ACR CONVERGENCE 2020—In patients with connective tissue diseases, such as systemic sclerosis (SSc), pulmonary hypertension (PH) remains one of the leading causes of morbidity and mortality. In her lecture on Friday, Nov. 6, Pulmonary Hypertension: An Update, Mardi Gomberg-Maitland, MD, MSc, professor of medicine and medical director of the Pulmonary Hypertension Program at The George Washington School of Medicine & Health Sciences, Washington, D.C., discussed the history of defining PH and how updates to this definition may impact the diagnosis and treatment of patients with this condition.
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In 1961, the World Health Organization (WHO) Expert Committee on Chronic Cor Pulmonale published a report noting that 1) mean pulmonary arterial pressure (mPAP) does not usually exceed 15 mmHg when a patient is resting in the supine position, and 2) mPAP should never exceed 20 mmHg.1 Based on this information, the first World Symposium on Pulmonary Hypertension (WSPH), held in 1973, defined PH as an mPAP ≥25 mmHg at rest, as measured by right heart catheterization (RHC).2 Even though this definition used a high pressure threshold compared with the mPAP found in the general population, it remained unchanged in subsequent meetings of the WSPH through 2013 to prevent overdiagnosis of PH.
However, defining PH based on mPAP alone fails to take into account the different mechanisms that can elevate PAP, such as increased cardiac output (CO) and elevation of pulmonary arterial wedge pressure (PAWP) in left heart disease. Thus, from the third WSPH in 2003 to the fifth WSPH in 2013, pulmonary vascular resistance [PVR=(mPAP–PAWP)/CO)] was included in the definition of pre-capillary PH of group 1 (i.e., pulmonary arterial hypertension [PAH]) and this category was defined as mPAP ≥25 mmHg with a normal PAWP ≤15 mmHg and elevated PVR ≥3 Wood Units (WU).3-5
In 2018, the sixth WSPH revised the hemodynamic definition of PH for the first time since 1973, changing the threshold mPAP from ≥25 mmHg at rest as measured by RHC to ≥20 mmHg. In addition, three hemodynamic profiles for PH were constructed: 1) isolated pre-capillary PH, defined as mPAP ≥20 mmHg with PAWP <15 mmHg and PVR >3 WU; 2) isolated post-capillary PH, defined as mPAP ≥20 mmHg with PAWP >15 mmHg and PVR <3 WU; and 3) combined pre- and post-capillary PH, defined as mPAP ≥20 mmHg with PAWP >15 mmHg and PVR >3 WU.6
What do these changes mean for rheumatologists? As Dr. Gomberg-Maitland pointed out, this new definition should help identify more patients with PH earlier in the course of their disease. This is important because, although idiopathic PAH is rare, PAH associated with connective tissue disease is not. Indeed, in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL Registry), connective tissue disease-associated PAH accounts for about 25% of all forms of PAH.7 This includes patients with SSc, systemic lupus erythematosus, rheumatoid arthritis and other conditions.
Although there is presently no cure for PH, significant advances have been made in treatment options, and this has resulted in increased survival compared to that seen in the 1980s.8 Dr. Gomberg-Maitland discussed several diagnostic algorithms that have been developed to identify intermediate- to high-risk patients and quickly connect these patients to referral centers that focus on PH, and she urged the audience to consider employing such algorithms in their clinical practice.9
Dr. Gomberg-Maitland discussed the pathways that have been explored in PAH therapeutic trials over the past four decades, beginning with the use of early conventional therapies (i.e., supplemental oxygen, calcium channel blockers and vasodilators) and progressing to involve the prostacyclin, endothelin and nitric oxide pathways. She stressed that some treatment options are often underutilized, such as digoxin, to increase contractility in right heart failure and reduce sympathetic nervous system activation, and diuretics, to reduce peripheral edema, intravascular volume and venous pressure.
Twelve medications are currently approved by the U.S. Food & Drug Administration for the treatment of PAH, and it is likely the cadre of available treatments will continue to expand.
An important point raised in the talk was that no single class of drug has proved to be consistently effective in the treatment of PAH in all patients, implying that no single pathway exists to explain all cases. With this in mind, it is rational to consider combination therapy with more than one agent in order to target several different disease pathways at the same time.
