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.