Epidemiology of Pulmonary Arterial Hypertension Darren B. Taichman, MD, PhDa,b,*, Jess Mandel, MDc KEYWORDS Pulmonary arterial hypertension Idiopathic pulmonary arterial hypertension HIV infection Portopulmonary hypertension Systemic sclerosis Hemolytic anemia Pulmonary veno-occlusive disease Anorectic drugs
KEY POINTS Changes in the epidemiology of pulmonary arterial hypertension (PAH) have resulted in changes in classification schemes and an increased emphasis on diagnosis because of the availability of effective therapies. The terms primary pulmonary hypertension and secondary pulmonary hypertension are considered inappropriate, confusing, and should not be used. Recent registries of patients with PAH have provided improved data regarding prognosis in the era of advanced therapies.
The last 2 decades have seen an expansion of interest in pulmonary arterial hypertension (PAH) as new treatments have been introduced and new insights into pulmonary vascular biology obtained. Over this period the epidemiology of PAH has evolved as echocardiography became ubiquitous, the availability of treatments promoted clinicians to pursue the diagnosis of PAH with greater vigor, and the classification of PAH underwent several revisions.
Changes in the Classification of the Pulmonary Hypertensive Diseases An unexplained sclerosis of the pulmonary arteries was first documented in 1891 by Ernst von Romberg,1 and again described as cardiacos negros in 1901 by Abel Ayerza because of the degree of cyanosis that patients could develop. Thereafter, his colleagues referred to the entity as Ayerza
disease, and thought it was a consequence of luetic (syphilitic) vasculitis, although some cases were described in patients with advanced lung disease. Little more was understood until the 1940s when Oscar Brenner reported the histopathologic changes in the arteries of 100 patients with pulmonary hypertension (PH), notably lacking findings that suggested syphilis as a cause. In the 1950s, when the advent of cardiac catheterization allowed an investigation of the disease’s hemodynamic abnormalities,2 Dresdale and colleagues3 performed cardiac catheterization and described a hypertensive vasculopathy of the pulmonary circulation. It was characterized by vasoconstriction, an increase in pulmonary arterial pressures, and a measurable response to the injection of tolazoline, a vasodilator with both pulmonary and systemic effects. When no cause such as mitral stenosis or emphysema could be identified in these patients, the entity was termed primary PH. Cases of PH for which a cause could be established
a Annals of Internal Medicine, American College of Physicians; b Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104, USA; c University of California, San Diego School of Medicine, 9500 Gilman Drive #0606, La Jolla, CA 92093-0606, USA * Corresponding author. Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104. E-mail address: [email protected]
Clin Chest Med 34 (2013) 619–637 http://dx.doi.org/10.1016/j.ccm.2013.08.010 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
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Taichman & Mandel
Box 1 Classification of the pulmonary hypertensive diseases Group 1: PAH Idiopathic PAH
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure Adapted from Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl): S43–54; with permission.
Heritable BMPR2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown Drug and toxin induced Associated with: Connective tissue diseases Human immunodeficiency infection
virus
[HIV]
Portal hypertension Congenital heart diseases Schistosomiasis Chronic hemolytic anemia Persistent PH of the newborn Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis Group 2: PH caused by left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Group 3: PH caused by lung diseases and/or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 4: chronic thromboembolic PH Group 5: PH mechanisms
with
unclear
multifactorial
Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell Histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
were thereafter labeled secondary PH (eg, PH secondary to left ventricular failure, chronic pulmonary diseases, hypoxemia).4 Later, using acetylcholine, a vasodilator that was cleared exclusively within the pulmonary circulation, Paul Wood showed a pulmonary-specific hemodynamic improvement in patients with primary PH.2 Intense pathologic evaluation in a series of 156 patients permitted Wagenvoort and Wagenvoort5 to describe extensive vascular injury and remodeling, which they termed plexogenic pulmonary arteriopathy, thought to be the pathognomonic hallmark of the disease. Although the terms primary, secondary, and plexogenic PH were used for many years, an appreciation of important similarities and differences in the histopathologic and clinical characteristics of varying patient groups has prompted the adoption of more precise terminology. In part to reach consensus on clinically useful classification schemes for the pulmonary hypertensive disorders, there have been several international working groups under the sponsorship of the World Health Organization (WHO) since 1973. These classification schemes have evolved as new information has emerged regarding both pathophysiologic mechanisms and clinical characteristics. Histologic findings are no longer the cornerstone of clinical classification because few of the pathologic patterns observed are disease specific, biopsies are now rarely performed, and postmortem diagnoses are, by definition, not clinically useful. The current approach to classification (Box 1) is based on a hemodynamic definition of PH, coupled with clinical and associated characteristics. PH is deemed present when the mean pulmonary artery pressure exceeds 25 mm Hg at rest. The presence of PAH further requires normal left heart filling pressures (ie, a normal left ventricular end diastolic pressure directly measured, or indirectly approximated by a pulmonary artery wedge pressure less than or equal to 15 mm Hg). Classification as PAH further requires the absence of significant chronic respiratory disease or thromboembolic disease. The distinction between the entities classified as PAH and the other known causes of PH (eg,
Epidemiology of Pulmonary Arterial Hypertension
Box 2 Risk factors for the development of PAH
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(12 Suppl S):5S–12S; with permission.
