Age and Ageing 2017; 46: 168–174 © The Author 2016.

r 2016. Published by Oxford University Press on behalf of the British Geriatrics Society.
doi: 10.1093/ageing/afw211 All rights reserved. For permissions, please email: journals.permissions@oup.com
Published electronically 17 November 2016

NEW HORIZONS

New Horizons in orthostatic hypotension

Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
JAMES FRITH1,2, STEVE W. PARRY1,2
1
Newcastle University—Institute of Cellular Medicine, Newcastle upon Tyne NE1 7RU, United Kingdom of Great Britain and
Northern Ireland
2
The Newcastle upon Tyne Hospitals NHS Foundation Trust—Falls and Syncope Service, Newcastle upon Tyne, United
Kingdom of Great Britain and Northern Ireland
Address correspondence to: J. Frith. Tel: 01912083868; Fax: 01912080723. Email: james.frith@ncl.ac.uk

Abstract
Background: orthostatic hypotension (OH) is a common disabling condition associated with increased morbidity and
mortality. Much of the evidence available is derived from younger populations with chronic neurological disease leading to
uncertainty for the diagnosis and management of older people.
Objective: to provide an overview of recent and emerging evidence for the diagnosis, management and prognosis of OH
in older persons.
Methods: a narrative review of recent studies, emerging therapies and relevant regulatory updates.
Findings: revisions to the diagnostic criteria for OH include the duration of the blood pressure drop, specific criteria for
initial and delayed OH and OH with hypertension. Non-drug therapies remain the first-line treatment option and
Comprehensive Geriatric Assessment appears to result in lower rates of OH. Recent evidence concerning withdrawal of
causative medication is inconsistent. Midodrine has recently become the only licenced medication for OH in the UK. Other
emerging treatments include atomoxetine and droxidopa but these require further evaluation. Many other agents may be used
but are not supported by high-quality evidence. The increase in mortality associated with OH is less apparent in older people.
Summary: OH remains common in older people, the new diagnostic criteria address some of the previous uncertainty but
evidence concerning withdrawal of antihypertensives is conflicting. Midodrine is now the only licenced medication for OH
in the UK, but non-drug therapies remain first line and fludrocortisone may be considered before midodrine. We may see
other agents such as droxidopa becoming increasingly used over the coming years.

Keywords: orthostatic hypotension, geriatrics, older people

Introduction associated with an increased risk of myocardial infarction,

Orthostatic hypotension (OH) is often a disabling condi-
tion, characterised by a reduction in blood pressure (BP) on
standing upright. Although there is a great deal of hetero-
geneity in prevalence studies, it remains a highly prevalent
condition affecting approximately 25% of people with type
2 diabetes, 30% of community-dwelling people aged ≥65
years and 70% of people with Parkinson’s disease (PD) [1].
An estimated 30% of cases of OH experience dizziness/
light-headedness, however, the true prevalence of symptom-
atic OH may be greater than this due to its broad range of
non-specific symptoms (dizziness, fatigue, loss of concen-
tration, vision disturbance and tremulousness) [2], which
result in a reduced quality of life. Furthermore, OH is
stroke and death [3, 4]. In this New Horizons article we
discuss recently published evidence, emerging therapies and
updates to guidelines and regulations concerning OH, with
a particular focus on older people.
Diagnosis
Since 1996 the diagnosis of OH has been dependent upon
a well-defined drop in BP, a 20 mm Hg drop in systolic
pressure and/or a 10 mm Hg drop in diastolic pressure [5].
These criteria may be considered as overly rigid by some
[6], but fortunately the consensus definition was updated in
2011 with the addition of some new criteria [7]:

