Commissioning Brief - Background Information HTA no 17/129 Exercise training for people with pulmonary hypertension This background document provides further information to support applicants for this call. It is intended to summarize what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. Searches and information provided were up to date as of September 2017. Background information Source of topic This topic was first suggested at an engagement event with NHS England's Specialised Commissioning Group, with a focus on people with pulmonary arterial hypertension. A similar, but wider research recommendation came out of a newly published Cochrane review (Morris 2017), 1 where the patient groups of interest are people with pulmonary hypertension of any cause. This research brief will follow the research recommendation specified in the Cochrane review. Patient group Pulmonary hypertension (PH) is a condition that is characterised by an increase in mean pulmonary arterial pressure ( 25 mm Hg at rest). It can be caused by or associated with a variety of conditions, but can also be inherited or idiopathic. Patients with PH usually present with progressive dyspnoea or other nonspecific symptoms, e.g. weakness and tiredness. PH is a serious condition that can cause right heart failure. It can progress rapidly and is associated with high morbidity and mortality. People of any age can be affected, including adults, children and neonates. The definition of PH is evolving, which makes it difficult to define incidence and prevalence. International guidelines currently classify PH into the following five clinical groups: Group 1: Pulmonary arterial hypertension (PAH). This form of PH is rare, with an estimated prevalence of 15-52 cases per million people; incidence is estimated at 1-3.3 cases per million people per year. In the UK, most of the patients diagnosed with PAH are managed in one of the seven specialist centres. Group 2: PH due to left heart disease (e.g. systolic dysfunction, diastolic dysfunction, valvular disease, congenital cardiomyopathies, pulmonary vein stenosis). PH occurs in 7-83% of people with diastolic heart failure. Group 3: PH due to lung diseases or hypoxia, or both (e.g. COPD, interstitial lung disease, sleepdisordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, or developmental abnormalities). Group 3 PH is found in 18-50% of patients assessed for transplantation or lung volume reduction surgery. Group 4: chronic thromboembolic PH (CTEPH). Incidence is estimated to be 1.75-3.7 cases per million people per year. Between 0.5% and 4% of patients with acute pulmonary embolism subsequently develop CTEPH. Group 5: PH with unclear multifactorial mechanisms. Page 1 of 5
The exact number of people living with PH in the UK is not known. A recent audit of PH services in England and Scotland concluded that more than 9000 patients are currently managed by one of the seven specialist centres. However, patients with milder forms of PH may be managed outside these centres. Some experts believe that the condition is under-diagnosed, given its unspecific symptoms and gradual onset. [Sources: Patient.info https://patient.info/doctor/pulmonary-hypertension-pro; Pulmonary Hypertension Association UK http://www.phauk.org/; National Audit of Pulmonary Hypertension, published on 23 March 2017 http://content.digital.nhs.uk/ph]. NICE and other guidance European Society of Cardiology (ESC) Clinical Practice Guideline: Pulmonary Hypertension (Guidelines on Diagnosis and Treatment of). Published 2015. 2 These guidelines suggest that treatment of underlying conditions should be optimised in the first instance, followed by PH specific drugs. For pulmonary arterial hypertension (PAH), supervised exercise training should be considered in physically deconditioned PAH patients under medical therapy. The guideline authors acknowledge that the supporting evidence is of moderate strength and quality. They point out that there is uncertainty around the best method of exercise therapy, the intensity, and the duration of exercise programmes. The guidelines recommend that patients should be in stable clinical condition before taking up exercise therapy. Exercise therapy is not mentioned in the context of any of the remaining PH groups. There are currently no UK clinical guidelines for pulmonary hypertension in adults. NICE has published two interventional guidelines (IPG) and one evidence summary on unlicensed and off-label medicines (ESUOM) in this disease area (not relevant to the research question). IPG554 Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension. Published date: April 2016. IPG505 Telemetric adjustable pulmonary artery banding for pulmonary hypertension in infants with congenital heart defects Published date: November 2014 ESUOM51 Pulmonary hypertension in neonates: sildenafil Published date: March 2016 Current practice and proposed intervention Current practice As described above, treatment of underlying conditions should be optimised in the first instance, followed by PH specific drugs as required. In the UK, patients with advanced or severe forms of PH should be referred to a specialist centre. There are six PH centres in England, and one in Scotland. Some people with PH may be offered surgery, such as pulmonary endarterectomy, balloon pulmonary angioplasty, atrial septostomy, lung transplant, or heart-lung transplant. Proposed intervention There is some evidence of modest quality to suggest clinical and economic benefits of exercise therapy in people with PAH (Group 1 PH). However, only very little evidence exists on the effects of exercise training in other, larger PH groups, such as those with underlying or associated heart or lung conditions. A recent Cochrane review 1 of studies investigating exercise-based rehabilitation programmes for pulmonary hypertension identified a variety of exercise programmes. These included elements of aerobic and strength training, with the intention to improve patients' compromised aerobic capacity and muscle strength. Study participants engaged in cycling or walking exercise of 20 to 40 minutes duration (aerobic training) and/or in sets of repetitive muscle exercises of upper and lower limbs (strength training). Programmes were offered in in-patient and outpatient settings, but for the purpose of this research topic, only outpatient settings are of interest. The exercise programmes reviewed in the Cochrane review are similar to those that may already be offered to people with chronic lung diseases. They are considered safe and effective in these patients. However, until recently, guidelines discouraged exercise in people with PH, and some clinicians may be concerned about adverse effects in people with PH, such as worsening of symptoms and of cardiac function during exercise and/or in the longer term. Page 2 of 5