A. Drugs and toxins 1. Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Dasatinib 2. Very likely Amphetamines L-Tryptophan Interferon 3. Possible Meta-amphetamines Cocaine Chemotherapeutic agents Antidepressants 4. Unlikely Oral contraceptives Estrogen therapy Cigarette smoking B. Demographic and medical conditions 1. Definite Female gender 2. Possible Pregnancy Systemic hypertension 3. Unlikely Obesity C. Diseases 1. Definite HIV infection 2. Very likely Portal hypertension/liver disease Collagen vascular diseases Congenital systemic-pulmonary-cardiac shunts Splenectomy 3. Possible Thyroid disorders Adapted and updated from the assessment of risk factors evaluated at the 1998 World Symposium on Pulmonary Hypertension in Evian. France; and
chronic left heart or chronic respiratory disease) is important because therapy is different. From similarities in histologic and clinical features of patients with various forms of PAH, entities are grouped as WHO group 1 diseases; this includes patients with identifiable genetic causes of PAH (ie, those with heritable PAH) and those with collagen vascular diseases or other conditions known to be associated with PAH (associated PAH). Patients with PAH in whom no known associated disease entity or genetic cause can be found are classified as having idiopathic PAH (IPAH), rather than the previously used term primary PH. Abandonment of the name primary PH is important as a means of discouraging the confusing and clinically inappropriate term secondary PH. Use of such primary and secondary groupings inappropriately suggests similarities in the pathophysiology and treatment of patients with many different diseases. As an example, patients with chronic obstructive pulmonary disease, chronic thromboembolic disease, and those with congenital heart disease might each be loosely labeled as having secondary PH, although the pathogenesis is distinct in each category and the appropriate therapy is different. Conceptualizing patients as having either primary or secondary disease may also obscure important clinical similarities (including appropriate treatment) between what was previously called primary PH and other entities labeled secondary (eg, patients with congenital heart disease or human immunodeficiency virus [HIV] infection). Although understanding of the cellular and molecular mechanisms that produce PH remains incomplete, several clearly identifiable risk factors for the development of PAH are recognized. The causal relationship of some risk factors has been firmly established by controlled epidemiologic studies (eg, exposure to fenfluramine-derived anorectic agents), whereas others (eg, thyroid disease) are less well established (Box 2).6–8
IDIOPATHIC PAH IPAH is a rare disease with an estimated incidence of 1 to 2 cases per million in industrialized countries.9–12 The paucity of patients with IPAH and the likelihood that diverse causes might produce similar clinical syndromes have complicated descriptions of the natural history of the disease. To
621
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overcome the limitations of sporadic reports, the National Institutes of Health (NIH) established the prospective National Registry for the Characterization of Primary Pulmonary Hypertension in the early 1980s, enrolling 187 patients from 32 centers between 1981 and 1985.13 The disease affected all ages, both men and women, and many different ethnic groups. The mean age of patients in the registry was 36.4 years and was similar for women and men. However, women were affected more frequently, with a female/male ratio of 1.7:1 (Fig. 1). Nine percent of patients were older than 60 years. The race and ethnicity of the cohort were similar to the general population. Similar demographic trends have been reported in series from France, Israel, Japan, Mexico, and China.11,14–17 Dyspnea was the most common presenting symptom, and the mean time from the onset of symptoms to diagnosis among patients in the NIH registry was approximately 2 years. In a more recent series, 674 patients referred for treatment of PAH were enrolled in a French national registry over a 1-year period during 2002 and 2003.12 Both prevalent and incident patients were evaluated, making up 18% and 82% of the study population, respectively. Patients with IPAH accounted for 39% of the registry and, as in prior studies, disease was seen more commonly 35
Prognostic Factors in IPAH Although a diagnosis of IPAH has been associated with an invariably dismal prognosis, therapies developed in the last two decades have significantly improved the prognosis of the condition and yielded many long-term survivors. However, no currently available medical treatment is considered curative and lung transplantation continues to be an important therapeutic consideration. Box 3 WHO functional classification
