On February 18th 2014, the US Food and Drug Administration (FDA) approved droxidopa
(Northera®), an orally active synthetic precursor of norepinephrine, for the treatment
of symptomatic neurogenic orthostatic hypotension (nOH). It was the first new drug
approval for nOH in almost 20 years. Two years before, the FDA Cardiovascular and
Renal Drugs Advisory Committee had voted 7 out of 13 in favor of approval, but the
FDA requested more data. With the results of a new clinical trial, a second Committee
meeting voted almost unanimously to approve droxidopa (16 in favor out of 17). Droxidopa
was approved for the treatment of symptomatic nOH in patients with primary autonomic
failure, a group of disorders that includes Parkinson disease (PD), pure autonomic
failure (PAF), multiple system atrophy (MSA), dopamine beta-hydroxylase deficiency,
and non-diabetic autonomic neuropathies. PD, MSA, and PAF are now classified as synucleinopathies,
while non-diabetic autonomic neuropathy is a broad term that includes autoimmune,
genetic, and other autonomic neuropathies.
Droxidopa is not a new compound. It was first synthesized in 1919 by German chemists
[9] who thought it could be a catecholamine precursor. In the late 1940s, Blaschko
and colleagues in England showed that droxidopa could be converted to norepinephrine,
in vivo, and that this step required the action of the enzyme DOPA decarboxylase,
a.k.a. aromatic amino acid decarboxylase [1, 3, 4]. In 1989 it was reported that in
patients with familial amyloid polyneuropathy and symptomatic nOH treatment with 600 mg
of droxidopa increased plasma norepinephrine levels and standing blood pressure [10].
Subsequent studies in Japan led to its approval in 1989 for the treatment of nOH in
patients with PD, MSA, and familial amyloid polyneuropathy [6].
Eventually, three pivotal double blind clinical trials led to the FDA approval of
droxidopa (Northera®) in the USA. The trials showed that patients with symptomatic
nOH receiving droxidopa had both symptomatic improvement and higher blood pressure
when standing than those on placebo. Each of these trials and the integrated analysis,
in which almost 1000 patients were screened, have recently been published [2, 5, 8].
In summary, 226 patients received droxidopa and 236 received placebo. Symptoms of
nOH were measured with a validated scale, the Orthostatic Hypotension Questionnaire
[7], which assesses the presence of clinical manifestations of hypotension-related
organ hypoperfusion including dizziness, lightheadedness, fatigue, or “coat-hanger”
pain, on a scale from 0 (no symptoms/no interference) to 10 (worst possible/complete
interference). The scale also includes measures of activity of daily living (i.e.,
how much interference the patient has when performing activities that require standing
for a short time or for a long time). Those who received droxidopa improved in virtually
all nOH symptom scores compared to those receiving placebo (Fig. 1). Droxidopa also
increased upright systolic blood pressure significantly (+11.5 ± 20.5 mmHg vs. placebo
+4.8 ± 21.0 mmHg; p < 0.001).
Fig. 1
Mean score change from baseline to week 1 in the Orthostatic Hypotension Questionnaire
(OHQ) from the integrated analysis of clinical trials of droxidopa. a Orthostatic
Hypotension Symptoms Assessment (OHSA) and b Orthostatic Hypotension Daily Activity
Scale (OHDAS). Score change on a rating scale from 0 (none/no interference) to 10
(worst possible/complete interference). A negative change represents a decrease in
symptom burden
Clinical trials in a rare and clinically heterogeneous disorder like nOH pose a number
of challenges. Recruitment can take a long time and the number of patients in each
diagnostic category is always relatively small. With this limitation in mind, post
hoc combined analysis of these trials showed a number of interesting leads. Droxidopa
was particularly effective in patients with PD and PAF, but appeared less so in patients
with MSA. The most puzzling finding is that among patients with MSA, treatment with
droxidopa resulted in a larger decrease in symptom burden than in patients with other
synucleinopathies; however, this improvement was not statistically better than placebo
[2]. This is, perhaps, due to a greater placebo effect in this patient group, or to
the presence of the Hawthorne effect, i.e., patients are particularly compliant with
non-pharmacological measures to treat nOH (liberalization of salt and water, avoiding
carbohydrates and alcohol, etc.) because they are participating in a clinical trial.
It may also be related to the different site of pathology in MSA (central sympathetic
denervation), in contrast to PD and PAF (mostly peripheral sympathetic denervation).
Another important issue is whether patients taking DOPA decarboxylase inhibitors (DDCI,
e.g., carbidopa), which are always combined with levodopa in the treatment of PD,
get less benefit from droxidopa. DDCI block the conversion of droxidopa to norepinephrine
and could, theoretically, block droxidopa’s blood pressure-raising effect. In the
integrated analysis, the magnitude of improvement observed in patients on droxidopa
not taking DDCI was more pronounced than in those taking DDCI [10]. However, because
none of the studies were designed to specifically assess this, no statistical model
could confirm the significance of the difference. Moreover, the dosages of DDCI were
not collected and the dose–response effect could not be analyzed. The combined analysis
did show, however, that patients receiving droxidopa still had an increase in their
blood pressure and symptomatic improvement when taking DDCI at clinically indicated
dosages.
During the trials, droxidopa was given in a fixed three times a day schedule. Now
that the drug has been on the market for some time, clinical experience suggests that
a better strategy is to use different dosages of droxidopa throughout the day. A higher
dosage in the morning when blood pressure standing is at its lowest is a strategy
used by most experienced clinicians when treating symptomatic nOH.
Droxidopa has been available in the USA for almost 4 years now. For many patients
with different autonomic disorders droxidopa is well tolerated and improves their
symptoms of nOH and quality of life. Still, like with any drug, some patients fail
to respond. Why droxidopa appears not to be effective in this subpopulation remains
an important clinical and research question. It is also important to remember that,
in order to be effective, droxidopa must be given with clear explanations of the need
for non-pharmacologic measures, which constitute the necessary background for all
pressor agents to exert their beneficial effect in patients with symptomatic nOH.
In this special supplement of Clinical Autonomic Research entitled “Neurogenic orthostatic
hypotension: grand rounds”, eight practicing clinicians from different medical centers
across the USA discuss their own real-life experience in treating patients with nOH,
when and how to start droxidopa, and several challenging situations. This supplement
also includes a basic glossary with information on treatments of nOH and supine hypertension,
based on a recent expert consensus criteria and other publications.
Our hope is that this basic information is useful to our readership and can assist
them in managing their patients with nOH.