Figure 3 - available via license: Creative Commons Attribution-NonCommercial 4.0 International
Content may be subject to copyright.
![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.](publication/333246678/figure/fig3/AS:761042728665090@1558458134879/Effect-of-treatment-on-proportion-of-patients-with-orthostatic-hypotension-Classic.png)
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.
Source publication
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 pa...
Contexts in source publication
Context 1
... the 78-week follow-up, there was no statistically significant difference between nilvadipine and placebo in the proportion of patients at a study visit meeting the criteria for classic OH (odds ratio [OR] Figure 3). In addition, there was no clinically relevant effect of nilvadipine on DSBP upon standing (in mm Hg: b=À0.8 [À1.7 to 0.2], P=0.13, in %: b=À0.6 [À1.3 to 0.2], P=0.12, see Figure 4). ...
Context 2
... the number of reported events of fractures, falls, syncope, and dizziness were similar between the groups. None of the 35 We did not see any short-term effects of our intervention after 6 weeks of treatment ( Figure 3). Although not statistically significant, the upper limits of the CIs of our findings do not completely rule out a small effect of nilvadipine. ...
Context 3
... not statistically significant, the upper limits of the CIs of our findings do not completely rule out a small effect of nilvadipine. However, as can be seen in Figures 3 and 4, the magnitude of such an effect would still not lie within clinically relevant margins. The antihypertensive properties of nilvadipine are comparable to other, more common dihydropyridine calcium-channel blockers, such as nifedipine and amlopdipine. ...
Similar publications
Background and purpose:
Management of antihypertensive therapy is challenging in patients with symptomatic orthostatic hypotension, a population often excluded from randomised controlled trials of antihypertensive therapy. In this systematic review and meta-analysis, we sought to determine whether the association of antihypertensive therapy and ad...
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 p...
Background
Drug-induced orthostatic hypotension (OH) is common, and its resulting cerebral hypoperfusion is linked to adverse outcomes including falls, strokes, cognitive impairment, and increased mortality. The extent to which specific medications are associated with OH remains unclear.
Methods and findings
We conducted a systematic review and me...
Background and Aims: Low systolic blood pressure (SBP) levels while being treated with antihypertensives may cause hypotension-related adverse events (hrAEs), especially in the elderly, women, and frail patients. We aimed to assess the association between the occurrence of hrAEs and low SBP levels, age, sex, and polypharmacy among patients with typ...
Background: Gender wise differences exist in anti-hypertensive treatment outcomes, yet still un-explored in
Pakistan. Thus, we aimed to estimate the clinical efficacy of four different anti-hypertensive regimens in
hypertensive women of Punjab, Pakistan.
Methods: A longitudinal cohort study of 12 months duration was conducted by enrolling 300 hyper...
Citations
... While SPRINT did not include persons with prevalent dementia, it is important to recall that concerns of autonomic dysfunction in dementia are mainly based on Lewy body dementia and Parkinson's disease dementia, with limited evidence of autonomic dysfunction in AD and vascular dementia. In the NILVAD trial testing the CCB nilvadipine in AD patients, 47 and in several smaller studies, there was also no evidence of increased risk of OH in patients with dementia, also with prolonged standing (up to 5 min). 42 Orthostatic hypotension: Summary For older people without dementia, OH appears not to be a major concern in BP lowering, and the prevalence of autonomic dysfunction is low (in view of physiological data from patients with AD, as well as SPRINT-MIND). ...
A large interventional trial, the Systolic Blood Pressure Intervention Trial sub-study termed Memory and Cognition in Decreased Hypertension (SPRINT-MIND), found reduced risk of cognitive impairment in older adults with intensive, relative to standard, blood-pressure-lowering targets (systolic BP < 120 vs. <140 mm Hg). In this perspective, we discuss key questions and make recommendations for clinical practice and for clinical trials, following SPRINT-MIND. Future trials should embody cognitive endpoints appropriate to the participant group, ideally with adaptive designs that ensure robust answers for cognitive and cardiovascular endpoints. Reliable data from diverse populations, including the oldest-old (age > 80 years), will maximize external validity and global implementation of trial findings. New biomarkers will improve phenotyping to stratify patients to optimal treatments. Currently no antihypertensive drug class stands out for dementia risk reduction. Multi-domain interventions, incorporating lifestyle change (exercise, diet) alongside medications, may maximize global impact. Given the low cost and wide availability of antihypertensive drugs, intensive BP reduction may be a cost-effective means to reduce dementia risk in diverse, aging populations worldwide.