30
Class I: patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
25
FREQUENCY
in women, with a ratio to men of 1.6:1. The mean age of patients with IPAH was 52 years, older than that seen in prior series. Although data specific to IPAH were not available, one-quarter of patients with PAH of any form were older than 60 years, and some patients were diagnosed in their 80s. However, despite the significant advances in therapy that had occurred in the 20 years since the NIH registry, a significant delay in the diagnosis of IPAH continued; 80% of patients with IPAH had WHO functional class III or IV symptoms (Box 3) at the time of diagnosis, which is similar to what was reported in the National Registry for the Characterization of Primary Pulmonary Hypertension in the early 1980s.13 Exercise capacity was severely impaired in these patients, with a mean 6-minute walk distance of only 328 m, and hemodynamic values were nearly identical to those of the NIH registry population.
20
Class II: patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
15
Class III: patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
10
5
1-10 11-20 21-30 31-40 41-50 51-60 61-70
AGE (Years)
Fig. 1. Distribution of patients with idiopathic PAH entered into the NIH registry. Patients entered into the Registry of the Characterization of Primary Pulmonary Hypertension were most often in their third and fourth decades of life, with a similar ratio of women to men (1.7:1) in all decades. Open bars represent women; shaded bars represent men.
Class IV: patients with PH with inability to perform any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Adapted from Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP EvidenceBased Clinical Practice Guidelines. Introduction. Chest 2004;126:7S–10S.
Epidemiology of Pulmonary Arterial Hypertension The prognosis of IPAH is poor in the absence of effective therapy. The median survival of patients in the NIH registry was 2.8 years, with estimated survival rates of 68% at 1 year, 48% at 3 years, and 34% at 5 years.13 Similar outcomes have been reported in other series from various countries,18,19 with most patients dying of right heart failure. Although multiple studies have evaluated the outcome of patients with IPAH treated with new therapies and studies have frequently included patients with PAH with the scleroderma spectrum of collagen vascular disease, information on patients with other forms of PAH is sparse. Most subjects in controlled clinical trials of treatment with calcium channel antagonists, prostanoids, endothelin receptor antagonists, or phosphodiesterase inhibitors have had IPAH. Fewer patients with either hereditary or various forms of associated PAH have been studied. It is important to bear in mind this paucity of data when informing patients with some forms of PAH about the expected outcomes of treatment. It is also important to acknowledge the limits in understanding the relative efficacy of available agents. Data from head-to-head comparisons are minimal. Most often, patients treated with intravenous prostanoids have been sicker than those treated with oral therapies, making comparisons between studies problematic. In the French national registry population from 2002 to 2003, after advanced therapies had become available, the 1-year survival of patients with PAH with either IPAH, familial, or anorexigen-associated PAH was 89.3%. Although information regarding specific treatments involved was not reported, the expected survival from the NIH registry equation was 71.8%.12 The multicenter observational Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL registry) is the largest registry of patients with PAH in the era of advanced PAH therapies.20 Based on data from 2716 patients, a risk score calculator for newly diagnosed patients with PAH has been developed and validated and is shown in Fig. 2 and Table 1. As can be seen, the strongest contributors to a poor prognosis were a diagnosis of portopulmonary hypertension or heritable PAH, male sex combined with age greater than 60 years, New York Heart Association/WHO functional class IV, and pulmonary vascular resistance (PVR) greater than 32 Wood units. Objective measurements of exercise capacity also predict survival. Among 43 patients treated predominantly with infused or oral prostanoids, the pretreatment 6-minute walk distance was
