links header


Raymond L. Benza, MD
Allegheny General Hospital, West Penn Allegheny Health System

Printer Friendly PDF

raymond benzaPulmonary arterial hypertension (PAH), is characterised by proliferative and fibrotic changes in the small pulmonary arteries, leading to increased pressure, vessel obstruction, right-sided ventricular failure, and death.1 Despite recent progress in the treatment of PAH, patient outcomes remain poor.2 Consequently, improvements in the diagnosis and management of patients with PAH are essential. Interestingly, subtypes of PAH share a similar underlying pathology, suggesting that parameters capable of measuring disease progression might be applicable across PAH subgroups, allowing the development of comprehensive therapeutic tools. Documentation of clinical changes and outcomes associated with PAH permits the development of models that predict disease progression and survival.

The ability to identify and evaluate factors that affect survival in patients with PAH remains of critical interest to clinicians because it facilitates clinical care and directs research. Simply put, the ability to predict a patient's morbidity or imminent mortality prompts the clinician to escalate therapy, or refer for transplant and forewarns the patients and his/her family. Although shown to be a powerful tool for improving our understanding of PAH, interpretations of data from the NIH registry, developed over 30 years ago, have become limited by the era in which these data were collected and prior to the availability of approved pulmonary vascular-targeted therapies. Thus, the survival equation derived from NIH registry data is only applicable to patients who have not yet received treatment. In addition, due to changes in PAH classification since the NIH registry, the NIH prognostic equation4 may not be applicable to the present classification of group 1 PH as a whole5 and may not accurately reflect current survival rates.2 Thus, the PAH community has sought to improve epidemiologic data with newer registries, with the aim of producing a prognostic equation that can be used in all patients with PAH at any time during their disease history.

Among a number of important national PAH registries6-12, four modern registries acquiring data on the management and treatment of patients with PAH have evaluated and developed improved prognostic equations10,13-16 as suggested by the original NIH data.3 The largest of these modern registries is the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL).12 Analysis of outcome data in REVEAL identified nineteen independent predictors of survival, which were and used to generate a prognostic equation based on the Cox proportional hazard multivariable analysis.13 This equation was then validated and a simplified calculator developed for everyday clinical use (Figure 1).14 The importance of this calculator is that it is applicable to all forms of PAH and can be used serially to predict on-going survival. july linksChanges in parameters, scores and risk profiles using this calculator also have prognostic importance and were featured presentations at the ISHLT's annual meetings for the last 3 years. In this year's scientific sessions the group from UCSF presented data suggesting this equation and calculator can be utilized with excellent discriminatory ability in other forms of PH and thus may serve as a global predictive equation for most forms of pulmonary hypertension. Importantly, those PH patients with Risk Scores ≥10 identifies a subgroup in eminent danger of early death and therefore prime candidates for consideration of lung or combined heart-lung transplantation. Interestingly the REVEAL predictive elements have also been utilized by the United Network for Organ Sharing (UNOS) to reevaluate the lung allocation score (LAS), as it pertains to those PH patients listed for transplant.

It is known that the formula for calculating the LAS, which is used in all diagnoses (COPD, IPF, IPAH, etc) places PH patients at a disadvantage. To address this, UNOS currently employs an expedited appeals process so that patients who meet certain criteria will be moved to the 90th percentile on the list. To meet these criteria, patients must be deteriorating on optimal medical therapy and have a right atrial pressure greater than 15mmHg or a cardiac index less than 1.8 L/min/m2. These factors are reflective of the stability of the right ventricle, which is ultimately tied to prognosis in all PAH patients. Due to the potential for these appeals, it is important for patients to follow up routinely pre-transplant.

Data from REVEAL showed that additional factors, if incorporated into the LAS calculation, would more accurately predict survival and thereby better reflect organ prioritization in patients with PH.17 These additional factors included estimates of right ventricular function, which as stated earlier, are key in determining survival in PH. The LAS in its current construct, weigh factors reflective of "pure lung dysfunction," like FEV1 (a measure of airway capacity) more heavily since these predict survival better for patients with "lung diseases" like COPD. Although PH does occur in the lung and is hence considered a 'lung disease,' these parameters are not useful in predicting survival in PH. This is why it was imperative to have these new "heart-related" parameters added to the LAS. This is currently under review by UNOS, and a revised formula incorporating these changes went out for public vote in April of 2012.

Disclosure Statement: Raymond L Benza has received grant support from Actelion, Bayer, GeNO, Ikaria, Gilead, Lung Rx, Novartis and United Therapeutics. He is on steering committes for Actelion, Ikaria and Bayer. He is on advisory boards for Bayer, Novartis, Gilead, and United Therapeutics.


  1. Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the 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 the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493-2537.
  2. Benza RL, Miller DP, Barst RJ, et al. An Evaluation of Long-Term Survival From Time of Diagnosis in Pulmonary Arterial Hypertension From REVEAL. Chest. 2012 Jan 26
  3. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107: 216-223.
  4. 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.
  5. Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54: S43-54.
  6. Jing ZC, Xu XQ, Han ZY, et al. Registry and survival study in chinese patients with idiopathic and familial pulmonary arterial hypertension. Chest 2007; 132: 373-379.
  7. Fasnacht MS, Tolsa JF, Beghetti M. The Swiss registry for pulmonary arterial hypertension: the paediatric experience. Swiss Med Wkly 2007; 137: 510-513.
  8. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006; 173: 1023-1030.
  9. Thenappan T, Shah SJ, Rich S, et al. A USA-based registry for pulmonary arterial hypertension: 1982-2006. Eur Respir J 2007; 30: 1103-1110.10.
  10. Kane GC, Maradit-Kremers H, Slusser JP, et al. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest 2011; 139: 1285-1293.
  11. Peacock AJ, Murphy NF, McMurray JJ, et al. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007; 30: 104-109.
  12. McGoon MD, Krichman A, Farber HW, et al. Design of the REVEAL registry for US patients with pulmonary arterial hypertension. Mayo Clin Proc 2008; 83: 923-931.
  13. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122: 164-172.
  14. Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012 Feb;141(2):354-62. Epub 2011 Jun 16
  15. 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 Jul 13;122(2):156-63.
  16. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010; 35: 1079-1087.
  17. Benza RL, Miller DP, Frost A, et al. Analysis of the lung allocation score estimation of risk of death in patients with pulmonary arterial hypertension using data from the REVEAL Registry. Transplantation. 2010 Aug 15;90(3):298-305.

Figure 1 reproduced with permission from the American College of Chest Physicians. Original work citation: Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012 Feb;141(2):354-62. Epub 2011 Jun 16.