More recent guidelines encourage people with PH to be active within their limits. The Cochrane review 1 'suggests that supervised exercise-based rehabilitation is likely to be safe for people with pulmonary hypertension (PH) who are stable on medical therapy and can lead to meaningful improvements in exercise capacity.' The review also suggests that people with PH may be able to receive exercise therapy through participation in standard pulmonary or heart failure rehabilitation programmes, albeit with modified exercise prescription and monitoring practices. There is currently no evidence available to guide exercise therapy in this patient group, e.g. regarding dose, intensity, and supervision. There is also a need to assess the clinical and economic benefits as well as the potential harms of exercise therapy in different PH groups, especially in those groups that are under-researched. The suggested research is expected to provide information for physicians, patients and commissioners, and guide decision-making in the management of people with PH. Completed research Evidence Synthesis One Cochrane review (the source of this research topic) and one German cost-effectiveness analysis were identified. Exercise-based rehabilitation programmes for pulmonary hypertension. Morris (2017). 1 This Cochrane review assessed the efficacy and safety of supervised exercise-based rehabilitation compared with usual care or no exercise-based rehabilitation for people with any type of pulmonary hypertension. It included six RCTs (206 participants; searches up to August 2016), and data were extracted from five studies (165 participants). The majority of participants were Group 1 PH (i.e. those with pulmonary arterial hypertension), and a small number were Group 4 PH (chronic thromboembolic PH). None of the studies included participants from other PH groups, such as those with associated cardiac or lung conditions. The study durations were short and ranged from three to 15 weeks. The quality of evidence was generally low. No studies reported allocation concealment, and there was potential selection bias. Exercise programmes included both inpatient- and outpatient-based rehabilitation. The exercise protocols consisted mainly of walking or cycling, usually with resistance exercises for the upper and lower limbs. These protocols are similar to those recommended for standard pulmonary and cardiac rehabilitation programmes. Some studies included stretching, breathing techniques, body perception, yoga, and/or strengthening of respiratory muscles as additional components. Main results: The included studies reported large and clinically significant improvements in exercise capacity, using validated assessment tools. However, due to a high degree of heterogeneity across trials, it was not possible to determine whether these effects were due to differences in study populations (PAH vs. other), settings (inpatient vs. outpatient) or severity of the disease. There was also improvement in health-related quality of life, although it was not clear whether the magnitude of these changes was clinically important. Only one adverse event was reported. Most of the secondary outcomes pre-specified by the authors were not reported (cardiopulmonary haemodynamics, functional class, B-type natriuretic peptide, effects of rehabilitation, time to clinical worsening or mortality). The authors conclude that the limitations of the included studies make it difficult to generalise these results. They suggest that future trials should investigate exercise-based rehabilitation across the spectrum of people with PH, i.e. such studies should ideally include participants from all PH groups and of all grades of disease severity. Economic evaluation of exercise training in patients with pulmonary hypertension. Ehlken (2014). 3 The purpose of this German economic analysis was to analyse the impact of exercise training on healthcare costs in patients with PH. The study followed two cohorts of people with PH (types of PH not reported). A prospective cohort (N=58) received exercise therapy in addition to routine medical treatment. The comparator group, a retrospective age- and gender-matched cohort (N=46), had received routine medical treatment only. During a follow-up of 24±12 months, the exercise group had significantly better survival rates at one and three years and less worsening events (death, lung transplantation, hospitalization due to PH, new PAH-targeted medication) than the control group (15 vs. 25 events, p < 0.05). This led to lower Page 3 of 5