independently associated with survival, which was significantly better for those who could walk farther than 332 m (Fig. 3).21 In randomized trials of epoprostenol therapy, patients with a lower baseline 6-minute walk distance similarly had poorer survival.22,23 Maximal oxygen consumption during cardiopulmonary exercise testing also correlates with survival.24 Findings on echocardiography, including right atrial enlargement or the presence and size of a pericardial effusion, can be useful in assessing prognosis.25–27 An index of right ventricular function derived by dividing the combined isovolumetric contraction and relaxation times by the right ventricular ejection time (Tei index) also predicts survival, with a higher index associated with a poorer prognosis.28 The degree of tricuspid annular displacement during systole was associated with right ventricular function, hemodynamic measurements, as well as survival in a cohort of patients with various forms of PAH, as well as others with PH associated with chronic respiratory or thromboembolic disease (Fig. 4).29 The right ventricular diameter and some measures of right ventricular free wall strain also can also provide prognostic information.30,31 Hemodynamic measurements have been predictors of survival in numerous studies, including both observational and clinical trials. Despite isolated differences, overall these studies indicate that values reflecting a declining right ventricular function (eg, an increased right atrial pressure and a decreased cardiac index) are associated with poorer survival.11,15,16,32,33 Survival is less consistently linked with mean pulmonary artery pressures (mPAPs), and both increasing and decreasing values have been associated with worsened outcomes. This finding reflects the natural history of right heart failure in PAH: mPAP increases progressively as the vascular derangements worsen, only to decrease later as the right heart progressively fails and is no longer able to generate increased pressures (Fig. 5). Many serum markers are increased in patients with IPAH and are associated with a worse prognosis. Uric acid levels are increased in hypoxic states, and the degree of increase correlates with hemodynamic and functional decline in patients with IPAH.34,35 Levels of B-natriuretic peptide are also increased in patients with IPAH, reflecting right heart failure analogous to that seen in patients with left-sided heart dysfunction. In one series of 60 patients with IPAH, serum brain natriuretic peptide (BNP) concentrations were increased versus control, and inversely correlated with both functional status and survival.36 BNP levels declined as hemodynamic measures improved with therapy, and a
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Fig. 2. REVEAL Registry PAH risk score calculator. Calculated risk scores can range from 0 (lowest risk) to 22 (highest risk). If N-terminal proBNP is available and BNP is not, listed cut points are replaced with less than 300 pg/mL and more than 1500 pg/mL. APAH, associated pulmonary arterial hypertension; BNP, brain natriuretic peptide; BPM, beats per minute; CTD, connective tissue disease; DLco, diffusing capacity of lung for carbon monoxide; FPAH, familial PAH; HR, heart rate; mRAP, mean right atrial pressure; NYHA, New York Heart Association; POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; SBP, systolic blood pressure. (From 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;141(2):354–62; with permission.)
persistently increased BNP (>180 pg/mL) despite therapy predicted a poorer prognosis. Serum concentrations of endothelin-1,37 catecholamines,38 and atrial natriuretic peptide39 in serum have also been correlated with disease severity. Increases in von Willebrand factor, D-dimer, and troponin-T, or a decrease in the serum albumin level have been individually associated with poorer survival in patients with
IPAH.35,39,40 However, none of these putative prognostic markers are routinely incorporated into clinical decision making. The prognosis of patients with IPAH who have had cardiac arrest is dismal even when resuscitative efforts are initiated promptly. In one retrospective review of records from more than 3000 patients, 132 episodes of attempted cardiopulmonary resuscitation (CPR) following cardiac arrest
Epidemiology of Pulmonary Arterial Hypertension
Table 1 Predicted 12-month survival based upon the calculated REVEAL risk score
Score
Risk Group
Predicted 12-mo Survival (%)
0–7 8 9 10–11 >12
Low Average Moderately high High Very high
95–100 90–
KEY POINTS Changes in the epidemiology of pulmonary arterial hypertension (PAH) have resulted in changes in classification schemes and an increased emphasis on diagnosis because of the availability of effective therapies. The terms primary pulmonary hypertension and secondary pulmonary hypertension are considered inappropriate, confusing, and should not be used. Recent registries of patients with PAH have provided improved data regarding prognosis in the era of advanced therapies.
