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Managing Pulmonary Arterial Hypertension and Optimizing Treatment Options: Prognosis of Pulmonary Artery Hypertension
Managing Pulmonary Arterial Hypertension and Optimizing Treatment Options: Prognosis of Pulmonary Artery Hypertension Vallerie McLaughlin, MD, FACC, FAHA, FCCP* Survival in patients with pulmonary artery hypertension has improved, but outcomes are still suboptimal. Therapeutic focus must shift from short-term functional changes to improvements in long-term outcomes. Several outcome predictors, both at baseline and on therapy, offer guidance for clinicians treating pulmonary artery hypertension. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;111[suppl]:10Ce15C) This article discusses the prognosis for pulmonary artery hypertension, and the following outcome predictors in particular are considered. Functional class (FC): this is a prognostic variable both at baseline and on treatment, with a better prognosis for baseline FC III or IV improving to FC I or II on therapy than vice versa. Exercise capacity: absolute capacity may be more important to prognosis than change in 6-minute walk distance (6MWD) with therapy, and maximum oxygen consumption independently predicts survival. Hemodynamics: right atrial pressure and cardiac output are the most important prognostic hemodynamic parameters at baseline. On therapy, right ventricular function hemodynamics correlate most consistently with survival. Imaging: on echocardiography, any pericardial effusion predicts mortality. Change in right ventricular ejection fraction on magnetic resonance imaging may predict outcome better than pulmonary vascular resistance. Biomarkers: both atrial natriuretic peptide and brain natriuretic peptide (BNP) have been shown to correlate with survival. Elevated troponin also predicts adverse outcomes. Etiology: compared with idiopathic pulmonary artery hypertension (PAH), scleroderma-related PAH, portal hypertension with connective tissue disease, and familial PAH have a poorer prognosis, whereas survival with HIV-associated PAH is similar to that of idiopathic PAH. Therapeutic goals: World Health Organization functional I or II symptoms, 6MWD >380 to 440 m, cardiac index 2.5 L/min/m2, normal or near normal right ventricular function on echocardiogram or magnetic resonance imaging, and normal/near normal BNP or N-terminal proBNP. On follow-up, World Health Organization FC I or II without detectable signs of right heart failure.
Professor, Internal Medicine, Director, Pulmonary Hypertension Program, University of Michigan Cardiovascular Center, Ann Arbor, MI. Publication of this supplement was supported by an educational grant from Gilead Sciences, Inc. Successful Completion: To access your CME certificate, you must complete the post-test with a score of 70% or higher and complete the evaluation. To take the post-test for this article you will need to visit http://www.cmeuniversity.com. Complete the registration form to begin the testing process. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Vallerie McLaughlin, MD, FACC, FAHA, FCCP, University of Michigan Cardiovascular Center, Department of Internal Medicine, 1500 East Medical Center Drive, Ann Arbor, Michigan. E-mail address: [email protected] (V. McLaughlin). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.01.319
As the field of pulmonary arterial hypertension (PAH) matures, it is time we shifted our focus from short-term functional changes to improvements in long-term outcomes. Lessons from the past 2 decades provide the basis to target our current therapies to achieve important treatment goals in the hope of improving long-term survival. Review of Prognosis of PAH The natural history of PAH was well described by the National Institutes of Health (NIH) Registry, which enrolled 194 patients at 32 clinical centers from 1981 through 1985, before the availability of any disease-specific therapy.1 The patients’ mean age was 36.4 years, with a female-to-male ratio of 1.7:1. Twenty-nine percent of patients had mild symptoms and were classified as functional class (FC) II. At entry, the mean pulmonary artery pressure was 60 18 mm Hg, the right atrial pressure was 9 6 mm Hg, and the cardiac index was 2.27 0.9 L/min/m2. The median survival was 2.8 years with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34% respectively.2 Advanced FC and hemodynamic parameters, including elevated mean right atrial pressure, decreased cardiac index, and elevated mean pulmonary arterial pressure, were associated with a poor prognosis. More recently, 2 large registries have shed light on the prognosis of patients with PAH. The French Registry recently characterized survival and important prognostic indicators in patients with PAH. This registry demonstrated that the survival of patients with PAH has improved compared with the predicted survival based on the NIH Registry, although it still remains suboptimal with 1-, 2-, and 3-year survival of 85.7%, 69.5%, and 54.9% for incident cases.3 Important predictors of survival included gender, FC, exercise tolerance as measured by the 6-minute walk distance (6MWD), and hemodynamics, specifically right atrial pressure and cardiac output. Similarly, in a large US-based registry, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) registry, important prognostic variables were described.4 Key predictors of outcome in this study included etiology of PAH, FC, gender, exercise tolerance, and hemodynamics that reflect right ventricular (RV) function. Baseline Predictors of Outcome Functional class: FC is also routinely used to assess PAH disease severity and prognosis. In the NIH registry, patients with New York Heart Association (NYHA)-FC III www.ajconline.org
Continuing Medical Education/Prognosis of PAH
or IV were at increased risk of death. Median survival time for FC I or II, III, and IV was 6 years, 2.5 years, and 6 months, respectively.2 Even with current therapy, baseline functional class is highly predictive of outcomes. Baseline functional assessment was shown to be highly predictive of outcome among patients treated with long-term epoprostenol in 2 retrospective studies. Among 162 patients with idiopathic PAH (IPAH) who were treated with epoprostenol, survival after 3 and 5 years was 81% and 70%, respectively, for those in NYHA-FC III at presentation, whereas for patients who were in FC IV at baseline, the survival at the same time points were 47% and 27%.5 This observation was corroborated in another retrospective study of 178 patients treated with epoprostenol. The 1- and 3-year survival differed significantly among patients who were in FC III versus IV at presentation (90% and 71% vs 76% and 47%, respectively).6 Both the recent French and REVEAL registries have confirmed the importance of FC as a prognostic variable at baseline and on treatment.3,4 This highlights the importance of screening and timely diagnosis. Exercise capacity: Exercise capacity as measured by both the 6MWD and cardiopulmonary exercise testing (CPET) is a major determinant of PAH disease severity and prognosis. The 6MWD is advantageous because it is simple, inexpensive, and reproducible; furthermore, patients with severe disease are frequently incapable of vigorous exercise, and the 6MWD is a submaximal marker of exercise performance in which even patients with advanced PAH can participate. Both the French and REVEAL registries also demonstrated the prognostic importance of 6MWD.3,4 Interestingly, absolute 