PROGNOSIS

PAH is a progressive, life-limiting condition, which continues to get worse over time.

Without treatment, PAH carries a poor prognosis.1 Although there is no cure, recent advances in therapies can offer an improvement in prognosis and survival.2

The course of PAH is variable and the rate at which disease progression occurs depends on several factors, such as the underlying aetiology of the patient's disease.3,4 However, even patients with mild disease (World Health Organization Functional Class [WHO FC] II) can show significant deterioration over 6 months, without treatment.5,6

The prognosis of PAH varies dependent on the type of PAH as well as several other factors including age, associated conditions and comorbidities.3

 

Figure 1. Survival curves from diagnosis of patients with pulmonary hypertension (PH) in Great Britain (2009–2017).7 Adapted from National Audit of Pulmonary Hypertension Great Britain, 2016-2017.

 

In the 2018 national audit of PH, the median survival from diagnosis of patients in Great Britain with idiopathic, heritable or anorexigen-induced PAH, with treatment, was 3.7 years.7 Disease progression may be delayed by identifying and treating patients as early as possible.6,8 Patients with less severe disease, or those with a higher number of low-risk criteria at diagnosis, have significantly improved survival.9,10

 

Figure 2. Transplant-free survival for newly diagnosed patients according to the number of low-risk criteria ([WHO FC I/II, 6-minute walk distance >440m, right atrial pressure <8 mmHg, cardiac index ≥2.5 L/min/m2] n=1017).9 Adapted from Boucly, Eur Respir J 2017.

 

PAH associated with connective tissue disease (PAH-CTD)

Outcomes in patients with PAH-CTD differ from those observed in other forms of PAH.11 Patients with systemic sclerosis (SSc) have a particularly poor prognosis compared with patients with idiopathic PAH (IPAH).3,12 This may be due to difficulties in diagnosis alongside other comorbidities, the relatively poor response to treatment and differences in pathogenesis.11-13 PAH is one of the leading causes of mortality in patients with SSc.11

 

PAH associated with congenital heart disease (PAH-CHD)

Patients with PAH-CHD represent a varied patient population whose clinical presentation may differ. Eisenmenger syndrome is the most severe form of PAH-CHD;3 however, even these patients may survive into their seventh decade.14 The high survival outcomes may result from the preservation of right ventricular function as the right ventricle does not undergo remodelling at birth and remains hypertrophied. Some of the strain is also relieved by the right-to-left shunt, although this comes at the expense of cyanosis.3

 

PAH associated with HIV infection

The prognosis of PAH associated with HIV is worse than for HIV infection alone or IPAH.15 Treatment with highly active antiretroviral therapy significantly improves survival in these patients, including deaths directly attributable to PAH, as well as other causes.16 Interestingly, unlike with IPAH, the normalisation of haemodynamic parameters in response to targeted therapy has been seen in a substantial number of patients.17

 

PAH associated with portal hypertension

The median survival rates of patients with portopulmonary hypertension in the UK is similar to that of IPAH,7 but the long-term prognosis is related to the severity of cirrhosis and cardiac function.17

Click here for more information about the different types of PH.

 

DETERMINANTS OF PROGNOSIS

Regular, comprehensive assessments of patients in the expert PH centres are recommended to determine evidence of clinical deterioration. The risk status of patients can be categorised as either low, intermediate or high. This corresponds to an estimated 1-year mortality of <5%, 5–10% or >10% respectively and is based on a number of determinants including WHO FC, exercise capacity and haemodynamic parameters. There is no single variable that can provide sufficient prognostic information on its own, and a multidimensional approach to investigations and imaging is required.3

Table 1. Risk assessment in PH.3 Adapted from Galiè, Eur Heart J 2016 (click to view full image).


TREATMENT

While there is currently no cure for the disease, modern PAH therapies can markedly improve a patient's symptoms and slow the rate of clinical deterioration.2

Over the past decade, there has been considerable research into the causes of PAH, and recent advances in our understanding of the mechanisms behind the development of the disease have led to major progress in treatment options for patients.

