3. Results
3.1 Study Selection
Using the aforementioned search strategy, 4,677 studies were identified.
50 other studies were identified from hand-searching previously
published reviews. After excluding duplicates, the titles and abstracts
were used to screen the 3,174 studies, among which 206 studies were
selected for full text review. 19 studies met the inclusion criteria for
the systematic review and six studies (18 treatment arms) could be used
for quantitative analysis, as summarised in Figure 1. The updated search
using clinicaltrials.gov did not produce any additional studies.
3.2. Risk of Bias 2 Analysis
ROB2 analysis was conducted on the studies and is reported in Figure 2.
13 studies had some concerns of bias, three studies were at a high risk
of bias and two studies were low risk for concern.
3.3 Study characteristics
Among the studies that met the eligibility criteria, 19 studies
enrolling 806 subjects (range of 12 – 147 participants per study) were
included in the systematic review. Table 1 summarises the medications
which were evaluated in this review (10, 11). Five studies employed
midodrine as the experimental drug, two studies assessed a combination
of pyridostigmine and midodrine for the experimental arm, and three
studies used midodrine as the control/standard of care. Droxidopa was
investigated in four studies, atomoxetine in two studies, one study
evaluated atomoxetine in combination with pyridostigmine and one study
investigated atomoxetine in combination with yohimbine. One randomised
control study each with active arms studying pyridostigmine, yohimbine,
and ergometrine and caffeine in combination, were included. Full details
of the studies are in Table 2. Notably, there was only one study which
examined fludrocortisone that met our inclusion criteria, the reasons
for exclusion are discussed below and detailed in table 3.
All included studies were randomised control trials (RCT), two of which
used an additional open-label period, and 12 studies used a crossover
design. There was extensive heterogeneity between studies in regard to
the length of exposure of the study intervention, ranging from a single
day of exposure (nine studies) to three months.
All studies included patients with existing OH, with most patients
diagnosed with nOH. Within this broad category, aetiological diagnoses
varied from Parkinson’s disease to primary autonomic failure to patient
groups with mixed aetiological diagnosis. Seven studies had primary
outcomes focussed on both the OHQ and changes in standing BP. While one
study used the OHQ alone, three studies used the OHQ and CGIs, three
used standing BP alone and three utilised standing BP in combination
with a global symptom assessment (unique for each study). Two studies
measured orthostatic tolerance using the HUT test, while another used
the mean BP as established by ambulatory BP monitoring (ABPM).
3.3.1 Atomoxetine
Four RCTs studied atomoxetine, three studies assessed impact on standing
BP and one assessed impact of BP using HUT test (12-15). Three out of
the four studies used a single dose exposure with crossover design,
except one study, which assessed orthostatic BP improvement at one
month. This study also involved an open label phase lasting for three
months designed to assess long term impact; both the atomoxetine and
midodrine arms resulted in improvement in orthostatic drop in BP at one
month compared to baseline, but only atomoxetine led to significant
reduction in orthostatic symptoms at one month (12). In another study,
atomoxetine produced a greater increase in standing SBP (mean difference
(95% CI): 7.5 (0.6, 14.5) mmHg, p=0.03) and significantly increased
standing DBP compared to midodrine, and both atomoxetine and midodrine
were superior to placebo (15). In keeping with the earlier study, only
atomoxetine showed significant improvement in orthostatic symptoms as
compared to placebo. Combination medications of atomoxetine and
yohimbine and atomoxetine and pyridostigmine were considered in two
studies (13, 14). The combination arms significantly increased the
seated SBP and orthostatic tolerance (measured as standing SBP and
ability to remain standing), however none of the medications alone
significantly improved BP nor symptoms compared to placebo in both
studies.
3.3.2 Midodrine
Six studies included midodrine as the primary study intervention arm,
three used standing BP measurements, two used HUT testing, and one used
standing BP measurements and symptom scores (16-21). Three studies
looked at single day exposure in a crossover fashion, while the other
three studies involved taking midodrine for a longer duration ranging
from 4-12 weeks. Midodrine and pyridostigmine individually and in
combination reduced orthostatic drop in BP over three months, however
there was no significant differences between groups, but midodrine alone
led to improvement in OH-associated symptom scores (12, 16). In this
study, OHQ composite score in midodrine arm was reduced by -15 in
comparison to pyridostigmine arm where the mean change in score was -9.6
(p <0.01). This trend of a better response with midodrine was
seen in all the studies irrespective of trial design and the outcome
measurement (17-20) and a summary of the OHQ scores can be found in
section 3.3.6. A crossover study demonstrated dose-related impact of
midodrine on standing SBP with a peak at one-hour post-administration
along with a global improvement of symptoms scores (21).
