No Cognitive Benefit From Heart Meds, HOPE-3 Shows

Long-term cholesterol- or blood pressure-lowering drugs produced no cognitive benefit for older adults in a large substudy of the HOPE-3 trial.

Treatment with candesartan (Atacand) plus hydrochlorothiazide to lower blood pressure, or rosuvastatin (Crestor) to lower cholesterol, or a combination of the two, did not slow cognitive decline over a median of 5.7 years, reported Jackie Bosch, PhD, of McMaster University in Hamilton, Ontario, and colleagues in Neurology.

But participants who had highest baseline systolic blood pressure and low-density lipoprotein cholesterol (LDL-C) — about 10% of those included in the substudy — showed slower cognitive decline in a post hoc analysis.

Moreover, rosuvastatin did not worsen cognitive decline: “Statin use has previously been associated with cognitive impairment, but this study demonstrated that there was none, which is an important finding for those taking statins,” Bosch said in a statement.

The main HOPE-3 study of primary prevention randomized participants in 21 countries without known cardiovascular disease or need for treatment to candesartan (16 mg) plus hydrochlorothiazide (12.5 mg) or placebo, and to rosuvastatin (10 mg) or placebo. In 2016, HOPE-3 investigators reported that statin therapy with rosuvastatin lowered cardiovascular events by 25%, but antihypertensive therapy did not have a significant effect.

The cognitive substudy restricted eligibility to participants over age 70 and looked at 1,626 people from the main HOPE-3 cohort. This group had a mean age of 74; 59% were female and 45% had a history of hypertension.

These participants had cognitive testing at baseline and study end with Digit Symbol Substitution Test (DSST) scores as the primary outcome measure. They also completed modified Montreal Cognitive Assessment (mMoCA), the Trail Making Test Part B (TMT-B), and functional status tests.

In this group, candesartan/hydrochlorothiazide reduced systolic blood pressure by 6.0 mm Hg, and rosuvastatin reduced LDL-C by 24.8 mg/dL, compared with placebo.

Over a median follow-up of 5.7 years, the mean difference in change in DSST scores was −0.91 (95% CI −2.25 to 0.42) for candesartan/hydrochlorothiazide compared with placebo, and −0.54 (95% CI −1.88 to 0.80) for rosuvastatin compared with placebo. It was −1.43 (95% CI −3.37 to 0.50) for combination therapy vs double placebo. No significant differences were seen in other measures of cognition or function.

In an exploratory subgroup analysis of 181 participants who had the highest tertile of baseline systolic blood pressure (cutoff point of >145.0 mm Hg; mean of 156 mm Hg) and the highest tertile of baseline LDL-C (cutoff >140.0 mg/dL; mean 164.7 mg/dL), the group treated with the combination of blood-pressure lowering drugs and rosuvastatin showed a significant reduction in the DSST compared with double placebo (reduction in score 5.84 vs 10.30 points, P for interaction 0.04).

“Does treatment need to be targeted toward those at highest risk?” asked Christopher Chen, MD, PhD, of the National University Health System in Singapore and Craig Anderson, MD, PhD, of the University of New South Wales in Sydney, Australia, in an accompanying editorial.

Other large-scale studies of dementia prevention, like the FINGER trial, have used risk scores to select people with a greater likelihood of cognitive decline, Chen and Anderson noted. By comparison, the HOPE-3 participants were at intermediate cardiovascular risk (with an annual risk of cardiovascular events estimated to be 1%), with good control of cardiovascular risk factors and no cognitive dysfunction. “Although the high cardiovascular risk subgroup suggests a benefit, the small sample raises the likelihood of a random effect,” they observed.

It’s also possible that preventive treatment needs to start much earlier in life, Chen and Anderson added: “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.”

In addition, the follow-up period in HOPE-3 may not have been long enough, Bosch and colleagues suggested, noting that the SPRINT MIND trial, recently extended for 2 more years, may provide further insights about the effect of intensive blood pressure lowering on cognition.

The HOPE-3 substudy analysis had several limitations, the researchers said, including loss of participants to death over the course of the study. People who agreed to participate in HOPE-3 also may have been healthier than others, with lower risks of cognitive decline, they added.