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Figure 1.
Classification of Pulmonary Hypertension Subgroups
Classification of Pulmonary Hypertension Subgroups

Pulmonary hypertension is defined by a mean pulmonary artery pressure (mPAP) of at least 25 mm Hg measured by right heart catheterization supine at rest. Patients meeting this criterion are classified further according to comorbid left-sided heart disease causing left atrial hypertension, parenchymal or hypoxic lung disease, chronic thrombembolic pulmonary hypertension (CTEPH), or other predisposing diseases associated with pulmonary vascular remodeling. In the case of CTEPH, in situ thrombotic and fibrotic remodeling of subsegmental pulmonary arterioles occurs in most patients as a maladaptive response to prior luminal pulmonary embolism. By contrast to these forms of pulmonary hypertension, pulmonary arterial hypertension (PAH) is characterized by a plexogenic, hypertrophic, and fibrotic vasculopathy that affects distal pulmonary arterioles, occurs primarily owing to interplay between genetic and molecular factors, and requires meeting the following additional cardiopulmonary hemodynamic criteria: pulmonary vascular resistance (PVR) of greater than 3.0 Wood units and pulmonary artery wedge pressure (PAWP) of no greater than 15 mm Hg. The most common forms of PAH in industrialized countries are idiopathic PAH, heritable PAH caused primarily to a mutation in the gene for bone morphogenetic protein receptor type 2 (BMPR2), and PAH in association with connective tissue disease (CTD) or congenital heart disease. COPD indicates chronic obstructive pulmonary disease; HD, hemodialysis; HIV, human immunodeficiency virus; and LV, left ventricular.

Figure 2.
Kaplan-Meier Curves for the Effect of Sequential or Initial Combination Therapy in Treatment of PAH
Kaplan-Meier Curves for the Effect of Sequential or Initial Combination Therapy in Treatment of PAH

A, The effect of macitentan as monotherapy or as sequential combination therapy in addition to phosphodiesterase type 5 inhibitors (predominantly sildenafil) or prostacyclin analogues on the outcome. In the SERAPHIN study, patients were randomized to receive macitentan, 3 mg or 10 mg, or placebo. Kaplan-Meier curves for the primary composite end point of death (from any cause) or a complication related to pulmonary arterial hypertension (disease progression or worsening of pulmonary arterial hypertension that resulted in initiation of intravenous or subcutaneous prostanoid therapy or the need for lung transplantation or balloon atrial septostomy) up to the end of the treatment period in the macitentan and placebo groups. A significant treatment effect in favor of macitentan, 10 mg (approved dose), vs placebo was observed (1-sided log-rank test). Reproduced with permission from Pulido et al.41 B, The effect of selexipag as monotherapy or sequential combination to endothelin receptor antagonists (ERAs) and/or phosphodiesterase type V inhibitors (PDE-Vis) on the outcome. In the GRIPHON (Prostacyclin Receptor Agonist In Pulmonary Arterial Hypertension) study,43 patients were randomized to receive selexipag or placebo. Kaplan-Meier curves for the primary composite end point of death (due to any cause) or a complication related to pulmonary arterial hypertension (PAH) (disease progression or worsening of PAH that resulted in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or the need for lung transplant or balloon atrial septostomy) to the end of the treatment period in the selexipag and placebo groups. A significant treatment effect in favor of selexipag vs placebo was observed (1-sided log-rank test). Reproduced with permission from Sitbon et al.43 C and D, The effect of initial combination therapy with ambrisentan plus tadalafil on PAH outcome in treatment-naive patients. In the AMBITION trial (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension), treatment-naive patients with PAH were randomized to receive monotherapy standard of care with the selective type A ERA ambrisentan (10 mg/d) or the PDE-Vi tadalafil (40 mg/d), or combination therapy with both drugs. The primary end point included first event of clinical failure, which was a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response. Analyses were significant comparing combination therapy with monotherapy with either drug as well as with pooled monotherapy, which refers to all patients randomized to receive either ambrisentan alone or tadalafil alone. Reproduced with permission from Galiè et al.44 HR indicates hazard ratio.

Figure 3.
Evidence-Based Treatment Algorithm for Patients With Pulmonary Arterial Hypertension (PAH)
Evidence-Based Treatment Algorithm for Patients With Pulmonary Arterial Hypertension (PAH)

CCB indicates calcium channel blocker; DPAH, drug-induced PAH; HPAH, heritable PAH; iPAH, idiopathic PAH; PCA, prostacyclin analogue; and WHO FC, World Health Organization functional class. Adapted with permission from Galiè et al.6,7

aNote: Some patients with WHO FC III status may be considered high risk (see Table).

bInitial combination with ambrisentan plus tadalafil has proven to be superior to initial monotherapy with ambrisentan or tadalafil in delaying clinical failure.

cIntravenous epoprostenol should be prioritized.

dConsider also balloon atrial septostomy.