168

• OH—a sustained reduction in systolic BP of 20 mm Hg
or diastolic BP of 10 mm Hg within three minutes of
standing or head-up tilt.
• Initial OH—a rapid, transient drop in systolic pressure of
40 mm Hg and/or diastolic pressure of 20 mm Hg within
the first 15 s of standing.
• OH in people with hypertension—a drop in systolic BP
of 30 mm Hg or more may be more appropriate for a
diagnosis of OH, given the higher baseline.
• Delayed OH—a reduction in orthostatic BP that occurs
after 3 min of standing.
It is thought that the 20/10 mm Hg BP drop criteria
arose from a small study in 1988 which described the normal
BP response to standing in 98 healthy hospital workers [8].
These findings are largely supported by the more recent Irish
Longitudinal study on Ageing (TILDA) which characterised
the pattern of orthostatic BP in 4475 people aged over 50
years [9]. The resulting normograms show that 5% of men
aged 50–59 years have a drop in systolic BP > 20 mm Hg
between 30 and 120 s of standing. This prevalence increases
for each decade such that 20–25% of men aged over 80
years have a systolic drop >20 mm Hg.
There is no accepted time duration that constitutes a sus-
tained drop in BP. In an attempt to address this, one small
retrospective study of 103 people (aged 22–94 years, attend-
ing a specialist falls and syncope clinic) compared to 5-year
outcomes for those who had a transient (<30 s) reduction in
BP with those who had a sustained (>30 s) drop. Those
with a sustained BP drop were significantly more likely to
have received pharmacological treatment of their OH and
were more likely to have died within 5 years [10]. In keeping
with this finding are the BP profiles derived from the
TILDA study which demonstrate that 95% of BP drops in
their older population have recovered/stabilised within 30 s
of standing.
Identifying the duration of a short-lived drop is realistic-
ally, only possible with continuous BP monitoring. This is
particularly true for the diagnosis of initial OH which is
practically impossible on intermittent BP measurement,
given that it occurs within 15 s of standing. But despite the
technological advances in non-invasive, continuous BP mon-
itoring, it remains unknown whether it has any clinical
advantage over intermittent BP measurement (with the
exception of initial OH). In a study of 326 community-
dwelling older adults (aged > 65 years) who underwent tilt-
testing and continuous BP monitoring, 59% were found to
have a drop in BP meeting diagnostic criteria [11]. This is in
stark contrast to other studies using intermittent measure-
ments, in which the prevalence ranges from 5 to 30% [1],
raising the possibility of a high false positive rate with con-
tinuous monitoring. However, in the absence of a gold
standard it will be difficult to fully resolve this issue.
The aforementioned TILDA study found that in 95% of
participants undergoing an active stand, the drop in BP
occurred within the first 30 s of standing [9]. This confirms
the finding of another Irish study in which 110 people
New Horizons in orthostatic hypotension
(mean age 75) with a clinical diagnosis of OH underwent
tilt-table testing with continuous BP monitoring [12]. In
almost 70% of the participants, the BP had reached its
nadir within 30 s, with almost all reaching a nadir within the
first 60 s of standing. These results suggest that when using
intermittent BP measurements, the first measurement
Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
should be taken within 60 s of standing, ideally within the
first 30 s. How frequently the BP should be measured
thereafter remains uncertain. For a comprehensive review
of evidence for the diagnosis of OH we recommend Frith’s
recent narrative review [13].
The use of ambulatory BP measurement is becoming
increasingly common, particularly in the field of hypertension;
however, its use for OH has not yet been determined. It
does not have a diagnostic role, but may be used to evaluate
the BP profile in more detail, specifically, the identification of
post-prandial hypotension (PPH) and reverse dipping (an
increase in nocturnal BP compared to daytime). Reverse dip-
ping may be found in approximately 84% of people with
OH, however, it is also a common finding in older people
without OH, affecting approximately 20% [14, 15]. Similarly,
PPH may be identified on ambulatory BP in 83% of people
with OH, but it is not a specific finding, affecting 59% of
older people with hypertension [15, 16]. A further use of
ambulatory BP is to monitor for hypertension when the with-
drawal of antihypertensive medication is undertaken to treat
OH. However, there is no guidance or evidence to direct clin-
ical practice in this situation, and as is explained below, evi-
dence for the withdrawal of antihypertensives is conflicting.
Aetiology
When OH is identified, consideration should be made to
possible underlying causes which may help direct manage-
ment. There are no systematic reviews or comprehensive
studies collating possible causes of OH, however, potential
causes derived from a small prospective study and two nar-
rative reviews, have been listed in Table 1 simply for back-
ground information. Unfortunately the majority of evidence
we have for the diagnosis and treatment of older people is
derived from younger people with neurogenic OH, how-
ever, most older people with OH do not have an underlying
neurogenic cause [17]. In a recent Dutch study of 242 con-
secutive older patients attending a falls and syncope clinic,
there were no differences in autonomic function between
those who did or did not have a hypotensive disorder sup-
porting previous theories that OH in older people is a mul-
tisystem decompensation rather than down to a single
aetiological factor [18, 19].
Conservative management
Non-drug therapies are the first-line option for most
people with OH and include water-drinking, compression
hosiery, withdrawal of provoking agents and physical
counter-manoeuvres. There is little in the way of recent or
169
J. Frith and S. W. Parry

