Take a look at the Recent articles

Health-Related Quality of Life and Socio-Economic Correlates in Patients with Pulmonary Arterial Hypertension

Katleen Swinnen

Department of Respiratory Diseases, KU Leuven, University of Leuven and University Hospitals of Leuven, Leuven, Belgium

Marion Delcroix

Department of Respiratory Diseases, KU Leuven, University of Leuven and University Hospitals of Leuven, Leuven, Belgium

Catharina Belge

Department of Respiratory Diseases, KU Leuven, University of Leuven and University Hospitals of Leuven, Leuven, Belgium

DOI: 10.15761/GIMCI.1000167

Article
Article Info
Author Info
Figures & Data

Abstract

Pulmonary Arterial Hypertension (PAH) imposes a substantial burden on individuals with the disease. The symptoms of PAH are unspecific and of varying severities; breathlessness, fatigue, edema of the lower limbs, dizziness and syncope. The importance of measuring the associated impact on health-related quality of life (HRQoL) is increasingly recognized and new instruments are available. This article reviews the validation and use of recently published questionnaires to evaluate HRQoL in PAH, the economic burden of PAH and new evidence in non-pharmacological supportive treatments.

Introduction

Pulmonary hypertension (PH) is defined by an elevation of the pulmonary arterial pressure and pulmonary vascular resistance, which will eventually lead to heart failure and death. Pulmonary arterial hypertension (PAH) (World Health Organization, WHO, Group I of the pulmonary hypertension classification), is a subset of PH and is a rare, severe and progressive form of PH [1].  PAH may be idiopathic, heritable, toxin-or drug induced or associated with other systemic conditions [2]. The most common symptoms of PAH are non-specific and related to progressive right ventricle dysfunction for instance complaints of dyspnea, fatigue, weakness, angina, dizziness, syncope. Less frequent but troublesome symptoms are a dry cough or exercise-induced nausea and vomiting. Reported frequencies differ depending on the severity of the disease.  Symptoms of right heart failure e.g. ankle edema and abdominal distention, may also be present in more advanced stages of the disease [2]. While a right heart catheterization is required for diagnosis of PAH, the evaluation of symptoms and HRQoL is increasingly acknowledged in current guidelines, which recommend to regularly assess patients clinically. This evaluation can provide valuable information for determining disease severity, improvement, deterioration or stability [2,3-5] In addition, the HRQol is proven to correlate with  survival in PAH [6] We present an overview of the disease burden of PAH in terms of quality of life, daily activities, physical activity, sleep, comorbid anxiety and depression, as well as risk of disease prognosis.

Impact on quality of life

For patients with PAH, the disease can be devastating and exert an adverse impact on all aspect of life [7] Due to the obstructed flow in the pulmonary artery and the resulting impaired uptake of oxygen into the blood, a lack of energy and fatigue is commonly reported during the course of their disease [8-10] This can undermine daily functioning and lead to negative effects on quality of life.

Although, the physical consequences of PAH are widely acknowledged, the relative importance of psychological (e.g., depression, anxiety) and situational (e.g., sleep deprivation) factors is usually unclear. Interest in characterizing the health-related quality of life of PAH-related factors has intensified in recent years. Newly validated PAH-specific patient reported outcome (PRO) instruments might help ensure a standardized assessment of HRQoL in research settings and clinical practice. Recently, two proposed PAH-specific questionnaires were validated and showed good psychometric properties.

The pharmaceutical industry has engaged with US investigators to develop the Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire (PAH-SYMPACT) according to the 2009 US Food and Drug Administration PRO guidance [11] The questionnaire measures important, patient-relevant aspects of PAH symptoms and impacts that are not captured by other clinical endpoints. With 11 symptom items and 11 impact items, this brief questionnaire is easy to apply. It was validated in the SYMPHONY trial and approved for administering in clinical practice and clinical studies [11,12]. SYMPHONY is  a phase III study including 278 patients treated with macitentan 10 mg once daily, who completed four times the PAH-SYMPACT [11,12] Its main limitation was a selection bias, with a lack of untreated patients, patients belonging to WHO functional class (FC) IV and patients with heritable PAH or with PAH associated with congenital heart disease or HIV infection [12]  Correlations with other commonly used questionnaires like the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire and the 36-item Medical Outcomes Study Short Form Survey (MOS SF-36) were moderate to high ([r]=0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity.