Table.  
Point of Care Risk Stratification for Patients With PAHa
Point of Care Risk Stratification for Patients With PAHa
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Humbert  M, Sitbon  O, Chaouat  A,  et al.  Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156-163.
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Benza  RL, Miller  DP, Gomberg-Maitland  M,  et al.  Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122(2):164-172.
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Hoeper  MM, Huscher  D, Ghofrani  HA,  et al.  Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol. 2013;168(2):871-880.
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Rich  S, Dantzker  DR, Ayres  SM,  et al.  Primary pulmonary hypertension: a national prospective study. Ann Intern Med. 1987;107(2):216-223.
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Levy  D, Kenchaiah  S, Larson  MG,  et al.  Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347(18):1397-1402.
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Review
December 2016

Diagnosis, Treatment, and Clinical Management of Pulmonary Arterial Hypertension in the Contemporary EraA Review

Author Affiliations
  • 1Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 2Department of Cardiology, Boston Veterans Affairs Healthcare System, Boston, Massachusetts
  • 3Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
JAMA Cardiol. 2016;1(9):1056-1065. doi:10.1001/jamacardio.2016.4471
Abstract

Importance  Pulmonary arterial hypertension (PAH) is characterized by severe remodeling of the distal pulmonary arteries, increased pulmonary vascular resistance, and right ventricular dysfunction that promotes heart failure. Once regarded as largely untreatable, evidence-based decision making now guides clinical management of PAH and improves outcomes. However, misconceptions regarding the approach to PAH in the modern era are common and associated with substandard clinical care.

Observations  The clinical profile of PAH has changed substantially since its original description. Patients are older at diagnosis than previously reported; disease severity appears greater in men compared with women; and patients with PAH in association with connective tissue disease are identified as a particularly high-risk subgroup. Risk stratification scales for PAH are now available at point of care, which inform treatment goals, including a 6-minute walk distance of greater than 440 m, peak volume of oxygen consumption of greater than 15 mL/min/kg, right atrial area of less than 18 cm2, cardiac index of greater than 2.5 L/min/m2, and absent or low symptom burden with routine physical activity. At present, 14 therapies targeting 6 PAH-specific molecular intermediaries are used clinically. Recent landmark trial data have demonstrated the critical importance of initial combination therapy in treatment-naive patients. These findings underscore a global shift in PAH that couples early disease detection with aggressive pharmacotherapy. Indeed, recent longitudinal data from patients receiving combination therapy show that the 3-year survival rate in PAH may be as high as 84% compared with 48% from the original National Institutes of Health registry on idiopathic PAH (1980-1985). Despite these gains, incomplete clinical evaluation and misdiagnosis by referring clinicians is common and associated with inappropriate therapy.

Conclusions and Relevance  Compared with the original clinical experience, PAH has evolved into a contemporary and treatable disease characterized by improved survival and a high standard for defining therapeutic success. However, underawareness among clinicians regarding the importance of early and accurate PAH diagnosis persists and is a potentially reversible cause of adverse outcome in this disease.

Introduction

Twenty years ago, the first clinical trial demonstrating superiority of a disease-specific medical intervention in pulmonary arterial hypertension (PAH) was published based on findings from a small cohort of patients with end-stage idiopathic PAH (iPAH).1 In contradistinction to the original clinical experience, PAH has evolved into a treatable disease characterized by maintained quality of life and improved longevity in many patients.2 Despite these gains, the rate of adverse clinical events in PAH remains elevated. Fresh epidemiologic and clinical trial data suggest that missed opportunities to improve outcome in PAH may exist by virtue of delayed diagnosis and late implementation of disease-specific therapy.35 From this perspective, the contemporary approach to PAH diagnosis, management, and treatment is discussed further in detail.

