The Early Diagnosis of Pulmonary Arterial Hypertension: Can We Do Better?

Abstract

In 1981, 32 US medical centers began enrolling patients into the National Institutes of Health-sponsored Patient Registry for the Characterization of Primary Pulmonary Hypertension (NIH-PPH).1Rich S Dantzker DR Ayres SM et al.Primary pulmonary hypertension. A national prospective study.Ann Intern Med. 1987; 107: 216-223Crossref PubMed Scopus (1712) Google Scholar In the ensuing 30 years, considerable progress has been made in understanding the cellular, genetic, and biochemical processes underlying what is now designated pulmonary arterial hypertension (PAH). Clinical trials have led to the availability of multiple therapeutic agents in three pharmacologic classes, with additional agents in these and novel pharmacologic classes under development. Despite this progress in treatment, there remains an unacceptably long delay from the onset of clinical symptoms to diagnosis of PAH, and the majority of patients continue to be in an advanced functional class at the time of diagnosis.The NIH-PPH registry enrolled 187 patients between July 1981 and September 1985. This registry reported a mean time from the onset of symptoms to diagnosis of 2.03 ±4.9 years (median, 1.27 years [15.2 months]). At the time of diagnosis, 71% of the patients were in New York Heart Association (NYHA) functional class III or IV.Five years ago, the results from a national registry of PAH in France were published.2Humbert M Sitbon O Chaouat A et al.Pulmonary arterial hypertension in France: results from a national registry.Am J Respir Crit Care Med. 2006; 173: 1023-1030Crossref PubMed Scopus (1521) Google Scholar This registry included 674 patients seen between October 2002 and October 2003. The authors reported a mean delay between the onset of symptoms and diagnosis for these patients of 27 months (2.25 years), and similar to the NIH-PPH registry, 75% of patients were in NYHA functional class III or IV at presentation.The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) is the largest registry to date of patients with PAH and currently is obtaining follow-up data on previously enrolled patients in addition to analyzing available data. The baseline characteristics of patients from this registry have been reported previously in CHEST.3Badesch DB Raskob GE Elliott CG et al.Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.Chest. 2010; 137: 376-387Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar A total of 2,525 adult patients meeting traditional hemodynamics criteria for PAH were enrolled between March 2006 and September 2007. The mean time from symptom onset to diagnostic right-sided heart catheterization (RHC) was 34.1 ±1.2 months, with a median time of 13.6 months. Similar to the two previous registries, patients tended to have advanced disease, with 73.6% being in NYHA functional class III or IV at the time of diagnostic RHC.Review of the data from these registries suggests that there has been little improvement in the early recognition of PAH during the more than 16 years from the start of the NIH-PPH registry to the completion of enrollment in the REVEAL Registry. In this issue of CHEST (see page 19), Brown et al4Brown LM Chen H Halpern S et al.Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry.Chest. 2011; 140: 19-26Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar attempt to understand this delay in recognition of PAH by further analyzing data from the REVEAL Registry. The authors used a very conservative definition of delayed diagnosis of PAH by analyzing the data from patients who had >2 years between the onset of symptoms and either having received a diagnosis after RHC, having received a diagnosis of PAH without RHC, or having been started on PAH-specific therapies. Of the patients in the REVEAL Registry, 21.1% met these criteria for a delay in diagnosis of >2 years. The patients most likely to experience a delay in diagnosis were those who experienced the onset of symptoms before age 36 or those who had confounding histories of obstructive airways disease or sleep apnea. Patients who had a 6-min walk test of <250 m also had a delayed recognition of PAH, as did patients with a right atrial pressure of <10 mm Hg or a pulmonary vascular resistance of <10 Wood units. These last two hemodynamic parameters suggest that the delay in diagnosis is most frequently an issue in patients with less advanced disease, an observation supported by the patient's stage at diagnosis in each of the registries cited here.The challenge facing us remains the early detection of patients with PAH. The earliest symptom that the majority of patients present with is dyspnea upon exertion,5McGoon M Gutterman D Steen V American College of Chest Physicians et al.Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.Chest. 2004; 126: 14S-34SAbstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar a nonspecific symptom where the majority of patients who have it do not have pulmonary vascular disease. However, to optimize our chances of making an early diagnosis of PAH as well as any other of the myriad conditions that can present with dyspnea on exertion, it is important that this symptom be evaluated fully, which may require an assessment of the patient during exertion (exercise). Postexercise pulmonary function testing may be informative in patients with exercise-associated asthma; cardiopulmonary exercise testing also may be informative in that patients with PAH will manifest a pattern of response suggestive of cardiac impairment. Exercise echocardiography either alone or in addition to cardiopulmonary exercise testing may suggest the need for an exercise RHC to establish a diagnosis of early PAH. A study by Tolle et al6Tolle JJ Waxman AB Van Horn TL Pappagianopoulos PP Systrom DM Exercise-induced pulmonary arterial hypertension.Circulation. 