6MWD may be more important in prognosis than the change in 6MWD with therapy. In an analysis of 178 FC III and IV patients treated with epoprostenol, those who walked above the mean of 380 meters on therapy had a better prognosis than those who walked below the mean.6 However, a change in 6MWD of >112 meters vs <112 meters did not predict outcome. The 6MWD has been used in a number of important studies as the primary outcome measure and/or the primary end point. CPET is used less frequently in PAH because of inconsistencies in methodologies among treatment centers. Nevertheless, maximum oxygen consumption has been found to be an independent predictor of survival. Hemodynamics: Hemodynamic parameters have a strong influence on survival, and those that reflect RV function are the most important. In the NIH registry, 3 variables were associated with an increased mortality risk by univariate analysis: increased mean pulmonary artery pressure (mPAP; odds ratio [OR] 1.16, 95% confidence interval [95% CI] 1.05e1.28), increased mean right atrial pressure (mRAP; OR 1.99; 95% CI 1.47e2.69), and decreased cardiac index (OR 0.62, 95% CI 0.46e0.82).2 These variables were also predictive in multivariate analysis and incorporated into a regression equation to estimate survival. Similarly, in both the French and REVEAL registries, the hemodynamics that were most important prognostically were right atrial pressure and cardiac output.3,4 Additional variables, such as a decreased mixed venous oxygen saturation (MVO2) and increased heart rate have also been shown to predict
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mortality.7 Although mRAP, CI, and mPAP all predict survival, several exceptions to this rule merit consideration. First, as PAH progresses and the right ventricle (RV) fails, mPAP declines; therefore, survival estimates for individual patients frequently rely on mRAP and cardiac index. Another consideration is that the prognostic value of hemodynamics may be affected by epoprostenol. In an analysis of patients on epoprostenol, a lower mPAP and higher mRAP increased mortality risk on univariate analysis and mRAP only on multivariate analysis.6 In another study, only the mRAP was predictive of survival.5 In addition to specific hemodynamic parameters, the vasodilator response during right heart catheterization is also predictive of outcome because responders have an excellent prognosis, with up to a 95% 5-year survival rate.8 RV function by imaging techniques (Echocardiography/ Magnetic Resonance Imaging): Echocardiography plays a major role in screening for PAH, but evidence for the prognostic value of specific parameters is based on relatively small data series. The presence of a pericardial effusion to any extent has consistently been shown to predict mortality, and larger effusions are directly correlated to right atrial dilatation and inversely correlated to exercise performance.4,9 In addition, the Tei index, or Doppler echocardiographic index (an index of the combined RV systolic and diastolic function obtained by dividing the sum of both isovolumetric contraction and relaxation intervals by the ejection time) may predict adverse outcomes. Cardiac magnetic resonance imaging (MRI) also provides an excellent assessment of RV function. In response to chronic pulmonary hypertension, the RV dilates with reducing function and stroke volume. The interventricular septum bows in to the left ventricle in diastole and systole. Commensurate with this, a RV end-diastolic volume index <84 ml/m2, left ventricular end-diastolic volume index >40 ml/m2, and stroke volume index >25 ml/m2 are associated with better survival in patients with IPAH.10 RV ejection fraction of <35% by MRI is also predictive of mortality.11 Biomarkers: Data are emerging about the clinical utility of natriuretic peptides in the assessment of PAH. Both atrial natriuretic peptide and brain natriuretic peptide (BNP) have been shown to correlate with survival. Nagaya et al showed that baseline BNP was an independent predictor of mortality; patients with BNP levels 150 pg/ml had significantly lower survival rates than those with lower BNP; furthermore, an on-treatment BNP obtained 90 days after therapy initiation was also predictive of outcomes.12 In addition, Park et al found that a BNP reduction of 50% 3 months after initiation of epoprostenol was predictive of event-free survival.13 N-terminal proBNP has also been shown to correlate with 6MWD, cardiac index, pulmonary vascular resistance, and right atrial pressure 123.14 Increased uric acid levels, which are thought to reflect poor oxidative metabolism, are inversely correlated with FC and hemodynamics and also predict survival. Finally, elevated troponin is also predictive of adverse outcomes, potentially as a result of the negative effects of RV ischemia in PAH. In a series of 56 patients, positive serum troponin T was associated with an increased hazard ratio for mortality, including a multivariate Cox analysis
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(hazard ratio 4.89; 95% CI: 1.18e20.39; P ¼ 0.03) of 6MWD and pulmonary vascular resistance.15 Forfia et al showed that hyponatremia (serum sodium 136 mEq/L) is strongly associated with right heart failure and poor survival in PAH and suggested that hyponatremia in PAH results from neurohormonal activation in response to advanced RV dysfunction.16 Similarly, serum sodium at time of admission has been shown to correlate with survival in PAH patients suffering from acute right heart failure.17 Demographics: Etiology of disease has a major influence on survival.18 Patients with PAH related to a connective tissue disease clearly have a worse prognosis than those with IPAH, a disadvantage that may persist despite epoprostenol therapy. In an observational study of patients with PAH who were treated with epoprostenol therapy, those with scleroderma had a higher mortality rate. However, there is evidence that in the current treatment era, the prognosis of PAH in scleroderma is improving: Williams et al compared 47 patients treated with bosentan to a historical controls and found a significantly greater survival in those on bosentan.19 Patients with HIV-associated PAH appear to have a similar survival course as those with IPAH; in this population, the cause of death is usually related to PAH complications. Congenital heart diseaseeassociated PAH portends a better prognosis than IPAH, with patients surviving well into the third or fourth decade if managed appropriately. On the basis of observational data, survival estimates at 30, 40, and 55 years of age are 75%, 70%, and 55%, respectively.20 The reason for the higher survival rate is not fully understood. Several factors are thought to contribute, including (1) younger patient age, (2) the RV in congenital heart disease is exposed to higher pressures early and has better adaptive properties, and (3) an associated shunt allows for increased cardiac output during exercise, albeit at the expense of cyanosis. More recently, Dimopoulos et al described better outcomes of complex congenital heart disease patients treated with advanced PAH therapies compared with those who were not.21 In the REVEAL registry, patients with portal hypertension and connective tissue disease had a worse prognosis, as did those with familial PAH.4 The prognostic implications of demographic variables are inconsistent.18 In the NIH registry, age, time from onset of symptoms to diagnosis, and gender were not predictive of survival. Both the French and REVEAL registries suggested that men had worse outcomes than women.3,4 On-Therapy Predicators of Outcome Functional class: Even with therapy, FC remains a powerful predictor of outcome. FC assessments made during the initial follow-up period on chronic intravenous epoprostenol therapy were shown to correlate significantly with long-term outcome. Patients who were reported to be NYHA-FC I or II by first follow-up period (17 15 months) had 3- and 5-year survival rates of 89% and 73%, respectively, compared with 62% and 35% for patients who were FC III.5 Patients who were FC IV at the same time period suffered the worst outcome, with 42% survival at 2 years and 0% at 3 years. A comparable observation was reported in a similar cohort, in that patients who were in FC I or II after 3 months of epoprostenol therapy demonstrated markedly