... In the Nilvad trial, the intervention resulted in a reduction of BP of 7.5/3.0 mmHg compared to placebo [25]. Blinding and randomization steps are described in detail in the trial protocol [18]. ...
... While we did see effects on heart rate (i.e. a reduction in the initial heart rate response following standing), and on vascular tone (i.e. a larger reduction in BP immediately after standing), BRS was not reduced, but rather increased, and there was no increase in orthostatic hypotension. This observation is confirmed by the larger Nilvad trial, wherein we showed that there was no increased prevalence of OH in patients with AD, and no increase in OH following nilvadipine [25]. ...
Objective
Dynamic cerebral autoregulation (dCA) and baroreflex sensitivity (BRS) are key mechanisms involved in the homeostasis of blood pressure (BP) and cerebral blood flow. We assessed changes in these mechanisms in Alzheimer's disease (AD) during a 1.5 year follow-up.
Methods
In this secondary analysis of a randomized controlled trial we measured beat-to-beat BP, heart rate, and cerebral blood flow velocity at baseline, 0.5 and 1.5 years, during: rest (spontaneous oscillations), repeated sit-stand maneuvers (induced oscillations), an orthostatic challenge, and hypo- and hypercapnia. dCA was estimated using transfer function analysis and the autoregulatory index on spontaneous and induced oscillations. BRS was estimated by calculating the heart rate response to BP changes during induced oscillations. Linear mixed models were used to assess changes over time.
Results
56 patients were included (mean age:73±6 years, 57% female). BRS did not change over time. dCA parameters showed small changes after 0.5 years, suggestive of a reduction in efficiency (e.g. higher gain [linear mixed effect model: B= 0.09, SE= 0.03, P= 0.008] and lower phase [B= -9.7, SE= 3.2, P= 0.004] in the very low frequency domain, and lower autoregulatory index during induced oscillations [B= -0.69, SE= 0.26, P= 0.010]). These changes did not show further progression after 1.5 years of follow-up.
Discussion
In this sample of patients with dementia due to AD we found no evidence that dCA or BRS become impaired during AD progression. This paves the way for further studies that investigate the safety and benefits of antihypertensive treatment in patients with AD.
Antipsychotic use in Alzheimer disease (AD) is associated with adverse events and mortality. Whilst postulated to cause/exacerbate orthostatic hypotension (OH), the exact relationship between antipsychotic use and OH has never been explored in AD—a group who are particularly vulnerable to neuro-cardiovascular instability and adverse effects of medication on orthostatic blood pressure (BP) behaviour.
We analysed longitudinal data from an 18-month trial of Nilvadipine in mild–moderate AD. We assessed the effect of long-term antipsychotic use (for the entire 18-month study duration) on orthostatic BP phenotypes measured on eight occasions, in addition to the relationship between antipsychotic use, BP phenotypes and incident falls.
Of 509 older adults with AD (aged 72.9 ± 8.3 years, 61.9% female), 10.6% (n = 54) were prescribed a long-term antipsychotic. Over 18 months, long-term antipsychotic use was associated with a greater likelihood of experiencing sit-to-stand OH (ssOH) (OR: 1.21; 1.05–1.38, p = 0.009) which persisted on covariate adjustment. Following adjustment for important clinical confounders, both antipsychotic use (IRR: 1.80, 1.11–2.92, p = 0.018) and ssOH (IRR: 1.44, 1.00–2.06, p = 0.048) were associated with a greater risk of falls/syncope over 18 months in older adults with mild–moderate AD.
Even in mild-to-moderate AD, long-term antipsychotic use was associated with ssOH. Both antipsychotic use and ssOH were associated with a greater risk of incident falls/syncope over 18 months. Further attention to optimal prescribing interventions in this cohort is warranted and may involve screening older adults with AD prescribed antipsychotics for both orthostatic symptoms and falls.
In-silico drug repositioning or predicting new indications for approved or late-stage clinical trial drugs is a resourceful and time-ecient strategy in drug discovery. However, inferring novel candidate drugs for a disease is challenging, given the heterogeneity and sparseness of the underlying biological entities and their relationships (e.g., disease/drug annotations). By integrating drug-centric and disease-centric annotations as multiviews, we propose a multi-view graph attention network for indication discovery (MGATRx). Unlike most current similaritybased methods, we employ graph attention network on the heterogeneous drug and disease data to learn the representation of nodes and identify associations. MGATRx outperformed four other state-of-art methods used for computational drug repositioning. Further, several of our predicted novel indications are either currently investigated or are supported by literature evidence, demonstrating the overall translational utility of MGATRx.
Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure, 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO 2 )], 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans), and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO 2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the inter-relationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.
This review summarizes the current literature on the epidemiology of orthostatic hypotension (OH) in the elderly and in patients with autonomic impairment also known as neurogenic OH (nOH); these two conditions have distinct pathophysiologies and affect different patient populations. The prevalence of OH in the elderly varies depending on the study population. In community dwellers, OH prevalence is estimated at 16%, whereas in institutionalized patients, it may be as high as 60%. The prevalence of OH increases exponentially with age, particularly in those 75 years and older. Multiple epidemiological studies have identified OH as a risk factor for all-cause mortality and cardiovascular disease including heart failure and stroke. Real-world data from administrative databases found polypharmacy, multiple co-morbid conditions, and high health-care utilization as common characteristics in OH patients. A comprehensive evaluation of medications associated with OH is discussed with particular emphasis on the use of anti-hypertensive therapy from two large clinical trials on high-intensive versus standard blood pressure management. Finally, we also review the epidemiology of nOH based on the underlying neurodegenerative disorder (either Parkinson's disease or multiple system atrophy), and the presence of co-morbid conditions such as hypertension and cognitive impairment.
In-silico drug repositioning or predicting new indications for approved or late-stage clinical trial drugs is a resourceful and time-eficient strategy in drug discovery. However, inferring novel candidate drugs for a disease is challenging, given the heterogeneity and sparseness of the underlying biological entities and their relationships (e.g., disease/drug annotations). By integrating drug-centric and disease-centric annotations as multi-views, we propose a multi-view graph attention network for indication discovery (MGATRx). Unlike most current similarity-based methods, we employ graph attention network on the heterogeneous drug and disease data to learn the representation of nodes and identify associations. MGATRx outperformed four other state-of-art methods used for computational drug repositioning. Further, several of our predicted novel indications are either currently investigated or are supported by literature evidence, demonstrating the overall translational utility of MGATRx.
Background
Impaired recovery of blood pressure (BP) after standing has been shown to be related to cognitive function and mortality in people without dementia, but its role in people with Alzheimer’s disease (AD) is unknown. The aim of this study was to investigate the association of the orthostatic BP response with cognitive decline and mortality in AD.
Methods
In this post-hoc analysis of a randomized controlled trial (Nilvad), we measured the beat-to-beat response of BP upon active standing in mild-to-moderate AD. This included the initial drop (nadir within 40 seconds) and recovery after 1-minute, both expressed relative to resting values. We examined the relationship between a small or large initial drop (median split) and unimpaired (≥100%) or impaired recovery (<100%) with 1.5-year change in Alzheimer’s Disease Assessment-cognitive subscale (ADAS-cog) scores and all-cause mortality.
Results
We included 55 participants (age 73.1±6.2 years). Impaired BP recovery was associated with higher increases in ADAS-cog scores (systolic: β [95% CI]=5.6 [0.4-10.8], p=0.035; diastolic: 7.6 [2.3-13.0], p=0.006). During a median follow-up time of 49 months, 20 participants died. Impaired BP recovery was associated with increased mortality (systolic: HR [95% CI]=2.9 [1.1-7.8], p=0.039; diastolic: HR [95% CI]=5.5 [1.9 -16.1], p=0.002). The initial BP drop was not associated with any outcome. Results were adjusted for age, sex and intervention group.
Conclusions
Failure to fully recover BP after 1-minute of standing is associated with cognitive decline and mortality in AD. As such, BP recovery can be regarded as an easily obtained marker of progression rate of AD.
Recent findings indicate that the human cardiovascular system is regulated by a cortical network comprised of the insular cortex (Ic), anterior cingulate gyrus, and amygdala which is necessary for the regulation of the central autonomic network system. Alzheimer disease (AD) affects the Ic at a preclinical stage. The pathology of AD at the Ic is suggested to predispose the cardiovascular system to detrimental changes such as increased blood pressure variability (BPV). In this review article, we focus on the physiology of the Ic in the relationship between the central autonomic network and BPV. We provide a summary of the published evidence regarding the relationship between Ic damage and exaggerated BPV in the context of AD pathology.