3.3.3 Droxidopa
Droxidopa was the active intervention in four studies included of which
three used the OHQ and one used standing BP and orthostatic tolerance
(ability to stand for three minutes) (22-25) as the primary outcome. In
a small single-blind, crossover study, L-DOPS (droxidopa) increased both
supine mean arterial pressure (MAP) (101±4 to 141±5 mmHg) and standing
MAP (60±4 to 100±6 mmHg) along with improved orthostatic tolerance (25).
Another early study (n=51) using droxidopa, showed a mean rise in
standing SBP of 12.5 mmHg at 1 week in comparison to the placebo arm
(p=0.04)(22). This was followed by other studies planned with an
intention of gaining marketing approval for this unmet need and the
primary outcomes were now measured in terms of OHQ with BP improvement
as secondary outcomes as detailed din section 3.3.6. Accordingly, a
further larger (n=171) study confirmed improvement in SBP of about 6.4
mmHg (SD:18.9) versus 0.7 mmHg (SD:20.2) in placebo arm (p=0.03)(23).
Further a study designed to evaluate efficacy and safety of droxidopa
for a longer duration (approximately 12 months) in patients with nOH
showed both significant improvement in standing BP and symptoms
improvement in the droxidopa arm, however, the improvement was not
significantly different in the double blind phase of the trial(24), thus
depicting the nature the condition which is prone to a large placebo
effect. Interestingly, the open label phases of the study continued to
show improvement up to a year.
3.3.4 Pyridostigmine
Two studies focussed on pyridostigmine, both used a crossover design
with the primary outcome of change in standing DBP (26, 27). In one of
the studies, yohimbine, but not pyridostigmine significantly improved
standing DBP and improved pre-syncope symptoms compared to placebo (p
<0.001) (27). In contrast, in another crossover trial using
pyridostigmine and midodrine, the fall in standing DBP was significantly
reduced (p=0.02) with all treatment. Subgroup analysis found that both
pyridostigmine alone (p=0.04) and pyridostigmine in combination of 5 mg
of midodrine hydrochloride (p=0.002) showed a beneficial impact (26).
3.3.5 Other medications
Of the other studies included, one investigated ergometrine and caffeine
against midodrine and the other yohimbine vs placebo (28, 29). In a
single-blind crossover trial, neither ergometrine and caffeine nor
midodrine had a significant effect on orthostatic tolerance; however,
ergotamine/caffeine improved presyncope symptoms (p=0.03) (28). A
double-blind, crossover study of yohimbine, did not find any differences
between baseline, yohimbine or placebo measurements (29).
One study compared domperidone and fludrocortisone treatment with
baseline in a cross over fashion. In this small phase 2 study in
patients with OH in Parkinson’s disease, comparison was made to baseline
BP and between pre and post medication symptoms scores (30). Domperidone
performed better than fludrocortisone (fall in SBP reduced by 13 mmHg
versus 8 mmHg and DBP reduction improved by 8 mmHg versus 0 mmHg)
measured as BP after 5 mins of standing, in this small cohort of OH
associated with Parkinson’s. The study was however, precluded from
further quantitative analysis, due to the lack of placebo or midodrine
arms. Further, non-pharmacological treatments were used in head-to head
fashion against pharmacological treatment arms in the phase 1 of the
study and applied heterogeneously across patients, with reported poor
adherence. Other studies employing fludrocortisone included in other
systematic reviews and NICE guidance did not meet our inclusion and
exclusion criteria. (See table 3) (30-33).
3.3.6 Orthostatic symptom
Questionnaires:
Table 4 summarises the findings from studies which used OHQ and other
scores as part of study design.
Three studies examined the effect of midodrine on OHQ scores. Two
studies demonstrated a statistically significant improvement in the OHQ
composite score at three months of midodrine use (12, 16). The third
study found that midodrine showed a tendency towards improvement in the
total OHQ score, but it did not reach statistical significance (15). In
the same study there was no difference between the effect of midodrine
and atomoxetine, but atomoxetine did cause a significant decrease in the
OHQ composite score as well as OHSA against placebo whereas midodrine
decreased OHQ composite score only. A fourth study utilised patient and
investigator global evaluations of symptoms and found that scores
significantly improved with high dose midodrine (10 and 20 mg) (21).