improved survival over those who were in FC III or IV (1- and 3-year survivals 100% and 88% vs 77% and 33%, respectively).6 A more recent analysis of 109 patients with IPAH followed for a median of 38 months reinforced this observation.22 Patients underwent hemodynamic, functional, and biochemical assessments at baseline and 3 to 12 months after initiation of PAH-specific therapy. Although baseline FC was predictive of outcome, those who were FC III or IV at baseline but whose FC improved to I or II on therapy had a much better prognosis than those who remained FC III or IV, and even those who were FC I or II at baseline but deteriorated to FC III or IV at follow-up assessment. Exercise capacity: As discussed earlier in the article, modest changes in 6MWD in clinical trials correlate poorly with long-term outcomes. Perhaps the absolute value reached is more prognostic than the change on therapy. Sitbon and colleagues report among patients treated with epoprostenol, the 6MWD performed after 3 months of therapy correlated with long-term survival; specifically, patients who walked 380 meters demonstrated a significantly better outcome than the cohorts who did not. Interestingly, analyzing outcome based on the absolute increase in the distance walked from baseline on treatment showed no correlation.6 In the REVEAL registry, achieving a 6MWD of greater than 440 meters was predictive of survival.4 Hemodynamics: On therapy, hemodynamics that correlate most consistently with survival include those that reflect RV function. In the 2 large series of epoprostenol-treated patients, RAP and cardiac index predicted survival, but mPAP did not.5,6 In Nickel’s series of 109 PAH patients, baseline cardiac index was predictive of survival, but outcomes with changes in cardiac index were similar to those observed for functional class.22 Patients who started with a cardiac index <2.5 L/min/m2 that improved to normal did almost as well as those who started with and maintained a cardiac index >2.5 L/min/m2 and better than those who started with a normal cardiac index but deteriorated to <2.5 L/min/m2 during the observation period. RV function by imaging techniques (Echocardiography/ MRI): Using serial MRI assessments, van de Veerdonk and colleagues demonstrated that patients who show improvement in RV ejection fraction have a better survival than those who have a decline of RV ejection fraction.11 In fact, in this study, change in RV ejection fraction on MRI was a more powerful predictor of outcome than pulmonary vascular resistance. Biomarkers: In a series of 63 patients with IPAH during a mean follow-up period of 24 months that both baseline and on-therapy BNP levels correlated with hemodynamics and survival.23 Similarly, Parker et al found that a reduction in plasma BNP levels after 3 months of epoprostenol therapy correlated closely with changes in hemodynamics and was an independent predictor of survival.24 Rationale for Optimizing Risk Profile on Therapy Guidelines with specific recommendations on follow-up of PAH patients over time is lacking for several reasons: (1) the majority of randomized controlled trials to date have been short-term studies, primarily 12 to 16 weeks’ duration,
Continuing Medical Education/Prognosis of PAH
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Table 1 Longitudinal evaluation of the pulmonary arterial hypertension patient* Clinical Course
Stable (No Increase in Symptoms and/or Decompensation)
Physical examination Functional class 6MWD (meters) Echocardiogram Hemodynamics BNP Treatment
No evidence of right heart failure I/II >400 RV size/function normal RAP normal, CI normal Near normal/ remaining stable or decreasing Oral therapy
Frequency of evaluation FC Assessment 6MWD Echocardiogramx BNPk RHC
Every 3e6 mosz Every clinic visit Every clinic visit Yearly or center dependent Center dependent Clinical deterioration and center dependent
Unstable (Increase in Symptoms and/or Decompensation) FC III† 300e400
Signs of right heart failure IV <300 RV enlargement/dysfunction RAP high CI low Elevated/ increasing Intravenous prostacyclin and/or combination treatment Every 1e3 mos Every clinic visit Every clinic visit Every 6e12 mos or center dependent Center dependent Every 6e12 mos or clinical deterioration
CI ¼ cardiac index; RAP ¼ right atrial pressure; RHC ¼ right heart catheterization. * For patients in the high-risk category, consider referral to a pulmonary hypertension specialty center to consider advanced therapies, clinical trials, and/or lung transplantation. † The frequency of follow-up evaluation for patients in FC III and/or 6MWD from 300 to 400 meters would depend on composite of detailed assessments on other clinica and objective characteristics listed. z For patients who remain stable on established therapy, follow-up assessments can be performed by referring physician(s) or pulmonary hypertension specialty centers. x Echocardiographic measurement of PASP is estimation only; it is strongly advised not to rely on its evaluation as the sole parameter to make therapeutic decisions. k The utility of serial BNP levels to guide management in individual patients has not been established. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ; ACCF/AHA. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250–2294 and McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573e1619.27
(2) available long-term studies for the most part are singlecenter reports without a control arm, and (3) evolution of disease after treatment initiation is patient-specific, limiting the ability to make general predictions about response to therapy. In fact, 2 recent meta-analyses have raised questions about whether short-term changes in exercise tolerance during randomized controlled trials predict improvements in long-term outcomes. Savarese et al assessed 3,112 participants in 22 randomized clinical trials in PAH.25 They found that active treatment led to a significant reduction in allcause death, hospitalization for PAH and/or lung transplantation, initiation of PAH rescue therapy, and composite outcome. However, improvements in the primary end point of 6MWD over the short term did not correlate with these outcomes. In a similar analysis, Gabler et al assessed the correlation of 6MWD with clinical events in 10 randomized, placebo-controlled, short-term trials.26 The authors found that the change in 6MWD during the context of a short-term clinical trial had only modest validity as a surrogate end point for clinical events. These 2 studies highlight the caution that must be exercised when making long-term patient decisions based on short-term clinical trials.