Demystifying the Approach to PAH Diagnosis

Pulmonary hypertension is diagnosed based on a mean pulmonary artery pressure (mPAP) of at least 25 mm Hg determined by resting supine right heart catheterization (RHC).6,7 Although a wide spectrum of conditions promote pulmonary hypertension, PAH is characterized by remodeling of distal pulmonary arteries in the absence of other cardiopulmonary disease. Quiz Ref IDAn elevation in mPAP alone does not exclude left atrial hypertension or describe the disease severity because PAP may be only mildly increased in the setting of end-stage right ventricular (RV) failure. Therefore, a diagnosis of PAH is considered in patients with an mPAP of at least 25 mm Hg, pulmonary arterial wedge pressure (PAWP) of no more than 15 mm Hg, and pulmonary vascular resistance (PVR) of greater than 3.0 Wood units.6,7 Diagnosing PAH requires exclusion of comorbid cardiac, parenchymal lung, thromboembolic, and other diseases that predispose to abnormal cardiopulmonary hemodynamics (Figure 1).

The approach to PAH will often involve 2-dimensional Doppler echocardiography, complete pulmonary function testing, thoracic computed tomography, and nocturnal plethysmography to evaluate sleep-disordered breathing. A ventilation-perfusion scan to assess for chronic thromboembolic pulmonary hypertension is critical in all patients suspected of having PAH because this disease is curable by surgical endarterectomy in most cases and treatable medically or by balloon pulmonary angioplasty in patients who are poor operative candidates.8

Although iPAH is the most common PAH subgroup, serologic analysis for markers of connective tissue disease (CTD), liver failure, and human immunodeficiency virus infection also should be performed because results may inform a diagnosis of CTD-PAH, PAH associated with portal hypertension, and human immunodeficiency virus–associated PAH, respectively. In patients at risk for heritable PAH (HPAH), screening for a mutation in the bone morphogenetic protein receptor type 2 (BMPR-2 [HGNC 1078]) gene6,7 or other selected genes may be indicated. Pulmonary venoocclusive disease and pulmonary capillary hemangiomatosis are rare PAH subgroups caused by obstructive remodeling of pulmonary venules and proliferation of capillaries, respectively.9 Confirming the approach to diagnosing these diseases and PAH in patients with congenital heart disease or in pediatric patients requires consultation with a qualified specialist (Box).6,7

Box Section Ref ID
Box.

Conditions That Suggest Referral to a Pulmonary Hypertension Expert Center

  • Performance of vasoreactivity tests

  • Patients with PAH with intermediate- to high-risk status (Table)

  • Patients in need of patenteral prostanoids

  • PAH with connective tissue disease

  • PAH with congenital heart defects

  • Suspicion of heritable PAH

  • Suspicion of pulmonary venoocclusive disease

  • Elective surgery in patients with PAH

  • Decision making about pregnancy in patients with PAH

  • Patients with PH due to LHD or lung disease and severe PH or RV dysfunction

  • Suspicion of chronic thromboembolic PH

  • Any patients with severe PH and uncertain diagnosis

  • Pediatric patients with PH

Abbreviations: LHD, left-sided heart disease; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; RV, right ventricular.

Delayed Diagnosis in PAH Is Common

Inappropriate, incomplete, and delayed diagnosis of pulmonary hypertension is common and reported in as many as 85% of at-risk patients.10,11 This problem is likely caused, in part, by the high frequency of nonspecific symptoms at presentation, such as exertional dyspnea. Nonetheless, patients with PAH on average express symptoms 2 years before diagnosis.12 Misconceptions among clinicians regarding the diagnostic criteria for PAH, declining use of RHC despite its favorable safety profile, and overreliance on echocardiography despite its inadequate accuracy for measuring cardiopulmonary hemodynamics contribute to misdiagnosis of the disease in patients.13 In 1 multicenter cross-sectional analysis of patients diagnosed with PAH in community hospitals and referred to a quaternary specialty center,11 37% of patients had not yet undergone RHC, which ultimately resulted in diagnosis reclassification and the identification of prescribed therapy that was inappropriate in 52% and 57% of the cohort, respectively.

Novel Clues to the Clinical Spectrum of Risk in PAH

Accumulating evidence suggests that in CTD-PAH, an mPAP of less than 25 mm Hg is abnormal. For example, a resting mPAP of greater than 17 mm Hg corresponds to a significant decrease in the 6-minute walk distance (6-MWD) and peak volume of oxygen (pVo2) consumption during cardiopulmonary exercise testing compared with matched patients with an mPAP of less than 17 mm Hg.14 In 1 study of mixed clinical populations that includes patients with CTD-PAH, a resting mPAP of approximately 20 to 25 mm Hg was associated with significantly diminished exercise tolerance and a 4.8-fold increase in the 4-year mortality rate.15 Increases in PAP affect right heart physiology in vivo by disrupting RV work distribution in favor of maintaining pulmonary circulatory pressure relative to blood flow (and hence oxygen transport), which is referred to as RV–pulmonary arterial uncoupling.16 However, the extent to which RV–pulmonary arterial uncoupling underpins adverse outcome in CTD-PAH with an mPAP of less than 25 mm Hg requires further study. In addition, comprehensive data on the utility of treating any patient based on an mPAP of less than 25 mm Hg remain forthcoming. Nonetheless, a low clinical index of suspicion of PAH is warranted when encountering patients with CTD, irrespective of resting cardiopulmonary hemodynamics, and their early referral to specialty care centers is justified (Box).

