Regular Risk Assessment in Pulmonary Arterial Hypertension - A Whistleblower for Hidden Disease Progression.

Acta Cardiol Sin 2022;38:113-123 Review Article doi: 10.6515/ACS.202203_38(2).20211005A Regular Risk Assessment in Pulmonary Arterial Hypertension – A Whistleblower for Hidden Disease Progression Shu-Hao Wu1,2 and Yih-Jer Wu1,2 Despite developments in the treatment of pulmonary arterial hypertension, timely treatment is seldom achieved, and hidden progression is not uncommonly disguised as a seemingly “stable” condition. Appropriate risk assessment tools facilitate goal-oriented treatment strategies. This article aimed to review the development of these risk assessment tools including early assessment equations/scores, European guidelines-based risk assessment scores, and tools derived from the United States nationwide registry. A stepwise and regular approach with these assessment tools in clinical practice is highly recommended for timely treatment escalation to stop disease progression early. In this review, a practical and recommended algorithm of these assessment tools is also provided. Key Words: Guidelines · Pulmonary arterial hypertension · REVEAL · Risk assessment INTRODUCTION sticking to goal-oriented treatment can avoid disease progression and provide better long-term outcomes.1,3 Precise risk assessment is, therefore, highly recommended in current guidelines.4,5 However, there are several currently available assessment tools, and each has distinct strengths and weaknesses. In this study, we review these tools and attempt to re-organize them into a practical algorithm for better clinical use. Despite rapid advances in the medical therapy of pulmonary hypertension (PH), insufficient initial treatment or delayed medical adjustments are still frequently reported. It is not uncommon for pulmonary arterial hypertension (PAH) to progress without presenting with an obvious worsening of symptoms or single risk parameters. Consistent with this situation, about 40% of PAH patients with only monotherapy at three years of follow-up need further adjuvant therapy.1 More than 50% of PAH patients die without receiving intravenous prostacyclin, and 67% of patients who deteriorate to World Health Organization (WHO) functional class (FC) IV do not receive timely treatment escalation.2 A strategy of periodically performing risk assessment followed by RISK ASSESSMENT TOOLS Early risk equations and scores Several equations and scores have been developed for risk assessment since the 1990s (Table 1). However, with advances in treatment concepts, some tools may already be out of date. Each of these early tools should be applied with caution according to their original study design. Received: June 13, 2021 Accepted: October 5, 2021 1 Cardiovascular Center, Department of Internal Medicine, MacKay Memorial Hospital, Taipei; 2Department of Medicine, and Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan. Corresponding author: Dr. Yih-Jer Wu, Department of Medicine, MacKay Medical College, No. 46, Sec 3, Zhongzhen Road, Sanzhi Dist., New Taipei City, Taiwan. E-mail: National Institutes of Health (NIH) survival equation in primary PH The first prognostic equation was developed in 1991 by the National Heart, Lung, and Blood Institute of the 113 Acta Cardiol Sin 2022;38:113-123 Shu-Hao Wu et al. Table 1. Early risk equations and score Population Groups Patients Diagnosis to enrollment PAH drugs Assessment time Tool Predict survival at Variables Mean PAP RAP CI CO Sex 6MWD Age Etiology NIH6 PHC 9 Primary PH I/H/D I/H/D Incident (64%) Prevalent (36%) Median 19.2 m Unavailable Baseline Equation Following years Incident Prevalent Unavailable Excluded Baseline Equation Following years Incident (29%) Prevalent (71%) Median 12-24 m Allowed Baseline Equation 6 months to 3 years V V V V V V French equation 11 13 SCS I/H/D CTD/PoPH/HIV PVOD Incident Allowed Baseline Score 1, 2 years V V V V V V V V V CI, cardiac index; CO, cardiac output; CTD, connective-tissue disease-associated PAH; D, drug- and toxin-induced; PAH: H, heritable PAH; HIV, human immunodeficiency virus; I, idiopathic PAH; m, months; Mean PAP, mean pulmonary artery pressure; NIH, National Institutes of Health; PH, pulmonary hypertension; PHC, pulmonary hypertension connection; PoPH, portopulmonary hypertension; PVOD, pulmonary veno-occlusive disease; RAP, right atrial pressure; SCS, Scottish composite Score; 6MWD, 6-minute walk distance. NIH. 6 Patients were defined as incident if they were newly diagnosed, and as prevalent if the diagnosis of PH was previously known. Both incident and prevalent patients with primary PH were enrolled for further assessment. Risk evaluation was conducted at the time of diagnosis. After statistical analysis, mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI) were reported to be the main variables related to mortality. A regression equation was developed to predict the probability of survival. Although this equation was reported to have high sensitivity and low specificity in a Mexican population initially,7 a subsequent study reported opposite results.8 In addition, little PAH-targeted treatment was available at that time leading to poorer survival, which limits the application of this equation in the current era. anorexigen-associated PAH. Age, FC, RAP, and CI were reported to be important predictors of mortality after multivariable analysis, but the PHC equation derived from exponential regression analysis still only comprised mPAP, RAP, and CI. Unlike the NIH survival equation,6 patients with different responses to calcium channel blockers have been shown to correspond with different PHC equations, and better accuracy of survival prediction has been demonstrated with the PHC equation. Although the PHC equation was derived from patients not receiving targeted drugs, this equation was validated in two other cohorts receiving PAH-targeted therapies, providing evidence of the application in populations receiving targeted therapy. Subgroup analysis revealed significantly better survival in patients diagnosed after 2002, suggesting that evolving treatment may have improved the survival rate. Pulmonary hypertension connection (PHC) equation To update the NIH survival equation,6 the PHC equation was developed from a subgroup of the PHC registry,9 which included patients with idiopathic, familial, and Acta Cardiol Sin 2022;38:113-123 French equation The French equation10,11 was derived from patients with similar etiologies of PAH as the PHC equation,9 but 114 Risk Assessment Tools in PAH different variables were used in these two registry risk equations. The French equation is comprised of sex, 6minute walk distance (6MWD), and cardiac output (CO), which focuses on the importance of non-hemodynamic parameters. In addition, concerns over survival bias were raised. For example, prevalent patients will by nature have a better survival than incident patients because patients with worse conditions (...truncated)