For multiple practical reasons, follow-up assessment has never been standardized or incorporated into evidence based guidelines. However, consensus recommendations on reassessment are provided in the 2009 American College of Cardiology Foundation/American Heart Association Expert Consensus Document on Pulmonary Hypertension and rely on routine assessment of important prognostic indicators such as World Health Organization (WHO)-FC, 6MWD and echocardiographic and hemodynamic parameters (Table 1).27 Patients who achieve WHO functional class I or II with a 6MWD >400 meters, with normal RV function on echocardiogram and normal hemodynamic parameters, can be followed on a 3- to 6-month basis by either the referring physician or a pulmonary hypertension specialty center. Highrisk patients who remain WHO-FC III or IV with a 6MWD <300 meters and who have imaging evidence of V dysfunction and abnormal hemodynamics should be followed at 1- to 3-month intervals. Every assessment should include reevaluation of the WHO FC and 6MWD, with an echocardiogram performed approximately every 12 months or every 6 to 12 months, depending on the clinical course. For stable patients, right heart catheterization should be obtained if there are signs
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of clinical worsening; for unstable patients, hemodynamics should be obtained more frequently. Two general strategies exist to guide physicians in following patients over time: a clinical strategy and a goaloriented strategy.28 Clinical strategy: This protocol relies primarily on assessment of the patients’ symptoms with an emphasis on functional status. Therapeutic interventions may be considered effective when, on follow-up assessment, WHO FC is either I or II and there are no detectable signs of right heart failure. Additional assessment through noninvasive means, such as echocardiogram, may also be used. In cases of clinical stability, current treatment can be maintained with no changes, and patients can be monitored on a 3- to 6month basis. Goal-oriented strategy: This protocol relies on improving clinical markers that have prognostic significance and systematically escalating treatment until a specific goal is attained. This requires that certain parameters be identified early and followed over time and that a threshold value for each parameter be defined before starting therapy. For example, Hoeper et al assessed patients by 6MWD or CPET with a goal 6MWD >380 meters, peak oxygen consumption >10.4 ml/min/kg, and peak systolic blood pressure >120 mm Hg during exercise; patients were followed at 3- to 6month intervals, and treatment was escalated over time to achieve these parameters, using triple therapy if necessary.29 This strategy was associated with a 1-, 2-, and 3-year survival of 93.0%, 83.1%, and 79.9%, respectively, which was significantly better than a historical control group. The practice of using multidrug regimens for patients with PAH who have refractory symptoms and who do not achieve prespecified treatment goals is an area of active research. What Are the Goals of Therapy Today? Although the primarily observational studies discussed here do not allow for definitive conclusions, reasonable goals of therapy include the following: 1) 2) 3) 4)
WHO-FC I or II symptoms 6MWD >380 to 440 meters Cardiac index 2.5 L/min/m2 Normal or near normal RV function on imaging (echocardiography, MRI) 5) Normal, or near normal, BNP or N-terminal proBNP
Patients who achieve these goals, no matter which specific therapy or approached is used, seem to have a better prognosis than those who do not. A more aggressive approach to goal-oriented therapy may help us shift the survival curves further to the right. Despite the many observations that support attainment of such goals, many patients followed today fall far short of these targets. For example, approximately 60% of FC III patients and 50% of FC IV patients in the REVEAL registry are not being treated with a prostacyclin, despite their not being at the goal FC of I or II.30 Both patient and physician reluctance to proceed to the most aggressive therapy are contributing factors. In summary, survival in PAH has improved over the recent years, but outcomes are still suboptimal. Reasonable
therapeutic goals that primarily reflect right ventricular function have been established. Achieving such goals with optimal application of our current therapies, and further development of novel therapies may improve long-term outcomes in patients with this previously fatal disease. Acknowledgement Publication of this supplement was supported by an educational grant from Gilead Sciences, Inc. Author Disclosures Vallerie McLaughlin, MD, FACC, FAHA, FCCP receives consulting fees and fees for non-Continuing Medical Education services from Actelion, Gilead, United Therapeutics. V.M. performs contracted research for Actelion, Bayer, Novartis. 1. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216e223. 2. 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;115:343e349. 3. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156e163. 4. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164e172. 5. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477e1482. 6. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780e788. 7. Sandoval J, Baurle O, Palomar A, Martinez-Guerra ML, Beltran M, Guerrero L. Survival in primary pulmonary hypertension: validation of a prognostic equation. Circulation 1994;89:1733e1744. 8. Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Hervé P, Simonneau G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105e3111. 9. Eysmann SB, Palevsky HI, Reichek N, Hackney K, Douglas PS. Twodimensional and Doppler echocardiography and cardiac catheterisation correlates of survival in primary pulmonary hypertension. Circulation 1989;80:353e360. 10. van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg MD, Postmus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007;28: 1250e1257. 11. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011;58:2511e2519. 12. Nagaya N, Nishikimi T, Okano Y. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202e208.
Continuing Medical Education/Prognosis of PAH 13. Park MH, Scott RL, Uber PA, Ventura HO, Mehra MR. Usefulness of B-type natriuertic peptide as a predictor of treatment outcome in pulmonary arterial hypertension. Congest Heart Fail 2004;10: 221e225. 14. Fijalkowska A, Kurzyna M, Torbicki A, Szewczyk G, Florczyk M, Pruszczyk P, Szturmowicz M. Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension. Chest 2006;129:1313e1321. 15. Torbicki A, Kurzyna M, Kuca P, Fijałkowska A, Sikora J, Florczyk M, Pruszczyk P, Burakowski J, Wawrzynska L. Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 2003;108:844e848. 16. Forfia PR, Mathai SC, Fisher MR, Housten-Harris T, Hemnes AR, Champion HC, Girgis RE, Hassoun PM. Hyponatremia predicts right heart failure and poor survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;177:1364e1369. 17. Sztrymf B, Souza R, Bertoletti L, Jaïs X, Sitbon O, Price LC, Simonneau G, Humbert M. Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension. Eur Respir J 2010;35: 1286e1293. 18. McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G; American College of Chest Physicians. Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004;126:78Se92S. 19. Williams MH, Das C, Handler CE, Akram MR, Davar J, Denton CP, Smith CJ, Black CM, Coghlan JG. Systemic sclerosis associated pulmonary hypertension: improved survival in the current era. Heart 2006;92:926e932. 20. Cantor WJ, Harrison DA, Moussadji JS, Connelly MS, Webb GD, Liu P, McLaughlin PR, Siu SC. Determinants of survival and length of survival in adults with Eisenmenger syndrome. Am J Cardiol 1999;84: 677e681. 21. Dimopoulos K, Inuzuka R, Goletto S, Giannakoulas G, Swan L, Wort SJ, Gatzoulis MA. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010;121:20e25. 22. Nickel N, Golpon H, Greer M, Knudsen L, Olsson K, Westerkamp V, Welte T, Hoeper MM. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012;39:589e596.
