A review of ongoing trials in exercise based rehabilitation for pulmonary arterial hypertension.

Exercise based rehabilitation for patients with pulmonary arterial hypertension (PAH) is a new treatment option for these patients to improve their functional capacity and quality of life. Despite the benefits seen in cardiopulmonary rehabilitation in various other conditions, it has been underutilized for the patients with PAH. A review of currently registered ongoing trials on exercise training for patients with PAH from the World Health Organization International Clinical Trial Registry Platform was done using the key words "rehabilitation", "exercise training", "pulmonary artery hypertension" and "pulmonary hypertension" for a period of 10 years (2002-2012). The search revealed 57 registered trials in various trial registries from which seven met the inclusion criteria. The current studies are being carried out in Germany (n=4), Brazil (n=1), Australia (n=1) and India (n=1). This indicates a shift in focus from the only medical management to the rehabilitation and long term care for patients with PAH.

Introduction

Pulmonary arterial hypertension (PAH) is a condition in which there is an increase in pulmonary vascular resistance due to multiple, complex problems requiring a multidisciplinary approach1. Limitations of patients with PAH to perform cardiopulmonary exercise testing have been thought to be due to problems in the cardiovascular, pulmonary and peripheral skeletal systems thereby causing a decrease in aerobic capacity2. These factors lead to severe functional limitations causing a poor quality of life (QoL), emphasizing the need for rehabilitation among these patients with PAH.

Patients with PAH have severe exercise limitations which have been thought to be due to relative hypoperfusion of the well ventilated areas, low lactate threshold and hypoxemia leading to dyspnoea and fatigue3. Severe ventilation-perfusion mismatch has been shown to cause intolerable dyspnoea even at low workloads. Another abnormality seen is an impaired rise in stroke volume in response to exercise. This is accompanied by an abnormal rise in heart rate to compensate for the decreased stroke volume. Along with this, the pulmonary vascular system shifts from a high flow/low resistance system to a low flow/high resistance system and there is also a poor recruitment of the vascular bed due to the absence of free vascular vessels4. Other reasons for the symptoms and clinical course are due to an increase in physiological dead space leading to an increase in the ventilatory requirement and exercise induced hypoxia5. Another proposed mechanism for exercise limitation is the existence of inspiratory muscle weakness6 and peripheral muscle weakness causing a “generalised myopathy” among patients with idiopathic pulmonary hypertension7.

The trend of advancement in rehabilitation and exercise training for patients with PAH appears to be following a similar trend as in exercise training in congestive heart failure (CHF) which began in 19808. At that time, patients with CHF were excluded from any form of exercise training as it was believed to be detrimental to their condition. However, with a better understanding of pathophysiology and the peripheral muscle involvement, the role of exercise was soon justified. Now, we have substantial evidence to support the need for exercise training in CHF. Even then, patients with class IV symptoms were not considered ideal candidates for rehabilitation and were excluded till the results of the recent HF-ACTION study showed that exercise training was safe in patients even with class IV symptoms9. These findings were also supported in a recently published study on home based exercises involving patients with CHF having class IV symptoms10.

Exercise training is now gaining popularity and is still in the early stages of research. The first randomized trial was published in 2006 by Mereles et al11. Following this study, there have been various case series and non-randomized controlled trials published assessing the effects of various rehabilitation interventions on functional capacity and quality of life in patients with PAH. However, most of the studies were conducted on small sample sizes with short durations of follow up. Guidelines by the British Thoracic Society have recommended that patients with PAH ‘remain as active as their symptoms allow’ and that mild breathlessness is acceptable12. This is further re-emphasized by the European Society of Cardiology guidelines13.