In parallel, the Pulmonary Hypertension Association UK developed the emPHasis-10 quality-of-life questionnaire in collaboration with nationally designated specialist PH centers in the UK and Ireland, in order to provide an a PAH-specific HRQoL instrument that can be used in routine clinical practice [13]  The questionnaire consists of 10 items and is currently translated into multiple languages with cultural and linguistic validation [14] The emPHasis-10 assesses breathlessness, energy, feelings of dependency, and perceived control that PH has over life, among other relevant constructs. EmPHasis-10 items are rated on a zero to five Likert scale, with potential sum scores ranging from zero to fifty and higher scores indicating more disruption of life due to PH symptoms [13].

The emphasis-10 was recently used in a longitudinal cohort study that assessed symptom-based variables in PH and its effect on HRQoL in real-life clinical practice. 185 patients with PH (74% PAH) were included and followed for a 18-month period [15].

A strong relation between HRQoL as measured by emPHasis-10 and breathlessness, fatigue, depression, anxiety and sleep was found over time. Dyspnoea, fatigue, anxiety, depression, WHO FC and poor sleep quality were all found to be predictors of reduced HRQoL. These results were in line with a resembling study that assessed the HRQol with the Pulmonary Arterial Hypertension Symptom Interference Scale (PAHSIS) and the MOS SF-36 and the authors found similar interfering symptoms [5,16].

Recently, an initial investigation was performed, beyond the traditional domains of HRQoL, to assess the impact of PAH and PAH therapies on sexual health and intimacy. The authors demonstrated that women with PAH appear to have reduced sexual HRQol captured with the Female Sexual Dysfunction Scale-Revised (FSDS-R scale). The FSDS-R scale was well correlated to the emPHasis-10 and the Short Form 36 (SF-36 questionnaire). Participants treated with intravenous or subcutaneous prostanoids had worse FSDS-R scores than those on oral therapies while emPHasis-10 scores were similar across treatment types. This data demonstrated that PAH has an impact on both the patients but also their partners, who often play a central role in caregiving [17]. The debilitating effects of PAH on family relationships was already mentioned in the past by patients in a survey conducted by the European Pulmonary Hypertension Association and the Food and Drug Administration (FDA). Especially the inability to perform routine household activities and family activities was mentioned [8,9]. In this regard, a large scale survey was conducted with 174 Chinese participants (114 PAH patients and 60 caregivers) to assess the impact of PAH on patients and their caregivers [18] Caregivers reported being exhausted by the disease’s demands, which led to a subtle change in the patient-caregiver relationship and to stress. A reduction in intimacy and decreased sexual relations was reported by 84% of the caregivers since their partner became ill, that declined further as PAH progressed [18] Moreover, most patients also experience feelings of isolation, which may be potentiated by a lack of public understanding about the disease, resulting in less compassion towards PAH patients from the community and close relatives [18] In this regard, most patients and caregivers express a desire to talk about the impacts of PAH on their lives with their family and friends, followed by patient organizations, PAH specialists, other PAH patients. This was also demonstrated in surveys conducted in the UK and US. [8,19,20].

In this regard, a first clinically patient reported experience measurement (PREM) scale was developed and validated in 2018  for patients who visit a PAH outpatient clinic. This eight-item questionnaire can be a reliable instrument for evaluating patient experience of health care and provide structural information to address their needs [21].

Economic burden of PAH

Although the impact of PAH on patients HRQoL is well-described, PAH is also accompanied by a significant economic burden. A recent study showed that the total cost of respiratory disease in the 28 countries of the EU amounts to more than 380 billion euro annually. The economic burden of pulmonary vascular diseases could not be estimated and would also add to the economic burden, both for healthcare and work limitation [22] Several trials have shown that treatment earlier in the course of disease and a combination of multiple PAH drugs is beneficial [23-25] Combination therapy is shown to improve the outcome and as a result its use is recommended in current guidelines [2]. Of course, the use of a combination of drugs will also lead to an additive pharmacy cost. On the other hand, the benefits of a combination therapy include a decrease in hospitalisations [26,27]. This can result in a cost-reduction bearing in mind that, more than half of the PAH patients require at least one hospitalisation during a one year follow-up and that the length of stay is greater for patients with PAH than for those with other principal diagnoses [27]. A study including 504 subjects with PAH demonstrated that the estimated average total health care costs are substantively high relative to costs reported for other chronic diseases. It also confirmed that medical costs appeared to decrease following PAH medication use, but with a concomitant increase in pharmacy costs [28]. Due to the very expensive PAH treatment, in some countries a large financial burden is carried by the patient’s family.  A large survey conducted in a Chinese PAH population and their caregivers, demonstrated that treatment expenses represent a major financial burden and a source of stress to families, particularly those with lower-than-average income [18]. Also a survey conducted in Europe, revealed that in the majority of the patients their work or employment was affected by PAH and both patients and caregivers reported a major impact on family finances [8]. In Europe, national health insurance or social security systems offer support, which alleviates the stress and let patients benefit from long-term therapy. Currently, most clinical trials lack an economic endpoint. It is therefore recommended to incorporate specific economic endpoints to facilitate more accurate financial modelling [26]. Results from a recent study indicate that PAH disease severity, measured by functional class (FC), is associated with increase healthcare costs. These findings suggest that if higher risk patients, according to the current recommendations, are treated more aggressively, their risks could be lowered, leading to improvements in their function and QoL, and potentially lowering median healthcare costs. Therefore, the authors state that disease severity documentation could be an important tool as part of a PAH patient’s management plan [29].