2008; 118: 2183-2189Crossref PubMed Scopus (264) Google Scholar has helped us to focus on exercise-induced PAH as the earliest opportunity to diagnose PAH (until the development of reliable serum biomarkers) and emphasized that this finding is clinically relevant. Only by a thorough evaluation of patients presenting with exertional symptoms will we be able to reduce the delay from the onset of clinical symptoms to the diagnosis of PAH, which has not changed appreciably over the past 2 decades. In 1981, 32 US medical centers began enrolling patients into the National Institutes of Health-sponsored Patient Registry for the Characterization of Primary Pulmonary Hypertension (NIH-PPH).1Rich S Dantzker DR Ayres SM et al.Primary pulmonary hypertension. A national prospective study.Ann Intern Med. 1987; 107: 216-223Crossref PubMed Scopus (1712) Google Scholar In the ensuing 30 years, considerable progress has been made in understanding the cellular, genetic, and biochemical processes underlying what is now designated pulmonary arterial hypertension (PAH). Clinical trials have led to the availability of multiple therapeutic agents in three pharmacologic classes, with additional agents in these and novel pharmacologic classes under development. Despite this progress in treatment, there remains an unacceptably long delay from the onset of clinical symptoms to diagnosis of PAH, and the majority of patients continue to be in an advanced functional class at the time of diagnosis. The NIH-PPH registry enrolled 187 patients between July 1981 and September 1985. This registry reported a mean time from the onset of symptoms to diagnosis of 2.03 ±4.9 years (median, 1.27 years [15.2 months]). At the time of diagnosis, 71% of the patients were in New York Heart Association (NYHA) functional class III or IV. Five years ago, the results from a national registry of PAH in France were published.2Humbert M Sitbon O Chaouat A et al.Pulmonary arterial hypertension in France: results from a national registry.Am J Respir Crit Care Med. 2006; 173: 1023-1030Crossref PubMed Scopus (1521) Google Scholar This registry included 674 patients seen between October 2002 and October 2003. The authors reported a mean delay between the onset of symptoms and diagnosis for these patients of 27 months (2.25 years), and similar to the NIH-PPH registry, 75% of patients were in NYHA functional class III or IV at presentation. The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry) is the largest registry to date of patients with PAH and currently is obtaining follow-up data on previously enrolled patients in addition to analyzing available data. The baseline characteristics of patients from this registry have been reported previously in CHEST.3Badesch DB Raskob GE Elliott CG et al.Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry.Chest. 2010; 137: 376-387Abstract Full Text Full Text PDF PubMed Scopus (838) Google Scholar A total of 2,525 adult patients meeting traditional hemodynamics criteria for PAH were enrolled between March 2006 and September 2007. The mean time from symptom onset to diagnostic right-sided heart catheterization (RHC) was 34.1 ±1.2 months, with a median time of 13.6 months. Similar to the two previous registries, patients tended to have advanced disease, with 73.6% being in NYHA functional class III or IV at the time of diagnostic RHC. Review of the data from these registries suggests that there has been little improvement in the early recognition of PAH during the more than 16 years from the start of the NIH-PPH registry to the completion of enrollment in the REVEAL Registry. In this issue of CHEST (see page 19), Brown et al4Brown LM Chen H Halpern S et al.Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry.Chest. 2011; 140: 19-26Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar attempt to understand this delay in recognition of PAH by further analyzing data from the REVEAL Registry. The authors used a very conservative definition of delayed diagnosis of PAH by analyzing the data from patients who had >2 years between the onset of symptoms and either having received a diagnosis after RHC, having received a diagnosis of PAH without RHC, or having been started on PAH-specific therapies. Of the patients in the REVEAL Registry, 21.1% met these criteria for a delay in diagnosis of >2 years. The patients most likely to experience a delay in diagnosis were those who experienced the onset of symptoms before age 36 or those who had confounding histories of obstructive airways disease or sleep apnea. Patients who had a 6-min walk test of <250 m also had a delayed recognition of PAH, as did patients with a right atrial pressure of <10 mm Hg or a pulmonary vascular resistance of <10 Wood units. These last two hemodynamic parameters suggest that the delay in diagnosis is most frequently an issue in patients with less advanced disease, an observation supported by the patient's stage at diagnosis in each of the registries cited here. The challenge facing us remains the early detection of patients with PAH. The earliest symptom that the majority of patients present with is dyspnea upon exertion,5McGoon M Gutterman D Steen V American College of Chest Physicians et al.Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.Chest. 2004; 126: 14S-34SAbstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar a nonspecific symptom where the majority of patients who have it do not have pulmonary vascular disease. However, to optimize our chances of making an early diagnosis of PAH as well as any other of the myriad conditions that can present with dyspnea on exertion, it is important that this symptom be evaluated fully, which may require an assessment of the patient during exertion (exercise). Postexercise pulmonary function testing may be informative in patients with exercise-associated asthma; cardiopulmonary exercise testing also may be informative in that patients with PAH will manifest a pattern of response suggestive of cardiac impairment. Exercise echocardiography either alone or in addition to cardiopulmonary exercise testing may suggest the need for an exercise RHC to establish a diagnosis of early PAH. A study by Tolle et al6Tolle JJ Waxman AB Van Horn TL Pappagianopoulos PP Systrom DM Exercise-induced pulmonary arterial hypertension.Circulation. 2008; 118: 2183-2189Crossref PubMed Scopus (264) Google Scholar has helped us to focus on exercise-induced PAH as the earliest opportunity to diagnose PAH (until the development of reliable serum biomarkers) and emphasized that this finding is clinically relevant. Only by a thorough evaluation of patients presenting with exertional symptoms will we be able to reduce the delay from the onset of clinical symptoms to the diagnosis of PAH, which has not changed appreciably over the past 2 decades.