Nilvadipine – hypertension drug – may hold promise for Alzheimer’s disease

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Seeking new treatments to slow the progression of Alzheimer’s disease, researchers found the blood pressure drug nilvadipine increased blood flow to the brain’s memory and learning center among people with Alzheimer’s disease without affecting other parts of the brain, according to new research in the American Heart Association’s journal Hypertension.

These findings indicate that the known decrease in cerebral blood flow in patients with Alzheimer’s can be reversed in some regions.

However, an important question is whether this observed increase in cerebral blood flow translates to clinical benefits, the authors note.

Alzheimer’s disease is the most common form of dementia.

The risk for the disease increases with age and the causes are largely unknown. Previous research has shown that blood flow to the brain declines in early Alzheimer’s disease.

Nilvadipine is a calcium channel blocker used to treat high blood pressure.

Researchers sought to discover whether nilvadipine could help treat Alzheimer’s disease by comparing the use of nilvadipine and a placebo among people with mild to moderate Alzheimer’s disease.

Researchers randomly assigned 44 participants to receive either nilvadipine or a placebo for six months. Neither researchers nor the participants knew who received the drug or the placebo that was evenly divided among the two groups.

At the study’s start and after six months, researchers measured blood flow to specific regions of the brain using a unique magnetic resonance imaging (MRI) technique.

Results showed that blood flow to the hippocampus – the brain’s memory and learning center – increased by 20% among the nilvadipine group compared to the placebo group. Blood flow to other regions of the brain was unchanged in both groups.

“This high blood pressure treatment holds promise as it doesn’t appear to decrease blood flow to the brain, which could cause more harm than benefit,” said study lead author Jurgen Claassen, M.D., Ph.D., associate professor at Radboud University Medical Center in Nijmegen, the Netherlands.

“Even though no medical treatment is without risk, getting treatment for high blood pressure could be important to maintain brain health in patients with Alzheimer’s disease.”

Researchers note that sample sizes were too small and follow-up time too short to reliably study the effects of this cerebral blood flow increase on structural brain measures and cognitive measures.

Study participants were screened between 2013 and 2015 as part of a larger research project comparing nilvadipine to placebo among more than 500 people with mild to moderate Alzheimer’s disease (average age 73, more than half female and most were Caucasian).

In that larger project, effects on cerebral blood flow were not measured. Overall, no clinical benefit was noted with use of nilvadipine.

However, a subgroup of patients with only mild symptoms of disease did show benefit, in the sense of a slower decline in memory.

Previous studies have hinted that high blood pressure treatment could reduce the risk of developing dementia.

The authors think that beneficial effects on brain blood flow could explain part of this effect.

The study is one of a few to use this MRI technique to probe the effects of treatment on cerebral blood flow, making additional research critical. In addition, the small number of participants of similar race and ethnicity mean that the results may not apply to other populations.

“In the future, we need to find out whether the improvement in blood flow, especially in the hippocampus, can be used as a supportive treatment to slow down progression of Alzheimer’s disease, especially in earlier stages of disease,” Claassen said.


Other point of view……

This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine.

Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease.

We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease.

Methods and findings

NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015.

The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine).

Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27.

Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo.

The a priori defined primary outcome was progression on the Alzheimer’s Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12.

The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease–specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4.

The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, −0.07–1.64) at 13 weeks, 6.41 (5.33–7.49) at 52 weeks, and 9.63 (8.33–10.93) at 78 weeks and on nilvadipine was 0.88 (0.02–1.74) at 13 weeks, 5.75 (4.66–6.85) at 52 weeks, and 9.41 (8.09–10.73) at 78 weeks.

Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated.

Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed.

There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid.

Conclusions

The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.

Trial registration

Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.


More information: Hypertension (2019). DOI: 10.1161/HYPERTENSIONAHA.119.12892

Journal information: Hypertension
Provided by American Heart Association

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