New Trends in the Epidemiology of PAH

The reported prevalence of PAH is 5 to 25 cases per 1 million persons (incidence, 2-5 cases per 1 million persons), although referral bias from registry studies is likely to underestimate the true rate of disease.17 The mean age of patients with PAH in the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management; United States, 2006-2007)18 and COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension; Europe, 2007-2013)19 registries was 54 and 68 years, respectively, compared with 36 years in the original US National Institutes of Health iPAH cohort (1980-1985).20 On the other hand, the large variability in the mean age of patients with iPAH in contemporary registries also may be explained by participation bias among centers and variable accuracy in the diagnostic process. In fact, auditing for diagnostic accuracy is not systematic in large registries, and the frequency of misclassification is unknown, particularly in patients with risk factors for left-sided heart disease (LHD) and PAWP of greater than 12 mm Hg, for whom adjudicating retrospectively PAH vs pulmonary hypertension owing to LHD is difficult. The prevalence of PAH favors women to men by approximately 3.1-fold21; however, the clinical profile, hemodynamics at diagnosis, and prognosis in men has appeared to be comparatively less favorable.17,22

Natural History

The original National Institutes of Health registry included mainly HPAH and iPAH, and 64% of patients had incident disease. The median survival was 2.8 years; the 1- and 3-year mortality rates were 68% and 48%, respectively; and the use of standard therapy at the time (digitalis, diuretics, or anticoagulants) likely did not influence the outcomes.23 In 2010, data were organized for 298 prevalent and 56 incident cases of iPAH, HPAH, and anorexigen-associated PAH followed up for 3 years in the French Network on Pulmonary Hypertension.17 In that study, 76% of patients were prescribed PAH-specific therapy, and the 1- and 3-year survival rates were 85.7% and 54.9%, respectively, although only 2 patients were reported to receive at least 1 PAH-specific therapy. However, from the REVEAL registry, which tracks patients with PAH from 54 US centers, an analysis on outcome that included 40% of patients receiving combination PAH therapy indicated that the 1- and 3-year survival rates were 91% and 69%, respectively.24 Directionally similar findings were observed in registries from Spain, the United Kingdom, and China and from a European series reporting that the 3-year survival of patients receiving combination therapy for PAH was 84%.25 It is notable that mortality among patients with PAH is now akin to, or perhaps lower than, that for patients with left ventricular heart failure, for which the age-adjusted 1-year survival was 69% in 2010 and 67% in 1980 to 1989.26

Pathogenesis and Current Drug Targets in PAH
Histopathologic Features

In PAH, effacement of distal pulmonary arteries involving the intima, media, and adventitial layers occurs owing to hypertrophic, fibrotic, plexogenic, and inflammatory vascular remodeling without primary involvement of the arterial systemic beds. Small pulmonary veins are also variably affected, particularly in PAH, owing to the classic form of pulmonary venoocclusive disease.27Quiz Ref ID In addition to endothelial dysfunction and dysregulated pulmonary arterial smooth muscle cell growth, pathogenic changes to the structure and function of pulmonary arterial pericytes, myofibroblasts, and adventitial fibroblasts are now understood to play a key role in the vascular remodeling process.28 Increased accumulation of vascular-reactive oxygen species, a shift in mitochondrial bioenergetics toward glycolysis, overactivation of hypoxia-inducible factor 1α signaling, and maladaptive epigenetic modifications that promote DNA damage are all implicated in apoptosis resistance, unopposed proliferation, and/or transdifferentiation of pulmonary vascular cells.29,30 Ultimately, profound vascular cell proliferation ensues and results in luminal obliteration and impaired vascular reactivity.