In an event-driven, double-blind, randomized, controlled trial of 500 patients with WHO functional class II or III symptoms of PAH who had not previously received treatment, initial combination therapy with ambrisentan (i.e., a potent type-A selective endothelin receptor antagonist) and tadalafil (i.e., an inhibitor of phosphodiesterase type 5, also known as PDE5) resulted in a significantly lower risk of clinical failure events than ambrisentan or tadalafil monotherapy.10 These types of trials have informed, and will continue to inform, decisions on which patients should receive combination therapy.
Dr. Gomberg-Maitland also described work she has been involved with on the Pulmonary Hypertension Outcomes Risk Assessment (PHORA) tool. This multi-platform clinical decision support system uses data from the REVEAL Registry to risk stratify patients with PAH and help guide therapeutic decisions and optimize clinical trial design using advanced computer learning and data mining technology. In a 2020 paper on this tool, researchers demonstrated this Bayesian, network-derived risk prediction model (compared with existing models) could discriminate between low-, intermediate- and high-risk PAH groups.11
In the final portion of the talk, Dr. Gomberg-Maitland discussed new concepts in clinical trial design and endpoints, as well as new delivery methods for therapeutics and new targets for therapy. Although early trials in PH were single agent, placebo controlled, short in duration and focused on changes in measures of exercise capacity, more recent trials on PAH have become larger and longer in duration, and use background therapy and upfront combination therapy. Moreover, event-driven studies that have looked at sequential combination therapy effects on clinical worsening have encouraged development of more clinically relevant, novel, efficacy endpoints.
An example of a trial that challenged the existing paradigm was the drug macitentan (i.e., an endothelin receptor antagonist), which showed a significant reduction in the risk of clinical worsening (as measured by a primary composite endpoint of morbidity and mortality) that was not reflected by the change in the six-minute walk test, which had long been the most frequently used endpoint in PH trials.12
With respect to new ways to deliver treatment, Dr. Gomberg-Maitland discussed SynchroMed II pump and catheter system, an implantable system used for the direct intravascular delivery of treprostinil to the circulatory system.13
This talk represented a thorough and thought-provoking update on the subject of pulmonary hypertension and, in highlighting past, present and future directions in this field, Dr. Gomberg-Maitland allowed the audience to much better appreciate the landscape of this important condition.
Jason Liebowitz, MD, completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his medical degree. He is currently in practice with Skylands Medical Group, N.J.
- Chronic cor pulmonale. Report of an expert committee. World Health Organ Tech Rep Ser. 1961;213:35.
- Hatano S, Strasser T, eds. Primary Pulmonary Hypertension. Report on a WHO Meeting. Geneva, World Health Organization, 1975.
- Barst RJ, McGoon M, Torbicki A, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004 Jun 16;43(12 Suppl S):40S–47S.
- Badesch DB, Champion HC, Sanchez MAG, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S55–S66.
- Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D42–D50.
- Condon DF, Nickel NP, Anderson R, et al. The 6th World Symposium on Pulmonary Hypertension: What’s old is new. F1000Res. 2019 Jun 19;8:F1000 Faculty Rev-888.
- Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: Baseline characteristics from the REVEAL Registry. Chest. 2010 Feb;137(2):376–387.
- McGoon MD, Benza RL, Escribano-Subias P, et al. Pulmonary arterial hypertension: Epidemiology and registries. J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D51–D59.
- Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J. 2019 Jan 24;53(1):1801904.
- Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015 Aug 27;373(9):834–844.
- Kanwar MK, Gomberg-Maitland M, Hoeper M, et al. Risk stratification in pulmonary arterial hypertension using Bayesian analysis. Eur Respir J. 2020 Aug 27;56(2):2000008.
- Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809–818.
- Bourge RC, Waxman AB, Gomberg-Maitland M, et al. Treprostinil administered to treat pulmonary arterial hypertension using a fully implantable programmable intravascular delivery system: Results of the DelIVery for PAH trial. Chest. 2016 Jul;150(1):27–34.