The last 2 decades have seen an expansion of interest in pulmonary arterial hypertension (PAH) as new treatments have been introduced and new insights into pulmonary vascular biology obtained. Over this period the epidemiology of PAH has evolved as echocardiography became ubiquitous, the availability of treatments promoted clinicians to pursue the diagnosis of PAH with greater vigor, and the classification of PAH underwent several revisions.
Changes in the Classification of the Pulmonary Hypertensive Diseases An unexplained sclerosis of the pulmonary arteries was first documented in 1891 by Ernst von Romberg,1 and again described as cardiacos negros in 1901 by Abel Ayerza because of the degree of cyanosis that patients could develop. Thereafter, his colleagues referred to the entity as Ayerza
disease, and thought it was a consequence of luetic (syphilitic) vasculitis, although some cases were described in patients with advanced lung disease. Little more was understood until the 1940s when Oscar Brenner reported the histopathologic changes in the arteries of 100 patients with pulmonary hypertension (PH), notably lacking findings that suggested syphilis as a cause. In the 1950s, when the advent of cardiac catheterization allowed an investigation of the disease’s hemodynamic abnormalities,2 Dresdale and colleagues3 performed cardiac catheterization and described a hypertensive vasculopathy of the pulmonary circulation. It was characterized by vasoconstriction, an increase in pulmonary arterial pressures, and a measurable response to the injection of tolazoline, a vasodilator with both pulmonary and systemic effects. When no cause such as mitral stenosis or emphysema could be identified in these patients, the entity was termed primary PH. Cases of PH for which a cause could be established
a Annals of Internal Medicine, American College of Physicians; b Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104, USA; c University of California, San Diego School of Medicine, 9500 Gilman Drive #0606, La Jolla, CA 92093-0606, USA * Corresponding author. Penn Presbyterian Medical Center, University of Pennsylvania Perelman School of Medicine, 190 North Independence Mall West, Philadelphia, PA 19104. E-mail address: [email protected]
Clin Chest Med 34 (2013) 619–637 http://dx.doi.org/10.1016/j.ccm.2013.08.010 0272-5231/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
620
Taichman & Mandel
Box 1 Classification of the pulmonary hypertensive diseases Group 1: PAH Idiopathic PAH
Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure Adapted from Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(1 Suppl): S43–54; with permission.
Heritable BMPR2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia) Unknown Drug and toxin induced Associated with: Connective tissue diseases Human immunodeficiency infection
virus
[HIV]
Portal hypertension Congenital heart diseases Schistosomiasis Chronic hemolytic anemia Persistent PH of the newborn Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis Group 2: PH caused by left heart disease Systolic dysfunction Diastolic dysfunction Valvular disease Group 3: PH caused by lung diseases and/or hypoxia Chronic obstructive pulmonary disease Interstitial lung disease Other pulmonary diseases with mixed restrictive and obstructive pattern Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 4: chronic thromboembolic PH Group 5: PH mechanisms
with
unclear
multifactorial
Hematologic disorders: myeloproliferative disorders, splenectomy Systemic disorders: sarcoidosis, pulmonary Langerhans cell Histiocytosis: lymphangioleiomyomatosis, neurofibromatosis, vasculitis Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
were thereafter labeled secondary PH (eg, PH secondary to left ventricular failure, chronic pulmonary diseases, hypoxemia).4 Later, using acetylcholine, a vasodilator that was cleared exclusively within the pulmonary circulation, Paul Wood showed a pulmonary-specific hemodynamic improvement in patients with primary PH.2 Intense pathologic evaluation in a series of 156 patients permitted Wagenvoort and Wagenvoort5 to describe extensive vascular injury and remodeling, which they termed plexogenic pulmonary arteriopathy, thought to be the pathognomonic hallmark of the disease. Although the terms primary, secondary, and plexogenic PH were used for many years, an appreciation of important similarities and differences in the histopathologic and clinical characteristics of varying patient groups has prompted the adoption of more precise terminology. In part to reach consensus on clinically useful classification schemes for the pulmonary hypertensive disorders, there have been several international working groups under the sponsorship of the World Health Organization (WHO) since 1973. These classification schemes have evolved as new information has emerged regarding both pathophysiologic mechanisms and clinical characteristics. Histologic findings are no longer the cornerstone of clinical classification because few of the pathologic patterns observed are disease specific, biopsies are now rarely performed, and postmortem diagnoses are, by definition, not clinically useful. The current approach to classification (Box 1) is based on a hemodynamic definition of PH, coupled with clinical and associated characteristics. PH is deemed present when the mean pulmonary artery pressure exceeds 25 mm Hg at rest. The presence of PAH further requires normal left heart filling pressures (ie, a normal left ventricular end diastolic pressure directly measured, or indirectly approximated by a pulmonary artery wedge pressure less than or equal to 15 mm Hg). Classification as PAH further requires the absence of significant chronic respiratory disease or thromboembolic disease. The distinction between the entities classified as PAH and the other known causes of PH (eg,
Epidemiology of Pulmonary Arterial Hypertension
Box 2 Risk factors for the development of PAH
Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(12 Suppl S):5S–12S; with permission.