The Syndrome of PAH

Structural abnormalities to the alveolar-capillary interface, the left atrium, and the left ventricle (owing to underfilling) occur as a consequence of pulmonary vascular remodeling in PAH. Upregulation of neurohumoral signaling in concert with impaired renal or hepatic function is an important systemic manifestation of PAH,31 whereas diminished strength and fiber size in volitional (eg, quadriceps) and nonvolitional (eg, diaphragm) muscles is well documented and contributes to symptom burden.32

Pathophysiologic Features and RV Involvement in PAH

A predominantly vasoconstrictive pathophenotype is observed in only approximately 10% of patients with PAH.6,7 By contrast, decreased arterial compliance and elevations in PVR are universal across the PAH spectrum and, ultimately, induce RV dilation, impaired diastolic function, and diminished contractile reserve. Therefore, analyzing the RV is important in PAH and includes echocardiographic measurement of right atrial and RV volumes and RV function.33 In PAH, RV–pulmonary arterial uncoupling measured by transduction catheter and magnetic resonance imaging precedes frank right heart failure and in clinical studies corresponds to decreased exercise tolerance.34 The pathophysiologic features of CTD-PAH appear to be somewhat unique because these patients fail to augment RV contractility during exercise at RV afterload levels that are associated with maintained RV function in patients with iPAH.35 Thus, RV performance differs across PAH subgroups, possibly as a function of disease-specific factors rather than solely by elevated RV afterload levels.

Genetics of PAH

A germline mutation coding for the BMPR-2 gene, which is part of the transforming growth factor β superfamily of receptors, is implicated in 70% of patients with HPAH and as many as 40% of patients with iPAH.36 As many as 80% of carriers of the BMPR-2 mutation are positive for the genotype and negative for the phenotype, and, thus, the contribution of reduced penetrance to underrecognition of BMPR-2 mutation status in patients with PAH who do not have a familial history of the disease is not known.37 A smaller percentage of HPAH and PAH-associated hereditary hemorrhagic telangiectasia is attributed to mutations in genes coding for other transforming growth factor β family receptor proteins, including activin receptor–like kinase 1 (ALK1 [OMIM 601284]), endoglin, and SMAD family member 9 (SMAD9 [OMIM 603295]). Other rarer genetic causes of PAH include mutations in caveolin 1 (CAV1 [OMIM 601047]), which regulates SMAD2/3 (OMIM 601366 and 603109, respectively) and modifies transforming growth factor signaling, and potassium channel subfamily K member 3 (KCNK3 [OMIM 603220]), which encodes for the potassium channel protein TASK-1.38 Mutations in eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4 [OMIM 609280]) also have been identified as causative of heritable pulmonary venoocclusive disease.39

Novel Drug Therapies and Care Strategies in PAH

In the previous 5 years, 3 mainstream trends have emerged in the pharmacotherapeutic management of PAH.40 First, the efficacy of phosphodiesterase type V inhibitors (PDE-Vi), endothelin type A and type B receptor antagonists (ERAs), and prostaglandin I2 replacement therapies, administered as monotherapy or in sequential combination, have each achieved evidence-based validation for their ready use in PAH when patients are under the care of an expert pulmonary hypertension clinician (eFigure in the Supplement). Second, the following recent clinical trials show the effects of 3 novel PAH drug therapies: the SERAPHIN trial (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome) with macitentan (an ERA),41 the PATENT-1 trial (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1) with riociguat (a soluble guanylyl cyclase stimulator),42 and the GRIPHON trial (Prostacyclin Receptor Agonist In Pulmonary Arterial Hypertension) with selexipag (a prostaglandin I2 receptor agonist).43 Third, findings from the recent AMBITION trial (Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension)44 mark a strategic shift in PAH therapy by providing definitive evidence in favor of initial combination therapy over monotherapy for treatment-naive patients with newly diagnosed PAH.

In the SERAPHIN trial,41 a total of 742 patients with PAH were randomized to receive placebo or macitentan (10 mg/d vs 3 mg/d), which was a modified ERA with optimal receptor-binding kinetics. Most of the enrolled patients had iPAH or CTD-PAH (87%), New York Heart Association (NYHA) functional class II or III status (97%), and severe pulmonary hypertension (mPAP, approximately 55 mm Hg; cardiac index, approximately 2.3 L/min/m2; and PVR, approximately 12.5 Wood units) and were receiving some form of background PAH therapy (64%), most of which was the PDE-Vi sildenafil citrate. Compared with placebo (mean duration of treatment, 85.3 weeks), the hazard ratio for achieving the composite primary end point of PAH-related clinical worsening, which included death or disease progression, was 0.70 (95% CI, 0.52-0.96; P = .01) in the 3-mg dose arm and 0.55 (97.5% CI, 0.32-0.76; P < .001) in the 10-mg dose arm (mean duration of treatment, 100 weeks for the 3-mg arm and 104 weeks for the 10-mg arm) (Figure 2A). Directionally similar findings were observed for PVR and the cardiac index at 6 months compared with baseline. However, given that the 3-mg dose was associated with only a subtle improvement in other study measures, only the 10-mg dose received approval for clinical use in the United States and Europe.