Non-pharmaceutical therapeutic options

Despite optimized combination-medical therapy most patients remain symptomatic, have reduced exercise capacity, quality of life and reduced survival rates, with an annual mortality rate of approximately 5 -15 % or even higher [2]. Supportive therapies may be beneficial in addition to targeted medical treatment. European guidelines provide recommendations for supportive care and general measures, however its use varies largely between countries and can be challenging in routine clinical care. Recently, some new evidence of beneficial supportive therapies of interest became available.

Exercise rehabilitation for PH

Evidence shows that in patients with severe chronic heart and lung diseases, a rehabilitation program results in an improved exercise tolerance, quality of life and survival [30] Rehabilitation was for long time not recommended in patients with PH because of the fear to aggravate the symptoms and the potential of negatively influencing the heart function [31] In 2006, a first randomized controlled trial was published, showing an improvement of exercise capacity and quality of life as result of a (partly inpatient) rehabilitation program. Recently published reviews show that based on the available small number of studies, supervised pulmonary rehabilitation is safe when performed in expert centers. The weighted results show an increase of mean walked distance measured during a six-minute walk test, largely exceeding the minimal important difference of 30 meters. In addition, a weighted between group difference in HRQol questionnaire scores was concluded [32-34] A study even shows an improvement of pulmonary hemodynamics, in addition to the exercise tolerance improvement [35] On the other hand, the most optimal duration, methodology and follow-up of the patients is still unknown.  A study published in 2017 showed that that oscillatory whole-body vibration (WBV) can be a feasible and easily accessible method of continuous and potentially home-based physical exercise for patients with PAH [36].

We can conclude that given the small number of available studies and the small sample sizes, more studies have to be performed, in order to provide hard evidence to support the benefit of exercise in PAH.

Sleep disturbances

Recently, increasing occurrence of sleep disturbance are reported caused by insomnia or restless leg syndrome and associated with worse PAH symptoms, psychological states, and health-related quality of life [15,37-39] Moreover, a study published in 2015 even found that poor quality of sleep was associated with impaired exercise capacity besides the reduction of the HRQoL [39]. However, this was contradicted in a previous study, where no significant difference was observed in 6MWD of patients with a good and poor sleep quality [37] Interventions that decrease sleep disturbances may improve symptoms and HRQOL. In this regard, a pilot study was performed in order to assess the feasibility and efficacy of daily slow-paced respiration therapy to treat dyspnea, fatigue and sleep disturbance in women with PAH. Although only ten patients were included, improved sleep along with an improvement of the HRQoL, dyspnea and fatigue was suggested [40] On the other hand, a study that attempted to identify predictors of reduced HRQoL in PAH patients, the relationship between poor sleep and HRQoL was not significant. Although, sleep quality in the sample was poor overall. Many of the factors affecting HRQoL, such as physical and psychological symptoms, may have also affected quality of sleep in these patients [15]. Further investigation is warranted in order to better understand the nature of sleep disturbances.

Conclusion

Although the life expectancy of PAH has increased the past decades, the disease can still not be cured and patients are faced with a considerable burden and impact on their HRQol. Whether facing pain in severe PAH or ongoing headache, jaw pain and diarrhea caused by PAH treatment, patients endure a long road of discomfort. While, the assessment of HRQoL has some barriers, clinicians currently better accept to collect meaningful data on patients subjective experiences. It is becoming clear that HRQoL information may, in some settings, lead to improvements in the clinical state of the individual patient. HRQoL can be effectively improved with the combination of pharmacological and non-pharmacological therapies.

