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

Rianne A A de Heus, Rogier Donders, Angelina M M Santoso, Marcel G M Olde Rikkert, Brian A Lawlor, Jurgen A H R Claassen, Nilvad Study Group, Rianne A A de Heus, Rogier Donders, Angelina M M Santoso, Marcel G M Olde Rikkert, Brian A Lawlor, Jurgen A H R Claassen, Nilvad Study Group

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.

Keywords: Alzheimer disease; adverse drug event; antihypertensive agent; calcium channel blocker; orthostatic hypotension; randomized controlled trial.

Figures

Figure 1
Figure 1
Flow of participants. *Patients who discontinued the intervention before attending the first follow‐up visit at week 6. †Patients who were not compliant with the study medication (compliance <80%) during any of the 3‐month windows preceding a follow‐up visit. ‡One patient deceased before the first follow‐up visit at week 6 occurred. BP indicates blood pressure; MMSE, Mini‐Mental State Examination score.
Figure 2
Figure 2
Effect of treatment on mean sitting SBP and DBP. Mean sitting SBP (A) and DBP (B) per visit and the number of patients included per visit. After 13 weeks of treatment, sitting SBP and DBP had fallen by −7.8±14.0 and −3.9±8.7 mm Hg for nilvadipine and by −0.4±14.1 and −0.8±9.1 mm Hg for placebo (P<0.001 for SBP and DBP). Error bars indicate SEM. DBP indicates diastolic blood pressure; No., number; SBP, systolic blood pressure.
Figure 3
Figure 3
Effect of treatment on proportion of patients with orthostatic hypotension. Classic orthostatic hypotension (A): drop of ≥20 mm Hg in systolic BP or ≥10 mm Hg in diastolic BP after 1 minute (OR [95% CI] =1.1 [0.8–1.5], P=0.62). Sit‐to‐stand orthostatic hypotension (B): of ≥15 mm Hg in systolic BP or ≥7 mm Hg in diastolic BP after 1 minute (OR [95% CI] =1.2 [0.9–1.5], P=0.15). Symptomatic orthostatic hypotension (C): presence of symptoms upon standing, irrespective of drop in BP (OR [95% CI]=0.8 [0.3–2.3], P=0.67). Delayed orthostatic hypotension (D): presence of classic orthostatic hypotension after 5 minutes of standing (OR [95% CI]=1.2 [0.9–1.6], P=0.15). No. indicates number; OR, odds ratio.
Figure 4
Figure 4
Effect of treatment on standing minus sitting BP. The figure displays ΔSBP (standing‐sitting SBP) and ΔDBP (standing‐sitting DBP) for nilvadipine and placebo at all visits. As can be seen in the figure, the mean ΔSBP is negative, indicating that standing SBP was lower than sitting SBP. The mean ΔDBP is positive, indicating that standing DBP was higher than sitting DBP. BP indicates blood pressure; DBP, diastolic blood pressure; No., number; SBP, systolic blood pressure.
Figure 5
Figure 5
Effect of treatment on proportion of reported clinical outcomes related to orthostatic hypotension. Odds ratio results from logistics regression. No. indicates number; OR, odds ratio.

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