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23. Nagaya N, Nishikimi T, Uematsu M, Satoh T, Kyotani S, Sakamaki F, Kakishita M, Fukushima K, Okano Y, Nakanishi N, Miyatake K, Kangawa K. Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000;102:865e870. 24. Parker KM, Houston Miller N, DeBusk RF. Optimal use of spironolactone for treatment of heart failure. Congest Heart Fail 2001;7: 315e318. 25. Savarese G, Paolillo S, Costanzo P, D’Amore C, Cecere M, Losco T, Musella F, Gargiulo P, Marciano C, Perrone-Filardi P. Do changes of 6-minute walk distance predict clinical events in patients with pulmonary arterial hypertension?: a meta-analysis of 22 randomized trials. J Am Coll Cardiol 2012;60:1192e1201. 26. Gabler NB, French B, Strom BL, Palevsky HI, Taichman DB, Kawut SM, Halpern SD. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012;126:349e356. 27. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573e1619. 28. Badesch DB, Champion HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, McGoon M, Naeije R, Olschewski H, Oudiz RJ, Torbicki A. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54:S55eS66. 29. Hoeper MM, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858e863. 30. Badesch DB, Raskob GE, Elliott CG, Krichman AM, Farber HW, Frost AE, Barst RJ, Benza RL, Liou TG, Turner M, Giles S, Feldkircher K, Miller DP, McGoon MD. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest 2010;137:376e387.
Professor, Internal Medicine, Director, Pulmonary Hypertension Program, University of Michigan Cardiovascular Center, Ann Arbor, MI. Publication of this supplement was supported by an educational grant from Gilead Sciences, Inc. Successful Completion: To access your CME certificate, you must complete the post-test with a score of 70% or higher and complete the evaluation. To take the post-test for this article you will need to visit http://www.cmeuniversity.com. Complete the registration form to begin the testing process. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Vallerie McLaughlin, MD, FACC, FAHA, FCCP, University of Michigan Cardiovascular Center, Department of Internal Medicine, 1500 East Medical Center Drive, Ann Arbor, Michigan. E-mail address: [email protected] (V. McLaughlin). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.01.319
As the field of pulmonary arterial hypertension (PAH) matures, it is time we shifted our focus from short-term functional changes to improvements in long-term outcomes. Lessons from the past 2 decades provide the basis to target our current therapies to achieve important treatment goals in the hope of improving long-term survival. Review of Prognosis of PAH The natural history of PAH was well described by the National Institutes of Health (NIH) Registry, which enrolled 194 patients at 32 clinical centers from 1981 through 1985, before the availability of any disease-specific therapy.1 The patients’ mean age was 36.4 years, with a female-to-male ratio of 1.7:1. Twenty-nine percent of patients had mild symptoms and were classified as functional class (FC) II. At entry, the mean pulmonary artery pressure was 60 18 mm Hg, the right atrial pressure was 9 6 mm Hg, and the cardiac index was 2.27 0.9 L/min/m2. The median survival was 2.8 years with 1-year, 3-year, and 5-year survival rates of 68%, 48%, and 34% respectively.2 Advanced FC and hemodynamic parameters, including elevated mean right atrial pressure, decreased cardiac index, and elevated mean pulmonary arterial pressure, were associated with a poor prognosis. More recently, 2 large registries have shed light on the prognosis of patients with PAH. The French Registry recently characterized survival and important prognostic indicators in patients with PAH. This registry demonstrated that the survival of patients with PAH has improved compared with the predicted survival based on the NIH Registry, although it still remains suboptimal with 1-, 2-, and 3-year survival of 85.7%, 69.5%, and 54.9% for incident cases.3 Important predictors of survival included gender, FC, exercise tolerance as measured by the 6-minute walk distance (6MWD), and hemodynamics, specifically right atrial pressure and cardiac output. Similarly, in a large US-based registry, the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) registry, important prognostic variables were described.4 Key predictors of outcome in this study included etiology of PAH, FC, gender, exercise tolerance, and hemodynamics that reflect right ventricular (RV) function. Baseline Predictors of Outcome Functional class: FC is also routinely used to assess PAH disease severity and prognosis. In the NIH registry, patients with New York Heart Association (NYHA)-FC III www.ajconline.org
Continuing Medical Education/Prognosis of PAH
or IV were at increased risk of death. Median survival time for FC I or II, III, and IV was 6 years, 2.5 years, and 6 months, respectively.2 Even with current therapy, baseline functional class is highly predictive of outcomes. Baseline functional assessment was shown to be highly predictive of outcome among patients treated with long-term epoprostenol in 2 retrospective studies. Among 162 patients with idiopathic PAH (IPAH) who were treated with epoprostenol, survival after 3 and 5 years was 81% and 70%, respectively, for those in NYHA-FC III at presentation, whereas for patients who were in FC IV at baseline, the survival at the same time points were 47% and 27%.5 This observation was corroborated in another retrospective study of 178 patients treated with epoprostenol. The 1- and 3-year survival differed significantly among patients who were in FC III versus IV at presentation (90% and 71% vs 76% and 47%, respectively).6 Both the recent French and REVEAL registries have confirmed the importance of FC as a prognostic variable at baseline and on treatment.3,4 This highlights the importance of screening and timely diagnosis. Exercise capacity: Exercise capacity as measured by both the 6MWD and cardiopulmonary exercise testing (CPET) is a major determinant of PAH disease severity and prognosis. The 6MWD is advantageous because it is simple, inexpensive, and reproducible; furthermore, patients with severe disease are frequently incapable of vigorous exercise, and the 6MWD is a submaximal marker of exercise performance in which even patients with advanced PAH can participate. Both the French and REVEAL registries also demonstrated the prognostic importance of 6MWD.3,4 Interestingly, absolute 6MWD may be more important in prognosis than the change in 6MWD with therapy. In an analysis of 178 FC III and IV patients treated with epoprostenol, those who walked above the mean of 380 meters on therapy had a better prognosis than those who walked below the mean.6 However, a change in 6MWD of >112 meters vs <112 meters did not predict outcome. The 6MWD has been used in a number of important studies as the primary outcome measure and/or the primary end point. CPET is used less frequently in PAH because of inconsistencies in methodologies among treatment centers. Nevertheless, maximum oxygen consumption has been found to be an independent predictor of survival. Hemodynamics: Hemodynamic parameters have a strong influence on survival, and those that reflect RV function are the most important. In the NIH registry, 3 variables were associated with an increased mortality risk by univariate analysis: increased mean pulmonary artery pressure (mPAP; odds ratio [OR] 1.16, 95% confidence interval [95% CI] 1.05e1.28), increased mean right atrial pressure (mRAP; OR 1.99; 95% CI 1.47e2.69), and decreased cardiac index (OR 0.62, 95% CI 0.46e0.82).2 These variables were also predictive in multivariate analysis and incorporated into a regression equation to estimate survival. Similarly, in both the French and REVEAL registries, the hemodynamics that were most important prognostically were right atrial pressure and cardiac output.3,4 Additional variables, such as a decreased mixed venous oxygen saturation (MVO2) and increased heart rate have also been shown to predict