References

  1. Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, et al. (2013) Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 24: 34-41. [Crossref]
  2. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, et al. (2016) ‘2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 37: 67-119. [Crossref]
  3. Matura LA, McDonough A, Annette RN, Diane LC (2012) Predictors of Health-Related Quality of Life in Patients With Idiopathic Pulmonary Arterial Hypertension. J Hosp Palliat Nurs 14: 283-292.
  4. Matura LA, McDonough A, Carroll DL (2014) Health-related quality of life and psychological states in patients with pulmonary arterial hypertension. J Cardiovasc Nurs 29: 178-184. [Crossref]
  5. Matura LA, McDonough A, Carroll DL (2015) Symptom Interference Severity and Health-Related Quality of Life in Pulmonary Arterial Hypertension. J Pain Symptom Manage 51: 25-32. [Crossref]
  6. Mathai SC, Suber T, Khair RM, Kolb TM, Damico RL, et al. (2016) Health-related quality of life and survival in pulmonary arterial hypertension. Ann Am Thorac Soc 13: 31-39. [Crossref]
  7. Reis A, Santos M, Vicente M, Furtado I, Cruz C, et al. (2018) Health-Related Quality of Life in Pulmonary Hypertension and Its Clinical Correlates: A Cross-Sectional Study. Biomed Res Int 19: 3924517. [Crossref]
  8. Guillevin L, Armstrong I, Aldrighetti R, Howard LS, Ryftenius H, et al. (2013) Understanding the impact of pulmonary arterial hypertension on patients’ and carers’ lives. Eur Respir Rev 22: 535-542. [Crossref]
  9. FDA (2014) The Voice of the Patient: Pulmonary Arterial Hypertension.
  10. Tartavoulle TM, Karpinski AC, Aubin A, Kluger BM, Distler O, et al. (2018) Multidimensional fatigue in pulmonary hypertension: prevalence, severity and predictors. ERJ Open Res 23: 00079-2017. [Crossref]
  11. McCollister D, Shaffer S, Badesch DB, Filusch A, Hunsche E, et al. (2016) Development of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) questionnaire: A new patient-reported outcome instrument for PAH. Respir Res 17: 72. [Crossref]
  12. Chin KM, Gomberg-Maitland M, Channick RN, Cuttica MJ, Fischer A, et al. (2018) Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial. Chest 154: 848–861. [Crossref]
  13. Yorke J, Corris P, Gaine S, Gibbs JS, Kiely DG, et al. (2014) EmPHasis-10: Development of a health-related quality of life measure in pulmonary hypertension. Eur Respir J 43: 1106-1113. [Crossref]
  14. Foster E, Guillen A, Lara K, Oh P, Popielnicki A, et al. (2015) Linguistic Validation of The Emphasis-10 Questionnaire: A Patient-Reported Outcome Instrument For Assessing Qol In Pulmonary Hypertension (Ph). Value Health 18: A744. [Crossref]
  15. Yorke J, Deaton C, Campbell M, McGowen L, Sephton P, et al. (2018) Symptom severity and its effect on health-related quality of life over time in patients with pulmonary hypertension: A multisite longitudinal cohort study. BMJ Open Respir Res 5: e000263. [Crossref]
  16. Kukkonen M, Puhakka A, Halme M (2016) Quality of life among pulmonary hypertension patients in Finland. Eur Clin Respir J 3: 10. [Crossref]
  17. Banerjee D, Vargas SE, Guthrie KM, Wickham BM, Allahua M, et al. (2018) Sexual health and health-related quality of life among women with pulmonary arterial hypertension. Pulm Circ 8: 204589401878827. [Crossref]
  18. Zhai Z, Zhou X, Zhang S, Xie W, Wan J, et al. (2017) The impact and financial burden of pulmonary arterial hypertension on patients and caregivers. Medicine 96: e6783. [Crossref]
  19. Pulmonary Arterial Hypertension Association (2013)The impact of pulmonary arterial hypertension (PAH) on the lives of patients and caregivers: results from a US study.
  20. Yorke J, Armstrong I, Bundock S (2014) Impact of living with pulmonary hypertension: A qualitative exploration. Nurs Health Sci 16: 454-460. [Crossref]
  21. Waldréus N, Jaarsma T, Ivarsson B, Strömberg A, Årestedt K (2018) Development and Validation of a Questionnaire to Measure Patient’s Experiences of Health Care in Pulmonary Arterial Hypertension Outpatient Clinics. Heart Lung Circ. [Crossref]
  22. Union E (2013) The economic burden of lung disease. The European Lung White Book: Respiratory Health and Disease in Europe 16-27.
  23. Galiè N, Rubin Lj, Hoeper M, Jansa P, Al-Hiti H, et al. (2008) Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 371: 2093-2100. [Crossref]
