Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in October 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
Two randomised controlled trials (RCTs) (n=171 and n=97) found that midodrine significantly increased standing blood pressure 1 hour post‑dose compared with placebo in people with symptomatic orthostatic hypotension due to autonomic dysfunction. There was also limited evidence that midodrine improved some symptoms of orthostatic hypotension, such as syncope (fainting) and low energy levels. However, results for other symptoms such as light‑headedness and dizziness were less positive, and the studies did not assess quality of life, falls or ability to carry out daily activities.
Adverse events seen more commonly with midodrine than with placebo in the RCTs included piloerection (goose bumps), itching and tingling of the scalp, urinary retention and increased blood pressure when lying down (supine hypertension). These adverse events sometimes led to discontinuation of treatment.
Regulatory status: Midodrine (Bramox) is the first medicine to receive a UK marketing authorisation for orthostatic hypotension. It is indicated only for people with orthostatic hypotension due to autonomic dysfunction: use for other types of orthostatic hypotension is off‑label.
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Effectiveness
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Safety
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Patient factors
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Resource implications
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Introduction and current guidance
Orthostatic (or postural) hypotension results from an inadequate physiological response to postural changes in blood pressure. In people with the condition, standing leads to an abnormally large drop in blood pressure, which can result in symptoms such as light‑headedness, dizziness, blurring of vision, syncope and falls.
Orthostatic hypotension may be idiopathic or may arise as a result of disorders affecting the autonomic nervous system (for example, Parkinson's disease, multiple system atrophy or diabetic autonomic neuropathy), from a loss of blood volume or dehydration, or because of certain medications such as antihypertensive drugs.
The European Federation of Neurological Societies recommends individually tailored therapy for orthostatic hypertension. Non‑pharmacological management options are recommended first‑line (including compression stockings, blood pressure monitoring and increased water and salt ingestion). If these do not resolve symptoms, pharmacological treatment with fludrocortisone or midodrine, alone or in combination, may be considered. Use of both of these medicines was 'off‑label' for orthostatic hypotension when the guidance was updated in 2011.
Midodrine (Bramox) is now licensed for orthostatic hypotension due to autonomic dysfunction: use for other types of orthostatic hypotension is off‑label. Use of fludrocortisone (Florinef) for treating any type of orthostatic hypotension is still off‑label (see the NICE evidence summary: unlicensed off-label medicine on fludrocortisone for orthostatic hypotension for more information). In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using midodrine or fludrocortisone outside their authorised indications.
Product overview
Midodrine (Bramox, Brancaster Pharma Limited) received a marketing authorisation in March 2015 and was launched in the UK in July 2015. It is licensed for treating adults with severe orthostatic hypotension due to autonomic dysfunction when corrective factors have been ruled out and other forms of treatment are inadequate.
Bramox is a branded generic and licensing was based on a bioequivalence study demonstrating equivalence to the European product, Gutron.
Evidence review
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This evidence review is primarily based on 2 RCTs (Low et al. 1997, n=171 and Jankovic et al. 1993, n=97) that compared midodrine (2.5−10 mg 3 times daily) with placebo over 3−4 weeks in people with symptomatic orthostatic hypotension caused by autonomic dysfunction.
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Low et al. (1997) found that midodrine 10 mg 3 times daily increased standing systolic blood pressure statistically significantly more than placebo 1 hour after receiving the dose during all 3 weeks of treatment (change after midodrine dose: between +19.5 mmHg and +22.4 mmHg; change after placebo dose: between –1.3 mmHg and +2.8 mmHg; p<0.01 for midodrine compared with placebo in all 3 weeks).
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Jankovic et al. (1993) found that, after 4 weeks, the average change in pre- to post‑dose standing systolic blood pressure was statistically significantly higher with midodrine 10 mg 3 times daily (+22 mmHg, a 23% increase) than with placebo (+3 mmHg, a 3% increase; p<0.001).
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In Low et al. (1997), statistically significantly less light‑headedness was seen with midodrine 10 mg 3 times daily than with placebo at week 2 of the treatment period (p=0.02). This difference was not statistically significant at weeks 1 or 3. Patient- and investigator‑rated improvements in global orthostatic symptoms were statistically significantly greater with midodrine than with placebo after 3 weeks of treatment (p=0.03 and p<0.001 respectively).
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In Jankovic et al. (1993), there was no statistically significant improvement in the percentage of patients reporting improvement from baseline with any dose of midodrine (2.5 mg, 5 mg or 10 mg 3 times daily) for dizziness, weakness or fatigue, blurred vision or ability to stand for over 15 minutes, compared with placebo. At all doses studied, midodrine statistically significantly increased the proportion of patients reporting improvement in syncope compared with placebo (p<0.05), with the greatest improvement seen with 10 mg 3 times daily (p<0.001).