Table 1. Potential causes to consider when diagnosing and • Bolus water-drinking may improve orthostatic BP in people
managing OH [2, 17, 20]. with neurogenic OH.
• Eating smaller, more frequent meals improves symptoms
Acute causes/Chronic causes Medicationa in people with neurogenic OH.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adrenal insufficiency (I) Diuretics

Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
Central nervous system: (II) Sympatholytics (e.g.
(I) Multiple system atrophy atenolol, doxazosin) Comprehensive geriatric assessment
(II) Wernicke Korsakoff syndrome (III) Vasodilators (e.g. nitrates) In addition to the aforementioned measures, a Comprehen-
(III) Posterior fossa tumours (IV) Antihypertensives
sive Geriatric Assessment (CGA) may both prevent and
(IV) Baroreflex failure (V) Antidepressants
(V) Olivopontocerebellar atrophy (particularly tricyclics) improve OH. In a subgroup analysis of the GeMS study
(VI) Dementia with Lewy bodies (VI) Anti-parkinsonism (Geriatric Multidisciplinary Strategy for the Good Care of
(VII) Adult-onset autosomal dominant medications the Elderly), 695 Finnish people, aged ≥75 years, were ran-
leukodystrophy domised to annual CGA or to usual care, 96% resided in
Arrhythmia
their own home. Over the following 3 years, compared to
Spinal cord:
(I) Traumatic tetraplegia baseline there was a 7% reduction in the prevalence of OH
(II) Syringomyelia in the CGA cohort compared to an increase of 8% in the
(III) Subacute combined degeneration standard care group [22]. The main effect seems to have
(IV) Multiple sclerosis been the significantly greater rate of stopping causative drugs
(V) Spinal cord tumours
in those with OH undergoing CGA, however the precise
(VI) Amyotrophic lateral sclerosis
Myocardial ischaemia mechanism is unknown. One limitation of this study was a
Autonomic neuropathy: higher prevalence of diabetes in the usual-care group, which
(I) Parkinson’s disease may explain the increase in OH at follow-up.
(II) Pure adrenergic neuropathy
(III) Amyloid
(IV) Diabetes Medication withdrawal
(V) Paraneoplastic
(VI) Familial dysautonomia Although international guidelines and expert consensus
(VII) Autoimmune documents recommend the withdrawal of provoking agents,
(VIII) Ageing over 250 medications are reported to cause OH [7, 23–25].
(IX) Human immunodeficiency virus
Fortunately, the 2011 international consensus statement
(X) Syphilis
Sepsis recommends focussing on six principle classes of medication
Acute hypovolaemia: (Table 1) [7].
(I) Burns There have been a few recent studies examining the
(II) Diarrhoea/vomiting association between antihypertensives and OH [26–29].
(III) Haemorrhage
Although these studies support this association, their obser-
(IV) Pyrexia
(V) Heat vational nature limits their impact on clinical practice. For
Acute autonomic neuropathy: an in depth review of these studies we recommend a recent
(I) Autoimmune autonomic ganglionopathy publication by Tan’s group [30].
(II) Guuillain–Barre syndrome Randomised evidence for the withdrawal of medication
(III) Lambert–Eaton myasthenic syndrome
as a treatment option is now available from a post-hoc, sub-
(IV) Botulism
(V) Porphyria group analysis of the Discontinuation of Antihypertensive
(VI) Drug induced (e.g vincristine) treatment in Elderly (DANTE) Study [31]. All 162
a community-dwelling participants (aged ≥75 years) had
Over 250 medications are reported to cause OH. Those listed are considered
causative medications by international consensus [7]. hypertension (<160 mm Hg systolic), cognitive impairment
(but not dementia) and OH (diagnosed on standing from a
sitting position). They were randomised to either continue
high-quality evidence for these therapies. However, a recent
or discontinue antihypertensive medications and a repeat
systematic review of 23 studies reached the following con-
sit-to-stand BP was measured at 4-month follow-up. In a
clusions [21]:
per-protocol analysis, limited to those who stopped all anti-
• Home-based resistance training does not improve ortho- hypertensives, there was a significantly greater reduction in
static BP in older people. the prevalence of OH [to 28/46 (40%), P = 0.001], how-
• Compression (30 mm Hg of pressure) of the lower limb ever, numbers were small and the diagnosis of OH was not
(ankle to hip) improves orthostatic BP and symptoms in based on recommended methods. Furthermore, when per-
older people. forming the intention to treat analyses, the prevalence of
• Although not specific to older people, physical counter- OH was statistically similar between groups (50% in discon-
manoeuvres can improve orthostatic BP and symptoms. tinuation, 62% in continuation, P = 0.13).
• Sleeping with head up does not appear to be effective at More recently, the Systolic blood PRessure Intervention
improving orthostatic BP or symptoms. Trial (SPRINT) has clouded the issue further [32]. This study