  24. Galiè N, Barberà JA, Frost AE, Ghofrani HA, Hoeper MM, et al. (2015) Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 373: 834-844. [Crossref] 
  25. Pulido T, Adzerikho I, Channick RN, Delcroix M, Galiè N, et al. (2013) Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 369: 809-818. [Crossref] 
  26. Burger CD, Long PK, Shah MR, McGoon MD, Miller DP, et al. (2014) Characterization of first-time hospitalizations in patients with newly diagnosed pulmonary arterial hypertension in the REVEAL registry. Chest 146: 1263-1273. [Crossref]
  27. Burke JP, Hunsche E, Régulier E, Nagao M, Buzinec P, et al. (2015) Characterizing pulmonary hypertension-related hospitalization costs among Medicare Advantage or commercially insured patients with pulmonary arterial hypertension: a retrospective database study. Am J Manag Care 21: 47-58. [Crossref]
  28. Sikirica M, Iorga SR, Bancroft T, Potash J (2014) The economic burden of pulmonary arterial hypertension (PAH) in the US on payers and patients. BMC Health Serv Res 14: 1-11. [Crossref]
  29. Dufour R, Pruett J, Hu N, Lickert C, Stemkowski S, et al. (2017) Healthcare resource utilization and costs for patients with pulmonary arterial hypertension: real-world documentation of functional class. J Med Econ 20: 1178-1186. [Crossref]
  30. Spruit MA, Singh SJ, Garvey C, ZuWallack R, Nici L, et al. (2013) An Official American Thoracic Society/European Respiratory Society Statement: Key Concepts and Advances in Pulmonary Rehabilitation. Am J Respir Crit Care Med 188: e13-64. [Crossref]
  31. Mereles D, Ehlken N, Kreuscher S, Ghofrani S, Hoeper MM, et al. (2006) Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension. Circulation 114: 1482. [Crossref]
  32. Buys R, Avila A, Cornelissen VA (2015) Exercise training improves physical fitness in patients with pulmonary arterial hypertension: A systematic review and meta-analysis of controlled trials. BMC Pulm Med 15: 40. [Crossref]
  33. Morris NR, Kermeen FD, Holland AE (2017) Exercise-based rehabilitation programmes for pulmonary hypertension. Cochrane Database Syst Rev 1: CD011285. [Crossref]
  34. Leggio M, Fusco A, Limongelli G, Sgorbini L (2018) Exercise training in patients with pulmonary and systemic hypertension: A unique therapy for two different diseases. Eur J Intern Med 47: 17-24. [Crossref]
  35. Ehlken N, Lichtblau M, Klose H, Weidenhammer J, Fischer C, et al. (2016) Exercise training improves peak oxygen consumption and haemodynamics in patients with severe pulmonary arterial hypertension and inoperable chronic thrombo-embolic pulmonary hypertension: A prospective, randomized, controlled trial. Eur Heart J 37: 35-44. [Crossref]
  36. Gerhardt F, Dumitrescu D, Gärtner C, Beccard R, Viethen T, et al. (2017) Oscillatory whole-body vibration improves exercise capacity and physical performance in pulmonary arterial hypertension: A randomised clinical study. Heart 103: 592-598. [Crossref]
  37. Batal O, Khatib OF, Bair N, Aboussouan LS, Minai OA (2011) Sleep quality, depression, and quality of life in patients with pulmonary hypertension. Lung 189: 141-149. [Crossref] 
  38. Matura LA, McDonough A, Hanlon AL, Carroll DL, Riegel B (2014) Sleep disturbance, symptoms, psychological distress, and health-related quality of life in pulmonary arterial hypertension. Eur J Cardiovasc Nurs 14: 423-430. [Crossref]
  39. Tiede H, Rorzyczka J, Dumitrascu R, Belly M, Reichenberger F, et al. (2015) Poor sleep quality is associated with exercise limitation in precapillary pulmonary hypertension. BMC Pulm Med. [Crossref]
  40. Matura LA, Fargo J, Fritz JS, Smith KA, Vaidya A, et al. (2017) Slow-paced respiration therapy to treat symptoms in pulmonary arterial hypertension. Heart Lung 46: 7-13. [Crossref]

Editorial Information

Editor-in-Chief

Dario Marchetti
Baylor College of Medicine

Article Type

Review Article

Publication history

Received date: October 16, 2018
Accepted date: October 23, 2018
Published date: October 26, 2018

Copyright

© 2018 Swinnen K. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Swinnen K (2018) Health-related quality of life and socio-economic correlates in patients with pulmonary arterial hypertension. Gen Int Med Clin Innov 3: DOI: 10.15761/GIMCI.1000167

Corresponding author

Delcroix M

Department of Respiratory Diseases, KU Leuven, University of Leuven and university Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

No Figures.