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mortality.7 Although mRAP, CI, and mPAP all predict survival, several exceptions to this rule merit consideration. First, as PAH progresses and the right ventricle (RV) fails, mPAP declines; therefore, survival estimates for individual patients frequently rely on mRAP and cardiac index. Another consideration is that the prognostic value of hemodynamics may be affected by epoprostenol. In an analysis of patients on epoprostenol, a lower mPAP and higher mRAP increased mortality risk on univariate analysis and mRAP only on multivariate analysis.6 In another study, only the mRAP was predictive of survival.5 In addition to specific hemodynamic parameters, the vasodilator response during right heart catheterization is also predictive of outcome because responders have an excellent prognosis, with up to a 95% 5-year survival rate.8 RV function by imaging techniques (Echocardiography/ Magnetic Resonance Imaging): Echocardiography plays a major role in screening for PAH, but evidence for the prognostic value of specific parameters is based on relatively small data series. The presence of a pericardial effusion to any extent has consistently been shown to predict mortality, and larger effusions are directly correlated to right atrial dilatation and inversely correlated to exercise performance.4,9 In addition, the Tei index, or Doppler echocardiographic index (an index of the combined RV systolic and diastolic function obtained by dividing the sum of both isovolumetric contraction and relaxation intervals by the ejection time) may predict adverse outcomes. Cardiac magnetic resonance imaging (MRI) also provides an excellent assessment of RV function. In response to chronic pulmonary hypertension, the RV dilates with reducing function and stroke volume. The interventricular septum bows in to the left ventricle in diastole and systole. Commensurate with this, a RV end-diastolic volume index <84 ml/m2, left ventricular end-diastolic volume index >40 ml/m2, and stroke volume index >25 ml/m2 are associated with better survival in patients with IPAH.10 RV ejection fraction of <35% by MRI is also predictive of mortality.11 Biomarkers: Data are emerging about the clinical utility of natriuretic peptides in the assessment of PAH. Both atrial natriuretic peptide and brain natriuretic peptide (BNP) have been shown to correlate with survival. Nagaya et al showed that baseline BNP was an independent predictor of mortality; patients with BNP levels 150 pg/ml had significantly lower survival rates than those with lower BNP; furthermore, an on-treatment BNP obtained 90 days after therapy initiation was also predictive of outcomes.12 In addition, Park et al found that a BNP reduction of 50% 3 months after initiation of epoprostenol was predictive of event-free survival.13 N-terminal proBNP has also been shown to correlate with 6MWD, cardiac index, pulmonary vascular resistance, and right atrial pressure 123.14 Increased uric acid levels, which are thought to reflect poor oxidative metabolism, are inversely correlated with FC and hemodynamics and also predict survival. Finally, elevated troponin is also predictive of adverse outcomes, potentially as a result of the negative effects of RV ischemia in PAH. In a series of 56 patients, positive serum troponin T was associated with an increased hazard ratio for mortality, including a multivariate Cox analysis
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(hazard ratio 4.89; 95% CI: 1.18e20.39; P ¼ 0.03) of 6MWD and pulmonary vascular resistance.15 Forfia et al showed that hyponatremia (serum sodium 136 mEq/L) is strongly associated with right heart failure and poor survival in PAH and suggested that hyponatremia in PAH results from neurohormonal activation in response to advanced RV dysfunction.16 Similarly, serum sodium at time of admission has been shown to correlate with survival in PAH patients suffering from acute right heart failure.17 Demographics: Etiology of disease has a major influence on survival.18 Patients with PAH related to a connective tissue disease clearly have a worse prognosis than those with IPAH, a disadvantage that may persist despite epoprostenol therapy. In an observational study of patients with PAH who were treated with epoprostenol therapy, those with scleroderma had a higher mortality rate. However, there is evidence that in the current treatment era, the prognosis of PAH in scleroderma is improving: Williams et al compared 47 patients treated with bosentan to a historical controls and found a significantly greater survival in those on bosentan.19 Patients with HIV-associated PAH appear to have a similar survival course as those with IPAH; in this population, the cause of death is usually related to PAH complications. Congenital heart diseaseeassociated PAH portends a better prognosis than IPAH, with patients surviving well into the third or fourth decade if managed appropriately. On the basis of observational data, survival estimates at 30, 40, and 55 years of age are 75%, 70%, and 55%, respectively.20 The reason for the higher survival rate is not fully understood. Several factors are thought to contribute, including (1) younger patient age, (2) the RV in congenital heart disease is exposed to higher pressures early and has better adaptive properties, and (3) an associated shunt allows for increased cardiac output during exercise, albeit at the expense of cyanosis. More recently, Dimopoulos et al described better outcomes of complex congenital heart disease patients treated with advanced PAH therapies compared with those who were not.21 In the REVEAL registry, patients with portal hypertension and connective tissue disease had a worse prognosis, as did those with familial PAH.4 The prognostic implications of demographic variables are inconsistent.18 In the NIH registry, age, time from onset of symptoms to diagnosis, and gender were not predictive of survival. Both the French and REVEAL registries suggested that men had worse outcomes than women.3,4 On-Therapy Predicators of Outcome Functional class: Even with therapy, FC remains a powerful predictor of outcome. FC assessments made during the initial follow-up period on chronic intravenous epoprostenol therapy were shown to correlate significantly with long-term outcome. Patients who were reported to be NYHA-FC I or II by first follow-up period (17 15 months) had 3- and 5-year survival rates of 89% and 73%, respectively, compared with 62% and 35% for patients who were FC III.5 Patients who were FC IV at the same time period suffered the worst outcome, with 42% survival at 2 years and 0% at 3 years. A comparable observation was reported in a similar cohort, in that patients who were in FC I or II after 3 months of epoprostenol therapy demonstrated markedly
