third of the cohort. In the placebo group, these higher-risk participants declined by 10.3 points on the DSST, while those in the double treatment group declined by 5.84 points.

Why did neither treatment slow cognitive decline across the cohort? For one, Bosch said, participants averaged 74 years of age. Perhaps starting treatment that late cannot undo years of cumulative damage done to the brain by slightly elevated blood pressure or cholesterol, she said. For another, the study was underpowered to detect subtle cognitive benefits. Furthermore, the antihypertensive treatment may have been insufficient.

In an accompanying editorial, Chris Chen from the National University Health System in Singapore and Craig Anderson of the University of New South Wales in Sydney also raised age as an issue. “Because the mean age of HOPE-3 participants was >70 years, when rates of dementia are exponentially increasing, 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 wrote.

They agreed with the possibility that the interventions may have worked in people with higher cardiovascular risk, as suggested by the post-hoc analysis. The cognitive tests may have been too blunt an instrument to detect cognitive changes across a broad range of people with diverse ethnicities and levels of education, they noted.—Jessica Shugart