170

randomised 9,361 hypertensive participants (28% aged
≥75 years) to either an intensive BP target of (<120 mm Hg)
or standard target (<140 mm Hg). The eligibility criteria were
complex, extensive and excluded those with a standing sys-
tolic BP < 110 mm Hg. Interestingly, over 12 months the
prevalence of OH in the intensive group was 16.6%, signifi-
cantly lower than in the standard group (18.3%, P = 0.01).
However, in those aged ≥75 years, there was no difference
in the prevalence of OH (21 and 21.8%, P = 0.53) between
groups.
The results of these studies do little to reduce the uncer-
tainty regarding the withdrawal of medication for the treat-
ment of OH.
Pharmacological management
Pharmacological therapy should be considered when non-
drug therapies fail to improve symptoms adequately.
Eighteen agents were identified in Logan and Witham’s
2012 systematic review [33]. This well-conducted compre-
hensive review confirmed that there is a lack of good qual-
ity evidence for the pharmacological management of OH
and concluded that many commonly used agents have not
demonstrated beneficial effects on BP or symptoms. Below,
we present recent evidence, relevant regulatory and licen-
cing changes and emerging pharmacological agents.
Fludrocortisone
Fludrocortisone, a synthetic mineralocortoid, promotes renal
sodium uptake, thereby expanding plasma volume. It also
appears to sensitise alpha-adrenoceptors [34]. Although there
are no recent trials evaluating the efficacy of fludrocortisone
in OH, NICE produced an evidence summary in 2013
because of its frequent off-label use [35]. This summary was
based on three randomised trials, one of which was in people
with chronic fatigue syndrome who may or may not have
had OH. The resulting evidence from 123 individuals (23 of
whom we can be certain have OH), describes a significant
improvement in tilt-table BP and autonomic symptoms but
highlights that the long-term effects and safety are unknown.
The European Federation of Neurological Sciences (EFNS)
recommend a dose of 100–200 µg, in conjunction with
adequate fluid and dietary salt [36]. Doses higher than this
should be used with caution and it should be avoided in
those with hypoalbuminaemia or congestive cardiac failure.
Its actions may result in hypokalaemia and supine hyperten-
sion, and as such, monitoring of serum potassium and
supine BP is recommended [24]. There are no registered
clinical trials currently evaluating the use of fludrocortisone
for OH in the WHO clinical trial registry.
Midodrine
The evidence base supporting the use of this alpha-
adrenoceptor agonist, for people with OH has consistently
been graded as low or very low in systematic reviews [33, 37].
New Horizons in orthostatic hypotension
A recent meta-analysis of adults with neurogenic OH, found
that midodrine had no effect on systolic BP drop when com-
pared to placebo [four studies, 161 participants, difference
in means (MD): −4.9 (95% confidence interval: −25.9, 16.0),
P = 0.645, I2 95%]. However, there was an improvement in
patient-reported global symptoms [two studies, 208 partici-
Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
pants, MD: 0.7 (95% CI: 0.3, 1.1), P < 0.001, I2 97%]. Given
the risk of bias of the included studies, and the high levels of
heterogeneity the authors graded the evidence for midodrine
as low. Despite this, early in 2015 the UK MHRA granted a
licence to Brancaster Pharma for its drug Bramox (midodrine
hydrochloride) for people with severe, neurogenic OH that
had failed to respond to other treatments. This makes mido-
drine the only licenced pharmacological agent for the treat-
ment of OH in the UK.
Doses typically start at 2.5 mg once or twice per day,
increasing as required to 10 mg three times per day [24].
The first dose should usually be taken one hour before ris-
ing (30 min for absorption and 30 min to be metabolised to
the active form—desglymidodrine). The final dose should
be taken approximately 4 h before recumbency to avoid
supine hypertension, which may occur in 25% of users. It
should be avoided in those with liver disease, severe heart
disease, acute kidney injury, urinary retention, phaeochro-
mocytoma and thyrotoxicosis [38].
Ongoing clinical trials of midodrine include one US
Study evaluating the efficacy of midorine in people with PD
and orthostatic intolerance, and a Korean study in which
people with OH are randomised to midodrine, pyridostig-
mine or midodrine with pyridostigmine [39, 40].
Droxidopa
Droxidopa is an oral prodrug, metabolised by DOPA
decarboxylase into noradrenaline [41]. It has been used to
treat neurogenic OH in Japan for decades, but only recently
has been approved by the FDA in the US [42]. There have
been several randomised trials demonstrating a degree of
efficacy. A recent meta-analysis, which includes four rando-
mised controlled trials of 494 people with neurogenic OH
(aged 18–92 years) concluded that there is a moderate level
of evidence for the use of droxidopa in reducing dizziness
[MD: −0.97 (95% CI: −1.51, −0.42), p < 0.001, I2 0%] and
improving daily activity [MD: −0.86 (95% CI: −1.34, −0.38),
P < 0.001, I2 10%] [43]. The effect on standing systolic BP
was relatively small, with inconsistent results between studies
[MD: 3.9 (95% CI: 0.1, 7.69), P 0.04, I2 10%]. Risk of bias
was present in all included studies which were funded by
industry and used highly selective inclusion criteria.
There are current ongoing studies assessing the long-
term efficacy and safety; side effects include headache
(11%), dizziness (8%) and fatigue (6%) and it should be
