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Progress in PAH Prognostics and Therapy: Improving the State of the Disease

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Richa Agarwal, MD
West Penn Allegheny Hospital
Pittsburgh, Pennsylvania, USA

Pulmonary arterial hypertension is a progressive, fatal disease characterized by progressive vascular proliferation and remodeling of the pulmonary arteries (PA), ultimately leading to increased pulmonary vascular resistance (PVR) and right sided heart failure (RHF). The field of PAH has seen remarkable improvements in patient outcomes, owing to heightened awareness with emphasis on earlier diagnosis and referral, creation of predictive models for disease progression and prognostication, as well as advancements in drug therapy.

The National Institutes of Health (NIH) registry in 1981 was the first registry evaluating survival in PAH patients in an era when modern, standard therapies were not yet available, and therefore does not accurately reflect the current state of the disease [1]. Four modern day registries, the French Registry, the Pulmonary Hypertension Connection registry (PHC), Mayo Clinic PAH registry, and the largest of all, the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), have consistently demonstrated improvement in PAH survival across PAH subgroups, compared with the historical NIH control group [2-3] (Figure 1). The prognostic equations generated from these registries, which incorporate multiple, incremental clinical and hemodynamic data, are useful in clinical practice for predicting survival in patients with similar cohort population characteristics. If further studies confirm the utility of these equations for serial risk prediction over time, individual disease trajectories could be ascertained and targeted with timely medical interventions to avoid future morbid and mortal events. In this manner, an incremental benefit in survival may be realized by facilitating a personalized management profile for individual patients. It is important to recognize however, that more contemporary predictors of survival, using modern imaging techniques and biomarkers, may emerge as important and more accurate predictors of survival. In particular, evaluations of right ventricular (RV) function, RV-PA coupling, and RV energetics by cardiac magnetic resonance imaging and PET, respectively, will likely provide additive prognostic power if incorporated into future risk models. Given the power of RV function in mortality prediction, identification of novel imaging or biomarker signals of early RV failure, and studies assessing the direct effects of newer therapeutic agents on the RV, should remain a top research priority.

links imageFigure 1. Survival from time of diagnostic RHC in the REVEAL cohort compared to the estimated survival in the historical NIH cohort (matched for age, sex, and mean PAP). Median contemporary survival improved to greater than 7 years in the REVEAL registry, compared with a dismal median survival of 2.8 years in "untreated" patients by the NIH registry [2].

On the treatment front, two new therapeutic agents have demonstrated promise for treatment in PAH. Riociguat, an oral soluble guanylate cylcase stimulator, designed to increase cyclic guanosine monophosphage (cGMP) for enhanced pulmonary vasodilation, was shown to improve PVR and exercise capacity by six minute walk distance in two recent, placebo-controlled randomized studies of PAH (PATENT-1) [4] and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent PH following pulmonary endartectomy (PEA) (CHEST-1) [5-6]. The latter is particularly important, as until now, there have been no specific medical therapies for CTEPH. Pulmonary endarectomy remains the treatment of choice in patients who are suitable surgical candidates with operable disease, despite the complexity of the procedure and significant complication rates [7-8], and the limited number of experienced centers. The potential benefit of medical therapy in these patients represents a significant advancement with targeted PAH therapies, although it is important to recognize that patients should firstly be considered for PEA which remains the superior and curative treatment option. Riociguat was unanimously approved by the US Food and Drug Administration in August 2013 for use in CTEPH patients and in WHO Group I PAH patients to prevent clinical worsening.

Macitentan is a new ERA with dual receptor antagonism (ETA and ETB) shown in the large, placebo-controlled trial, SERAPHIN [9] to significantly decrease morbidity and mortality over long-term follow-up in PAH patients, with the primary combined endpoint driven by reduction in reductions in PAH worsening. Historically, drug approval for PAH therapies have been on the basis of short-term studies showing improvements in 6MWD. The PH community will continue to demand more event-driven trials such as this one, with emphasis on assessing disease stabilization and long-term benefit with current and future therapies. The beneficial effects of macitentan were observed in both treatment-naïve patients and in those already on background PAH therapies, and minimal liver toxicity was observed. FDA review is presently underway for macitentan.

This is an exciting time in PAH, as drug development and approval is entering a new phase. It has been some time since we have seen new promising therapies for this debilitating, progressive disease. Current developments in PAH therapeutics and better trial design with robust clinical outcome measures will undoubtedly continue to improve the state of the disease.

Disclosure Statement: the author has no conflicts of interest to report.


  1. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115;343-349.
  2. Benza RL, Miller DP, Barst RJ, et al. An Evaluation of Long-Term Survival From Time of Diagnosis in Pulmonary Arterial Hypertension from the REVEAL Registry. Chest 2012; 142 (2); 448-456.
  3. Benza RL, Gomberg-Maitland M, Frost AE, et al. Development of prognostic tools in pulmonary arterial hypertension: Lessons from modern day registries. Thrombosis and Haemostasis 2012; 108: 1049-1060.
  4. Ghofrani H-A, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369:330-40.
  5. Ghofrani H-A, D'Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013; 369;319-29.
  6. Archer SL. Riociguat for Pulmonary Hypertension- A glass half full. N Engl J Med 2013; 369(4); 386-8.
  7. Jamieson SW, Kapelanski DP, Sakakibara N et al. Pulmonary endarterctomy: experience and lessons learned in 1,500 cases. Ann Thorac Surg 2003; 76: 1457-62.
  8. Mayer E, Jenkins D, Lindner J, et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011; 141(3); 702-10.
  9. Pulido T, Adzerikho I, Channick R, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809-819.

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