Four studies used the OHQ to assess atomoxetine. Two studies
demonstrated that atomoxetine improves the total OHQ score compared to
baseline and placebo respectively (12, 15). In both studies reduction in
OHQ composite score and in particular the QH related symptom severity
(Q1) was statistically significant in atomoxetine group in comparison to
midodrine group. Interestingly, combination therapy of midodrine and
atomoxetine did not result in symptom improvement or BP improvement over
and above individual therapy. Atomoxetine also had improvement in the
scores of the daily activity and depression score. An RCT studying
atomoxetine and pyridostigmine found that atomoxetine tended towards
symptom improvement but did not reach statistical significance; however,
when used in combination with pyridostigmine there was a statistically
significant improvement in symptoms (14). In another study atomoxetine
or yohimbine alone did not improve OH symptoms but achieved statistical
significance when used in combination (13).
Droxidopa was assessed using the OHQ in three studies. In one study,
despite droxidopa not showing any significant improvement on the OHQ
composite score, fewer falls and fewer fall-related injuries (22) were
reported in the droxidopa arm. In a subsequent expansion on the previous
study, at one week, the dizziness and light-headedness components of the
OHQ score favoured droxidopa over placebo (p=0.018), but this effect was
not persistent on follow up (23). Another year-long study with three
phases (three-month open-label, two-week withdrawal, nine-month
open-label) found that during the three-month initial phase, there was a
>50% reduction from baseline in the OHQ composite score in
the droxidopa arm compared to placebo arm, which was sustained
throughout the 12 months of open-label use, and was also reflected in
the reduced nOH severity scoring by clinicians and patients using the
CGI-S (24). However, the secondary analysis of this expanded dataset did
demonstrate that droxidopa significantly improved the symptom aspect of
the OHQ (OHSA) vs placebo (p=0.018) (23). In a separate study both
droxidopa and placebo improved OHQ and CGI scores, however during the
double-blind withdrawal aspect of the trial there was no significance
between the two groups, but the improvement in the OHQ and CGI scores
were maintained (24).
Pyridostigmine was assessed in two studies, one of which found that
pyridostigmine improved OHQ scores at three months of usage but was less
effective than midodrine (16). On the contrary, the other study found
that pyridostigmine did not improve OH associated symptoms, except when
used in combination with atomoxetine (14).
A quantitative analysis of the OHQ composite or OHSA scores could not be
undertaken further due to heterogeneity in reporting methods, trial
design and small number of studies.
4. Meta-analysis
Five studies comparing medications to placebo using mean SBP
measurements before and after dosing were chosen for meta-analysis. Mean
SBP differences and the pooled standard deviation (SD) values were
calculated (Table 5). Studies were excluded from meta-analysis if data
were not reported for baseline values, if there were unclear datasets or
if they used symptoms and questionnaires as their primary outcome, as
opposed to absolute BP changes. The differences in measures taken and
reported from the questionnaires made further analysis impossible.
Analysis of droxidopa could not be completed either due to the main
outcomes being symptom change and/or lack of baseline BP data and/or
missing standard deviations. Atomoxetine and yohimbine could not be
further assessed individually vs placebo due to fewer studies comparing
them with placebo, or their concurrent use in combination with another
medication.
Our meta-analysis showed that pharmacotherapy (pyridostigmine,
atomoxetine, midodrine, yohimbine and combinations) lead to rises in
postural SBP which was higher in the experimental arm compared to
placebo, with a pooled rise in SBP of 12.50 mmHg [95% CI, 6.01 to
18.98; p<0.001]] (heterogeneity: I2 =
97%, p<0.001) (Figure 3).
On subgroup analysis of single medication versus placebo, there was a
mean difference [95% CI] of 12.96 mmHg [4.69, 21.23 p = 0.02]
in favour of the experimental medication (heterogeneity:
I2 = 98%, p < 0.001). There was a
moderately higher mean difference in combined medications vs placebo,
13.81 mmHg [2.68, 24.94, p = 0.02] (heterogeneity:
I2 = 81%, p = 0.002), although the difference between
combined and single medications did not reach significance on an
unpaired t test (p=0.66) (Figure 3).
In the analysis of midodrine vs placebo the mean rise in postural SBP
was higher in the experimental midodrine arm, with an overall effect
size of 16.11 mmHg [95% CI: 5.59, 26.63], p=0.003 (heterogeneity:
I2 =99%, p<0.01) (Figure 4).
Subgroup analysis based on improvement in SBP data comparing
experimental medications (pyridostigmine, midodrine and pyridostigmine,
and atomoxetine) vs midodrine, demonstrated that overall midodrine was
favoured, but that this did not reach significance with an effect size
(95% CI) of -0.50 (-2.96, 4.32), p = 0.47) (12, 16).
Funnel plots were produced for each subgroup analysis (Supplementary -
Figures 1-3). While asymmetry of the plots was noted and could
potentially be caused by selection bias, the cylindrical shape of the
plots may be due to the heterogeneity of the studies as evident by a
high I2 values which could be accounted by several
factors mentioned before.