Given the progressive nature of PAH, the overall aim of treatment is to achieve and maintain a low-risk status in order to reduce the risk of clinical deterioration.3

The management of PAH is complex and involves the use of a range of treatment options, such as supportive and general measures, disease-targeted therapy and surgical intervention.3,18

 

GENERAL MEASURES

General measures include physical activity and supervised rehabilitation; patients should be encouraged to remain active within their symptom limits. There are also recommendations on avoiding pregnancy, prevention and prompt treatment of chest infections and awareness of the potential effects of high altitude.3

PAH can also have a significant impact on the psychological, financial and emotional functioning of patients, carers and their families. Psychological, as well as social and welfare support, should be offered.3

 

SUPPORTIVE THERAPY

A range of supportive treatment options have been shown to provide symptomatic benefit for patients with PAH:3

  • Oral anticoagulants: Patients with IPAH have an increased risk of venous thromboembolism, and frequently have reduced mobility. The benefits of prophylaxis are less clear in associated PAH (APAH), where comorbid conditions may increase the risk of bleeding
  • Diuretics: Patients with decompensated right heart failure may become overloaded with fluid. Diuretics can help relieve the symptoms associated with ascites, peripheral oedema and hepatic congestion
  • Oxygen therapy: This may provide symptomatic relief, although there is no evidence to support benefit in the long term, except in patients with consistently low oxygen saturations
  • Digoxin: Digoxin has been shown to improve cardiovascular output in the short term

Calcium channel blockers (CCBs) may also be of benefit in a small proportion of patients with PAH. Suitable patients are detected by acute vasoreactivity testing during right heart catheterisation (RHC).3 A positive vasoreactive response, indicating potential suitability for CCB therapy is shown by around 10% of patients,3 and approximately 7% of these patients have a sustained response.19 Patients with a negative status should not be started on CCBs because of the potential risk of severe side effects including hypotension, syncope and right ventricular failure.3,20

Click here to read more about RHC and other diagnostic techniques.

 

TARGETED THERAPY

In the last decade, the treatment options available have progressed considerably, and therapies are now available that can target the underlying mechanisms of the disease.2

Specialist PAH drugs should only be given to patients with PAH; therefore, all patients should have a diagnosis confirmed by RHC before starting treatment.7 In the UK, only the designated PH centres are able to initiate treatment with a disease-targeted medicine.21

It is important to start treatment of PAH in a timely manner, to try to avoid deterioration as the disease progresses. Newly diagnosed patients should begin drug therapy within 12 weeks of referral to the specialist centre, as evidence shows waiting beyond this timeframe can compromise survival.21 Once treatment is initiated, patients should be monitored regularly and their response to therapy assessed using a range of clinical, exercise, haemodynamic and echocardiographic parameters (Table 1).3

PAH-specific therapies have been developed to target one of three major pathways known to be involved in the development of PAH and have, to varying degrees, been shown to affect the disease process.20

Click here to read about the pathogenesis of PAH.

 

THERAPEUTIC TARGETS

 

Endothelin pathway

Endothelin receptor antagonists (ERAs):

Endothelin induces vasoconstriction and stimulates the proliferation of vascular smooth muscle cells. ERAs are oral treatments that act by blocking the binding of endothelin to its receptors to lessen this process. Clinical trials have shown that treatment with ERAs has a beneficial effect on exercise capacity, haemodynamics and long-term outcomes.20,22,23

Nitric oxide pathway

Phosphodiesterase-5 (PDE-5) inhibitors and soluble guanylate cyclase (sGC) stimulators:

