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Pulmonary Hypertension Summit Proceedings Online Monograph

Session IV – Therapeutic Choices for Pulmonary Artery Hypertension

Franck Rahaghi, MD; Jinesh Mehta, MD; Adriano Tonelli, MD

Precision Medicine in PAH Therapy

The 5-year survival rate for pulmonary artery hypertension (PAH) is 60% to 70%, according to the US registry. In clinical practice, response to treatment and prognosis in patients with PAH is determined by functional class, right ventricle size on echocardiogram, right ventricular function, 6-min walk test, peak VO2 in cardiopulmonary exercise testing, and B-type natriuretic peptide (BNP). Patients who improve from functional class III to class II/I have better survival. Apart from PAH-targeted therapies, medications include anticoagulants, diuretics, digoxin, oxygen, and calcium channel blockers in selected subgroups with reversibility.

Choice of PAH-targeted medicines should be tailored to the particular patients, especially by assessing the guidelines, comorbidities, dosage, cost, and drug interactions.

Patients who are functional class II or III should be started on oral monotherapy or combination sequential therapy. Those who are functional class IV should have intravenous patient-controlled analgesics and prostanoids. Patients should be considered for lung transplant if the response to recommended therapy is submaximal.

Consensus guidelines have established the following combinations as level I recommendations:

  • Ambrisentan plus tadalafil,
  • Macitentan plus sildenafil,
  • Riociguat plus bosentan,
  • Selexipag and an endothelin-receptor antagonist (bosentan, ambrisentan, and macitentan) or a phosphodiesterase type 5 inhibitor (sildenafil and tadalafil).

The remaining combinations are either a level IIa, IIb, or level III recommendation.

Treatment selections should also be based on comorbidities and side effect profiles. For example, PDE5 inhibitors cannot be used if the patient is on nitrates or riociguat or if the patient has sickle cell disease. Personalized medicine to choose the best pathway for a patient is available, but it is still in its infancy and requires more study.

Key Points

  • Treatment of PAH is complex and challenging.
  • Background therapies such as anticoagulation, diuretics, digoxin, oxygen, and calcium channel blockers have specific indications and may aid PAH specific treatments.
  • Mean survival in patients with PAH remains inadequate despite PAH-targeted therapy.
  • Initial combination therapy is becoming the standard of care.
  • Several tools are available to help determine the best PAH-specific treatment; however, further research is needed to guide treatment.

Combination Therapy

Three distinct pathways have been identified in PAH pathogenesis and targeting more than one pathway proportionately decreases pulmonary pressures.

There are two ways to use combination therapy:

  1. Sequential combination and
  2. Upfront combinations.

Sequential addition of medications has been the conventional method for decades. Upfront combinations have been studied since 2004 with initially smaller studies but better outcomes than sequential combinations. Some of the studies are as follows:

  • BREATHE 2 trial: Epoprostenol plus bosentan vs epoprostenol alone — Combination group fared better but the results were not significant.
  • AMBITION study: Largest upfront combination study of ambrisentan plus tadalafil vs monotherapy — Event-driven outcomes were better with the combination group.
  • Retrospective registry study of four groups: Bosentan with sildenafil, bosentan plus tadalafil, ambrisentan plus tadalafil, and ambrisentan plus sildenafil — Survival rates exceeded expectations.
  • COMPASS-2 trial: Bosentan or placebo added to sildenafil — Only study with combination therapy outcomes worse than monotherapy, partly because half the patients in the study dropped out.
  • GRIPHON study: Selexipag added to an endothelin-receptor antagonist or a phosphodiesterase type 5 inhibitor — More treatment discontinuity in combination group due to side effects.

Based on these studies, practitioners have switched from monotherapy to combination therapy for PAH. There is still a role for monotherapy but only in a small subset of patients: vasoreactive patients treated with calcium channel blockers. Overall, outcomes are better with combination therapy but more adverse effects occur.

Key Points

  • Combination therapy in PAH has better overall outcomes than monotherapy.
  • Combination therapy results in fewer hospitalizations and slower progression of disease.
  • There may be more adverse events with combination therapy.
  • There is a limited role for persistent monotherapy in PAH.
  • Challenges with combination therapy include sequential vs upfront combination therapy, choice of combination therapy, and cost effectiveness.