5. Discussion
In our meta-analysis, we demonstrated statistically significant effects
of pharmacological intervention on standing SBP compared to placebo
treatment, which was especially apparent at higher dose ranges of
midodrine and improvement in OHQ composite square especially apparent
for atomoxetine and droxidopa. The meta-analysis also demonstrated a
lack of effect of pyridostigmine alone at improving SBP, suggesting that
it may not be a suitable single intervention for individuals with nOH.
Whether this impact would be sufficient in mild to moderate
non-neurogenic OH, with or without additional therapy is difficult to
assess using available data. There have not been enough studies of
atomoxetine vs placebo or atomoxetine vs midodrine to make valid
conclusions, but the data suggest that either alone or in combination
with yohimbine or pyridostigmine, atomoxetine could be a useful
pharmacological intervention for OH. Atomoxetine also seems to have more
sustained impact with improvement in symptoms lasting at 3 months (12).
Atomoxetine improves depression scores and that is indeed strength in
its own right as most patients with OH tend to be elderly with
multimorbidity including mental health illness. Additive improvement in
SBP or symptoms was not demonstrated with combination of midodrine and
atomoxetine, which probably is due to similar mechanism of action on the
post ganglionic neurons. As such further studies are warranted to
validate these findings.
Droxidopa gained popularity for treating OH and seemed to result in both
SBP improvement and symptom improvement. Unfortunately, we were unable
to analyse it specifically due to the lack of data on the change in SBP
from baseline. Despite the relatively common usage of fludrocortisone in
practice for decades and its approval by NICE (31) (but not approved by
FDA), there is a lack of strong evidence base for its use. There were 4
RCTs which we considered further for inclusion in this review (table 3).
However, these studies did not meet our inclusion on the basis of number
of participants, or by including patients with orthostatic intolerance
as opposed to OH, the former is encompassing OH, however the causes of
OH pathophysiological are different to other causes of orthostatic
intolerance such as postural orthostatic tachycardia and as such should
be studied separately.
Of particular note, some studies demonstrated that improvements in
standing SBP were not associated with symptom improvement, highlighting
the need to re-consider the primary outcomes and trial designs for
future studies assessing medications for OH (16). It is possible that
there is an element of high “placebo effect” in treating this
condition. Symptom improvement may be postulated to lead to a greater
increase in the quality of life of the patient, and as such the OHQ or
CGI scores could be used in conjunction with BP readings in clinical
practice and future pharmacotherapy trials after clinical validation.
The downside is the subjective nature of the scoring, which makes
extrapolation of results to large populations problematic. Long term
studies may help validate these patient related outcome measurements.
This study intended to provide an updated, robust assessment of the
evidence for pharmacological intervention in treating OH, as
demonstrated in RCTs. Previously published reviews have generally
focussed on single medications (34-36), pharmacotherapy and included
non-RCT studies and do not include the newer medications such as
droxidopa (37) and atomoxetine(38). Additionally, compared to previously
published reviews we included studies which used symptom questionnaires
in order to broaden the perspective of a successful treatment for OH.
Our inclusion criteria were also more stringent in regard to
participants per arm and exclusion of head-to-head comparison of
pharmacological and non-pharmacological treatments as active arms.
Though data from RCTs is considered more robust, the RCTs included in
this meta-analysis have included small numbers of patients belonging to
particular phenotypes, hence it can be argued that real world data could
fare better in this condition. As such non-inclusion of non RCTs in this
study may be perceived as a limitation and this certainly is the case
for medications such as fludrocortisone, as shown in this recent
systematic review (39). It is prudent to re-visit and possibly study
long term effects of the older approved medications prospectively in
phase 4 trials such as NCT04128137 and trials such as CONFORM-OH (40)
and/or in registries.
Our study was limited by the inability to perform extensive subgroup
analyses, an inadequacy of data showing impact on DBP and the
significant heterogeneity in study design and reporting. Further, we did
not assess adverse effects, which is a principal element of prescribing
and continued adherence. We also excluded non-English languages studies
and hence it is possible we missed some useful studies published in
other languages.
Conclusion and future
Though there is sufficient evidence that pharmacological treatment for
OH significantly increases standing SBP, especially for midodrine, the
newer medications need further evidence for establishing both reduction
in postural BP, symptom improvement and sustained impact. There is a
further need for delineating the adverse effects of these medications.
The lack of consensus on the most appropriate patient reported outcome
measures, the heterogeneity in trial designs and outcome reporting
reduce the ability to directly compare different medications and their
impact. Further research and efforts to develop guidance on the outcome
measures incorporating both symptoms and/or improvement in the postural
drop and supine hypertension especially more consistent use of the
symptom scores both clinically and in trial settings could aid testing
novel medications appropriately.