These oral agents act on the nitric oxide pathway to induce vasodilation, and they have antiproliferative effects on vascular smooth muscle cells.3 Clinical trials have shown that treatment with PDE-5 inhibitors has favourable results on symptoms, exercise capacity and haemodynamics.3 PDE-5 inhibitors or ERAs, either as monotherapy or in combination, are typically used as first-line treatment.24

sGC stimulators also act on the nitric oxide pathway. Treatment with sGC stimulators resulted in improvements in exercise capacity and time to clinical worsening in a clinical trial. sGC stimulators and PDE-5 inhibitors cannot be used in combination.25

Prostacyclin pathway

Prostacyclin receptor agonists and prostacyclin analogues:

These agents act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH.3,26 Prostacyclin induces the relaxation of vascular smooth muscle.20 These therapies are generally used in patients with more advanced disease, often in combination with other therapies. Previously only available via continuous intravenous infusion, subcutaneous injection or inhalation, oral therapies targeting the prostacyclin pathway are now available.24

 

Combination therapy (using two or more classes of drugs together) is an option in the management of PAH to simultaneously target multiple pathways involved in the disease pathogenesis. Evidence to support combination therapy is growing; studies have shown that combined treatment with an ERA and a PDE-5 inhibitor, either as sequential or as an initial regimen, can significantly delay disease progression and improve long-term outcomes.22,23 Triple therapy, with the addition of a therapy targeting the prostacyclin pathway, is an important treatment strategy in more advanced disease.24, 27

 

SURGICAL INTERVENTION

For patients with severe PAH who do not respond to treatment with advanced therapies, surgery may be the only option.

Balloon atrial septostomy (creating a right-to-left shunt through the atria) can reduce the strain on the right heart and improve the cardiac output. Lung transplantation may offer prolonged survival and continued good quality of life. Given the waiting time and shortage of organ donors, patients should be referred as soon as inadequate response to initial treatment is identified.3

References

  1. D’Alonzo G, et al. Ann Intern Med 1991;115:343–49
  2. Montani D, et al. Orphanet J Rare Dis 2013;8:97
  3. Galiè N, et al. Eur Heart J 2016;37:67–119
  4. Barst R, et al. Chest 2013;144:160–8
  5. Humbert M, et al. Eur Respir Rev 2012;21:306–12
  6. Galiè N, et al. Lancet 2008;371:2093–100
  7. NHS Digital (2017). National Audit of Pulmonary Hypertension Great Britain, 2016-17
  8. Sitbon O and Gaine S. Eur Respir Rev 2016;25:408­–17
  9. Boucly A, et al. Eur Respir J 2017;50:1700889
  10. Farber H, et al. Chest 2015;148:1043–54
  11. Mathai S and Hassoun P. Heart Fail Clin 2012;8:413–25
  12. Chaisson N and Hassoun P. Chest 2013;144:1346–56
  13. Avouac J, et al. Ann Rheum Dis 2008;67:808–14
  14. Daliento L, et al. Eur Heart J 1998;19:1845–55
  15. Barnett C and Hsue P. Advances in Pulmonary Hypertension 2017;15:138–43
  16. Zuber JP, et al. Clin Infect Dis 2004;38:1178–85
  17. Simonneau G, et al. J Am Coll Cardiol 2013;62:D34–41
  18. NHS England (2014). Clinical Commissioning Policy: National Policy for Targeted Therapies for the Treatment of Pulmonary Hypertension in Adults, NHS England/A11/Pb
  19. Sitbon O, et al. Circulation 2005;111:3105–11
  20. Humbert M, et al. N Engl J Med 2004;351:1425–36
  21. NHS England (2013). 2013/2014 NHS Standard Contract for Pulmonary Hypertension: Centres (Adult), A11/S/a
  22. Pulido T, et al. N Engl J Med 2013;369:809–18
  23. Galiè N, et al. N Engl J Med 2015;373:834–44
  24. Gaine S and McLaughlin V. Eur Respir Rev 2017;26:170095
  25. Tsai H, et al. F1000Research 2016;5:2755
  26. Mitchell J, et al. Glob Cardiol Sci Pract 2014;53:382–90
  27. Sitbon O, et al. N Engl J Med 2015;373:2522–33

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