estimated healthcare costs of 657 (approx. 570) within a period of 2 years. The savings were mainly due to reduced medication costs. Primary Research We identified one new RCT that was not included in the Cochrane review. Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi + 12 trial. Gonzalez-Saiz (2017). 4 This small Spanish RCT investigated the effects of an eight-week supervised inpatient intervention combining muscle resistance, aerobic and inspiratory pressure-load exercises. Outcomes of interest were upper and lower-body muscle power and other functional variables. Participants were patients with pulmonary arterial hypertension or with chronic thromboembolic pulmonary hypertension (N=40). Adherence to training sessions was good, and muscle power (the primary outcome measure) improved during the programme. There were no adverse events due to exercise. Research in progress Evidence Synthesis Which physiotherapeutic treatment influences the improvement of the quality of life of adult patients with pulmonary arterial hypertension? (Pereira & Machado). Anticipated completion date: 01 September 2017. PROSPERO 2017:CRD42017057781 http://www.crd.york.ac.uk/prospero/display_record.asp?id=crd42017057781. This review will include studies in people with pulmonary arterial hypertension. The patient groups specified in this research brief will not be represented in this review. Primary Research A small number of ongoing studies were identified. These are not expected to answer this topic's research question. UK STUDIES NAtional cohort study of Idiopathic AnD heritable pulmonary arterial hypertension This a multicentre observational cohort study aims to explore the genetic causes of PAH. Participants are those with heritable and idiopathic pulmonary arterial hypertension and some of their relatives. Target sample size: 3,600. Estimated completion: 31 August 2018. Funders: British Heart Foundation and Medical Research Council (MRC). ISRCTN91688209 / NCT01907295 The Effect of Adding Exercise Training to Optimal Therapy in PAH The aims of this small RCT are (1) to demonstrate that exercise training can enhance exercise capacity and quality of life when added to optimal drug therapy; and (2) to explore mechanisms of exercise limitation and factors that improve with training, assessing cardiac function, skeletal muscle function, autonomic function, respiratory muscle strength, and serum and muscle profile of inflammation. Target sample size: 30 (15 in each arm). Estimated completion: November 2017. UK single centre randomised study (Glasgow). Funder: NHS. NCT02961023. Habitual physical activity and exercise capacity in pulmonary hypertension Target sample size: 15. Estimated completion: 28/02/2017. Follow-up: 15 weeks. Funder: Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital. ISRCTN14072554. This trial is completed, but not yet published. Only little detail is provided in the study registration, but this appears to be a nonrandomised, single-centre pilot study with a mechanistic research interest at a muscular and cellular level (the CI is an Associate Clinical Researcher at the Institute of Cellular Medicine, Newcastle University). Using Step Count to Enhance Daily Physical Activity in Pulmonary Hypertension (STEP in PH) Target sample size: 42. Expected completion: June 2018. Imperial College Healthcare NHS Trust. NCT03043976. The purpose of the study is to demonstrate whether providing patients with their daily step count can increase their levels of daily activity if they have some basic targets to achieve. Investigators also wish to compare the effects of this approach in increasing daily physical activity, with the benefit gained when a drug therapy for pulmonary hypertension is initiated, in patients that have just been diagnosed. Eligibility: Nice Classification Groups 1 and 4 Pulmonary Hypertension (pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension). Page 4 of 5
INTERNATIONAL STUDIES Effect of Exercise Training in Patients With Pulmonary Hypertension The objectives of this study are to test a 'standardized 3 week in-hospital exercise training program' and to investigate the effects of oxygen administration during training. Target sample size: 32. Estimated completion: December 2020. Follow-up: 12 months. Single centre randomised study. Switzerland. NCT02558582. Aerobic Exercise Training in Pulmonary Arterial Hypertension This study investigates the effects of upper extremity aerobic exercise training in patients with pulmonary arterial hypertension. Target sample size: 30. Estimated completion: December 2017. Follow-up: 6 weeks. Single centre randomised study. Turkey. NCT02371733. Influence of Respiratory and Exercise Therapy on Oxygen Uptake, Quality of Life and Right Ventricular Function in Severe Pulmonary Hypertension Target sample size: 90. Estimated completion: June 2016. Current status not known (register was last updated in July 2014). Follow-up: 15 weeks. Single centre RCT. Germany. NCT01394367. Exercise Training in Pulmonary Hypertension (ExTra_PH): A randomised controlled trial examining short and long-term outcomes of an outpatient-based exercise training in pulmonary hypertension The study will investigate the safety and effectiveness of exercise training for people with PH (subgroups not specified, but participants will be recruited from tertiary centres). Follow-up: 2 years min. Target sample size: 50. Estimated completion: Not reported. According to the trial register, the trial is not yet recruiting (last checked: 29/03/2017). Australia. ACTRN12616001467426. NIHR Evaluation Trials and Studies (NETS) research NETS programmes have not yet funded any projects in this disease area, with the exception of a NICE TAR (05/24/01 Clinical and cost effectiveness of epoprostenol, iloprost, bosentan, sitaxentan, and sildenafil for the treatment of pulmonary arterial hypertension in adults: a systematic review and economic evaluation; published). References 1. Morris NR, Kermeen FD, Holland AE. Exercise-based rehabilitation programmes for pulmonary hypertension. The Cochrane database of systematic reviews 2017;1:CD011285. doi: 10.1002/14651858.CD011285.pub2 2. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). European heart journal 2016;37(1):67-+. doi: 10.1093/eurheartj/ehv317 3. Ehlken N, Verduyn C, Tiede H, et al. Economic Evaluation of Exercise Training in Patients with Pulmonary Hypertension. Lung 2014;192(3):359-66. doi: 10.1007/s00408-014-9558-9 4. Gonzalez-Saiz L, Fiuza-Luces C, Sanchis-Gomar F, et al. Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi+12 trial. Int J Cardiol 2017;231:277-83. doi: 10.1016/j.ijcard.2016.12.026 Page 5 of 5