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Dropout from the study by Low et al. (1997) was higher in the midodrine arm (23/82, 28.0%) than in the placebo arm (9/89, 10.1%; based on figures reported as not completing the trial; statistical comparison not reported). In the midodrine group, 3 people dropped out because of pilomotor reactions, 7 for urinary urgency or retention, 5 for supine hypertension, and 8 for other reasons. In Jankovic et al. (1993), 5/74 patients taking midodrine (6.8%, mainly due to supine hypertension) and 3/104 taking placebo (2.9%) discontinued because of adverse effects.
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The most common adverse effects related to midodrine therapy (occurring in more than 1 in 10 people) are piloerection, pruritus of the scalp and dysuria, which lead to discontinuation of treatment in some people. Patients should be monitored for supine hypertension, which occurs in between 1 in 10 and 1 in 100 people. Reducing the dose of midodrine may resolve supine hypertension but, if it does not, treatment must be stopped. See the summary of product characteristics for more information.
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The main limitation of the 2 RCTs is the focus on disease‑oriented outcomes (changes in standing blood pressure), as opposed to patient‑oriented outcomes such as quality of life, falls or ability to carry out daily activities. Symptoms were assessed in the studies but any validity assessment of the measurement scales used was not reported, and data on patient‑reported symptoms recorded at follow‑up appointments may be subject to recall bias. In addition, it is unclear whether any statistically significant differences in symptoms between midodrine and placebo were clinically important. Both studies compared midodrine with placebo, possibly because other pharmacological treatment options for orthostatic hypotension are limited making studies with an active comparator difficult. The studies were also of short duration meaning the long‑term efficacy and safety of midodrine is unclear.
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Three systematic reviews and meta‑analyses have considered midodrine for orthostatic hypotension (Ong et al. 2013, Parsaik et al. 2013 and Izcovich et al. 2014). They included studies in various types of orthostatic hypotension, although the results are largely driven by the 2 RCTs in orthostatic hypotension due to autonomic dysfunction that are the focus of this evidence summary. Overall, the systematic reviews and meta‑analyses concluded that the quality of the evidence supporting the use of midodrine in orthostatic hypotension is limited by the lack of robust clinical data.
Context
The European Federation of Neurological Societies advises that, rather than achieving a target blood pressure, goals of treatment for orthostatic hypotension are improving functional capacity and quality of life, and preventing injury. More evidence from well‑designed RCTs is needed assessing midodrine for orthostatic hypotension on outcomes such as these, over periods of more than 4 weeks.
The European Federation of Neurological Societies currently recommends fludrocortisone as the usual first‑line pharmacological treatment option for orthostatic hypotension. Their guidance was updated in 2011 and, at that time, midodrine was considered a second‑line option, alone or in combination with, for example, fludrocortisone.
Midodrine (Bramox) is now licensed for treating a limited cohort of adults with severe orthostatic hypotension due to autonomic dysfunction in whom corrective factors have been ruled out and other forms of treatment are inadequate. Other forms of treatment recommended by the European Federation of Neurological Societies are physical measures including compression stockings, carefully controlled and individualised exercise training, blood pressure monitoring and increased water and salt ingestion.
The summary of product characteristics does not define severe orthostatic hypotension because assessment of severity is subjective, based on symptoms and the impact of the condition on the person's lifestyle and quality of life. Midodrine is commonly associated with adverse effects, which can sometimes be serious (for example, supine hypertension), and it seems sensible to consider a trial of the drug only when other options have been tried and the patient's quality of life remains adversely affected by the condition. As highlighted in the summary of product characteristics, a careful evaluation of the response to treatment and of the overall balance of the expected benefits and risks should be undertaken with the person before any dose increase or advice to continue therapy for long periods.
Local decision makers need to take safety, efficacy, patient factors and cost into account when considering the likely place in therapy of midodrine for orthostatic hypotension caused by autonomic dysfunction.
Estimated impact for the NHS
According to the NHS prescription cost analysis for England 2014, in that year, the cost of midodrine 5 mg was between £1.27 and £1.66 per tablet and the cost of midodrine 2.5 mg was between £1.84 and £2.21 per tablet. The acquisition cost of the licensed midodrine product is lower (Bramox, £0.75 per 5 mg tablet and £0.55 per 2.5 mg tablet; MIMS, August 2015).
The manufacturer of Bramox, Brancaster Pharma Limited, considers that up to around 3500 people in the UK may be eligible for midodrine treatment under the terms of the marketing authorisation.
Full text of estimated impact for the NHS.
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About this evidence summary 'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance. |