A. Drugs and toxins 1. Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Dasatinib 2. Very likely Amphetamines L-Tryptophan Interferon 3. Possible Meta-amphetamines Cocaine Chemotherapeutic agents Antidepressants 4. Unlikely Oral contraceptives Estrogen therapy Cigarette smoking B. Demographic and medical conditions 1. Definite Female gender 2. Possible Pregnancy Systemic hypertension 3. Unlikely Obesity C. Diseases 1. Definite HIV infection 2. Very likely Portal hypertension/liver disease Collagen vascular diseases Congenital systemic-pulmonary-cardiac shunts Splenectomy 3. Possible Thyroid disorders Adapted and updated from the assessment of risk factors evaluated at the 1998 World Symposium on Pulmonary Hypertension in Evian. France; and
chronic left heart or chronic respiratory disease) is important because therapy is different. From similarities in histologic and clinical features of patients with various forms of PAH, entities are grouped as WHO group 1 diseases; this includes patients with identifiable genetic causes of PAH (ie, those with heritable PAH) and those with collagen vascular diseases or other conditions known to be associated with PAH (associated PAH). Patients with PAH in whom no known associated disease entity or genetic cause can be found are classified as having idiopathic PAH (IPAH), rather than the previously used term primary PH. Abandonment of the name primary PH is important as a means of discouraging the confusing and clinically inappropriate term secondary PH. Use of such primary and secondary groupings inappropriately suggests similarities in the pathophysiology and treatment of patients with many different diseases. As an example, patients with chronic obstructive pulmonary disease, chronic thromboembolic disease, and those with congenital heart disease might each be loosely labeled as having secondary PH, although the pathogenesis is distinct in each category and the appropriate therapy is different. Conceptualizing patients as having either primary or secondary disease may also obscure important clinical similarities (including appropriate treatment) between what was previously called primary PH and other entities labeled secondary (eg, patients with congenital heart disease or human immunodeficiency virus [HIV] infection). Although understanding of the cellular and molecular mechanisms that produce PH remains incomplete, several clearly identifiable risk factors for the development of PAH are recognized. The causal relationship of some risk factors has been firmly established by controlled epidemiologic studies (eg, exposure to fenfluramine-derived anorectic agents), whereas others (eg, thyroid disease) are less well established (Box 2).6–8
IDIOPATHIC PAH IPAH is a rare disease with an estimated incidence of 1 to 2 cases per million in industrialized countries.9–12 The paucity of patients with IPAH and the likelihood that diverse causes might produce similar clinical syndromes have complicated descriptions of the natural history of the disease. To
621
Taichman & Mandel
622
overcome the limitations of sporadic reports, the National Institutes of Health (NIH) established the prospective National Registry for the Characterization of Primary Pulmonary Hypertension in the early 1980s, enrolling 187 patients from 32 centers between 1981 and 1985.13 The disease affected all ages, both men and women, and many different ethnic groups. The mean age of patients in the registry was 36.4 years and was similar for women and men. However, women were affected more frequently, with a female/male ratio of 1.7:1 (Fig. 1). Nine percent of patients were older than 60 years. The race and ethnicity of the cohort were similar to the general population. Similar demographic trends have been reported in series from France, Israel, Japan, Mexico, and China.11,14–17 Dyspnea was the most common presenting symptom, and the mean time from the onset of symptoms to diagnosis among patients in the NIH registry was approximately 2 years. In a more recent series, 674 patients referred for treatment of PAH were enrolled in a French national registry over a 1-year period during 2002 and 2003.12 Both prevalent and incident patients were evaluated, making up 18% and 82% of the study population, respectively. Patients with IPAH accounted for 39% of the registry and, as in prior studies, disease was seen more commonly 35
Prognostic Factors in IPAH Although a diagnosis of IPAH has been associated with an invariably dismal prognosis, therapies developed in the last two decades have significantly improved the prognosis of the condition and yielded many long-term survivors. However, no currently available medical treatment is considered curative and lung transplantation continues to be an important therapeutic consideration. Box 3 WHO functional classification
30
Class I: patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.