avoided in people with hypertension (180/110), significant
cardiac, hepatic or renal disease and in people taking nor-
epinephrine uptake inhibitors or tricyclic antidepressants
[43, 44]. Starting dose is 100 mg three times daily, titrated
171
J. Frith and S. W. Parry
to maximum dose of 600 mg three times daily. It is not yet
widely available in Europe.
Emerging agents
Better known for its use in attention deficit hyperactivity dis-
order, atomoxetine is a noradrenaline reuptake inhibitor
which exerts a vasopressor effect, with hypertension develop-
ing in 10% of users [45]. In a recent proof of concept study,
65 people (aged 65 ± 9 years) with severe, neurogenic OH
were randomised to a single dose of midodrine, atomoxetine
or placebo [46]. While both midodrine and atomoxetine
increased standing systolic BP, the increase was much more
pronounced with atomoxetine [20 (13–27) mm Hg, MD:
7.5 (95% CI: 0.6, 14.5), P = 0.03]. Atomoxetine also resulted
in a slight improvement in dizziness when compared to pla-
cebo [MD: 0.6 (95% CI: −0.1, 1.7), P = 0.03], but not when
compared to midodrine (P = 0.42). Further clinical trials
are required before considering this agent for use in clinical
practice. Mirabegron is a beta-3 adrenergic receptor agonist
licenced for the treatment of overactive bladder (OAB).
Given its stimulatory effects on the cardiovascular system,
it has been considered a potential agent for the treatment
of OH. Anecdotally, it has been used in people with OAB
and OH as a means of avoiding the vasodepressor effects
of anticholinergic alternatives. However, the UK MHRA
has recently issued a drug safety update concerning the risk
of severe hypertension with mirabegron [47]. In the absence
of evidence for use in OH, the risks and benefits should be
clearly discussed with patients. There is one planned study
of mirabegron in people with PD and OAB which will
evaluate the effects on OH as a secondary outcome [48].
New agents currently under early-phase evaluation
include TD-9855 (Theravance Biopharma R&D, Inc.), a
novel noradrenaline and serotonin reuptake inhibitor, cur-
rently undergoing phase 2 studies in 30 people with neuro-
genic OH [49]. Further information on this experimental
drug is limited, although it appears to have had limited suc-
cess for the treatment of fibromyalgia-associated pain with
high rates of adverse events [50].
A planned future study of a rather idiosyncratic inter-
vention, intends to evaluate the effects of ‘dawn simulation’
(using light therapy) on reducing the postural drop in BP
on first standing in the morning [51]. The hypothesis is that
a gradual arousal the nervous system, by mimicking dawn,
will stimulate and prepare the cardiovascular system before
rising. The study will recruit 36 adults aged 55–85 years
with a history of dizziness or falls on rising.
Prognosis
The natural history of OH is not well-defined, particularly
for those with initial OH. However, studies have previously
described the increased risk of cardiovascular events and
increase in mortality. The results of these studies have
recently been pooled in a meta-analysis (13 studies, 121 913
individuals) [3]. It confirms a significantly increased 5-year
172
mortality [relative risk 1.5 (95% CI: 1.24, 1.81), I2 93%],
however, the significance reduced when focussing on those
aged over 65 years [1.26 (95% CI: 0.99, 1.62)].
The significance of delayed OH has been unknown until
very recently. The hypothesis that it represented a partial
dysautonomia now looks likely in light of recent evidence. A
Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
10-year follow-up of 48 cases, from a specialist autonomic
clinic (mean age: 51 years), with delayed OH found that 54%
of cases progressed to OH within three minutes. Interestingly,
one third also developed an alpha-synuclieopathy during
follow-up (PD, dementia with Lewy bodies, multisystem atro-
phy and pure autonomic failure). A 10-year mortality for
delayed OH was 29% (9% in controls, 64% in those with
OH at baseline) [52].
Conclusion
OH is a common condition associated with a reduced qual-
ity of life and increase in mortality. Existing diagnostic cri-
teria appear adequate and are supported by recent evidence.
There is some evidence that conservative measures can
improve orthostatic BP and symptoms although these may
be limited by adherence and acceptability. Midodrine is now
the only licenced medication for OH in the UK. There are
several ongoing studies evaluating the effects of some newer
pharmacological agents, however, whether the results can be
easily applied to older people remains to be seen.
Keypoints
• Diagnostic criteria now exist for initial and delayed ortho-
static hypotension, as well as orthostatic hypotension in
hypertension.
• Comprehensive Geriatric Assessment appears to reduce
to prevalence of orthostatic hypotension.
• Midodrine is now the only licenced medicine for ortho-
static hypotension in the UK.
• Emerging treatments under evaluation include droxidopa
and atomoxetine.
• It remains unclear whether withdrawal of antihyperten-
sives improves orthostatic hypotension.
Sources of funding
This is an independent report arising from a Clinician
Scientist award (CS-2014-002, James Frith) supported by
the National Institute for Health Research. The views
expressed in this publication are those of the authors and
not necessarily those of the NHS, the National Institute for
Health Research or the Department of Health.
References
1. Low PA. Prevalence of orthostatic hypotension. Clin Auton
Res 2008; 18(S1):8–13.