The PATENT-1 study42 compared the effect of riociguat (2.5 mg 3 times daily) or placebo on change in 6-MWD from baseline at study week 12 in a cohort of 443 patients with PAH. Most of the participants in the PATENT-1 study had iPAH (61%) and NYHA functional class II or III status (95%) and were already prescribed background PAH therapy (50.1%) at the time of study enrollment (mainly bosentan). Compared with placebo, the riociguat dosage was associated with a significant increase in 6-MWD (+30 m vs +6 m; P < .001), decreased PVR (−2.8 vs −0.1 Wood units; P < .001), and improvements to mPAP, cardiac output, N-terminal pro–brain-type natriuretic peptide level, World Health Organization (WHO) functional class status, and dyspnea burden. Riociguat was generally well tolerated; syncope was the most common serious adverse event and occurred in 1% of patients.

The GRIPHON trial43 randomized 1156 patients from 39 countries to receive placebo (median duration, 64 weeks) or selexipag (median duration, 71 weeks) therapy titrated to the maximal tolerated dose. Most patients had NYHA functional class II or III status (98%) and iPAH or HPAP (86%) or PAH due to a corrected congenital shunt (9.5%). Baseline PAH therapies included an ERA (15%), a PDE-Vi (32%), an ERA combined with a PDE-Vi (33%), or no drug (20%). The primary end point of morbidity and mortality occurred in 41.6% of placebo-treated patients and 27.0% of selexipag-treated patients (hazard ratio, 0.6; P < .001) (Figure 2B). The effect of therapy on 6-MWD was negligible, and the adverse effect profile of selixipag was consistent with that of prostaglandin I2 analogues (eg, headache, diarrhea, nausea, jaw pain) and corresponded to a drug therapy discontinuation rate of 14% owing to adverse symptoms.

Strategic Shift in the Management of PAH

Meta-analyses studying patients who use sequential combination therapy suggested a signal toward superior clinical benefit among patients prescribed multiple drugs compared with patients prescribed monotherapy or who receive placebo.45Quiz Ref ID To address this further, the AMBITION trial44 included 500 treatment-naive newly diagnosed participants who were randomized (2:1:1) to receive initial combination therapy with the selective type A ERA ambrisentan, 10 mg/d, plus the PDE-Vi tadalafil, 40 mg/d, or standard of care monotherapy with either drug alone. Patients in the AMBITION trial were diagnosed with PAH a mean of 20 days before study drug day 1 and had NYHA functional class II or III status and moderate-to-severe cardiopulmonary hemodynamic severity at enrollment. At a median of 517 days, an end point of death, hospitalization for PAH, disease progression, or unsatisfactory clinical response occurred in 18%, 34%, and 28% of patients randomized to combination therapy, ambrisentan monotherapy, and tadalafil monotherapy, respectively. Furthermore, a 50% (95% CI, 0.35-0.72; P < .001) reduction in the hazard for achieving the primary end point, which was a composite of the clinical events, was observed in the combination therapy group compared with patients randomized to either monotherapy treatment (Figure 2C and D). Initial combination therapy was also associated with a decrease in the hazard for the primary end point by 79% (P = .005) among patients with NYHA functional class II status, providing evidence in support of initial combination therapy in mildly symptomatic patients.

Approach to Patients With PAH in Practice
Pulmonary Vasoreactivity Testing, Risk Stratification, and Initial Management Steps

Assessing the effect of inhaled nitric oxide, intravenous prostacyclin, or intravenous adenosine on cardiopulmonary hemodynamics for the purpose of determining vasoreactivity, and, thus, treatment should be confined primarily to HPAH, iPAH, and drug-induced PAH and performed at a PAH referral center. Quiz Ref IDA positive test result is defined by a decrease in mPAP of at least 10 mm Hg to reach an mPAP of no greater than 40 mm Hg with a decrease (or no change) in cardiac output.6,7 In such patients, high-dose calcium channel antagonism therapy is indicated as first-line treatment owing to relevant improved clinical outcomes after treatment in this PAH subgroup.