Adverse Event Management

Increased use of combination medications in PAH increases the number of adverse events. Up to 30% of patients self-discontinue combination medications because of adverse effects and lack of perceived benefits. The Needs-Concerns Framework (NCF) describes adherence as a function of the patient-perceived need for medication versus the concern for adverse effects.

The main problems with discontinuation of medications are two-fold: Lack of communication regarding adverse effects and lack of guidance on prevention and management of adverse effects. The FDA recommends classifying adverse effects in severity ranging from grade I (asymptomatic or mild symptoms) to grade 5 (death). The FDA also recommends avoiding giving patients the “exhaustive list of every reported adverse event.” Instead, discussions of adverse effects with patients should be based on probability and severity.

A lack of general consensus and awareness exists regarding how to deal with the adverse effects of PAH medications. Our institution has successfully used the Delphi process to create recommendations on controlling adverse effects. We recommend that providers should be more proactive in discussing the adverse effects with patients. Until clinical trials collect information regarding the solutions for reducing and treating adverse effects, the Delphi process can being used to identify and guide treatments.

Key Points

  • Adverse event management should be a general area of focus for pulmonary hypertension and pulmonary medicine.
  • There is a need for better vocabulary and understanding of adverse events for both patients and physicians.
  • There is a need for practitioners to appropriately counsel patients regarding adverse effects to help improve adherence to medications.
  • There is a need for clinical trials to include adverse event management into their design.
  • The Delphi process may be used to provide guidance for practitioners until clinical trials collect information on adverse event management.

Session IV – Therapeutic Choices for Pulmonary Artery Hypertension References

Precision Medicine in PAH Therapy Related References

  1. Ascha M, Zhou X, Rao Y, et al. Impact on survival of warfarin in patients with pulmonary arterial hypertension receiving subcutaneous treprostinil. Cardiovasc Ther. 2017;35(5).
  2. Farber HW, Miller DP, Poms AD, et al. Five-Year outcomes of patients enrolled in the REVEAL Registry. Chest. 2015;148(4):1043-54.
  3. Galiè N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D60-72.
  4. Humbert M, Ghofrani HA. The molecular targets of approved treatments for pulmonary arterial hypertension. Thorax. 2016;71(1):73-83.
  5. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156-63.
  6. McLaughlin VV, Gaine SP, Howard LS, et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25 Suppl):D73-81.
  7. Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129(1):57-65.
  8. Preston IR, Roberts KE, Miller DP, et al. Effect of warfarin treatment on survival of patients with pulmonary arterial hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation. 2015;132(25):2403-11.
  9. Tonelli AR, Zein J, Ioannidis JP. Geometry of the randomized evidence for treatments of pulmonary hypertension. Cardiovasc Ther. 2013;31(6):e138-46.
  10. Tsai H, Sung YK, de Jesus Perez V. Recent advances in the management of pulmonary arterial hypertension. F1000Res. 2016;5:2755.

Combination Therapy Related References

  1. Galiè 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). Eur Heart J. 2016;37(1):67-119.
  2. Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation. 2014;130(24):2189-208.
  3. Lajoie AC, Bonnet S, Provencher S. Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges. Pulm Circ. 2017;7(2):312-25.
  4. Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. Eur Respir Rev. 2016;25(142):408-17.

Adverse Event Management Related References

  1. Benner JS, Nichol MB, Rovner ES, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105(9):1276-82.
  2. Rahaghi FF, Alnuaimat HM, Awdish RLA, et al. Recommendations for the clinical management of patients receiving macitentan for pulmonary arterial hypertension (PAH): A Delphi consensus document. Pulm Circ. 2017;7(3):702-711.
  3. Samples H, Mojtabai R. Antidepressant self-discontinuation: results from the collaborative psychiatric epidemiology surveys. Psychiatr Serv. 2015;66(5):455-62.
  4. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE). Published May 28, 2009. Accessed April 19, 2018.
  5. U.S. Department of Health and Human Services. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Published September 2007. Accessed April 19, 2018.