25
FREQUENCY
in women, with a ratio to men of 1.6:1. The mean age of patients with IPAH was 52 years, older than that seen in prior series. Although data specific to IPAH were not available, one-quarter of patients with PAH of any form were older than 60 years, and some patients were diagnosed in their 80s. However, despite the significant advances in therapy that had occurred in the 20 years since the NIH registry, a significant delay in the diagnosis of IPAH continued; 80% of patients with IPAH had WHO functional class III or IV symptoms (Box 3) at the time of diagnosis, which is similar to what was reported in the National Registry for the Characterization of Primary Pulmonary Hypertension in the early 1980s.13 Exercise capacity was severely impaired in these patients, with a mean 6-minute walk distance of only 328 m, and hemodynamic values were nearly identical to those of the NIH registry population.
20
Class II: patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.
15
Class III: patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.
10
5
1-10 11-20 21-30 31-40 41-50 51-60 61-70
AGE (Years)
Fig. 1. Distribution of patients with idiopathic PAH entered into the NIH registry. Patients entered into the Registry of the Characterization of Primary Pulmonary Hypertension were most often in their third and fourth decades of life, with a similar ratio of women to men (1.7:1) in all decades. Open bars represent women; shaded bars represent men.
Class IV: patients with PH with inability to perform any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Adapted from Rubin LJ. Diagnosis and management of pulmonary arterial hypertension: ACCP EvidenceBased Clinical Practice Guidelines. Introduction. Chest 2004;126:7S–10S.
Epidemiology of Pulmonary Arterial Hypertension The prognosis of IPAH is poor in the absence of effective therapy. The median survival of patients in the NIH registry was 2.8 years, with estimated survival rates of 68% at 1 year, 48% at 3 years, and 34% at 5 years.13 Similar outcomes have been reported in other series from various countries,18,19 with most patients dying of right heart failure. Although multiple studies have evaluated the outcome of patients with IPAH treated with new therapies and studies have frequently included patients with PAH with the scleroderma spectrum of collagen vascular disease, information on patients with other forms of PAH is sparse. Most subjects in controlled clinical trials of treatment with calcium channel antagonists, prostanoids, endothelin receptor antagonists, or phosphodiesterase inhibitors have had IPAH. Fewer patients with either hereditary or various forms of associated PAH have been studied. It is important to bear in mind this paucity of data when informing patients with some forms of PAH about the expected outcomes of treatment. It is also important to acknowledge the limits in understanding the relative efficacy of available agents. Data from head-to-head comparisons are minimal. Most often, patients treated with intravenous prostanoids have been sicker than those treated with oral therapies, making comparisons between studies problematic. In the French national registry population from 2002 to 2003, after advanced therapies had become available, the 1-year survival of patients with PAH with either IPAH, familial, or anorexigen-associated PAH was 89.3%. Although information regarding specific treatments involved was not reported, the expected survival from the NIH registry equation was 71.8%.12 The multicenter observational Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL registry) is the largest registry of patients with PAH in the era of advanced PAH therapies.20 Based on data from 2716 patients, a risk score calculator for newly diagnosed patients with PAH has been developed and validated and is shown in Fig. 2 and Table 1. As can be seen, the strongest contributors to a poor prognosis were a diagnosis of portopulmonary hypertension or heritable PAH, male sex combined with age greater than 60 years, New York Heart Association/WHO functional class IV, and pulmonary vascular resistance (PVR) greater than 32 Wood units. Objective measurements of exercise capacity also predict survival. Among 43 patients treated predominantly with infused or oral prostanoids, the pretreatment 6-minute walk distance was
