Ivabradine in the treatment of orthostatic intolerance

This editorial refers to ‘Single centre experience of ivabradine in postural orthostatic tachycardia syndrome’ by C. McDonald et al., on page 427. Attention was drawn to postural orthostatic tachycardia syndrome (POTS) in 1993 by Philip Low's team at Mayo Clinic.1 Postural orthostatic tachycardia syndrome has remained difficult to treat despite almost 2 decades of expanding research and recognition. The typical patient is a young female, 15–40 years of age, whose symptoms are usually multiple. In combination, the symptoms are very debilitating and those most common are fatigue, orthostatic intolerance, palpitation manifest as sinus tachycardia, oedema and discolouration of the lower limbs, and occasionally syncope. Two sub-types of POTS have been described. In the first of these, a primary neurological defect is present, possibly triggered by a viral infection. This defect takes the form of a partial autonomic denervation leading to excessive venous pooling in the legs and, sometimes, additional affection of the renal innervation resulting in a reduced plasma renin activity. The second sub-type is considered to have central sympathetic activation, termed the hyperadrenergic type.2,3 In 2005, a possible third sub-type was described that clinically presents facial and/or upper thoracic flushing, in some triggered by exercise, together with the typical symptoms noted above.4 The explanation of the finding is postulated to be the release of a vasodilator from activated mast cells, supported by a raised urinary methylhistamine.4 These patients, as might be expected, may be worsened by beta-blockers but may respond to H1 and H2 histamine blockers with or without alpha-methyldopa. This third sub-type of POTS may present raised blood pressure at times in association with flushing and offer a differential diagnosis from phaeochromocytoma. This sub-type may only be a small percentage of those with POTS but, for them, there may be a specific therapy, anti-histamines not beta-blockade. For the majority, therapy remains incompletely effective. Contemporary therapy includes increased fluids and salt, support stockings, counter-pressure manoeuvres,5 exercise, fludrocortisone, beta-blockers, midodrine, pyridostigmine, octreotide, erythropoietin, and the inspiratory impedance valve.6 These have been well described in a recent review in the Journal.7 Combinations of these measures frequently offer a greater response. McDonald et al.8 implied the benefit in symptomatic terms for POTS patients from the use of ivabradine and may thus be pointing us a new direction. Ivabradine9 is a novel If channel inhibitor which slows phase 4 sinus node diastolic depolarization directly promoting bradycardia. The drug is approved in many countries for treatment of angina on an evidence base10 but, in the UK, it is currently not licensed for the POTS indication. By reducing or preventing the symptomatic sinus tachycardia, McDonald et al. have shown, in a retrospective case series, that control of one symptom is not only valuable in itself but might also contribute to resolution of others in this complex syndrome. In addition to the reported benefit in POTS, there may be some in vasovagal syncope from ivabradine therapy. In the original VASIS classification of vasovagal collapse patterns, an exception to the standard ones (mixed, cardioinhibitory, and vasodepressor) was excessive heart rate response, where the heart rate was >130 bpm just prior to collapse, in a few per cent of tilt-positive patients.11 At our centre, we see 1000 patients per year with orthostatic intolerance and currently have 20 patients on ivabradine therapy (10 with vasovagal syncope and excessive heart rate response and 10 with POTS). We use 5 mg twice daily in the majority and have found help in combination with midodrine in a few. Two patients have abandoned therapy because of lack of benefit, and side-effects have been minimal without serious visual disturbances. The remaining 18 patients continue therapy, with a maximum duration, to date, of 18 months. All have notable benefits in terms of palpitation and others of their symptoms. Now seems an appropriate time to consider a randomized controlled trial so as to provide, if possible, a firm evidence base for the use of ivabradine in POTS. Conflict of interest: none declared.