Systems for classifying patients according to 1-year mortality risk are now available for use in clinical practice.6,7 Low (<5% per year), intermediate (5% to 10% per year), and high (>10% per year) risk is determined based on a collective analysis of clinical, hemodynamic, biochemical, and echocardiographic data (Table). These and other criteria and warning signs that should prompt referral to a pulmonary hypertension expert center are provided in the Box. Achieving low clinical risk also functions as the principal treatment goal and includes 6-MWD of greater than 440 m, peak Vo2 of greater than 15 mL/min/kg, right atrial area of less than 18 cm2, and cardiac index of greater than 2.5 L/min/m2.

Initiating PAH Therapy

For patients with a positive vasoreactivity study but calcium channel antagonist nonresponder status or patients without a positive vasoreactivity study, treatment selection hinges on risk level (Figure 3). According to evidence in the literature, adoption of initial combination therapy with an ERA and a PDE-Vi is recommended for treatment-naïve patients with low or intermediate risk, which often equates to NYHA functional class II or III status. As an alternative, monotherapy that includes an ERA, a PDE-Vi, a soluble guanylyl cyclase stimulator, or a prostacyclin analogue may be considered as initial treatment in low- or intermediate-risk patients. For patients at high risk at the first clinical encounter, initial combination therapy that includes intravenous prostacyclin analogues should be considered, with intravenous epoprostenol prioritized for its favorable effect on survival in high-risk patients, even when administered as monotherapy.1

Therapeutic Escalation

Medical assessment that includes 6-MWD testing should be undertaken every 3 to 6 months (at least twice annually) to observe for a decline in exercise status. Additional studies, such as echocardiography or RHC, are often performed at least annually or if indicated by a change in clinical status. Quiz Ref IDDetermining timing of therapeutic escalation is challenging and should be tailored to individual patients. An overarching goal is to maintain WHO functional class II or I status, 6-MWD of greater than 440 m, and cardiac index of at least 2.5 L/min/m2. Therefore, if drug treatment fails to accomplish this objective within 3 to 6 months of its initiation, or if clinical decline is precipitous (decrease of ≤1 WHO functional class), then the addition of therapies is warranted. High-risk findings that suggest advanced RV failure, for example, may alter the timeline of treatment escalation. The recently proposed strategy of initial combination therapy with oral compounds in patients with newly diagnosed PAH and WHO functional class II and III status6,7 will leave in the future only 1 additional escalation step to reach the criteria for maximal triple combination medical therapy.

Escalation of therapy by the sequential addition of PAH-specific drugs is common for patients with progressive disease, despite initial treatment selection of the maximal tolerated dose. The addition of macitentan to sildenafil, riociguat to bosentan, and selexipag to an ERA or a PDE-Vi are each class I recommendations for most patients from the 2015 European Society of Cardiology and European Respiratory Society guidelines,6,7 and triple medical therapy in refractory disease is increasingly common. It is important to note that the combination of PDE-Vi and riociguat is prohibited owing to severe adverse events.46

Referral for lung transplant evaluation is recommended in patients prescribed maximal medical therapy. The preferred procedure in patients with PAH is a double lung transplant; an inverse correlation between preoperative frailty and posttransplant outcome has been observed.47 The introduction of a right-to-left shunt using balloon atrial septostomy or a Potts shunt may be a consideration to palliate the clinical sequelae of right heart failure in PAH, but should only be implemented on an individualized basis at referral centers with expertise in these procedures.

Prescription Exercise in PAH Treatment

Although once regarded as potentially dangerous in PAH owing to concern for provoked sudden death, exercise training has become an important therapy in the management of PAH. Mereles and colleagues48 first established prescription aerobic exercise as a safe and effective strategy to improve exercise tolerance and quality of life in patients with severe PAH. A recent meta-analysis of 16 prospective studies in PAH49 (n = 469) showed that exercise was associated with a significant improvement at follow-up (median, 15 weeks) in 6-MWD (+53.3 m), pVo2 (+1.8 mL/kg), and pulmonary artery systolic pressure (−3.7 mm Hg). Generally, inspiratory muscle training that achieves greater than 30% of maximal inspiratory pressure (30-minute session, 1-2 times per day) and aerobic exercise that achieves 50% to 85% maximal aerobic capacity (30-minute session, 3-7 days per week) is recommended to patients.50 However, the practical application of exercise programs for a rare disease in the real world requires further developments and adaptations to the different health care systems.51

