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

Q: What are the key findings of this study?

Nilvadipine 8 mg/day did not increase the prevalence of classic orthostatic hypotension compared to placebo (OR 1.1, 95% CI 0.8-1.5, P=0.62) in patients with mild-to-moderate Alzheimer disease.

Q: What is the clinical evidence from this study?

Study design: RCT. Population: Mild-to-moderate probable Alzheimer disease (n=477). Intervention: Nilvadipine vs. Placebo. Primary outcome: Prevalence of classic orthostatic hypotension (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) at a study visit across 78 weeks (OR 1.1, 95% CI 0.8-1.5, p=0.62).

Q: What does this research mean for the field?

Blood pressure lowering with nilvadipine does not increase the prevalence of orthostatic hypotension or related adverse events in patients with mild-to-moderate Alzheimer disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Rianne A.A. de Heus; Rogier Donders; Angelina M.M. Santoso; Marcel G. M. Olde Rikkert; Brian Lawlor; Jurgen A.H.R. Claassen; Ricardo Segurado; Robert Howard; Florence Pasquier; Anne Börjesson‐Hanson; Magda Tsolaki; Ugo Lucca; D. William Molloy; Robert F. Coen; Matthias W. Riepe; János Kálmán; Rose Anne Kenny; Fiona Cregg; Sarah O’Dwyer; Cathal Walsh; Jessica Adams; Rita Banzi; Laëtitia Breuilh; Leslie Daly; Suzanne Hendrix; Paul Aisen; Siobhán Gaynor; Ali Sheikhi; Diana G. Taekema; Frans R.J. Verhey; Raffaello Nemni; Flavio Nobili; M. Franceschi; Giovanni B. Frisoni; Orazio Zanetti; Anastasia Konsta; Anastasios Orologas; Styliani Nenopoulou; Fani Tsolaki-Tagaraki; Magdolna Pákáski; Olivier Dereeper; Vincent de La Sayette; Isabelle Lavenu; Agnès Devendeville; Gauthier Calais; Fiona Crawford; Michael Mullan; Pauline Aalten; Maria A. Berglund; Daan L. K. de Jong; Olivier Godefroy; Siobhán Hutchinson; Aikaterini Ioannou; Michael Jonsson; Annette Kent; Jürgen Kern; Petros Nemtsas; Minoa‐Kalliopi Panidou; Laila Abdullah; Daniel Paris; Gerrita J. van Spijker; Martha Spiliotou; Georgia Thomoglou; Anders Wallin; Oliver Gupta

doi:10.1161/jaha.119.011938

May 15, 2019Journal of the American Heart AssociationOpen Access

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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Key result

Nilvadipine does not increase orthostatic hypotension risk compared to placebo in Alzheimer disease.

OR 1.1
95% CI 0.8-1.5
P=0.62
n=477

Figures

Why the study?

Patients with Alzheimer disease have been excluded from hypertension trials, leaving a lack of evidence regarding the safety of antihypertensive treatment and its effect on orthostatic hypotension in this population.

Does blood pressure lowering with nilvadipine 8 mg/day increase the prevalence of orthostatic hypotension and related adverse events compared with placebo in patients with mild-to-moderate Alzheimer disease?

Key Points

To determine whether blood pressure lowering with nilvadipine increases the prevalence of orthostatic hypotension or related clinical adverse events in patients with mild-to-moderate Alzheimer disease.
Secondary analysis of a randomized, double-blind, placebo-controlled trial (NCT02017340) including 477 patients with mild-to-moderate Alzheimer disease assigned to nilvadipine 8 mg/day (n=240) or placebo (n=237) for 78 weeks.
Orthostatic hypotension (systolic drop ≥20 mm Hg or diastolic drop ≥10 mm Hg after 1 minute of standing) and related adverse events were assessed across 7 follow-up visits.
At 13 weeks, blood pressure decreased by -7.8±14.0 / -3.9±8.7 mm Hg in the nilvadipine group versus -0.4±14.1 / -0.8±9.1 mm Hg in the placebo group (P<0.001 for both systolic and diastolic blood pressure).
Across 78 weeks, the odds of orthostatic hypotension at a visit did not differ between nilvadipine and placebo (odds ratio [95% CI] = 1.1 [0.8–1.5], P=0.62), nor did the proportion of visits meeting orthostatic hypotension criteria (7.7±13.8% versus 7.3±11.6%).
Prevalence of related clinical adverse events, including falls, syncope, dizziness, and fractures, showed no significant differences between the intervention and placebo groups.

Study Design

Type

RCT (n=477)

Blinding

Double-blind

Randomization

1:1 allocation ratio, stratified by study site

Multicenter

Yes

Structured PICO

Does blood pressure lowering with nilvadipine 8 mg/day increase the prevalence of orthostatic hypotension and related adverse events compared with placebo in patients with mild-to-moderate Alzheimer disease?

P

Population

477 older adults (mean age 72.2 years, 61.6% female) with mild-to-moderate probable Alzheimer disease (53.4% with Grade I hypertension) and baseline blood pressure 100-159/65-99 mm Hg, followed over 78 weeks.

I

Intervention

Nilvadipine 8 mg oral capsule once daily for 78 weeks (with allowed concomitant non-excluded antihypertensive and Alzheimer medications)

C

Comparator

Matching placebo capsule once daily for 78 weeks (with allowed concomitant non-excluded antihypertensive and Alzheimer medications)

O

Outcome

Presence of classic orthostatic hypotension (defined as a drop of ≥20 mm Hg in systolic BP or ≥10 mm Hg in diastolic BP after 1 minute of standing compared with sitting BP) and proportion of visits meeting criteria for OH across 7 follow-up visits over 78 weekssafety

Main Result

Odds Ratio: 1.1 (95% CI 0.8–1.5)

Absolute Event Rate: 32.9% vs 34.6%

p-value: p=0.62

Initiating low-dose antihypertensive therapy with nilvadipine in patients with mild-to-moderate Alzheimer disease safely lowers blood pressure without increasing the risk of orthostatic hypotension, falls, syncope, or fractures, regardless of baseline blood pressure or frailty.

Limitations

Secondary post hoc analysis not prespecified as the primary trial outcome
Exclusion of patients with severe hypertension (≥160/99 mm Hg) and younger sample compared to general AD population
Blood pressure was measured from sitting to 1 minute of standing rather than supine to 3 minutes of standing
Potential underreporting of adverse events and symptoms upon standing due to cognitive impairment
Secondary post hoc analysis not prespecified in the trial protocol
Relatively younger sample of AD patients compared with the general AD population and exclusion of severe hypertension (≥160/99 mm Hg)
BP measured from sitting rather than supine position and after 1 minute rather than 3 minutes of standing
Potential underreporting of symptoms and adverse events due to cognitive impairment

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Implication

Supports safe nilvadipine initiation for blood pressure lowering in mild-to-moderate Alzheimer disease; extends randomized safety data on 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.

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Cite This Study

Heus et al. (2019) conducted an RCT in Mild-to-moderate probable Alzheimer disease (n=477). Nilvadipine vs. Placebo was evaluated on Prevalence of classic orthostatic hypotension (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) at a study visit across 78 weeks (OR 1.1, 95% CI 0.8-1.5, p=0.62). Nilvadipine 8 mg/day did not increase the prevalence of classic orthostatic hypotension compared to placebo (OR 1.1, 95% CI 0.8-1.5, P=0.62) in patients with mild-to-moderate Alzheimer disease.

synapsesocial.com/papers/6a7f199351ccd13efb9c4897 https://doi.org/10.1161/jaha.119.011938

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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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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