1. Introduction
The evolution to bipedalism in humans required development of precisely
programmed and complex physiological processes, along with anatomical
changes to perform activities while standing. Postural or orthostatic
hypotension (OH) is attributed to a failure in physiological systems
that help adapt one’s blood pressure (BP) to a change in posture. OH, is
defined as a sustained symptomatic drop in systolic blood pressure (SBP)
of at least 20 mmHg or diastolic blood pressure (DBP) of at least 10
mmHg within the first three minutes of standing from a supine position
(or of tilting the body (head up) to at least a 60-degree angle on a
tilt table) (1).
OH, is a topic of concern for physicians for two reasons, the first
being its relatively high prevalence in the general population,
estimated to be between 6 and 55%, with the higher prevalence rates in
older age groups and patients with multiple comorbidities (2-4).
Worryingly, more than two thirds of patients in acute geriatric wards
may have OH (5). The second reason is the association of OH with an
increased risk of ischaemic stroke, coronary events, heart failure and
all-cause mortality (6), especially in populations with a higher
cardiovascular burden such as patients with hypertension and diabetes
mellitus (DM) (4). Hence it is important to identify and manage OH
appropriately.
Various aetiologies present with OH as a symptom or a sign and can be
further classified into non-neurogenic OH such as secondary to fluid
loss, drug induced and vasovagal reflex and neurogenic OH (nOH) such as
Parkinson’s disease associated pure autonomic failure. Once symptomatic
OH is confirmed, nonpharmacological interventions are commonly used as a
first step. These may range from medicines rationalisation and
deprescribing i.e., stopping contributory medications (such as
vasodilators), increasing fluid and salt intake, counterpressure
manoeuvres (e.g., sleeping with the bedhead raised), and compression
stockings (7).
When non-pharmacological options fail or are ineffective on their own,
then pharmacological options are often employed. In the UK, mainly
fludrocortisone, midodrine, and pyridostigmine are prescribed, while the
FDA approved the short-term use of droxidopa for symptomatic nOH in
2014. Yohimbine, atomoxetine, pyridostigmine, and caffeine have been
studied in a few trials. The most commonly used surrogate for OH is the
improvement in standing SBP at 1 min. Other commonly utilised trial
outcomes include changes in ambulatory BP, head-up tilt (HUT) test and
symptom improvement questionnaires in particular Orthostatic Hypotension
Questionnaire (OHQ). The OHQ has two components, a six-question symptom
assessment (“dizziness, light-headedness, feeling faint or feeling like
you might black out” and a four-item daily activity scale (8). The
Clinical Global Impressions scale (CGI-S) is the next most frequently
used patient related outcome measures (PROM), which consists of two
companion measures, the first evaluates the severity of psychopathology
from 1 to 7 and the second assesses the change from the initiation of
treatment on a similar seven-point scale (9). As reduction in postural
BP drop does not always translate into symptomatic benefit, PROM may be
considered better markers of efficacy analysis. Midodrine gained FDA
approval in 1996 on the basis of a surrogate endpoint of improvement in
standing systolic blood pressure at 1 min, though the long-term and
real-world evidence for benefit is unclear. In comparison, droxidopa
received an accelerated approval in 2014 for nOH for short-term use
based on two trials which used improvement in item of orthostatic
hypotension symptom assessment., section 1 of the OHQ score, which is
considered as a validated PROM tool for nOH. The approval included a box
warning for supine hypertension and recommends monitoring, with an
agreement that a large post marketing study would be undertaken to show
sustained clinical benefit. The existing evidence base for both
nonpharmacological and pharmacological treatment options suffer from
significant heterogeneity stemming from differing clinical trial designs
with extremely short follow ups, and a lack of consensus on appropriate
outcome measure acceptable worldwide for this condition. The aim of this
systematic review and meta-analysis is to fill the knowledge gap on the
exact benefits of pharmacological treatment options for OH by providing
an updated review of the literature on efficacy parameters.