2. Low PA, Opfer-Gehrking TL, McPhee BR et al. Prospective
evaluation of clinical characteristics of orthostatic hypoten-
sion. Mayo Clin Proc 1995; 70: 617–622.
3. Ricci F, Fedorowski A, Radico F et al. Cardiovascular mor-
bidity and mortality related to orthostatic hypotension: a
meta-analysis of prospective observational studies. Eur Heart
J 2015; 36: 1609–17.
4. Romero-Ortuno R, Cogan L, Foran T, Kenny RA, Fan CW.
Continuous noninvasive orthostatic blood pressure measure-
ments and their relationship with orthostatic intolerance, falls,
and frailty in older people. J Am Geriatr Soc 2011; 59: 655–65.
5. Anonymous. Consensus statement on the definition of
orthostatic hypotension, pure autonomic failure, and multiple
system atrophy. The Consensus Committee of the American
Autonomic Society and the American Academy of Neur-
ology. Neurology 1996; 46: 1470.
6. Wieling W, Schatz IJ. The consensus statement on the definition
of orthostatic hypotension: a revisit after 13 years. J Hypertens
2009; 27: 935–8.
7. Freeman R, Wieling W, Axelrod FB et al. Consensus state-
ment on the definition of orthostatic hypotension, neurally
mediated syncope and the postural tachycardia syndrome.
Clin Auton Res 2011; 21: 69–72.
8. Streeten DH, Anderson GH Jr., Richardson R, Thomas FD.
Abnormal orthostatic changes in blood pressure and heart
rate in subjects with intact sympathetic nervous function: evi-
dence for excessive venous pooling. J Lab Clin Med 1988;
111: 326–35.
9. Finucane C, O’Connell MD, Fan CW et al. Age related nor-
mative changes in phasic orthostatic blood pressure in a large
population study: findings from the Irish Longitudinal Study
on Ageing (TILDA). Circulation 2014; 130: 1780–89.
10. Frith J, Bashir AS, Newton JL. The duration of the ortho-
static blood pressure drop is predictive of death. QJM 2016;
109: 231–5.
11. Cooke J, Carew S, Quinn C et al. The prevalence and patho-
logical correlates of orthostatic hypotension and its subtypes
when measured using beat-to-beat technology in a sample
of older adults living in the community. Age Ageing 2013;
42: 709–14.
12. Deegan BMT, O’Connor M, Donnelly T et al. Orthostatic
hypotension: a new classification system. Europace 2007;
9: 937–41.
13. Frith J. Diagnosing orthostatic hypotension: a narrative
review of the evidence. Br Med Bull 2015; 115: 123–34.
14. Yan B, Peng L, Han D et al. Blood pressure reverse-dipping
is associated with early formation of carotid plaque in senior
hypertensive patients. Medicine 2015; 94: e604.
15. Ejaz AA, Haley WE, Wasiluk A, Meschia JF, Fitzpatrick PM.
Characteristics of 100 consecutive patients presenting with
orthostatic hypotension. Mayo Clin Proc 2004; 79: 890–4.
16. Zou X, Cao J, Li J-H et al. Prevalence of and risk factors for
postprandial hypotension in older Chinese men. J Geriatr
Cardiol 2015; 12: 600–4.
17. Gupta V, Lipsitz LA. Orthostatic hypotension in the elderly:
diagnosis and treatment. Am J Med 2007; 120: 841–7.
18. Lagro J, Meel-van den Abeelen A, de Jong DL, Schalk BW,