improved survival over those who were in FC III or IV (1- and 3-year survivals 100% and 88% vs 77% and 33%, respectively).6 A more recent analysis of 109 patients with IPAH followed for a median of 38 months reinforced this observation.22 Patients underwent hemodynamic, functional, and biochemical assessments at baseline and 3 to 12 months after initiation of PAH-specific therapy. Although baseline FC was predictive of outcome, those who were FC III or IV at baseline but whose FC improved to I or II on therapy had a much better prognosis than those who remained FC III or IV, and even those who were FC I or II at baseline but deteriorated to FC III or IV at follow-up assessment. Exercise capacity: As discussed earlier in the article, modest changes in 6MWD in clinical trials correlate poorly with long-term outcomes. Perhaps the absolute value reached is more prognostic than the change on therapy. Sitbon and colleagues report among patients treated with epoprostenol, the 6MWD performed after 3 months of therapy correlated with long-term survival; specifically, patients who walked 380 meters demonstrated a significantly better outcome than the cohorts who did not. Interestingly, analyzing outcome based on the absolute increase in the distance walked from baseline on treatment showed no correlation.6 In the REVEAL registry, achieving a 6MWD of greater than 440 meters was predictive of survival.4 Hemodynamics: On therapy, hemodynamics that correlate most consistently with survival include those that reflect RV function. In the 2 large series of epoprostenol-treated patients, RAP and cardiac index predicted survival, but mPAP did not.5,6 In Nickel’s series of 109 PAH patients, baseline cardiac index was predictive of survival, but outcomes with changes in cardiac index were similar to those observed for functional class.22 Patients who started with a cardiac index <2.5 L/min/m2 that improved to normal did almost as well as those who started with and maintained a cardiac index >2.5 L/min/m2 and better than those who started with a normal cardiac index but deteriorated to <2.5 L/min/m2 during the observation period. RV function by imaging techniques (Echocardiography/ MRI): Using serial MRI assessments, van de Veerdonk and colleagues demonstrated that patients who show improvement in RV ejection fraction have a better survival than those who have a decline of RV ejection fraction.11 In fact, in this study, change in RV ejection fraction on MRI was a more powerful predictor of outcome than pulmonary vascular resistance. Biomarkers: In a series of 63 patients with IPAH during a mean follow-up period of 24 months that both baseline and on-therapy BNP levels correlated with hemodynamics and survival.23 Similarly, Parker et al found that a reduction in plasma BNP levels after 3 months of epoprostenol therapy correlated closely with changes in hemodynamics and was an independent predictor of survival.24 Rationale for Optimizing Risk Profile on Therapy Guidelines with specific recommendations on follow-up of PAH patients over time is lacking for several reasons: (1) the majority of randomized controlled trials to date have been short-term studies, primarily 12 to 16 weeks’ duration,
Continuing Medical Education/Prognosis of PAH
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Table 1 Longitudinal evaluation of the pulmonary arterial hypertension patient* Clinical Course
Stable (No Increase in Symptoms and/or Decompensation)
Physical examination Functional class 6MWD (meters) Echocardiogram Hemodynamics BNP Treatment
No evidence of right heart failure I/II >400 RV size/function normal RAP normal, CI normal Near normal/ remaining stable or decreasing Oral therapy
Frequency of evaluation FC Assessment 6MWD Echocardiogramx BNPk RHC
Every 3e6 mosz Every clinic visit Every clinic visit Yearly or center dependent Center dependent Clinical deterioration and center dependent
Unstable (Increase in Symptoms and/or Decompensation) FC III† 300e400
Signs of right heart failure IV <300 RV enlargement/dysfunction RAP high CI low Elevated/ increasing Intravenous prostacyclin and/or combination treatment Every 1e3 mos Every clinic visit Every clinic visit Every 6e12 mos or center dependent Center dependent Every 6e12 mos or clinical deterioration
CI ¼ cardiac index; RAP ¼ right atrial pressure; RHC ¼ right heart catheterization. * For patients in the high-risk category, consider referral to a pulmonary hypertension specialty center to consider advanced therapies, clinical trials, and/or lung transplantation. † The frequency of follow-up evaluation for patients in FC III and/or 6MWD from 300 to 400 meters would depend on composite of detailed assessments on other clinica and objective characteristics listed. z For patients who remain stable on established therapy, follow-up assessments can be performed by referring physician(s) or pulmonary hypertension specialty centers. x Echocardiographic measurement of PASP is estimation only; it is strongly advised not to rely on its evaluation as the sole parameter to make therapeutic decisions. k The utility of serial BNP levels to guide management in individual patients has not been established. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, Harrington RA, Anderson JL, Bates ER, Bridges CR, Eisenberg MJ, Ferrari VA, Grines CL, Hlatky MA, Jacobs AK, Kaul S, Lichtenberg RC, Lindner JR, Moliterno DJ, Mukherjee D, Pohost GM, Rosenson RS, Schofield RS, Shubrooks SJ, Stein JH, Tracy CM, Weitz HH, Wesley DJ; ACCF/AHA. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250–2294 and McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/ AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573e1619.27
(2) available long-term studies for the most part are singlecenter reports without a control arm, and (3) evolution of disease after treatment initiation is patient-specific, limiting the ability to make general predictions about response to therapy. In fact, 2 recent meta-analyses have raised questions about whether short-term changes in exercise tolerance during randomized controlled trials predict improvements in long-term outcomes. Savarese et al assessed 3,112 participants in 22 randomized clinical trials in PAH.25 They found that active treatment led to a significant reduction in allcause death, hospitalization for PAH and/or lung transplantation, initiation of PAH rescue therapy, and composite outcome. However, improvements in the primary end point of 6MWD over the short term did not correlate with these outcomes. In a similar analysis, Gabler et al assessed the correlation of 6MWD with clinical events in 10 randomized, placebo-controlled, short-term trials.26 The authors found that the change in 6MWD during the context of a short-term clinical trial had only modest validity as a surrogate end point for clinical events. These 2 studies highlight the caution that must be exercised when making long-term patient decisions based on short-term clinical trials.