independently associated with survival, which was significantly better for those who could walk farther than 332 m (Fig. 3).21 In randomized trials of epoprostenol therapy, patients with a lower baseline 6-minute walk distance similarly had poorer survival.22,23 Maximal oxygen consumption during cardiopulmonary exercise testing also correlates with survival.24 Findings on echocardiography, including right atrial enlargement or the presence and size of a pericardial effusion, can be useful in assessing prognosis.25–27 An index of right ventricular function derived by dividing the combined isovolumetric contraction and relaxation times by the right ventricular ejection time (Tei index) also predicts survival, with a higher index associated with a poorer prognosis.28 The degree of tricuspid annular displacement during systole was associated with right ventricular function, hemodynamic measurements, as well as survival in a cohort of patients with various forms of PAH, as well as others with PH associated with chronic respiratory or thromboembolic disease (Fig. 4).29 The right ventricular diameter and some measures of right ventricular free wall strain also can also provide prognostic information.30,31 Hemodynamic measurements have been predictors of survival in numerous studies, including both observational and clinical trials. Despite isolated differences, overall these studies indicate that values reflecting a declining right ventricular function (eg, an increased right atrial pressure and a decreased cardiac index) are associated with poorer survival.11,15,16,32,33 Survival is less consistently linked with mean pulmonary artery pressures (mPAPs), and both increasing and decreasing values have been associated with worsened outcomes. This finding reflects the natural history of right heart failure in PAH: mPAP increases progressively as the vascular derangements worsen, only to decrease later as the right heart progressively fails and is no longer able to generate increased pressures (Fig. 5). Many serum markers are increased in patients with IPAH and are associated with a worse prognosis. Uric acid levels are increased in hypoxic states, and the degree of increase correlates with hemodynamic and functional decline in patients with IPAH.34,35 Levels of B-natriuretic peptide are also increased in patients with IPAH, reflecting right heart failure analogous to that seen in patients with left-sided heart dysfunction. In one series of 60 patients with IPAH, serum brain natriuretic peptide (BNP) concentrations were increased versus control, and inversely correlated with both functional status and survival.36 BNP levels declined as hemodynamic measures improved with therapy, and a
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Fig. 2. REVEAL Registry PAH risk score calculator. Calculated risk scores can range from 0 (lowest risk) to 22 (highest risk). If N-terminal proBNP is available and BNP is not, listed cut points are replaced with less than 300 pg/mL and more than 1500 pg/mL. APAH, associated pulmonary arterial hypertension; BNP, brain natriuretic peptide; BPM, beats per minute; CTD, connective tissue disease; DLco, diffusing capacity of lung for carbon monoxide; FPAH, familial PAH; HR, heart rate; mRAP, mean right atrial pressure; NYHA, New York Heart Association; POPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; SBP, systolic blood pressure. (From 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;141(2):354–62; with permission.)
persistently increased BNP (>180 pg/mL) despite therapy predicted a poorer prognosis. Serum concentrations of endothelin-1,37 catecholamines,38 and atrial natriuretic peptide39 in serum have also been correlated with disease severity. Increases in von Willebrand factor, D-dimer, and troponin-T, or a decrease in the serum albumin level have been individually associated with poorer survival in patients with
IPAH.35,39,40 However, none of these putative prognostic markers are routinely incorporated into clinical decision making. The prognosis of patients with IPAH who have had cardiac arrest is dismal even when resuscitative efforts are initiated promptly. In one retrospective review of records from more than 3000 patients, 132 episodes of attempted cardiopulmonary resuscitation (CPR) following cardiac arrest
Epidemiology of Pulmonary Arterial Hypertension
Table 1 Predicted 12-month survival based upon the calculated REVEAL risk score
Score
Risk Group
Predicted 12-mo Survival (%)
0–7 8 9 10–11 >12
Low Average Moderately high High Very high
95–100 90–