Olde Rikkert MG, Claassen JA. Geriatric hypotensive syn-
dromes are not explained by cardiovascular autonomic dysfunc-
tion alone. J Gerontol A Biol Sci Med Sci 2013; 68: 581–9.
19. Lipsitz LA. What’s different about syncope in the aged? Am J
Geriatr Cardiol 1993; 2: 37–41.
New Horizons in orthostatic hypotension
20. Metzler M, Duerr S, Granata R, Krismer F, Robertson D,
Wenning GK. Neurogenic orthostatic hypotension: patho-
physiology, evaluation, and management. J Neurol 2013; 260:
2212–9.
21. Mills PB, Fung CK, Travlos A, Krassioukov A. Nonpharma-
cologic management of orthostatic hypotension: a systematic
Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
review. Arch Phys Med Rehabil 2015; 96: 366–75 e6.
22. Lampela P, Lavikainen P, Huupponen R, Leskinen E,
Hartikainen S. Comprehensive geriatric assessment decreases
prevalence of orthostatic hypotension in older persons. Scand
J Public Health 2013; 41: 351–8.
23. Kuhn M, Letunic I, Jensen LJ, Bork P. The SIDER database
of drugs and side effects. Nucleic Acids Res 2016; 44:
D1075–9.
24. Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W,
Tassinari M. EFNS guidelines on the diagnosis and man-
agement of orthostatic hypotension. Eur J Neurol 2006;
13: 930–6.
25. Moya A, Sutton R, Ammirati F et al. Guidelines for the diag-
nosis and management of syncope (version 2009). Eur Heart
J 2009; 30: 2631–71.
26. Coutaz M, Iglesias K, Morisod J. Is there a risk of orthostatic
hypotension associated with antihypertensive therapy in geri-
atric inpatients? Eur Geriatr Med 2012; 3: 1–4.
27. Kamaruzzaman S, Watt H, Carson C, Ebrahim S. The associ-
ation between orthostatic hypotension and medication use in
the British Women’s Heart and Health Study. Age Ageing
2010; 39: 51–6.
28. Zia A, Kamaruzzaman SB, Myint PK, Tan MP. The associ-
ation of antihypertensives with postural blood pressure and
falls among seniors residing in the community: a case-control
study. Eur J Clin Invest 2015; 45: 1069–76.
29. Valbusa F, Labat C, Salvi P, Vivian ME, Hanon O, Benetos A.
Orthostatic hypotension in very old individuals living in nursing
homes: the PARTAGE study. J Hypertens 2012; 30: 53–60.
30. Zia A, Kamaruzzaman SB, Tan MP. Blood pressure lowering
therapy in older people: does it really cause postural hypoten-
sion or falls? Postgrad Med 2015; 127: 186–93.
31. Moonen JE, Foster-Dingley JC, de Ruijter W, van der Grond J,
de Craen AJ, van der Mast RC. Effect of discontinuation of
antihypertensive medication on orthostatic hypotension in older
persons with mild cognitive impairment: the DANTE Study
Leiden. Age Ageing 2016; 45: 249–55.
32. The SRG. A randomized trial of intensive versus standard
blood-pressure control. N Engl J Med 2015; 373: 2103–16.
33. Logan IC, Witham MD. Efficacy of treatments for ortho-
static hypotension: a systematic review. Age Ageing 2012; 41:
587–94.
34. Davies B, Bannester R, Sever P, Wilcox C. The pressor
actions of noradrenaline, angiotensin II and saralasin in
