Dataset Information

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

ABSTRACT: Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ?20/?10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2±8.2 years and mean Mini-Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo ( P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8-1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340.

SUBMITTER: de Heus RAA

PROVIDER: S-EPMC6585342 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

de Heus Rianne A A RAA Donders Rogier R Santoso Angelina M M AMM Olde Rikkert Marcel G M MGM Lawlor Brian A BA Claassen Jurgen A H R JAHR

Journal of the American Heart Association 20190501 10

Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the ...[more]

PMID: 31088188

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Project description:BackgroundThis 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 findingsNILVAD 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.ConclusionsThe results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease.Trial registrationClinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Project description:AimsSystematically reviewing the literature found orthostatic hypotension (OH) to be associated with an increased risk of incident dementia but limited data were available in those at highest risk, the hypertensive oldest-old. Our aim was to analyse the relationship between OH and incident cognitive decline or dementia in this group and to synthesize the evidence base overall.Method and resultsParticipants aged ≥80 years, with hypertension, were from the Hypertension in the Very Elderly Trial (HYVET) cohort. Orthostatic hypotension was defined as a fall of ≥15 mmHg in systolic and or ≥7 mmHg in diastolic pressure after 2 min standing from a sitting position. Subclinical orthostatic hypotension with symptoms (SOH) was defined as a fall <OH but with unsteadiness, light-headedness, or faintness in the week before blood pressure measurement. Proportional hazard regression was used to examine the relationship between baseline OH, SOH, and cognitive outcomes. There were 3121 in the analytical sample, 538 with OH. Orthostatic hypotension was associated with increased risk of cognitive decline (906 events), hazard ratio (HR) 1.36 (95% confidence interval 1.14-1.59). For incident dementia (241 events), HR 1.34 (0.98-1.84). When competing risk of cardiovascular events were taken into account results were HR 1.39 (1.19-1.62) and HR 1.34 (1.05-1.73), respectively. Subclinical orthostatic hypotension was associated with an increased risk of cognitive decline HR 1.56 (1.12-2.17) and dementia HR 1.79 (1.00-3.20). Combining the results from the HYVET cohort in a meta-analysis with the existing published literature in this area found a 21% (9-35%) increased risk of dementia with OH.ConclusionOrthostatic hypotension indicates an increased risk of dementia and cognitive decline. SOH may also be considered a risk factor, at least in older hypertensive adults. Questions remain regarding the mechanisms and whether interventions to reduce impact of OH could protect cognition.

Dataset Information

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

Publications

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

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