Difficult Clinical Scenarios
Patients With a Borderline mPAP Increase

Several reports in unselected populations that included patients with LHD and pulmonary disease describe an increase in clinical risk associated with PAP beginning at levels currently classified as normal.52 In the largest study (21 727 patients),53 a continuous association between mPAP and the adjusted hazard for all-cause mortality was observed beginning at 19 mm Hg. Furthermore, the range of mPAP of 19 to 24 mm Hg was common and corresponded to a 23% increase in mortality risk. However, whether an mPAP of less than 25 mm Hg is sufficient to induce right heart pathophysiologic changes and account for adverse clinical outcome in these patients or whether events are caused by comorbid disease is unknown. Determining whether this subphenotype is an early disease state has important implications on patient risk stratification and merits future investigation. At present, data informing clinical decision making in patients with an mPAP of 19 to 24 mm Hg are lacking and, therefore, such patients should not be treated with PAH-approved therapy.

Mixed Clinical Phenotypes

Encountering patients with multiple risk factors for LHD and cardiopulmonary hemodynamics consistent with PAH is becoming common.6,7 A subgroup analysis of the AMBITION study44 involving patients with PAH with at least 3 risk factors for LHD and a PAWP of no greater than 15 mm Hg suggested a signal toward clinical benefit. Determining the manner by which this patient subgroup contrasts with PAH (ie, precapillary pulmonary hypertension) and bona fide LHD with a preserved ejection fraction thus bears important ramifications on PAH diagnosis and treatment. Opitz and colleagues54 showed that patients with PAH and risk factors for LHD and patients with LHD with preserved ejection fraction in the COMPERA registry were incrementally older and had greater body mass index compared with patients with PAH without LHD risk factors. However, patients with PAH with LHD risk factors were treated commonly with PAH-specific drugs, which apparently was associated with meaningful improvements in functional status and 6-MWD. However, the magnitude of treatment effects was inferior compared with those in patients with PAH without risk factors, outlining the potential negative effects of comorbidities.

On the other hand, we need to acknowledge the important limitations of the data provided by the COMPERA study, which is a voluntary, noninterventional registry that is not systematically audited and, as such, cannot provide definitive results on the comparative effects of treatments in the studied patient groups. The differential diagnosis between iPAH with multiple risk factors for LHD and LHD with preserved ejection fraction and pulmonary hypertension is based substantially on PAWP, which is greater than 15 mm Hg in the latter clinical phenotype.6,7 The assessment of PAWP may present technical difficulties and artifacts, which can lead to uncertainties in the PAWP, particularly from 12 to 18 mm Hg. In cases with the diagnosis in doubt, a direct assessment of left ventricular end-diastolic pressure may be helpful. Fluid challenge or exercise hemodynamics have been suggested in cases of persisting uncertainties, but unfortunately the heterogeneity of protocols and the lack of age-related normal thresholds for PAWP limit their diagnostic reliability. In clinical practice, the differential diagnosis in these cases should be based not only on a borderline value of PAWP but also a comprehensive assessment that includes the patient’s history, the severity of comorbidities, and the response to medications such as diuretics.

Conclusions

During the preceding 2 decades, PAH has evolved into a treatable cardiovascular disease associated with improved survival and decreased morbidity. Optimizing clinical outcome hinges on higher clinical index of suspicion for PAH at the point of care, understanding the broad clinical spectrum of risk, and recognition of the importance of early aggressive therapy in patients with newly diagnosed PAH.

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Article Information

Corresponding Author: Bradley A. Maron, MD, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, New Research Bldg, Room 0630-O, Boston, MA 02115 (bmaron@partners.org).

Accepted for Publication: September 30, 2016.

Published Online: November 16, 2016. doi:10.1001/jamacardio.2016.4471

Author Contributions: Drs Maron and Galiè had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Both authors.

Drafting of the manuscript: Both authors.

Critical revision of the manuscript for important intellectual content: Both authors.

Administrative, technical, or material support: Maron.

Study supervision: Galiè.

Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Maron reports receiving funding from Gilead Sciences to research pulmonary hypertension. Dr Galiè reports receiving grants and personal fees from Actelion Pharmaceutical LTD, Bayer Healthcare, GlaxoSmith Kline, and Pfizer Inc. No other disclosures were reported.

Funding/Support: This study was supported by grant K08HL111207-01A1 from the National Institutes of Health, grant 15GRNT25080016 from the American Heart Association, the Cardiovascular Medical Research and Education Foundation, and the Klarman Foundation at Brigham and Women’s Hospital (Dr Maron).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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