Since 2006 until July 2012, there are currently nine published trials/studies on exercise training in patients with PAH from various parts of the world111415161718192021. Of these studies, there is only one randomized controlled trial and the remaining are either pre-post designs or case series/reports. One study from UK was presented at the British Thoracic Society conference in which the effects of a rehabilitation programme were studied. However, only the abstract from the conference proceedings is available22. Another presentation by Boutet and colleagues found improvements in endurance with a 12 week exercise programme23. Apart from these studies, recent reviews have been published on exercise testing22425 and training22627 for patients with PAH. These studies have assessed various forms of training like aerobic training and a combination of aerobic, resistance and respiratory muscle training in patients with idiopathic PAH1114171819, PAH secondary to congenital heart disease16, secondary to connective tissue disorders1521 and among various forms of PAH20. These studies also found improvements in the six minute walk distance (6 MWD) ranging from 32-87 m following supervised exercise training for 12-18 wk. The studies and their key findings have been summarised in Table I. Grunig and colleagues recently published their study on 183 patient with PAH wherein they found that 13 per cent of those undergoing exercise training experienced adverse events like pre-syncope and supraventricular tachycardia occurring directly due to the exercise20. Other adverse events like syncope, respiratory infections and haemoptysis were not linked directly to exercise. Overall, they found patients tolerating exercises well with no worsening of the clinical condition. In another study they showed that exercise training was useful in patients with connective tissue disorders suffering from PAH21.

Table I

Summary of published studies on exercise training in pulmonary artery hypertens

The need for more research in this area is apparent and currently there have been several trials registered in the various clinical trial registries in the world. Therefore, to create awareness and raise interest in exercise training for upcoming researchers and to facilitate more collaborative research in this area, this review was aimed at highlighting the ongoing trials on exercise training in patients with PAH.

Search strategy

The World Health Organization-International Clinical Trial Registry Platform (WHO-ICTRP) was searched using the key words “pulmonary hypertension”, “pulmonary artery hypertension” “rehabilitation” and “exercise”. The ongoing trials on exercise training (any mode of training) or rehabilitation on patients with PAH were included. Completed and published trials were excluded from the review.Trials were searched between January 2002 and January 2012.

Observations

The search revealed 56 trials of which seven met the inclusion criteria. The 49 trials were excluded because these did not include exercise training as part of the intervention (n=45) or were completed trials with their results published (n=4). The included trials registered in the WHO-ICTRP (which is an international platform that links the various trial registries like Australian New Zealand Clinical Trials Registry, ClinicalTrials.gov, ISRCTN and other national registries from Brazil, China, India, Korea, Cuba, Germany, Iran, Japan, Pan Africa, Sri Lanka and Netherlands) are summarised in Table II. Recently, Ganderton and colleagues published their study protocol on the short term effects of exercise training in patients with PAH28. The National Heart, Lung, and Blood Institute in their recent multidisciplinary workshop has identified exercise training as a primary thrust area for future research29.

Table II

Summary of ongoing trials registered in various databases

The studies currently in process began in 2008. Consequently, there have been studies which have been registered in 2009 and 2010 with three studies being registered in 2011. Of these trials, four are being conducted in Germany and one each in Brazil, Australia and India.

The future

Physiological responses of persons with various aetiologies of PAH will be worth exploring to establish if different forms of exercise training are more beneficial for PAH of different aetiologies. Dose-response relationships and benefits of various forms of training (either in isolation or combination) with long term follow up need to be assessed. Inspiratory muscle dysfunctions and the effects of training in PAH is an understudied area of research in this domain. The role of peripheral muscle dysfunction has been investigated over the last few years. However, more in-depth studies with cellular, biochemical and radiological outcomes will help in obtaining better insight into the natural course of peripheral muscel dysfunctions and benefits of exercise.

Understanding the cellular response to exercise, both in PAH and healthy subjects, will help understand the benefits seen with exercise training in this group of patients. The influence of exercise on various biomarkers seen in PAH (e.g., NT-proBNP, BNP, Troponin-T, etc.) will also need to be explored in future studies. Lastly, epidemiological studies from various geographical regions of the world are essential in determining the burden of the disease. Development of National registries will help in obtaining this information and should be the primary focus of researchers in PAH.

More trials need to focus on rehabilitation of patients with PAH who suffer from severe morbidity. Collaborative studies with those ongoing trials will help expand the horizons of rehabilitation in PAH.