chronic autonomic failure treated with fludrocortisone. Br J
Clin Pharmacol 1979; 8: 253–60.
35. NICE [ESUOM20]. 2013. Accessed at National Instite for
Health and Clinical Excellence at http://www.webcitation.
org/6dLnSVbP1 (27 November 2015, date last accessed).
36. Lahrmann H, Cortelli P, Hilz M, Mathias CJ, Struhal W,
Tassinari M. Orthostatic hypotension. In: Gilhus NE, Barnes
MR, Brainin M (eds.), European Handbook of Neurological
Management, 2nd edition. Blackwell Publishing Ltd, 2011:
pp. 469–75.
37. Izcovich A, Gonzalez Malla C, Manzotti M, Catalano HN,
Guyatt G. Midodrine for orthostatic hypotension and
173
J. Frith and S. W. Parry
recurrent reflex syncope: a systematic review. Neurology
2014; 83: 1170–7.
38. McClellan KJ, Wiseman LR, Wilde MI. Midodrine. A review
of its therapeutic use in the management of orthostatic hypo-
tension. Drugs Aging 1998; 12: 76–86.
39. Chu K. 2016. Accessed at ClinicalTrials.gov at https://
clinicaltrials.gov/show/NCT02308124 (29 September 2016,
date last accessed).
40. Morley JE. 2016. Accessed at ClinicalTrials.gov at https://
clinicaltrials.gov/show/NCT02365012 (29 September 2016, date
last accessed).
41. Mathias CJ. L-dihydroxyphenylserine (Droxidopa) in the treat-
ment of orthostatic hypotension. Clin Auton Res 2008; 18: 25–9.
42. Goldenberg MM. 2014. Pharmaceutical approval updateP
T393378+44.
43. Strassheim V, Newton JL, Tan MP, Frith J. Droxidopa for
orthostatic hypotension: a systematic review and meta-
analysis. J Hypertens 2016; 34: 1933–41.
44. Biaggioni I, Freeman R, Mathias CJ et al. Randomized withdrawal
study of patients with symptomatic neurogenic orthostatic hypo-
tension responsive to droxidopa. Hypertension 2015; 65: 101–7.
45. MHRA. 2012. Accessed at gov.uk at http://www.webcitation.
org/6d9zu8A4E (19 November 2015, date last accessed).
174
46. Ramirez CE, Okamoto LE, Arnold AC et al. Efficacy of ato-
moxetine versus midodrine for the treatment of orthostatic
hypotension in autonomic failure. Hypertension 2014; 64:
1235–40.
47. MHRA. 2015. Accessed at gov.uk at http://www.webcitation.
org/6dLqnZooZ (27 November 2015, date last accessed).
Downloaded from https://academic.oup.com/ageing/article/46/2/168/2548925 by Pontif�cia Universidade Cat�lica de Minas Gerais user on 29 August 2023
48. Burdick D. 2016 Accessed at ClinicalTrials.gov at https://
clinicaltrials.gov/show/NCT02092181 (29 September 2016, date
last accessed).
49. Theravance Biopharma R & D Inc. 2016. Accessed. at
ClinicalTrials.gov at http://www.webcitation.org/6krT4Mvi2
(28 September 2016, date last accessed).
50. Inc T 2014. Accessed at ClinicalTrials.gov at http://www.
webcitation.org/6ksc9bBQy (29 September 2016, date last
accessed).
51. Zeitzer J. 2016 Accessed at ClinicalTrials.gov at http://www.
webcitation.org/6krUgcFmF (28 September 2016, date last
accessed).
52. Gibbons CH, Freeman R. Clinical implications of delayed
orthostatic hypotension: a 10-year follow-up study. Neurology
2015; 85: 1362–7.
Received 11 July 2016; editorial decision 27 October 2016