For multiple practical reasons, follow-up assessment has never been standardized or incorporated into evidence based guidelines. However, consensus recommendations on reassessment are provided in the 2009 American College of Cardiology Foundation/American Heart Association Expert Consensus Document on Pulmonary Hypertension and rely on routine assessment of important prognostic indicators such as World Health Organization (WHO)-FC, 6MWD and echocardiographic and hemodynamic parameters (Table 1).27 Patients who achieve WHO functional class I or II with a 6MWD >400 meters, with normal RV function on echocardiogram and normal hemodynamic parameters, can be followed on a 3- to 6-month basis by either the referring physician or a pulmonary hypertension specialty center. Highrisk patients who remain WHO-FC III or IV with a 6MWD <300 meters and who have imaging evidence of V dysfunction and abnormal hemodynamics should be followed at 1- to 3-month intervals. Every assessment should include reevaluation of the WHO FC and 6MWD, with an echocardiogram performed approximately every 12 months or every 6 to 12 months, depending on the clinical course. For stable patients, right heart catheterization should be obtained if there are signs
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of clinical worsening; for unstable patients, hemodynamics should be obtained more frequently. Two general strategies exist to guide physicians in following patients over time: a clinical strategy and a goaloriented strategy.28 Clinical strategy: This protocol relies primarily on assessment of the patients’ symptoms with an emphasis on functional status. Therapeutic interventions may be considered effective when, on follow-up assessment, WHO FC is either I or II and there are no detectable signs of right heart failure. Additional assessment through noninvasive means, such as echocardiogram, may also be used. In cases of clinical stability, current treatment can be maintained with no changes, and patients can be monitored on a 3- to 6month basis. Goal-oriented strategy: This protocol relies on improving clinical markers that have prognostic significance and systematically escalating treatment until a specific goal is attained. This requires that certain parameters be identified early and followed over time and that a threshold value for each parameter be defined before starting therapy. For example, Hoeper et al assessed patients by 6MWD or CPET with a goal 6MWD >380 meters, peak oxygen consumption >10.4 ml/min/kg, and peak systolic blood pressure >120 mm Hg during exercise; patients were followed at 3- to 6month intervals, and treatment was escalated over time to achieve these parameters, using triple therapy if necessary.29 This strategy was associated with a 1-, 2-, and 3-year survival of 93.0%, 83.1%, and 79.9%, respectively, which was significantly better than a historical control group. The practice of using multidrug regimens for patients with PAH who have refractory symptoms and who do not achieve prespecified treatment goals is an area of active research. What Are the Goals of Therapy Today? Although the primarily observational studies discussed here do not allow for definitive conclusions, reasonable goals of therapy include the following: 1) 2) 3) 4)
WHO-FC I or II symptoms 6MWD >380 to 440 meters Cardiac index 2.5 L/min/m2 Normal or near normal RV function on imaging (echocardiography, MRI) 5) Normal, or near normal, BNP or N-terminal proBNP
Patients who achieve these goals, no matter which specific therapy or approached is used, seem to have a better prognosis than those who do not. A more aggressive approach to goal-oriented therapy may help us shift the survival curves further to the right. Despite the many observations that support attainment of such goals, many patients followed today fall far short of these targets. For example, approximately 60% of FC III patients and 50% of FC IV patients in the REVEAL registry are not being treated with a prostacyclin, despite their not being at the goal FC of I or II.30 Both patient and physician reluctance to proceed to the most aggressive therapy are contributing factors. In summary, survival in PAH has improved over the recent years, but outcomes are still suboptimal. Reasonable
therapeutic goals that primarily reflect right ventricular function have been established. Achieving such goals with optimal application of our current therapies, and further development of novel therapies may improve long-term outcomes in patients with this previously fatal disease. Acknowledgement Publication of this supplement was supported by an educational grant from Gilead Sciences, Inc. Author Disclosures Vallerie McLaughlin, MD, FACC, FAHA, FCCP receives consulting fees and fees for non-Continuing Medical Education services from Actelion, Gilead, United Therapeutics. V.M. performs contracted research for Actelion, Bayer, Novartis. 1. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216e223. 2. 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;115:343e349. 3. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaïci A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Cottin V, Degano B, Jaïs X, Montani D, Souza R, Simonneau G. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156e163. 4. Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, Liou TG, McGoon MD. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010;122:164e172. 5. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477e1482. 6. Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Hervé P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780e788. 7. Sandoval J, Baurle O, Palomar A, Martinez-Guerra ML, Beltran M, Guerrero L. Survival in primary pulmonary hypertension: validation of a prognostic equation. Circulation 1994;89:1733e1744. 8. Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Hervé P, Simonneau G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105e3111. 9. Eysmann SB, Palevsky HI, Reichek N, Hackney K, Douglas PS. Twodimensional and Doppler echocardiography and cardiac catheterisation correlates of survival in primary pulmonary hypertension. Circulation 1989;80:353e360. 10. van Wolferen SA, Marcus JT, Boonstra A, Marques KM, Bronzwaer JG, Spreeuwenberg MD, Postmus PE, Vonk-Noordegraaf A. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. Eur Heart J 2007;28: 1250e1257. 11. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011;58:2511e2519. 12. Nagaya N, Nishikimi T, Okano Y. Plasma brain natriuretic peptide levels increase in proportion to the extent of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol 1998;31:202e208.
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